Dermatol Clin 21 (2003) xi – xii
Preface
Infectious diseases
Ted Rosen, MD Guest Editor
This plague has come upon us by infection, and it will spread still further, just as in the fields the scab of one sheep or the mange of one pig, destroys the entire herd. —Juvenal, from Satires, II.78, c. 120 A.D. You never win because microbes are part of nature. They will constantly emerge. If we come to terms with that and if we are smart and quick. . .we’ll be ahead of them. —Dr. Mike Ryan
In the nearly 1900 years that elapsed between the time of the Roman satirist and poet, Juvenal, and the current era, mankind has remained at constant risk from infectious diseases. The virtual planetary eradication of smallpox has proven the potential power rational beings can have over nature. By contrast, the relatively recent emergence of the Human Immunodeficiency and Ebola viruses and the development of resistance to routine treatments (now manifested by lowly head lice) demonstrate the never-ending capacity of microbes to maintain the upper hand in this epic struggle. In this issue of Dermatologic Clinics I have used my position as guest editor to select topics that highlight this constant battle between nature and
mankind. The ability of unusual organisms such as Vibrio species from sea water, achloric algae from stagnant fresh water, tick-borne microbes, and saprophytic fungi from soil to act as human pathogens is discussed herein. The increasingly commonplace practice of keeping exotic animals as household pets also has led to the real probability of acquiring cutaneous and systemic disease. This subject is explored in depth with an emphasis on the most common unusual pets (hedgehog, chinchilla, iguana, flying squirrel, and cockatoo). Industrious and energetic pharmaceutical researchers have created new drugs to combat disease. Cidofovir, ivermectin, albendazole, imiquimod, and various vaccine products are such medications, all of which are summarized in this issue. New drugs explored include agents designed to counter primarily viral and parasitic diseases. The host of choices awaiting the practitioner confronted with acyclovirresistant herpetic infection is outlined along with some of the more promising anti-herpetic drugs of the future that are not yet commercially available. The expanding role of simple and complex cutaneous surgery performed by dermatologists has added yet another dimension to the potential for infectious
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00091-8
xii
T. Rosen / Dermatol Clin 21 (2003) xi–xii
disease. This issue addresses wound infections and the somewhat controversial role of antibiotic prophylaxis associated with dermatologic surgery. The fact that Bacillus anthracis recently was used as a weapon of bioterrorism, and that the correct diagnosis was made by a dermatologist, underscores the necessity for all health care providers—including those of us who practice cutaneous medicine—to have a broad depth of knowledge regarding infectious
diseases. I hope this issue will fill in gaps in the readers’ information base. Ted Rosen, MD Department of Dermatology Baylor College of Medicine Houston VA Medical Center Houston, TX, USA E-mail address:
[email protected]
Dermatol Clin 21 (2003) 229 – 236
Infectious threats from exotic pets: dermatological implications Ted Rosen, MDa,*, Jennifer Jablon, MDb b
a Department of Dermatology, Baylor College of Medicine, 2815 Plumb, Houston, TX 77005, USA Department of Internal Medicine, St. Joseph’s Mercy Hospital, 5301 E. Huron Drive, Ann Arbor, MI 48106, USA
During the past five decades, a considerable body of information regarding exotic animals has been generated. Such information has largely been utilized to study survival skills, migrating habits, or causes for a decline in species number; however, this body of information has also become important for a new reason: many Americans are inviting these exotic animals into their homes as pets. Neither pet owners nor non-veterinary health care providers are sufficiently knowledgeable about the possible medical problems caused by these animals. Hedgehogs, flying squirrels, iguanas, chinchillas, and cockatoos comprise a major part of this trend toward novel exotic pets residing in American households. Such animals can be associated with cutaneous infections, acute and chronic systemic illness with skin signs, and even fatality. Moreover, such animals have been found to harbor dangerous microorganisms that, although not yet directly linked to human infection, have the potential to cause devastating disease. Health care providers need to be more aware of the risks entailed by exotic pet ownership and to remember to inquire about such pets while obtaining a medical history or formulating a differential diagnosis.
Hedgehog There are eleven species of hedgehog, the most prevalent being the European hedgehog, the Pruner’s
* Corresponding author. E-mail address:
[email protected] (T. Rosen).
(or Cape) hedgehog, the Egyptian (or long-eared) hedgehog, and the species Atelerix albiverntris, better known as the African pygmy hedgehog [1 – 3]. The African pygmy hedgehog has become a common household addition, with an estimated 40,000 households in the United States harboring this pet [4]. Although hedgehogs are often considered to be benign, easily maintained, small versions of porcupines, they can pose some rather unique threats to their human owners, including fungal and salmonella infections, contact urticaria, and possibly mycobacterium infections. The African pygmy hedgehog has recently been strongly implicated as a cause of moderate to severe cutaneous dermatophytosis [3]. The three individuals described in this report were in contact with an African pygmy hedgehog, and lesional cultures yielded an organism (Trichophyton mentagrophytes), which is known to be frequently carried on the quills and the underbelly in this particular species of hedgehog [5]. One of the patients reported merely handling the hedgehog in a pet store for a period of 1 to 2 minutes, indicating that this infection might be highly contagious if the animal is heavily colonized (Fig. 1). Additional cases of tinea corporis [6 – 9] and tinea capitis [10,11] have been reported following contact with wild European hedgehogs and their natural habitat, further suggesting that hedgehog pets might truly be a viable source of dermatophytosis in their unsuspecting owners. The hedgehog has also been implicated in one case of contact urticaria, which was most likely caused by a hypersensitivity response to hedgehog saliva, which the animal deposits on its quills [12]. The worst hazard to human owners of hedgehogs has been salmonellosis. The African pygmy hedgehog has
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00090-6
230
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
Fig. 1. Massive tinea manum following exposure to an African pygmy hedgehog.
been clearly implicated in human salmonellosis in the United States and Canada [13,14]. Although it has been presumed that this infection results from ingestion of food inadvertently contaminated by hedgehog feces, the actual mechanism of salmonellosis acquired from hedgehogs has not been clearly established. Human salmonellosis can vary from dehydrating dysentery to meningitis and toxic bacteremia. It can be a serious illness, especially in the young, old, and immunocompromised. Although the African pygmy hedgehog has not yet been documented to carry any mycobacterial diseases, the European hedgehog has been found to carry the Mycobacterium species M. marinum and M. avium – intracellulare [15,16], which suggests that it is possible for the former variety to do so as well. Such organisms readily cause infection—even of a fatal nature—in immunocompromised patients [17]. Such patients should strictly avoid any potential sources of these organisms, and hedgehogs are not recommended pets for patients with HIV disease.
Flying squirrel There are two distinct groups of rodents that are often referred to as ‘‘flying squirrels.’’ Members of the first group, consisting of African rodents with scaly tails in the family Anomaluridae, are not sold as pets. The second group contains the more familiar North American and Eurasian flying squirrels and the Australian sugar glider from the subfamily Petauristinae of the family Sciuridae. The term ‘‘flying squirrel’’ is somewhat of a misnomer because these animals actually make gliding leaps of up to 150 feet
utilizing parachute-like membranes that are connected on each side to their forelegs and hindlegs. There are 35 species of flying squirrels in the family Sciuridae, but only two are found in North America, Glaucomys volans and Glaucomys sabrinus [18]. These animals are known to nest in birdhouses or buildings. These closely related species, collectively known as New World flying squirrels, have recently become popular household pets, with the estimated 5000 to 8000 owners in the United States [4]. Although the flying squirrel has been proclaimed to be a friendly and intelligent pet, especially when domesticated as a newborn, it should be noted that such animals might be the source of a number of dangerous infections. Some flying squirrels have been reported to harbor the proliferative stages of Toxoplasma gondii, the organism responsible for potentially fatal toxoplasmosis in humans [19]. It is not known how the squirrels were infected; it is hypothesized that Toxoplasma gondii might be a congenitally acquired infection because the squirrel is an herbivore and the main method of parasite acquisition is ingestion of raw meat containing cysts. Although there are no documented reports of human toxoplasmosis from flying squirrels, the fact that a herbivore such as the flying squirrel can acquire this disease leaves open the possibility that owners could be at risk. Other potentially dangerous microorganisms harbored by flying squirrels are unusual and aggressive species of the bacterium Staphylococcus. In one study, virtually all of the flying squirrels captured in Raleigh, North Carolina carried three atypical strains of staphylococcus on their skin: Staphylococcus sp. 3, S. sciuri, and S. xylosus [20]. In the same study, these three strains were found
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
(uncommonly) on human skin, with the prevalence being 0%, 10%, and 42% respectively. S. sciuri and S. xylosus grow poorly on agar at pH 5.3 or below, explaining why they are rare on human skin (pH 5.0); however, these species grow well at pH 7.0 or above, making them a danger if, as a human skin contaminant, they enter the bloodstream through a wound. The in vivo pH of human tissues is between 7.35 and 7.45, an ideal environment for this organism to proliferate. In this same study, Staphylococcus sp. 3 was isolated only from the flying squirrel, raccoon, opossum, and the eastern gray squirrel, but not from human skin. Considering its novelty, this species would pose a threat to a human who would have little to no immunity against it. There is evidence Glaucomys species serve as an extrahuman reservoir for typhus. Epidemic typhus is caused by infection with Rickettsia prowazekii and is usually transmitted from person-to-person by way of the human body louse. The last major outbreak of louse-borne typhus in the United States was in the 1920s, but sporadic cases of a milder form of typhus occurring in people living in rural environments have been attributed to contact with flying squirrels [21 – 24]. The mode of transmission between flying squirrel and human has not been firmly established, although experimental work suggests that transmission to humans might occur through inhalation of aerosolized ectoparasite feces or directly by way of the bite of an infected ectoparasite [25]. In one study, serological evidence of typhus infection was established only in flying squirrels, not the lice or ticks found on their skin [22], whereas another study found that commensal fleas and lice—and their host flying squirrels—were infected [24]. Although such disease has been a milder form of typhus, all patients presented with one or more of the following symptoms: fever, typical louse-born epidemic typhus rash (blanchable erythematous macules spreading to the trunk and extremities from the axillary folds), nausea, vomiting, headache, myalgia, photophobia, malaise, and dizziness. One woman died from renal complications [23]. Thus, the combination of fever, rash, and systemic toxicity in an owner of a flying squirrel should suggest typhus as a possible diagnosis.
Iguana There are thirteen iguana species within the larger members of the lizard family Iguanidae. The best known and most common is the reptile Iguana iguana, which naturally inhabits Southern Mexico and Brazil. This particular lizard is inexpensive to
231
purchase, and there are now some 700,000 such pets in the United States [4]. Other well-known species include I. delicatissima of the Caribbean islands, Cyclura cornuta of Haiti, Dipsosaurus dorsalis, the desert iguana of Mexico and the United States, Amblyrhynchus cristatus, the marine iguana, and the Conolophus iguanas of the Galapagos Islands. I. iguana is a greenish-colored animal with overlaid brown bands. It usually eats fruit and leaves, but it will also eat small birds and mammals. This 20-pound reptile can grow up to 6 feet long and poses a domicilliary challenge that is often met by allowing it to reside/sleep in an extra household bathtub! Many potentially pathogenic bacteria have been isolated from the iguana pharynx, including Staphylococcus sp, Streptococcus sp, Serratia sp, Corynebacterium sp, Alcaligenes sp, and from the cloaca, including Micrococcus sp, Bacillus subtilis, Salmonella marina, Salmonella chameleon, Escherichia coli, and Hafnialike species [26]. The organisms from the pharynx have the potential to cause serious cellulitis if the iguana bites. In fact, there are several such reports in the literature [27 – 29]. Serratia marcescens infection, as determined by wound culture in one reported case [27], is particularly difficult in that it might manifest as rapidly progressive, bullous cellulitis associated with extreme systemic toxicity (Fig. 2). Iguanas are commonly treated by breeders with broad-spectrum prophylactic antibiotics to prevent disease and discoloration [30]. Although this practice is frequently unsuccessful, it might result in the development of drug-resistant bacteria, further complicating the management of cellulitis following an iguana bite. A series of investigations in the 1970s led to the discovery of a new herpes-type virus isolated from the pharynx of the common pet iguana [31,32]. This virus was the first to be isolated from reptiles, and it appeared to possess a capability for causing latent or unapparent infections consistent with mammalian herpesviruses. This virus has not been implicated in human infection to date, but it remains another potential complication of an iguana bite. Most allergic responses to pets occur in association with the fur (dander) of the implicated animal; however, at least one well-documented case of allergic rhinitis, asthma, and urticaria has been reported to be caused by an iguana [33]. The allergic nature of this reaction was verified by demonstrating a positive intradermal skin test to an aqueous extract prepared from iguana scale. The iguana is best known for its potential for transmitting salmonella to humans. There has been a significant increase in nontyphoidal salmonellosis, which is generally acquired from animals. Approx-
232
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
Fig. 2. Serratia marcescens cellulitis following an iguana bite.
imately 4 million such cases were tabulated in 1995; these infections were believed to be caused by infected eggs and poultry and pet iguanas [6]. There have been many reports of enteric salmonellosis acquired from pet iguanas in the United States [34 – 36], an 83% rate of fecal shedding of salmonella from pet iguanas [37], and scattered reports of salmonella meningitis associated with iguana ownership [38]. From a dermatological standpoint, nontyphoidal salmonella infection can be associated with a nondescript, generalized erythematous papular eruption. Thus, the clinical situation of diarrhea and a rash in an iguana owner should strongly suggest salmonellosis as the etiology.
Chinchilla The chinchilla is a small South American herbivore of the family Chinchilladae of the order Rodentia. There is some debate regarding whether the chinchilla is one species (Chinchilla laniger) or two species, the long-tailed C. laniger and the short-tailed C. brevicaudata. These animals, long known for soft, attractive fur, naturally inhabit the rocky regions of the Chilean and Bolivian Andes and subsist on grain, herbs, and moss. Once hunted almost to extinction and still scarce in the wild, chinchillas are now raised commercially in ‘‘farms.’’ Almost all of the chinchillas in captivity used for commercial breeding are descended from a few animals introduced into the United States in the 1920s. Some 80,000 chinchillas are kept as household pets [4]. The skin and fur of the chinchilla often harbors several common superficial fungi. Trychophyton
mentagrophytes and Microsporum gypseum have been recovered from chinchillas; these organisms have actually been responsible for symptomatic animal dermatophytosis [39 – 42]. Because these organisms are well established as etiologic for human disease, it is not unreasonable to suspect the chinchilla as the source of infection in an owner who presents with acute, inflammatory tinea corporis or tinea capitis (Fig. 3). Several nondermatophytes have also been isolated from the chinchilla, including Aspergillus niger, Cladosporium spp, and Rhizopus species [43]. Such saprophytes might become opportunistic pathogens in select individuals such as diabetics, organ transplant patients, bone marrow transplant recipients, and leukemia patients. Hence, the chinchilla might not be a good choice for a pet in these circumstances. Chinchillas also have a predilection for harboring Klebsiella pneumoniae and Pseudomonas aeruginosa [44,45]. These organisms can be isolated from chinchillas with unapparent disease, or they might be discovered after the chinchilla’s demise from bacterial sepsis. Because these organisms are well recognized as potential human pathogens, signs and symptoms suggestive of Gram-negative sepsis in a chinchilla owner (especially an owner who is immunocompromised or diabetic) should be heeded carefully.
Cockatoo The colorful cockatoo is among the most popular of ornamental pet birds. There are 18 distinct species falling into the overall category of ‘‘cockatoo.’’ The majority of these parrot relatives are native to Aus-
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
233
Fig. 3. Inflammatory tinea corporis in a chinchilla owner.
tralia, Indonesia, and the Philippine Islands. Though not possessing as prolific a vocabulary retention as a parrot, the cockatoo offers the singular advantage of being a long-lived pet; birds in this category survive 30 to 80 years in a comfortable home environment. In common with pigeons, the cockatoo is a potential source of infection caused by Cryptococcus neoformans serotypes A and D. Generally, the bird remains well, but sheds the fungus in its feces, contaminating the birdcage and ambient air in close proximity to the cage [46,47]. On rare occasions, the cockatoo itself can develop cryptococcal disease [48]. A recent case report elegantly demonstrated that cryptococcosis can be transmitted from an infected
pet cockatoo to a susceptible human owner, in this instance an elderly renal transplant patient [49]. In the report cited, patient and cockatoo isolates were indistinguishable based upon biochemical profiles, monoclonal antibody binding patterns, restriction fragment length polymorphism analysis, and karyotyping. From the dermatologist’s viewpoint, cryptococcosis can present in many fashions, including cellulitis, lesions resembling molluscum and herpes, and Kaposi’s sarcoma-like papulonodules (Fig. 4). The close association of the cockatoo with cryptococcal disease has led to the strong suggestion that immunosuppressed and immunocompromised patients should avoid choosing this bird as a pet [49,50].
Fig. 4. Nodular cutaneous cryptococcosis in an HIV+ cockatoo owner.
234
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
As is true of almost any bird, the cockatoo can carry avian mites such as the northern fowl mite (Ornithonyssus sylvarium) and the chicken mite (Dermanyssus gallinae). Although such ectoparasites are more commonly associated with the commercial poultry industry or with wild nesting birds (eg, starlings and pigeons), they can also infest various birds used as house pets (eg, canaries, doves, finches, parakeets, and other psitticine species) [51,52]. Avian mites can cause an intensely pruritic, localized to generalized, papular to papulovesicular eruptions in an unsuspecting and incidental human host. Avian mites can be introduced into the environment not only by affected birds but also by other pets that seemingly acquired acariasis from birds housed at the same pet store. For example, two cases of avian mite dermatitis were recently reported to arise from infested pet gerbils [53]. Because avian mites cannot reproduce on a human host, infection with this type of organism is self-limiting if the source of the mites is permanently removed, or if the birdcage is cleaned and the pet bird disinfected with acaricide; temporary relief from pruritus in the incidental human host can be obtained with application of potent topical steroids.
Summary Zoonoses are diseases that can be transmitted from animals to humans. More than 250 distinct zoonoses have been described in the literature. It is estimated that 56% of United States households contain at least one pet, and although considerable research has been performed regarding the more common household animals including dogs, cats, small birds, and rodents, surprisingly little is known about the zoonotic hazards of owning the more exotic pets [54 – 57]. According to the 1997 USPHS/IDSA Report on the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus, the immunocompromised patient should avoid contact with feces-laden soil, litter boxes, reptiles, most pet birds, and any animal less than 6 months old [58]. It has also been documented that because of their inquisitive nature, children are at even higher risk for infection from animals than adolescents or immunocompetent adults [54]. In this article the authors have reviewed the available data regarding hazards associated with the hedgehog, flying squirrel, iguana, chinchilla, and cockatoo. With the growing popularity of such exotic pets, further observation and research is warranted. Physicians need to be aware of the possibility of
zoonotic disease related to exotic pet ownership, and they should address this issue when obtaining a history and formulating a differential diagnosis of cutaneous lesions suggestive of such illnesses.
References [1] Anonymous. Sea World/Busch Gardens animal bytes: hedgehog. Available at: http://seaworld.org/ animal bytes/hedgehogab.html. Accessed October 2, 2002. [2] Johnson-Delaney CA. Common disorders and care of pet hedgehogs. Available at: http://www.whh.org/help/ africa/africa22.htm. Accessed December 28, 2002. [3] Rosen T. Hazardous hedgehogs. South Med J 2000; 93:936 – 8. [4] Blakeley K. Forget Fido. Forbes 2000;165:152. [5] Smith JMB, Marples MJ. Trichophyton metagrophytes var erinacei. Sabouraudia 1963;3:1 – 10. [6] Flemmer M, Oldfield III EC. The night of the iguana. Am J Gastroenterol 1995;90:2243. [7] Klingmuller G, Heymer T, Sobich E. Trichophyton mentagrophytes var erinacei infection contracted from a hedgehog. Hautarzt 1979;30:140 – 3. [8] Philpot CM, Bowen RG. Hazards from hedgehogs. Two case reports with a survey of the epidemiology of hedgehog ringworm. Clin Exp Dermatol 1992; 17:156 – 8. [9] Quaife RA. Human infection due to the hedgehog fungus Trichophyton mentagrophytes var erinacei. J Clin Pathol 1966;19:177 – 8. [10] Jury CS, Lucke TW, Bilsland D. Trichphyton erinacei: an unusual cause of kerion. Br J Dermatol 1999;141: 606 – 7. [11] Roger H, d’Incan M, Cambon M, et al. Inflammatory tinea capitis caused by Trichophyton erinacei in a 3 yearold child. Ann Dermatol Venereol 1991;118:839 – 40. [12] Fairley JA, Suchnaik J, Paller AS. Hedgehog hives. Arch Dermatol 1999;135:561 – 3. [13] Anonymous. From the Centers for Disease Control and Prevention: African pygmy hedgehog-associated salmonelloses—Washington, 1994. JAMA 1995; 274:294. [14] Craig C, Styliadis S, Woodward D, et al. African pygmy hedgehog-associated Salmonella tilene in Canada. Can Commun Dis Rep 1997;23:129 – 31. [15] Matthews PR, McDiarmid A. Mycobacterium avium infection in freeliving hedgehogs (Erinaceus europaeus L). Res Vet Sci 1977;22:388. [16] Tappe JP, Weitzman I, Liu S, et al. Systemic Mycobacterium marinum infection in a European hedgehog. J Am Vet Med Assoc 1983;183:1280 – 1. [17] Lifson AR, Olson R, Roberts SG, et al. Severe opportunistic infections in AIDS patients with late-stage disease. J Am Board Fam Pract 1994;7:288 – 91. [18] Anonymous. Flying squirrel. Available at http://www. britannica.com. Accessed December 28, 2002.
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236 [19] Cross J, Lien J, Hsu M. Toxoplasma isolated from the Formosan giant flying squirrel. Taiwan I Hsueh Hui Tsa Chih 1969;68:678 – 83. [20] Kloos WE, Zimmerman RJ, Smith RF. Preliminary studies on the characterization and distribution of Staphylococcus and Micrococcus species on animal skin. App Environ Microbiol 1976;31:53 – 9. [21] Anonymous. Centers for Disease Control. Current trends: epidemic typhus associated with flying squirrels—United States. MMWR 1982;31:555 – 61. [22] Duma RJ, Sonenshine DE, Bozeman FM, et al. Epidemic typhus in the United States associate with flying squirrels. JAMA 1981;245:2318 – 23. [23] McDade JE, Shepard CC, Redus MA, et al. Evidence of Rickettsia prowazekii infections in the United States. Am J Trop Med Hyg 1980;29:277 – 84. [24] Sonenshine DE, Bozeman FM, Williams MS, et al. Epizootiology of epidemic typhus (Rickettsia prowazekii) I flying squirrels. Am J Trop Med Hyg 1978;27: 339 – 49. [25] Bozeman FM, Soneshine DE, Williams MS, et al. Experimental infection of ectoparasite arthropods with Rickettsia prowazekii (GvF-16 strain) and transmission to flying squirrels. Am J Trop Med Hyg 1981; 30:253 – 63. [26] Boam GW, Sanger VL, Cowan DF, et al. The pathogenicity for mice of two species of salmonella isolated from the green iguana (Iguana iguana). J Am Vet Med Assoc 1970;157:689 – 90. [27] Hsieh S, Babl FE. Serratia marcescens cellulitis following an iguana bite. Clin Infect Dis 1999;28: 1181 – 2. [28] Kelsey J, Ehrlich M, Henderson SO. Exotic reptile bites. Am J Emerg Med 1997;15:536 – 7. [29] Teitel AD. Bite of the iguana [letter]. Am J Emerg Med 1990;8:567 – 8. [30] Barten SL. The medical care of iguanas and other common pet lizards. Vet Clin N Am Small Anim Pract 1993;23:1213 – 49. [31] Clark HF, Karzon DT. Iguana virus, a herpes-like virus isolated from cultured cells of a lizard, Iguana iguana. Infect Immun 1972;5:559 – 69. [32] Zeigel RF, Clark HF. Electron microscopy observation on a new herpes-type virus isolated from Iguana iguana and propagated in reptilian cells in vitro. Infec Immun 1972;5:570 – 82. [33] Kelso JM, Fox RW, Jones RT, et al. Allergy to iguana. J Allergy Clin Immunol 2000;106:369 – 72. [34] Dalton C, Hoffman R, Pape J. Iguana-associated salmonellosis in children. Pediatr Infect Dis J 1995;14: 319 – 20. [35] Mermin J, Hoar B, Angulo FJ. Iguanas and Salmonella marina infection in children: a reflection of the increasing incidence of reptile-associated salmonellosis in the United States. Pediatrics 1997;99:399 – 402. [36] Mitchell MA, Shane SM. Preliminary findings of Salmonella spp. in captive green iguanas (Iguana iguana) and their environment. Prev Vet Med 2000;45: 297 – 304.
235
[37] Burnham BR, Atchley DH, DeFusco RP, et al. Prevalence of fecal shedding of Salmonella organisms among captive green iguanas and potential public health implications. J Am Vet Med Assoc 1998; 213:48 – 50. [38] Sam WI, Mackay AD. Salmonella meningitis and a green iguana. J R Soc Med 2000;93:318 – 9. [39] Cabanas FJ, Abarca ML, Bragulat MR. Dermatophytes from domestic animals in Barcelona, Spain. Mycopathologia 1997;137:107 – 13. [40] Hagen KW, Gorham JR. Dermatomycoses in fur animals: chinchilla, ferret, mink, and rabbit. Vet Med Small Anim Clin 1972;67:43 – 8. [41] Male O, Fritsch P. Trychophyton mentagrophytes caused epidemic and enzootic disease in a chinchilla farm. Mykosen 1966;4:74 – 84. [42] Morganti L, Gomez Portugal EA. Microsporum gypseum infection in chinchillas. Sabouraudia 1970;8: 39 – 40. [43] Aho R. Saprophytic fungi isolated from the hair of domestic and laboratory animals with suspected dermatophytosis. Mycopathologia 1983;83:65 – 73. [44] Bartoszcze M, Matras J, Palec S, et al. Klebsiella pneumoniae infection in chinchillas. Vet Rec 1990; 127:119. [45] Doerning BJ, Brammer DW, Rush HG. Pseudomonas aeruginosa infection in a Chinchilla lanigera. Lab Anim 1993;27:131 – 3. [46] Staib F. Sampling and isolation of Cryptococcus neoformans from indoor air with the aid of the Reuter Centrifugal Sampler and guizotia abyssinica creatinine agar. Zentralbl Bakteriol Mikrobiol Hyg 1985;180: 567 – 75. [47] Staib F, Schulz-Dieterich J. Cryptococcus neoformans in fecal matter of birds kept in cages. Control of Cr. Neoformans habitats. Zentralbl Bakteriol Mikrobiol Hyg 1984;179:179 – 86. [48] Fenwick B, Takeshita K, Wong A. A moluccan cockatoo with disseminated cryptococcosis. J Am Vet Med Assoc 1985;187:1218 – 9. [49] Nosanchuk JD, Shoham S, Fries BC, et al. Evidence of zoonotic transmission of Cryptococcus neoformans from a pet cockatoo to an immunocompromised patient. Ann Intern Med 2000;132:205 – 8. [50] Blaschke-Hellmessedn R. Cryptococcus species—etiological agents of zoonoses or sapronosis? Mycoses 2000;43(Suppl 1):48 – 60. [51] Jeffrey JS, McCrea B. Identification and treatment of common mites and lice of birds. 1999. Available at: http://www.animal science.ucdavis.edu/Avian/ pfs31.htm. Accessed March 31, 1999. [52] Schulze KE, Cohen PR. Dove-associated gamasoidosis: a case of avian mite dermatitis. J Am Acad Dermatol 1994;30:278 – 80. [53] Lucky AW, Sayers C, Argus JD, et al. Avian mites acquired from a new source-pet gerbils. Report of two cases and review of the literature. Arch Dermatol 2001;137:167 – 70. [54] Chomel BB. Zoonoses of house pets other than
236
T. Rosen, J. Jablon / Dermatol Clin 21 (2003) 229–236
dogs, cats and birds. Pediatr Infect Dis J 1992;11: 479 – 87. [55] Chretien JH, Garagusi VF. Infections associated with pets. Am Fam Physician 1990;41:832 – 45. [56] Morrison G. Zoonotic infections from pets. Understanding the risks and treatment. Postgrd Med 2001; 110:24 – 6, 29 – 30, 35 – 6.
[57] Parish LC, Schwartzman RM. Zoonoses of dermatological interest. Semin Dermatol 1993;12:57 – 64. [58] Anonymous. 1997 USPHS/IDSA report on the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Pediatrics 1998; 102:1064 – 85.
Dermatol Clin 21 (2003) 237 – 244
Tick-borne infections Divya Singh-Behl, MD, Steven P. La Rosa, MD, Kenneth J. Tomecki, MD* The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Ticks, obligate, blood-sucking members of the order Acarina and class Arachnida, are the most common agents of vector-borne diseases in the United States [1]. Ticks play an important role in transmitting viruses, bacteria, spirochetes, parasites, and rickettsia. In this article the authors review the epidemiology, microbiology, clinical presentation, diagnosis, and treatment of the major tick-borne diseases in the United States. Ticks are divided into three families, only two of which are capable of causing infection: soft ticks (Argasidae) and hard ticks (Ixodidae), the latter being responsible for most tick-related diseases [1,2]. The life cycle of ticks is 2 years and includes egg, larva, nymph, and adult. All stages except egg require a blood meal for morphogenesis. Ticks have either one or two indistinct body regions. The larvae (or seed tick) are six-legged, whereas adult and nymphs are eight-legged [1,2]. Hard ticks possess a dorsal plate, the scutum, which the soft ticks lack. Hard ticks are found in wooded areas with dogs, deer, and cattle and might remain attached to the host for several hours or days at a time during feeding [1,2]. In the United States, the most common Ixodidae genera of ticks to transmit disease to humans include Amblyomma, Ixodes, and Dermacentor. Among the most common in the United States are I. scapularis (or I. dammini), I. Pacificus, Amblyomma americanum (Lone Star Tick), Dermacentor andersoni (American wood tick), and Dermacentor variabilis (American dog tick). I. ricinus and I. persulcatus are the most common hard ticks in Europe. Soft ticks (so named because of their flexible cuticle) are found in animal dwellings and run-down human habitats. They are long-lived
* Corresponding author. E-mail address:
[email protected]
and can survive without feeding for several years. In United States, the most common genus of Argasidae to cause infection is Ornithodoros [1,2].
Lyme disease Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States. It has been reported in 49 of the 50 U.S. states, but, most cases occur in the Northeastern, Midwest, and North Central regions of the United States. Nine states account for more than 90% of the nationally reported cases, with Connecticut leading the group. The other states (in decreasing order) are Rhode Island, New York, Pennsylvania, Delaware, New Jersey, Maryland, Massachusetts, and Wisconsin [3,4]. In Europe the dermatological and neurological features of this disease have been recognized since 1883 and 1922, respectively [5]. The earliest American cases were described in 1977 when a group of children with juvenile rheumatoid arthritis were diagnosed after a tick bite that resulted in erythema chronicum migrans (ECM) in Lyme, Connecticut. The illness was termed Lyme disease, and when Burgdorferi et al isolated the tick, the term Lyme borreliosis was coined [6]. The etiologic agent is the slow-growing, motile spirochete of the Borrelia genus, Borrelia burgdorferi sensu lato, which is transmitted by ticks. Three species can cause Lyme disease: B. burgdorferi sensu lato in Europe and the United States and B. afzelli and B. garinii in Europe. An infected nymphal tick of the I. ricinus complex is the most common vector. In the Midwest and North Central United States, the deer tick I. scapularis, formerly known as I. dammini; in the West, the black-legged tick I. pacificus; in Europe and Asia sheep-tick I. ricinus and I. persulcatus [7]. The white-
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00092-X
238
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
footed mouse, Peromyscus leucopus, is the preferred host in the United States for the nymphal and larval stages and white-tailed deer are the preferred host for the adult stage of I. scapularis [4]. Although B. burgdorferi has been isolated in other tick species (dermacentor and amblyomma), mosquitoes’, fleas’, horses’, and deer flies’ transmission of the spirochete to humans has not been described from these vectors. During their 2-year life cycle, ticks typically feed once during each of the three stages, usually the late summer for larval ticks, the following spring for nymphs, and autumn for the adults. I. scapularis nymphs appear to be the most important vector for transmission of B. burgdorferi. According to laboratory studies, a minimum of 36 – 48 hours of attachment of the tick is required for transmission. In the United States, most cases involving B. burgdorferi occur between May and August, which corresponds with increased outdoor human activity and nymphal activity. The risk of developing Lyme disease after a tick bite is low, even in endemic areas. Furthermore, less than half of affected patients recall receiving a tick bite because of the small size of the tick [8]. Lyme disease affects all age groups and both sexes. Although transplacental transmission of B. burgdorferi has been reported, it seems to be infrequent [9,10]. Markowitz et al retrospectively reviewed 19 cases of Lyme disease during pregnancy and noted adverse fetal outcomes in five cases [11]. Clinically, Lyme disease has three stages and can be best categorized into an early – localized infection, early – disseminated infection, and late-stage disease. Most patients do not follow this course; the features of the stages can overlap, and many patients do not develop the features of each stage. Asymptomatic infections may occur. Once the spirochete is injected in the skin, ECM develops in 60% to 80% of patients at the site of the bite; ECM is the classic lesion of the early – localized stage [12]. The incubation period is typically 1 week, but the rash might develop as late as 16 weeks after the tick bite. The rash develops centrifugally as an erythematous, annular, round to oval, well-demarcated plague and can reach a diameter of more than 30 centimeters (median is 15 cm). Occasionally, the lesions might be hemorrhagic or nonmigratory. The rash might be accompanied by constitutional symptoms such as myalgias, arthralgias, low-grade fever, and regional lymphadenopathy. Untreated ECM typically resolves in 3 to 4 weeks [5,8,12]. Within days to a few weeks after the infection, hematogenous and lymphatic dissemination of the spirochete to distant sites commonly occurs, leading to the early – disseminated stage [5,8,12]. Although a number of different organ systems can be affected in
this stage, the most characteristic manifestations are in the skin, musculoskeletal system, and neurologic system [13]. Other annular plagues resembling ECM develop in up to half of patients; they are the most characteristic feature of this stage. Borrelial lymphocytomas, bluish – red nodules most commonly seen on the earlobe or nipples, are usually encountered at this stage [5,12]. The most common neurologic feature is cranial neuropathy, unilateral or bilateral facial paralysis. Other features include peripheral neuropathy, meningitis, or meningoencephalitis. About 6 months after infection, approximately 60% of the patients develop musculoskeletal symptoms. Arthralgias and myalgias represent early involvement, and asymmetric, oligoarticular arthritis (primarily of the large joints, especially the knee) is common later in the disease. Cardiac involvement, most commonly atrioventricular block within several weeks after the infection can be seen in up to 8% of patients. Other abnormalities include left ventricular dysfunction, pericarditis, or fatal pancarditis [5,8,12]. The manifestations of late-stage disease can occur months to years after the initial infection. The organs most commonly involved include the skin, musculoskeletal system, and neurologic system [8]. Acrodermatitis chronica atrophicans, which occurs primarily in Europe, and localized scleroderma-like lesions may occur in late-stage disease. Approximately 10% of patients in United States with untreated ECM will develop chronic Lyme arthitis, an asymmetric oligoarticular or monoarticular arthritis and have an increased frequency of the haplotype HLA-DR4. The number of patients who develop recurrences decreases by 10% to 20% each year, and permanent joint disease is unusual [5,8]. The central and peripheral nervous system can be affected, leading to a spectrum of manifestations ranging from the rare subacute encephalopathy, chronic encephalomyelitis, and axonal polyradiculopathy to the more common intermittent distal paraesthesias or radicular pain. In the United States, only a few patients with neurological abnormalities caused by Lyme disease have been described [7,8] Although the gold standard for the diagnosis of an infectious disease is isolating the causative organism, such confirmation is often difficult in Lyme borreliosis, and the reliability of other methods available remains questionable [7]. The diagnosis of Lyme disease is therefore based on the history of a tick bite in an endemic area and characteristic clinical findings. Serology using Enzyme-Linked immunosorbet assay (ELISA) is the most common laboratory test to screen for antibodies to B. burgdorferi; however, the test is not standardized, results vary among labora-
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
tories, and false-negatives (or, more commonly, false positives) are common [8]. To increase serological specificity, a two-step sequential approach has been proposed. When a positive or equivocal test is obtained using ELISA, an immunoblot should be performed on the same serum sample to detect IgM and IgG antibodies to individual B. burgdorferi antigens. If the immunoblot is negative, the ELISA is likely a false-positive, and if the IgG immunoblot is positive, a diagnosis of Lyme borreliosis can be confirmed in a patient with clinical evidence of Lyme disease [7]. Other diagnostic tests, including histopathological detection of spirochetes and polymerase chain reaction (PCR) to detect antigen sequences specific for B. burgdorferi are not reliable [7,8]. In patients with only cutaneous disease, laboratory testing is neither necessary nor recommended; however, in suspected cases of extracutaneous Lyme borreliosis, laboratory support is essential. Treatment for lyme disease is always warranted, even though some manifestations of the disease may resolve spontaneously. Given the diagnosis of Lyme borreliosis, antimicrobials should be started as soon as possible. There is a general agreement that tetracyclines are highly active against B. burgdoferi, and penicillin, third-generation cephalosporins, and macrolides show moderate activity. In general, doxycycline and amoxicillin are the antibiotics of choice, and ceftriaxone, cefotaxime, and penicillin G as parenteral treatment. For early disease, doxycycline 100 mg twice a day for 2 to 3 weeks is the agent of choice. For pregnant or nursing women and children less that 8 years of age, amoxicillin 500 mg three times a day or 25 to 50 milligrams per kilogram per day divided in three doses for 2 to 3 weeks can be used in. Cefuroxime 500 mg and 250 mg twice a day for adults and children, respectively, for 2 to 3 weeks is an alternative for patients who are allergic to doxycycline and amoxicillin [14 – 16]. Limited data comparing the different treatment regimens are available for late-stage Lyme disease [8,15]. For patients with facial nerve palsy alone, treatment should be a 3- to 4-week course or doxycycline 100 mg twice a day or amoxicillin three times a day. Patients with serious neurologic disease should be treated with a 2- to 4-week course of intravenous ceftriaxone (2 g/day), cefotaxime (2 g/8 hours), or Penicillin G (20 – 24 million units/day). Similarly, for late-stage cardiac or joint disease treatment [15]. Prophylactic or empirical treatment with antibiotics after a tick bite is not recommended because the risk of infection is less than 1%; however, a single 200 mg dose of doxycycline has been shown to be effective in preventing Lyme disease when given within 72 hours of the tick bite [14,16,17].
239
Vaccination, with a single recombinant vaccine consisting of outer-surface protein A (OspA) has been highly effective in animals and appears to be safe and efficacious, in humans based on two large U.S. human clinical trials with three injections of the recombinant OspA protein [15,18,19]. Vaccination is recommended for patients between the ages of 15 to 70 living or visiting an endemic area with I. scapularis and patients who are being treated for Erythema migrans (EM) because they might become reinfected [20]. Three injections are recommended, the second injection 1 month after the first and the third 12 months after the first. Booster injections need to be given every 3 to 4 years [21].
Tick-borne relapsing fever Tick-borne relapsing fever, recognized since the early 1900s, is caused by at least 13 borrelial species and transmitted by soft tick genus Ornithodoros [22,23]. A specific tick vector from the genus Ornithodoros appears to transmit the infection for each borrelial species. The borrelia that cause relapsing fever are capable of antigenic variation, which is thought to be the cause of relapsing episodes in humans [24]. Rodents and small mammals are the primary reservoirs. The tick species capable of transmitting the disease in the United States tends to exist in remote, undisturbed settings and include O. hermsi and O. parkeri (Western states), O. talaje (Southern states), and O. turicatae (Southwestern and Northern states) [25,26]. Exact incidence of disease is unknown; however, it is known that the incidence peaks in summer [27,28]. After an incubation period of 1 week, the disease is characterized by acute onset of high fever with chills, headache, myalgias, tachycardia, arthralgias, and malaise [23,25]. Neurologic involvement is frequent and can be severe with O. turicatae. Rash is a variable finding and usually occurs at the end of the first febrile episode. If untreated, the primary episode lasts for 3 to 6 days and rapid defervescence followed by drenching sweats marks the resolution of disease. If left untreated, a second, shorter course and as many as 3 to 5 relapses per year can occur with febrile episodes followed by afebrile episodes, although the severity of illness decreases [8,23,25]. Demonstration of borreliae species in peripheral blood of febrile patients has 70% sensitivity and high specificity, which can be achieved by observing spirochetes on a Giemsa or Wright stain peripheral smear or by darkfield microscopy [8,28]. Serologic assays are neither widely available nor have they been standardized
240
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
because of the antigenic variation [25]. Tetracyclines are the drug of choice, though serologic tests for syphilis and Lyme disease may be positive in affected patients. A single 200 mg dose of doxycycline is adequate therapy for louse-borne disease. Tick-borne relapsing fever warrants treatment with either tetracycline or erthromycin for 5 – 10 days. Penicillin G has also been effective [29]. In as many as one third of patients, treatment with antimicrobials might provoke the Jarisch-Herxheimer reaction, which consists of fever, chills, tachycardia, hypotension, and (rarely) rash [8].
Rocky Mountain spotted fever Rickettsiae are small, pleomorphic, coccobacillary, obligate, intracellular parasites that are transmitted to humans by arthropods and can produce systemic infections of varying severity [30]. Spotted fever, typhus, trench fever, Q fever, and ehrlichiosis are illnesses that can be caused by different rickettsial species. Among the spotted fevers are Rocky Mountain Spotted Fever (RMSF), Boutonnese fever, South African tick-bite fever, Siberian fever, Queensland tick typhus, and rickettsialopox; ticks transmit all of these diseases except rickettsialopox. RMSF, the most common acute rickettsial infection in the United States, is caused by R. rickettsi. In the United States, the disease is most commonly seen in Southeastern, Western, and South Central states. The infection is seasonal, typically occurring in spring and summer, and the exposure is usually in rural or suburban areas [30,31]. Small mammals are the primary reservoirs of R. rickettsi [32]. Primary offenders in the Western United States are the wood tick, D. andersoni, and in the Eastern United States the dog tick D. variabilis [33]. Within 1 to 2 weeks after the tick bite, acute onset of fever, chills, severe headache, and myalgias develop. In most patients, fever and severe headache precede the characteristic rash that generally appears on the fourth day starting on the wrists, ankles, and forearms as blanching red macules that progress to form papules centrally to the arms, thigh, trunk, and face. Gradually, the rash develops petechial, purpuric, and ecchymotic features. In rare cases, areas of gangrene might develop at acral sites [32,33]. Diffuse vasculitis compounded with myocarditis can lead to impaired circulatory dynamics; affected patients may become edematous and ill. In about 10% of the patients, the rash might either be absent (Spotless often so in dark skinned patients and older patients) or present in an atypical distribution [33,34]. During the course of disease, respiratory
failure, renal dysfunction, hepatosplenomegaly, abdominal pain and distention, lymphadenopathy, and neurologic damage such as mental confusion, seizures, or coma might develop [33]. The diagnosis of RMSF is based largely on clinical presentation in a patient with history of tick exposure. Laboratory tests are nonspecific but might show anemia, elevated or depressed white blood cell count, thrombocytopenia, coagulation abnormalities, elevated hepatic transaminases, and elevated blood urea nitrogen. Direct immunofluorescence of a vasculitic area looking for R. rickettsi, is the most specific test currently available for RMSF [35]. Unfortunately it is not widely used because of its poor sensitivity and impracticality. Various serological tests are available to confirm the diagnosis. Indirect immunofluorescence with a titer of 1:64 is diagnostic of infection. The Weil-Felix assay, with OX-19 and OX-2 antigens of Proteus vulgaris, has only historical significance because the test lacks specificity and sensitivity. Culture and PCR for rickettsia are available, but they are not used for diagnostic purposes [36]. When administered early in the disease, tetracycline and chloramphenicol (orally and intravenously) are extremely effective. In adults, doxycycline 100 mg twice a day or tetracycline four times a day, and in children chloramphenicol 50 to 100 milligrams per kilogram per day four times a day should be given for 7 days or for at least 2 days after the patient becomes afebrile. The usual course should run for 10 to 14 days [33,37].
Ehrlichiosis Ehrlichiae are a group of small, Gram-negative, obligate, intracellular, pleomorphic bacteria that are closely related to rickettsiae. Tick-transmitted ehrlichioses have been recognized in animals since the early 1990s, causing an illness characterized by fever, weight loss, bleeding, and pancytopenia caused by the infection of leukocytes in susceptible wild and domestic animals, particularly dogs [38,39]. In the United States, the first case of human ehrlichiosis was described in 1987 [40]. Since then, more than 700 cases have been diagnosed in the United States [41]. Five species can cause human disease: (1) Ehrlichiae chaffeensis (human monocytic ehrlichiosis), an agent closely related to (2) E. phagocytophila and E. equi (human granulocytic ehrlichiosis); (3) E. sennetsu (mononucleosis-type illness in Japan and Malaysia); (4) E. ewingii (ehrlichiosis ewingii); and (5) E. canis (single asymptomatic case in Venezuala). Ehrlichiae grow within their target cells intracellularly and form a
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
colony of elementary bodies called morulae. The target cells for each species differ and include neutrophils, monocytes, platelets, erythrocytes, and endothelium. Ehrlichioses follow the bite of an infected tick, and despite the causative organisms the disease presentation is similar [38]. Human monocytic ehrlichiosis (HME) with E. chaffeensis has been seen mainly in the midAtlantic, South Central, Southeastern states, and California in the United States [38]. In states with the highest incidence, active population-based surveys have estimated rates as high as 10 to 100 cases per 100,000 population each year [41]. In the endemic areas, infected white-tailed deer and dogs serve as the primary reservoir, and A. americanum (Lone Star tick) is the primary vector [38,42]. E. chaffeensis infects primarily monocytes and macrophages. Most cases occur during the summer and autumn, and a history of tick exposure occurs in more than 80% of patients. HME is a multisystem disease with clinical manifestations similar to RMSF. Compared to patients with RMSF, patients with ehrlichiosis have a greater incidence of leucopenia and a lesser likelihood of rash. Approximately 7 to 10 days after the tick bite, the most common presenting features are fever, chills, malaise, headache, nausea, diaphoresis, gastrointestinal complaints, cough, and (less commonly) confusion. The spectrum of the illness can range from subclinical to fatal in (3% to 5%) of patients. Anywhere from 40% to 60% of patients become progressively ill, requiring hospital admission for hypotension, respiratory failure, acute renal failure, disseminated intravascular oagulation, cardiac failure, or meningoencephalitis. Although the rash is not usually present at the time of onset, a maculopapular presentation and (less commonly) a petechial rash occurs in about one third of patients. The most frequent laboratory abnormalities include leukopenia, thrombocytopenia, anemia, and elevated hepatic transaminases. HME should be considered in a patient who develops constitutional symptoms 3 to 4 days after a tick bite. Early in the presentation, laboratory testing and peripheral smear searching for morulae in monocytes might not be helpful, since the yield is low (less than 100%). However, the presence of antibodies to E. chaffeensis detected by an indirect immunofluorescene assay accomplished by the comparison of acute and convalescent titers establishes the diagnosis. A fourfold or greater rise in antibody titer confirms a clinically compatible case. In general, the treatment of choice for ehrlichioses is a tetracycline, specifically doxycycline 100 mg twice daily. Rifampin and chloramphenicol have activity against the organism, and 300 mg twice daily of oral rifampin is an alternative
241
therapy for tetracycline-allergic patients. The antibiotics should be given for 2 weeks to assure treatment of coexisting Lyme disease or until the patient is afebrile for several days. Human granulocytic ehrlichiosis (HGE) with E. phagocytotophila first appeared in 1990 [43], and by 1997 more than 500 cases had occurred in the United States [41]. The infection was first recognized in Minnesota and Wisconsin. Since then it has been reported in Northeast, upper Midwest, and regions of Northern California. On average, an annual incidence of 3 to 5 cases per 100,000 population has been estimated [44]; however, in endemic areas such as Connecticut and northwestern Wisconsin, the yearly incidence is 51 and 58 cases per 100,000 population, respectively [42,45]. Small mammals such as the white-footed mouse serve as the reservoir, and ticks of the I persulatcus complex serve as the principal vector for E. phagocytotophila. Other principal vectors are I. scapularis (Northeast America), I. pacificus (Western United States), and I. ricinus (Europe). E. phagocytotophila infects mostly neutrophils. Many patients may concomitantly have ehrlichiosis, babesiosis, and borreliosis, because of the common vector, I. Scapularis. Most cases of HGE occur during the summer months, and the majority of patients recall a tick bite. The clinical presentation for HGE is indistinguishable from HME. Although most patients experience only mild illness, fatality is low (less than 1% of patients) [39]. Although serologic assays are the most sensitive test, most patients will have thrombocytopenia, leukopenia, and elevated hepatic transaminases. A peripheral smear should be performed to examine for the presence of intraneutrophilic morulae, which may be present in 20 – 80% of affected patients. Treatment of HGE is similar to that of HME.
Tularemia Tularemia, also known as Ohara’s disease or deer fly fever, is caused by Francisella tularensis, an organism named after Francis for conducting the early studies of tularemia. F. tularensis is a short, Gram-negative, nonmotile, non – spore-forming coccobacillus. Two strains exist, the more virulent type A and the less virulent type B. Although cases have been reported in all parts of the United States, the disease is most commonly seen in Southern and Western United States [46 – 48]. Wild rabbits, ticks, and hares are the primary reservoirs. Inoculation of organisms into the skin most frequently occurs from bites of deer flies or ticks and direct contact with infected animals, primarily wild rabbits, especially
242
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
after skinning their hides. Other modes of transmission include ingestion of contaminated meat or water, inhalation of organisms, and bites of infected mammals or mosquitoes [48]. The organism is important as a potential ‘‘bioterrorist’’ agent. The tick in the Southeastern and South Central United States is A. americanum, in the West it is D. andersoni, and the most widely distributed is D. variabilis [8]. Tularemia is characterized by acute onset of fever, headache, chills, myalgias, fatigue, and leukocytosis. The typical incubation period is 3 to 5 days, and several clinical presentations exist. The most common is the ulceroglandular type, which begins at the site of the tick bite, usually on the lower extremities or perineum, as a papule or nodule that rapidly ulcerates. A lymphatic spread occurs with painful regional lymphadenopathy, usually inguinal or femoral, which might progress to ulceration. In the typhoidal form, the second most common presentation, the site on inoculation is not known and cutaneous involvement does not occur. Persistent fever, chills, malaise, gastrointestinal complaints, and the presence of specific agglutinins in the serum characterize typhoidal type. Other clinical presentations include oculoglandular type, oropharyngeal type, glandular type, and primary pneumonic fever. The severity of illness varies from mild to the rare cases of fatal fulminant septic shock. Increased morbidity and mortality is seen with the typhoidal form and secondary pneumonia [8,49]. Laboratory tests show leukocytosis, elevated hepatic transaminases, and patchy, ill-defined infiltrates on the chest radiograph. Serology testing demonstrating agglutinating antibodies to F. tularensis is most frequently used to confirm the diagnosis. In majority of patients, the titers become positive in 2 weeks, and a fourfold increase between acute and convalescent phase is diagnostic, or a single convalescent titer of 1:160 confirms current or previous diagnosis. Staining the exudate or lymph nodes, blood, or pleural fluid, with fluorescent antibody to F. tularensis and growth on culture help to establish diagnosis. Special media containing cystine glucose blood agar and thioglyollate (or other selective media) are needed to culture the organism [8,25,49]. If tularemia is suspected, laboratory workers should be notified. Streptomycin given intramuscularly 0.5 mg every 12 hours for 10 to 14 days is the treatment of choice; gentamicin is equally effective. Tetracycline and chloramphenicol are other alternatives; however, relapses and treatment failure are more common with these agents and they are only useful if the duration of therapy is greater than 15 days. Clinical improvement is noted as early as 48 hours after starting the treatment. Individuals with frequent exposure to rabbits should
wear protective clothing, and they might also benefit from the live-attenuated vaccine, which provides partial protection [8,25,49].
Tick paralysis Tick paralysis, although well recognized in animals, occurs rarely in humans, usually in children. Most cases in the United States occur in the Northwest in the spring or summer months, and the ticks usually attach to the scalp or neck. Tick paralysis can be transmitted by 43 different species, but in the United States most cases are attributed to D. andersoni, D. variabilis, A. americanum, and I. scapularis. Paralysis usually occurs 4 to 7 days after attachment of tick, and it is caused by the production of a neurotoxin secreted in the saliva of tick, which causes a presynaptic neuromuscular blockade and involvement of peripheral nerves. An acute, ascending lower motor neuron paralysis beginning in the legs develops, sparing the sensory function. If the tick is removed symptoms disappear promptly, but dysarthria, dysphagia, and eventually death from respiratory failure can occur in 10% to 12% of patients if the tick is not removed [8].
Babesiosis Babesiosis is a malaria-like disease caused by an intracellular parasite that invades red blood cells. The disease occurs primarily in the United States. Scholtens et al reported the first case of human American babesiosis in 1968 [50], and between 1968 and 1993 more than 450 cases were reported [51]. The major endemic areas in the United States are Massachusetts (Martha’s Vineyard, Nantucket), New York (Eastern and South Long Island), Connecticut, and other offshore islands in the Northeast. The causative agent is Babesia microti, which is transmitted by the larvae of I. dammini tick. The principal reservoir of B. microti in the United States is the whitefooted mouse [8]. The illness usually occurs in older patients or in asplenic or immunocompromised patients. Patients with splenectomy and depressed T cell counts are at risk. The incubation period after a tick bite is about 1 week, but it varies between 5 to 33 days. The classic clinical presentation is high fever, drenching sweats, myalgias, and hemolytic anemia. Blood smear may be confusing; the tetrad of merozoites of babesiosis can be confused with the ring forms of Plasmodium falciparum-induced malaria. In less than
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244
10% of patients, progression to renal failure, CHF, DIC, hypotension, and (rarely) death occur. Laboratory findings include anemia, thrombocytopenia, hemoglobinuria, and elevated hepatic transaminases. The presence of intracellular red blood cell parasites, usually seen in a ring form, on a Giemsa-stained peripheral smear establishes the diagnosis, but the tetrad or ‘‘Maltese Cross’’ is considered to be diagnostic [52]. P. falciparum can be distinguished from babesia species on peripheral smear by the presence of pigment deposits and lack of tetrads. Indirect immunofluorescence, with titer of 1:256, and PCR for B. microti can also help confirm the diagnosis. A 7- to 10-day concomitant course with quinine (650 mg tid) and intravenous clindamycin (900 mg tid) is used most commonly to treat the infection [53]. Atovaquone (750 mg tid) in combination with azithromycin (500 – 1000 mg/day) is another option that has similar efficacy but fewer side effects when compared with clindamycin and quinine [52]. In severe cases or in patients with splenectomy, exchange transfusions and antibiotics have been helpful [52,53].
Prevention of tick bites The key to controlling tick-borne diseases is preventing tick bites in endemic areas where exposure is likely. This can be achieved by applying appropriate repellent containing DEET (N, N-diethyl-m-toluamide) to exposed skin, treatment of clothing by permethrin, wearing protective clothing, and avoiding walking through woods that have brushy vegetations. Tick repellents containing DEET are most effective in concentrations that range from 15% to 33% — for children concentrations of less than 7% should be used. Permethrin, which kills ticks on contact, is not approved for direct application to the skin [25]. Skin and clothing should be carefully examined routinely while in tick-infested areas in an attempt to remove them before transmission of disease can occur. If patients present with attached ticks, removal using blunt forceps and steady pulling of the tick perpendicular to the skin is recommended. Punch or shave biopsy is an alternative approach. After the tick is isolated, attempts should be made to store the organism in the event that the patient develops a disease and detection of the causative agent is needed. Suffocating ticks with substances such as petrolatum, sun tan oil, or burning the tick with a match or other hot subjects should be avoided because this might cause the tick to regurgitate and increase the risk of transmission of disease.
243
References [1] Sonenshine DE. Biology of ticks, Vol. 1. New York (NY): Oxford University; 1991. [2] Cupp EW. Biology of ticks. Vet Clin N Am Small Anim Pract 1991;21:1 – 26. [3] Massachusetts Medical Society. Morbidity and Mortality Weekly Report 2001;50:181 – 4. [4] Melski JW. Lyme borreliosis. Semin Cutan Med Surg 2000;19:10 – 8. [5] Pfister HW, Wilske B, Weber K. Lyme borreliosis: basic science and clinical aspects. Lancet 1994;343: 1013 – 6. [6] Steere AC, Malawista SE, Syndman DR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 1977;20:7 – 17. [7] Nadelman RB, Wormser GP. Lyme borreliosis. Lancet 1998;352:557 – 65. [8] Spach DH, Liles WC, Campbell GL, et al. Tick-borne diseases in the United States. N Engl J Med 1993;329: 936 – 47. [9] Schlesinger PA, Duray PH, Burke BA, et al. Maternalfetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 1985;103:67 – 9. [10] Weber K, Bratzke HJ, Neubert U, et al. Borrelia burgdorferi in a new born despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 1988;7:286 – 9. [11] Markowitz LE, Steere AC, Benach JL, et al. Lyme disease during pregnancy. JAMA 1986;225:3394 – 6. [12] Steere AC. Lyme disease. N Engl J Med 1989;321: 586 – 96. [13] Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifestations of Lyme disease. Ann Int Med 1983;99:76 – 82. [14] Weber K, Pfister HW. Clinical management of Lyme borreliosis. Lancet 1994;343:1017 – 20. [15] Treatment of Lyme disease. The Medical Letter 1997; 39:47 – 8. [16] Steere AC. Medical progress: Lyme disease. N Engl J Med 2002;345:115 – 25. [17] Shapiro ED, Greber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. The New England Journal of Medicine 1992;327:1769 – 73. [18] Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia Burgdoferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209 – 15. [19] Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of recombinant Borrelia Burgdoferi outer surface protein A to prevent Lyme disease. The New England Journal of Medicine 1998;339:216 – 22. [20] Recommendations for the use of Lyme disease vaccine: recommendations of the Advisory committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1999;48:1 – 17, 21 – 5. [21] Schoen RT, Sikand VK, Caldwell MC, et al. Safety and
244
[22]
[23] [24]
[25]
[26] [27]
[28]
[29] [30] [31] [32]
[33] [34]
[35]
[36]
[37] [38]
D. Singh-Behl et al. / Dermatol Clin 21 (2003) 237–244 immunogenicity profile of a recombinant outer-surface protein A Lyme disease vaccine: clinical trail of a 3-dose schedule at 0, 1, and 2 months. Clin Ther 2000;22: 315 – 25. Dutton JE, Todd JL. The nature of tick fever in the eastern part of the Congo Free State, with notes on the distribution and bionomics of the tick. BMJ 1905;2: 1259 – 60. Sonenshine DE. Biology of ticks, Vol. 2. New York (NY): Oxford University Press; 1993. Barbour AG. Antigenic variation of a relapsing fever Borrelia species. Annu Rev Microbiol 1990;44: 155 – 71. Phillips P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis 2001;32:897 – 928. Felsenfeld O. Borrelia; strains, vectors, human and animal borreliosis. St. Louis (MO): WH Gree; 1971. Fihn S, Larson EB. Tick-borne relapsing fever in the Pacific Northwest: an underdiagnosed illness? West J Med 1980;133:203 – 9. Burgdorfer W, Schwan TG. Borrelia. In: Balows A, Hausler Jr WJ, Herrmann KL, et al, editors. Manual of clinical microbiology. 5th edition. Washington DC: American Society for Microbiology; 1991. p. 560 – 8. Butler TC. Relapsing fever: new lessons about the antibiotic action. Ann Intern Med 1985;102:397 – 9. Weber DJ, Walker DH. Rocky Mountain spotted fever. Infect Dis Clin N Am 1991;5:19 – 35. Thorner AR, Walker DH, Petri WA. Rocky Mountain spotted fever. Clin Infect Dis 1998;27:1353 – 60. Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev 1997;10:694 – 719. Callhan EF, Adal KA, Tomecki KJ. Cutaneous (nonHIV) infections. Dermatol Clin 2000;18:497 – 507. Sexton DJ, Corey GR. Rocky Mountain ‘‘spotless’’ and ‘‘almost spotless’’ fever: a wolf in sheep’s clothing. Clin Infect Dis 1992;15:439 – 48. Procop GW, Burchette JL, Howell DN, et al. Immunoperoxidase and immunofluorescent staining of Rickettsia rickettsii in skin biopsies. Arch Pathol Lab Med 1997;121:894 – 9. Sexton DJ, Kanj SS, Wilson K, et al. The use of polymerase chain reaction as a diagnostic test for Rocky Mountain spotted fever. Am J Trop Med Hyg 1994;50: 59 – 63. Kamper CA, Chessman KA, Phelps SJ. Rocky Mountain spotted fever. Clin Pharm 1988;7:109 – 15. Dumler JS, Walker DH. Tick-borne ehrlichioses. Lancet Infect Dis 2001;April:21 – 8.
[39] McDade JE. Ehrlichiosis—a disease of animal and humans. J Infect Dis 1990;161:609 – 17. [40] Maeda K, Markowitz N, Hawley RC, et al. Human infection with Ehrlichia canis. N Engl J Med 1987; 316:853 – 6. [41] McQuiston JH, Paddock CD, Holma RC, et al. Human ehrlichioses in the United States. Emrg Infect Dis 1999;5:635 – 42. [42] Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 1996;275:199 – 205. [43] Chen S, Dumler JS, Bakken JS, et al. Identification of a granulocytotrophic Ehrlichiae species as the etiologic agent of human disease. J Clin Microbiol 1994;32: 589 – 95. [44] Standaert SM, Dawson JE, Shcaffner W, et al. Ehrlichiosis in a golf-oriented retirement community. N Engl J Med 1995;333:420 – 5. [45] Buller RS, Max A, Hmiel SP, et al. Ehrlichia Ewingii, a newly recognized agent of human ehrlichiosis. N Engl J Med 1999;341:148 – 55. [46] Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 1997. MMWR Morb Mortal Wkly Rep 1998;46:71 – 80. [47] Dennis DT. Tularemia. In: Wallace RB, editor. MaxcyRosenau—last public health and preventive medicine. 14th edition. Stamford (CT): Appleton & Lange; 1998. p. 354 – 7. [48] Boyce JM. Recent trends in the epidemiology of tularemia in the United States. J Infect Dis 1975;131: 197 – 9. [49] Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA 2001;285:2763 – 73. [50] Scholtens RG, Braff EH, Healy GR, et al. A case of babesiosis in a man in the United States. Am J Trop Med Hyg 1968;17:810 – 3. [51] Meldrum SC, Birkhead GS, White DJ, et al. Human babesiosis in New York state: an epidemiological description of 136 cases. Clin Infect Dis 1992;15: 1019 – 23. [52] Bonoan JT, Johnson DH, Cunha BA, et al. Life threatening babesiosis in an asplenic patient treated with exchange transfusion, azithromycin and atovaquone. Heart and Lung: Journal of Acute and Critical Care 1998;27:424 – 8. [53] Dorman SE, Cannon ME, Telford III SR, et al. Fulminant babesiosis treated with clindamycin, quinine, and whole-blood exchange transfusion. Transfusion 2000; 40:375 – 80.
Dermatol Clin 21 (2003) 245 – 248
Infections with Vibrio vulnificus Michael Borenstein, MD, PhDa, Francisco Kerdel, MDb,* a
Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1611 NW 12 Avenue, Rosensteil Building, 2nd Floor, Miami, FL 33136, USA b Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1400 NW 12th Avenue, 6 South—Dermatology, Miami, FL 33136, USA
Vibrio vulnificus (V. vulnificus) is a Gram-negative, halophilic (salt-loving) bacillus that is found in marine and estuarial waters and is an uncommon cause of serious skin infections and septicemia. V. vulnificus is part of the genus of Vibrio bacteria, which includes V. cholerae, V. parahaemolyticus, V. alginolyticus, and V. damselae. V. vulnificus infections occur most commonly in patients with underlying hepatic disease or patients who are immunocompromised secondary to disease or medication. Clinical infections present most commonly with wound infections and septicemia, which is accompanied by an extremely high mortality.
to 1.6% [9]. These affinities correlate with the significantly higher incidence of infections that occurs during warmer months (April – October), especially from oysters harvested from warm waters of the Gulf Coast of the Unites States [10]. Infections caused by V. vulnificus are not common; 422 cases from 22 states were reported to the CDC between 1988 and 1996 [10]. This number of cases is similar to other published reports from the United States and other countries.
Pathophysiology of infection Bacterial factors
Microbiology/epidemiology V. vulnificus is a Gram-negative, motile, halophilic bacillus that is a normal component of the marine environment [1]. V. vulnificus was first isolated by the Centers for Disease Control in 1964 and was given its current name in 1979 [2]. V. vulnificus has been identified worldwide [3 – 7]. In the United States it has been found in the Atlantic and Pacific oceans, the Gulf of Mexico, and waters in Utah, Hawaii, and Massachusetts [1]. V. vulnificus has been found in multiple types of fish, including mullet and sea bass [8], as well as filter feeders such as oysters, crabs, clams, and mussels [1]. The bacterium grows best in warm temperatures ( > 20 C) and in a salinity of 0.7%
* Corresponding author. E-mail address: dermatologydepartment@ hcahealthcare.com (F. Kerdel).
One of the bacterial factors related to the virulence of infection with V. vulnificus is the ability of the organism to bind to the intestinal mucosa and gain access to the blood rapidly [1]. V. vulnificus has an acid mucopolysaccharide capsule, which helps protect it from attack by the immune system [11]. The organism also produces numerous enzymes and proteins that contribute to its virulence, including proteases, lipase, hemolysin, cytolysin, hyaluronidase, mucinase, DNase, sulfatase, bradykinin, and Tumor Necrosis factor-a [12 – 14]. Host factors Infections with V. vulnificus occur more commonly in patients with liver disease and in immunocompromised patients. Patients with liver disease (eg, chronic cirrhosis or hemochromatosis) have an iron overload state in their blood. This state of iron overload has been shown to significantly lower the
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00088-8
246
M. Borenstein, F. Kerdel / Dermatol Clin 21 (2003) 245–248
bacterial inoculum necessary to cause overwhelming sepsis in animal studies [15,16]. Stelma et al showed that that the LD50 inoculum of virulent strains of V. vulnificus was greater than 3.5 log units lower in mice that were experimentally iron overloaded in comparison with normal controls [17]. Decreased phagocytic activity by neutrophils in patients with liver disease or patients who are immunocompromised is also considered to be another mechanism by which these individuals are more susceptible to disease. In a study by Hor et al, V. vulnificus survived longer in the blood of patients with hepatic disease (chronic hepatitis and cirrhosis) than in normal controls [18]. Furthermore, the patients with hepatic disease had a decreased neutrophilic phagocytic activity in the blood compared with the normal controls. Thus, patients with liver disease, cirrhosis, hemochromatosis, alcoholism, hemolytic anemia (caused by increased transferrin and serum iron), and immunosuppression are at higher risk for infections.
Clinical manifestations Severe soft tissue infection and septicemia are the two main clinical presentations of infection with V. vulnificus. Patients with V. vulnificus septicemia typically present with fever, chills, hypotension, and cutaneous manifestations. Hemorrhagic bullae are the most common cutaneous manifestation; however, erythema, purpura, necrotic ulcers, pustules, generalized papules and macules, vasculitic lesions, necrotizing fasciitis, gangrene, urticaria, and erythema multiforme-like lesions have been reported [1]. Skin lesions usually present on the extremities. The time of
onset of symptoms after exposure to the bacteria is typically short (hours to days). A study by Klontz showed a median of 18 hours after exposure to the source of bacteria until the onset of symptoms in patients who presented with primary septicemia [19]. The progression of sepsis is often rapid, with patients not showing any obvious source of the infection despite the severity of the presentation. Blood cultures are positive in almost all patients. Patients will typically have a history of recent consumption of raw seafood, especially oysters. Most patients also have an underlying disease such as cirrhosis, hepatitis, hemochromatosis, thalassemia major, or an immunocompromised state caused by medication or disease. Mortality has been typically greater than 50% in patients who present with primary septicemia despite appropriate therapy. Soft tissue infection with V. vulnificus occurs less commonly than primary sepsis. The patient will usually have a history of an acute injury or exposure of an existing wound to seawater or to raw shellfish. In a typical presentation, the patient will develop an intensely painful cellulitis with edema and bullae formation, which might progress to necrosis (Fig. 1). Wound infection can be fatal in up to one quarter of patients, especially those with underlying illness [19]. The differential diagnosis for wound infection includes necrotizing fasciitis/bullous hemorrhagic cellulitis, purpura fulminans, and ecthyma gangrenosum. V. vulnificus has previously been reported to cause a self-limited gastroenteritis [20] manifested by nausea, vomiting, and diarrhea. These symptoms might also be present in patients with wound infection or sepsis; however, some authors disagree as to whether V. vulnificus is a pathogen in gastroenteritis [1]. Further
Fig. 1. Bullous hemorrhagic cellulitis in patient with Vibrio vulnificus infection. (Photograph by F. Kerdel, MD).
M. Borenstein, F. Kerdel / Dermatol Clin 21 (2003) 245–248
studies need to be conducted to further elucidate its role, if any, as a cause of acute gastroenteritis. Corneal ulcers [21], epiglottitis [22], endometritis [23], meningitis [24], osteomyelitis [25], pneumonia [4], rhabdomyolysis [26], and spontaneous bacterial peritonitis [27] have also been reported as clinical manifestations of infection with V. vulnificus.
Treatment Early recognition of the possibility of infection with V. vulnificus is essential because of the rapid onset and severity of infection and the extremely high mortality. The clinician must consider the possibility of V. vulnificus infection in any patient who presents with sepsis or a severe cellulitis or wound infection, a history of liver disease, or an immunocompromised state and recent exposure to raw seafood or the ocean. Considering the severity of clinical infection, prevention is essential. Public education regarding the danger of eating raw seafood, especially oysters, is paramount. Individuals at high risk for infection must be educated to avoid eating or preparing raw seafood and avoid exposure of wounds to seawater. Currently, a tetracycline is the first-line therapy (usually doxycycline 100 mg IV bid) with cefotaxime (2 g IV q8h) or ciprofloxacin (400 mg IV bid) as second-line agents [28]. Early treatment with antibiotics is essential, but mortality remains high even if appropriate antibiotics and supportive care are given in a timely fashion. Standard measures for treatment of septic shock should be performed as appropriate, and patients must be monitored for signs of disseminated intravascular coagulopathy and rhabdomyolysis. Wound care should be aggressive, with antibiotic therapy, debridement of necrotic tissue, and other supportive care. Considering the high mortality of infection despite appropriate antibiotic therapy, amputation can be considered in extreme cases.
Summary V. vulnificus is an uncommon cause of soft tissue infection and primary septicemia, especially in patients with hepatic disease or who patients who are immunocompromised. The mortality of infection in these patients is extremely high despite timely antibiotic therapy. It is important to consider the possibility of infection with V. vulnificus in patients who present with high fever and rapidly progressive sepsis and have a history of consumption of raw seafood (especially oysters) or exposure of open wounds in a marine
247
environment. Public education regarding the risk of raw seafood consumption is essential to preventing infection with this virulent pathogen.
References [1] Kumamoto KS, Vukich DJ. Clinical infections of Vibrio vulnificus: a case report and review of the literature. J Emerg Med 1998;16:61 – 6. [2] Farmer JJ. Vibrio (‘‘Beneckea’’) vulnificus, the bacterium associated with sepsis, septicaemia, and the sea. Lancet 1979;8148:903. [3] Bisharat N, Agmon V, Finkelstein R, et al. Clinical, epidemiological, and microbiological features of Vibrio vulnificus biogroup 3 causing outbreaks of wound infection and bacteraemia in Israel. Lancet 1999;354: 1421 – 4. [4] Chuang YC, Yuan CY, Liu CY, et al. Vibrio vulnificus infection in Taiwan: report of 28 cases and review of clinical manifestations and treatment. Clin Infect Dis 1992;15:271 – 6. [5] Horre R, Becker S, Marklein G, et al. Necrotizing fasciitis caused by Vibrio vulnificus: first published infection in Turkey is the second time a strain is isolated in Germany. Infection 1998;26:399 – 401. [6] Melhus A, Holmdahl T, Tjernberg I. First documented case of bacteremia with Vibrio vulnificus in Sweden. Scand J Infect Dis 1995;27:81 – 2. [7] Park SD, Shon HS, Joh NJ. Vibrio vulnificus septicemia in Korea: clinical and epidemiologic findings in seventy patients. J Am Acad Dermatol 1991;24:397 – 403. [8] Nakafusa J, Misago N, Miura Y, et al. The importance of serum creatine phosphokinase level in the early diagnosis, and as a prognostic factor, of Vibrio vulnificus infection. Br J Dermatol 2001;145:280 – 4. [9] Koenig KL, Mueller J, Rose T. Vibrio vulnificus: hazard on the half shell. West J Med 1991;155:400 – 3. [10] Shapiro RL, Altekruse S, Hutwagner L, et al. The role of Gulf Coast oysters harvested in warmer months in Vibrio vulnificus infections in the United States, 1988 – 1996. J Infect Dis 1998;178:752 – 9. [11] Yoshida SI, Ogawa M, Mizuguchi Y. Relation of capsular materials and colony opacity to virulence of Vibrio vulnificus. Infect Immun 1985;47:446 – 51. [12] Espat NJ, Auffenberg T, Abouhamze A, et al. A role for tumor necrosis factor-alpha in the increased mortality associated with Vibrio vulnificus infection in the presence of hepatic dysfunction. Ann Surg 1996;223: 428 – 33. [13] Krovacek K, Baloda SB, Dumontet S, et al. Detection of potential virulence markers of Vibrio vulnificus strains isolated from fish in Sweden. Comp Immunol Microbiol Infect Dis 1994;17:63 – 70. [14] Maeda H, Akaike T, Sakata Y, et al. Role of bradykinin in microbial infection: enhancement of septicemia by microbial proteases and kinin. Agents Actions Suppl 1993;42:159 – 65.
248
M. Borenstein, F. Kerdel / Dermatol Clin 21 (2003) 245–248
[15] Morris Jr JG, Wright AC, Simpson LM, et al. Virulence of Vibrio vulnificus, association with utilization of transferrin bound iron, and lack of correlation with levels of cytotoxin or protease production. FEMS Microbiol Lett 1987;40:55 – 9. [16] Wright AC, Simpson LM, Oliver JD. Role of iron in the pathogenesis of Vibrio vulnificus infections. Infect Immun 1981;34:503 – 7. [17] Stelma Jr GN, Reyes AL, Peeler JT, et al. Virulence characteristics of clinical and environmental isolates of Vibrio vulnificus. Appl Environ Microbiol 1992;58: 2776 – 82. [18] Hor LI, Chang TT, Wang ST. Survival of Vibrio Vulnificus in whole blood from patients with chronic liver diseases: association with phagocytosis by neutrophils and serum ferritin levels. J Infect Dis 1999; 179:275 – 8. [19] Klontz KC, Lieb S, Schreiber M, et al. Syndromes of Vibrio vulnificus infections. Clinical and epidemiologic features in Florida cases, 1981 – 1987. Ann Intern Med 1988;109:318 – 23. [20] Hlady GW, Klontz KC. The epidemiology of Vibrio infections in Florida, 1981 – 1993. J Infect Dis 1996; 173:1176 – 83. [21] DiGaetano M, Ball SF, Strauss JG. Vibrio vulnificus
[22]
[23] [24]
[25] [26]
[27]
[28]
corneal ulcer. Case reports. Arch Ophthalmol 1989; 107:323 – 4. Mehtar S, Bangham L, Kalmanovitch D, et al. Adult epiglottitis due to Vibrio vulnificus. Brit Med J Clin Res 1988;296:827 – 8. Tison DL, Kelly MT. Vibrio vulnificus endometritis. J Clin Microbiol 1984;20:185 – 6. Katz BZ. Vibrio vulnificus meningitis in a boy with thalassemia after eating raw oysters. Pediatrics 1988; 109:261 – 3. Vartian CV, Septimus EJ. Osteomyelitis caused by Vibrio vulnificus. J Infect Dis 1990;161:363. Fernandez A, Justiniani FR. Massive rhabdomyolysis: a rare presentation of primary Vibrio vulnificus septicemia. Am J Med 1990;89:535 – 6. Wongpaitoon V, Sathaptayayongs B, Prachaktam R, et al. Spontaneous Vibrio vulnificus peritonitis and primary sepsis in two patients with alcoholic cirrhosis. Am J Gastroenterol 1985;80:706 – 8. Mandell GL, Bennett JE, Dolin R. Vibrio vulnificus infections. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious disease, 5th edition, Vol 2. Philadelphia, PA: Churchill Livingstone; 2000. p. 2274 – 6.
Dermatol Clin 21 (2003) 249 – 255
Protothecosis Sara M. Kantrow, Alan S. Boyd, MD* Division of Dermatology, Department of Pathology, Vanderbilt University, Dermatology 3900 The Vanderbilt Clinic, Nashville, TN 37232, USA
The genus Prototheca consists of unicellular, achloric, aerobic organisms believed to be related to the green algae Chlorella. Lacking chloroplasts, they are unable to produce energy by photosynthesis and must exist as saprophytes [1 – 3]. Classified as algae by Chodat in 1913 [1,4], several investigators have argued that Prototheca are better considered as fungi [5]; however, the organisms’ lack glucosamine and muramic acid in their cells walls [3] and phylogenetic studies have confirmed that they are more closely related to algae [6]. Although numerous species have been described, only three are currently recognized members of the genus: P. wickerhamii, P. zopfii, and P. stagnora [7]. P. wickerhamii is responsible for most human infections. These organisms were initially isolated from the stool of two patients with sprue [8], but they were later discounted as disease-associated pathogens [9]. The first reported cutaneous infection was in a rice farmer from Sierra Leone who had a foot ulcer [1]. P. zopfii was the causative organism. Only one other cutaneous infection with this microbe has been described [10,11]. P. zopfii most often affects cows, dogs, cats, and deer [3,12,13]. More than 100 cases of human infection with P. wickerhamii have been reported [10]. Immunocompetent and immunocompromised patients can be affected. Most infections have been cutaneous or subcutaneous in nature. Olecranon bursitis and systemic infections have also been described.
* Corresponding author.
Microbiology Prototheca are ubiquitous in nature [7]. Originally found in the slime flux of trees [14], they have since been reported in sewage collection systems, tap water, freshwater streams, marine water, swimming pools, vegetable surfaces, and on shrimp, clams, crabs, cow’s milk, and animal and human feces [1,7,11,15,16]. Tree sap and sewage systems provide an environment with adequate nutrition to sustain Prototheca because achloric organisms are unable to produce their own energy [7]. Location in other environs is transient, often a result of contamination [7], and susceptibility to chlorination varies among species [7,17]. Prototheca reproduce asexually by internal septation [2,15]. The parent cell contains internal spores (or endospores) and it eventually ruptures, passively releasing daughter cells (Fig. 1) [5,18,19]. The number of endospores produced varies with the media used [20]. These thick-walled structures range from 1.3 mm to 13.4 mm in diameter [19] and they vary depending on the species. P. wickerhamii sporangia range in size from 3 mm to 14 mm, whereas those of P. zopfii are generally larger, at 7 mm to 30 mm [21]. The morula form, containing two to 20 endospores in a spoke-like pattern, is characteristic of P. wickerhamii [22]. All strains of Prototheca grow at 30 C [7]. Optimal growth occurs at 25 C to 37 C, explaining the trend for infection of the extremities [23]. Growth is inhibited by temperatures over 40 C [3]. Smooth, white, creamy, yeast-like colonies appear at 48 hours on Sabouraud’s glucose agar, beef infusion broth, blood agar, and brain – heart infusion agar (Fig. 2)
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00089-X
250
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255
Fig. 1. Histologic characteristics of protothecosis. Septations are seen with formation of endospores. (Hematoxylin – eosin stain; 40.) (From Boyd AS, Langley M, King LE Jr. Cutaneous manifestations of Prototheca infections. J Am Acad Dermatol 1995;32:758 – 64; with permission.)
[15,24]. Cyclohexamide in culture media inhibits the growth of Prototheca [4,24].
32,34,38,50,51]. Lesions in immunocompromised patients are often vesicubullous and might ulcerate [2,49]. Several patients with chronic subcutaneous infections had received local steroid injections with recent exposure to water [33,52]. Kim et al hypothesized that these infections might have resulted from decreased local immunity combined with organism entry by way of the injection site [52]. A diabetic patient developed nasopharyngeal ulcerations and a soft tissue mass after prolonged intubation [53]. Other risk factors include surgery [15,33,44 – 46], diabetes mellitus [2,24,33,36,40,43,44,54], systemic corticosteroids [2,15,24,31,39,41,42,55], kidney transplantation [24,31,42,43,56], HIV/AIDS [48,57 – 59], and malignancy with chemotherapy or radiation treatment [2,23,37,42,54]. Localized cutaneous/subcutaneous infection and olecranon bursitis are not typically associated with systemic symptoms [46]. Disseminated cutaneous disease has been described in three patients. In one case, a patient with acute myeloid leukemia (AML) who was on antibiotics for neutropenic fever developed multiple nodules on the extremities that regressed with amphotericin B treatment [23]. Another patient with skin lesions presented with a clinical picture resembling infectious hepatitis. Peritoneal nodules were culturepositive for P. wickerhamii. The patient was thought to have defective cell-mediated immunity from a preceding viral illness [60]. Positive blood cultures after surgery for colon cancer were noted in a man with steroid-dependent lung disease, cutaneous abscesses, and a history of olecranon bursitis [61].
Clinical manifestations Infection has been described worldwide in males and females, children and adults. In a recent review of 39 cases over a 10-year period, patients were reported from the United States, Spain, Japan, France, Germany, Italy, and Slovakia [10]. Cutaneous and subcutaneous infections predominate (Table 1, Fig. 3). Lesions have often been present for months to years with slow progression [25 – 34] and varied appearance. Papules [2,35], nodules [22,34,36,37], eczematous patches [36], plaques [29,32,38], vesicles [27,39], ulcers [40,41], cellulitis [42,43], wound infections [15,33,44 – 47], tenosynovitis [45,48], lymphadenitis [4], and herpetiform lesions [49] have all been described. In immunocompetent patients, cutaneous manifestations often consist of localized papules and pustules with occasional eczematous patches on the extremities and face [26,
Fig. 2. Prototheca colonies appear smooth, creamy, and yeast-like on Sabouraud’s glucose agar.
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255 Table 1 Immune status of patients with Prototheca infections Immunocompetent Immunocompromised Cutaneous/ 24 subcutaneous Olecranon 16 bursitis Systemic 5
26 4 10
A subset of patients have presented with infection of the olecranon bursa manifesting as erythema and painful swelling [11,15,16,53,62,63]. This condition is believed to be related to regional trauma with secondary infection [16]. Such patients are usually otherwise healthy. Systemic disease includes peritonitis [17,64,65], algaemia [66,67], and meningitis [68 – 70]. Peritonitis was likely caused by contamination of peritoneal dialysis equipment [17,64,65]. Algaemia has been described in an adult leukemia patient [67] and a patient with an infected indwelling catheter [66]. Acute meningitis has been reported in patients who have HIV infection and AIDS [68,70]. Chronic meningitis has also been described [69]. Other unusual systemic presentations include intestinal protothecosis [71] and protothecal involvement of the liver, gallbladder, and duodenum [72]. Asymptomatic colonization by P. wickerhamii has been reported from skin scrapings in a patient with tinea pedis [5], in sputum [15,22], and in urine [22].
251
Location in human feces is uncommon; it is thought to be transient, acquired through ingestion of contaminated food and water [7]. Sporopollenin, an organic polymer in the cell wall, protects Prototheca from degradation in the gastrointestinal system [7]. The organism is not believed to incite an inflammatory reaction in the gastrointestinal tract, although it has been isolated from the stool of a child with treatment-resistant diarrhea [75]. Cholangitis [72] and infectious hepatitis [60] have also been reported. Colonization of skin of animals and humans is also transient [76]. Parental inoculation is required to produce infection in laboratory animals [7]. Pore et al suggested that Prototheca might be spread by the legs of insects that have contacted slime flux [7]. A case of disseminated cutaneous infection has been described following an arthropod bite [23]. Neutrophils are postulated to play a role in host defense by ingesting and eradicating protothecal organisms [32,77]. Two cases of progressive cutaneous disease have been described in patients with neutrophil-killing defects [32,77]. Carey et al de-
Pathogenesis Because of the limited number of cases, little is known about the pathogenesis of these infections [22]. Because Prototheca are found worldwide, the organisms are presumably indolent pathogens [7]. Protothecosis is not thought to be transmissible from person to person, and the incubation period is unknown [35]. Investigators have cited patient exposure to water and soil, which harbor the ubiquitous algae. Reported points of contact include swimming pools [38], a water tank ‘‘overgrown with scum’’[15], fish tanks [15], a bathtub [15], farm animals [35], clams and oysters [24], wet work sites [43], soil [50,73], rice paddies [1,4,25], lake water [18,58], river water and crabs [31], inland waters [33], and river mud [74]. In many cases, organisms are thought to gain entry through open wounds, surgical sites, and areas of trauma [23]. Protothecosis has also been described in otherwise healthy patients without evidence of cutaneous injury [53].
Fig. 3. Cutaneous infection with P. wickerhamii. Moderately well-demarcated erythema and induration are present with several flesh-colored nodules. (From Boyd AS, Langley M, King LE Jr. Cutaneous manifestations of Protheca infections. J Am Acad Dermatol 1995;32:758 – 64; with permission.)
252
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255
scribed cutaneous infection in an AIDS patient with a functional neutrophil defect [57]. Another patient with extensive skin lesions was thought to have defective cell-mediated immunity secondary to steroid and cyclophosphamide treatment for Systemic Lupus Erythematosus (SLE) [37].
Histopathology Tissue biopsy of an infected site reveals a granulomatous inflammatory infiltrate with epithelioid macrophages, histiocytes, and giant cells [22]. Lymphocytes, neutrophils, plasma cells, and (occasionally) eosinophils might also be seen along with areas of necrosis [3,15,22,24]. In some instances, the inflammatory response might be minimal [2,25,32]. Organisms can be visualized with periodic acidSchiff, Gomori methenamine – silver, and Gridley fungus stains [22]. They are found isolated or in clusters, or within granulomas, macrophages, giant cells, and necrotic tracts [33,35]. Sporangia containing endospores are visualized with Lactophenol cotton blue stain [31]. The frambesiform or daisy-like morula form of P. wickerhamii is characteristic. P. zopfii do not form multiseptate structures [22]. Carbohydrate assimilation patterns or immunofluorescence testing can be used for speciation [19,78]. Histologically, Prototheca must be differentiated from other algal and fungal infections. Electron microscopy shows that Chlorella species contain chloroplasts and a triple-layered wall rather than the double-layered wall of Prototheca [33]. Fungal organisms to consider include Blastomyces dermatitidis, Cryptococcus neoformans, Paracoccidiodes braziliensis, Pneumocystis carinii, and Rhinosporidium seeberi [3,5,24,53]. Prototheca differ from yeast in their lack of budding and pseudomycelia [44]. The sporangia of Coccidiodes and Rhinosporidia are larger and contain somewhat smaller endospores [22].
Treatment Therapy of Prototheca infections is not well defined. Because of the rarity of cases, limited data have been collected and controlled trials have not been performed [22]. Assays for defining in vitro antimicrobial susceptibility for algae are lacking [71] and they often do not correlate with in vivo success [30,46,62,77]. Treatment should be based on the patient’s general condition [52], with more aggressive therapy reserved for patients with concomitant underlying disease. Currently, the mainstays of treatment
include surgery, azole antifungals, and amphotericin B. Neutropenia should be corrected when applicable. For localized cutaneous infections, olecranon bursitis, and tenosynovitis, surgical debridement or excision has proven to be beneficial [29,33,45,47, 48,58]. Surgery has often been combined with antibacterial [31] and antifungal therapy [30,33]. In one case protothecosis recurred after excision, requiring a second procedure [58]. Prototheca cell walls contain 4% ergosterol. Successful eradication has been reported with azole antifungals and amphotericin B, all of which target this lipid. Azole antifungals ketoconazole, itraconazole, and fluconazole inhibit the cytochrome P-450 14-a demethylase enzyme, preventing the conversion of lanosterol to ergosterol and disrupting cell wall production [79]. Ketoconazole has been used successfully for cutaneous disease [25,38,46,51], but in one instance it induced hepatotoxicity [46]. A treatment failure has also been reported despite 6 months of oral therapy, with eventual cure by excision [33]. Another patient with a surgical wound infection relapsed despite taking 400 mg/day of ketoconazole [45]. Fluconazole eradicated a cutaneous infection after itraconazole had failed [52]. Gibb et al described a patient with protothecal peritonitis who was cured with intravenous fluconazole [64]; however, this drug failed in a patient with olecranon bursitis, extensive cutaneous disease, algaemia, and splenic involvement [61]. Itraconazole has also been used successfully in several cases of isolated cutaneous infection [22,28,30,55]. In one instance it was combined with local tioconazole and doxycycline [28] and in another case it was used in conjunction with surgical debridement [30]. Okuyama et al [55] reviewed 12 patients who were treated with itraconazole and reported that eight were cured with monotherapy. The authors recommend 200 mg/day for 2 months. Amphotericin B also inhibits ergosterol synthesis [62] and it is believed to have adjuvant properties, namely stimulation of host resistance to microbial pathogens [26]. McAnally et al reported synergy between amphotericin B and tetracycline in vitro [36]. Several reports of in vivo success have also been described [32,35,47]. Intravenous dosing has successfully eradicated isolated cutaneous [32,37, 41,43,45] and disseminated disease [23]; however, treatment failures have also been reported [34,71]. Amphotericin B administration followed by oral ketoconazole was used to treat a patient with systemic infection [72]. It has also been used successfully in combination with surgery after intravenous fluconazole failed [33] and intrabursally to resolve a case of olecranon bursitis [62].
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255
Interferon g improved the condition of a patient with intestinal protothecosis and chronic mucocutaneous candidiasis after amphotericin B and itraconazole had failed [71]. This cytokine has improved the fungicidal activity of alveolar and peritoneal macrophages [80,81]. Medications that have been tried without success include griseofulvin [1], pentamidine [4], clindamycin [24], cephalexin [24], gentamycin [24,56], cephalothin [46], flucytosine [29], oxacillin [45], erythromycin [22], and tetracycline [3,39,56,74].
[11]
[12]
[13]
[14]
Summary Intravenous amphotericin B remains the most effective drug for eradicating Prototheca infections. It should be used as a first-line agent in cases of disseminated disease and in patients with severe underlying illness or with immunosuppression or immunocompromise. Azole antifungals and surgery should be reserved for patients with more localized disease. Itraconazole appears to be the most effective agent of this drug class, and it should be administered at 200 mg/day for 2 months. Surgical excision should be considered as a first-line therapy in patients who present with olecranon bursal infections.
[15] [16]
[17]
[18] [19]
[20]
References [21] [1] Davies RR, Spencer H, Wakelin PO. A case of human protothecosis. Trans R Soc Trop Med Hyg 1964;58: 448 – 51. [2] Klintworth GK, Fetter BF, Nielsen HS. Protothecosis, an algal infection: report of a case in man. J Med Microbiol 1968;1:211 – 6. [3] Nosanchuk JS, Greenberg RD. Protothecosis of the olecranon bursa caused by achloric algae. Am J Clin Pathol 1973;59:567 – 73. [4] Davies RR, Wilkinson JL. Human protothecosis: supplementary studies. Ann Trop Med Parasitol 1967;61: 112 – 5. [5] Sudman MS. Protothecosis: a critical review. Am J Clin Pathol 1974;61:10 – 9. [6] Kwon-Chung KJ. Phylogenetic spectrum of fungi that are pathogenic to humans. Clin Infect Dis 1994;19: S1 – 7. [7] Pore RS, Barnett EA, Barnes WC, et al. Prototheca ecology. Mycopathologia 1983;81:49 – 62. [8] Ciferri O. Thiamine deficiency of Prototheca, a yeastlike achloric alga. Nature 1956;178:1475 – 6. [9] Klipstein FA, Schenk EA. Prototheca and sprue. Gastroenterology 1975;69:1372 – 3. [10] Krcme´ry Jr V. Systemic chlorellosis, an emerging in-
[22]
[23]
[24]
[25]
[26]
[27]
[28]
253
fection in humans caused by algae. Int J Antimicrob Agents 2000;15:235 – 7. Naryshkin S, Frank I, Nachamkin I. Prototheca zopfii isolated from a patient with olecranon bursitis. Diagn Microbiol Infect Dis 1987;6Z:171 – 4. Frank N, Ferguson C, Cross RF, et al. Prototheca, a cause of bovine mastititis. Am J Vet Res 1969;30: 1785 – 94. Kaplan W, Chandler FW, Holzinger EA, et al. Protothecosis in a cat: first recorded case. Sabouraudia 1976; 14:281 – 6. Kru¨ger W. Kurze characteristik einiger niederen organ¨ ber einen neuer ismen in saftflu¨sse der laubba¨ume: 1. U Pilztypus, repra¨sentiert durch die Gattung Prototheca ¨ ber zwei aus Saftflu¨ssen (P. moriformis et P. zopfii) 2. U rein gezu¨chtete Algen. Hedwigia 1894;33:241 – 66 [in German]. Tindall JP, Fetter BF. Infections caused by achloric algae (protothecosis). Arch Dermatol 1971;104:490 – 500. Vernon SE, Goldman LS. Protothecosis in the southeastern United States. South Med J 1983;76: 949 – 50. O’Connor JP, Nimmo GR, Rigby RJ, et al. Algal peritonitis complicating continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1986;8:122 – 3. Nabai H, Mehregan AH. Cutaneous protothecosis: report of a case from Iran. J Cutan Pathol 1974;1:180 – 5. Sudman MS, Kaplan W. Identification of the Prototheca species by immunofluorescence. Appl Microbiol 1973;25:981 – 90. Poyton RO, Branton D. Control of daughter-cell number variation in multiple fission: gene versus environmental determinants in Prototheca. Proc Natl Acad Sci USA 1972;69:2345 – 50. Nelson AM, Neafie RC, Connor DH. Cutaneous protothecosis and chlorellosis: extraordinary ‘‘aquaticborne’’ algal infections. Clin Dermatol 1987;5: 76 – 87. Boyd AS, Langley M, King Jr LE. Cutaneous manifestations of Prototheca infections. J Am Acad Dermatol 1995;32:758 – 64. Wirth FA, Passalacqua J, Kao G. Disseminated cutaneous protothecosis in an immunocompromised host: a case report and literature review. Cutis 1999;63: 185 – 8. Wolfe ID, Sacks HG, Samorodin CS, et al. Cutaneous protothecosis in a patient receiving immunosuppressive therapy. Arch Dermatol 1976;112:829 – 32. Matsuda T, Matsumoto T. Protothecosis: a report of two cases in Japan and a review of the literature. Eur J Epidemiol 1992;8:397 – 406. Mayhall CG, Miller CW, Eisen AZ, et al. Cutaneous protothecosis: successful treatment with amphotericin B. Arch Dermatol 1976;112:1749 – 52. Mendez CM, Silva-Lizama E, Logemann H. Human cutaneous protothecosis. Int J Dermatol 1995;34: 554 – 5. Monopoli A, Accetturi MP, Lombardo GA. Cutaneous protothecosis. Int J Dermatol 1995;34:766 – 7.
254
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255
[29] Otoyama K, Tomizawa N, Higuchi I, et al. Cutaneous protothecosis: a case report. J Dermatol 1989;16: 496 – 9. [30] Tang WY, Lo KK, Lam WY, et al. Cutaneous protothecosis: report of a case in Hong Kong. Br J Dermatol 1995;133:479 – 82. [31] Tejada E, Parker CM. Cutaneous erythematous nodular lesion in a crab fisherman. Protothecosis. Arch Dermatol 1994;130:244 – 5,247 – 8. [32] Venezio FR, Lavoo E, Williams JE, et al. Progressive cutaneous protothecosis. Am J Clin Pathol 1982;77: 485 – 93. [33] Walsh SV, Johnson RA, Tahan SR. Protothecosis: an unusual cause of chronic subcutaneous and soft tissue infection. Am J Dermatopathol 1998;20:379 – 82. [34] Yip SY, Huang CT, Clark WH. Protothecosis, an infection by algae: report of a case from Hong Kong. J Dermatol 1976;3:309 – 15. [35] Tyring SK, Lee PC, Walsh P, et al. Papular protothecosis of the chest: immunologic evaluation and treatment with a combination of oral tetracycline and topical amphotericin B. Arch Dermatol 1989; 125:1249 – 52. [36] McAnally T, Parry EL. Cutaneous protothecosis presenting as a recurrent chromomycosis. Arch Dermatol 1985;121:1066 – 9. [37] Thianprasit M, Youngchaiyud U, Suthipinittharm P. Protothecosis: a report of two cases. Mykosen 1983; 26:455 – 61. [38] Kuo TT, Hsueh S, Wu JL, et al. Cutaneous protothecosis: a clinicopathologic study. Arch Pathol Lab Med 1987;111:737 – 40. [39] Heitzman HB, Brooks TJ, Phillips BJ. Protothecosis. South Med J 1984;77:1477 – 8. [40] Schumann K, Hollandsworth K, Ormsby A. Nonhealing leg ulceration. Diagnosis: protothecosis. Arch Dermatol 2000;136:1263 – 8. [41] Tsuji K, Hirohara J, Fukui Y, et al. Protothecosis in a patient with systemic lupus erythematosus. Intern Med 1993;32:540 – 2. [42] Mezger E, Eisses JF, Smith MJ. Protothecal cellulitis in a renal transplant patient [abstract]. Lab Invest 1981; 44:81. [43] Wolfson JS, Sober AJ, Rubin RH. Dermatologic manifestations of infections in immunocompromised patients. Medicine (Baltimore) 1985;64:115 – 33. [44] Lee WS, Lagios MD, Leonards R. Wound infection by Prototheca wickerhamii, a saprophytic alga pathogenic for man. J Clin Microbiol 1975;2:62 – 6. [45] Moyer RA, Bush DJ, Dennehy JJ. Prototheca wickerhamii tenosynovitis. J Rheumatol 1990;17:701 – 4. [46] Pegram PS, Kerns FT, Wasilauskas BL, et al. Successful ketoconazole treatment of protothecosis with ketoconazole-associated hepatotoxicity. Arch Intern Med 1983;143:1802 – 5. [47] Sirikulchayanonta V, Visuthikosol V, Tanphaichitra D, et al. Prothecosis following hand injury: a case report. J Hand Surg 1989;14B:88 – 90. [48] Laeng RH, Egger C, Schaffner T, et al. Protothecosis in
[49] [50] [51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] [61]
[62]
[63] [64]
[65]
[66]
an HIV-positive patient. Am J Surg Pathol 1994;18: 1261 – 4. Goldstein GD, Bhatia P, Kalivas J. Herpetiform protothecosis. Int J Dermatol 1986;25:54 – 5. Mars PW, Rabson AR, Rippey JJ, et al. Cutaneous protothecosis. Br J Dermatol 1971;85(Suppl):76 – 84. Matsumoto Y, Shibata M, Adachi A, et al. Two cases of protothecosis in Nagoya, Japan. Australas J Dermatol 1996;37:S42 – 3. Kim ST, Suh KS, Chae YS, et al. Successful treatment with fluconazole of protothecosis developing at the site of an intralesional corticosteroid injection. Br J Dermatol 1996;135:803 – 6. Iacoviello VR, DeGirolami PC, Lucarini J, et al. Protothecosis complicating prolonged endotracheal intubation: case report and literature review. Clin Infect Dis 1992;15:959 – 67. Connor DH, Gibson DW, Ziefer A. Diagnostic features of three unusual infections: micronemiasis, pheomycotic cyst, and protothecosis. Monogr Pathol 1982; 23:205 – 39. Okuyama Y, Hamaguchi T, Teramoto T, et al. A human case of protothecosis successfully treated with itraconazole. Nippon Ishinkin Gakkai Zasshi 2001;42: 143 – 7. Dagher FJ, Smith AG, Pankoski D, et al. Skin protothecosis in a patient with renal allograft. South Med J 1978;71:222 – 4. Carey WP, Kaykova Y, Bandres JC, et al. Cutaneous protothecosis in a patient with AIDS and a severe functional neutrophil defect: successful therapy with amphotericin B. Clin Infect Dis 1997;25:1265 – 6. Polk P, Sanders DY. Cutaneous protothecosis in association with the acquired immunodeficiency syndrome. South Med J 1997;90:831 – 2. Woolrich A, Koestenblatt E, Don P, et al. Cutaneous protothecosis and AIDS. J Am Acad Dermatol 1994; 31:920 – 4. Cox GE, Wilson JD, Brown P. Protothecosis: a case of disseminated algal infection. Lancet 1974;2:379 – 82. Marr KA, Hirschmann JV, Thorning D, et al. Photo quiz. Protothecosis. Clin Infect Dis 1998;26:575, 756 – 7. Cochran RK, Pierson CL, Sell TL, et al. Protothecal olecranon bursitis: treatment with intrabursal amphotericin B. Rev Infect Dis 1986;8:952 – 4. Kapica L. First case of human protothecosis in Canada. Laboratory aspects. Mycopathologia 1981;73:43 – 8. Gibb AP, Aggarwal R, Swainson CP. Successful treatment of Prototheca peritonitis complicating continuous ambulatory peritoneal dialysis. J Infect 1991; 22:183 – 5. Sands M, Poppel D, Brown R. Peritonitis due to Prototheca wickerhamii in a patient undergoing chronic ambulatory peritoneal dialysis. Rev Infect Dis 1991; 13:376 – 8. Heney C, Greeff M, Davis V. Hickman catheter-related protothecal algaemia in an immunocompromised child. J Infect Dis 1991;163:930 – 1.
S.M. Kantrow, A.S. Boyd / Dermatol Clin 21 (2003) 249–255 [67] Kunova A, Kollar T, Spanik S, et al. First report of Prototheca wickerhamii algaemia in an adult leukemic patient. J Chemother 1996;8:166 – 7. [68] Kaminski ZC, Kapila R, Sharer LR, et al. Meningitis due to Prototheca wickerhamii in a patient with AIDS. Clin Infect Dis 1992;15:704 – 6. [69] Takaki K, Okada K, Umeno M, et al. Chronic Prototheca meningitis. Scand J Infect Dis 1996;28:321 – 3. [70] Vedeal JC, Saddy F, Concha ML, et al. Central nervous system infection by Prototheca wickerhamii in an HIV infected patient [abstract]. Int Conf AIDS 1998;12:563. [71] Raz R, Menachem R, Bisharat N, et al. Intestinal protothecosis in a patient with chronic mucocutaneous candidiasis. Clin Infect Dis 1998;27:399 – 400. [72] Chan JC, Jeffers LJ, Gould EW, et al. Visceral protothecosis mimicking sclerosing cholangitis in an immunocompetent host: successful antifungal therapy. Rev Infect Dis 1990;12:802 – 7. [73] Dogliotti M, Mars PW, Rabson AR, et al. Cutaneous protothecosis. Br J Dermatol 1975;93:473 – 4. [74] Sonck CE, Koch Y. Vertreter der gattung Prototheca als schmarotzer auf der haut. Mykosen 1971;14:475 – 82 [in German].
255
[75] Casal M, Zerolo J, Linares UJ, et al. First human case of possible protothecosis in Spain. Mycopathologia 1983;83:19 – 20. [76] Modly CE, Burnett JW. Cutaneous algal infections: protothecosis and chlorellosis. Cutis 1989;44:23 – 4. [77] Phair JP, Williams JE, Bassaris HP, et al. Phagocytosis and algicidal activity of human polymorphonuclear neutrophils against Prototheca wickerhamii. J Infect Dis 1981;144:72 – 6. [78] Padhye AA, Baker JG, D’Amato RF. Rapid identification of Prototheca species by the API 20C system. J Clin Microbiol 1979;10:579 – 82. [79] Moossavi M, Bagheri B, Scher R. Systemic antifungal therapy. Dermatol Clin 2001;19:35 – 52. [80] Beaman L. Fungicidal activation of murine macrophages by recombinant gamma interferon. Infect Immun 1987;55:2951 – 5. [81] Brumer E, Morrison C, Stevens D. Recombinant and natural gamma interferon activation of macrophages in vitro: different dose requirements for induction of killing activity against phagocytizable and non phagocytizable fungi. Infect Immun 1995;49:724 – 30.
Dermatol Clin 21 (2003) 257 – 268
Non-dermatophyte onychomycosis Aditya K. Gupta, MD, PhD, FRCP(C)a,b,c,*, Jennifer E. Ryder, HBScc, Robert Baran, MDd, Richard C. Summerbell, PhDe a
Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Center (Sunnybrook site), Toronto, Canada b University of Toronto, Toronto, Canada c Mediprobe Laboratories Inc., Toronto, Ontario, Canada d The Nail Disease Center, 42 Rue des Serbes 06400, Cannes, France e Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
The prevalence of onychomycosis is increasing, and the number of organisms recognized as possible fungal pathogens is growing [1]. Dermatophytes, particularly Trichophyton rubrum and Trichophyton mentagrophytes, are the most common cutaneous fungal pathogens, accounting for approximately 90% of nail infections [2]. Non-dermatophyte pathogens are fungi with known habitats in soil, decaying plant debris, or plant disease. They have been traditionally regarded as uncommon or secondary pathogens of already diseased nails. The prevalence of non-dermatophyte molds as nail invaders ranges between 1.45% and 17.60% [3]. The variation in incidence might be because of geographic differences in mold distribution or diagnostic methods [3]. The proportion of individuals with pedal onychomycosis caused by non-dermatophyte molds is highest among older patients ( > 60 years old) [4]. Non-dermatophyte molds such as Scopulariopsis, Fusarium, and Aspergillus might be primary pathogens that cause onychomycosis [5]. Alternaria and Paecilomyces species might also cause onychomycosis; however, this is rarely observed [6,7]. In addition, Candida species cause between 1% and 32% of toenail infections and 51% to 70% of fingernail infections, either as the primary pathogen or in combination with dermatophytes or molds [8].
* Corresponding author. A.K. Gupta, 490 Wonderland Road South, Suite 6, London, Ontario, Canada, N6K1L6. E-mail address:
[email protected] (A.K. Gupta).
Although dermatophyte infections are more commonly discussed in the literature, non-dermatophyte organisms have become increasingly prevalent as etiologic agents of onychomycosis. Some non-dermatophyte molds that cause infections of the nail include species of Scopulariopsis, Scytalidium, Fusarium, Aspergillus, and Onychocola canadensis. Candida species, especially C. albicans and C. parapsilosis, are the major yeasts that cause onychomycosis.
Clinical presentations Clinical patterns of onychomycosis include distal and lateral subungual onychomycosis (DLSO), superficial white onychomycosis (SWO), proximal subungual onychomycosis (PSO), and Candida onychomycosis [9]. Total dystrophic onychomycosis (TDO) results when any of the above clinical patterns progresses to involve the entire nail plate [10]. Endonyx onychomycosis has only been described recently in the literature [10,11]. DLSO is the most common pattern of infection. Dermatophytes, in particular T. rubrum, are the most frequently encountered causal agents. Non-dermatophyte molds such as Scytalidium dimidiatum can produce this clinical pattern of disease, but in these cases DLSO is often associated with onycholysis and (possibly) with paronychia in fingernails [12]. Other molds that can be responsible for DLSO include Fusarium oxysporum, Scopulariopsis brevicaulis, Aspergillus spp, and Acremonium spp [5,13].
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00086-4
258
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
SWO is caused mostly by dermatophytes, with the most common organism being interdigital-type T. mentagrophytes. Non-dermatophyte molds such as Aspergillus terreus, F. oxysporum, and Acremonium spp [5,13], and yeasts (eg, C. albicans) can also result in this clinical pattern. PSO is an uncommon pattern of onychomycosis caused predominantly by Trichophyton species. Non-dermatophytes that can also cause this clinical pattern of infection include Fusarium spp and S. brevicaulis [14,15]. A patient with chronic mucocutaneous candidiasis (CMCC) was recently reported to show transverse cloudy leukonychia that appeared beneath the normal cuticle of several fingernails; this pattern of infection is typical of PSO [16]. Proximal white superficial onychomycosis (PWSO) has been associated with immune disorders and might even be a clinical marker for an immunocompromised state, particularly among individuals who are HIV positive [13]. Endonyx onychomycosis (EO) begins at the distal edge of the nail plate and moves proximally [11,12]. Unlike in DLSO, however, the fungal elements directly invade and penetrate the nail plate, where they form milky white patches without subungual hyperkeratosis or onycholysis [12,17]. There is little or no involvement of the nail bed and no subungual debris. Endonyx onychomycosis has been associated with Trichophyton soudanense and Trichophyton violaceum [18].
Diagnosis Identifying a type of nail infection normally caused by non-dermatophytes requires careful diagnostic attention [19]. Some organisms such as Scytalidium species produce infections that clinically mimic the signs and symptoms seen in dermatophyte infections. Correct identification becomes imperative because many non-dermatophyte molds respond poorly to therapy [1]. Unlike tinea unguium, non-dermatophyte onychomycosis is often diagnosed inaccurately. In such cases, stringent criteria are required for the attribution of etiology to non-dermatophyte molds and yeasts. Direct microscopic examination (ie, potassium or sodium hydroxide, or, alternatively, histopathology) is mandatory. Non-dermatophyte mold infections should yield a corresponding positive microscopic result showing fungal filaments/hyphae consistent with the organism that is isolated (eg, dark if the organism is a melanized fungus) in the subungual keratin. Yeast infections should yield pseudohyphae in direct micro-
scopy; these structures will ordinarily bear occasional budding outgrowths that can be used to confirm them as yeast elements [5,20,21]. To confirm that a nondermatophyte mold is the sole etiologic agent, there should be repeated isolation of the suspected causal organism on two or more separate occasions (ie, from samples taken at different time points, not just from multiple sample pieces taken at one time point) in the absence of any growth of a dermatophyte. A repeated culture reduces the statistical probability that the nondermatophyte is a contaminant; furthermore, it aids in the diagnosis of mixed infections (eg, a dermatophyte with a non-dermatophyte) [5]. English [20] suggested that at least five of 20 inocula (ie, separate pieces of nail material planted onto growth medium) must yield the same mold to establish the mold as a causative agent. Recent work has suggested that this ratio would generate more false-positive than true-positive results for non-dermatophyte mold infections, but that a count of 11 or more culture-positive inocula out of 15 planted (in combination with a positive KOH result) has a much stronger statistical correlation with the likelihood that the non-dermatophyte is the etiologic organism [5]. Histologic examination of the nail plate enables confirmation of invasive ungual infection; however, this technique does not identify the infecting organism. The type of medium used to culture nail samples can affect the results and limit the identification of the causative organism. Historically, culture media have contained cycloheximide, which might prevent nondermatophyte growth, thereby hindering detection of potential pathogens. Thus, it is imperative that nail samples are cultured on cycloheximide-free media as well as cycloheximide-supplemented media [21]. Clues that onychomycosis might be caused by non-dermatophyte molds include absence of tinea pedis, involvement of only one or two toenails, history of trauma preceding nail dystrophy, and a lack of response to systemic antifungal therapy (eg, fluconazole, itraconazole, and terbinafine) [22]. In onychomycosis caused by non-dermatophyte molds, there might also be inflammation/redness of the nail matrix [14,15,23].
Scopulariopsis species Scopulariopsis is a common mold found in soil and dead organic matter. It grows especially well on protein-rich surfaces [24]. Some Scopulariopsis species (eg, S. brevicaulis, S. brumptii, S. candida, S. carbonaria, and S. koningii) are capable of digesting a-keratins [19,25]. Some of these organisms,
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
259
especially S. brevicaulis, have been associated with onychomycosis, occasionally as a primary invader but more often as a secondary pathogen following dermatophytosis or trauma [13,26]. Onychomycosis caused by Scopulariopsis affects mainly toenails, particularly the great toenail [13,27]. The infection generally begins at the free or lateral edge of the nail and less often at the proximal edge [13,28]. The nail might discolor to white, gray, or yellow, often with a yellow – orange ochre or occasionally with a green tinge [28]. Seven species have been reported as human pathogens: S. brevicaulis, S. candida, S. brumptii, S. acremonium, S. fusca, S. asperula, and S. koningii [29]. It should be noted, however, that not all published reports are reliable. In addition, some nail-infecting Scopulariopsis species forming a Microascus sexual state in culture have been reported under these teleomorph (sexual state) names, viz Microascus cinereus and Microascus cirrosus [30]. Onychomycosis caused by S. brevicaulis is diagnosed most often in elderly patients, with equal frequency in men and women [31].
tropical parts of the world and Mediterranean-type climate areas of the western United States [36]. It might also be endemic to the southern part of the United States [37]. A closely related pathogenic species, S. hyalinum, occurs less commonly over a more limited range of tropical and subtropical areas. Like T. rubrum infections, S. hyalinum and S. dimidiatum tend to be chronic, suggesting that the immune response of the host is deficient or ineffective [13]. S. dimidiatum and S. hyalinum can produce tinea pedis, tinea manuum, and onychomycosis [38]. Infections caused by these organisms clinically mimic those caused by dermatophytes [38,39]. The clinical pattern of onychomycosis caused by Scytalidium species is generally DLSO. S. dimidiatum, as an invader of keratin, is able to infect normal nails [13]. Characteristics of onychomycosis caused by S. dimidiatum include onycholysis, paronychia, infection of a single nail, and transverse fracture of the proximal nail plate [40,79].
Culture and microscopy
S. dimidiatum and S. hyalinum grow well in standard fungal growth media, which provides a source of carbon and organic nitrogen (ie, Sabouraud dextrose). The colonies grow quickly or slowly according to the variant involved, and they produce deeply wooly aerial mycelium in fast-growing strains and compact and domed mycelium with a velvety or wire-wool textured surface in the slower-growing strains associated with the Indian subcontinent and its global diaspora [13,30]. In S. dimidiatum, the initially pale surface rapidly darkens to olivaceous gray, mouse gray, or fuscous black. In fast-growing variants, much of the aerial mycelium differentiates within 7 days into chains of cylindrical, oblong, or square-ish arthroconidia that can be one- or twocelled and that vary in size and degree of pigmentation. In slow-growing variants, similar arthroconidia form, but up to 5 weeks of cultivation might be required. Arthroconidia of S. hyalinum generally form within 14 days and are hyaline. S. hyalinum colonies are powdery white on the surface and pale yellow on the reverse [30]. In Scytalidium infections the hyphae have the following characteristics: irregularity in width, sinuous pattern, and a double-contoured appearance, which is brought about by formation of an unusually thick, glassy-looking cell wall [13,41]. Hyphae in S. dimidiatum infections are almost always hyaline and smooth but they might rarely be pigmented and sometimes also rough walled [13]. The hyphae in S. hyalinum infections are hyaline [13,35].
Scopulariopsis species grow rapidly and produce conidial structures within 7 days on Sabouraud dextrose agar at room temperature [13]. Initially, the colony surface is white, velvety, and rugose, but it soon becomes light tan or brown in S. brevicaulis and closely related species and dark gray in ‘‘black Scopulariopsis’’ species such as S. brumptii [13,24]. In direct examination in potassium hydroxide (KOH) mounts of scrapings or clippings, the hyphae are colorless or, rarely, light brown, branched, septate, and variable in width, with some elongated cells [32,33]. Conidiophores in culture are either branched in a penicillate, broom-like pattern or unbranched and short [32]. These conidia can occasionally be seen occurring in large masses in direct microscopy of heavily affected nails. Mature conidia are thickwalled, round with a flattened base, smooth to coarsely roughened, and hyaline to tan in mass, with a broad, truncate base [34].
Hendersonula toruloidea and Scytalidum species The pycnidial plant pathogenic fungus Nattrassia mangiferae, previously known as Hendersonula toruloidea, can infect human skin and nails [35]. The associated synanamorph seen in culture is Scytalidium dimidiatum [35]. S. dimidiatum is a keratinolytic organism that is widely distributed in tropical and sub-
Culture and microscopy
260
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
Table 1 Treatment of Scopulariopsis onychomycosis No. of patients (evaluable) Treatment and results
Reference
Study type
Tosti et al, 1996 [15]
Case report
3 (3)
Tosti et al, 1996 [15]
Case report
3 (3)
Fischer, 1960 [24] Fischer, 1960 [24] Fischer, 1960 [24]
Case report Case report Case report
1 (1) 1 (1) 1 (1)
Onsberg et al, 1980 [64]
Open
Gupta et al, 2001 [65]
Open, prospective
4 (4)
Gupta et al, 2001 [65]
Open, prospective
1 (1)
Ulbricht et al, 1994 [66]
Open, multicenter
51 (NS)
Nolting et al, 1994 [57]
Multicenter
7 (7)
De Doncker et al, 1997 [70]
Multicenter
21 (21)
De Doncker et al, 1997 [70]
Multicenter
2 (2)
Gupta et al, 2001 [47]
Prospective, comparative, 11 (11) parallel-group, SB, randomized
Gupta et al, 2001 [47]
Prospective, comparative, 12 (12) parallel-group, SB, randomized
Gupta et al, 2001 [47]
Prospective, comparative, 12 (12) parallel-group, SB, randomized
Gupta et al, 2001 [47]
Prospective, comparative, 12 (12) parallel-group, SB, randomized
Gupta et al, 2001 [47]
Prospective, comparative, 12 (12) parallel-group, SB, randomized
15 (7)
ITR(P) (4 pulses)a 8 mo after discontinuation of therapy: MC: 1/3, CC: 1/3 TER 250 mg/d for 4 mo 8 mo after discontinuation of therapy: MC: 0/3, CC: 0/3 Information is not available Patient did not report for treatment GRIS 250 mg 4/d Drug discontinued because S. brevicaulis is resistant to GRIS 1% natamycin in 60% dimethylsulphoxide for 5 wk At follow-up (15 mo after completion of treatment), 2 patients reported permanent improvement and 3 a complete cure ITR(P) (3 pulses)a At month 12: MC 4/4, clinical cure: 2/4 TER 250 mg/d for 12 wk At month 12: MC 0/1, clinical cure: 0/1 Ciclopirox nail lacquer 8% for 6 mo Data not provided for individual species TER 250 mg/d for 12 mo At end of treatment: MC: 3/7, CC: 3/7 ITR(P) (2 – 4 pulses)a At follow-up (12 mo after start of therapy): MC: 17/21, clinical cure: 17/21 ITR 200 mg/d for 6 – 12 wk At follow-up (12 mo after start of therapy): MC: 2/2, clinical cure: 2/2 GRIS 600 mg bid for 12 mo At month 12: MC: 0/11, clinical cure: 3/11, CC: 0/11 KETO 200 mg/d for 4 mo At month 12: MC: 8/12, clinical cure: 10/12, CC: 8/12 ITR(P) (3 pulses)a At month 12: MC: 12/12, clinical cure: 12/12, CC: 12/12 TER 250 mg/d for 12 wk At month 12: MC: 11/12, clinical cure: 12/12, CC: 11/12 FLUC 150 mg/d for 12 wk At month 12: MC: 8/12, clinical cure: 8/12, CC: 8/12
Abbreviations: CC, complete cure; FLUC, fluconazole; GRIS, griseofulvin; KETO, ketoconazole; MC, mycological cure; NS, not stated; SB, single-bind; TER, terbinafine. a Itraconazole Pulse [ITR(P)] given for 200 mg bid for 1 wk on followed by 3 wk off
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
261
Fusarium species
Culture and microscopy
Fusarium species are widely distributed in soil and on subterranean and aerial plant parts, plant debris, and other organic substrates [42]. They are common in tropical and temperate regions and are known pathogens of plants, animals, and humans [22]. The genus includes more than 60 species, 10 of which are known human pathogens, with F. oxysporum, F. verticillioides (F. moniliforme), and F. solani being the most frequently isolated [29,43]. In humans, Fusarium species can cause disease that is localized, focally invasive, or disseminated [44]. Onychomycosis caused by Fusarium species—in particular F. oxysporum—features characteristic milky lesions [42,45]. The clinical patterns described include SWO, DLSO, and PSO [22]. Though PSO is uncommon, Baran et al [14] found that the combination of PSO with subacute or acute paronychia in an immunocompetent individual is a typical manifestation of Fusarium nail invasion. Leukonychia or periungual inflammation can also be associated with PSO [5]. The great toenails are almost always involved; fingernails only rarely manifest this combination of symptoms. F. oxysporum can penetrate and invade the keratinous part of the nail plate [42]. Onychomycosis caused by Fusarium species is generally a localized infection in immunocompetent individuals; however, in neutropenic individuals, it can act as a source of dissemination leading to a widespread, systemic Fusarium infection [22,42,44].
Colonies of species causing human infection are fast growing and white to pale purple, pale tan, or (less commonly) orange on the surface, with colony reverse colors becoming vinaceous, purple, tea brown, chestnut red – brown, orange, or (rarely) carmine on potato dextrose agar [29]. Many isolates rapidly form typical canoe-shaped, multi-celled macroconidia with a distinctive foot cell within 7 to 14 days on potato dextrose or specialized Fusarium media [29]. Nearly all human pathogenic species also form copious single-celled, ellipsoidal, club- or sausage-shaped microconidia. Formation of structures on Sabouraud agar is often abnormal; this medium cannot be used in species identification.
Aspergillus species Aspergillus species, when implicated in colonization of dystrophic nails, are usually considered to be opportunists invading keratins that were altered previously by other diseases [23]; however, studies have often documented Aspergillus species as the primary cause of onychomycosis, with SWO being the clinical pattern that is most often seen [23]. Onychomycosis caused by members of the Asperigillus versicolor complex is predominantly seen in elderly individuals (>60 years old) and features chronic involvement of the great toenail [46]. When
Table 2 Treatment of Scytalidium onychomycosis Reference
Study type
No. of patients (evaluable) Treatment and results
Elewski, 1996 [36]
Case report
1 (1)
Rollman et al, 1987 [67] Case report
1 (1)
Downs et al, 1999 [68] Case report
1 (1)
Hay et al, 1985 [69]
3 (3)
Open
Ulbricht et al, 1994 [66] Open, multicenter 1 (NS) Abbreviations: FLUC, fluconazole; mc, mycological cure.
FLUC 300 mg/wk for 6 wk; increased to FLUC 400 mg/wk then discontinued when organism was identified Affected nails partially avulsed using 40% urea ointment prior to application of 1% ciclopiroxolamine cream for 2 – 4 mo (re-treated if necessary) At follow-up (12 mo after cessation of treatment) all 4 fingernails were MC and clinically cured Topical 5% amorolfine bid At 8 wk nails markedly improved Tioconazole 28% solution for up to 12 mo At follow-up (3 mo after therapy) 1 patient in clinical and mycological remission Ciclopirox nail lacquer 8% for 6 mo Data not provided for individual species
262
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
proximal subungual onychomycosis is associated with periungual inflammation and black pigmentation of the proximal nail fold, the possibility of onychomycosis caused by Aspergillus niger should be considered [23]. The color of the proximal nail fold might result from A. niger black conidia within the nail keratin. When similar features are present and associated with greenish discoloration of the nail plate, the possibility of onychomycosis caused by A. nidulans and A. glaucus should be considered [23].
Purulent discharge from the proximal nail fold might also be present. Culture and microscopy In direct microscopy, Aspergillus infections show hyaline hyphae that are generally somewhat wider than dermatophyte hyphae. They also tend to bear irregular swellings and vesicles that are distinct from the regular chains of substrate arthroconidia produced in tissue by
Table 3 Treatment of Fusarium onychomycosis Reference
Study type
No. of patients (evaluable)
Fusarium spp Tseng et al, 2000 [22]
Case report
1 (1)
De Doncker et al, 1997 [70]
Multicenter
1 (1)
De Doncker et al, 1997 [70]
Multicenter
2 (2)
Gupta et al, 2001 [65]
Open, prospective
1 (1)
Gupta et al, 2001 [65]
Open, prospective
1 (1)
F. oxysporum Romano et al, 1998 [7]
Case report
NS (4)
Romano et al, 1998 [7]
Case report
NS (2)
Baran et al, 1997 [14]
Case report
1 (1)
Baran et al, 1997 [14]
Case report
1 (1)
Baran et al, 1997 [14] DiSalvo et al, 1980 [71]
Case report Case report
1 (1) 1 (1)
Gianni et al, 1997 [72]
Case report
2 (2)
Gianni et al, 1997 [72]
Case report
2 (2)
De Doncker et al, 1997 [70]
Multicenter
1 (1)
Treatment and results TER cream bid for 4 wk, on follow-up visit patient given cephalexin for 1 wk. Treatment changed to FLUC 100 mg/d then to FLUC 300 mg/wk and increased to FLUC 300 mg bid with periodic nail debridement Significant improvement seen with resolution of paronychia and slow regrowth of normal nail ITR 200 mg/d for 6 – 12 wk At follow-up (12 mo after start of therapy): MC: 1/1, clinical cure: 1/1 ITR(P) (2 – 4 pulses)a At follow-up (12 mo after start of therapy): MC: 2/2, clinical cure: 0/1 ITR(P) (3 pulses)a. At month 12: MC 1/1, clinical cure: 1/1 TER 250 mg/day for 12 weeks. At month 12: MC 0/1, clinical cure: 0/1
ITRA(P) (4 pulses)a At follow-up (1 y): 3 patients achieved MC and clinical cure Ciclopirox nail lacquer for 6 – 8 mo 1 patient completely recovered Ciclopirox ointment and bifonazole ointment MC and clinical cure achieved Partial nail avulsion and 8% ciclopirox nail lacquer Complete clearing of the nail lesions No therapy Surgically excised Toe appeared to be healed and asymptomatic TER 250 mg/d for 3 mo Complete recovery achieved ITR 200 mg/d for 3 mo Nail resolved ITR(P) (2 – 4 pulses)a At follow-up (12 mo after start of therapy): MC: 1/1, clinical cure: 1/1
Abbreviations: CC, complete cure; FLUC, fluconazole; KETO, ketoconazole; MC, mycological cure; NS, not stated; TER, terbinafine. a Itraconazole Pulse [ITR(P)] given for 200 mg bid for 1 wk on followed by 3 wk off
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
dermatophytes. In some cases, conidiophores and conidia might be produced in nail fissures. In culture, Aspergillus species feature thick-walled, upright conidiophores, each ending in a swollen vesicle that is coated with fertile, conidiogenous cells or short branches bearing tufts of such cells. These cells give rise to rough- or smooth-walled, more or less rounded conidia in long chains. Colonies might commonly be blue, green, tan, white, or black, and they are usually deeply powdery from massive conidial formation.
263
Onychocola canadensis Onychocola canadensis is an uncommon organism whose natural habitat is unknown [13,47]. This organism has been identified in Canada, New Zealand, and (more recently) in France and Britain [48,49]. Sigler et al [50] first described this nondermatophyte in three cases of chronic infection of the great toenail. O. canadensis frequently affects individuals who are gardeners or farmers, which
Table 4 Treatment of Aspergillus onychomycosis Reference
Study type
No. of patients (evaluable)
Aspergillus spp Gupta et al, 2001 [65]
Open, prospective
6 (6)
De Doncker et al, 1997 [70]
Multicenter
1 (1)
Lebwohl et al, 2001 [73]
DB, randomized, placebo-controlled, multicenter DB, randomized, placebo-controlled, multicenter
2 (2)
5 (5)
TER 250 mg/d for 24 wk At month 6: MC: 3/5, CC: 2/5
A. flavus Scher et al, 1990 [74]
Case report
1 (1)
De Doncker et al, 1997 [70]
Multicenter
1 (1)
De Doncker et al, 1997 [70]
Multicenter
1 (1)
Whitfield’s ointment bid for several months followed by ITR(C) 100 mg/d for 5 mo At 4 mo almost all of nail plate was normal ITR 100 mg/d for less than 20 wk At follow-up (12 mo after start of therapy): MC: 1/2, clinical cure: 1/1 ITR 200 mg/d for 6 – 12 wk At follow-up (12 mo after start of therapy): MC: 1/2, clinical cure: 1/1
A. niger Tosti, 1998 [23]
Case report
2 (2)
Ulbricht et al, 1994 [66]
Open, multicenter
6 (NS)
De Doncker et al, 1997 [70]
Multicenter
3 (3)
A. fumigatus Rosenthal et al, 1968 [75]
Case report
1 (1)
Ulbricht et al 1994 [66]
Open, multicenter
2 (NS)
Lebwohl et al, 2001 [73]
Treatment and results ITR(P) (3 pulses)a At month 12: MC 5/6, clinical cure: 3/6 ITR(P) (2 – 4 pulses)a At follow-up (12 months after start of therapy): MC: 1/1, clinical cure: 1/1 TER 250 mg/d for 12 wk At month 6: MC: 2/2, CC: 1/2
TER 250 mg/d for 3 mo Patients clinically and mycologically cured 6 mo after therapy Ciclopirox nail lacquer 8% for 6 mo Data not provided for individual species ITR 200 mg/d for 6 – 12 wk At follow-up (12 mo after start of therapy): MC: 2/3, clinical cure: 2/3.
Whitfield’s ointment for 6 mo Nail appeared normal at month 6 Ciclopirox nail lacquer 8% for 6 mo Data not provided for individual species
Abbreviations: CC, complete cure; DB, double-blind; MC, mycological cure; NS, not stated; TER, terbinafine. a Itraconazole Pulse [ITR(P)] given for 200 mg bid for 1 wk on followed by 3 wk off
264
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
suggests that it might originate in soil [4]. Patients have more often been females than males, and the majority are older individuals [48,49,51]. O. canadensis causes onychomycosis, and it has been suspected—but not demonstrated—to cause lesions of the palms or the toewebs [13]. The clinical pattern of onychomycosis most commonly seen is DLSO. The nail becomes white or yellow in color and is often hyperkeratotic and friable [47]. O. canadensis can also cause SWO, which suggests that it has the ability to degrade keratin [47].
to 21 days and are broad ellipsoidal to nearly spherical, smooth, usually single-celled (but occasionally two-celled), and they are often found in long, more or less upright chains that do not readily fragment into separate conidia [47]. Old cultures might form distinctive broad, brown, thick-walled, nodose hyphae resembling peridial appendages of the Arachnomyces sexual state [51].
Culture and microscopy
Candida onychomycosis affects fingernails more often than toenails. Primary Candida infection is seen in patients with CMCC or in individuals who are immunocompromised, such as patients who are HIV positive. In these patients, DLSO might be present initially and might progress to total dystrophic dis-
O. canadensis is slow growing in culture. The surface texture is velvety, and the colony is typically yellow to pale sandy brown with a deep brown – gray reverse [30,47,51]. Arthroconidia are formed after 14
Candida species
Table 5 Treatment of Onychocola canadensis onychomycosis Reference
Study type
No. of patients (evaluable)
Sigler et al, 1990 [50]
Case report
1 (1)
Sigler et al, 1990 [50] Sigler et al, 1990 [50] Sigler et al, 1994 [51]
Case report Case report Case report
1 (1) 1 (1) 1 (1)
Sigler et al, 1994 [51] Sigler et al, 1994 [51]
Case report Case report
3 (3) 1 (1)
Sigler et al, 1994 [51] Sigler et al, 1994 [51]
Case report Case report
1 (1) 1 (1)
Gupta et al, 1998 [47] Gupta et al, 1998 [47]
Case report Case report
7 (7) 1 (1)
Gupta et al, 1998 [47]
Case report
1 (1)
Gupta et al, 1998 [47] Koenig et al, 1997 [49] Campbell et al, 1997 [76] Contet-Audonneau et al, 1997 [48] Contet-Audonneau et al, 1997 [48] Contet-Audonneau et al, 1997 [48] Gupta et al, 2001 [65]
Case Case Case Case
1 3 4 1
report report report report
(1) (3) (4) (1)
Case report
3 (3)
Case report
1 (1)
Open, prospective
1 (1)
Treatment and results Debridement, thymol 4% in chloroform bid for 2 mo Marked clinical improvement, but direct microscopy still positive for fungal filament 9 mo after therapy Refused treatment Surgical excision; lost to follow-up Griseofulvin 6 mo Treatment discontinued because of gastrointestinal distress No data Oral ketoconazole for 10 d; topical nystatin KETO discontinued because of hepatotoxicity Betnovate for psoriasis; no other treatment Surgical excision New growth beginning No therapy TER 250 mg/d for 12 wk then 16 wk; ITR(C) for 4 pulses No data ITR(P) (5 pulses)a Clinical response; MC T. rubrum responded to therapy Refused treatment No data Econazole powder and TER 250 mg/d No data Amorolfine nail lacquer No data Ciclopirox nail lacquer No data ITR(P) (3 pulses)a At month 12: MC 1/1, clinical cure: 1/1
Abbreviations: KETO, ketoconazole; MC, mycological cure; TER, terbinafine. a Itraconazole Pulse [ITR(P)] given for 200 mg bid for 1 wk on followed by 3 wk off
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
ease, which involves the entire nail plate. In CMCC, the nail unit and surrounding soft tissues might also be involved [10]. In otherwise healthy individuals, Candida can merely cause onycholysis of constantly wetted or damaged nails; in this case the clinical presentation might be distal or lateral onycholysis with or without paronychia [52 – 54]. Candida albicans is the most common cause of candidal onychomycosis; it accounts for approximately 80% of such infections [53]. More recently, Candida parapsilosis is being recognized as a major cause of onychomycosis [55]. For instance, the most frequent Candida species stated to cause onychomycosis in Israel is C. parapsilosis (39.5% in toenails, 36.7% in fingernails) [56]. In a multicenter study, C. albicans and C. parapsilosis were implicated in an almost equal number of cases [57]. Other Candida species, such as C. tropicalis, C. krusei, and C. guilliermondii have also less commonly been im-
265
plicated as causative agents of dermatological infections [52]. In addition, C. ciferrii has been associated with onychomycosis in elderly patients with trophic disorders of the legs [58].
Treatment Studies have reported success in treating nondermatophyte molds and Candida species using terbinafine, itraconazole, and fluconazole. These oral therapies have higher cure rates, higher compliance, and lower relapse rates than the older agents (eg, griseofulvin), and they cause fewer adverse events while requiring shorter treatment durations [59]. Griseofulvin would not be expected to be effective against onychomycosis caused by Candida species or nondermatophyte molds [60]. Compared to dermatophytes, non-dermatophytes might require treatment
Table 6 Treatment of Candida onychomycosis Reference
Study type
No. of patients (evaluable)
Candida spp Segal et al, 1996 [8]
Open
28 (20)
Lestringant GG et al, 1996 [77]
Open
32 (32)
Rashid et al, [80]
Open, noncomparative
13 (13)
Gupta et al, 2000 [78]
Open, multicenter
44 (32)
Lebwohl et al, 2001 [73]
DB, randomized, placebo-controlled, multicenter DB, randomized, placebo-controlled, multicenter
12 (12)
11 (11)
TER 250 mg/day for 24 weeks. At mo 6: MC: 11/11, CC: 6/11
C. albicans Nolting et al, 1994 [57]
Multicenter
NS (26)
TER 250 mg/d for 12 mo At mo 6: MC: 18/26, CC: 14/26
C. parapsilosis Nolting et al, 1994 [57]
Multicenter
NS (32)
TER 250 mg/day for 12 months. At mo 6: MC: 27/32, CC: 20/32
C. albicans and C. parapsilosis Nolting et al, 1994 [57]
Multicenter
NS (2)
TER 250 mg/day for 12 months. At mo 6: MC: 2/2, CC: 0/2
Lebwohl et al, 2001 [73]
Treatment and results TER 250 mg/d for 16 wk At wk 48: MC: 2/20, CC: 12/20 Amorolfine 5% applied twice weekly for up to 67 wk 90% of nails were cured or showed only minor residual dystrophy ITR(P) (3 pulses)a At wk 12: CC: 13/13 ITR(P) (2 – 3 pulses)a MC: 29/32, CC: 24/32 TER 250 mg/d for 12 wk At mo 6: MC: 10/12, CC: 4/12
Abbreviations: CC, complete cure; DB, double-blind; MC, mycological cure; NS, not stated; TER, terbinafine. a Itraconazole Pulse [ITR(P)] given for 200 mg bid for 1 wk on followed by 3 wk off
266
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268
for a longer period of time [57,61]. Non-dermatophytes have been successfully treated with ciclopirox nail lacquer topical solution 8%. This agent has a broad spectrum of action with activity against dermatophytes and non-dermatophytes (molds and Candida species) [61,62]. Tables 1 – 6 summarize the therapies used to treat onychomycosis caused by non-dermatophytes. It is important to note that not all of the studies present adequate mycological or clinical details, nor are complete cure rates always documented, which suggests a need for improved reporting of results. S. dimidiatum and O. canadensis might be poorly responsive or unresponsive to systemic treatments [61]. C. parapsilosis responds better to terbinafine treatment than does C. albicans because terbinafine is fungicidal towards C. parapsilosis but is only fungistatic towards C. albicans [8,57,63].
Summary Non-dermatophyte organisms are becoming increasingly prevalent in onychomycosis. This apparent emergence might be an artifact of improved diagnostic techniques and increased awareness that these fungi are potential etiologic agents. It is important to bear in mind that all isolated organisms should be evaluated as potential pathogens when diagnosing fungal infections, especially given the increasing use of immunosuppressive drugs and the increasing numbers of chronically immunocompromised individuals. While many patients with non-dermatophyte mold onychomycosis will respond to oral or topical antifungal therapy, poor or incomplete response might still be expected in some patients.
References [1] Midgley G, Moore MK. Nail infections. Dermatol Clin 1996;14:41 – 9. [2] Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists’ offices in Ontario, Canada—a multicenter survey of 2001 patients. Int J Dermatol 1997;36:783 – 7. [3] Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000;42:217 – 24. [4] Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physician’s offices: a multicenter survey of 15,000 patients. J Am Acad Dermatol 2000;43:244 – 8.
[5] Gupta AK, Cooper EA, MacDonald P, et al. Utility of inoculum counting (Walshe and English Criteria) in clinical diagnosis of onychomycosis caused by nondermatophyte filamentous fungi. J Clin Microbiol 2001;39:2115 – 21. [6] Fletcher CL, Hay RJ, Midgley G, et al. Onychomycosis caused by infection with Paecilomyces lilacinus. Br J Derm 1998;139:1133 – 5. [7] Romano C, Miracco C, Difonzo EM. Skin and nail infections due to Fusarium oxysporum in Tuscany. Italy. Mycoses 1998;41:433 – 7. [8] Segal R, Kritzman A, Cividalli L, et al. Treatment of Candida nail infection with terbinafine. J Am Acad Dermatol 1996;35:958 – 61. [9] Zaias N. Onychomycosis. Derm Clin 1985;3:445 – 59. [10] Hay RJ, Baran R, Haneke E. Fungal (Onychomycosis) and other infections involving the nail apparatus. In: Baran R, Dawber RPR, de Berker DAR, et al, editors. Baran and Dawber’s Diseases of the Nails and their management. Oxford, UK: Blackwell Science Ltd; 2001. p. 129 – 71. [11] Tosti A, Baran R, Piraccini BM, et al. ‘‘Endonyx’’ onychomycosis: a new modality of nail invasion by dermatophytes. Acta Derm Venereol 1999;79:52 – 3. [12] Baran R, Hay R, Haneke E, et al, editors. Onychomycosis the current approach to diagnosis and therapy. UK: Martin Dunitz; 1999. p. 10 – 9. [13] Gupta AK, Elewski BE. Nondermatophyte causes of onychomycosis and superficial mycoses. Curr Top Med Mycol 1996;7:87 – 97. [14] Baran R, Tosti A, Piraccini BM. Uncommon clinical patterns of Fusarium nail infection: report of three cases. Br J Dermatol 1997;136:424 – 7. [15] Tosti A, Piraccini BM, Stinchi C, et al. Onychomycosis due to Scopulariopsis brevicaulis: clinical features and response to systemic antifungals. Br J Dermatol 1996;135:799 – 802. [16] Baran R. Proximal subungual Candida onychomycosis: an unusual manifestation of chronic mucocutaneous candidosis. Br J Dermatol 1997;137:286 – 8. [17] Fletcher CL, Moore MK, Hay RJ. Endonyx onychomycosis due to Trichophyton soudanense in two Somalian siblings. Br J Derm 2001;145:687 – 8. [18] Baran R, Hay RJ, Tosti A, et al. A new classification of onychomycosis. Br J Dermatol 1998;139:567 – 71. [19] Midgley G, Moore MK, Cook JC, et al. Mycology of nail disorders. J Am Acad Dermatol 1994;31:S68 – 74. [20] English MP. Nails and fungi. Br J Dermatol 1976;94: 697 – 701. [21] Greer DL. Evolving role of nondermatophytes in onychomycosis. Int J Dermatol 1995;34:521 – 4. [22] Tseng SS, Longley BJ, Scher RK, et al. Fusarium fingernail infection responsive to fluconazole intermittent therapy. Cutis 2000;65:352 – 4. [23] Tosti A, Piraccini BM. Proximal subungual onychomycosis due to Aspergillus niger: report of two cases. Br J Dermatol 1998;139:156 – 7. [24] Fischer JB. Onychomycosis caused by Scopulariopsis brevicaulis. Can Med Assoc J 1960;83:1264 – 5.
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268 [25] Marchisio VF, Fusconi A. Morphological evidence for keratinolytic activity of Scopulariopsis spp. isolates from nail lesions and the air. Med Mycol 2001;39: 287 – 94. [26] Marchisio VF, Fusconi A, Querio FL. Scopulariopsis brevicaulis: a keratinophilic or a keratinolytic fungus. Mycoses 2000;43:281 – 92. [27] Gianni C, Cerri A, Crosti C. Non-dermatophytic onychomycosis. An underestimated entity? A study of 51 cases. Mycoses 2000;43:29 – 33. [28] Fragner P, Belsan I. Scopulariopsis Bainier as causative agent of onychomycosis (mycological and clinical study). Part II: clinical study. Acta Univ Carol [Med] 1974;20:333 – 58. [29] De Hoog GS, Guarro J, Gene´ J, et al. Atlas of clinical fungi, 2nd edition. Utrecht, Netherlands: Centraalbureau voor Schimmelcultures; 2001. [30] Summerbell RC. Non-dermatophytic fungi causing onychomycosis and tinea. In: Kane J, Summerbell RC, Sigler L, Krajden S, et al, editors. Laboratory handbook of dermatophytes. A clinical guide and laboratory manual of dermatophytes and other filamentous fungi from skin, hair and nails. Belmont (CA): Star Publishers; 1997. p. 213 – 59. [31] Onsberg P. Scopulariopsis brevicaulis in nails. Dermatologica 1980;161:259 – 64. [32] Frey D, Muir DB. Onychomycosis caused by Scopulariopsis brevicaulis. Aust J Derm 1981;22:123 – 6. [33] Naidu J, Singh SM, Pouranik M. Onychomycosis caused by Scopulariopsis brumptii. Mycopathologia 1991;113:159 – 64. [34] Kennedy MJ, Sigler L. Aspergillus, Fusarium, and other opportunistic moniliaceous fungi. In: Murray PR, editor. Manual of clinical microbiology. Washington DC: ASM Press; 1995. p. 765 – 90. [35] Schell WA, Pasarell L, Salkin IF, et al. Bipolaris, Exophiala, Scedosporium, Sporothrix, and other dematiaceous fungi. In: Murray PR, editor. Manual of clinical microbiology. Washington DC: ASM Press; 1995. p. 825 – 46. [36] Elewski BE. Onychomycosis caused by Scytalidium dimidiatum. J Am Acad Dermatol 1996;35:336 – 8. [37] Greer DL, Gutierrez MM. Tinea pedis caused by Hendersonula toruloidea: a new problem in dermatology. J Am Acad Dermatol 1987;16:1111 – 5. [38] Elewski BE, Greer DL. Hendersonula toruloidea and Scytalidium hyalinum: review and update. Arch Dermatol 1991;127:1041 – 4. [39] Abramson C. Athlete’s foot and onychomycosis caused by Hendersonula toruloidea. Cutis 1990;46: 128 – 32. [40] Frankel DH, Rippon JW. Hendersonula toruloidea infection in man. Mycopathologia 1989;105:175 – 86. [41] Campbell CK, Kurwa A, Abdel-Aziz A-H, et al. Fungal infection of skin and nails by Hendersonula toruloidea. Br J Dermatol 1973;89:45 – 52. [42] Nelson PE, Dignani MC, Anaissie EJ. Taxonomy, biology, and clinical aspects of Fusarium species. Clin Microbiol Rev 1994;7:479 – 504.
267
[43] Romano C, Paccagnini E, Difonzo EM. Onychomycosis caused by Alternaria spp. in Tuscany, Italy from 1985 to 1999. Mycoses 2001;44:73 – 6. [44] Gupta AK, Baran R, Summerbell RC. Fusarium infections of the skin. Cur Options Inf Dis 2000;13: 121 – 8. [45] Rush-Munro FM, Black H, Dingley JM. Onychomycosis caused by Fusarium oxysporum. Aust J Derm 1971;12:18 – 29. [46] Torres-Rodriguez JM, Madrenys-Brunet N, Siddat M, et al. Aspergillus versicolor as cause of onychomycosis: report of 12 cases and susceptibility testing to antifungal drugs. J Eur Acad Derm Venereol 1998;11: 25 – 31. [47] Gupta AK, Horgan-Bell CB, Summerbell RC. Onychomycosis associated with Onychocola canadensis: ten case reports and a review of the literature. J Am Acad Dermatol 1998;39:410 – 7. [48] Contet-Audonneau N, Schmutz J, Basile A, et al. A new agent of onychomycosis in the elderly: Onychocola canadensis. Eur J Dermatol 1997;7:115 – 7. [49] Koenig H, Ball C, de Bie´vre C. First European cases of onychomycosis caused by Onychocola canadensis. J Med Vet Mycol 1997;35:71 – 2. [50] Sigler L, Congly H. Toenail infection caused by Onychocola canadensis gen. et sp. nov. J Med Vet Mycol 1990;28:405 – 17. [51] Sigler L, Abbott SP, Woodgyer AJ. New records of nail and skin infection due to Onychocola canadensis and description of its teleomorph Arachnomyces nodosetosus sp. nov. J Med Vet Mycol 1994;32:275 – 85. [52] Daniel III CR, Gupta AK, Daniel MP, et al. Candida infection of the nail: role of Candida as a primary or secondary pathogen. Int J Dermatol 1998;37:904 – 7. [53] Del Rosso JQ, Zellis S, Gupta AK. Itraconazole in the treatment of superficial cutaneous and mucosal Candida infections. JAOA 1998;98:497 – 502. [54] Hay RJ, Baran R, Moore MK, et al. Candida onychomycosis—an evaluation of the role of Candida species in nail disease. Br J Dermatol 1988;118:47 – 58. [55] Gautret P, Rodier MH, Kauffmann-Lacroix C, et al. Case report and review: onychomycosis due to Candida parapsilosis. Mycoses 2000;43:433 – 5. [56] Segal R, Kimchi A, Kritzman A, et al. The frequency of Candida parapsilosis in onychomycosis: an epidemiological survey in Israel. Mycoses 2000;43:349 – 53. [57] Nolting S, Brautigam M, Weidinger G. Terbinafine in onychomycosis with involvement by non-dermatophytic fungi. Br J Dermatol 1994;130(Suppl 43): 16 – 21. [58] de Gentile L, Bouchara J, Le Clec’h C, et al. Prevalence of Candida ciferrii in elderly patients with trophic disorders of the legs. Mycopathologia 1995; 131:99 – 102. [59] Gupta AK, Shear NH. The new oral antifungal agents for onychomycosis of the toenails. J Eur Acad Dermatol Venereol 1999;13:1 – 13. [60] Gupta AK, Gregurek-Novak T. Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin and keto-
268
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
A.K. Gupta et al. / Dermatol Clin 21 (2003) 257–268 conazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the toes. Dermatology 2001; 202:235 – 8. Gupta AK, Shear NH. A risk – benefit assessment of the newer oral antifungal agents used to treat onychomycosis. Drug Saf 2000;22:35 – 52. Bohn M, Kraemer K. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol 2000;43: S57 – 69. Roberts DT, Richardson MD, Dwyer PK, et al. Terbinafine in chronic paronychia and Candida onychomycosis. J Dermatol Treat 1992;3:39 – 42. Onsberg P, Stahl D. Scopulariopsis onychomycosis treated with natamycin. Dermatologica 1980;160: 57 – 61. Gupta AK, Gregurek-Novak T, Konnikov N, et al. Itraconazole and terbinafine treatment of some nondermatophyte molds causing onychomycosis of the toes and a review of the literature. J Cutan Med Surg 2001;5:206 – 10. Ulbricht H, Worz K. Therapy with ciclopirox lacquer of onychomycosis caused by molds. Mycoses 1994; 37(Suppl 1):97 – 100. Rollman O, Johansson S. Hendersonula toruloidea infection: successful response of onychomycosis to nail avulsion and topical ciclopiroxolamine. Acta Derm Venereol (Stockholm) 1987;67:506 – 10. Downs AMR, Lear JT, Archer CB. Scytalidium hyalinum onychomycosis successfully treated with 5% amorolfine nail lacquer. Br J Dermatol 1999;140: 538 – 68. Hay RJ, Mackie RM, Clayton YM. Tioconazole nail solution—an open study of its efficacy in onychomycosis. Clin Exp Dermatol 1985;10:111 – 5. De Doncker PRG, Scher RK, Baran RL, et al. Itraconazole therapy is effective for pedal onychomycosis caused by some nondermatophyte molds and in mixed
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
infection with dermatophytes and molds: a multicenter study with 36 patients. J Am Acad Dermatol 1997;36: 173 – 7. DiSalvo AF, Fickling AM. A case of nondermatophytic toe onychomycosis caused by Fusarium oxysporum. Arch Dermatol 1980;116:699 – 700. Gianni C, Cerri A, Crosti C. Unusual clinical features of fingernail infection by Fusarium oxysporum. Mycoses 1997;40:455 – 9. Lebwohl MG, Daniel CR, Leyden J, et al. Efficacy and safety of terbinafine for nondermatophyte and mixed nondermatophyte and dermatophyte toenail onychomycosis. Int J Dermatol 2001;40:358 – 60. Scher RK, Barnett JM. Successful treatment of Aspergillus flavus onychomycosis with oral itraconazole. J Am Acad Dermatol 1990;23:749 – 50. Rosenthal SA, Stritzler R, Villafane J. Onychomycosis caused by Aspergillus fumigatus. Arch Derm 1968;97: 685 – 7. Campbell CK, Johnson EM, Warnock DW. Nail infection caused by Onychocola canadensis: report of the first four British cases. J Med Vet Mycol 1997;35: 423 – 5. Lestringant GG, Nsanze H, Nada M, et al. Effectiveness of amorolfine 5% nail lacquer in the treatment of long-duration Candida onychomycosis with chronic paronychia. J Dermatol Treat 1996;7:89 – 92. Gupta AK, De Doncker P, Haneke E. Itraconazole pulse therapy for the treatment of Candida onychomycosis. J Eur Acad Dermatol Venereol 2000;15:112 – 5. Hay RJ, Moore MK. Clinical features of superficial fungal infections caused by Hendersonula toruloidea and Scytalidium hyalinum. Br J Dermatol 1984;110: 677 – 83. Rashid A, De Doncker P. Pulse-dose regimen of oral itraconazole in the treatment of Candida paronychia [poster]. Presented at Clinical Dermatology 2000. Vancouver, Canada, May 28 – 31, 1996.
Dermatol Clin 21 (2003) 269 – 276
New and emerging pediatric infections Denise Metry, MDa,*, Rajani Katta, MDb a
Department of Dermatology, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin Street, CC 620.16 6560, Houston, TX 77030-2399, USA b Department of Dermatology, Baylor College of Medicine, 6560 Fannin Street, Suite 802, Houston, TX 77030, USA
A number of new and emerging pediatric cutaneous infections pose an array of challenges to the clinician, particularly in the areas of diagnosis and treatment. In this review article the authors highlight five specific subjects of importance to the pediatrician and dermatologist: (1) new and unusual presentations of parvovirus infection, including a discussion of populations particularly prone to complications from such infections; (2) cutaneous mold infections in children, which are an increasing concern, particularly given the rising numbers of immunocompromised children in this United States; (3) incidence of pediatric, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections, which are on the rise, coinciding with concerns over limited antibiotic susceptibility for MRSA and other pathogens; (4) antibiotics such as linezolid, which are emerging as promising new treatments for multi-drug resistant organisms; and (5) discussion of the controversial use of fluoroquinolones in the pediatric population.
Human parvovirus B19 Erythema infectiosum, also known as ‘‘Fifth’’ or ‘‘slapped cheek’’ disease, is a long-recognized and clinically distinct viral exanthem of childhood. The clinical features known as erythema infectiosum were originally described by a dermatologist more than two centuries ago [1]. Only in the last few decades,
* Corresponding author. E-mail address:
[email protected] (D. Metry).
with the aid of serologic and molecular studies, has the causative organism of erythema infectiosum, human parvovirus B19 (HPV B19), been linked to other dermatological manifestations. These include the unique papular purpuric ‘‘gloves and socks’’ syndrome (PPGSS), associations with other dermatological entities such as Gianotti-Crosti syndrome, and a host of otherwise nonspecific dermatological findings. Infection with HPV B19 has also been reported to mimic the cutaneous and systemic findings of certain collagen vascular diseases, specifically juvenile rheumatoid arthritis and systemic lupus erythematosus. Furthermore, it is now recognized that HPV B19 infection can lead to potentially serious complications in susceptible populations. HPV B19, which occurs worldwide, is the only parvoviral infection clearly linked with human disease. The prevalence of prior infection increases with age, and can be demonstrated in approximately 40% of children and adolescents and 75% of adults [2]. IgG antibody to parvovirus has been demonstrated to persist for many years. It is probably life-long, and it confers long-lasting immunity. The virus itself is a non-enveloped, singlestranded DNA virus belonging to the family Parvoviridae and the genus Erythrovirus [3]. Originally discovered in 1974, the name B19 refers to the blood bank code by which the original positive serum sample was labeled [1]. Transmission of the virus occurs primarily through the respiratory route [4]. Transplacental as well as hematogenous transmission by way of contaminated pooled blood products [5,6] or bone marrow [7] occurs less commonly. The average incubation period is 6 to 18 days. Viremia resolves as antibody responses develop.
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi: 10.1016/S0733-8635(02)00087-6
270
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
Infection with HPV B19 occurs primarily in younger children, in whom more than half of infections are asymptomatic; however, infection can result in a variety of clinical findings in children, ranging from subclinical illness to dermatologic, rheumatologic, or hematologic manifestations. Joint manifestations, which might be poly- or pauciarticular, have been reported in 12% to 33% of patients, whereas hematologic complications occur in one-sixth to onethird of patients [8,9]. Dermatologic manifestations, reported in up to half of patients infected with HPV B19, are comprised of three main groups: reticular erythema, maculopapular eruptions, and petechiae and purpura [8 – 10]. Case reports of widespread desquamation [11] and generalized livedo reticularis have also been described [12]. HPV B19 has also been linked (with a number of other infectious causes) to known dermatologic entities such as Gianotti-Crosti syndrome (papular acrodermatitis of childhood) [9,13], Henoch-Schonlein purpura [9,14,15], thrombotic thrombocytopenic purpura [16], Kawasaki disease [17,18], and erythema nodosum [9]. Papular purpuric ‘‘gloves and socks’’ syndrome (PPGSS) is a distinctive parvoviral eruption only described in the last decade [19]. PPGSS typically occurs in young adults, with the majority of cases occurring in the spring and summer [20]. Clinical findings include symmetric, painful erythema and edema of the hands and feet with gradual progression to petechiae and purpura. A hallmark of PPGSS is sharp demarcation at the wrists and ankles, hence the name ‘‘gloves and socks’’ syndrome. Mucosal involvement, which can include the lips, buccal mucosa, and palate, is another common finding in which oral erosions, petechiae, and edema can be seen. Unlike erythema infectiosum, patients with PPGSS are considered to be infectious when skin lesions are present [20]. Although otherwise healthy children can develop low-grade fever or arthralgias in association with PPGSS, patients usually appear to be nontoxic. Clinical resolution typically occurs within 1 to 2 weeks with no permanent sequelae, and symptomatic treatment alone is generally adequate. In immunosuppressed patients, however, PPGSS might be prolonged, leading to persistent skin lesions and associated anemia [21]. The etiologic link of HPV B19 to PPGSS is widely accepted. Although other viral etiologies have been postulated, including cytomegalovirus, Coxsackievirus, measles virus, and human herpesviruses 6 and 7 [22], the evidence linking the syndrome to HPV B19 is the most convincing. Serologic studies
of patients with PPGSS have shown the prevalence of IgM antibodies to HPV B19 [23]. In addition, immunohistochemical studies have demonstrated the presence of viral antigens in dermal vessel walls and keratinocytes. Parvoviral DNA can be found in skin biopsies of patients with PPGSS by way of polymerase chain reaction [24]. The association of HPV B19 with acute and chronic rheumatologic symptomatology has led many to suspect that the virus might play a role in specific rheumatologic disease. Clinical manifestations of HPV B19 indistinguishable from those of Still’s disease (juvenile rheumatoid arthritis) have been reported. In a study by Nocton et al, six of 22 children with joint complaints and recent B19 infection developed persistent arthritis that fulfilled criteria for the diagnosis of juvenile rheumatoid arthritis [25]. Striking similarities of HPV B19 infection to systemic lupus erythematosus have also been observed. Moore et al reported seven such cases, in which all patients experienced prolonged arthralgias and fatigue; the vast majority also had a history of a malar skin eruption and positive serologic antinuclear antibody titers. Symptoms persisted for months in some patients [26]. Whether parvoviral infection is an inciting or causal agent in such cases or if it is simply coincidental remains to be determined [1]. In most cases of parvoviral infection, the diagnosis rests upon recognition of the characteristic clinical features, although serology might be helpful in atypical cases [27]. Detection of IgM antibody to HPV B19 infection is diagnostic of infection within the past several months. A skin biopsy is not typically needed or performed in most patients, and the virus cannot be cultured using routine diagnostic methods. Chronic infection in the immunocompromised can be established by polymerase chain reaction or nucleic acid hybridization assays on blood specimens. Treatment of patients is primarily supportive, and in the majority of immunocompetent individuals the prognosis is excellent, with acute symptoms typically resolving without sequelae. HPV B19 exhibits tropism for erythroid progenitor cells, leading to a fall in erythrocyte count in all patients. Thus, any individual who has a shortened RBC survival time is at risk for the development of aplastic crisis, including patients with sickle-cell anemia, hereditary spherocytosis, thalassemia, and autoimmune hemolytic anemia, among others [1]. Immunocompromised patients are at risk for chronic anemia and prolonged cutaneous lesions and symptoms [21]. If a pregnant woman develops active infection, the risk of fetal infection is approximately 33%, although the risk might be higher in late
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
pregnancy. The vast majority of infants born to mothers who seroconvert during pregnancy are healthy; however, fetal infection with B19 during the first trimester might cause spontaneous abortion. During the second or third trimester, hydrops fetalis or fetal death can occur as a result of cardiac failure secondary to anemia. The maximum risk of fetal loss is between 10 and 26 weeks of gestation [28]. It is recommended that susceptible pregnant health-care workers not care for patients with aplastic crises or immunocompromised patients with suspected parvoviral infection because these patients will continue to excrete the virus. If exposure to a susceptible individual occurs, notification of the patient with close observation by their treating physician is necessary. If infection results, the use of highdose intravenous immunoglobulin (IVIG) might be indicated, which results in fast and effective reversal of the anemia [29]. IVIG has been used to treat HPV B19-induced anemia in patients with immunodeficiency [30], transplant recipients [31,32], and AIDS [33]. Because the absolute risk of fetal death is low, maternal infection is not grounds for pregnancy termination. Fetal blood transfusions have been performed in infected infants with hydrops fetalis [34].
Cutaneous mold infections An increasing number of reports have described severe cutaneous and systemic fungal infections among immunocompromised children. With advances in the treatment of malignancies and transplantation medicine, the number of immunocompromised children in the United States continues to rise, leading to a larger population susceptible to such infections. In prior years, Candida albicans was the overwhelming pathogen isolated; however, Aspergillus, Mucor, and Fusarium species, which are categorized as molds based on morphology, are increasingly recognized as potentially serious pathogens [35]. Such mold species are present in soil, plants, and other environmental sources. Cutaneous involvement can take the form of primary infection (usually caused by inoculation) or secondary infection (caused by systemic dissemination). The major pathogens causing cutaneous mold infections mirror those causing systemic illness. The clinician must be alert to the possibility of cutaneous mold infection in an immunocompromised child whenever skin lesions manifest at or near an intravenous access site—even in the absence of systemic symptoms. The causative organism is most often of the Aspergillus species, although cases caused by Mucor are increasingly recognized. Local trauma
271
from intravenous catheters and macerated skin from occlusive dressings play a major pathogenic role by providing a portal of entry for infection [36]. The portal can occur at the site of needle insertion, under surrounding tape, or under adjoining armboards [37 – 45]. Contaminated elastic bandages used over operative sites are another reported source, and contamination of equipment has been confirmed from sterile, unopened packages [46] and in supplies kept in a contaminated storeroom [39]. Less commonly, primary cutaneous mold infections in the absence of any obvious portal of entry have occurred [44,47]. Primary cutaneous mold infections often begin as ill-defined erythema and thus might not be suspected initially, posing diagnostic difficulties. The clinical appearance of developed lesions is variable. While necrotic lesions or ulcers with necrotic eschars are most commonly seen, presentation can vary with the causative agent. For example, skin lesions associated with primary cutaneous aspergillosis have also been reported as erythematous papules, hemorrhagic bullae, purpuric lesions, and cellulitis [39,47]. In primary cutaneous infection with mucormycosis (which is most commonly caused by Rhizopus species), two clinical forms have been described dependent on the immune status of the patient. In normal hosts, a superficial, subacute form occurs with vesicles or pustules that progress slowly to eschar formation, whereas immunocompromised patients might develop rapidly progressive, gangrenous lesions [48]. Cutaneous infection with Fusarium species is less common and has been described as echthyma-like [43] or as a blackened eschar [49]. The presence of ill-defined, erosive lesions with extensive crusting in a severely premature neonate (22 – 25 gestational weeks) might also portend a cutaneous mold infection [50]. Definitive diagnosis of the primary cutaneous mold infection requires tissue culture or histologic examination, although potassium hydroxide touch preparation of a skin lesion might reveal hyphae, providing a presumptive diagnosis. Initiation of antifungal therapy prior to definitive diagnosis might be indicated in the immunocompromised child or in an extremely premature newborn that is not responding to conventional antibiotics. Intravenous amphotericin B is the treatment of choice [51], although its use might be associated with significant toxicity. Amphotericin B lipid complex, although more expensive, might be indicated in some cases because of its greater potential efficacy with fewer side effects [52]. The successful use of itraconazole has also been reported in adult patients with primary cutaneous infection [41]. Another key aspect of therapy in select cases is surgical debridement.
272
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
Methicillin-resistant Staphylococcus aureus The incidence of antibiotic resistance among Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA), has risen dramatically over the past decade and it is reaching epidemic proportions [53]. MRSA now accounts for approximately 50% of nosocomial S. aureus isolates nationwide [54]. Even more recently identified is an increasing incidence of non-nosocomial, community-acquired MRSA infections among otherwise healthy children without known risk factors [55 – 58]. Year 2000 data from the authors’ pediatric hospital showed that 67% of community-acquired Staphylococcal infections were methicillin-resistant [58]. MRSA strains are virulent and capable of causing serious disease in children. The potential severity of communityacquired infection was demonstrated by the recent report of four fatal pediatric cases [59]. Risk factors for MRSA infection in children include a history of underlying illness predisposing to frequent hospitalizations (eg, immune deficiency, cystic fibrosis, malignancy, or chronic renal failure). Family member hospitalization, visitation to a hospital emergency room within the previous 6 months, inpatient or outpatient surgery, indwelling catheters, endotracheal tubes, and prolonged or recurrent antibiotic exposure are other known risk factors in the pediatric population [60 – 62]. Furthermore, healthcare worker or nursing home resident contact— and even child day care attendance—has been associated with MRSA transmission resulting in clinical infection [63,64]. Chronic skin disease, particularly childhood atopic dermatitis, is a known source of MRSA infection [56,65], and it should be suspected in children with disease flares or signs of secondary infection unresponsive to standard antibiotic therapy. Community-acquired MRSA infection is more likely to manifest as superficial skin and subcutaneous skin infections, whereas deep-seated infections such as osteomyelitis or bacteremia are more likely to be methicillin-susceptible [58,65,66]. The reason for this (and the increasing frequency of communityacquired MRSA infections among otherwise healthy children) is uncertain. Current investigations are addressing whether MRSA is arising de novo within the community or simply being spread through the community from contact with patients with known risk factors. A recent study from the authors’ institution demonstrated no significant differences in the exposure to known risk factors between children with community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcal infections. Like-
wise, there were no significant differences in the presence of risk factors among household contacts between the two groups [58]. Additional findings of distinct DNA [56,58,59] and antibiotic susceptibility patterns and clinical manifestations between nosocomial and community-acquired isolates strongly suggest that some MRSA strains are originating within the community, most likely as a result of increased selection pressure from antimicrobials [67]. The fact that community-acquired MRSA is now being described in several areas of the United States suggests that this phenomenon is unlikely to remain a regional concern in the near future [68]. Most nosocomially-acquired MRSA strains demonstrate multi-drug resistance, which is related to errors within the S. aureus mecA gene. This gene encodes a novel penicillin binding protein, and it is often acquired within a larger DNA fragment called the mec region. Multiple insertion sequences are likely present within this region because transposons mediating resistance to quinolones, clindamycin, erythromycin, trimethoprim, and gentamycin have been identified [61]. In contrast, the resistance spectrum of community-acquired MRSA isolates from children without identified risk factors has tended to be limited to methicillin and erythromycin with retained susceptibility to clindamycin and trimethoprim – sulfamethoxazole. Thus, at the authors’ institution, empiric vancomycin is used for severe infections, and clindamycin or trimethoprim – sulfamethoxazole is used for mild to moderate infections in which S. aureus is a potential pathogen [58]. As Fergie et al have noted, however, some of the authors’ patients with superficial infections caused by community-acquired MRSA demonstrated clinical resolution of their cutaneous infections despite treatment with antibiotics to which the organism was not susceptible [58,67]. Thus, in the normal host with superficial MRSA infection, the role of antibiotic therapy for resolution of infection might not be as critical as it is for more serious infections or infections in the immunocompromised host [58]. The four children who died of community-acquired MRSA had severe, deep-seated infections or sepsis, and they were initially treated with cephalosporin antibiotics [59]. Endemic hospital transmission of MRSA might be limited by isolating potentially infected children who have been previously hospitalized elsewhere until appropriate screening tests are negative. In the event that a child within the community is identified with MRSA infection, parents of the exposed children should be informed of potential exposure. If an exposed child then develops severe illness, the physi-
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
cian can obtain cultures and initiate appropriate empiric antibiotic therapy, thus avoiding protracted use of ineffective antibiotics [64].
Linezolid Several investigational agents, including fourthgeneration quinolones, synthetic glycopeptides, glycylcyclines, streptogramins, and oxazolidinones have recently emerged as potential treatments for drugresistant pathogens such as MRSA [69]. Of these, linezolid (Zyvox, Pharmacial & UpJohn, Kalamazoo, MI), the newest of the synthetic oxazolidinones, is among the most promising. Linezolid effectively inhibits the growth of a large number of Gram-positive organisms regardless of resistance phenotype, providing a therapeutic alternative for MRSA infection [70]. Linezolid is currently being marketed in the United States, and clinical trials in adult and pediatric patients are ongoing. Linezolid binds to the 50S ribosomal subunit and inhibits bacterial growth by way of inhibition of protein synthesis. The specific mechanism of action appears to occur early in the process of protein synthesis, possibly distorting the binding site for the initiation transfer of RNA [71]. Although linezolid shares a similar binding site with chloramphenicol and lincomycin, its mechanism of action appears to be unique, thus it lacks cross-resistance with other currently marketed antibiotics [72]. Linezolid has 100% oral bioavailability (a major advantage over vancomycin) and it is available in multiple equivalent dosage forms: intravenous solution (2 mg/mL), tablets (400 mg or 600 mg), and oral suspension (100 mg/5 mL). Absorption is unaffected by food, and the primary route of elimination occurs by way of nonrenal pathways [73]. No dosage adjustments are needed based on route of administration, relationship to meals, gender, age, or hepatic or renal impairment. Furthermore, in vitro metabolic screens show that linezolid does not interact with any of the major human P450 cytochromes as either a substrate or an inhibitor [74]; however, linezolid is a reversible, nonselective inhibitor of monoamine oxidase and thus has the potential for interaction with adrenergic and serotonergic agents. Preliminary safety and efficacy data in children treated with linezolid are encouraging. Though maximum plasma concentrations between adults and children are similar, clearance of linezolid (when corrected by body weight) appears to be age-dependent, with a slight increase in clearance and lower maximum plasma concentrations observed in younger
273
children. A linezolid dose of 10 mg/kg given two to three times daily has been suggested for use in pediatric therapeutic trials in children older than 3 months of age [70]. More definitive pharmacokinetic studies in neonates are in progress. The most common pediatric side effects of linezolid include diarrhea (9%), vomiting (4%), loose stools (3.5%), skin rash (2.8%), and neutropenia (2%). Mild, transient thrombocytopenia has also been reported; thus, it is recommended that platelet counts be monitored in patients with a history of thrombocytopenia or other bleeding tendencies, or patients who might require longer than 2 weeks of therapy.
The use of ciprofloxacin in pediatrics The fluoroquinolones provide broad-spectrum coverage against a number of Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa and other intracellular organisms, and are thus a useful antibiotic option for the treatment of a wide variety of infections. Ciprofloxacin, the most frequently used fluoroquinolone in children, has been used in millions of pediatric patients despite its lack of FDA approval. In 1996, more than 8 million prescriptions for ciprofloxacin were written for children younger than 18 years old; 12,000 of these were for infants younger than 1 year old [75]. Fluoroquinolone use in pediatrics has been restricted because of potential cartilage toxicity, which occurred during animal research trials. It is apparent that all quinolones can cause cartilage damage when administered to immature animals; however, these effects vary among animal species. For example, dogs were the most sensitive compared with rats and mice, whereas an unnamed species of monkey was unaffected. The mechanism of quinolone-associated arthropathy in immature animals is uncertain, although direct inhibition of mitochondrial DNA synthesis in immature chondrocytes, direct fluoride toxicity, and cartilage magnesium deficiency caused by chelation with quinolones have all been hypothesized [76,77]. Cartilage toxicity in association with fluoroquinolones has not been reported in humans. Arthralgia and arthropathy, a known side effect of the fluoroquinolones, has mainly been reported in adults and children with cystic fibrosis (CF); however, up to 10% of CF patients without an exposure history to these agents complain of arthropathy [78], and it has been suggested that arthropathy is a frequently unrecognized and underreported complication of CF [79]. Pediatric safety information currently available from ciprofloxacin compassionate use data
274
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
appears to be similar to that of adults, in whom the drug is well tolerated [80,81]. Tendinitis and (rarely) tendon rupture are additional adverse effects that have been reported from fluoroquinolone use in humans. Because the mechanism of this side effect is unknown, it remains unclear whether or not cartilage toxicity in experimental animals and tendon disorders in humans are related conditions [79]. Additional research is needed to define the optimal dosage regimen of ciprofloxacin in pediatric patients. Although the fluoroquinolones appear to be well tolerated, further investigations are needed to determine the risk of arthropathy in children. Their pediatric usage should not be withheld when the benefits of treatment outweigh the risks, however.
[6] [7]
[8]
[9]
[10]
[11]
Summary Several aspects of emerging pediatric cutaneous infections are of importance to the clinician. New manifestations of parvovirus infection should be recognized promptly, especially because transmission to susceptible populations might lead to serious complications. In the immunocompromised pediatric population, the outcome of cutaneous mold infections can be improved with prompt recognition and initiation of treatment. The incidence of communityacquired MRSA infections in pediatrics is becoming more than a regional concern, and this coincides with the issue of limited antibiotic susceptibility for MRSA as well as other infections. New antibiotics such as linezolid are emerging as potential treatments for drug-resistant pathogens. An older group of antibiotics, the fluoroquinolones, appear to be well tolerated in children and should not be withheld from this population when the benefits of treatment outweigh the risks.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
References [1] Cherry JD. Parvovirus infections in children and adults. Adv Pediatr 1999;46:245 – 69. [2] Kelly HA, Siebert D, Hammond R, et al. The agespecific prevalence of human parvovirus immunity in Victoria, Australia compared with other parts of the world. Epidemiol Infect 2000;124:449 – 57. [3] Kerr JR. Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 2000;59:672 – 83. [4] Naides SJ. Infection with parvovirus B19. Curr Inf Dis Reports 1999;1:273 – 8. [5] Koenigbauer UF, Eastlund T, Day JW. Clinical illness due to parvovirus B19 infection after infusion of
[20] [21]
[22]
[23]
solvent/detergent-treated pooled plasma. Transfusion 2000;40:1203 – 6. Teitel JM. Viral safety of haemophilia treatment products. Ann Med 2000;32:485 – 92. Heegaard ED, Laub Petersen B. Parvovirus B19 transmitted by bone marrow. Br J Haematol 2000;111: 659 – 61. Azua B, Rodriguez R, Calleja T, et al. Description of 31 pediatric cases of infection caused by human parvovirus B19. Enferm Infecc Microbiol Clin 1996;14: 21 – 6. Borreda D, Palomera S, Gilbert B, et al. 24 cases of human parvovirus B19 infection in children. Ann Pediatr 1992;39:543 – 9. Seishima M, Kanoh H, Izumi T. The spectrum of cutaneous eruptions in 22 patients with isolated serological evidence of infection by parvovirus B19. Arch Dermatol 1999;135:1556 – 7. Yetgin S, Cetin M, Yenicesu I, et al. Acute parvovirus B19 infection mimicking juvenile myelomonocytic leukemia. Eur J Haematol 2000;65:276 – 8. Dereure O, Montes B, Guilhou JJ. Acute generalized livedo reticularis with myasthenia-like syndrome revealing parvovirus B19 primary infection. Arch Dermatol 1995;131:744 – 5. Carrascosa JM, Just M, Ribera M, et al. Papular acrodermatitis of childhood related to poxvirus and parvovirus B19 infection. Cutis 1998;61:265 – 7. Hakim A. Concurrent Henoch-Schonlein purpura and papular-purpuric gloves-and-socks syndrome. Scand J Rheumatol 2000;29:131 – 2. Lefrere JJ, Courouce AM, Kaplan C. Parvovirus and idiopathic thrombocytopenic purpura. Lancet 1989; 1:279. Kok RH, Wolfhagen MJ, Klosters G. A syndrome resembling thrombotic thrombocytopenic purpura associated with human parvovirus B19 infection. Clin Infect Dis 2001;32:311 – 2. Holm JM, Hansen LK, Oxhoj H. Kawasaki disease associated with parvovirus B19 infection. Eur J Pediatr 1995;154:633 – 4. Nigro G, Zerbini M, Krzysztofiak A, et al. Active or recent parvovirus B19 infection in children with Kawasaki disease. Lancet 1994;343:1260 – 1. Harms M, Feldmann R, Saurat JH. Papular-purpuric ‘‘gloves and socks’’ syndrome. J Am Acad Dermatol 1990;23:850 – 4. Nelson JS, Stone MS. Update on selected viral exanthems. Curr Opin Pediatr 2000;12:359 – 64. Ghigliotti G, Mazzarello G, Nigro A, et al. Papularpurpuric gloves and socks syndrome in HIV-positive patients. J Am Acad Dermatol 2000;43(5 Pt 2): 916 – 7. Ongradi J, Becker K, Horvath A, et al. Simultaneous infection by human herpesvirus 7 and human parvovirus B19 in papular-purpuric gloves-and-socks syndrome. Arch Dermatol 2000;136:672. Trattner A, David M. Purpuric ‘‘gloves and socks’’ syndrome: histologic, immunofluorescence and poly-
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
merase chain reaction study. J Am Acad Dermatol 1994;30:267 – 8. Aractingi S, Bakhos D, Flageul B, et al. Immunohistochemical and virological study of skin in the papularpurpuric gloves and socks syndrome. Br J Dermatol 1996;135:599 – 602. Nocton JJ, Miller LC, Tucker LB, et al. Human parvovirus B19-associated arthritis in children. J Pediatr 1993;122:186 – 90. Moore TL, Bandlamudi R, Alam SM, et al. Parvovirus infection mimicking systemic lupus erythematosus in a pediatric population. Semin Arthritis Rheum 1999;28: 314 – 8. Sloots T, Devine PL. Evaluation of four commercial enzyme immunoassays for detection of immunoglobulin M antibodies to human parvovirus B19. Eur J Clin Microbiol Infect Dis 1996;15:758 – 61. Public Health Laboratory Service Working Party on Fifth Disease. Prospective study of human parvovirus (B19) infection in pregnancy. BMJ 1990;200: 1166 – 70. Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Micriobiol Rev 2000;13:602 – 14. Kurtzman GJ, Ozawa K, Cohen B, et al. Chronic bone marrow failure due to persistent B19 parvovirus infection. N Engl J Med 1987;317:287 – 94. Mathias RS. Chronic anemia as a complication of parvovirus B19 infection in a pediatric kidney transplant patient. Pediatr Nephrol 1997;11:355 – 7. Nour B, Green M, Micahels M, et al. Parvovirus B19 infection in pediatric transplant patients. Transplantation 1993;56:835 – 8. Frickhofen N, Abkowitz JL, Safford M, et al. Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type I (HIV-1): a treatable cause of anemia in AIDS. Ann Intern Med 1990; 113:926 – 33. Morley AL, Nicolini U, Welch CR, et al. Parvovirus B19 infection and transient fetal hydrops. Lancet 1991; 337:496 – 9. Radentz WH. Oportunistic fungal infections in immunocomprised hosts. J Am Acad Dermatol 1989;20: 989 – 1003. Khardori N, Hayat S, Rolston K, et al. Cutaneous rhizopus and aspergillus infections in five patients with cancer. Arch Dermatol 1989;125:952 – 6. Allo MD, Miller J, Townsend T, et al. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med 1987;317:1105 – 8. Estes SA, Hendricks AA, Merz WG, et al. Primary cutaneous aspergillosis. J Am Acad Dermatol 1980;3: 397 – 400. Grossman ME, Fithian EC, Behrens C, et al. Primary cutaneous aspergillosis in six leukemic children. J Am Acad Dermatol 1985;12:313 – 8. McCarty JM, Flam MS, Pullen G, et al. Outbreak of primary cutaneous aspergillosis related to intravenous arm boards. J Pediatr 1986;108:721 – 4.
275
[41] Murakawa GJ, Harvell JD, Lubitz P, et al. Cutaneous aspergillosis and acquired immunodeficiency syndrome. Arch Dermatol 2000;136:365 – 9. [42] Papouli M, Roilides E, Bibashi E, et al. Primary cutaneous aspergillosis in neonates: a case report and review. Clin Infect Dis 1996;22:1102 – 4. [43] Repiso R, Garcia-Patos V, Martin N, et al. Disseminated fusariosis. Pediatr Dermatol 1996;13:118 – 21. [44] Ryan ME, Ochs D, Ochs J. Primary cutaneous mucormycosis: superficial and gangrenous infections. Pediatr Infect Dis 1982;1:110 – 4. [45] Walmsley S, Devi S, King S, et al. Invasive Aspergillus infections in a pediatric hospital: a ten year review. Pediatr Infect Dis J 1993;12:673 – 82. [46] Dennis JE, Rhodes KH, Cooney DR, et al. Nosocomial Rhizopus infection (zygomycosis) in children. J Pediatr 1980;96:824 – 8. [47] Katta R, Bogle MA, Levy M. Cutaneous mold infections in a pediatric population [poster]. American Academy of Dermatology annual meeting, March 2001 Washington DC. [48] Wirth F, Perry R, Eskenazi A, et al. Cutaneous mucormycosis with subsequent visceral dissemination in a child with neutropenia: a case report and review of the pediatric literature. J Am Acad Dermatol 1996; 35:336 – 41. [49] Alvarez-Franco M, Reyes-Mugica M, Paller AS. Cutaneous fusarium infection in an adolescent with acute leukemia. Pediatr Dermatol 1992;9:62 – 5. [50] Rowen JL, Atkins JT, Levy ML, et al. Invasive fungal dermatitis in the 1000-gram neonate. Pediatr 1995;95: 682 – 7. [51] Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996; 14:137 – 40. [52] Patterson TS, Barton LL, Shehab ZM, et al. Amphotericin B lipid complex treatment of a leukemic child with disseminated Fusarium solani infection. Clin Pediatr 1996;35:257 – 60. [53] Wise R, Andrews JM, Boswell FJ, et al. The in-vitro activity of linezolid (U-100766) and tentative breakpoints. J Antimicrob Chemother 1999;42:721 – 8. [54] Lowy FD. Staphylococcal aureus infections. N Engl J Med 1998;339:520 – 32. [55] Boyce JM. Are the epidemiology and microbiology of methicillin-resistant Staphylococcus aureus changing? JAMA 1998;279:623 – 4. [56] Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593 – 8. [57] Marcinak JF, Mangat PD, Frank AL, et al. Community acquired and clindamycin sensitive methicillin resistant Staphylococcus aureus in children [abstract 370]. In: Program and abstracts of the 35th annual meeting of the Infectious Diseases Society of America, San Francisco, 1997. [58] Sattler CA, Mason EO, Kaplan SL. Communityacquired, methicillin-resistant vs. methicillin-susceptible Staphylococcus aureus infection in children: pro-
276
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68] [69]
[70]
[71]
D. Metry, R. Katta / Dermatol Clin 21 (2003) 269–276 spective comparison of risk factors, demographic, and clinical characteristics. (Publication pending). Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997 – 1999. MMWR 1999;48:707 – 10. Dunkle LM, Naqvi SH, McCallum R, et al. Eradication of epidemic methicillin – gentamycin-resistant Staphylococcus aureus in an intensive care nursery. Am J Med 1981;70:455 – 8. Hiramatsu K. Molecular evolution of methicillin-resistant Staphylococcus aureus. Microbiol Immunol 1995; 39:531 – 43. Ribner BS, Landry MN, Kidd K, et al. Outbreak of multiply resistant Staphylococcus aureus in a pediatric intensive care unit after consolidation with a surgical care unit. Am J Infect Control 1989;17:244 – 9. Adcock PN, Pastor P, Medley F, et al. Methicillin-resistant Staphylococcus aureus in two child care centers. J Infect Dis 1980;178:577 – 80. Shahin R, Johnson IL, Jamieson F, et al. Methicillinresistant Staphylococcus aureus carriage in a child care center following a case of disease. Arch Pediatr Adolesc Med 1999;153:864 – 8. Bukharie HA, Abdelhadi MS, Saeed IA, et al. Emergence of methicillin-resistant Staphylococcus aureus as a community pathogen. Diagn Microbiol Infect Dis 2001;40:1 – 4. Kline MW, Mason Jr EO, Kaplan SL. Outcome of heteroresistant Staphylococcus aureus infections in children. J Infect Dis 1987;156:205 – 8. Fergie JE, Purcell K. Community-acquired methicillinresistant Staphylococcus aureus in South Texas children. Pediatr Infect Dis J 2001;20:860 – 3. Chambers HF. The changing epidemiology of Staphylococcal aureus? Emerg Infect Dis 2001;7:178 – 83. Moellering RC. A novel antimicrobial agent joins the battle against resistant bacteria. Ann Intern Med 1999; 130:155 – 7. Kearns GL, Abdel-Rahman SM, Blumer JL, et al. Single dose pharmacokinetics of linezolid in infants and children. Pediatr Infect Dis J 2000;19:1178 – 84. Swaney SM, Aoki H, Ganoza MC, et al. The oxazolidinone linezolid inhibits initiation of protein synthesis
[72]
[73]
[74]
[75] [76]
[77]
[78]
[79]
[80]
[81]
in bacteria. Antimicrob Agents Chemother 1998;42: 3251 – 5. Lin AH, Murray RW, Vidmar TJ, et al. The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother 1997;41: 2127 – 31. Feenstra KL, Slatter JG, Stalker DJ, et al. Metabolism and excretion of the oxazolidinone antibiotic linezolid (PNU-100766) following oral administration of [C]PNU-100766 to healthy human volunteers [Abstract A-53]. In: 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, 1998. p. 17. Wienkers LC, Wynalda MA, Feenstra KL, et al. In vitro metabolism of linezolid (PNU-100766): lack of induction or inhibition of cytochrome P450 enzymes and studies on the mechanism of formation of the major human metabolite, PNU-142586 [session 3-A, poster 11]. In: 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, 1999. Nelson JD, McCracken Jr GH. Fluoroquinolones in pediatrics. Pediatr Infect Dis J (newsletter) January 1998. Burkardt JE, Hill MA, Carlton WW, et al. Histologic and histochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone. Vet Pathol 1990;27:162 – 70. Linseman DA, Hampton LA, Branstetter DG. Quinolone-induced arthropathy in the neonatal mouse. Morphological analysis of articular lesions produced by pipemidic acid and ciprofloxacin. Fundam Appl Toxicol 1995;28:59 – 64. Dixey J, Redington AN, Butler RC, et al. The arthropathy of cystic fibrosis. Ann Rheum Dis 1988; 47:218 – 23. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. Pediatr Infect Dis J 1997;16:118 – 22. Mastuno K, Yamatoya O, Miyata K, et al. Surveillance of adverse reactions due to ciprofloxacin in Japan. Drugs 1995;49:495 – 6. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45:59 – 64.
Dermatol Clin 21 (2003) 277 – 282
Ivermectin George W. Elgart, MD*, Terri L. Meinking, BA Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1444 North West 9th Avenue, Miami, FL 33136, USA
Ivermectin is an important antiparasitic medication that was first identified in the 1970s. The structure of ivermectin is that of a macrocyclic lactone, and the chemical is naturally produced in soil by Streptomyces avermitilis. This compound was first identified from soil samples obtained from a Japanese golf course. While initially considered solely for veterinary applications, the responsible research team quickly appreciated the potential for human use. These efforts culminated in the approval of the drug by French regulatory authorities in 1987. Since that time, ivermectin has been appreciated as a remarkably safe and dramatically effective drug in the treatment of onchocerciasis. Multiple case reports, small series, and a few formal studies have also demonstrated its value in the therapy of many systemic and cutaneous parasitic diseases including filariasis, cutaneous larva migrans, scabies, and pediculosis. Ivermectin was approved by the United States Federal Food and Drug Administration (FDA) in 1996 for strongyloidiasis and onchocerciasis; however, unapproved (off-label) use is widespread. It should be noted that Ivermectin is currently available only as a 3 mg. tablet and care exercised in comparing published regimens which may be based on a previously available 6 mg. formulation. Controversies regarding dosing regimens and potential adverse events in off-label situations will be reviewed in this article.
History of ivermectin In 1975, workers at Merck laboratories were screening compounds for therapeutic effects with * Corresponding author. E-mail address:
[email protected] (G.W. Elgart).
the strategy of developing them for veterinary use. They received 54 samples from the Kitsato Institute in Japan and identified a factor with significant antiparasitic effects. While studying the response of equine Onchocerca cervicalis to this compound, Dr. William Campbell, the leader of the Merck team and the scientist responsible for the development of thiabendazole, was the first to recognize that ivermectin possessed properties suggesting utility against an analogous human pathogen, Onchocerca volvulus. Ivermectin was subsequently developed and tested for its antiparasitic effects in humans and in animals. Dr. Campbell spearheaded this effort. Dr. Mohamed Aziz led the initial clinical trials in Dakar, Senegal in 1981 [1 – 3]. Ivermectin proved to be remarkably effective in humans, leading to the hope that a cure for river blindness (as onchocerciasis is colloquially known) was possible. The major hurdles to be overcome revolved around the problem of how affected populations could receive therapy. Three issues were considered: 1. What price, if any, should be charged for ivermectin? 2. What would be the company’s liability if some previously undetected side effects occurred with widespread use? 3. Would donation of this new drug prompt a decrease in research on antiparasitic medications if companies were expected to donate the products of such research efforts? The company exhausted all possible third party payers as intermediaries for donation of ivermectin, including the World Health Organization (WHO), the U.S. Agency for International Development (USAID), and others. In the end, no organization
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00095-5
278
G.W. Elgart, T.L. Meinking / Dermatol Clin 21 (2003) 277–282
offered sufficient assistance. At that point, Dr. Roy Vagelos, then Merck’s chairman, stepped in and decreed that Merck would donate ivermectin— free of charge—to those who needed it for as long as it was needed. At that time, Merck’s action was unprecedented as an example of pharmaceutical industry philanthropy. The lengthy story of developing distribution systems for patients in need is well documented on the company’s website (www.merck. com/about/cr/mectizan/home.html). This remarkable tale has served as a model for the philanthropic efforts of other companies in the intervening years.
Mechanism of action of ivermectin Ivermectin is an agonist of ligand-gated chloride ion-driven peripheral neruochannels. There are conflicting data in the literature; some authors indicate that ivermectin is an agonist for glutamate-gated chloride channels [4,5], whereas others suggest an interaction with glycine-gated structures [6]. In either case, ivermectin simulates the ligand by ‘‘opening the gate’’ and allowing an efflux of chloride ions, which generates sufficient current to allow the release of the associated neurotransmitter, g-aminobutyric acid (GABA). In high doses, continual neuronal discharge would be expected to paralyze the organism completely; however, this is not believed to be the actual mode of action in most ivermectin-susceptible parasites. At achievable levels, many authorities believe that ivermectin primarily interferes with the function of the gastrointestinal tract of target parasites. Thus, these creatures essentially starve to death under the influence of the drug [6 – 8]. The selective therapeutic action of ivermectin might well be based upon the fact that it stimulates excessive neurotransmitter release in the peripheral nervous system of parasites. By contrast, in mammals, analogous GABA-secreting neurons are found only in the central nervous system, a region not readily penetrated by this agent [4,9].
Risks and side effects The Mazotti reaction is a unique reaction seen in affected onchocerciasis patients undergoing treatment. In this setting, the death of the microfilariae in onchocerciasis following treatment with diethylcarbamazine (DEC) might result in a strong allergic reaction. The major features are the development of a massive morbilliform skin eruption and the risk of anaphylactic shock. Thus, DEC must usually be administered in
conjunction with corticosteroids to reduce the ensuing inflammatory response. This complication was a concern in initial studies. Despite its marked efficacy against microfilariae, ivermectin does not appear to induce this allergic reaction in onchocerciasis, and no such reaction would be expected in therapy of superficial parasites such as scabies or head lice. A single oral dose of at least 200 micrograms per kilogram is apparently effective to clear the microfilaremia in onchocerciasis. Biannual dosing is required because the female adult Onchocerca parasite continues to produce microfilaria for 12 to 15 years. A major concern for therapy with ivermectin is the possibility of untoward effects in human use because of the direct toxic effects of the agent. This concern was based in some measure on concerns from animal experience, in which certain susceptible breeds, notably collie dogs and some inbred strains of mice, were found to be exquisitely sensitive to ivermectin. Such animals were subject to tremors, ataxia, and sweating, which in some cases progressed to lethargy, coma, and death [10]. These concerns seemed to be justified. Barkwell and Shields reported excessive deaths following use of ivermectin in an extended care facility that had experienced an outbreak of scabies [11]. This outbreak had been uncontrolled despite multiple topical therapies including lindane, permethrin, and benzyl benzoate, but it was subsequently brought under control with a single dose of 150 to 200 micrograms per kilogram of ivermectin to the affected patients. The authors then noted an excess of deaths over the following 6 months in the treated group, and they later constructed a case – control study that appeared to confirm this anomalous death rate. This report was subsequently criticized because of several structural details. By design, the study was retrospective and the patients were treated sequentially, not contemporaneously. In addition, the authors controlled for age and sex but they made no attempt to control for associated diseases including the presence of dementia, a factor known to correlate with early death in nursing home inhabitants. In addition, the authors followed deaths for 6 months after the single ivermectin treatment, clearly an unusual step considering the more immediate toxic effects identified in susceptible animals. Finally, and perhaps most importantly, the authors could not control for the extensive and repeated topical medications used before ivermectin was employed, regimens known to have toxic sequelae in some humans and animals [12]. Other authors have assessed their own data in search of similar increases in death rates without corroborating Barkwell and Shields findings [13 – 16].
G.W. Elgart, T.L. Meinking / Dermatol Clin 21 (2003) 277–282
Of some interest have been recent data more specifically evaluating the risk factors for ivermectin-induced neurological symptoms in animals. It appears that ivermectin is an excellent substrate for the multidrug resistance (MDR) gene product that is responsible for the lack of efficacy of some chemotherapeutic agents in selected cancers. The MDR gene product functions as a cellular pump, moving some drugs (including ivermectin) outside the cell. The MDR gene product is entirely absent or dysfunctional in the susceptible animals [17,18]. Apparently, MDR, in association with the blood – brain barrier, functions as a potent protector of the human central nervous system. Thus, nearly all humans appear to be largely protected from the potential toxic effects of the drug. Many authors, and the package insert, advise caution in administering the drug to young children ( < 15 kg or < 2 years of age). This is (in part) because of a diminished blood – brain barrier in young individuals. In addition, it is conceivable that there are individuals with specific sensitivity to ivermectin either because of defective MDR or other mechanisms. Evidence from the extensive use of ivermectin in worldwide onchocerciasis programs suggests that these individuals, if they exist, must be quite rare [19]. Occasional patients might develop transient tachycardia, flushing or nausea following ingestion of ivermectin; however, these events are rarely of significant magnitude.
Approved indications Ivermectin is approved in the United States for the treatment of strongyloides and onchocerciasis. Both indications are specifically stated in the package insert [3]. The concern for immunosuppressed individuals—including those with AIDS who suffer from strongyloides—was partially responsible for the approval of ivermectin by the FDA in 1996. Both of these parasitic conditions are highly susceptible to ivermectin [20 – 23]. Strongyloides appears to be remarkably susceptible to low doses of ivermectin. In a recent Japanese comparison trial, ivermectin was 97% effective in a single 6 mg dose, whereas albendazole at a 400 mg dosage for 3 days was only 77% effective [24]. An analogous comparative study performed in Zanzibar demonstrated strongyloides cure rates of 83% for ivermectin and 45% for albendazole [17]. An earlier study suggested similar efficacy and noted a lower incidence of treatment-associated side effects in a comparison of the two drugs. Ninety-five percent of
279
thiabendazole-treated patients noted short-term side effects after therapy, whereas only 18% of the ivermectin-treated group noted similar problems [25]. Ivermectin is efficacious for strongyloides in the setting of HIV. This is particularly important because systemic strongyloides infection is a serious and potentially fatal complication of advanced HIV disease [26].
Off-label uses: ectoparasitic infestation By far the most important off-label use for ivermectin in the United States is for the treatment of ectoparasite infestations, notably scabies and head lice. While topical formulations of the drug appear to hold great potential for the future [27,28], it is clear that systemically administered ivermectin is highly effective for pediculosis and scabies. A single oral dose is associated with an approximate 85% cure rate in these conditions. Most authorities recommend a second dose 5 to 14 days after the first dose because the medication is not expected to be ovicidal. Scabies Several studies support the use of ivermectin in the treatment of scabies. In the largest study to date, a single 150 micrograms per kilogram dose was given to 1153 inmates suffering from scabies in a Tanzanian prison. Cure rates of 30%, 88%, and 95% were noted at 1, 4, and 8 weeks. This regimen eradicated scabies from the prison [29]. Seven of 16 patients with crusted scabies required additional topical therapy. Numerous smaller studies demonstrate similar findings; however, it is notable that an approximate 85% success rate follows a single 200 micrograms per kilogram oral dose [30] and that single dose ivermectin appears to be of equal or better efficacy compared with topical lindane [31]. Two doses of ivermectin, each at 200 micrograms per kilogram and administered 1 to 2 weeks apart, appear to be equivalent to topical permethrin in efficacy [32]. Of substantial importance is the effectiveness of ivermectin therapy noted in treating scabies among patients with concomitant HIV infection. While some authorities favor the use of adjunctive topical therapy (particularly in cases of crusted scabies), in most instances immunosuppressed individuals appear to respond well to modest doses of at least 200 micrograms per kilogram. As is the case in hosts with normal immune status, the drug should be given in a repeat dose in 7 to 14 days (most often in 7 – 10 days) [33 – 35].
280
G.W. Elgart, T.L. Meinking / Dermatol Clin 21 (2003) 277–282
Despite the foregoing, it has been rightly emphasized by several authors that the optimum dose/ dosing regimen for scabies remains somewhat uncertain [36,37]. The dose of 200 micrograms per kilogram seems to be the most widely employed, but whether one, two, or three such doses should be routinely given is open to speculation. When multiple doses have been administered, the time between doses has varied from 1 to 4 weeks, the optimum interval being subject to conjecture. Some authors have also suggested a therapeutic regimen utilizing a single high dose of 400 micrograms per kilogram [36]. Thus, a multi-arm comparative study needs to be performed to clarify these issues. While a variety of therapies are available for scabies, it appears that ivermectin will play an important role in selected cases. When used properly, it can avoid some concerns regarding the apparent development of lindane- or permethrin-resistant strains [38,39]. Ivermectin has the additional potential advantage of being a systemic medication. Therefore, concern about a patient’s ability to properly apply the medication is avoided. It is clearly easier to be certain that a patient has taken an appropriate oral dose of ivermectin than to be similarly certain that an appropriate topical medication has been applied effectively. As noted previously, however, topical ivermectin (1% in propylene glycol) has been used effectively in single- and double-dose regimens for scabies infestation in adults and children [27,28].
Head lice Head lice have proven to be a formidable adversary in dermatologic practice. Many patients respond well to the topical formulations that have been the mainstay of therapy for decades; however, evidence is accumulating in vitro and in vivo that Pediculus capitis has developed mechanisms for significant resistance to many topical pedicuilcides [40,41]. These data suggest that new strategies will be needed to maintain control of this difficult problem, and the efficacy of ivermectin in the treatment of head lice (including some ‘‘resistant’’ cases) appears to be promising. The therapeutic dose is about twice the usual dose for scabies, or 400 micrograms per kilogram. Doses of 400 micrograms per kilogram, which are commonly employed for Wucheria bancrofti and loiasis, are well tolerated. Therapy should be repeated in 7 to 10 days because the treatment is not ovicidal. Studies of single-dose therapy at lower dosages have not been as promising [42].
Filariasis From a global perspective, filariasis is a major cause of morbidity. It is estimated that more than 120 million individuals are affected with more than 1.2 billion at risk in the 80 poorest countries of the world [15]. Ivermectin has been shown to be effective in several types of filariasis, including three major studies in Bancroftian filariasis and one involving loiasis. Each of these studies demonstrated excellent efficacy [43 – 46]. The standard dose of ivermectin for filariasis is 400 micrograms per kilogram, repeated twice yearly. Such treatment seems particularly well suited to endemic areas where there is a high prevalence of concomitant infection with onchocerciasis and loiasis. Larva migrans Ivermectin is also a potentially helpful agent in the management of cutaneous larva migrans caused by dog and cat hookworms. A prospective trial in travelers demonstrated a cure rate of 77% in 64 patients diagnosed with creeping eruption. All patients treated to date have been given a single dose of 200 micrograms per kilogram [47 – 50]. Rosacea A single case report of ivermectin in refractory rosacea suggested remarkable benefit in a patient who had failed extensive topical and systemic therapy. The patient had biopsy-documented demodicidosis. While the case is flawed because concomitant oral metronidazole was employed, the authors would consider ivermectin in a refractory case in which there is some indication that demodex mites might have been involved [51]. Myiasis There is a single report of ivermectin use in a case of cutaneous myiasis. Most cases of myiasis are easily treated if the larva is alive because the organism can be induced to extend out of the ‘‘warble’’ lesion by occlusion with a variety of substances (eg, petrolatum, lard, and bacon). When the larva moves outward in attempt to breathe, it can be extracted with gentle pressure. These authors used ivermectin in a single case. The larva expired, and the subsequent immune reaction was fairly marked [52]. Nevertheless, ivermectin could be considered in a sufficiently extensive case.
G.W. Elgart, T.L. Meinking / Dermatol Clin 21 (2003) 277–282
Summary Ivermectin is a potent antiparasitic drug and the first commercially available member of a new class of drugs (macrocyclic lactones) that has been approved for human use. Ivermectin has already proven to be highly effective in the elimination of river blindness as a public health burden. Side effects have been minor, and patient acceptance is good. Promising results in off-label applications for ectoparasitic infestations are increasingly important as resistance to topical therapy becomes more prevalent. Ivermectin represents an advance in the therapeutic armamentarium and should be considered in appropriate cases.
Acknowledgement The authors wish to thank Jeffrey L. Jacobs of Merck, who reviewed the portions of the manuscript related to the international ivermectin donation project.
References [1] Ottesen EA, Campbell WC. Ivermectin in human medicine. J Antimicrob Chemother 1994;34:195 – 203. [2] Overview of Philanthropy. The story of mectizan, Merck. Available: http://www.merck.com/overview/ philanthropy/mectizan/home.html. Accessed January 5, 2002. [3] Stromectol (ivermectin). Package insert, Merck & Co. West Point, PA. 1996. [4] Burkhart CN. Ivermectin: an assessment of its pharmacology, microbiology and safety. Vet Hum Toxicol 2000;42:30 – 5. [5] Kane NS, Hirschberg B, Qian S, et al. Drug-resistant Drosophilia indicate glutamate-gated chloride channels are targets for the antiparasitics nodulispordic acid and ivermectin. Proc Natl Acad Sci USA 2000; 97:13949 – 54. [6] Shan Q, Haddrill JL, Lynch JW. Ivermectin, an unconventional agonist of the glycine receptor chloride channel. J Biol Chem 2001;276:12556 – 64. [7] Ros-Moreno RM, Moreno-Guzman MJ, JimenezGonzalez A, et al. Interaction of ivermectin with gamma-aminobutyric acid receptors in Trichinella spiralis muscle larvae. Parasitol Res 1999;85: 320 – 3. [8] Shoop WL. Structure and activity of avermectins and milbemycins in animal health. Vet Parasitol 1995;59: 139 – 56. [9] Bredal WP. Deaths associated with ivermectin for scabies. Lancet 1997;350:216.
281
[10] Seward RL. Reactions in dogs given ivermectin. J Am Vet Med Assoc 1983;183(5):493. [11] Barkwell R, Shields S. Deaths associated with ivermectin treatment of scabies. Lancet 1997;349:1144 – 5. [12] Coyne P, Addiss D. Deaths associated with ivermectin for scabies. Lancet 1997;350:215 – 6. [13] Alexander NDE, Bockarie MJ, Kastens WA, et al. Absence of ivermectin-associated excess deaths. Trans R Soc Trop Med Hyg 1998;92:342. [14] Currie B, Huffam S, O’Brien D, et al. Ivermectin for scabies. Lancet 1997;350(9090):1551. [15] Dean M. Lymphatic filariasis: the quest to eliminate a 4000-year old disease. Hollis (NH): Puritan Press, Hollis Publishing Company; 2001. [16] Reintjes R, Hoek C. Deaths associated with ivermectin for scabies. Lancet 1997;350:215. [17] Marti H, Haji HJ, Savioli L, et al. A comparative trial of a single-dose ivermectin versus three days of albendazole for the treatment of strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg 1996;55:477 – 81. [18] Schinkel AH, Wagenaar E, Mol CA, et al. P-glycoprotein in the blood – brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996;97:2517 – 24. [19] Smith AJ, van Helvoort A, van Meer G, et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 2000;275:23530 – 9. [20] Brieger WR, Awedoba AK, Eneanya CI, et al. The effects of ivermectin on onchocercal skin disease and severe itching: results of a multicentre trial. Trop Med Int Health 1998;3:951 – 61. [21] Brown KR, Neu DC. Ivermectin—clinical trials and treatment schedules in onchocerciasis. Acta Leiden 1990;59:169 – 75. [22] Newell ED. Effect of mass treatments with ivermectin, with only partial compliance, on the prevalence and intensity of O. volvulus infection in adults and in untreated 4 and 5 year old children in Burundi. Trop Med Int Health 1997;2:912 – 6. [23] Ngoumou P, Essomba RO, Godin C. Ivermectin-based onchocerciasis control in Cameroon. World Health Forum 1996;17:25 – 8. [24] Toma H, Sato Y, Shiroma Y, et al. Comparative studies on the efficacy of three antihelminthics on treatment of human strongyloidiasis in Okinawa, Japan. Southeast Asian J Trop Med Public Health 2000;31:147 – 51. [25] Gann PH, Neva FA, Gam AA. A randomized trial of single- and two-dose ivermectin versus thiabendazole for treatment of strongyloidiasis. J Infect Dis 1994; 169:1076 – 9. [26] Celedon JC, Mathur-Wagh U, Fox J, et al. Systemic strongyloidiasis in patients infected with the human immunodeficiency virus. A report of 3 cases and review of the literature. Medicine (Baltimore) 1994;73: 256 – 63. [27] Victoria J, Trujillo R. Topical ivermectin: a new suc-
282
[28]
[29]
[30]
[31]
[32]
[33]
[34] [35]
[36]
[37]
[38] [39]
[40]
G.W. Elgart, T.L. Meinking / Dermatol Clin 21 (2003) 277–282 cessful treatment for scabies. Pediatr Dermatol 2001; 18:63 – 5. Youssef MY, Sadaka HA, Eissa MM, et al. Topical application of ivermectin for human ectoparasites. Am J Trop Med Hyg. 1995;53:652 – 3. Leppard B, Naburi AE. The use of ivermectin in controlling an outbreak of scabies in a prison. Br J Dermatol 2000;143:520 – 3. Conti Diaz IA, Amaro J. Treatment of human scabies with oral ivermectin. Rev Inst Med Trop Sao Paulo 1999;41:259 – 61. Madan V, Jaskiran K, Gupta U, et al. Oral ivermectin in scabies patients: a comparison with 1% topical lindane lotion. J Dermatol 2001;28:481 – 4. Usha V, Gopalakrishnan-Nair TV. A comparative study of oral ivermectin and topical permethrin cream in the treatment of scabies. J Am Acad Dermatol 2000;42: 236 – 40. Alberici F, Pagani L, Ratti G, et al. Ivermectin alone or in combination with benzyl benzoate in the treatment of human immunodeficiency virus-associated scabies. Br J Dermatol 2000;142:969 – 72. Huffam SA, Currie BJ. Ivermectin for Sarcoptes scabiei hyperinfestation. Int J Infect Dis 1998;2:152 – 4. Meinking TL, Taplin D, Hermida JL, et al. The treatment of scabies with ivermectin. N Engl J Med 1995; 333:26 – 30. Burkhart CG, Burkhart CN. Optimal treatment for scabies remains undetermined. J Am Acad Dermatol 2001;45:637 – 8. Haas N, Henz BM, Ohlendorf D. Is a single oral dose of ivermectin sufficient in crusted scabies? Int J Dermatol 2001;40:599 – 600. Elgart ML. A risk – benefit assessment of agents used in the treatment of scabies. Drug Safety 1996;14:386 – 93. Walton SF, Myerscough MR, Currie BJ. Studies in vitro on the relative efficacy of current acaricides for Sarcoptes scabiei var. hominis. Trans R Soc Trop Med Hyg 2000;94:92 – 6. Downs AM, Stafford KA, Hunt LP, et al. Widespread insecticide resistance in head lice to the over-the-counter pediculocides in England, and the emergence of carbaryl resistance. Br J Dermatol 2002;146:88 – 93.
[41] Meinking TL, Serrano L, Hard B, et al. Comparative in vitro pediculocidal efficacy of treatments in a resistant head lice population in the United States. Arch Dermatol 2002;138:220 – 4. [42] Glaziou P, Nyguyen LN, Moulia-Pelat JP, et al. Efficacy of ivermectin for the treatment of head lice (Pediculosis capitis). Trop Med Parasitol 1994;45:253 – 4. [43] Das PK, Ramaiah KD, Vanamail P, et al. Placebo-controlled community trial of four cycles of single-dose diethylcarbamazine or ivermectin against Wuchereria bancrofti infection and transmission in India. Trans R Soc Trop Med Hyg 2001;95:336 – 41. [44] El Haouri M, Erragragui Y, Sbai M, et al. [Cutaneous filariasis Loa Loa: 26 Moroccan cases of importation]. Ann Dermatol Venereol 2001;128:899 – 902. [45] Ismail MM, Jayakody RL, Weil GJ, et al. Efficacy of single dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of Bancroftian filariasis. Trans R Soc Trop Med Hyg 1998;1:94 – 7. [46] Nguyen NL, Moulia-Pelat JP, Cartel JL. Control of Bacroftian filariasis in an endemic area of Polynesia by ivermectin 400micrograms/kg. Trans R Soc Trop Med Hyg 1996;90:689 – 91. [47] Bouchaud O, Houze S, Schiemann R, et al. Cutaneous larva migrans in travelers: a prospective study, with assessment of therapy with ivermectin. Clin Infect Dis 2000;31:493 – 8. [48] Caumes E, Datry A, Paris L, et al. Efficacy of ivermectin in the therapy of cutaneous larva migrans. Arch Dermatol 1992;128:994 – 5. [49] Caumes E, Carriere J, Datry A, et al. A randomized trial of ivermectin versus albendazole for the treatment of cutaneous larva migrans. Am J Trop Med Hyg 1993; 49:641 – 4. [50] Caumes E. Treatment of cutaneous larva migrans. Clin Infect Dis 2000;30:811 – 4. [51] Forstinger C, Kittler H, Binder M. Treatment of rosacealike demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol 1999;41(5 Pt 1): 775 – 7. [52] Jelenek T, Nothdurft HD, Rieder N, et al. Cutaneous myiasis: review of 13 cases in travelers returning from tropical countries. Int J Dermatol 1995;34:624 – 6.
Dermatol Clin 21 (2003) 283 – 290
Albendazole: a new drug for human parasitoses Giancarlo Albanese, MDa,*, Caterina Venturi, MDb b
a Dermatology and Tropical Dermatology, CAM Medical Centre, Viale Brianza, 21 20052 Monza (MI), Italy Dermatology Department, Clinica Dermatologica Ospedale Maggiore di Parma, Via Gramsci 14 43100 Parma, University of Parma, Italy
It is extremely hard to eradicate helminthiases because of the close association between these diseases and poverty [1]. The clinical development of these common and ubiquitous infections is such that they are generally neglected until they become manifest [1]. They are more frequent in hot climates and in places with poor sanitary conditions, the presence of large water tanks and carriers of parasites, and contaminated food and water [1]. This does not mean, however, that good economic conditions constitute a complete safeguard against such infections [1]. Moreover, individuals from more affluent countries might well acquire such infections during travel to more endemic regions. Until such time as effective vaccines can be discovered, antihelminthic chemotherapy is the only effective, practical, and inexpensive way of keeping such infections under control. Periodic treatment with the appropriate drugs limits the transmission by reducing the parasitic load. Despite the fact that some drugs have now been in widespread use for many years, resistance to them is not currently a problem; resistance has only been recorded in some infested animals [1]. Brown and colleagues’ 1961 discovery that thiobendazoles were highly effective against gastrointestinal nematodes led to the development of benzimidazoles as wide-spectrum antihelminthoid agents against major animal and human parasites [1]. The most useful derivates for treatment have modifications in position two or five of the benzim-
* Corresponding author. E-mail address:
[email protected] (G. Albanese).
idazole ring [1]. Thiabendazole, mebendazole, and albendazole belong to this class of drugs. Albendazole is the authors’ first choice as a potential drug in the treatment of cutaneous larva migrans because it is well tolerated and fast acting. Albendazole is the most recently developed of the benzimidazole derivates, and it is used worldwide against numerous helminths [1]. The structure of albendazole is depicted in Fig. 1.
Clinical pharmacology and drug safety Albendazole causes a series of biochemical alterations in susceptible nematodes, although how it effectively does so is not completely understood. The drug might act by selectively and irreversibly reducing or blocking the glucose uptake in parasites sensitive to its action, affecting various stages of its development [1 – 3]. The net result of this alteration is that glycogen reserves are depleted, thus reducing or interrupting the production of adenosine triphosphate (ATP) [1,3]. Energy levels are reduced to the point of becoming inadequate for the parasite to survive. Following a state of paralysis caused by the exhaustion of its exogenous energy sources, the parasite dies [1,3]. The drug does not interfere, however, with the metabolism of glucose in human hosts [1,3]. Derivates of benzimidazole can also inhibit fumarate – reductase or maleate – dehydrogenase to decouple oxidative phosphorilation or induce degeneration of cytoplasmatic microtubules. In the latter case, the parasite dies from the lysis induced by the release of proteolytic and hydrolytic enzymes into the cytoplasm [3]. Numerous trials have shown that this drug’s main
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00085-2
284
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
Fig. 1. Chemical formula of albendazole.
effect is to inhibit the polymerization of microtubules by way of the compound’s link with b-tubulin [1]. The toxicity of albendazole is selective because the parasite’s specific and highly selective link with b-tubulin takes place at much lower concentrations than those necessary for the link with the mammalian protein [1]. The rare strains of nematode that are resistant to albendazole usually have a reduced highaffinity link to b-tubulin and alterations in the expression of the gene of the isotype of b-tubulin itself [1]. Two mechanisms are usually involved in building up resistance to albendazole: the progressive loss of the b-tubulin ‘‘susceptible’’ isotype and the appearance of a ‘‘resistant’’ form with a conserved point mutation that encodes a tyrosine instead of a phenylalanine at position 200. It is unlikely that newer but structurally similar compounds can overcome this problem because the tyrosine in position 200 is also present in human protein [1]. The appearance of resistant species is still not a problem in the treatment of human helminthiases, although it has been recorded in the treatment of some infested animals [1]. Like other benzimidazole compounds, albendazole is not very soluble in water; small variations in solubility have a great effect on its absorption [1]. Following oral administration, it is absorbed in a variety of ways, although the consumption of fatty foods at the same time (and perhaps biliary salts) might aid absorption [1]. In the intestine, absorption does not generally exceed 5%. Because of the presence of the carbamate molecule in the structure, it is quite resistant to enzymatic degradation and inactivation [4,5]. After an oral dose of 400 mg, the presence of the parent drug in plasma is not detected because it is rapidly metabolized in the liver to sulphoxide albendazole, mainly by oxidation of the lateral chain. The formation of this compound is catalyzed primarily by microsomal flavinic monoxygenases and, to a lesser degree, by some forms of cytochrome P450 in the liver and (probably) in the intestine [1]. Both the (+) and ( ) enantiomorphs of that metabolite are formed, although in humans the (+) form, which is produced mainly by the activity of hepatic
flavinic monoxygenases, reaches decidedly greater peaks of concentration and is eliminated much more slowly compared with the ( ) form, which is catalyzed mainly by cytochrome P450 [1]. This metabolite reaches concentrations of about 300 ng/mL, though with considerable inter-individual variability. About 70% of the metabolite is linked to plasma proteins and has a half-life of between 4 and 15 hours, with a peak 2 to 3 hours after being administered [1,5]. It is distributed in various tissues, even in hydatid cysts, where it reaches a concentration of one-fifth of that in plasma [1]. In part, it is further oxidized to a pharmacologically inactive sulphonic metabolite [1,6]. Various metabolites are mainly excreted through the urine within 24 hours from the time of administration [1,4]. Only a small amount is excreted through bile. Tissue accumulation/deposition does not occur. Albendazole demonstrates few side effects when administered for a short period of time, even in patients with a high parasitic load [1]. Only occasionally have transitory abdominal pains, diarrhea, nausea, dizziness, and headaches been observed. Even when used in the long term (in the treatment of diseases such as hydatid cysts and neurocysticercosis), it is well tolerated by most patients [1]. In long-term use the most common side effect is an increase in hepatic transaminase [1]. Overt jaundice and cholestasis are rare [1]. Enzymatic activity returns to normal values when treatment is discontinued [1]. From a practical standpoint, hepatic function should be monitored during prolonged treatment, and the drug is not recommended for patients who are already suffering from cirrhosis of the liver [1]. Other side effects associated with prolonged treatment include gastrointestinal pains, severe headaches, fever, generalized asthenia, alopecia, leucopenia, and thrombocytopenia [1 – 5,7 – 9]. In prolonged or high-dosage courses of treatment it is advisable to check the blood count periodically. Literature does not mention cases of interaction of albendazole with the mechanism or metabolism of other compounds, but the concomitant administration of steroids (and perhaps praziquantel) increases the
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
plasma levels of albendazole’s sulphoxide metabolites [1,10]. Albendazole has been shown to be teratogenic and embryotoxic in rats and rabbits. Thus, it would be inadvisable to administer the drug to women of fertile age or during pregnancy [1,3 – 5,7]. Recent studies have demonstrated, however, that in areas where parasitoses are endemic, the combined use of albendazole and iron and folate supplements reduces the risk of infections and the appearance of serious anemias throughout pregnancy [11]. Contraception should be advised for women of child-bearing potential during treatment and in the period immediately following suspension [12]. Albendazole appears to be neither mutagenic nor carcinogenic, and there are no reliable data regarding the presence of the drug in mother’s milk. It should not, however, be routinely recommended while breast feeding. The toxicity of albendazole in children under 2 years old has not yet been systematically assessed, although an experimental study with a single dose of 200 mg has given satisfactory results. Moreover, in countries in which intestinal parasitoses are rife, treatment associating antihelminth drugs with iron supplements can improve the health of numerous schoolchildren, whereas in adults it increases productivity and reduces the number of working days lost because of sickness [13 – 15]. No evidence suggests that albendazole should not be used in the geriatric population. Albendazole tablets can be chewed, swallowed whole, or mixed with food. It is not necessary to fast or to clean out the intestine; however, because food increases systemic absorption, it is advisable to take the drug after a meal when high intraluminal concentration is required to solve intestinal infections [1]. Albendazole’s trade name varies from country to country. Albendazole is known as Zentel (SmithKline Beacham Pharmaceuticals, Wynberg, Johannesburg) in Europe and as Albenza (GlaxoSmithKline, Environment Health and Safety, King of Prussia, PA) in the United States. It is supplied as 400 mg tablets or in a 20 mg/mL suspension for oral administration.
Therapeutic uses Albendazole has become a popular drug for treating cysticercosis and tapeworm; moreover, it has shown to be a promising candidate for global control of lymphatic filariasis and of related infections of the tissues, especially in association with ivermectin or diethylcarbamazine [1,6,12,16]. Alben-
285
dazole is also effective for ascaridiasis, intestinal capillariosis, enterobiasis, tricuriasis, strongyloidiasis, and infections from single or mixed hookworm diseases (Ancylostoma duodenale and Necator americanus), particularly in children [1,4]. Albendazole acts against some anaerobic protozoa such as Trichomonas vaginalis and Giardia lamblia [1]. Albendazole is a safe and effective treatment against infections from gastrointestinal nematodes, including mixed ones from Ascaris, Trichuria and Anchilostosoma [1]. The use of albendazole in Ascariases prevents the nematode from migrating into the biliary ducts, where it is more difficult to cure, whereas in children resident in endemic areas it increases the reaction of antibodies to the cholera vaccination [17,18,35]. It is effective against the larvae and the adult stages of the nematodes responsible for these infections. Albendazole is acknowledged as a widespectrum antihelminth that acts as a vermicide, ovicide, and larvicide [1]. For most of these infections, albendazole is usually administered in a single 400 mg oral dose in adults and children over the age of 2 years, with a percentage of cure of over 97% [1]. In the most serious cases, treatment can be prolonged for 2 to 3 days [1]. At a dose of 400 mg/ day for 3 days albendazole can be used in the treatment of strongyloidosis with variable percentages of recovery [1]. The same dose can be repeated 3 days later [1]. Albendazole is the drug of choice in cases of inoperable hydatid cysts and in prophylaxis before surgical or suction removal and percutaneous drainage of the cysts [1,6,12,16,19]. The course of treatment includes the administration of 400 mg twice a day for 28 days. The administration of 10 to 12 mg/kg/day in doses split over 28 consecutive days, to be repeated 3 to 4 times at 2-week intervals, has not led to any important side effects [1,6,12,16]. More prolonged courses of treatment are required for less accessible cysts such as those situated in the bones or in the brain [1,6,12,16]. Patients usually respond with a reduction of the cysts, and if surgery follows, the risk of relapse is low [1,6,12,16]. One study published reports the formation of a halo around the cysts and the disappearance of the daughter cysts after treatment with the drug [16]. Albendazole is the optimum treatment for neurocysticercosis at a dosage of 400 mg twice a day with continued therapy for intervals varying from 3 to 28 days, and lasting variable lengths of time according to the clinical manifestations and according to the number and location of the cysts [1]. The use of albendazole is also important because the reduction of the cysts and of their consequent inflammatory
286
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
Fig. 2. Distribution of cases by year.
effect might alter the course of important sequelae such as epilepsy or increased intracranial pressure [20]. Corticosteroids, administered a few days before the onset of treatment, reduce the incidence of acute side effects and neurological residua sequels, the latter deriving from the inflammatory reaction triggered by the death of the parasites and by the presence of dead cysticerca [1].
A single dose of albendazole (400 or 600 mg) in association with diethylcarbamazine (6 mg/kg) or ivermectin (0.2 to 0.4 mg/kg) has been proven to be a safe and effective combination for eliminating the microfilaremia from Bancroftian filariasis [1, 21,22]. Yearly doses for 4 to 6 years can keep microfilaremia at such reduced levels as to prevent transmission [1]. Albendazole is also considered to
Fig. 3. Endemic areas for creeping eruption.
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290 Table 1 Characteristics of the patients studied Number of patients
56
Age Median Range
30.43 2 – 60
Sex Male Female
35 (63%) 21 (37%)
Incubation period Median Range
< 1.5 mo < 1 – 5 mo
Type of stay Tourist Business
56 (100%) 0 (0%)
Presence of dogs on beach Yes No Don’t remember
45 (80%) 5 (9%) 6 (11%)
Type of lesion Localized Widespread Unilateral Bilateral Single Multiple
49 (88%) 7 (12%) 39 (70%) 17 (30%) 35 (63%) 21 (37%)
Sites Trunk Arm Scrotum Buttock Thigh Knee Shin Foot Sole Instep Side
9 (16%) 1 (2%) 2 (4%) 8 (14%) 8 (14%) 1 (2%) 2 (4%) 40 (71%) 28 (50%) 19 (34%) 9 (16%)
Treatment Cryotherapy Thiabendazole Thiabendazole + cryotherapy Albendazole + cryotherapy Albendazole
13 (23%) 6 (11%) 1 (2%) 2 (4%) 34 (60%)
be the drug of choice for some microsporidioses; it is effective against gnathostomiasis, enterobiasis, and loiasis. Two hundred mg/day for 5 days is also active against Oesophagostumum bifurcum, endemic in East Africa [17,23 – 28]. Moreover, it reportedly has
287
powerful antiproliferative effects against colon – rectal carcinoma and carcinoma of the liver [29,30]. Various studies in the past, starting from Sivayathorn, who treated 14 patients in Thailand in 1986, and many studies still underway suggest albendazole as the compound of choice for treating larva migrans cutanea [1,2,4,5,7,8,31,32,36]. Use in this situation is discussed in detail in the next section. In a few studies, albendazole has been used to treat visceral larva migrans at a dosage of 5 mg/kg twice a day for 5 days or for ocular localization [33].
Treatment of cutaneous larva migrans Among the various parasitoses that respond to treatment with albendazole, cutaneous larva migrans is most frequently diagnosed by dermatologists. The authors conducted a study in which they observed 56 patients from March 1987 through December 1999 (Fig. 2). This study enabled the authors to verify the effectiveness of albendazole compared with traditional therapy in the treatment of.
Table 2 Seaside resorts visited by authors’ patients Central America Jamaica Mexico Cuba S. Domingo Barbados Grenada Caribbean
29 (52%) 12 9 3 2 1 1 1
Africa Kenya Tunisia Tanzania Senegal Egypt
10 (18%) 6 1 1 1 1
South America Brazil Venezuela
8 (14%) 6 2
Asia Malaysia Indonesia Thailand Maldives Middle East
7 (12%) 3 1 1 1 1
Europe Italy (Apulia, Sardinia)
2 (4%) 2
288
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
Fig. 4. Distribution of the authors’ survey by continent.
Cutaneous larva migrans is a parasitosis that is endemic to tropical and subtropical areas with a hot, humid climate (Fig. 3). From a clinical standpoint, cutaneous larva migrans demonstrates meandering erythematous tracts caused by the penetration and subsequent migration into the skin of the larvae of nematodes. The causative organisms generally infest cats and dogs; humans act only as occasional, incidental hosts. The most common causative organism is Ancylostoma braziliense, and, less commonly, larva migrans might be caused by Ancylostoma caninum, Uncinaria stenochephala, Bunostomum phlebotumun, and the human larvae of Necator americanus and Ancylostoma duodenale [4,7,8,36,38]. If a human accidentally comes into contact with soil contaminated by animal droppings, these larvae can penetrate through the skin [36,38]. After a varying length of time, they start to migrate into the epidermis, especially at night, causing creeping, linear lesions that are intensely itchy. Lesions are mostly localized on the feet, but they also appear on the buttocks and thighs [7,38]. The diagnosis of this parasitosis is essentially clinical and should be differentiated from other pathologies of helminthoid etiology (eg, from eruptions caused by Strongyloides stercolaris and other Strongyloides species), from myiasis, and from simpler cutaneous dermatoses (contact dermatitis, factitial disease, and pyoderma) [31,34]. Although the infestation usually undergoes spontaneous resolution in 1 to 6 months, the intense itching (which often causes insomnia) and the potential for allergic or
infectious complications suggest institution of treatment to reduce its duration [4,34,36]. There are various treatment options, but they are not always effective or practical. To assess the best treatment that can be adopted, the authors recruited a total of 56 patients (Table 1), 21 female (37%) and 35 male (63%), aged between 2 and 60 years (average 30.43 years). Almost all patients (53/56) reported that they had been on holiday to tropical seaside resorts (Table 2), mostly in areas endemic for this parasitosis: 52% in Central America, 14% in South America, 18% in Africa, and 12% in Asia (Fig. 4). The increased incidence of cases observed in the authors’ clinic, especially after
Fig. 5. Clinical view of patient before treatment.
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
the summer and Christmas holiday periods, coincides with the increasing number of holiday-makers going to these hot, humid areas. Two local Italian cases were also observed (4%): one in Apulia and one in Sardinia. This phenomenon appears to demonstrate that under the proper climatic conditions, this pathology can occur in non-endemic areas [38]. Patients showed the typical creeping cutaneous lesions (Fig. 5), which appeared at different times after presumed exposure, but mostly at about 4 weeks. The lesions appeared in localized places in 49 patients (88%), and were more widespread in seven patients (12%). The body parts (Fig. 6) mainly affected by the dermatosis were the feet (70%), but the authors also noted outbreaks on the trunk, limbs, and particularly thighs, knees, and buttocks. Only two patients (who had multiple lesions) showed signs of the infestation on the scrotum. All 56 patients achieved a complete recovery as a result of the treatment chosen. Of the 13 patients (23%) treated first with physical therapy (cryotherapy), none reported relapses or particular scars. Nonetheless, this technique is laborious, painful, and ill-suited to multiple or widespread lesions. It is difficult to assess the exact position of the parasite, which withstands exposure to 20 C/ 25 C for several minutes [4,7,34,36]. Patients treated with systemic therapy with thiabendazole in a dosage of 25 to 50 mg/kg/day for 2 days (11%) showed a regression in pruritus and cutaneous lesions, but they reported systemic side effects: nausea, diarrhea, and dizziness. By contrast, none of the 36 patients (64%) who completed the cycle of therapy with albendazole at a dosage of
289
400 mg/day for 3 consecutive days reported the appearance of adverse reactions despite the prompt and definitive cure. Although new and promising compounds such as ivermectin and flubendazole have been proposed for the treatment of this dermatosis, further studies are needed to elucidate optimum dosage regimens and safety parameters. The use of topical compounds (eg, 10% thiabendazole, 2% gammexane, 25% piperazine ointment, metriphonate) is all too frequently accompanied by irritation, recurrence, and poor patient compliance [7,34,37]. Albendazole, on the other hand, is effective and fast: 24 to 48 hours are enough at the dosages proposed to stop the larvae migrating into the skin with consequent regression of pruritus. The skin heals in 2 to 3 weeks and the reduced therapeutic regime means that adverse reactions are practically nonexistent, so patient compliance improves. These considerations also make it an excellent candidate for being considered the firstchoice drug for this parasitosis.
Summary In 1961 Brown and his team discovered that thiobendazoles were highly effective against gastrointestinal nematodes. This discovery led to the development of albendazole, the most recent of the benzimidazolic drugs. Albendazole is used against numerous animal and human parasites and it is the authors’ first choice as drug treatment of cutaneous larva migrans.
References
Fig. 6. Sites most affected by parasitic disease.
[1] Hardman JG, Limbird LE, Molinoff PB, et al. Goodman & Gilman’s: the pharmacological basis of therapeutics, 10th edition. Nashville TN: McGraw-Hill; 2001. [2] Jones SK, Reynolds NJ, Oliwiecki S, et al. Oral albendazole for the treatment of cutaneous larva migrans. Br J Dermatol 1990;122:99 – 101. [3] Rizzitelli G, Scarabelli G, Veraldi S. Albendazole: a new therapeutic regimen in cutaneous larva migrans. Int J Dermatol 1995;34:570 – 1. [4] Di Carlo A, Vassallo D, Iacovelli P, et al. Due casi di creeping disease: risultati del trattamento con albendazolo. Chron Dermatol 1995;5:225 – 31. [5] Williams HC, Monk B. Creeping eruption stopped in its tracks by albendazole. Clin Exp Dermatol 1989;14: 355 – 6. [6] Albendazole: worms and hydatid disease [editorial]. Lancet 1984;2(8404):675 – 6.
290
G. Albanese, C. Venturi / Dermatol Clin 21 (2003) 283–290
[7] Celano G, Ruatti P. Larva migrans cutanea (creeping eruption). Osservazioni su un caso autoctono trattato con albendazolo. Chron Dermatol 1996;6: 517 – 28. [8] Lavaroni G, Briscik E, Kokelj F. Larva migrans cutanea trattata con albendazolo. Giorn It Dermatol Venereol 1995;130:405 – 7. [9] Montesu MA, Masala MV. Alopecia da albendazolo: descrizione di un caso. Dermatol Clin 1995;1:31 – 3. [10] Sirivichayakul C, Pojjaroen-Anant C, Wisetsing P, et al. A comparison trial of albendazole alone versus combination of albendazole and praziquantel for treatment of Trichuris trichiua infection. Southeast Asian J Trop Med Public Health 2001;32:297 – 301. [11] Torlesse H, Hodges M. Albendazole therapy and reduced decline in haemoglobin concentration during pregnancy (Sierra Leone). Trans R Soc Trop Med Hyg 2001;95:195 – 201. [12] Saimot AG, Cremieux AC, Hay JM, et al. Albendazole as a potential treatment for human hydatidosis. Lancet 1983;2(8351):652 – 6. [13] Gilgen D, Mascie-Taylor CGN, Rosetta L. Intestinal helminth infections, anaemia and labour productivity of female tea pluckers in Bangladesh. Trop Med Int Health 2001;6:449 – 57. [14] Guyatt HL, Brooker S, Kihamia CM, et al. Evaluation of efficacy of school-based anthelmintic treatments against anaemia in children in the United Republic of Tanzania. Bull World Health Organ 2001;79:695 – 703. [15] Taylor M, Jinabhai CC, Couper I, et al. The effect of different anti-helminthic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in Kwazulu-Natal, South Africa: a randomised controlled trial. Trans R Soc Trop Med Hyg 2001;95:211 – 6. [16] Morris DL, Dykes PW, Marriner S, et al. Albendazole: objective evidence of response in human hydatid disease. JAMA 1985;253:2053 – 7. [17] De Vries PJ, Kerst JM, Kortbeek LM. Migrating swellings from Asia. Gnathostomiasis. Ned Tijdschr Geneeskd 2001;145:322 – 5. [18] Gonzalez AH, Regalado VC, Van Den Ende EJ. Noninvasive management of Ascaris lumbricoides biliary tract migration: a prospective study in 69 patients from Ecuador. Trop Med Int Health 2001;6:146 – 50. [19] Aygun E, Sahin M, Odev K, et al. The management of liver hydatid cysts by percutaneous drainage. Can J Surg 2001;44:203 – 9. [20] Kobayashi E, Guerriero C, Cendes F. Late onset temporal lobe epilepsy with MNR evidence of mesial temporal sclerosis following acute neurocysticercosis. Arq Neuropsiquiatr 2001;59:255 – 8. [21] Ismail MM, Jayakody RL, Weil GJ, et al. Long-term efficacy of single-dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of Bancroftian filariasis. Trans R Soc Trop Med Hyg 2001;95:332 – 5.
[22] Karam M, Ottesen E. The control of lymphatic filariasis. Med Trop 2000;60:291 – 6. [23] Chandenier J, Husson J, Canaple S, et al. Medullary gnathostomiasis in a white patient: use of immunodiagnosis and magnetic resonance imaging. Clin Infect Dis 2001;32:E154 – 7. [24] Conteas CN, Berlin OG, Ash LR, et al. Therapy for human gastrointestinal microsporidiosis. Am J Trop Med Hyg 2000;63:121 – 7. [25] Georgiev VS. Chemotherapy of enterobiasis (oxyuriasis). Expert Opin Pharmacother 2001;2:267 – 75. [26] Klion AD, Horton J, Nutman TB. Albendazole therapy for loiasis refractory to diethylcarbamazine. Clin Infect Dis 1999;29:680 – 2. [27] Storey PA, Faile G, Crawley D, et al. Ultrasound appearance of preclinical Oesophagostomum bifurcum induced colonic pathology. Gut 2001;48:565 – 6. [28] Storey PA, Bugri S, Magnussen P, et al. The effect of albendazole on Oesophagostomum bifurcum infection and pathology in children from rural northern Ghana. Ann Trop Med Parasitol 2001;95:87 – 95. [29] Morris DL, Jourdan JL, Pougholami MH. Pilot study of albendazole in patients with advanced malignancy. Effect on serum tumor markers/high incidence of neutropenia. Oncology 2001;61:42 – 6. [30] Pourgholami MH, Woon L, Almajd R, et al. In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer Lett 2001;165: 43 – 9. [31] Davies HD, Sakulus P, Keystone JS. Creeping eruption. A review of clinical presentation and management of 60 cases presenting to a tropical disease unit. Arch Dermatol 1993;129:588 – 91. [32] Orihuela AR, Torres JR. Single dose of albendazole in the treatment of cutaneous larva migrans. Arch Dermatol 1990;126:398 – 9. [33] Barisani-Asenbauer T, Maca SM, Hauff W, et al. Treatment of ocular toxocariasis with albendazole. J Ocul Pharmacol Ther 2001;17:287 – 94. [34] Caumes E, Gentilini M. Traitement de la larva migrans cutanee ankylostomienne. Ann Dermatol Venereol 1995;120:571 – 3 [in French]. [35] Cooper PJ, Chico ME, Losonsky G, et al. Albendazole treatment of children with ascariasis enhances the vibriocidal antibody response to the live attenuated oral cholera vaccine CVD 103-HgR. J Infect Dis 2000;182: 1199 – 206. [36] Pauluzzi P, Magaton Rizzi G, Mattighello P. Larva migrans: report of three cases and therapeutic advice. J Eur Acad Dermatol Venereol 1996;6:89 – 91. [37] Richey TK, Gentry RH, Fitzpatrick JE, et al. Persistent cutaneous larva migrans due to ancylostoma species. South Med J 1996;89:609 – 11. [38] Roest MA, Ratnavel R. Cutaneous larva migrans contracted in England: a reminder. Clin Exp Dermatol 2001;26:389 – 90.
Dermatol Clin 21 (2003) 291 – 300
Imiquimod Robert B. Skinner, Jr, MD Department of Medicine, Division of Dermatology, University of Tennessee Health Science Center, 956 Court Avenue, Room E336, Memphis, TN 38163, USA
Imiquimod, the first of a new class of compounds called immune response modifiers, is a non-nucleoside, low modular weight, heterocyclic amine (imidizoquinolone) with the chemical structure 1-(2 methypropyl)-IH-imidazo [4,5-c] quinolin-4-amine (Fig. 1). Imiquimod is available commercially as Aldara (3M Pharmaceuticals, St. Paul, MN), a 5% cream containing 50 mg of imiquimod in an oil-inwater vanishing cream base. It is approved in the United States as a patient-applied treatment for external genital and perianal warts/condyloma accuminata in adults, but the majority of imiquimod’s use has been for infectious and neoplastic offlabel indications.
Mechanism of action Imiquimod has been shown to have antiviral and antitumor effects in animal models but no direct antiviral or antitumor activity in vitro [1 – 3]. The exact mechanism of action of imiquimod in humans is not known. In general, however, application of imiquimod stimulates multiple proinflammatory cytokines, most notably interferon alfa (IFN-a) and tumor necrosis factor alpha (TNF-a), which upregulate the cellular immune response [4]. Thus, imiquimod promotes a local immune response by inducing cytokines. Imiquimod is thought to activate portions of the cell-mediated and innate arms of the immune system by way of local production of cytokines. Imiquimod has been shown to induce serum levels of IFN-a in mice, rats, guinea pigs, monkeys, and
E-mail address:
[email protected]
humans [5 – 8]. IFN-a is considered to be the primary natural defense mechanism against viral infections within cells [9]. IFN-a protects cells from viral infection until an appropriate defensive cell-mediated immune response is stimulated. In wart infections, the human papilloma virus (HPV) is protected in keratinocytes from the cellular-mediated immune response. Peptides elaborated by the HPV genome cause keratinocytes to proliferate, which in turn leads to the clinical presentation of a wart. Imiquimod induces the production of IFN-a, which inhibits viral reproduction in infected keratinocytes and protects adjacent keratinocytes from viral infection. Imiquimod induces (21 – 51)-oligoadenylate synthetase, the latter creating an ‘‘antiviral state’’ including upregulation of natural killer cell activity [9]. In the hairless mouse model, application of 1% imiquimod cream produced in 4 hours a 50-fold increase in skin levels of INF-a from local transcription as shown by increased mRNA in the treated skin [4]. This quick induction of IFN-a might be responsible for the protective effect of imiquimod in herpes simplex infection in guinea pigs when imiquimod is used within 48 hours of animal inoculation [10]. In other animal models, imiquimod has been shown to be effective against acute herpes simplex virus type 2 (HSV-2) infection [11,12], recurrent HSV-2 in guinea pigs [13], arbovirus infection in mice [14], and cytomegalovirus infection in guinea pigs [15]. The inhibition of viral replication seen with imiquimod appears to result from induction of IFN. IFN-a proteins are produced by a large family of genes (IFNA) with related structures, which are found in lymphoid tissue [16]. Imiquimod stimulates IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8 from peripheral blood mononuclear cells, B cells, and monocytes/macrophages, whereas Sendai virus infection stimulates IFNA1,
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00094-3
292
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
Fig. 1. The chemical structure of imiquimod, 1-(2-ethylpropyl)-1 H-imidazo [4, 5-c] quinolin-4-amine. (From http:// www.lk-online.dk/images/strukturformler/3043.gif ).
IFNA2, and IFNA8 [16]. A higher degree of IFN-a subtype heterogenicity was found in imiquimodtreated Peripheral blood monocyte (PBMC) than in Sendai virus-infected cells. Imiquimod was also found to induce interleukin (IL)-8 more efficiently than did a natural viral infection. In vitro treatment of keratinocytes with imiquimod results in production of IL-6 and IL-8 [17]. Along with IFN-a, these cytokines can stimulate natural killer cells and cytotoxic T cells and act as chemokines for polymorphonuclear leukotcytes and mononucledar phagocytes. Peripheral blood monocytes appear to be one predominant target of imiquimod. Eliminating peripheral blood mononuclear cells through cell depletion methods revealed that the imiquimod-derived increase in cytokine production was halted. This phenomenon was not observed following depletion of B cells, T cells, natural killer cells, or dendritic cells [18]; however, other studies have shown that imiquimod stimulates not only peripheral blood monocytes but also macrophages and dendritic cells to produce IFN-a, IL-12, and TNF-a [18]. IL-12 is needed for the development of activated, functional T helper type 1 cells, which are directly involved with cellular immunity [19]. Induction of IFN-a and activation of cytotoxic lymphocytes are mediated by IL-12 [20]. Interleukins 4 and 5 (IL-4, IL-5) are T-helper factors associated with the T helper type 2-type immune response (humoral or antibody-mediated immunity). Production by peripheral blood mononuclear cells of IL-4 and IL-5 is inhibited by imiquimod, and this inhibition is partly mediated by IFN-a
[21]. As imiquimod-induced IFN-a inhibits Th2 responses and IL-12, IFN-a and TNF-a induced by imiquimod promote the Th1 response. Imiquimod appears to potentiate the Th1 cytokine response while simultaneously suppressing Th2 cytokine release [22,23]. Langerhans’ cell functional maturation and migration to regional lymph nodes is enhanced by imiquimod [24,25]. This enhancement of antigen presentation by Langerhans’ cells to naive T cells in the regional lymph nodes might make the immune response induced by imiquimod a more specific antigen attack. The low recurrence rates noted in imiquimod genital wart clinical trials might be because of recall of such a specific immune response. Imiquimod further induces proliferation of mouse and human purified B cells. It also induces immunoglobulin secretion in B cell culture [26]. Imiquimod can induce expression of B cell markers and stimulate differentiation of B cells into antibody-secreting cells [26]; however, these effects do not appear to be a primary feature of the in vivo functional mechanism of action. Tyring [27] recently summarized the multiple inflammatory mediators induced by imiquimod, including IFN-a, TNF-a, IL-7, IL-1RA, IL-6, IL-8, IL-10, and IL-12p40. Also induced are granulocyte/ macrophage colony stimulating factor, macrophage inflammatory proteins (MIP) 1 and 18, and macrophage chemotactic protein. It is not clear exactly how all these factors interact to mediate the anti-infective properties that are associated with imiquimod. Imiquimod has been shown to activate immune cells by the toll-like receptor (TLR)-7 [28]. TLRs are a family of receptors for early recognition of different microbial antigens. Ten human TLRs have been identified, and they reportedly respond to lipopolysaccharide of Gram-negative bacteria, lipopeptides of Gram-positive cell walls, and bacterial DNA and flagellar components [29].
Human papilloma virus Warts or verrucae result from infection with HPV, a double-stranded DNA virus with more than 80 genotypes. HPV infection produces slow-growing, benign, proliferative tumors that are usually subclinical for long periods of time. Anogenital warts (condyloma accuminata, genital or venereal warts) are sexually transmitted verrucous (cauliflower-like) nodules, papules, or plaques on the perineum, genitalia, anus, or cural folds. The majority of genital warts result from HPV-6 and HPV-11 and are benign.
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
HPV-16 and HPV-18 are associated with Bowenoid papulosis, Bowen’s disease of the genitalia, and cervical cancer. Genital warts are usually asymptomatic, but they can be painful, bleed, and interfere with sexual intercourse. Traditional treatments include office-based ablative therapy with cryotherapy, electrodessication, trichloroacetic acid, or CO2 laser and home-applied podophyllotoxin and 5-fluroruracil. Imiquimod represents the most recent addition to the therapeutic armamentarium available to combat anogenital HPV infection, and it remains the sole FDA-approved indication for the drug. An early, randomized, dose-ranging study evaluated the treatment of external genital warts in men using imiquimod 5% cream applied three times per week, once daily, or three times per day [30]. Complete clearance rates over a 16-week treatment period were 35% (three times a week), 28% (once daily), 24% (twice daily), and 27% (three times daily). Although complete clearance rates were somewhat disappointing, all treatment groups showed a median of more than a 90% reduction in lesion area at the end of treatment period. In this study, more frequent application of imiquimod did not increase clearance, but it did increase local skin adverse effects. There was a significant increase in erythema, vesiculation, ulceration, and excoriation as the application frequency increased from three times per week to three times per day. A Phase II, multicenter (three outpatient centers, a public health clinic, a university-based clinic, and a private practice), prospective, double-blind, placebocontrolled, parallel design clinical trial compared 5% imiquimod cream with vehicle cream in 108 patients with external genital warts [31]. Medication was applied three times weekly for up to 8 weeks, and patients who cleared completely were observed for 10 weeks to determine the recurrence rate. Forty percent of imiquimod-treated patients had complete clearance compared with 0% of the placebo group. The median time to complete clearance was 7 weeks. The median percentage in wart area reduction was 90% at week 8 for imiquimod users with no significant reduction noted in the placebo group. The recurrence rate was 19% for imiquimod patients. The most commonly reported side effects of imiquimod treatment were itching, erythema, and burning. No differences in systemic side effects or laboratory abnormalities were reported between the imiquimod and placebo groups. Several Phase III, multicenter, randomized, double-blind, placebo-controlled clinical trials similarly demonstrated a positive response. In one such study, safety and efficacy of 5% imiquimod cream, 1% imiquimod cream, and vehicle cream was studied in
293
311 patients with external genital warts [32]. Study creams were applied to all warts overnight, three times weekly, for 16 weeks. In the intent-to-treat analysis, 50% with 5% imiquimod cream, 21% with 1% imiquimod cream, and 11% with vehicle cream experienced complete clearance of all baseline warts. Patients with complete wart clearance entered a 12-week follow-up period to monitor recurrence rates. The effectiveness of 5% imiquimod cream over vehicle cream was statistically significant, whereas 1% imiquimod cream was not significantly beneficial compared with vehicle cream. The overall median time to clearing was 10 weeks (5% cream), 12 weeks (1% cream), and 12 weeks (vehicle). Clearance rates for men were 40% (5% cream), 10% (1% cream), and 6% (vehicle), whereas clearance rates for women were 77% (5% cream), 6% (1% cream), and 28% (vehicle). Median time to clearance for imiquimod treatment groups was 12 weeks for men and 8 weeks for women. Recurrence rates were 14% (5% cream), 0% (1% cream), and 10% (vehicle). The most common adverse reaction was erythema. In a second such study, safety and efficacy of patient-applied 1% and 5% imiquimod cream for up to 16 weeks was studied in 279 patients [33]. Recurrence of warts was evaluated in a 12-week follow-up period. Patients applied study creams three nights per week and washed them off in the morning. In the intent-to-treat analysis, baseline warts cleared in 52% with 5% imiquimod cream, 14% with 1% imiquimod cream, and 4% with vehicle. Among subjects with complete clearing recurrence rates who completed the follow-up period, recurrence rates were 19% (5% cream), 17% (1% cream), and 0% (vehicle). There were no systemic reactions, and the most common adverse reactions were erythema, flaking, and erosion. A randomized, controlled trial comparing 5% imiquimod cream with vehicle cream analyzed the possible molecular mechanisms involved in wart clearance [34]. Study patients had biopsies taken at baseline, week 6 of treatment, and the end of treatment. Wart clearance was associated with elevation of mRNA for IFN-a, IFN-b, IFN-g, and TNF-a. A patient with spontaneous clearing of warts did not have elevated mRNA for IFN-a or TNF-a. Wart clearance with imiquimod was associated with decreased HPV DNA and decreased mRNA for early (E7) and late (L1) viral proteins, demonstrating that clinical clearance correlated with the actual disappearance of wart virus. This study also clearly showed that imiquimod increases the cell-mediated immune response in clearing warts. A double-blind, placebo-controlled study evaluated the safety, clinical efficacy, and tolerability of
294
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
2% imiquimod cream to treat external warts in men [35]. The cream was applied to warts once daily for three consecutive days of a week. Wart clearance was achieved in 70% of imiquimod-treated patients and in 10% of placebo-treated patients ( P > 0.001). Overall, imiquimod cleared 86.8% of all warts treated with 10.3% of warts cleared in placebo-treated patients. At the end of 14 months, recurrence rates were 3% for imiquimod and 8% for placebo. No drug-related side effects were experienced by 82% of patients. The erythema, erosion, and edema reported in a few patients were not significant enough to stop treatment with imiquimod. The significance of this study is questionable, however, because the 2% concentration of imiquimod is not commercially available. A randomized, double-blind, vehicle-controlled study of 5% imiquimod cream versus placebo was conducted with HIV-infected patients with external anogenital warts [36]. Study medication was applied for 8 hours, three times per week. There was no significant difference between treatment groups with regard to complete wart clearance (imiquimod 11% versus vehicle 6%); however, 38% of imiquimodtreated patients achieved greater than 50% reduction in wart area over 14% for vehicle-treated patients ( P = 0.013). An open-label, Phase IIIB study using imiquimod 5% cream was conducted with 943 patients in 114 clinic sites in 20 countries [37]. Imiquimod 5% cream was applied three times per week for up to 16 weeks. Patients with complete clearance were monitored for 6 months, whereas patients with partial clearance had an additional 16 weeks of therapy. Complete clearance of warts occurred in 47.8% of patients in the first 16 weeks, and another 5.5% cleared with the additional 16 weeks of treatment for an overall clearance rate of 53.3%. Recurrence rates were 8.8% at 3 months and 23% at 6 months. Local erythema was the most common side effect. Case reports further confirm the utility of imiquimod, even in difficult cases. O’Mahony [38] reported successful use of imiquimod 5% cream in four such instances. The cases included flat warts on the penile shaft, extensive penile warts, extensive warts on the glans penis, and penile and perianal warts. All patients had failed treatment with cryotherapy, trichloroacetic acid, and podophyllin. All warts cleared with imiquimod 5% cream applied from three times per week to three times per day. Eggleton and Tang [39] described the successful use of imiquimod 5% cream in 10 patients (5 men, 5 women) in whom prior conventional therapy had failed (defined by < 50% response to treatment over a minimum of 3 months). Three of five women resolved or improved and three
of five men improved. One female patient who was excluded because of late start of treatment also cleared and remained free of recurrence for 6 months. Weinberg et al [40] reported a patient with extensive condyloma of the inguinal area and thigh (1,770 mm2) who was resistant to cryotherapy, podophyllin, podofilox, and CO2 laser, but who cleared with 5% imiquimod cream. An audit [41] of patients with anogenital warts treated with 5% imiquimod cream at Royal Victoria Hospital, Belfast, Ireland, showed a 54% clearance rate in men and 44% clearance rate in women. An 82-year-old man with a chest intraepidermal carcinoma, PCR positive for HPV type 33, cleared with 5% imiquimod cream three times per week for 17 weeks with no recurrence at 15 months of follow-up [42]. Although the majority of data concerns the use of imiquimod in adults, imiquimod has been reported successful in adolescents, children, and infants [43 – 45]. Wagman et al [45] described 42 adolescent girls aged 11 to 18 (six were HIV+) with external genital warts. Seventy-nine percent of the adolescent girls were cleared of warts with imiquimod 5% cream and 95% had greater than 50% reduction in wart size. Moresi et al [43] reported 75% clearing of anogenital warts in infants and young children with imiquimod 5% cream. Schaen [44] had successful resolution of genital warts with imiquimod 5% cream in a 6-month-old girl delivered from a mother with diagnosed genital warts. The infant’s warts cleared in 3 weeks. It should be noted that imiquimod is FDA approved only for patients aged 12 years or older. Surveys taken of healthcare providers and genital wart patients [46,47] as well as cost effectiveness studies [48] have generally garnered favorable responses. O’Mahony et al [47] reported the results of a questionnaire associated with an imiquimod 5% cream anogenital wart trial. Pre- and post-study questionnaires were completed by 902 and 629 patients, respectively. Seventy percent of patients had previously been treated for genital warts with other modalities, and most expressed dissatisfaction with previous treatment; by contrast, 61% of imiquimod-treated patients rated imiquimod as ‘‘better’’ than previous therapies in terms of overall satisfaction, time to clearance, convenience, and lack of pain. Nelson [46] assessed healthcare providers and genital wart patients before and after imiquimod use (744 patients pretreatment and 399 patients posttreatment). Imiquimod received favorable ratings from patients treated for the first time and from patients with recurrent warts. Healthcare providers rated imiquimod favorably for compliance, patient acceptance, and convenience. In a cost effectiveness study, Lang-
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
ley et al [49] found that provider-administered ablative therapies were more costly and less effective for sustained clearance when compared with imiquimod. Common and plantar warts result from HPV types 1, 2, 4, 27, and 29. These warts are usually rough, scaly, keratotic papules that can occur on any skin surface. Common warts most often occur as single or grouped lesions on the hands and fingers. Plantar and palmar warts are hyperkeratotic, endophytic lesions that can be painful. Traditional treatments include office-based cryosurgery, electrodesiccation, CO2 laser, intralesional bleomycin, and cantharidin or home-applied salicylic acid and lactic acid. Although not approved for this indication, imiquimod’s efficacy for anogenital warts suggests potential benefit in dealing with other types of warts. Hengge et al [50] treated common warts with imiquimod 5% cream as monotherapy applied overnight for 5 days weekly. Fifty-six percent of patients had a total clearance (30%) or greater than 50% reduction in wart size (26%). Wart patients had averaged 2.7 prior wart treatments and had a mean disease duration of 29.2 months. Sparling et al [51] obtained even better results with imiquimod 5% cream by adding cryotherapy and occlusion. A 14-year-old girl with ten periungual warts that were unresponsive to cryotherapy was treated with imiquimod 5% cream applied nightly under occlusion (duct tape) following a single cryotherapy session. All warts resolved in 12 weeks. A 17-year-old girl with a plantar wart on each foot (left foot, 2.0 4.8 cm) was treated with a nightly application under occlusion of 5% imiquimod cream with complete clearance at 6 weeks. Because of the heavy keratinization of common and plantar warts, imiquimod probably does not penetrate enough to activate an immune response to the wart virus. Better results than those in the Hengge et al [50] study appear to be obtained by combining imiquimod applied nightly under occlusion with cryosurgery every 2 to 3 weeks. The addition of the keratolytics tazarotene gel (Tazorac Allergan, Inc., Irvine, CA) or 40% urea gel (Carmol 40, Doak Dermatologics, Fairfield, NJ) applied on alternating nights with imiquimod under occlusion (or applied in the evening and imiquimod at bedtime under occlusion) appears to increase the effectiveness of the latter. The combination of imiquimod and CO2 laser [52] was reported to be beneficial in treatment of verrucae vulgaris in immunocompromised patients. Rinne et al [53] found clearing in extensive lip papillomatosis (warts) with imiquimod 5% cream applied three times a week for 3 months in three HIV+ women who were previously resistant to cryosurgery and topical beta interferon (IFN-b).
295
Flat warts (verruca plana) result from HPV types 3, 10, 28, and 49. These warts are flat, 2- to 4-mm, slightly elevated, flat-topped, flesh-colored papules that usually appear on the face, hands, and lower legs. Flat warts are of considerable cosmetic concern. Traditional treatments include cryosurgery, electrodessication, 5-fluorouracil cream, salicylic acid, and tretinoin. Schwab and Elston [54] reported a 21-year-old woman with a 2-year history of multiple facial flat warts that were resistant to retinoic acid, adapalene gel, 5-fluorouracil, cryosurgery, and oral cimetidine. Imiquimod 5% cream applied 3 nights per week completely cleared the flat warts in 3 weeks. Complete clearing of facial flat warts in an HIV+ man was reported [69] with imiquimod 5% cream applied 3 times per week. Flat warts on the fingers and dorsum of the hands of a 42-year-old man were cleared with imiquimod applied three times a week for 6 weeks [55].
Herpes simplex Imiquimod was administered intravaginally to guinea pigs (5 mg/kg/12h) for 5 days beginning 12 hours after inoculation with HSV-2. Vaginal viral replication was greatly reduced, and the guinea pigs were completely protected against primary HSV-2 infection. Recurrence of HSV-2 genital infection was dramatically reduced [11]. IFN was shown to be induced, and, as expected, enhanced cell mediated immunity against HSV-2 was demonstrated. Imiquimod-stimulated immunity was associated with less than 36 hours of vaginal shedding of HSV-2. Imiquimod-treated guinea pigs had decreased HSV-2 antibody but increased HSV-2 – specific in vitro IL-2 production [11]. In a subsequent companion study, therapy with imiquimod twice per day was started 12 hours after genital HSV-2 inoculation vaginally in guinea pigs. HSV was recovered from neural tissue in 1 of 84 imiquimod-treated guinea pigs but in 43 of 56 placebo-treated animals [56]. Imiquimod once per day beginning 36 hours after HSV inoculation reduced the total mean lesion score in the acute disease and shortened vaginal virus shedding. Imiquimod-treated animals had markedly fewer HSV-2 recurrences compared with controls. Twenty-three of 24 dorsal root ganglia from controls showed latent HSV-2, whereas only 2 of 30 imiquimod-treated animals demonstrated latent HSV in the dorsal root ganglia [56]. Imiquimod has also been studied as an HSV vaccine adjuvant in guinea pigs. An adjuvant for
296
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
HSV-2 vaccine should increase the ability of the vaccine to decrease viral replication at the mucosal site, prevent clinical disease, and decrease recurrences after primary infection [56]. Subcutaneous imiquimod and vaccine decreased vaginal virus titers by greater than 3 logs on day 1 compared with vaccine without imiquimod and by greater than 4 logs in control (unimmunized) animals [56]. No guinea pigs developed acute or recurrent herpes infection. In this study, imiquimod was comparable to complete Freund’s adjuvant. Topical imiquimod given along with vaccine decreased vaginal viral shedding and acute viral infection, though not as completely as subcutaneous imiquimod [56]. Imiquimod was used topically alone and in combination with acyclovir to treat established HSV-2 genital infection in guinea pigs, using 10 days of therapy started after lesions appeared [10]. Combination therapy was effective in reducing acute disease severity at 2 days and vaginal viral shedding at 1 day after therapy began [10]. Such therapy did not affect the number of days guinea pigs experienced recurrent lesions. Imiquimod increased the lymphoproliferative response to HSV-2 [10]. Imiquimod and acyclovir appeared to be an effective combination therapy for genital HSV-2, even when therapy was initiated after lesion development. Treating primary HSV-2 infection in guinea pigs with imiquimod reduced the level of genital disease by 90% [13]. Imiquimod administered intravaginally once per day for 5 days reduced recurrences, whereas a 21-day treatment regimen reduced recurrences for 8 weeks. After 10 weeks, recurrences remained reduced by 67% with the 21-day regimen. The number of clinical recurrences and the levels of HSV-2 antibody were reduced for 6 weeks when compared with placebo treatment. Enhanced HSV-2 antigen-specific IL-2 production persisted for 4 weeks after treatment. Imiquimod suppressed recurrent HSV-2 genital disease during treatment and for weeks after therapy, reduced the levels of HSV-2 antibody response, and elevated the memory-dependent cytokine and T cell response to HSV-2 [13]. Despite the various guinea pig data demonstrating the response of herpes to imiquimod, there is only one report of imiquimod treatment for herpes infection in humans. Gilbert et al [57] reported a 34-yearold HIV+ Hispanic man who developed an HSV-2 penile infection. This infection was unresponsive to acyclovir (400 mg tid), valacyclovir (1 g bid), and famciclovir (500 mg tid). Imiquimod 5% cream was applied for 8 hours every other night for 1 week. Pain decreased after 4 days, and after 1 week the lesions improved with complete re-epithelialization of the
glans. There were no recurrences at 1 month of follow-up.
Molluscum contagiosum Molluscum contagiosum is a common, benign, viral infection of the skin usually seen in children, although it can occur in adults as a sexually transmitted disease. The molluscum contagiosum virus is a DNA poxvirus. Lesions are usually 3- to 6-mm, smooth, dome-shaped, flesh-colored papules with a central, umbilicated white core. Molluscum contagiosum is of cosmetic and social concern because it is easily spread to others. Tradtional treatments include office-based curettage, cryosurgery, electrodesiccation, cantharidin, and home-applied retinoic acid and podophyllotoxin. Molluscum lesions persist, in part, because the etiologic virus produces proteins that antagonize chemokines and impair host cell programmed death (apoptosis). IFN is known to induce chemokines and enhance apoptosis; therefore, a local IFN inducer such as imiquimod appears to be reasonable to use in this situation. In an open-label study, Liota et al [58] reported that 14 of 19 immunocompetent adults and 6 of 13 normal children cleared all Molluscum lesions by applying 5% imiquimod cream three times per week for up to 6 weeks. In a double-blind, placebo-controlled study using 1% imiquimod cream three times per day, 5 days per week for 1 month, Syed et al [59] noted that 82% of the patients cleared the molluscum contagiosum lesions. An open-label safety study of 5% imiquimod cream [60] involved 13 children (mean age 7 years) treated with imiquimod 5% cream every night for 4 weeks. Complete clearance occurred in 33% of patients with no systemic toxicity found from imiquimod (no change in complete blood count or temperature). Adverse reactions were limited to mild irritation at application sites. The authors concluded that imiquimod 5% cream was safe for treating children with molluscum contagiosum [60]. Hengge et al [50] used 5% imiquimod cream applied daily for 5 days per week; 80% of patients with molluscum contagiosum cleared completely or had greater than 50% reduction in molluscum area. Skinner et al [61] reported eradication of molluscum contagiosum with nightly applications of 5% imiquimod cream over 8 weeks. Brown [62] and Strauss [63] reported single cases of HIV+ patients with molluscum contagiosum that was recalcitrant to multiple modalities who cleared with application of 5% imiquimod cream.
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
Parainfluenza Imiquimod has been used in the treatment of experimental parainfluenza type 1 virus infection in rats [64]. Such infection in rats produces virusinduced airway obstruction and inflammation, similar to that encountered in naturally infected humans [65]. Imiquimod was administered orally before and during acute viral respiratory infection. Peak viral titers were delayed and reduced with imiquimod such that at day 3 the virus was undetectable in the airway. This result was because of cytokine reduction of viral replication [65]. IFN levels increased for several hours after imiquimod administration, but they showed no increase in water-treated (control) rats. Imiquimod also prevented the usual virus-associated weight loss. The decreased airway inflammation and positive lung physiology was thought to result from IFN-a inhibiting production of IL-5 (an eosinophil activator) by CD4+ T cells. The investigators felt that imiquimod could possibly decrease the development of analogous airway inflammation and dysfunction seen in viral respiratory infections in humans and might treat or prevent viral-induced asthma [64]. This theory remains speculative to date.
Leishmaniasis Leishmaniasis is an infectious disease caused by various species of the protozoan organism that are transmitted to the human host by way of the bite of an infected sandfly. Although not an endemic disorder in North America, leishmaniasis is a prevalent infection
297
in tropical climates, with some 12 million people infected and some 350 million people at risk. Cutaneous leishmaniasis is the most common form of the disorder. Resulting skin lesions might spontaneously remit (with scarring) or they might persist and become destructive. There is no suitable vaccine and treatment options are limited; the most widely used treatment is pentavalent antimonials, which are administered by intramuscular injection or intravenous infusion. Serious adverse events associated with this therapy include hepatotoxicity, cardiotoxicity, hematological abnormalities, and pancreatitis. Malaise, nausea, headache, myalgia/arthralgia, and anorexia are common. Based upon clinical efficacy demonstrated in a murine model of leishmaniasis, Arevalo and colleagues [66] recently utilized topical imiquimod (1 packet applied to each lesion every other day for 20 days) in combination with ongoing antimonial therapy. Patients treated in this study had already failed a standard 20-day course of parenteral antimonial treatment. Twenty-one lesions in 12 patients were treated. At the end of the 20-day therapy, 57.1% of lesions and 50% of patients were clinically ‘‘cured.’’ At 2 to 4 months posttreatment, all lesions that had partially healed continued to improve or were entirely resolved. At a 6-month follow-up involving 10 of the 12 original study patients, 90% were clinically ‘‘cured.’’ The authors postulate that imiquimod-induced IFN results in upregulation of nitric oxide synthesis, yielding a synergistic antiparasitic effect when used in combination with traditional antimonial therapy [66]. They further speculate that imiquimod might represent a significant advance in
Table 1 Summary of genital wart trials with 5% imiquimod cream
Investigator
Trial type
Beutner et al, 1998 [31] Edwards et al, 1998 [32] Beutner et al, 1998 [33] Gilson et al, 1999 [36]
Phase II, multicenter, double-blind, placebo-controlled Phase III, multicenter, randomized, double-blind, placebo-controlled Phase III, multicenter, randomized, double-blind, placebo-controlled Multicenter, double-blind, vehicle-controlled, parallel group
Garland et al, 2001 [37]
Phase IIB, open-label
Adapted from Tyring [27] with permission.
Number of genital warts patients
Complete wart clearance with 5% imiquimod cream
Recurrence rate
108
40%
19%
180 men 131 women 154 men 125 women 97 men 3 women HIV + 943 114 clinic sites 20 countries
50%
13%
71%
19%
11%
–
53.3%
23% at 6 mo
298
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300
the management of cutaneous leishmaniasis by potentially reducing the total amount of antimonial required, reducing the total duration of therapy, or decreasing the development of protozoal resistance to the antimonial compounds. This preliminary report is encouraging, although additional studies are obviously required to substantiate the conclusions.
[5]
[6]
Summary [7]
Imiquimod is the first of the immune response modifiers to stimulate a localized immune response to treat infectious skin conditions. The reported TLR-7 activation to provoke an immune response suggests that imiquimod might mimic a microbial antigen. The immune response initiated by induced production of IFN-a and TFN-a is specifically aimed at an infectious antigen and appears mediated (in part) by enhanced migration of Langerhans’ cells to regional lymph nodes. The approved indication for imiquimod is for treatment of genital warts. The drug has demonstrated a 50% to 60% clearance rate and a 12% to 20% recurrence rate for this indication (Table 1). This recurrence rate is the lowest reported among the currently recommended treatment modalities. The self-applied treatment avoids costly and painful office-based procedures. Case reports and open-label studies have demonstrated the efficacy of imiquimod in treating some cases of common, plantar, and flat warts, as well as molluscum contagiosum and leishmaniasis. Common and plantar warts respond better to imiquimod in combination with cryosurgery, occlusion, and keratolytics. Reports of successful imiquimod treatment of granuloma annulare [48], alopecia areata [67], and vitiligo [68] might suggest an infectious etiology to those conditions, although this hypothesis is highly speculative.
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
References [1] Slade HB, Owens ML, Tomai MA, et al. Imiquimod 5% cream (Aldara). Exp Opin Invest Drugs 1998;7: 437 – 49. [2] Tomai MA, Gibson SJ, Imbertson LM, et al. Immunomodulating and antiviral activities of the imidazoquinolone S-28463. Antiviral Res 1995;28:253 – 64. [3] Wagner TL, Horton VL, Carlson GL, et al. Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609 and S-28463. Cytokine 1997;9:837 – 45. [4] Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless mouse and rat skin after
[17]
[18]
[19]
topical application of the immune response modifiers imiquimod and S-28463. J Invest Dermatol 1998;110: 734 – 9. Gibson SJ, Elrod SV, Miller RL, et al. Oral R837 induces alpha interferon in cynomolgus monkeys [abstract]. J Interferon Res 1990;10:5124. Miller RL, Imbertson LM, Reiter MJ, et al. Interferon induction by antiviral S-26308 in guinea pigs [abstract]. Presented at the ASM 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1986. Reiter MJ, Testerman TL, Miller RL, et al. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol 1994;55:234 – 40. Wick KA, Kvam DC, Weeks CE, et al. Oral R-837 induces interferon in healthy volunteers [abstract]. Proc Am Assoc Cancer Res 1991;32:257. Dahl MV. An immune response modifier. J Am Acad Dermatol 2000;43:S1 – 5. Bernstein DI, Miller RL, Harrison CJ. Effects of therapy with an immunomodulator (imiquimod R837) alone and with acylovir on genital HSV-2 infection in guinea pigs when begun after lesion development. Antiviral Res 1993;20:45 – 55. Harrison CJ, Jenski L, Voychehovski T, et al. Modification of immunological responses and clinical disease during topical R-837 treatment of genital HSV-2 infection. Antiviral Res 1988;10:209 – 23. Miller RL, Imbertson LM, Reiter MJ, et al. Inhibition of herpes simplex virus infection in a guinea pig model by S-26308 [abstract]. ASM 26th Interscience Conference on Antimicrobial Agents Chemotherapy, 1985. Harrison CJ, Miller RL, Bernstein DI. Posttherapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemother 1994;38:2059 – 64. Kende M, Lupton HW, Canonico PG. Treatment of experimental viral infections with immunomodulators. Adv Biosci 1988;68:51 – 63. Chen M, Griffith RP, Lucia HL, et al. Efficacy of S-26308 against guinea pig cytomegalovirus infection. Antimicrob Agents Chemother 1988;32:678 – 83. Megyeri K, Au WC, Rosztoczy I, et al. Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. Mol Cell Biol 1995;15: 2207 – 18. Miller R, Birmachu W, Gerster J, et al. Imiquimod cytokine induction and antiviral activity. Int Antiviral News 1995;3:111 – 3. Gibson SJ, Imbertson LM, Wagner TL, et al. Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. J Interferon Cytokine Res 1995;15:537 – 45. Hsieh CS, Macatonia SE, Tripp CS, et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 1993;260: 547 – 9.
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300 [20] Trinchieri G. Interleukine-12 and its role in the generation of TH1 cells. Immunol Today 1993;14: 335 – 8. [21] Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R848 and imiquimod. Cell Immunol 1999;191:10 – 9. [22] Parronchi P, DeCarli M, Manetti R, et al. Il-4 (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by TH1 or TH2 human T cell clones. J Immunol 1992;149:2977 – 83. [23] Parronchi P, Mohapatra S, Sampognaro S, et al. Effects of interferon-alpha on cytokine profile, T cell receptor repertoire and peptide reactivity of human allergen-specific T cells. Eur J Immunol 1996;26:697 – 703. [24] Burns Jr RP, Ferbel B, Tomai M, et al. The imidazoquinolones, imiquimod and R-848 induce functional, but not phenotypic, maturation of human Langerhans’ cells. Clin Immunol 2000;94:13 – 23. [25] Suzuki H, Wang B, Shivji GM, et al. Imiquimod, a topical immune response modifier, induces migration of Langerhans’ cells. J Invest Dermatol 2000;114: 135 – 41. [26] Tomai MA, Imbertson LM, Stanczak TL, et al. The immune response modifiers imiquimod and R-848 are potent activators of B lymphocytes. Cell Immunol 2000;203:55 – 65. [27] Tyring S. Imiquimod applied topically: a novel immune response modifier. Skin Therapy Lett 2001;6: 1 – 4. [28] Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 My088-dependent signaling pathway. Nat Immunol 2002;3:196 – 200. [29] Read RC, Wyllie DH. Toll receptors and sepsis. Curr Opin Crit Care 2001;7:371 – 5. [30] Fife KH, Ferenczy A, Douglas Jr JM, et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily or three times a day. Sex Transm Dis 2001;28: 226 – 31. [31] Beutner KR, Spruance SL, Hougham AJ, et al. Treatment of genital warts with an immune-ressponse modifier (imiquimod). J Am Acad Dermatol 1998; 38:230 – 9. [32] Edwards L, Ferenczy A, Eron L, et al. Self administered topical 5% imiquimod cream for external genital warts. HPV Study Group. Human Papilloma Virus. Arch Dermatol 1998;134:25 – 30. [33] Beutner KR, Tyring SK, Trofatter KF, et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998;42:789 – 94. [34] Tyring SK, Arany T, Stanley MA, et al. A randomized, controlled molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis 1998;178:551 – 5. [35] Syed TA, Hadi SM, Qureshi ZA, et al. Treatment of external genital warts in men with imiquimod 2%
[36]
[37]
[38] [39] [40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
299
cream. A placebo-controlled, double-blind study. J Infect 2000;41:148 – 51. Gilson RJ, Shupack JL, Friedman-Kien AE, et al. A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIVinfected patients. AIDS 1999;13:2397 – 404. Garland SM, Sellors JW, Wikstrom A, et al. Imiquimod 5% cream is a safe and effective self-applied treatment for anogenital warts-results of an open-label multicentre phase III B trial. Int J STD AIDS 2001; 12:722 – 9. O’Mahony C. Difficult wart cases—use of imiquimod cream 5%. Int J STD AIDS 2001;12:400 – 3. Eggleton S, Tang A. Management of difficult anogenital warts. Sex Trans Infect 1999;75:449 – 50. Weinberg JM, Stewart A, Stern JO. Successful treatment of extensive condyloma accuminata of the inguinal area and thigh with topical imiquimod cream. Acta Derm Venerol 2001;81:76 – 7. Maitland JE, Maw R. An audit of patients who have received imiquimod cream 5% for the treatment of anogenital warts. Int J STD AIDS 2000;11:268 – 70. Hengge UR, Stark R. Topical imiquimod to treat intraepidermal carcinoma. Arch Dermatol 2001;137: 709 – 11. Moresi JM, Herbert CR, Cohen BA. Treatment of anogenital warts in children with topical 0.05% Podofilox gel and 5% imiquimod cream. Pediatr Dermatol 2001;18:448 – 50. Schaen L, Mercurio MG. Treatment of human papilloma virus in a 6-month-old infant with imiquimod 5% cream. Pediatr Dermatol 2001;18:450 – 2. Wagman FA, Estape RE, Angiolo R, et al. Self-administered topical 5% imiquimod cream for external anogenital warts in adolescent girls. Obstet Gynecol 2001;97(4 Suppl 1):S14. Nelson AL. The importance of patient and healthcare provider perceptions in the evaluation of imiquimod and other prior treatments for anogenital warts. Int J STD AIDS 2002;13:29 – 35. O’Mahony C, Law C, Gollick HP, et al. New patient applied therapy for anogenital warts is rated favorably by patients. Int J STD AIDS 2001;12:565 – 70. Kuwahara RT, Skinner Jr RB. Granuloma annulare resolved with topical application of imiquimod. Pediatr Dermatol 2002;19(4):368 – 71. Langley PC, Tyring SK, Smith MH. The cost effectiveness of patient-applied versus provider-administered intervention strategies for the treatment of extragenital warts. Am J Manag Care 1999;5:69 – 77. Hengge UR, Esser S, Schultewolter T, et al. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol 2000;143:1026 – 31. Sparling JD, Checketts SR, Chapman MS. Imiquimod for plantar and periungual warts. Cutis 2001;68: 397 – 9. Weisshaar E, Gollnick H. Potentiating effect of imiquimod in the treatment of verrucae vulgares in immuno-
300
[53]
[54] [55]
[56]
[57]
[58]
[59]
[60]
[61]
R.B. Skinner Jr / Dermatol Clin 21 (2003) 291–300 compromised patients. Acta Derm Venerol 2000;80: 305 – 7. Rinne D, Linhart C, Schofer H. Lip papillomatosis in immunodeficiency: therapy with imiquimod. Br J Dermatol 2000;142:196 – 7. Schwab RA, Elston DM. Topical imiquimod for recalcitrant flat warts. Cutis 2000;65:160 – 2. Oster-Schmidt C. Imiquimod: a new possibility for treatment of resistant verrucae planae. Arch Dermatol 2001;137:666 – 7. Bernstein DI, Miller RL, Harrison CJ. Adjuvant effects of imiquimod on a herpes simplex virus 2 glycoprotein vaccine in guinea pigs. J Infect Dis 1993;167:731 – 5. Gilbert J, Drehs MM, Weinberg JM. Topical imiquimod for acyclovir-unresponsive herpes simplex virus 2 infection. Arch Dermatol 2001;137:1015 – 7. Liota E, Smith KJ, Buckley R, et al. Imiquimod therapy for molluscum contagiosum. J Cutan Med Surg 2001;4:76 – 82. Syed TA, Goswami J, Ahmadpour OA, et al. Treatment of molluscum contagiosum in males with an analog of imiquimod 1% cream. A placebo-controlled doubleblind study. J Dermatol 1998;25:309 – 13. Barba AR, Kapoor S, Berman B. An open label safety study of topical imiquimod 5% cream in the treatment of molluscum contagiosum in children. Dermatol Online J 2001;7:20. Skinner RB, Ray S, Talinin NY. Treatment of molluscum contagiosum with topical 5% imiquimod cream. Pediatr Dermatol 2000;17(5):420.
[62] Brown Jr CW. Recalcitrant molluscum contagiosum in an HIV-afficated male treated successfully with topical imiquimod. Cutis 2000;65:363 – 6. [63] Strauss RM, Doyle EL, Mohsen AH, et al. Successful treatment of molluscum contagiosum with topical imiquimod in a severly immunocompromised HIV-positive patient. Int J STD AIDS 2001;12:264 – 6. [64] Stokes JR, Sorkness RL, Kaplan MR, et al. Attenuation of virus-induced airway dysfunction in rats treated with imiquimod. Eur Respir J 1998;11:324 – 9. [65] Castleman WL, Brundage-Anguish LJ, Kreitzer L, et al. Pathogenesis of bronchiolitis and pneumonia induced in neonatal and weanling rats by parainfluenza (Sendai) virus. Am J Pathol 1987;129:277 – 86. [66] Arevalo I, Ward B, Miller R, et al. Successful treatment of drug-resistant cutaneous leishmaniasis by use of imiquimod, an immunomodulator. Clin Inf Dis 2001; 33:1847 – 51. [67] Goldstein A, Spinelli N, Groper C, et al. Self-administered topical 5% imiquimod cream for the treatment of alopecia areata [poster]. Presented at the American Acadmey of Dermatology’s 59th Annual Meeting. Washington DC, March 2001. [68] Kahn AM. Imiquimod as adjunct for vitilgo (letter). J Clin Dermatol 1998;1:8 – 9. [69] Cutler K, Kagen MH, Don PC, et al. Treatment of facial verrucae with topical imiquimod cream in a patient with human immunodeficiency virus. Acta Derm Venerol 2000;80:134 – 5.
Dermatol Clin 21 (2003) 301 – 309
Topical cidofovir for the treatment of dermatologic conditions: verruca, condyloma, intraepithelial neoplasia, herpes simplex and its potential use in smallpox Jorge R. Toro, MDa,*, Samuel Sanchez, MDa,b, George Turiansky, MDc, Andrew Blauvelt, MDd a
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Room 7012, Rockville, MD 20892-7231, USA b Department of Dermatology, University of Puerto Rico, Puerto Rico c Walter Reed Army Medical Center, Washington DC, USA d Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Cidofovir is a promising new drug that demonstrates pharmacologic activity against a wide variety of DNA viruses. Recent studies have shown that topical cidofovir (1% gel or cream) is effective in the treatment of recalcitrant and otherwise unmanageable viral cutaneous lesions induced by herpesviruses, poxviruses, and papillomaviruses. The authors review the pharmacology and uses of cidofovir in selected infectious dermatologic conditions.
Mechanism of action and pharmacology Cidofovir ([S]-1-[3-hydroxy-2-phosphonylmethoxypropyl] cytosine; HPMPC, Vistide) is a nucleotide analog of deoxcytidine monophosphate. In 1997 the U.S. Food and Drug Administration (FDA) approved an intravenous formulation of cidofovir for the treatment of cytomegalovirus retinitis in patients with AIDS [1]. Cidofovir also has antiviral activity against other DNA viruses, including herpes simplex virus (HSV) [2], human papillomavirus (HPV) [3,4], and molluscum contagiosum virus [5,6]. Cidofovir diphosphate, cidofovir’s active metabolite, acts as
* Corresponding author. E-mail address:
[email protected] (J.R. Toro).
a competitive inhibitor of DNA polymerase [7,8]. The agent inhibits viral DNA polymerase more selectively than human DNA polymerase [9], and it is not dependent upon thymidine kinase for activation. Thus, strains of HSV that are resistant to acyclovir, ganciclovir, or foscarnet are usually sensitive to cidofovir [10]. The pharmacokinetic properties of cidofovir in humans have only been reported for the intravenous preparation [11,13]. Approximately 90% of cidofovir is recovered in the urine within 24 hours after a single intravenous (IV) bolus dose. Probenecid reduces the renal clearance of cidofovir. Therefore, cidofovir can be eliminated from the systemic circulation by active tubular secretion in addition to filtration. The IV formulation of cidofovir can be extemporaneously compounded for topical use. It costs approximately $50 to $75 per gram when compounded in a cream base containing a 3% concentration. No studies have been performed to investigate the bioavailability of topical or intralesional cidofovir in humans; however, several animal studies on topical administration of cidofovir are available. Cundy et al [11] observed the pharmacokinetic properties of cidofovir in African green monkeys by IV, oral, and subcutaneous routes of administration. In the latter investigations, subcutaneous bioavailability of cidofovir was noted to be 9.8% to 15.8%. Recently, Cundy et al [12] also investigated the availability of
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00116-X
302
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
topical cidofovir on abraded and intact skin of rabbits; the bioavailability of topical cidofovir was 0.2% to 2.1% in intact skin and 41% in abraded skin. Furthermore, these investigators found that the bioavailability of cidofovir was enhanced in vehicles containing propylene glycol. The authors have used Dermovan (Galderma Laboratory Inc, Forth Worth, TX), a vehicle that contains propylene glycol, to compound topical cidofovir. The authors believe that the combination of a vehicle such as Dermovan and the use of occlusion significantly enhances the delivery of cidofovir. Most likely, occlusion increases the efficacy and absorption of the drug by increasing the skin surface area, hydration, and temperature, as well as by maintaining a reservoir of the drug within the stratum corneum. Inflammation and erosions produced by this form of delivery might also further increase absorption. The authors did not occlude facial skin or mucous membranes because of the known increased absorption of topical formulations in these areas. Topical application of cidofovir on intact rabbit skin leads to negligible systemic exposure to the drug. In humans, a systemic adverse reaction has been reported in a single patient treated with intralesional cidofovir (2.5 mg/mL) for recurrent laryngeal papillomatosis [14]. This individual developed ‘‘precardial complaints,’’ but no cardiac abnormalities were found. The pharmacokinetics of 0.3% and 1% cidofovir gel in HSV subjects has been described briefly [2]. Nephrotoxicity, neutropenia, and metabolic acidosis are potential serious systemic adverse effects of IV cidofovir therapy. In a bone marrow transplant patient with chronic renal failure and treatment-resistant condyloma, Bienvenu et al [15] recently reported topical-induced acute renal failure. After topical cidofovir application (1% once daily for 5 days, then 4% for 12 days), the lesions improved, whereas local erosions appeared. Acute renal failure with features of tubular acidosis occurred at day 19, but spontaneous recovery was observed after cidofovir was withdrawn. Cidofovir has been reported to be embryotoxic in animals, including rats and rabbits. Furthermore, fetal soft tissue and skeletal anomalies have been reported in rabbits treated with 1.0 mg/kg IV daily. The use of cidofovir, even in topical form, should therefore be avoided in infants and pregnant women. Andrei et al [16] reported that in vitro treatment of HPV-positive cells (compared with normal primary human keratinocytes) with cidofovir results in a concentration- and time-dependent inhibition of cell proliferation. These authors also measured different parameters of apoptosis in HPV-positive cell lines,
including induction of caspase-3 protease activity, translocation of phosphatidylserine from the inner part of the plasma membrane to the outer layer, disintegration of the nuclear matrix protein, DNA fragmentation, and the number of cells in apoptotic phase following cell cycle analysis. These studies showed that cidofovir induced apoptosis in HPVpositive cells. They also found that treatment of HPV-positive cells with cidofovir was associated with the accumulation of the tumor suppressor proteins p53 and Rb, as well as the cyclin-dependent kinase inhibitor p21/WAF-1. These findings suggest that the regression of papillomatous tumors observed in patients treated with cidofovir might be caused by (at least in part) the induction of apoptosis.
Clinical effects Anogenital squamous cell carcinoma in situ HIV-infected individuals are at increased risk for persistent HPV infection and HPV-associated anogenital intrasquamous epithelial neoplasms, including squamous cell carcinoma (SCC). Anogenital SCC is emerging as a major problem in HIV-infected individuals [17]. Homosexual and bisexual men with HIV are also at increased risk for persistent HPV infection and anogenital squamous intraepithelial lesions (ASIL), with prevalence rates of 20% to 45% [18 – 20]. Risk factors for ASIL include low CD4+ T cell counts and HPV infection [21,22]. Studies on the natural history of anal disease have shown that ASIL can progress to high-grade disease in a relatively short time and that spontaneous regression of high-grade ASIL is rare [19,20]. Like cervical cancer, anogenital SCC is associated with particular oncogenic HPV subtypes, specifically types 16, 18, 31, 33, and 51 [23,24]. Perianal Bowen’s disease (SCC in situ) is also most likely associated with HPV infection [25]. Recently, the authors treated three AIDS patients with recurrent anogenital Bowen’s disease that was resistant to cryotherapy and electrosurgery with topical cidofovir. Clinically, the patients exhibited multiple inguinal, perineal, and perianal pigmented papules in a mosaic pattern. Some areas exhibited multiple solitary lesions, whereas other areas showed confluence of papules to form plaques. The surfaces of the lesions were velvety with a dark brown, pink, or white discoloration. Anoscopic exam did not reveal anal lesions. Microscopic examination of lesional skin revealed SCC in situ. Sections revealed fullthickness atypia of the epidermis with cell crowding
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
and an irregular ‘‘windblown’’ arrangement of the nuclei and scattered atypical mitotic. Patients were treated with 3% cidofovir in Dermovan once daily, 5 days a week, for 3 weeks. Topical 3% cidofovir was compounded as follows: 15 mL of cidofovir (75 mg/mL) was mixed with 22.5 g of Dermovan. The most common adverse effects were irritation and painful erosions during the first 2 weeks of treatment. All patients developed erythema and painful erosions at sites of previous lesions 5 to 13 days following application of the drug. Upon development of erosions, therapy was withheld for 3 to 5 days because erosions healed within 4 to 5 days. Treatment was then continued for a total of 3 weeks. After completion of treatment, lesions healed with postinflammatory hypopigmentation and hyperpigmentation. Surrounding perilesional skin appeared to be unaffected by treatment. No systemic side effects were noted. The patients achieved complete remission without clinical and histologic evidence of remaining disease 3 months following treatment. All individuals achieved complete remission without clinical and histologic evidence of remaining disease 18 months after discontinuation of therapy. It is unlikely that concomitant highly active antiretroviral therapy (HAART) therapy contributed to the regression of SSC in situ in these men because all patients initially developed lesions while receiving HAART for more than 6 months. In addition, there was no apparent difference in absolute CD4+ T cell counts and viral loads before and after topical therapy with 3% cidofovir. Furthermore, none of the antiretroviral agents that target HIV has known or predicted antiviral activity against HPV or any known anticancer activity. Current therapeutic modalities for SCC in situ such as cryosurgery and 5-fluorouracil might be suboptimal because patients commonly experience multiple recurrences. In addition, anogenital SCC in situ is commonly multifocal, involving a large surface area, making complete surgical excision difficult. Thus, effective topical treatment of anogenital SSC in situ with antiviral medications might represent a significant therapeutic advance. As mentioned above, HIV+ homosexual and bisexual men are at increased risk for persistent HPV infection, ASIL (including SCC in situ), and invasive anal SCC [17 – 20]. Recently, it was shown that screening for anal ASIL in homosexual and bisexual men at all stages of HIV infection is cost effective [26]. The natural history of perianal ASIL is uncertain; however, recent studies of the natural history of anal disease have shown that the early stage of ASIL can progress to high-grade lesions in a short time period and that regression of high-grade
303
ASIL is rare. Although HAART can suppress HIV replication for at least 2 years [27,28], the long-term impact of potent combination antiretroviral therapy on the incidence of new anal and perianal neoplasia and regression is unknown. It is possible that the risk of ASIL, SCC in situ, and SCC might increase because of the longer life expectancy of HIV-infected individuals with sustained viral suppression [27]; therefore, early eradication of these lesions might significantly decrease morbidity and mortality of HPV-associated disease. In this regard, safe, effective, nonsurgical treatment modalities for HPV-associated anogenital lesions are needed. The prompt and dramatic response to topical cidofovir in the treatment of SSC in situ suggests that anogenital SCC in situ might be (in some cases) virally induced. Further studies on the use of topical cidofovir in benign and malignant HPV-associated mucocutaneous diseases are needed. Vulvar intraepithelial neoplasias Vulvar intraepithelial neoplasia is difficult to eradicate completely without extensive surgical intervention. Koonsaeng et al [29] reported that cidofovir might have a therapeutic role in this disease. She reported that topical cidofovir 1% in Beeler base (cetylic alcohol, 15 g; white wax, 1 g; propylene glycol, 10 g; sodium lauryl sulfate, 2 g; and water, 72 g) completely eradicated extensive vulvar intraepithelial neoplasia III in a 43-year-old woman with a 20-year history of genital warts who refused surgical resection. Human papillomavirus (HPV) has been clearly associated with such lesions in the female genital tract. Recently, Snoeck et al [30] reported on the use of cidofovir as a novel treatment of cervical intraepidermal neoplasia. Cidofovir 1% in gel was applied three times every other day on the cervix under colposcopic examination by a gynecologist. Within 1 month after the start of treatment, the cervix was removed surgically. Histology and Polymerase Chain Reaction (PCR) for HPV DNA were performed on surgical specimens. In seven of the 15 patients there was complete histologic response; four of these seven also has no evidence of HPV DNA by PCR. Thus, this report documented that cidofovir 1% gel partially or completely inhibited cervical dysplasia lesions after only three applications, and the drug effects were specific to dysplastic epithelium. Bowenoid papulosis Bowenoid papulosis is another tumor strongly associated with HPV infection that is difficult to
304
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
differentiate clinically and pathologically from SSC in situ. Treatment alternatives include surgical excision, laser therapy, cryotherapy, or 5-fluorouracil. Snoeck et al [31] reported on a 38-year-old homosexual man with AIDS who presented with a fibrotic lesion of the penis that microscopically showed Bowenoid papulosis. Initially, the patient was treated with 1% topical cidofovir reformulated in Beeler base (see preceding section) once a daily for 5 days. At 2 weeks, the patient was treated for another cycle of once daily application for 5 days with improvement of the lesion. One month after beginning cidofovir therapy, significant improvement was noted and a third application course (5 days) was initiated. Two months later, the lesion appeared to be completely healed, and at almost 4 years after therapy there was no evidence of recurrence. Condylomata acuminata Anogenital condylomata acuminata are the most frequent clinical manifestation of genital HPV infection. Concomitant infection of HIV and HPV is frequent (26 – 60% in men). Snoeck et al [3] first reported on the use of topical cidofovir for relapsing anogenital condylomata in three individuals with AIDS. A 44-year-old homosexual man with recurrent penile lesions that were resistant to podofilox and curretage was treated with 1% topical cidofovir once daily for 5 days. On day 7, the patient developed small ulcerations at the sites of previous lesions. The lesions cleared and he remained free of disease 1 year later. Similarly, a 20-year-old man with recurrent genital condylomata that was resistant to electrodessication was treated with 1% topical cidofovir. After 11 days, verrucous lesions were replaced with erosions that healed in 7 days. Six months later, no recurrence was evident. A 34-year-old woman with recurrent condyloma acuminata of the vulva and surrounding skin was clear after treatment with 1% topical cidofovir gel applied once daily for 5 weeks. She remained disease-free for 6 months following discontinuation of therapy. Snoeck et al [32] conducted the first double-blind, placebo-controlled study of the use of topical cidofovir for the treatment of genital HPV infections in immunocompetent Belgian patients. Thirty patients were enrolled in the study; 19 received cidofovir and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine of 19 (47%) patients in the cidofovir group had a complete response, compared with none of the patients in the placebo group ( P = 0.006). None of the patients in the cidofovir group experi-
enced disease progression, compared with five (45%) of 11 patients in the placebo group. Side effects observed in both groups were comparable. Treatment options for anogenital warts in patients infected with HIV are unsatisfactory because they fail to eradicate latent HPV. Matteelli et al [33] conducted a study to determine the efficacy of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected patients. They conducted a randomized, placebo-controlled, single-blind, crossover pilot study of either 1% cidofovir cream or placebo applied once daily, 5 days a week for 2 weeks followed by 2 weeks of observation. Six patients were randomized to 1% cidofovir cream and six to placebo. The placebo patients eventually received 1% cidofovir cream. Thus, 12 treatment rounds of cidofovir were compared with six rounds of placebo. A reduction of more than 50% in the total wart area was achieved by seven cidofovir treatments (58%), compared with no reductions in patients treated with placebo ( P = 0.02). Local erosion at the site of application occurred in 10 of the 12 patients treated with cidofovir, as compared with none of the six subjects in the placebo group ( P < 0.001). These investigators found that 1% cidofovir cream was significantly more effective than vehicle cream in the eradication of anogenital warts, even in HIVinfected patients. Verruca vulgaris Verrucae represent a therapeutic challenge in immunocompetent and immunocompromised individuals. Zabawski et al [4] reported on two cases of verruca vulgaris refractory to conventional therapy that responded to treatment with topical cidofovir. A 7-year-old girl with hundreds of verrucae on both legs was treated with topical 3% cidofovir cream twice daily for 10 days. She developed local inflammation followed by postinflammatory hyperpigmentation and subsequently complete clearing of the lesions. She remained completely free of warts for more than 40 weeks. Similarly, a 13-year-old girl who presented with verrucae of the distal fingers of both hands that were resistant to laser destruction was treated with cidofovir 3% cream base once daily for 10 weeks. She developed minor local irritation acutely, but she was free of lesions at the end of therapy and 12 months following treatment. Topical cidofovir has also been found to be effective in the treatment of verruca in HIV-infected individuals. Davis et al [34] reported on a 37-year-old HIV+ woman who presented with a large verrucous plaque involving her right foot. HPV-66 was iden-
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
tified in the lesional skin biopsy sample. The wart responded rapidly to topical cidofovir therapy. Recently, Calista et al [35] reported on a case of a 45-year-old man with AIDS and multiple warts on his gingival mucosa that were recalcitrant to conventional therapies but were successfully treated with cidofovir 1% cream. This represents the first case in which topical cidofovir has been reported to be effective for the treatment of a HPV infection of the oral mucosa. Calista [36] treated 14 HIV+ individuals with 1% cidofovir cream, 10 of whom had extensive HPV lesions and four of whom had molluscum contagiosum (MCV); all patients were reportedly unresponsive to conventional therapies. The subjects had been on treatment with HAART for almost on1 year before applying cidofovir cream. Thirteen of the 14 patients (92.8%) completed the therapy; one dropped out. All 13 patients eventually responded. In nine individuals, the lesions regressed 2 weeks from the end of the first cycle of therapy. Three patients needed two cycles and the last three consecutive courses of topical therapy before the lesions healed. No recurrence was observed in nine patients over an average follow-up period of 24.1 months (range 12 – 30 months). Four patients had isolated relapses that were successfully treated with simple curettage. All patients experienced local side effects, including inflammation, erosions, and burning sensations. Postinflammatory hyperpigmentation was observed in six cases, whereas two patients developed local transient alopecia on the beard area. No systemic side effects were noted. Molluscum contagiosum MCV commonly affects children and individuals who are immunocompromised. The prevalence of MCVinfection among HIV-infected individuals ranges from 5% to 18%. Children with AIDS who exhibit extensive and recalcitrant MCV suffer from increased morbidity and disfigurement. Recalcitrant MCV in these patients represents a therapeutic challenge. In 1999 Meadows et al [5] reported that cidofovir induced clearing of MCV in three HIV+ adults who presented with extensive MCV lesions that were unresponsive to various treatments. Two patients received IV cidofovir and the third was treated with topical cidofovir. One patient demonstrated dramatic clearing of MCV lesions when IV cidofovir therapy was started for his treatment for coexisting CMV retinitis. In the second patient, IV cidofovir therapy was started for CMV retinitis and extensive facial MCV involvement. One month following treatment,
305
all clinical evidence of MCV had resolved. Both patients remained clear of MCV while receiving maintenance IV cidofovir at the time of the report. A third individual, 37-year-old man with extensive MCV facial lesions, was treated with cidofovir compounded as a 3% cream in Dermovan once daily, 5 days a week, for a total of 2 weeks. This patient experienced moderate inflammation during therapy and complete resolution of lesions 1 month later. Topical cidofovir has also been found to be efficacious for the treatment of MCV in HIV immunocompromised individuals. Davies et al [37] reported that topical cidofovir was effective in the treatment of MCV in a 12-year-old boy with Wiskott-Aldrich syndrome. More than 75% of the patient’s body surface was covered with MC lesions. Within 2 to 3 weeks, the lesions treated with cidofovir showed acute inflammation followed by complete resolution. Recently, the authors reported the successful use of topical 3% cidofovir in Dermovan in the treatment of recalcitrant facial and generalized MCV in two children with AIDS [6]. These children suffered from severe social isolation because of their facial disfigurement. Their MCV lesions were refractory to numerous therapeutic modalities, including liquid nitrogen, cantharidin, and 0.05% tretinoin gel. Both children had MCV lesions, elevated viral loads, and low CD4 T cell counts despite HAART for a median of 24 months. The patients exhibited hundreds of MC lesions that were disseminated over the entire body, including the face and perineal area. The authors found that topical cidofovir was effective in the treatment of generalized and recalcitrant MC in children with AIDS. The authors’ two patients had refractory MCV despite extensive treatment with HAART. Most nucleoside analogs are relatively specific for HIV except lamivudine, which has also shown activity against hepadena viruses [38]. None of the agents that target HIV has known predicted antiviral activity against MCV. Although these patients received concomitant HAART during topical cidofovir therapy, there was suboptimal control of HIV replication. It is therefore unlikely that HAART was responsible for the resolution of the MCV lesions. Topical cidofovir is a nonsurgical method that avoids the potential significant renal toxicity associated with systemic therapy. The authors’ findings suggest that topical 3% cidofovir is a safe and potentially effective treatment in recalcitrant MCV in children. Double-blind control trials of topical cidofovir in Dermovan for MCV in HIV-infected children will confirm the authors’ preliminary results.
306
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
Kaposi’s sarcoma Cidofovir has been shown to have marked activity against Kaposi’s sarcoma (KS)-associated herpes virus (KSHV; HHV-8) in vitro. Few studies have been performed to investigate the efficacy of cidofovir on KSHV in vitro, KSHV viremia, and KS lesions [39 – 41]. Kedes and Ganem evaluated the anti-KSHV activity of various antiviral agents (including cidofovir) in vitro [42]. They found that cidofovir was a more potent inhibitor of KSHV than acyclovir, cidofovir, foscarnet, and ganciclovir. Similarly, Medveczky et al [43] showed that cidofovir strongly inhibited KSHV DNA synthesis and virus secretion in vitro. Mazzi et al [44] described the effect of cidofovir treatment on cutaneous lesions and KSHV viremia in two AIDS patients with KS. The patients had developed multiple cutaneous KS lesions despite long-term, efficient HAART and treatment with multiple-agent cytotoxic chemotherapy (vinblastine, vincristine, and interferon-a). Cidofovir was administered at a dose of 5 milligrams per kilogram IV at 1-week intervals for the first two administrations and every 2 weeks thereafter. The overall cidofovir treatment period was 10 months for one patient and 12 months for the second patient. Regression of all cutaneous KS lesions was observed after 3 months of treatment. KSHV viremia also became undetectable. No adverse reactions occurred during therapy with cidofovir. Treatment was stopped after a 6- and 8-month period in which patients were period free of KS. Both patients experienced reactivation of old lesions or new KS lesions at 6 and 15 months after the end of treatment, respectively. These results, although promising, should be interpreted with caution. Unpublished results from the National Cancer Institute trial suggest that cidofovir is not effective for KS. Herpes simplex virus infection Various reports suggest that cidofovir is efficacious in the treatment of HSV infection. SaintLeger et al [45] reported on a case of an AIDS patient who presented with a history of recurrent scrotal ulcerations secondary to HSV type II (HSV-II). After several hospitalizations and treatment with acyclovir, valacyclovir, and foscarnet, IV cidofovir was initiated and complete healing was obtained. This particular viral strain of HPV-II was found to be resistant to acyclovir, valacyclovir, and foscarnet. Similarly, Lateef et al [46] reported on the use of topical cidofovir 1% in the treatment of a 4-year-old
boy with AIDS and a facial HSV ulcer. Initially, the patient was treated with oral and IV acyclovir with only partial response. The patient then developed an aggressive recurrence and cultures demonstrated acyclovir-resistant HSV. Although foscarnet and fluorothymidine were added, the patient developed a 10 cm ulcer extending across the cheeks bilaterally. Prior treatment was stopped and 1% cidofovir cream every day was started. Several weeks later, the ulcer was healing well, with granulation tissue at the ulcer base. The authors comment that this is the first report that demonstrates the effectiveness and safety of topical cidofovir as an alternate treatment of multi – drug-resistant HSV in an immunocompromised patient. Snoeck et al [47] reported on the use of topical cidofovir in persistent mucocutaneous HSV infections in two individuals. The first patient had AIDS and a chronic perineal HSV-II ulceration that was unresponsive to acyclovir. The patient did not tolerate foscarnet, so daily topical cidofovir 3% gel was instituted. After 3 days of treatment, the lesions completely resolved; however, the lesions recurred 3 weeks later. Subsequent repeat treatment with daily application of cidofovir gel for 3 days again led to complete resolution of the lesion. A second recurrence 7 weeks later was also successfully treated with topical cidofovir. The second patient reported by Snoeck was a bone marrow transplant recipient who experienced severe oral HSV type I infection that was resistant to acyclovir and foscarnet. Two courses of topical cidofovir resulted in the emergence of an acyclovir-susceptible strain that then responded to treatment with acyclovir. Lalezari et al [48] conducted a randomized, double-blind, multicenter trial to evaluate the safety and efficacy of cidofovir gel for treatment of acyclovir-resistant HSV infections in 30 AIDS patients. Eleven patients received 0.3% gel, nine patients received 1.0% gel, and 10 patients were treated with a placebo gel once daily for 5 days. Half of the cidofovir-treated patients and none of the10 placebotreated patients demonstrated complete healing or greater than 50% improvement of the infection. One third of cidofovir-treated patients had complete healing in contrast with none of the placebo-treated patients. Viral shedding ceased in 87% of 15 cidofovir-treated patients and in none of the placebotreated patients. Application site reactions occurred in 25% of cidofovir-treated patients and 20% of placebo-treated patients. Cidofovir-treated patients showed a median of 21 days to achieve a complete or good response and a median of 2 days to have a negative HSV culture.
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
Smallpox Smallpox is caused by infection with the variola virus, a member of the Orthropoxvirus genus. Vaccination against smallpox is performed by inoculation with the vaccinia virus, a related Orthopoxvirus. Because of widespread vaccination programs, smallpox was officially eradicated from the world in December 1979; however, rare stocks of virus were preserved in restricted laboratories. Because of its potential use in bioterrorism, the identification of drugs with antiviral activity against the variola virus has become important. Furthermore, vaccination for smallpox with vaccinia virus can cause severe infections in immunocompromised individuals [49], and drugs are needed for this disease as well. Smee et al [50] reviewed the literature and reported on the characterization of wild-type (WT) and cidofovir-resistant (CDV-R) isolates of monkeypox and vaccinia viruses. CDV-R cytomegaloviruses have been isolated from treated patients [51] or derived by cell culture passage of WT viruses under drug pressure [52]. Mutations were found in the viral DNA polymerase gene that conferred drug resistance [53,54]. Resistance to cidofovir results in crossresistance to other antiviral drugs. The most serious clinical consequence of infection with drug-resistant viruses is the inability to treat the disease effectively with the specific medication and sometimes with other similar-acting drugs. It will be difficult to prove that cidofovir works against smallpox, because the disease was declared to be eradicated. It is therefore important to identify an appropriate animal model to study smallpox before the remaining stocks of variola are destroyed. In this regard, cidofovir has been used to control infection in mice inoculated with the vaccinia virus [55 – 57]. Recently, Smee and colleagues have shown that cidofovir is active against 31 different strains of variola virus in vitro. They also showed that cidofovir can protect monkeys exposed to monkeypox virus. This is an important finding because monkeypox virus infections have recently been reported in humans living in the Democratic Republic of the Congo (leading to death of some) [58]. Of all drugs approved by the FDA, cidofovir is the most effective anti-Orthopoxvirus agent. In cases of smallpox threats or outbreaks, cidofovir could be used in conjunction with vaccination to treat and prevent infections; however, some experts doubt that any antiviral drug would prove effective against symptomatic smallpox. Cidofovir therapy might play a role during the window of time between initial infection and onset of disease [55]. Regardless, cidofovir
307
should be useful as therapy for immunocompromised individuals who have disseminated infection following vaccination with the vaccinia virus. Promising results have been reported of a development of oral form of a related drug to cidofovir, hexadecyloxy propyl-cidofovir (HDP-cidofovir), by Hosterler and colleagues at the Fifteenth International Conference of Antiviral Research in Prague [59]. Unlike cidofovir, HDP-cidofovir is 93% orally available in mice. In addition, it is 100 to 1000 fold more active than cidofovir against herpesvirus and cytomegalovirus in vitro. These researchers also found that HDP-cidofovir was 100 to 200 fold more active against cidofovir against poxviruses, including small pox.
Summary Cidofovir is a new antiviral drug that has a broad spectrum of activity against several DNA viruses. Many of the disorders caused by these viruses do not have satisfactory therapy, and given the efficacy of this agent in treating many of these conditions, it holds great promise. It is hoped that ongoing studies will confirm the initial anecdotal reports regarding its therapeutic efficacy and lack of systemic side effects. It is also hoped that the cost to formulate and use cidofovir topically will eventually decrease to a level that will allow more widespread use of this drug.
References [1] Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 1997;126:257 – 63. [2] Lalezari J, Schacker T, Feinberg J, et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997;176:892 – 8. [3] Snoeck R, Ranst MV, Andrei G, et al. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. N Engl J Med 1995;333:943 – 4. [4] Zabawski EJ, Sands B, Goetz D, et al. Treatment of verruca vulgaris with topical cidofovir. JAMA 1997; 278:z1236. [5] Meadows KP, Tyring SK, Pavia AT, et al. Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Derrnatol 1997;133:987 – 90. [6] Toro JR, Wood L, Turner M. Topical cidofovir: a novel
308
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] [18]
[19]
[20]
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309 treatment for recalcitrant molluseum contagiosum in HIV infected children. Arch Dermatol 2000;136: 983 – 5. Xiong X, Smith JL, Chen MS. Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation. Antimicrob Agents Chemother 1997;41:594 – 5. Snoeck R, Sakuma T, De Clercq E, et al. (S)-1(3-hydroxy-2-phosphonylmethoxypropy l)cyto- sine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother 1988;32:1839 – 44. Ho HT, Woods KL, Bronson JJ, et al. Intracellular metabolism of the antiherpes agent (S)-1-(3-hydroxy2-phosphonylmethoxypropyl)-cytosine. Mol Pharmacol 1992;4l:197 – 202. Mendel DB, Barkhimer DB, Chen MS. Biochemical basis for increased susceptibility to cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity. Antimicrob Agents Chemother 1995;39:2120 – 2. Cundy KC, Li ZH, Hitchcock MJ, et al. Pharmacokinetics of cidofovir in monkeys: evidence for a prolonged elimination phase representing phosphorylated drug. Drug Metab Dispos 1996;24:738 – 44. Cundy KC, Lynch G, Lee WA. Bioavailability and metabolism of cidofovir following topical administration to rabbits. Antiviral Res 1997;35:113 – 22. Cundy KC, Petty BG, Flaherty J, et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1995;39:1247 – 52. Snoeck R, Wellens W, Deslooovere C, et al. Treatment of severe recurrent laryngeal papillomatosis by local injections of (S)-I-(3- hydroxy- 2-phosphonylmethoxypropyl)-cytosine (cidofovir). Abstract presented at the 9th International Conference on Antiviral Research, Urbandai, Fuku-shima, Japan, May 19 – 24, 1996. Bienvenu B, Martinez F, Devergie A, et al. Topical use of cidofovir induced acute renal failure. Transplantation 2002;73:661 – 2. Andrei G, Snoeck R, Schols D, De Clercq E. Induction of apoptosis by cidofovir in human papillomavirus (HPV)-positive cells. Oncology Research 2001; 12:397 – 408. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDSassociated malignant disorders. Lancet 1998;4:415 – 28. Palefsky JM, Holley EA, Gonzales J, et al. Natural history of anal cytologic abnormalities and papillomavirus infection among homosexual men with group IV HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol 1992;5:1258 – 65. Critchlow CW, Surawicz Holmes KK, et al. Prospective study of high grade and squamous intraepidermal neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 1995;9:1255 – 62. Unger ER, Vernon SD, Lee DR, et al. Human papi11omavirus type in anal epithelial lesions is influenced by
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
human immunodeficiency virus. Arch Pathol Lab Med 1997;121:820 – 4. Palefsky JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for human papillomavirus infection of the anal canal on HIV-positive and HIV-negative homosexual men. J Infect Dis 1998;177:361 – 7. Palefsky JM, Shiboski S, Moss A. Risk factors for anal human papillomavirus infection and anal cytology abnormalities in HIV-positive and HIV-negative homosexual men. J Acquir Immnu Defic Syndr Hum Retrovirol. 1994;7:599 – 606. Palefsky JM, Holley EA, Ralston ML, et al. High incidence of anal high-grade squamous intraepithelial lesions among HIV-positive and HIV-negative homosexual/bisexual men. AIDS 1998;12:495 – 503. Della Torre G, Donghi R, Longoni A, et al. HPV DNA in intraepithelial neoplasia and carcinoma of the vulva and penis. Diagn Mol Pathol 1992;1:25 – 30. Ikenberg H, Spitz C, Schmitt B, et al. Human papillomavirus DNA on locally recurrent cervical cancer. Gynecol Oncol 1994;52:332 – 6. Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999;19: 1822 – 9. Hammer SM, Squires KE, Hughes MD, et al. for the AIDS Clinical Trials Group 320 Study Team. A control trial of two nucleoside analogues plus indinavir in persons with human imrnununodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997;337:725 – 33. Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and larnuvidine for HIV-1 infection, 100 week follow-up. JAMA 1998;280:35 – 41. Koonsaeng S, Verschraegen C, Freedman R, et al. Successful treatment of recurrent vulvar intraepithelial neoplasia resistant to interferon and isotretinoin with cidofovir. J Med Virol 2001;6:195 – 8. Snoeck R, Noel JC, Muller C, De Clercq E, Bossens M. Cidofovir, a new approach for the treatment of cervical intraepithelial neoplasia grade III (CIN III). J Med Virol 2000;60:205 – 9. Snoeck R, Van Laethem Y, De Clercq E, et al. Treatment of a bowenoid papulosis of the penis with local applications of cidofovir in a patient with acquired immunodeficiency syndrome. Arch Intern Med 2001;161: 2382 – 4. Snoeck R, Bossens M, Parent D, et al. Phase II doubleblind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection. Clin Infect Dis 2001;33:597 – 602. Matteelli A, Beltrame A, Graifemberghi S, et al. Efficacy and tolerability of topical 1% cidofovir cream for the treatment of external anogenital warts in HIVinfected persons. Sex Transm Dis 2001;28:343 – 6. Davis MD, Gostout BS, McGovern RM, et al. Large
J.R. Toro et al. / Dermatol Clin 21 (2003) 301–309
[35]
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
plantar wart caused by human papillomavirus-66 and resolution by topical cidofovir therapy. J Am Acad Dermatol 2000;43:340 – 3. Calista D. Resolution of recalcitrant human papillomavirus gingival infection with topical cidofovir. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90:713 – 5. Calista D. Topical cidofovir for severe cutaneous human papillomavirus and molluscum contagiosum infections in patients with HIV/AIDS. A pilot study. J Eur Acad Dermatol Venereol 2000;14:484 – 8. Davies EG, Thrasher A, Lacey K, et al. Topical cidofovir for severe molluscum contagiosum. Lancet 1999; 12;353:2042. Bartlett JG. Protease inhibitors for HIV infection. Ann Intern Med 1996;124:1086 – 8. Campbell TB, Borok M, Gwanzura L, et al. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi’s sarcoma clinical stage. AIDS 2000;14:2109 – 16. Naesens L, Snoeck R, Andrei G, et al. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. Antivir Chem Chemother 1997;8:1 – 23. Simonart T, Noel JC, De Dobbeleer G, et al. Treatment of classical Kaposi’s sarcoma with intralesional injections of cidofovir: report of a case. J Med Virol 1998; 55:215 – 8. Kedes DH, Gane D. Sensitivity of Kaposi’s sarcoma associated herpes virus replication to antiviral drugs: implications for potential therapy. J Clin Invest 1997; 99:2082 – 6. Medveczky MM, Orvath E, Lund T, et al. In vitro antiviral druG sensitivity of the Kaposi’s sarcoma-associated herpes virus. AIDS 1997;11:1327 – 32. Mazzi R, Parisi SG, Sarmati L, et al. Efficacy of cidofovir on human herpesvirus 8 viraemia and Kaposi’s sarcoma progression in two patients with AIDS. AIDS 2001;15:2061 – 2. Saint-Leger E, Fillet AM, Malvy D, et al. Efficacy of cidofovir in an HIV infected patient with acyclovir and foscarnet resistant herpes simplex virus infection. Ann Dermatol Venereol 2001;128:747 – 9. Lateef F, Donn PC, Kaufmann M, et al. Treatment of acyclovir-resistant foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998;134:1169 – 70. Snoeck R, Andrei G, Gerard M, et al. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55] [56]
[57]
[58]
[59]
309
with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin Infect Dis 1994;8:570 – 8. Lalezari J, Schacker T, Feinberg J, et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997;176:892 – 8. Kesson AM, Ferguson JK, Rawlinson WD, et al. Progressive vaccinia treated with ribavirin and vaccinia immune globulin. Clin Infect Dis 1997;25:911 – 4. Smee DF, Sidwell RW, Kefauver D, et al. Characterization of wild-type and cidofovir-resistant strains of camelpox, cowpox, monkeypox, and vaccinia viruses. Antimicrob Agents Chemother 2002;46: 21329 – 35. Jabs DA, Enger C, Forman M, et al, for The Cytomegalovirus Retinitis and Viral Resistance Study Group. Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. Antimicrob Agents Chemother 1998;42:2240 – 4. Smee DF, Barnett BB, Sidwell RW, et al. Antiviral activities of nucleosides and nucleotides against wildtype and drug-resistant strains of murine cytomegalovirus. Antivir Res 1995;26:1 – 9. Tatti KM, Stang H, Barnard D, et al. Mutations occur in highly conserved domains of murine cytomegalovirus DNA polymerase in cidofovir- and lobucavirresistant strains. Antivir Res 1998;37:A70. Sullivan V, Biron KK, Talarico C, et al. A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrob Agents Chemother 1993;37:19 – 25. Cohen J. Blocking small pox. A second defense. Science 2001;294:500. De Clercq E, Holy A, Rosenberg I. Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob Agents Chemother 1989;33:185 – 91. Neyts J, De Clercq E. Efficacy of (S)-1-(3-hydroxy-2phosphonylmethoxypropyl)cytosine for the treatment of lethal vaccinia virus infections in severe combined immune deficiency (SCID) mice. J Med Virol 1993;41: 242 – 6. Heymann DL, Szczeniowski M, Esteves K. Re-emergence of monkeypox in Africa: a review of the past six years. Br Med Bull 1998;54:693 – 702. Bradbury J. Orally available cidofovir derivative active against smallpox. Lancet 2002;359:1041.
Dermatol Clin 21 (2003) 311 – 320
Management of acyclovir-resistant herpes simplex virus Suneel Chilukuri, MDa, Ted Rosen, MDa,b,* a
Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA b Dermatology Service, Houston VA Medical Center, 2002 Holcombe, Houston, TX 77030, USA
Herpes simplex virus infections (HSV), which are common in the oral, perioral, and genital areas, are seen in normal and immunocompromised patients. After primary infection, HSV establishes long-term latency in the ganglia of sensory nerves and reactivates intermittently because of various precipitating factors. Among immunocompetent patients, HSV infections are usually self-limiting and do not require antiviral therapy [1 – 3]. Reactivation is rapidly controlled by the host’s immune system, and herpetic ulcers in these patients are typically small and only slightly painful. They resolve in 7 to 14 days and heal without significant scarring. While HSV usually causes mild infections in immunocompetent host, in the immunocompromised person the virus reactivates frequently and might continue to replicate, forming large, slowly expanding, long-lasting ulcerative lesions [4 – 11]. Moreover, potentially fatal herpetic encephalitis or disseminated HSV infection is possible [12,13]. Human herpes viruses are distributed worldwide. The principal mode of transmission is by way of direct contact with infected secreted material. Herpes virus type I (HSV I) is largely transmitted by nongenital contact. By contrast, herpes virus type II (HSV II) is primarily a sexually transmitted disease; however, this distinction is less evident today because there is an increasing frequency of HSV I as an etiology of anogenital infection. While the true prevalence of anogenital HSV is unknown, researchers estimate that, based on seropeidemiologic studies, approximately 16% of the population in the United States is infected
* Corresponding author. Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. E-mail address:
[email protected] (T. Rosen).
[14]. Moreover, some researchers report that more than 50% of patients with human immunodeficiency virus (HIV) have HSV II antibodies [15]. Acyclovir (ACV) has been the mainstay of initial and episodic treatment and of suppressive prophylaxis for recurrent HSV infections in immunocompetent and immunosuppressed patient populations for nearly two decades [16 – 19]. This drug remains the ‘‘gold standard’’ against which all other anti-HSV medications are compared. Unfortunately, the herpes virus can become resistant to ACV [20 – 24]. Prior to the AIDS epidemic, there were few published reports of acyclovir resistance, and all cases were in severely immunocompromised patients [24 – 30]; however, immunocompromise is no longer a rare event because of the increasing prevalence of HIV/AIDS patients and to a parallel increase in the numbers of iatrogenically immunocompromised transplant and cancer patients. Thus, establishment of alternate protocols to treat acyclovir-resistant (ACV-R) HSV has become imperative. Herein, the authors review currently available antiviral drugs and discuss research drugs that might be used in the future treatment of HSV infection, including infection resistant to ACV and its analogues.
Acyclovir, valacyclovir, and penciclovir Acyclovir (ACV) is currently the standard therapy for prophylaxis of patients at high risk for HSV reactivation and for therapy. In use for more than 15 years, ACV is a synthetic acyclic analog of the nucleoside guanosine with marked inhibitory activity against HSV types I and II. More recently, the valacyclovir (VCV), the 1-valyl ester of ACV, has been introduced. Following oral administration, VCV is almost completely converted to ACV, with the
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00093-1
312
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
bioavailability being three to five times greater than that observed with oral ACV [31 – 33]. While ACV-R HSV isolates will likely be resistant to VCV, this drug might help prevent such resistance if used initially in the treatment of HSV in immunocompromised patients. Because ACV resistance has been attributed to inadequate exposure to the drug, the higher concentration of ACV achieved with VCV might decrease the chance of developing resistance. As pointed out in a comprehensive review by Beutner [31], compliance is also improved in the majority of patients because optimal drug levels can be achieved with a simpler dosing regimen of VCV. As a result, there is reduced incidence of resistant virus. Penciclovir (PCV), a nucleoside analog, likewise has selective activity against HSV replication in vitro and in animal models [34,35]. Penciclovir and famciclovir, the oral preparation of the pro-drug of PCV, require activation by the same mechanisms as ACV. Because these drugs are dependent on the same enzymatic activation sequence as acyclovir, they are almost always ineffective in treating ACV-R virus infections [35]. As is true of VCV, use of famciclovir early in the course of HSV infection among those at high risk for development of ACV-R strains might be advisable. To inhibit viral DNA synthesis, ACV (and PCV) must first be phosphorylated to the monophosphate form by viral thymidine kinase (TK). Subsequent conversion of ACV – monophosphate (and PCV – monophosphate) to the triphosphate form is mediated by cellular enzymes. This ACV – triphosphate functions as a substrate for viral DNA polymerase and, when incorporated into the viral DNA, it acts as a chain terminator [36]. In addition, the viral DNA polymerase is inactivated by irreversible binding to the ACV-terminated DNA chain [37,38]. There is some debate regarding the best method for detection of ACV resistance in HSV isolates. A number of in vitro assays currently exist which can be employed to determine susceptibility of HSV to various antiviral agents. Such assays include plaque reduction, DNA hybridization, plating efficiency, and plaque autoradiography [39 – 41]. In general, the plaque reduction assay is considered to be the best in vitro test, and modifications of plaque autoradiography can allow for detection of resistant isolates in as little as 48 hours [41]. While most HSV strains are sensitive to low concentrations of ACV ( f 0.l mcg/ mL), resistant strains require concentrations in excess of 2 micrograms per milliliter to reduce the number of plaques formed in culture by 50% or more [42]. A major problem is that in vitro results do not always correlate with the in vivo situation (ie, treat-
ment outcome). For example, ACV-R strains of HSV are easy to isolate in vitro and can exist even in natural populations of virions from patients who have never received ACV [30]; however, such isolates are rarely a problem in the normal host [21,43,44]. For instance, while Straus et al [45] found resistant HSV strains (based on in vitro testing) in 8% of their patients, all persons with recurrent genital herpes responded to ACV therapy. Similarly, Fife and colleagues [46] found that all of their patients responded to acyclovir despite noting 3% of those studied harbored ACV-R HSV strains as determined by in vitro assay. There has been one report of an immunocompetent host who was unresponsive to oral ACV therapy even when given a suprapharmacologic dose of 4.8 grams per day [47]. In contrast with immunocompetent patients, clinically significant ACV-R herpes infection is being reported with increasing frequency in patients with compromised immune systems [48]. In 1982, Crumpacker and associates [20] first described HSV resistance to antiviral agents in immunocompromised hosts. Since that time, HSV resistance to ACV has been reported in patients with leukemia, tissue and organ transplants [21 – 24,49 – 52], and HIV disease [53 – 58]. In addition to persistent mucocutaneous lesions, these patients can also develop serious or fatal esophagitis, meningoencephalitis, or pneumonia caused by HSV [12,53,59 – 63]. While there are three known mechanisms of ACV resistance, the most prevalent mechanism is TK deficiency [64,65]. In the normal host, a population of HSV includes wild-type virus and TK mutants (1/1,000 to 1/10,000) [66]. Resistance might be induced in vitro by serial passage of the virus in the presence of ACV. While TK mutants are present even in immunocompetent patients, ACV in combination with host defenses results in the rapid elimination of both wild-type virus and mutants; however, because immunocompromised patients have infections with a considerably larger viral burden, a greater chance exists for selecting mutants to become the predominant organism [30,67,68]. Other rare mechanisms of resistance include alteration of available TK into an enzyme, which phosphorylates (and thereby activates) ACV poorly [64,66,69] and alteration of native viral DNA polymerase to become resistant to the inhibitory effect of ACV – triphosphate [29,70]. In light of the fact that herpes simplex virus leads to significantly severe disease in the immunocompromised patient, alternate therapy is warranted for patients who are ACV nonresponders. In view of the frequency of TK-deficient HSV mutants, antiviral agents that are not TK-dependent for activation have been developed.
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
Foscarnet Foscarnet (trisodium phosphonoformate hexahydrate) is a pyrophosphate analogue that was approved by the Food and Drug Administration (FDA) in 1992 for treatment of cytomegalovirus retinitis in patients with AIDS [71,72]. Working as a noncompetitive and reversible inhibitor of viral DNA polymerase and HIV reverse transcriptase, foscarnet does not require phosphorylation to inhibit viral replication [73 – 75]. It should therefore theoretically maintain activity against TK-deficient or TK-modified ACV-R strains of HSV. In uncontrolled trials and case reports, foscarnet treatment of ACV-R HSV disease does show some antiviral efficacy among AIDS patients [76 – 79] and bone marrow transplant patients [61,63]. While current dosing guidelines are strictly empiric, investigators have successfully treated ACV-R herpes infection by administering 40 to 60 milligrams per kilogram intravenously every 8 hours. The infusion is administered over 1 hour [53,77,80,81]. Others have treated resistant HSV with continuous foscarnet infusions to a total dosage of 120 to 200 milligrams per kilogram per day [57,82]. Treatment duration depends on clinical response. Major adverse effects are secondary to foscarnet’s elimination by glomerular filtration and tubular secretion. Adverse effects include renal toxicity, seizures, hypocalcemia, and hypomagnesemia [81]. Foscarnet dosage requires adjustment in patients with renal dysfunction. Renal toxicity is also a matter of concern among patients such as transplant recipients who are concomitantly exposed to other potentially nephrotoxic agents [83]. In an attempt to avoid adverse events, some clinicians have utilized topical formulations of foscarnet, including a 1% cream [84] and a 2.4% solution [85]. Such formulations are not commercially available. Although topical foscarnet appears promising— with excellent response to complete healing following 1 to 2 months of use—considerable work remains to determine an optimum vehicle, concentration, and dosing regimen. Finally, foscarnet might not always be effective in ACV-R HSV disease because resistance to foscarnet might co-exist with ACV resistance or might develop during foscarnet therapy [86]. The herpes virus might become resistant to foscarnet by a mutation in the DNA polymerase gene [73]. Foscarnet resistance has already been described in six AIDS patients; it is suspected that resistance is achieved by specific selection of DNA polymerase mutants in the presence of foscarnet [86]. In these six patients, foscarnetresistant HSV isolates were found to be ACV sensi-
313
tive; however, in other patients with ACV-R herpes that was treated unsuccessfully with foscarnet, isolates were found to be resistant to both agents [82,87,88]; thus, other antiviral agents must be considered. Another available antiviral medication is vidarabine.
Vidarabine Vidarabine (adenine arabinoside) is an analog of adenine deoxyriboside that has activity against HSV I and HSV II. Once phosphorylated to the triphosphate form by cellular enzymes, vidarabine competitively inhibits HSV DNA polymerase [89]. It might also act as an HSV DNA chain terminator. While active against HSV, benefits in immunocompromised patients have been tempered by significant adverse events that occur at therapeutic doses [81,90]. Administered by infusion over a 12-hour period to achieve a total daily dose of 10 milligrams per kilogram per day, the drug’s important side effects include weakness, fatigue, diffuse myalgias, granulocytopenia, tremor, ataxia, and prerenal azotemia [91]. In addition, drug administration entails a significant fluid load, thereby limiting therapy in patients with congestive heart failure, renal dysfunction, or limited intravenous access. A randomized comparison of foscarnet and vidarabine for ACV-R mucocutaneous herpes simplex virus in patients with AIDS showed superior efficacy and less frequent toxicity in the group of patients receiving foscarnet [81]. In a similar study comparing intravenous foscarnet (40 mg/kg tid) with intravenous vidarabine (15 mg/kg/day), Safrin [92] showed that foscarnet had better efficacy and fewer side effects at therapeutic doses than vidarabine. Patients receiving foscarnet had a shorter median time to complete healing (13.5 days versus 38.5 days) and a shorter median time to stopped viral shedding (6 days versus 17 days). Moreover, patients receiving vidarabine frequently developed nausea and anemia, and 11% of the patients had dose-limiting azotemia or neutropenia [92]. These and other concurrent observations have led to the recent recommendation at a roundtable symposium of researchers and physicians who care for immunocompromised patients that foscarnet be used first in patients suspected to have ACV-R HSV infection, reserving vidarabine for treatment failures [93]. The dilemma of treating concurrent ACV-R and foscarnet-resistant HSV remains, and vidarabine is far from the ideal alternative treatment. Possible solutions might be use of trifluorothymidine (TFT) or cidofovir.
314
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
Trifluorothymidine TFT, a fluorinated pyrimidine nucleoside, inhibits HSV by thymidine substitution during viral DNA replication and inhibition of thymidylate synthetase [94]. A topical 1% solution of TFT is usually used for ophthalmic herpes infection. When applied every 8 hours to mucocutaneous lesions, complete healing was noted in 29% of treated patients, while another 29% experienced at least 50% reduction in lesional area [93,95,96]. Twenty-nine percent of patients failed to respond to therapy [95]. In addition, topical TFT in combination with interferon-a was successful in three AIDS patients who had failed ACV and foscarnet treatment [97]. While TFT might be effective when mucocutaneous lesions caused by ACV-R HSV are accessible for topical treatment, the physician must be able to treat systemic ACV-R HSV. Moreover, collective reported experience with TFT is limited, and larger-scale studies are indicated to verify the statistics quoted here.
Cidofovir (HPMPC) With antiviral properties first described by De Clercq et al [98] in 1987, HPMPC or (S)-1[(3-hydroxy-2-phosphonylmethoxy) propyl] cytosine (cidofovir) is a nucleotide analogue with potent in vitro and in vivo activity against a broad range of herpes viruses, including ACV-R and foscarnet-resistant HSV [87,99]. Phosphorylation by enzymes in host cells allows this compound to maintain activity against TK-deficient and TK-variant HSV as demonstrated in vitro [100,101]. In a mouse model, HPMPC showed greater efficacy than ACV against routine HSV II and TK-deficient HSV II infection [99,102]. Similarly, HPMPC proved to be effective in patients with severe ACV-R perineal HSV infection who received intravenous cidofovir at 5 milligrams per kilogram per week for 3 to 4 weeks [103,104]. To decrease the risk of nephrotoxicity associated with cidofovir, oral probenecid 2 grams and intravenous saline 1 liter must be administered at least 3 hours before infusion [55,105]. Probenecid hypersensitivity has been seen in multiple patients, presenting as a pruritic maculopapular rash, nausea, and headache [106]. HPMPC 0.3% and 1% gels applied topically once daily showed effective results during a double-blind, placebo-controlled study of 30 AIDS patients with ACV-R HSV infections [107]. Thirty percent of cidofovir-treated patients experienced complete healing of mucocutaneous lesions, while 50% of the patients so treated had a greater than 50% decrease
in lesion size. Another subsequent case report confirmed the benefit of topical 1% cidofovir gel in an AIDS-related ACV-R HSV facial ulceration [108]. A 3% gel applied once daily also led to resolution of ACV-R perianal and oral ulcerations in an AIDS and transplant patient, respectively [109]. The results seen with this formulation are promising. At present, however, topical cidofovir must be compounded extemporaneously; it is therefore extremely expensive and might not be covered by insurance benefits. An application to approve the use of topical cidofovir gel for the management of ACV-R HSV infections was denied in 1999 by the FDA because of a lack of sufficient Phase III data. According to the manufacturer, no further systematic studies of topical cidofovir for this specific indication are planned or in progress.
Combination therapy One possibility is to use a combination of drugs with different mechanisms of action. By blocking different metabolic pathways, additive and even synergistic effects have been seen with combinations of ACV and either vidarabine or TFT to treat HSV infections in mice [110]. Recently, three-dimensional computerized analytical methods have been proposed to design multidrug therapies to treat resistant HSV disease [111]. A recent combination therapy with intravenous foscarnet and intramuscular interferona-2a was utilized successfully to treat a perianal ulceration in an AIDS patient with CD4 count of 0.05 109/L [112]. The patient was finally able to sit after a year of having to lie on his side. In addition to using established antiviral medications, research efforts have disclosed other antiviral drugs that appear to be promising future solutions to the problem of ACV-R HSV infection.
Immune response modifiers A new class of topical drugs has been developed recently that serve as immune response modifiers. These drugs upregulate (enhance) the natural immune response to infectious organisms, such response being mediated primarily through induced production of interferon and cytokines from activated lymphocytes at the site of application. The prototype drug, imiquimod, is currently FDA-approved in a 5% cream formulation for the treatment of anogenital warts caused by human papillomavirus. Based upon encouraging results in various regimens employed in guinea pig studies, several authors have published
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
case reports in which genital herpes, including ACV-R HSV, have responded to three times weekly application of imiquimod 5% cream [90,113]; however, a phase II, double-blind, placebo-controlled, multicenter study involving over 100 patients with recurrent genital progenitalis failed to demonstrate clinical efficacy beyond that of a placebo [114]. Thus, the efficacy of imiquimod for ACV-R HSV remains uncertain. Clinical research studies are ongoing utilizing a related, but more potent, immune response modifier called resiquimod [115]. This product is not yet commercially available.
Thymidine kinase inhibitors The compound L-653180, a selective inhibitor of HSV TK, has been studied in guinea pigs infected with HSV [116]. In this animal model, recurrent HSV infections over a 10-week observation trial were decreased when compared with controls; however, mammalian administration is limited by the compound’s poor water solubility. While improved formulations of TK inhibitors might be produced, one must remember that HSV can survive without this enzyme; therefore, administration of TK inhibitors can eventually ‘‘select’’ mutant viral strains in which TK is an irrelevant enzyme.
315
Liuzzi et al [121] found some success in BILD 1263, which suppresses the replication of HSV I, HSV II, and ACV-R HSV strains in cell culture. In a murine ocular model, this compound displayed antiherpetic activity to HSV I-induced keratitis. In addition to preventing protein – protein interactions, this nonsubstrate-based antiviral agent strongly potentiated the antiviral activity of ACV. The same group of investigators noted that a similar compound (BILD 1633) when applied topically in a 5% cream significantly improved ACV-R herpetic infections in athymic nude mice [36]. This was true of thymidine kinase-deficient and DNA polymerase mutant HSV strains. The ribonucleotide reductase inhibitor likewise potentiated the antiviral effect of oral ACV in this experimental murine system. New strategies to treat herpes infection in humans might be based on these unique antiviral drugs. Finally, the ribonucleotide reductase inhibitor MDL 101,731 has been examined for antiviral activity against HSV I and HSV II in vitro [122]. Following in vitro success, researchers topically applied this substance (5%) in combination with ACV (5%) in the murine zosteriform model of HSV I infection. The topical combination was more effective than ACV alone and appeared to promote lesion resolution. Ribonucleotide reductase inhibitors appear to be promising for the future treatment of HSV and ACV-R HSV, and further investigation is mandated.
Ribonucleotide reductase inhibitors
Summary
By catalyzing the conversion of ribonucleotides to deoxyribonucleotides, ribonucleotide reductase is a key enzyme in the synthesis of viral DNA [117]. While herpes virus-encoded ribonucleotide reductase is not essential for growth in tissue culture or establishment of latency, the enzyme does appear to be essential for pathogenicity in mice [117 – 119]. This enzyme is being studied as a possible target for antiviral chemotherapy. To date, at least four ribonucleotide reductase inhibitors have been studied. The thiocarbonohydrazone 348U87, known to inactivate herpes simplex virus ribonucleotide reductase, was used as a topical preparation (3%) in combination with ACV (5%) to treat HIV-infected patients with ACV-R anogenital HSV infection [120]. While transient improvement with combination therapy occurred frequently, target lesions reepithelialized in only 1 of 10 patients. Thus, topical 348U87 offered little therapeutic benefit for ACV-R HSV ulcerations, and it has not been pursued as a viable therapeutic agent.
In immunocompetent patients, HSV is controlled rapidly by the human host’s immune system, and recurrent lesions are small and short lived. When treated with antiviral agents, these patients rarely develop resistance to these drugs. In contrast, immunocompromised patients might not be able to control HSV infection. Thus, frequent and severe reactivations are often seen and might lead to fatal herpetic encephalitis or disseminated HSV infection. Treatment in these patients is limited because immunocompromised hosts often develop severe herpes disease refractory to antiviral drug therapy. It is therefore imperative that physicians develop regimens to deal with both receptive and refractory HSV disease. The following treatment protocol (modified from Balfour and colleagues [93]) might serve as a guide until further investigation of new drugs is performed. In all patients standard oral ACV therapy should be initiated at a dose of 200 mg orally, five times a day for the first 3 to 5 days. Prior to treatment, cultures of the lesions should be obtained to verify HSV etiology.
316
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
If the response is poor, the dose of oral ACV should be increased to 800 mg five times a day. If no response is seen after 5 to 7 days, it is unlikely that the lesion will respond to intravenous ACV (or chemically and structurally related drugs such as VCV or famciclovir), so an alternative regimen must be assigned. First, repeat cultures for viral, fungal, and bacterial pathogens must be performed. In addition, ACV susceptibility studies should be ordered, if available. If the mucocutaneous lesion is accessible for topical treatment, TFT (as ophthalmic solution) should be applied to the area three to four times a day until the lesion is completely healed. If the lesion is inaccessible or if the response to TFT is poor, therapy with intravenous foscarnet should be given for 10 days or until complete resolution of the lesions. The dosage of foscarnet should be 40 milligrams per kilogram three times per day or 60 milligrams per kilogram twice daily. If foscarnet fails to achieve clinical clearing, consideration should be given to use of intravenous cidofovir (or application of compounded 1% to 3% topical cidofovir ointment). Vidarabine is reserved for situations in which all of these therapies fail. If lesions reoccur in the same location following clearing, the patient should started on high-dose oral ACV (800 mg, five times daily) or intravenous foscarnet (40 mg/kg tid or 60 mg/kg bid) as soon as possible. When lesions occur in a different location, the patient should be treated initially with standard doses of oral ACV (200 mg, five times daily) and the above protocol should be followed should there be clinical failure. In the future, new treatment options for patients with documented HSV resistance will be important in reducing the clinical impact of HSV.
[8]
[9]
[10] [11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
References [1] Brigden D. Skin infections. Br Med Bull 1985;41: 357 – 60. [2] Corey L, Spear PG. Infections with herpes simplex viruses. N Engl J Med 1986;314:686 – 91, 749 – 57. [3] Spruance SL. Pathogenesis of herpes simplex labialis: excretion of virus in the oral cavity. J Clin Microbiol 1984;19:675 – 9. [4] Cohen GS, Greenberg MS. Chronic oral herpes simplex virus infection in immunocompromised patients. Oral Surg Oral Med Oral Pathol 1985;59:465 – 71. [5] Kalb RE, Grossman ME. Chronic perianal herpes simplex virus infection in immunocompromised patients. Am J Med 1986;80:486 – 90. [6] Meyers JD, Flournoy N, Donnall T. Infection with herpes simplex virus and cell-mediated immunity after marrow transplant. J Infect Dis 1980;142:338 – 46. [7] Montgomery MT, Redding SW, LeMaistre CF. The
[19]
[20]
[21]
[22]
[23]
incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1986;61:238 – 42. Naraqi S, Jackson GG, Jonasson O, et al. Prospective study of prevalence, incidence and source of herpesvirus infections in patients with renal allografts. J Infect Dis 1977;136:531 – 40. Pass RF, Whitley RJ, Whelchel JD, et al. Identification of patients with increased risk of infection with herpes simplex virus after renal transplantation. J Infect Dis 1979;140:487 – 92. Prentice HG, Hann IM. Antiviral therapy in immunocompromised patients. Br Med Bull 1985;41:367 – 73. Siegel FP, Lopez C, Hammer GS. Severe acquired immunodeficiency in make homosexuals manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981;305:1439 – 44. Gateley A, Gander RM, Johnson PC, et al. Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis 1990; 161:711 – 5. Pagnan JS, Lemon SM. The herpes viruses. In: Braude AI, Davis CD, Fierer J, editors. Infectious diseases and clinical microbiology. Philadelphia (PA): WB Saunders; 1986. p. 47 – 76. Johnson RE, Nahmias AJ, Magder LS, et al. A seroepidemiological survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 1989;321:7 – 12. Safrin S, Ashley R, Houlihan C, et al. Clinical and serological features of herpes simplex virus infection in patients with AIDS. AIDS 1991;5:1107 – 10. de Ruiter A, Thin RN. Genital herpes: a guide to pharmacological therapy. Drugs 1994;2:297 – 304. O’Brien JJ, Campoli-Richards DM. Acyclovir: an updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989; 37:233 – 309. Richards DM, Carmine AA, Brogden RN, et al. Acyclovir: a review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1983;26: 378 – 438. Wagstaff AJ, Faulds D, Goa KL. Acyclovir: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994;47: 153 – 204. Crumpaker CS, Schnipper IE, Marlowe SI, et al. Resistance to antiviral drugs of herpes simplex isolated from a patient treated with acyclovir. N Engl J Med 1982;306:343 – 6. Dekker C, Ellis MN, McLaren C, et al. Virus resistance in clinical practice. J Antimicrob Chemother 1983;12(Suppl B):137 – 52. McLaren C, Corey L, Dekker C, et al. In vitro sensitivity to acyclovir in genital herpes simplex viruses from acyclovir-treated patients. J Infect Dis 1983; 148:868 – 75. Sibrack CD, Gutman LD, Wilfert CM. Pathogenicity of acyclovir-resistant herpes simplex virus type 1
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37] [38]
from an immunodeficient child. J Infect Dis 1982; 146:673 – 82. Wade JC, McLaren C, Meyers JD. Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of acyclovir. J Infect Dis 1983;148: 1077 – 82. Barry DW, Nusinoff-Lehrman S, Nixon EM. Clinical and laboratory experience with acyclovir-resistant herpes virus. J Antimicrob Chemother 1986;18(Suppl B):75 – 84. Christophers J, Sutton RNP, Noble RV, et al. Clinical resistance to acyclovir of herpes simplex virus infections in immunocompromised patients. J Antimicrob Chemother 1986;18(Suppl B):121 – 5. Crumpaker CS. Resistance of herpes simplex virus to antiviral agents. Is it clinically important? Drugs 1983;26:373 – 7. Norris SA, Kessler HA, Fife KH. Severe, progressive herpetic whitlow caused by acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 1988;157:209 – 10. Parker AC, Craig JO, Collins P, et al. Acyclovir resistant herpes simplex virus infection due to altered DNA polymerase. Lancet 1987;2:1461. Parris DS, Harrington JE. Herpes simplex virus variants resistant to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 1982;22:71 – 7. Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res 1995;28:281 – 90. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39:1546 – 53. Weller S, Blum MR, Doucette M. Pharmacokinetics of the acyclovir pro-drug valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595 – 605. Earnshaw DL, Bacon TH, Darlison SJ, et al. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2 and varicella-zoster virus. Antimicrob Agents Chemother 1992;36:2747 – 57. Safrin S, Phan L. In vitro activity of penciclovir against clinical isolates of acyclovir-resistant and foscarnet-resistant herpes simplex virus. Antimicrob Agents Chemother 1993;37:2241 – 3. Duan J, Liuzzi M, Paris W, et al. Antiviral activity of a selective ribonucleotide reductase inhibitor against acyclovir-resistant herpes simplex virus type 1 in vivo. Antimicrob Agents Chemother 1998;42: 1629 – 35. Dorsky DI, Crumpaker CS. Drugs five years later. Ann Intern Med 1987;107:859 – 74. Whitley RJ, Gnann Jr JW. Acyclovir: a decade later. N Engl J Med 1992;327:782 – 9.
317
[39] Cotarelo M, Catalan P, Sanchez-Carrillo C, et al. Cytopathic effect inhibition assay for determining the invitro susceptibility of herpes simplex virus to antiviral agents. J Antimicrob Chemother 1999;44:705 – 8. [40] Sarisky RT, Crosson P, Cano R, et al. Comparison of methods for identifying resistant herpes simplex virus and measuring antiviral susceptibility. J Clin Virol 2002;23:191 – 200. [41] Tebas P, Scholl D, Jollick J, et al. A rapid assay to screen for drug-resistant herpes simplex virus. J Infect Dis 1998;177:217 – 20. [42] Field HJ. Herpes simplex virus antiviral drug resistance: current trends and future prospects. J Clin Virol 2001;21:261 – 9. [43] Crumpaker CS. Significance of resistance of herpes simplex virus to acyclovir. J Am Acad Dermatol 1988;18:190 – 5. [44] Nusinoff-Lehrman S, Douglas JM, Corey L, et al. Recurrent genital herpes and suppressive oral acyclovir therapy. Ann Intern Med 1986;104:786 – 90. [45] Strauss SE, Takiff HE, Seidlin M. Suppression of frequently recurring genital herpes. A placebocontrolled double-blind trial or oral acyclovir. N Engl J Med 1984;310:1545 – 50. [46] Fife KH, Crumpacker CS, Mertz GJ, et al. Recurrence and resistance patterns of herpes simplex virus following cessation of 6 years of chronic suppression with acyclovir. J Infect Dis 1994;169:1338 – 41. [47] Kost RG, Hill EL, Tigges M, et al. Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N Engl J Med 1993;329:1777 – 82. [48] Englund JA, Zimmerman ME, Swierkosz EM, et al. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med 1990;12: 416 – 22. [49] Burns WH, Santos GW, Saral R, et al. Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Lancet 1982;1:421 – 3. [50] Strauss SE, Smith HA, Brickman C, et al. Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med 1982;96:270 – 7. [51] Vinckier F, Boogaerts M, DeClerq D, et al. Chronic herpetic infection in an immunocompromised patient: report of a case. J Oral Maxillofac Surg 1987;45: 723 – 8. [52] Westheim AI, Tenser RB, Marks JG. Acyclovir resistance in a patient with chronic mucocutaneous herpes simplex infection. J Am Acad Dermatol 1987;17: 875 – 80. [53] Ehrlich KS, Mills J, Chatis PS. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989;320:293 – 6. [54] MacPhail LA, Greenspan D, Schiodt M, et al. Acyclovir-resistant, foscarnet-sensitive oral herpes simplex type II lesion in a patient with AIDS. Oral Surg Oral Med Oral Pathol 1989;67:427 – 32. [55] Martinez CM, Luks-Golger DB. Cidofovir use in acy-
318
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320 clovir-resistant herpes infection. Ann Pharmacother 1997;31:1519 – 21. Schinazi RF, del Bene V, Scott RT, et al. Characterization of acyclovir-resistant and -sensitive herpes simplex viruses isolated from a patient with acquired immunodeficiency syndrome. J Antimicrob Chemother 1986;18(Suppl B):127 – 34. Youle MM, Hawkins D, Collins P. Acyclovir-resistant herpes in AIDS treated with foscarnet. Lancet 1988;2:341 – 2. Zimmerli W, Bianchi L, Gudat T. Disseminated herpes simplex type II and systemic candida infection in a patient with previous asymptomatic human immunodeficiency virus infection. J Infect Dis 1988;157: 597 – 8. Hill EL, Hunter GA, Ellis MN. In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1991;35:2322 – 38. Ljungman P, Ellis MN, Hackman RC, et al. Acyclovir-resistant herpes simplex virus causing pneumonia after marrow transplantation. J Infect Dis 1990;162: 244 – 8. Reusser P, Cordonnier C, Einsele H. European survey of herpes virus resistance to antiviral drugs in bone marrow transplant recipients. Bone Marrow Transplant 1996;17:813 – 7. Sacks SL, Wanklin RJ, Reece DE, et al. Progressive esophagitis from acyclovir-resistant herpes simplex: clinical role for DNA polymerase mutants and viral heterogenicity? Ann Intern Med 1989;111:893 – 9. Verdonck LF, Cornelissen JJ, Smit J. Successful foscarnet therapy for severe acyclovir-resistant mucocutaneous infection with herpes simplex virus in a recipient of allogenic BMT. Bone Marrow Transplant 1993;11:177 – 9. McLaren C, Chen MS, Ghazzouli I, et al. Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir. Antimicrob Agents Chemother 1985;28:740 – 4. Nugier F, Colin JN, Aymard M, et al. Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report of a two year sensitivity screening survey. J Med Virol 1992;36:1 – 12. Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 1986;18(Suppl B): 103 – 12. Ambinder R, Burns W, Leitman P, et al. Prophylactic acyclovir therapy and herpes simplex. Ann Intern Med 1984;100:920 – 1. Chatis PA, Crumpaker CS. Resistance of herpes virus to antiviral drugs. Antimicrob Agents Chemother 1992;36:1589 – 95. Ellis MN, Keller PM, Fyfe JA. Clinical isolate of herpes simplex virus type 2 that induces a thymidine kinase with altered substrate activity. Antimicrob Agents Chemother 1987;31:1117 – 25.
[70] Schnipper LE, Crumpaker CS. Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci. Proc Natl Acad Sci USA 1980;77:2270 – 3. [71] Balfour Jr HH, Drew WL, Hardy WD, et al. Therapeutic algorithm for treatment of cytomegalovirus retinitis in persons with AIDS. J Acquir Immune Defic Syndr 1992;5(Suppl 1):S37 – 44. [72] Chrisp P, Clissold SP. Foscarnet: a review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs 1991;41:104 – 29. [73] Crumpaker CS. Mechanism of action of foscarnet against viral polymerases. Am J Med 1992;92(Suppl 2A):S3 – 7. [74] Jacobson MA, Crowe S, Levy J. Effect of foscarnet therapy on infection with human immunodeficiency virus in patients with AIDS. J Infect Dis 1988;158: 862 – 5. [75] Leitman PS. Clinical pharmacology of foscarnet. Am J Med 1992;92(Suppl 2A):S8 – 11. [76] Alvarez-McLeod A, Havlik J, Drew KE. Foscarnet treatment of genital infection due to acyclovir-resistant herpes simplex virus type 2 in a pregnant patient with AIDS: case report. Clin Infect Dis 1999;29: 937 – 8. [77] Chatis PA, Miller CH, Schrager LE, et al. Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med 1989;320:297 – 300. [78] Ehrlich KS, Jacobson MA, Koehler JE. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infection in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1989; 110:710 – 3. [79] Safrin S, Assaykeen T, Follansbee S, et al. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients. Preliminary data. J Infect Dis 1990;161:1078 – 84. [80] Fletcher CV, Englund JA, Bean B, et al. Continuous infusion of high dose acyclovir for serious herpes virus infections. Antimicrob Agents Chemother 1989; 33:1375 – 8. [81] Safrin S, Crumpaker C, Chatis P. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med 1991; 325:551 – 5. [82] Birch CJ, Tachedjian G, Doherty RR, et al. Altered sensitivity to antiviral drugs of herpes simplex virus isolates from a patient with the acquired immunodeficiency syndrome. J Infect Dis 1990;162:731 – 4. [83] Reusser P, Gambertoglio JG, Lilleby K, et al. Phase I – II trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogenic marrow transplant recipients. J Infect Dis 1992;186:473 – 9. [84] Javaly K, Wohlfeiler M, Kalayjian R, et al. Treatment of mucocutaneous herpes simplex virus infections
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
[85]
[86]
[87]
[88]
[89]
[90]
[91] [92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study. J Acquir Immune Defic Syndr 1999;21:301 – 6. Pechere M, Wunderli W, Trellu-Toutous L, et al. Treatment of acyclovir-resistant herpetic ulceration with topical foscarnet and antiviral sensitivity analysis. Dermatology 1998;197:278 – 80. Safrin S, Kemmerly S, Plotkin B. Foscarnet-resistant herpes simplex virus infection in patients with AIDS. J Infect Dis 1994;169:193 – 6. Schmit I, Boivin G. Characterization of the DNA polymerase and thymidine kinase genes of herpes simplex virus isolates from AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. J Infect Dis 1999;180:487 – 90. Venard V, Dauendorffer JN, Carret AS, et al. Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogenic hematopoietic stem cell transplantation. Pathol Biol (Paris) 2001;49:553 – 8. Hayden FG, Douglas RG. Antiviral agents. In: Mandell GI, Douglas RG, Bennett JE, editors. Principles and practice of infectious diseases. New York (NY): Churchill Livingstone; 1990. p. 370 – 93. Christensen B, Hengge UR. Recurrent urogenital herpes simplex: successful treatment with imiquimod? Sex Transm Infect 1999;75:132 – 3. Sacks SL, Smith JL, Pollard RB. Toxicity of vidarabine. JAMA 1979;241:28 – 9. Safrin S. Treatment of acyclovir-resistant herpes simplex virus infections in patients with AIDS. J Acquir Immune Defic Syndr 1992;5(Suppl 1):S29 – 32. Balfour Jr HH, Benson C, Braun C, et al. Management of acyclovir-resistant herpes simplex and varicella-zoster infections. J Acquir Immune Defic Syndr 1994;7:254 – 60. Murphy M, Morley A, Eglin RP, et al. Topical trifluridine for mucocutaneous acyclovir-resistant herpes simplex II in an AIDS patient. Lancet 1992;340: 1040 – 1. Kessler HA, Hurwitz S, Farthing C, et al. Pilot study of topical trifluridine for the treatment of acyclovirresistant mucocutaneous herpes simplex disease in patients with AIDS. J Acquir Immune Def Syndr 1996;12:147 – 52. Weaver D, Weissbach N, Kapell K, et al. Topical trifluridine (TFT) treatment of acyclovir-resistant herpes simplex disease. Presented at the Thirty-first Interscience Conference on Antimicrobial Agents and Chemotherapeutics (ICAAC), 1993. Birch CJ, Tyssen DP, Tachedjian G, et al. Clinical effects and in-vitro studies of trifluorothymidine combined with interferon alpha for the treatment of drugresistant and sensitive herpes simplex virus infections. J Infect Dis 1992;166:108 – 12. DeClerq E, Sakuma T, Baba M, et al. Antiviral activity of phosphomethoxyalkyl derivatives of purines and pyrimidines. Antiviral Res 1987;8:261 – 72. Yang D, Datema R. Prolonged and potent therapeutic and prophylactic effects of (S)-1-[(3-hydroxy-2-phos-
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
319
phonylmethoxy) propyl] cytosine against herpes simplex virus type 2 infections in mice. Antimicrob Agents Chemother 1991;35:1596 – 600. Mendel DB, Barkhimer DB, Chen MS. Biochemical basis for increased susceptibility to cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity. Antimicrob Agents Chemother 1995;39:2120 – 2. Morphin F, Snoeck R, Andrei G, et al. Phenotypic resistance of herpes simplex virus 1 strains selected in vitro with antiviral compounds and combinations thereof. Antivir Chem Chemother 1996;7:270 – 5. DeClercq E, Holy A. Efficacy of (S)-1-[(3-hydroxy2-phosphonylmethoxy) propyl] cytosine in various models of herpes simplex virus infection in mice. Antimicrob Agents Chemother 1991;35:701 – 6. Kopp T, Geusau A, Rieger A, et al. Successful treatment of an aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS patient. Br J Dermatol 2002;147:134 – 8. Lalezari JP, Drew WL, Glutzer E, et al. Treatment with (S)-1-[(3-hydroxy-2-phosphonomethoxy) propyl] cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. J Infect Dis 1994;170:570 – 2. Reusser P. Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance, and therapeutic options. J Hosp Infect 1996;33:235 – 48. Myers KW, Katial RK, Engler RJ. Probenecid hypersensitivity in AIDS: a case report. Ann Allergy Asthma Immunol 1998;80:416 – 8. Lalezari JP, Schacker T, Feinberg J, et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infections in patients with AIDS. J Infect Dis 1997;176:892 – 8. Lateef F, Don PC, Kaufmann M, et al. Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998;134:1169 – 70. Snoeck R, Andrei G, Gerard M, et al. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC). Clin Infect Dis 1994;18:570 – 8. Schinazi RF, Peters J, Williams CC, et al. Effects of combinations of acyclovir with vidarabine or its 5V-monophosphate on herpes simplex viruses in cell culture and in mice. Antimicrob Agents Chemother 1982;22:499 – 507. Pritchard MN, Pritchard LE, Shipman Jr C. Strategic design and three-dimensional analysis of antiviral drug combinations. Antimicrob Agents Chemother 1993;37:540 – 5. Borrego L, Castro I, Frances A, et al. Treatment of acyclovir-resistant perianal herpetic ulceration with intramuscular interferon alpha. Arch Dermatol 1996; 132:1157 – 8.
320
S. Chilukuri, T. Rosen / Dermatol Clin 21 (2003) 311–320
[113] Gilbert J, Drehs MM, Weinberg JM. Topical imiquimod for acyclovir-unresponsive herpes simplex virus type 2 infection. Arch Dermatol 2001;137:1015 – 7. [114] Slade HB, Schacker T, Conant M, et al. Imiquimod and genital herpes. Arch Dermatol 2002;138:534. [115] Spruance SL, Tyring SK, Smith MH, et al. Application of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital herpes: a pilot study. J Infect Dis 2001; 184:196 – 200. [116] Bourne N, Bravo FJ, Ashton WT. Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653180) as therapy for experimental recurrent genital herpes. Antimicrob Agents Chemother 1992;36:2020 – 4. [117] Cameron JM, McDougall I, Marsden S, et al. Ribonucleotide reductase encoded by herpes simplex virus is a determinant of the pathogenicity of the virus in mice and a valid antiviral target. J Gen Virol 1988; 69:2607 – 12. [118] Jacobson JG, Leib DA, Goldstein DJ, et al. A herpes simplex virus ribonucleotide reductase deletion mu-
[119]
[120]
[121]
[122]
tant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells. Virology 1989;173:276 – 83. Yamada Y, Kimura H, Morishima T, et al. The pathogenicity of ribonucleotide reductase-null mutants of herpes simplex virus type 1 in mice. J Infect Dis 1991;164:1091 – 7. Safrin S, Schacker T, Delehanty J, et al. Topical treatment of infection with acyclovir-resistant mucocutaneous herpes simplex virus with the ribonucleotide reductase inhibitor 348U87 in combination with acyclovir. Antimicrob Agents Chemother 1993; 37:975 – 9. Liuzzi M, Deziel R, Moss N, et al. A potent peptidomimetic inhibitor of HSV ribonucleotide reductase with antiviral activity in vivo. Nature 1994;372: 695 – 8. Bridges CG, Ahmed SP, Sunkara PS, et al. The ribonucleotide reductase inhibitor (E)-2V-fluoromethylene-2Vdeoxycytidine (MDL 101,731): a potential topical therapy for herpes simplex virus infection. Antiviral Res 1995;27:325 – 34.
Dermatol Clin 21 (2003) 321 – 335
Unusual infectious complications of dermatologic procedures Mary E. Garman, BA, Ida Orengo, MD* Baylor College of Medicine, Department of Dermatology, 1 Baylor Plaza, Houston, TX 77030, USA
Surgical wound infections, which were once thought to be caused by elements in the air known as ‘‘contagions and miasmas,’’ have long plagued humankind. The contributions of numerous scientist – physicians have fostered progress toward modern surgery. Louis Pasteur’s revolutionary experiments into the nature of fermentation and putrefaction were not officially recognized by the Paris Academy of Science until 1862 [1]. Joseph Lister, an artist, surgeon, professor, scientist, and (according to some) heretic, pressed his bold new theories regarding antiseptic techniques throughout the 1860s [2]. In 1877, a young doctor, Robert Koch, demonstrated the existence of infectious microbes in his experiments with Bacillus anthrax [2]. A growing trend toward wearing gloves during operations also appeared around the turn of the century [3]; however, it was not until the 1940s that the antibiotic revolution ushered in the integral step in the prevention and control of postsurgical infections. Surgeons could finally perform invasive and technical procedures with a high degree of postoperative success [1]. Modern medicine now recognizes countless variables that predispose individuals to postoperative wound infection. Environmental factors such as length of operation and hospital stay, preoperative shaving, antiseptic showering, drain placement, presence of remote infection, and surgical technique affect the development of such infections. Patient risk factors for wound infection also include mal-
* Corresponding author. E-mail address:
[email protected] (I. Orengo).
nutrition, anergy, chronic renal failure, advanced age, obesity, diabetes mellitus, corticosteroid use, immunosuppression, and HIV infection [4]. Several billion dollars are spent annually in the United States on the care of postoperative wound infections [3]. With an enlarging repertoire of cutaneous surgical interventions including cosmetic surgery and skin rejuvenation procedures, postoperative wound infections are an increasingly important consideration in dermatology. Although dermatological procedures are not typically performed in a rigorously sterile environment, they seldom result in infectious complications. Wound infections following excisions and micrographically controlled procedures arise in less than 3% of cases [5], which is comparable to the expected rate for clean surgical procedures [6]. Pathogens complicating laser resurfacing and other surgical procedures include Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa [5,7 – 10]; however, atypical bacterial, fungal, viral, and parasitic infections occasionally occur. The clinical manifestations, diagnosis, and management of these unusual surgical complications are addressed in this article.
Bacterial complications Toxic shock syndrome Toxic shock syndrome (TSS), a potentially lethal disease characterized by the rapid onset of shock, often occurs in previously healthy individuals and primarily results from liberation of potent toxins from S. aureus. These superantigens result in massive
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00097-9
322
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
cytokine release (especially tumor necrosis factor and interleukin-1), direct capillary leakage, pyrogenicity, and other systemic effects [11]. TSS has long been coupled with tampon use, and toxic shock syndrome toxin-1 (TSST-1) is present in virtually all cases of TSS that occur in women within 2 days of menstruation [11]; however, most cases are unassociated with menstruation [12]. Half of individuals suffering from nonmenstrual TSS harbor TSST-1 – producing strains of S. aureus, whereas the remaining individuals appear to have disease secondary to staphylococcal enterotoxins B and C [11]. Nonmenstrual TSS most commonly occurs postoperatively. The disease also occurs in association with influenza, sinusitis, tracheitis, intravenous drug use, HIV infection, cellulitis, burn wounds, allergic contact dermatitis, gynecologic infection, and the postpartum period [12]. Numerous authors have documented TSS following dermatologic procedures such as excisions [13,14], chemical peels [15,16], laser resurfacing [10,17], and suction lipectomy [18,19]. A similar syndrome resulting from streptococcal infection has been reported to follow suction lipectomy [20,21]. In 1978 Todd and colleagues [22] first described TSS as a syndrome of fever, headache, profound hypotension, profuse diarrhea, erythroderma, mental confusion, and multiple organ failure. These symptoms still comprise the core features of the disease, but the development of specific criteria [23,24], which are shown in the text box below, now allows for a more definitive clinical evaluation and diagnostic approach. In general, initial symptoms might include fever, vomiting, and diarrhea. Confusion, syncopal hypotension, and an erythematous rash with mucosal hyperemia subsequently develop. Desquamation, particularly of the palms and soles, occurs 1 to 2 weeks after the onset of symptoms [25 – 27]. Autopsy findings of multisystem organ damage might include periportal hepatic inflammation, acute tubular necrosis, and the formation of hyaline membranes, which are characteristic of shock lung [28].
Toxic shock syndrome: diagnostic criteria Clinical criteria Temperature 102 F (38.9 C) Rash: diffuse macular erythroderma Desquamation:1 – 2 wk after illness onset; particularly on palms and soles
Hypotension: systolic pressure V 90 mmHg for adults or V fifth percentile children Orthostatic syncope, dizziness, or drop in diastolic pressure 15 mmHg Multisystem involvement ( 3 of the following): Gastrointestinal: vomiting or diarrhea at onset of illness Muscular: myalgia or CPK at least twice normal value Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia Renal: BUN or creatinine at least twice normal or urinary sediment without urinary tract infection Hepatic: total bilirubin, ALT, or AST at least twice normal Hematologic: platelets<100,000/mm3 Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent Laboratory criteria Negative results on the following tests, if obtained: Blood, throat, cerebrospinal fluid cultures (blood culture might be positive for S. aureus) Rise in titer to Rocky Mountain spotted fever, leptospirosis, or measles Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CPK, creatinine phosphokinase. Adapted from the Centers for Disease Control and Prevention guidelines [23,24] In addition to clinical manifestations, laboratory findings are crucial to TSS diagnosis. Basic laboratory studies to assess renal and hepatic function, a creatinine phosphokinase level, and a platelet count assist in diagnosis and evaluation of patient status. Blood culture and serologic tests for Rocky Mountain spotted fever, leptospirosis, and measles should be performed to narrow the differential diagnosis. Depending on the suspected focus of infection, vaginal and cervical or postoperative wound cultures might reveal Gram-positive cocci in clusters. With reference to the text box above, probable cases are
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
those that fulfill four of the five clinical criteria and meet all the laboratory criteria [24]. Confirmed cases are those that meet all criteria, including desquamation (unless the patient dies prior to desquamation) [24]. Management of TSS, which is a notifiable disease [23,24], demands close monitoring with aggressive fluid replacement and vasopressors as needed. The suspected focus of infection requires specific attention. Specifically, management includes the removal of any vaginal device in menstrual cases and the removal of packed dressings in conjunction with drainage and debridement in cases associated with postsurgical wounds [29]. Appropriate antibiotic therapy includes a b-lactamase-resistant antistaphylococcal agent such as oxacillin or nafcillin administered intravenously. Some authors suggest the addition of clindamycin, at least initially, because macrolides have been shown to decrease protein and TSST-1 synthesis in vivo [27]. With prompt recognition and administration of appropriate therapy, more than 95% of TSS patients survive [29]. Necrotizing fasciitis Necrotizing fasciitis is a rare but devastating infection primarily involving superficial fascia that results in extensive undermining of surrounding tissues. The media recently brought considerable attention to the disease popularly dubbed ‘‘flesh-eating bacteria,’’ but descriptions of similar processes date to Hippocrates in the fifth century BC [30]. The term necrotizing fasciitis was not definitively applied until 1952 [31], although numerous expressions describing similar processes compound the confusion over its exact definition [32]. Streptococcus pyogenes accounts for most cases of monomicrobial necrotizing soft tissue infections, although necrotizing fasciitis is often a polymicrobial disease [33]. As with TSS, necrotizing fasciitis often occurs in otherwise healthy individuals; however, risk factors include diabetes, alcohol abuse, intravenous drug abuse, immunosuppression, and peripheral vascular disease [32]. Breaches in the skin caused by varicella, minor cuts, penetrating trauma, burns, surgical procedures, and childbirth in addition to nonpenetrating injuries such as muscle strain and blunt trauma predispose individuals to streptococcal infection [20,34]. Dermatologic procedures complicated by necrotizing fasciitis have included botulinum toxin injection [35], suction lipectomy [19,36 – 38], and blepharoplasty [39 – 41]. Necrotizing fasciitis follows a characteristic and rapid clinical course. As early as several hours following the initial insult, erythema, edema, warmth,
323
and exquisite pain and tenderness develop and expand around the affected area as the infection spreads along superficial fascial planes. Violaceous bullae appear within days. They are rapidly replaced by dark eschars, necrosis, malodorous, purulent drainage, and hypesthesia caused by nerve destruction [20,32,34]. Necrotizing fasciitis is often associated with streptococcal TSS and multiorgan failure [20,21,42], and in one large series it had an overall mortality rate of 29% [33]. Necrotizing fasciitis is often difficult to distinguish clinically from cellulitis early in the disease. This can be mitigated with the use of additional diagnostic measures to prevent a delay in diagnosis. Imaging studies such as MRI or CT help map the extent of infection [43]. Intraoperatively, a lack of resistance to probing is diagnostic of necrotizing fasciitis [32]. Frozen sections of biopsy material are also useful [44]; tissue should be taken for Gram’s stain and culture. Debridement, appropriate antibiotics, and supportive care comprise the foundation of therapy for necrotizing fasciitis. Early and extremely aggressive debridement might improve survival [33,45], and it should be repeated if necrotic areas return. Broadcoverage antibiotics can be modified as identification of the organism is achieved. Additional care includes fluid replacement, nutritional support, and even transfer to a burn unit in cases in which large surface areas have been debrided. Hyperbaric oxygen therapy has been reported as a potentially useful ancillary treatment for necrotizing fasciitis [46,47]. Enterobacteriaceae Enterobacteriaceae is a family of aerobic, facultatively anaerobic, non – spore-forming bacteria that contain Gram-negative rods. Skin flora rarely includes Gram-negative rods except transiently as contamination from the gastrointestinal system or in the moist, intertriginous areas of some individuals [48]. Enterobacteriaceae organisms are not typically considered in postoperative wound infection; however, these bacteria infected postsurgical wounds in one series of patients undergoing laser facial resurfacing more frequently than any other, possibly because of choice of antibiotic prophylaxis [9]. Dermatologic procedures such as excision of basal cell and squamous cell carcinomas [5] and laser resurfacing [7 – 10,49] can be complicated by Gram-negative rod wound infection. Causative organisms include Escherichia coli [7 – 10], Enterobacter species [7,9,10,49], Serratia marcescens [5,9,10], Proteus mirabilis [5,9], and Klebsiella pneumoniae
324
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
[7,8,10]. Some isolates exhibit multiple drug resistance. K. pneumoniae infection is highly suggestive of a hospital-acquired infection [9]. Postoperative Enterobacteriaceae wound infections are often polymicrobial [5,7 – 10], and in one case an Enterobacteriaceae infection occurred as a herpes simplex virus superinfection [49]. One patient reported undergoing an enema 1 day postoperatively [8] and another patient recalled that the affected area had come in contact with toilet tissue paper prior to evidence of wound infection [49]. Because Enterobacteriaceae infections occur in numerous wound types and they can be caused by one or several organisms, clinical findings vary considerably. Clinical manifestations can present anywhere from 2 days [9] to 5 weeks [7] after laser resurfacing procedures. Symptoms include pain [7 – 9], burning [7,9], or itching [7,9] in the treated area, and these symptoms can occur without additional findings on examination [9]. More often, patients exhibit papules or pustules [7,9], erythema [7 – 9], swelling [8,9], crusting [7,8], purulent drainage [9], or fever [7,8]. Futoryan et al [5] described a patient who underwent excision of an auricular basal cell carcinoma requiring a full-thickness skin graft who developed pain, tenderness, and erythema consistent with chondritis 3 months after the procedure. The exact pathogenesis of the lesion is unclear, but culture of wound drainage grew S. marcescens and Candida species. Wound infection secondary to Gram-negative rods can be easily identified by way of Gram’s stain and routine bacterial culture. Escherichia, Proteus, and Klebsiella organisms typically respond to second-generation cephalosporins, but members of the Enterobacter and Serratia genera exhibit a higher degree of antimicrobial resistance, and they more often result from nosocomial spread [3]. Empiric therapy for these organisms involves a third-generation cephalosporin, expanded spectrum penicillin, monobactam, carbapenem, quinolone, or aminoglycoside [3]. When organism susceptibility results become available, definitive therapy can be administered. Corynebacterium diphtheriae The institution of immunization programs has reduced cutaneous diphtheria to a rare infection throughout the world [50]. The organism commonly colonizes the skin and it is especially abundant in intertriginous areas [48]. While generally considered to be nonpathogenic, Corynebacterium diphtheriae can complicate surgical wounds, burns, insect bites, and eczematous eruptions [51]. Individuals in lower
socioeconomic groups (eg, the homeless) who reside in temperate zones are more often affected [51,52]. A high index of suspicion should be maintained in returning travelers and individuals who have not received booster vaccinations. Reported dermatologic cases of Corynebacterium species wound infections include the Mohs’ micrographic surgical excision of auricular squamous cell carcinoma requiring a fullthickness skin graft [5] and laser resurfacing for photoaged skin [9]. Because cutaneous C. diphtheria infection results from the colonization of other skin lesions, the morphologic findings of cutaneous diphtheria are extremely variable [53]. Clinical features present after a 1- to 7-day incubation period [52]. Vesicles or pustules often precede the most typical finding of ulceration [50,51,53]. A round or oval, well-demarcated ulcer that is transiently associated with a thick yellowish to brownish – gray membrane or dark crust is suggestive of the disease [50,51,53,54]. The lesion progresses to a shallow, punched-out ulcer with a hemorrhagic base that might persist for months without treatment [51,53]. While initially tender, hypesthesia develops over time [51,53]. Toxin complications such as myocarditis and polyneuritis sometimes occur, but they are more common with respiratory diphtheria [53]. Corynebacterium species (non-C. diphtheriae) can produce postoperative wound infections in the form of erythrasma [9], which is characterized by reddish – brown patches. Diagnosis of diphtheria wound infection relies on Gram’s stain and culture of appropriate specimens. Performing an assay for diphtheria toxin determines the need for antidiphtheria serum [52]. Diphtheria antitoxin is an effective treatment [51,55] that should be administered early in cases with extended, multiple lesions and pseudomembrane formation [53]. Penicillin [50,51,53] and topical antibacterial agents [53] facilitate resolution of cutaneous diphtheria. Prevention entails booster vaccinations for travelers to endemic regions [55]. Unlike the pulmonary disease, reporting of cutaneous diphtheria is not required; however, all diphtheria isolates should be sent to the Diphtheria Laboratory, National Center for Infectious Diseases, Centers for Disease Control and Prevention, regardless of their association with disease [23,24]. Rapidly growing mycobacteria Mycobacterium chelonae, Mycobacterium abscessus, and Mycobacterium fortuitum comprise the dominant human pathogens of the Runyon subtype IV of nontuberculous (ie, environmental) mycobacteria
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
[56]. These rapidly growing mycobacteria exist in soil and domestic water supplies, and they can contaminate surgical materials. The organisms are widely distributed, but they are endemic in the Southeastern United States from Georgia to Texas [57]. Injections, surgery, and minor trauma often precede the generally chronic and localized cutaneous infections [58]. The organisms affect immunocompetent individuals of all ages, but disseminated disease is usually restricted to patients with immune deficits. Clinical evidence typically presents within 4 to 6 weeks of wound exposure to the organism, although the incubation period varies from 1 week to 2 years [59]. The rapidly growing mycobacteria can lead to pulmonary disease, osteomyelitis, lymphadenitis, postsurgical endocarditis, and cutaneous disease. Dermatologic manifestations include erythema, abscesses, and drainage. Diagnosis of the rapidly growing mycobacteria can be achieved by culture of drainage material or tissue biopsy. Histologic examination of the lesions reveals polymorphonuclear microabscesses, noncaseating granuloma formation, necrosis, and foreign body-type giant cells. Occasionally acid-fast bacilli are visible within the microabscesses [60]. Clinical manifestations and in vitro susceptibility patterns dictate antimicrobial therapy for rapidly growing mycobacteria. There is still variability among isolates, but speciation is also useful to provide general guidelines in treatment. Rapidly growing mycobacteria are resistant to the usual antituberculous agents. A clinically useful susceptibility panel for cutaneous disease should include amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, and a sulfonamide. Removal of foreign bodies is essential, and extensive disease, abscess formation, or difficulties with drug therapy necessitate surgical intervention [57]. Individual species of nontuberculous mycobacteria are discussed in the following subsections. Mycobacterium chelonae First isolated from a sea turtle in 1903 [61], M. chelonae (previously M. chelonae spp chelonae) experienced a confusing history of taxonomic classification that now complicates long-term data analysis of the organism. Corticosteroid use and previous trauma increase the risk of infection, which can affect the skin, soft tissue, lungs, and ears [62]. Cutaneous infections following excision of lower extremity basal cell carcinoma [63], liposuction or liposculpture [64], and blepharoplasty [65,66] have been reported. The source is often not identified, but contamination
325
of the domestic water supply [63] and surgical materials [64] have been implicated. Cutaneous manifestations of M. chelonae infection include nodules, abscesses, cellulitis, and catheter-related infections [67]. Papulopustules [63], fever, local inflammation, purulent drainage, and fistulae [64] have been described with M. chelonae infections following dermatologic procedures. Prolonged therapy (up to 6 months) with clarithromycin provides adequate treatment of M. chelonae cutaneous infection [57,60,68,69]. M. chelonae is generally susceptible to amikacin, tobramycin, and imipenem, but it is resistant to cefoxitin [57,62,70]. Complete resolution of cutaneous lesions might not be apparent for up to 18 months despite treatment [63]. Mycobacterium abscessus Formerly M. chelonae spp abscessus, M. abscessus rarely complicates dermatologic procedures. Ozluer et al [71] described a patient who underwent excision of two lower extremity lesions that were found to be squamous and basal cell carcinomas. Following wound exposure to saltwater and vegetation caused by a boating accident 8 days postoperatively, the patient developed M. abscessus infection of both surgical sites. Contaminated materials leading to postsurgical outbreaks of M. abscessus wound infections included tap water used in various surgeries at a pediatric facility [72], gentian violet skin-marking solution used for cosmetic surgery [73], and merbromin solution used as presurgical care for venous stripping [74]. Multiple cases following the injection of anesthetic solutions [75,76] and liposuction or liposculpture [64,77] have also been reported. The symptoms of M. abscessus infection arise (on average) 20 days postoperatively [72] and might initially involve wound erythema and pain [71]. Patients might subsequently develop cellulitis, nodules, abscesses, seropurulent discharge, or draining sinuses [67,71,72]. Systemic symptoms can include fever, chills, and weight loss [72]. As with M. chelonae, M. abscessus surgical wound infections benefit from prolonged treatment with clarithromycin [68,76,78]. Cefoxitin, clofazimine, or amikacin also effectively eradicate M. abscessus in most cases [57]. Mycobacterium fortuitum M. fortuitum is a ubiquitous organism that has been isolated from water, milk, soil, marine life, animals, and the saliva of healthy humans [59]. Dermatologic procedures that have reportedly been
326
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
Fungal complications
predispose individuals to candidiasis, as do occlusion, birth control pills, pregnancy, and immunosuppression [82]. Cutaneous candidiasis is probably an under-recognized complication of surgical wounds; it is generally innocuous and not confirmed by laboratory examination. It is difficult to establish a cause-and-effect relationship with this yeast [83]. Cutaneous candidiasis has been a reported complication of laser resurfacing [9,49,84], dermabrasion [82,83], and the treatment of nonmelanoma skin cancer such as excision and skin grafting [5,83] or electrodessication and curettage [83]. Affected patients gave a history of perle`che or concomitant vaginal candidiasis in some cases [84]. Following resurfacing procedures such dermabrasion or laser resurfacing, Candida infection can produce an array of manifestations over the subsequent 2 weeks, including itching [9,82], erythema [82,84], pustules [82,84], vesicles [9], or enlarged lymph nodes [82]. Failure of wounds to epithelialize after a prolonged period has also occurred because of postsurgical Candida infection following laser resurfacing [49], curettage and electrodessication, fullthickness skin graft repair, and dermabrasion [83]. Candida species have been reported to contribute to postoperative chondritis following two cases of auricular Mohs’ surgery [5,85]. While generally a clinical diagnosis, culture or microscopic visualization of hyphae, pseudohyphae, and yeast forms confirms the diagnosis of mucocutaneous candidiasis. Blood cultures should be drawn if there is any suspicion of disseminated disease. Avoidance of occlusive dressings and exposure of wounds to cool, dry air facilitates wound healing. Topical antifungal preparations such as nystatin or clotrimazole cream should be applied to affected areas three to four times daily. Alternatively, oral ketoconazole or fluconazole can be used. Lesions generally resolve without sequelae over the next 2 weeks [82,83]. Management of disseminated disease involves removal of central venous catheters and administration of either fluconazole or the more toxic amphotericin B. Because some non-Albicans species are resistant to fluconazole, speciation and susceptibility testing might be indicated.
Candida species
Aspergillus flavus
Candida, an ubiquitous yeast, is a normal inhabitant of the human oropharynx and gastrointestinal tract. It produces an array of disease manifestations. Because Candida grows on warm, moist surfaces, it frequently causes oral thrush, diaper rash, and vaginitis. Local or systemic antibiotics and corticosteroids
The genus Aspergillus includes more than 900 species that are ubiquitous in the soil and on decaying vegetation [86]. Cutaneous aspergillosis typically results from systemic dissemination, but primary cutaneous infection also occurs [86]. Immunocompromised patients, including burn victims, neonates,
complicated by M. fortuitum include the excision of a squamous cell carcinoma by Mohs’ technique (author’s unpublished observation), liposuction [64, 77,79], and even a simple punch biopsy in a 4-yearold boy [80]. As with M. abscessus, contaminated water sources have led to outbreaks of postsurgical M. fortuitum wound infections [81]. Cutaneous manifestations include nodules, abscesses, ulcers, draining sinus tracts, cellulitis, and a generalized morbilliform eruption [67]. A case observed by the authors involved a 67-year-old man who underwent excision of a squamous cell carcinoma of the lower extremity without complications. The wound exhibited good granulation tissue up to 3 months postoperatively, but following an excursion to India the patient developed a red painful rash with central ulceration at the excision site that became edematous, pruritic, and nontender over the next several weeks (authors’ unpublished observation); however, the presentation of M. fortuitum wound infection is highly variable. For example, a patient developed a tender, erythematous, submental nodule 2 months following liposuction [79], and another patient exhibited an erythematous and indurated plaque with peripheral papules 1 month after a punch biopsy [80]. Treatment of M. fortuitum, which is often highly susceptible to multiple agents, usually involves a combination of medications. An acceptable regimen includes intravenous amikacin and, until clinical improvement is apparent, high-dose cefoxitin [57,70]. Complete resolution of postsurgical lesions has been described following combinations of clarithromycin with minocycline [79] and, in a pediatric patient, a trimethoprim – sulfamethoxazole suspension [80]. No single morphologic or clinical feature readily allows the diagnosis of wound infection caused by nontuberculous mycobacteria. All wound infections that are unresponsive to conventional therapy and all unusual-appearing wound infections should be suspect for this complication.
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
individuals with cancer, and bone marrow and solidorgan transplant recipients are more susceptible to cutaneous aspergillosis [87]. Aspergillus fumigatus and Aspergillus flavus are responsible for most cases of opportunistic Aspergillus infection, although disease is not limited to the immunocompromised host [88]. Rarely, individuals with normal immune function develop cutaneous aspergillosis following surgery, traumatic inoculation, or heavy occupational exposure to the fungal spores [87]. Cutaneous A. flavus infection has been reported to complicate dermatologic procedures including a free muscle flap and skin graft to repair a diabetic foot ulcer [89] and the Mohs’ micrographic surgical excision of auricular Bowen’s disease [90]. Bryce et al [91] reported an outbreak of surgical and burn wound cutaneous aspergillosis that occurred because of contaminated packaging of dressing supplies. Clinical manifestations of primary cutaneous aspergillosis might not present until 1 month or more postoperatively [89,90]. Affected wounds are often associated with fever and might exhibit swelling, induration, tenderness, and changes in surface character [87]. Erythematous to violaceous, indurated plaques progressing to necrotic ulceration with central eschar formation characterize the disease [86]. Other reported findings following dermatologic procedures include a grayish – white exudate [90] or an indurated gray – yellow plaque [89]. Aspergillosis is often an indolent infection, but the course of the disease is highly variable and carries a mortality rate of 30% to 75% [87]. Diagnosis of Aspergillus wound infection requires demonstration of the organism from culture or within biopsy specimens. To differentiate Aspergillus species from other organisms, the observer should identify the septate filaments, which are approximately 3 mm thick and branch at 45 angles. Gomori’s methenamine – silver, Gridley’s, and periodic acid – Schiff stains help identify mycelia, although they can also be visualized with routine hematoxylin and eosin stain [86]. Early recognition and initiation of antifungal therapy are imperative for rapid recovery from cutaneous aspergillosis. Risk factors should be assessed and treated when feasible. Following an extensive review, Van Burik et al [87] recommend the use of itraconazole for localized cutaneous aspergillosis; however, patients should be monitored closely for treatment failure and changed to intravenous amphotericin in such cases. Cutaneous aspergillosis involving vascular catheter sites or tunnel infections, disseminated disease, or extensive primary cutaneous disease requires intravenous amphotericin B and surgical
327
therapy when clinically indicated [87]. Prior to final reconstructive procedures, biopsies and fungal cultures should be performed to ensure eradication of the organism [89].
Parasitic complications: Leishmania species Leishmaniasis is transmitted by the bite of an infected female sandfly. The disease has long affected humans. Historical references to leishmaniasis occur throughout the world; the Arab Persian philosopher and physician Avicenna (979 – 1037) recognized the cutaneous disease, and clay figurines depicting facial mutilation suggestive of leishmaniasis have been recovered from Inca tombs [92]. Cases in US Gulf War veterans, HIV-infected individuals, and overseas travelers as well as the use of leishmaniasis in research have stimulated interest in the disease in more developed countries [93]. Lesions can be cutaneous, mucocutaneous, or visceral. Localized cutaneous disease results from Leishmania major in the Old World and Leishmania mexicana and Leishmania braziliensis in the New World, although other species might cause disease in certain geographic locations [94]. L. braziliensis produces mucocutaneous leishmaniasis, which is found only in the New World. The obligate intracellular parasite is widely distributed throughout the Middle East, South Asia, Africa, and Latin America. Travelers might become infected even after brief visits to endemic areas [93]. Minor local trauma might precede the development of leishmaniasis [95], which has been reported to complicate dermatologic procedures of the nose such as basal cell carcinoma excision requiring a skin graft [96] and submucous resection [97]. Cutaneous leishmaniasis has a variety of clinical manifestations, with symptoms typically developing 1 week to 3 months after exposure [94]. Clinical evidence of New World leishmaniasis includes papules, erythematous raised plaques, or ulceration [98]. Old World lesions begin as indurated, red papules that progress to ulcerations with a central depression of granulating tissue surrounded by firm, raised borders. Czexhowicz and colleagues [96] described a patient with a remote history of travel to Old World endemic areas who experienced skin graft swelling, erythema, and ulceration following basal cell excision from the bridge of his nose. McWhinney et al [97] described a patient who traveled to Pakistan 1 year prior to undergoing submucous nasal resection. She was noted to have an enlarging postsurgical granuloma that developed central crusting with smaller satellite lesions over the next 2 years secondary to L. major.
328
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
The diagnosis of leishmaniasis is confirmed by demonstration of the parasite in relevant tissue, if possible. Giemsa staining improves visualization of the amastigotes, which exhibit a diameter of 2 to 4 mm, round to oval shape, and internal organelles (nucleus and rod shaped kinetoplast). Other mechanisms of diagnosis involve culture, animal inoculation, and molecular-based and monoclonal antibody analysis [93]. The primary treatment for cutaneous, mucocutaneous, and visceral leishmaniasis caused by Old World and New World species is a pentavalent antimonial such as stibogluconate [99 – 101]. Alternative therapies include amphotericin B deoxycholate or pentamidine isethionate [93]. Ketoconazole might be more effective than antimony treating infections caused by L. mexicana [102].
Viral complications: herpes simplex virus type 1 Herpes simplex virus (HSV), which is prevalent throughout the world [103], is transmitted when the infected cutaneous surface of one individual comes in contact with the skin or mucosa of another individual. The virus remains latent in nerve ganglia following primary infection and can undergo repeated reactivation throughout an individual’s lifetime. Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are typically associated with herpes labialis and anogenital disease, respectively; however, there is increasing crossover infection, possibly because of orogenital sexual exposure [104]. HSV-1 infection is a significant complication of laser resurfacing [9,49,84, 105,106], dermabrasion [107 – 109], chemical peels [108,110], and Mohs’ procedures [107]. Many patients who experience postsurgical HSV-1 infection report no prior history of herpes labialis [49,84, 105,108], although asymptomatic seroconversion is not unusual [111], and it might have occurred preoperatively in these cases. Current herpetiform vesicles—even if remote from the surgical site [107]—and postoperative exposure to active herpes stomatitis [106] have been described in patients who develop postoperative HSV-1 infection. Patients can develop HSV-1 reactivation following dermatologic procedures despite prophylaxis with acyclovir, valacyclovir, or famciclovir [9,84,105,108]. Clinical manifestations of HSV-1 infection following dermatologic procedures vary. Symptoms often present within the first week postoperatively, but initial findings in some cases do not occur until nearly 2 weeks after the procedure [9,84,106 – 108]. The characteristic grouped vesicles on an erythema-
tous base might not develop with HSV-1 reactivation following laser resurfacing because the epidermis often has not yet reformed [105]. Other findings suggestive of HSV-1 infection following laser resurfacing and dermabrasion include pain or tenderness [49], a ‘‘prickling’’ sensation [9], erythema [9,49, 107], erosions [9,49,107], crusting [49], or bacterial superinfection [9,49]. Disseminated disease following laser resurfacing has also been reported [9,84,105]. Following one reported case involving the Mohs’ excision of an upper lip basal cell carcinoma requiring a nasolabial subcutaneous island pedicle flap, the flap developed into a black eschar with surrounding erythema, edema, and clusters of herpetic vesicles [107]. Histologic examination reveals intraepidermal, acantholytic, and vesicular dermatitis with characteristic changes of epithelial cells. Large pink to purple intranuclear inclusions (Cowdry A bodies) cause margination of chromatin. Diagnosis is confirmed by Tzanck smear, viral culture, or antigen detection. Treatment with oral acyclovir, famciclovir, or valacyclovir for at least 1 week is usually effective. Intravenous acyclovir might be required for severe mucocutaneous HSV infection. Prevention and early recognition are particularly important because some patients might experience scarring. Some authors advocate antiviral prophylaxis for all patients undergoing laser resurfacing procedures regardless of prior history of HSV infection.
Summary Because dermatologic procedures disrupt skin integrity, they alter the body’s protective barrier and predispose individuals to cutaneous infection. Postoperative wound infections—even with common pathogens such as S. aureus—seldom complicate dermatologic procedures; however, unusual infections have been reported to complicate excisions, biopsies, skin grafts, chemical peels, dermabrasion, laser resurfacing, liposuction, blepharoplasty, and injections (eg, with anesthetic solutions or botulinum toxin). Numerous environmental and patient risk factors increase the rate of postoperative wound infections, but otherwise healthy individuals undergoing relatively simple procedures are sometimes affected. Obtaining a thorough patient history (including history of prior HSV infection or any immunocompromising factors) is crucial. Patients should be warned of potential complications, particularly when they are undergoing cosmetic procedures. It is important to maintain a high index of suspicion
Table 1 Features of unusual infections complicating dermatologic prodedures Key clinical points
Predisposing factors
Diagnostic indicators
Treatment
Toxic shock syndrome
Findings result form S. aureus toxin release and include fever, rash, desquamation, hypotension, multisystem involvement May be life-threatening
CPK, BUN, creatinine, total bilirubin, ALT, or AST might be elevated Platelets might be decreased Negative blood, throat, CSF (blood might be positive for S. aureus) No rise in titer to Rocky Mountain spotted fever, leptospirosis, or measles
Fluid replacement Vasopressors Drainage and debridement of wounds Oxacillin or nafcillin 2 g IV q4h
Necrotizing fasciitis
Often polymicrobial Monomicrobial infections usually due to S. pyogenes Rapid progression from erythema, edema, warmth, and pain to violaceous bullae, necrosis, purulent drainage with hypesthesia Life threatening
Gram’s stain and culture with susceptibility testing Lack of resistance to probing intraoperatively
Prompt and aggressive debridement Broad-spectrum antibiotic therapy Fluid replacement Hyperbaric oxygen therapy debated
Enterobacteriaceae
Often polymicrobial Causative organisms include E. coli, Enterobacter species, Serratia marcescens, P. mirabilis, K. pneumoniae Variable clinical presentation 1 – 7 d incubation period Variable clinical presentation Vesicles or pustules progress to ulceration with or without pseudomembrane formation, eventually with hypesthesia Rarely disseminates
Tampon use Postoperative state Also reported with influenza, sinusitis, tracheitis, intravenous drug use, HIV infection, burn wound, cellulitis, allergic contact dermatitis, gynecologic infection, postpartum period Reported following excision, chemical peels, laser resurfacing, lipectomy Diabetes Alcohol abuse Intravenous drug abuse Immunocompromise Peripheral vascular disease Breach in skin barrier Nonpenetrating trauma Reported following botulinum toxin injection, lipectomy, blepharoplasty Inadequate prophylaxis Wound contamination from gastrointestinal tract Reported following excision, laser resurfacing
Gram’s stain and culture with susceptibility testing
Antibiotic therapy according to speciation and susceptibility testing
Lower socioeconomic population Temperate zones Travel outside the United States Unvaccinated or no booster vaccine Reported following excision, laser resurfacing
Gram’s stain and culture on selective media (Loffler’s or tellurite agar) Diphtheria toxin assay
Antitoxin (20,000 – 40,000 units IM/IV) after testing for sensitivity to horse serum Procaine penicillin, 1.2 – 2.4 million units/d IM for 7 – 10 d Debridement of necrotic material Booster vaccine to prevent
Corynebacterium diphtheriae
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
Disease/organism
(continued on next page) 329
330
Disease/organism
Key clinical points
Predisposing factors
Diagnostic indicators
Treatment
Rapidly-growing mycobacteria
Organisms include M. chelonae, M. abscessus, M. fortuitum Symptoms often occur 4 – 6 wk following insult Contaminated surgical supplies or water sources implicated Varied findings include erythema, abscesses, wound drainage Typically chronic, localized infections
Postsurgical state Immunocompromise Reported following excision, injection, liposuction, and blepharoplasty
Gram’ stain and culture with susceptibility testing Tissue biopsy might reveal polymorphonuclear microabscesses, noncaseating granulomas, necrosis, foreign body type giant cells
Candida species
Ubiquitous yeast Variable clinical presentation including pruritis, erythema, pustules, vesicles, lymphadenopathy, failure of wound to epithelialize
Local or systemic antibiotics or corticosteroids Oral contraceptives Pregnancy Immunocompromise Reported following laser resurfacing, dermabrasion, electrodessication and curettage, excision with skin grafting
Wound culture with susceptibility testing Gram’s stain or KOH preparation of scraping might reveal pseudohyphae Blood culture if systemic disease suspected
Surgical intervention if extensive disease, abscess formation, or difficulties with drug therapy Susceptibility testing dictates options for prolonged antibiotic therapy General guidelines include clarithromycin 500 mg po bid for M. chelonae and M. abscessus; amikacin 15 mg/kg up to 1500 mg/d IM/IV divided q8 – 12h and cefoxitin 1 – 2 g IM/IV q6 – 8h for M. fortuitum Expose wounds to cool, dry air Localized infection: topical (nystatin or clotrimazole tid – qid) or oral (ketoconazole 200 – 400 mg qd) antifungal therapy; Systemic infection: fluconazole (400 mg po/IV qd) or amphotericin B (following test dose of 1 mg, advance to 0.3 – 0.7 mg/kg IV qd)
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
Table 1 (continued)
Ubiquitous mold Can contaminate surgical supplies Symptoms often present greater than 1 mo following insult Findings include fever with erythematous plaques that progress to necrotic ulcer with eschar Mortality rate of 30 – 75%
Immunocompromise Heavy occupational exposure Traumatic inoculation Reported following excision, skin grafting
Biopsy or wound culture Improved visualization with Gomori’s methenamine – silver, Gridley’s, or periodic acid – Schiff stains
Leishmania species
Obligate intracellular parasite Symptoms often present 1 – 3 mo following insult Variable clinical presentation Reactivation of latent virus in nerve ganglia Can occur despite prophylaxis Clinical findings include pain, erythema, erosion Characteristic grouped vesicles not necessarily present
Travel to endemic country Traumatic inoculation Reported following excision, skin grafting Current herpetiform vesicles Inadequate prophylaxis Reported following laser resurfacing, dermabrasion, chemical peels, excision
Biopsy with Giemsa stain to visualize amastigotes Culture Antibody testing also used Tzanck smear reveals multinucleated giant cells, often with intranuclear inclusions Viral culture Antigen detection
Herpes simplex virus type 1
Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CPK, creatinine phosphokinase.
Localized infection: itraconazole 200 mg solution (to increase absorption) po tid for 4 d, then 200 mg po bid Treatment failure or disseminated disease: amphotericin B (following test dose of 1 mg, advance up to 1 mg/kg qd IV) For extensive soft tissue infection, surgical debridement recommended Stibogluconate 20 mg/kg qd for 20 d
Oral acyclovir (500 mg 5 /day), famciclovir (500 mg tid), or valacyclovir (1000 mg tid) for at least 1 wk For severe cases, treat with acyclovir 5 – 10 mg/kg IV q8h
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
Aspergillus flavus
331
332
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
for possible wound infection in all patients that extends several months postoperatively. Manifestations of unusual postoperative infections are highly variable, and they might be secondary to bacterial, fungal, viral, or parasitic pathogens. Bacterial lesions are often polymicrobial, and bacterial superinfection can exacerbate other wound complications such as HSV reactivation. Most wound infections remain localized, but occasionally systemic disease occurs. For example, cutaneous diphtheria or rapidly growing mycobacteria rarely disseminate, whereas TSS results in systemic disease caused by toxin release. Some unusual postsurgical infections are self-limited, but they can still be potentially life threatening or disfiguring. Antimicrobial prophylaxis might reduce the risk of wound infection in some cases. Clinicians can better care for patients by becoming familiar with the causes and clinical manifestations of unusual dermatologic postoperative wound infections (Table 1). Following the recognition of an infectious process, appropriate diagnostic procedures allow for pathogen identification and the prompt institution of indicated therapy.
References [1] Kernodle DS, Kaise AB. Postoperative infections and antimicrobial prophylaxis. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell: principles and practice of infectious disease. 5th edition. New York (NY): Churchill Livingstone; 2000. p. 3177 – 91. [2] Francoeur JR. Joseph Lister: surgeon scientist (1827 – 1912). J Invest Surg 2000;13:129 – 32. [3] Dellinger EP. Surgical infections and choice of antibiotics. In: Townsend CM, Beauchamp DR, Evers MB, Mattox KL, Sabiston DC, editors. Sabiston textbook of surgery: the biological basis of modern surgical practice. Philadelphia (PA): WB Saunders; 2001. p. 171 – 88. [4] Haas AF, Grekin RC. Antibiotic prophylaxis in dermatologic surgery. J Am Acad Dermatol 1995;32: 155 – 76. [5] Futoryan T, Grande D. Postoperative wound infection rates in dermatologic surgery. Dermatol Surg 1995; 21:509 – 14. [6] Cruse PJE, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973;107: 206 – 10. [7] Christian MM, Behroozan DS, Moy RL. Delayed infections following full-face CO2 laser resurfacing and occlusive dressing use. Dermatol Surg 2000;26: 32 – 6. [8] Ross EV, Amesbury EC, Barile A, et al. Incidence of postoperative infection or positive blood culture after facial laser surgery: a pilot study, a case report, and a
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20] [21]
[22]
[23]
[24]
[25]
proposal for a rational approach to antibiotic prophylaxis. J Am Acad Dermatol 1998;39:975 – 81. Sriprachya-Anunt S, Fitzpatrick RE, Goldman MP, et al. Infections complicating pulsed carbon dioxide laser resurfacing for photoaged facial skin. Dermatol Surg 1997;23:527 – 35. Walia S, Alster TS. Cutaneous CO2 laser resurfacing infection rate with and without prophylactic antibiotics. Dermatol Surg 1999;25:857 – 61. Schlievert PM, Bohach GA, Ohlendorf DH. Molecular structure of staphylococcus and streptococcus superantigens. J Clin Immunol 1995;15(Suppl 6): 4S – 10S. Manders SM. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998; 39:383 – 98. Bosley AR, Bluett NH, Sowden G. Toxic shock syndrome after elective minor dermatological surgery. BMJ 1993;306:386 – 7. Huntley AC, Tanabe JL. Toxic shock syndrome as a complication of dermatologic surgery. J Am Acad Dermatol 1987;16(1 Pt 2):227 – 9. Dmytryshyn JR, Gribble MJ, Kassen BO. Chemical face peel complicated by toxic shock syndrome. A case report. Arch Otolaryngol 1983;109:170 – 1. LoVerme WE, Drapkin MS, Courtiss EH, et al. Toxic shock syndrome after chemical face peel. Plast Reconstr Surg 1987;80:115 – 8. Apfelberg DB. A critical appraisal of high-energy pulsed carbon dioxide laser facial resurfacing for acne scars. Ann Plast Surg 1997;38:95 – 100. Rhee CA, Smith RJ, Jackson IT. Toxic shock syndrome associated with suction-assisted lipectomy. Aesthetic Plast Surg 1994;18:161 – 3. Umeda T, Ohara H, Hayashi O, et al. Toxic shock syndrome after suction lipectomy. Plast Reconstr Surg 2000;106:204 – 7. Stevens DL. Invasive group A streptococcus infections. Clin Infect Dis 1992;14:2 – 11. Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 1989;321:1 – 7. Todd J, Fishaut M, Kapral F, et al. Toxic-shock syndrome associated with phage-group-1 staphylococci. Lancet 1978;2:1116 – 8. Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep 1997;46:1 – 55. Centers for Disease Control and Prevention. Epidemiology Program Office, Division of Public Health Surveillance and Informantics: case definitions for infectious conditions under public health surveillance. Part 1. Case definitions for nationally notifiable infectious disease. Available at: http://www.cdc.gov/epo/ dphsi/casedef/notifiable.htm. Accessed July 18, 2001. Davis JP, Chesney PJ, Wand PJ, et al. Toxic-shock syndrome: epidemiologic features, recurrence, risk
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
[26]
[27]
[28]
[29] [30] [31] [32] [33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
factors, and prevention. N Engl J Med 1980;303: 1429 – 35. Davis JP, Osterholm MT, Helms CM, et al. Tri-state toxic-shock syndrome study. II. Clinical and laboratory findings. J Infect Dis 1982;145:441 – 8. Wadvogel FA. Staphylococcus aureus (including staphylococcal toxic shock). In: Mandell GL, Bennett JE, Dolin R, editors. Mandell: principles and practice of infectious disease. 5th edition. New York (NY): Churchill Livingstone; 2000. p. 2069 – 92. Paris AL, Herwaldt LA, Blum D, et al. Pathologic findings in twelve fatal cases of toxic shock syndrome. Ann Intern Med 1982;96:852 – 7. Todd JK. Therapy of toxic shock syndrome. Drugs 1990;39:856 – 61. Descamps V, Aitken J, Lee MG. Hippocrates on necrotising fasciitis. Lancet 1994;344:556. Wilson B. Necrotizing fasciitis. Am Surg 1952;18: 416 – 31. Green RJ, Dafoe DC, Raffin TA. Necrotizing fasciitis. Chest 1996;110:219 – 29. McHenry CR, Piotrowski JJ, Petrinic D, et al. Determinants of mortality for necrotizing soft-tissue infections. Ann Surg 1995;221:558 – 63. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med 1996;334: 240 – 5. Latimer PR, Hodgkins PR, Vakalis AN, et al. Necrotising fasciitis as a complication of botulinum toxin injection. Eye 1998;12(Pt 1):51 – 3. Alexander J, Takeda D, Sanders G, et al. Fatal necrotizing fasciitis following suction-assisted lipectomy. Ann Plast Surg 1988;20:562 – 5. Barillo DJ, Cancio LC, Kim SH, et al. Fatal and nearfatal complications of liposuction. South Med J 1998;91:487 – 92. Gibbons MD, Lim RB, Carter PL. Necrotizing fasciitis after tumescent liposuction. Am Surg 1998;64: 458 – 60. Jordan DR, Mawn L, Marshall DH. Necrotizing fasciitis caused by group A streptococcus infection after laser blepharoplasty. Am J Ophthalmol 1998;125: 265 – 6. Ray AM, Bressler K, Davis RE, et al. Cervicofacial necrotizing fasciitis. A devastating complication of blepharoplasty. Arch Otolaryngol Head Neck Surg 1997;123:633 – 6. Suner IJ, Meldrum ML, Johnson TE, et al. Necrotizing fasciitis after cosmetic blepharoplasty. Am J Ophthalmol 1999;128:367 – 8. Davies HD, McGeer A, Schwartz B, et al. Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med 1996;335:547 – 54. Zittergruen M, Grose C. Magnetic resonance imaging for early diagnosis of necrotizing fasciitis. Pediatr Emerg Care 1993;9:26 – 8. Stamenkovic I, Lew PD. Early recognition of potentially fatal necrotizing fasciitis. The use of frozensection biopsy. N Engl J Med 1984;310:1689 – 93.
333
[45] Burge TS. Necrotizing fasciitis—the hazards of delay. J R Soc Med 1995;88:342P – 3P. [46] Brown DR, Davis NL, Lepawsky M, et al. A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy. Am J Surg 1994;167:485 – 9. [47] Riseman JA, Zamboni WA, Curtis A, et al. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery 1990;108:847 – 50. [48] Roth RR, James WD. Microbiology of the skin: resident flora, ecology, infection. J Am Acad Dermatol 1989;20:367 – 90. [49] Rendon-Pellerano MI, Lentini J, Eaglstein WE, et al. Laser resurfacing: usual and unusual complications. Dermatol Surg 1999;25:360 – 6. [50] Pandit N, Yeshwanth M. Cutaneous diphtheria in a child. Int J Dermatol 1999;38:298 – 305. [51] Adriaans B. Cutaneous diphtheria. In: Canizares O, Harman R, editors. Clinical tropical dermatology. 2nd edition. Boston (MA): Blackwell Scientific; 1992. p. 231 – 3. [52] Kain KC. Skin lesions in returned travelers. Med Clin N Am 1999;83:1077 – 102. [53] Hofler W. Cutaneous diphtheria. Int J Dermatol 1991; 30:845 – 7. [54] Monsuez JJ, Mathieu D, Arnout F, et al. Cutaneous diphtheria in a homeless man. Lancet 1995;346: 649 – 50. [55] Magill AJ. Fever in the returned traveler. Infect Dis Clin N Am 1998;12:445 – 69. [56] Runyon EH. Pathogenic mycobacteria. Bibl Tuberc 1965;21:235 – 87. [57] American Thoracic Society, Medical Section of the American Lung Association. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156:S1 – 25. [58] Wallace Jr RJ, Swenson JM, Silcox VA, et al. Spectrum of disease due to rapidly growing mycobacteria. Rev Infect Dis 1983;5:657 – 79. [59] Hautmann G, Lotti T. Atypical mycobacterial infections of the skin. Dermatol Clin 1994;12:657 – 68. [60] Wallace Jr RJ, Tanner D, Brennan PJ, et al. Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993;119:482 – 6. [61] Grange JM. Mycobacterium chelonei. Tubercle 1981; 62:273 – 6. [62] Wallace Jr RJ, Brown BA, Onyi GO. Skin, soft tissue, and bone infections due to Mycobacterium chelonae chelonae: importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin. J Infect Dis 1992;166:405 – 12. [63] Saluja A, Peters NT, Lowe L, et al. A surgical wound infection due to Mycobacterium chelonae successfully treated with clarithromycin. Dermatol Surg 1997;23:539 – 43. [64] Centers for Disease Control and Prevention. Rapidly
334
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335 growing mycobacterial infection following liposuction and liposculpture – Caracas, Venezuela, 1996 – 1998. MMWR Morb Mortal Wkly Rep 1998;47:1065 – 7. Kevitch R, Guyuron B. Mycobacterial infection following blepharoplasty. Aesthetic Plast Surg 1991; 15:229 – 32. Moorthy RS, Rao NA. Atypical mycobacterial wound infection after blepharoplasty. Br J Ophthalmol 1995; 79:93. Weitzul S, Eichhorn PJ, Pandya AG. Nontuberculous mycobacterial infections of the skin. Dermatol Clin 2000;18:359 – 77. Brown BA, Wallace Jr RJ, Onyi GO, et al. Activities of four macrolides, including clarithromycin, against Mycobacterium fortuitum, Mycobacterium chelonae, and M. chelonae-like organisms. Antimicrob Agents Chemother 1992;36:180 – 4. McCracken D, Flanagan P, Hill D, et al. Cluster of cases of Mycobacterium chelonae bacteraemia. Eur J Clin Microbiol Infect Dis 2000;19:43 – 6. Swenson JM, Wallace Jr RJ, Silcox VA, et al. Antimicrobial susceptibility of five subgroups of Mycobacterium fortuitum and Mycobacterium chelonae. Antimicrob Agents Chemother 1985;28:807 – 11. Ozluer SM, De’Ambyyrosis BJ. Mycobacterium abscessus wound infection. Australas J Dermatol 2001; 42:26 – 9. Chadha R, Grover M, Sharma A, et al. An outbreak of post-surgical wound infections due to Mycobacterium abscessus. Pediatr Surg Int 1998;13:406 – 10. Safranek TJ, Jarvis WR, Carson LA, et al. Mycobacterium chelonae wound infections after plastic surgery employing contaminated gentian violet skin-marking solution. N Engl J Med 1987;317: 197 – 201. Foz A, Roy C, Jurado J, et al. Mycobacterum chelonei iatrogenic infections. J Clin Microbiol 1978;7: 319 – 21. Rodriguez G, Ortegon M, Camargo D, et al. Iatrogenic Mycobacterium abscessus infection: histopathology of 71 patients. Br J Dermatol 1997;137:214 – 8. Villanueva A, Calderon RV, Vargas BA, et al. Report on an outbreak of postinjection abscesses due to Mycobacterium abscessus, including management with surgery and clarithromycin therapy and comparison of strains by random amplified polymorphic DNA polymerase chain reaction. Clin Infect Dis 1997;24: 1147 – 53. Murillo J, Torres J, Bofill L, et al. Skin and wound infection by rapidly growing mycobacteria: an unexpected complication of liposuction and liposculpture. Arch Dermatol 2000;136:1347 – 52. Mushatt DM, Witzig RS. Successful treatment of Mycobacterium abscessus infections with multidrug regimens containing clarithromycin. Clin Infect Dis 1995;20:1441 – 2. Behroozan DS, Christian MM, Moy RL. Mycobacterium fortuitum infection following neck liposuction: a case report. Dermatol Surg 2000;26:588 – 90.
[80] Buckley R, Cobb MW, Ghurani S, et al. Mycobacterium fortuitum infection occurring after a punch biopsy procedure. Pediatr Dermatol 1997;14:290 – 2. [81] Kuritsky JN, Bullen MG, Broome CV, et al. Sternal wound infections and endocarditis due to organisms of the Mycobacterium fortuitum complex. Ann Intern Med 1983;98:938 – 93. [82] Siegle RJ, Chiaramonti A, Knox DW, et al. Cutaneous candidosis as a complication of facial dermabrasion. J Dermatol Surg Oncol 1984;10:891 – 5. [83] Giandoni MB, Grabski WJ. Cutaneous candidiasis as a cause of delayed surgical wound healing. J Am Acad Dermatol 1994;30:981 – 4. [84] Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing. An evaluation of 500 patients. Dermatol Surg 1998;24:315 – 20. [85] Trizna Z, Chen SH, Lockhart S, et al. Candida parapsilosis chrondritis successfully treated with oral fluconazole. Arch Dermatol 2000;136:804. [86] Isaac M. Cutaneous aspergillosis. Dermatol Clin 1996; 14:137 – 40. [87] Van Burik JA, Colven R, Spach DH. Cutaneous aspergillosis. J Clin Microbiol 1998;36:3115 – 21. [88] Elewski BE, Radentz WH, Gupta AK. Opportunistic mycoses. In: Elewski BE, editor. Cutaneous fungal infections. 2nd edition. Malden (MA): Blackwell Science; 1998. p. 225 – 59. [89] Lai CS, Lin SD, Chou CK, et al. Aspergillosis complicating the grafted skin and free muscle flap in a diabetic. Plast Reconstr Surg 1993;92:532 – 6. [90] Anderson LL, Giandoni MB, Keller RA, et al. Surgical wound healing complicated by Aspergillus infection in a nonimmunocompromised host. Dermatol Surg 1995;21:799 – 801. [91] Bryce EA, Walker M, Scharf S, et al. An outbreak of cutaneous aspergillosis in a tertiary-care hospital. Infect Control Hosp Epidemiol 1996;17:170 – 2. [92] Kerdel-Vegas F, Harman R, Kerdel F, et al. Protozoan Infections II. In: Canizares O, Harman R, editors. Clinical tropical dermatology. 2nd edition. Boston (MA): Blackwell Scientific; 1992. p. 293 – 323. [93] Herwaldt BL. Leishmaniasis. Lancet 1999;354: 1191 – 9. [94] Grevelink SA, Lerner EA. Leishmaniasis. J Am Acad Dermatol 1996;34:257 – 72. [95] Wortmann GW, Aronson NE, Miller RS, et al. Cutaneous leishmaniasis following local trauma: a clinical pearl. Clin Infect Dis 2000;31:199 – 201. [96] Czechowicz RT, Millard TP, Smith HR, et al. Reactivation of cutaneous leishmaniasis after surgery. Br J Dermatol 1999;141:1113 – 6. [97] McWhinney PH, Mir N, Love WC, et al. Cutaneous leishmaniasis presenting as a postoperative granuloma. J R Soc Med 1993;86:236 – 7. [98] Lemons-Estes FM, Neafie RC, Meyers WM. Unusual cutaneous infections and parasitic diseases. Dermatol Clin 1999;17:151 – 85. [99] Aronson NE, Wortmann GW, Johnson SC, et al. Safety and efficacy of intravenous sodium stibogluconate in
M.E. Garman, I. Orengo / Dermatol Clin 21 (2003) 321–335
[100]
[101]
[102]
[103]
[104] [105]
the treatment of leishmaniasis: recent U.S. military experience. Clin Infect Dis 1998;27:1457 – 64. Berman JD. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 1997;24:684 – 703. Llanos-Cuentas A, Echevarria J, Cruz M, et al. Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment of mucocutaneous leishmaniasis. Clin Infect Dis 1997;25:677 – 84. Navin TR, Arana BA, Arana FE, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 1992;165: 528 – 34. Nahmias AJ, Lee FK, Beckman-Nahmias S. Sero-epidemiological and -sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis Suppl 1990;69:19 – 36. Brown TJ, Vander Straten M, Tyring SK. Antiviral agents. Dermatol Clin 2001;19:23 – 34. Alster TS, Nanni CA. Famciclovir prophylaxis of herpes simplex virus reactivation after laser skin resurfacing. Dermatol Surg 1999;25:242 – 6.
335
[106] Waldorf HA, Kauvar AN, Geronemus RG. Skin resurfacing of fine to deep rhytides using a char-free carbon dioxide laser in 47 patients. Dermatol Surg 1995;21:940 – 6. [107] Dzubow LM. Scarring following herpes simplex infection of postsurgical cutaneous sites. J Dermatol Surg Oncol 1989;15:65 – 70. [108] Perkins SW, Sklarew EC. Prevention of facial herpetic infections after chemical peel and dermabrasion: new treatment strategies in the prophylaxis of patients undergoing procedures of the perioral area. Plast Reconstr Surg 1996;98:427 – 33. [109] Silverman AK, Laing KF, Swanson NA, et al. Activation of herpes simplex following dermabrasion. Report of a patient successfully treated with intravenous acyclovir and brief review of the literature. J Am Acad Dermatol 1985;13:103 – 8. [110] Rapaport MJ, Kamer F. Exacerbation of facial herpes simplex after phenolic face peels. J Dermatol Surg Oncol 1984;10:57 – 8. [111] Langenberg AG, Corey L, Ashley RL. A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med 1999;341:1432 – 8.
Dermatol Clin 21 (2003) 337 – 348
Antibiotic use in dermatologic surgery Melissa Dawn Babcock, MD, Roy C. Grekin, MD* Dermatology Department, University of California at San Francisco, 1701 Divisadero Street, Room 356, San Francisco, CA 94115-3011, USA
Dermatologists performing cutaneous surgery are commonly faced with the question of whether or not to use antibiotic prophylaxis. Actual wound infections or the higher than normal probability of same, the risk for developing bacterial endocarditis, and the potential contamination of prosthetic devices are the main reasons that dermatologists consider antibiotic use. The current recommendations for antibiotic coverage remain controversial in several areas. For the first time, the subject of cutaneous surgery is addressed in the 1997 American Heart Association (AHA) recommendations on endocarditis prophylaxis. Antibiotics are not recommended by the AHA—regardless of the patient’s cardiac history—when the procedure is performed on surgically scrubbed skin. While most dermatologists agree that surgery on clean wounds does not require antibiotic coverage, there is little agreement on when prophylaxis is indicated when the patient possesses prosthetic implants. Moreover, the concomitant disadvantages of antibiotic prophylaxis should not be overlooked; these include added cost, adverse drug events, promotion of drug-resistant organisms, and medication interactions. In this article the authors address these controversies, review the current literature, and provide pragmatic recommendations regarding antibiotic prophylaxis in conjunction with dermatological surgery.
Prophylaxis for wound infection In deciding when to use antibiotics to prevent postoperative wound infection, the practitioner
* Corresponding author. E-mail address:
[email protected] (R.C. Grekin).
should first determine into which category the wound falls. These categories are based on the degree of wound contamination. By using this classification system, it can be easily determined whether or not antibiotics are needed before the procedure [1]. The four categories are described as follows: 1. Clean wounds (Class I). These are created on normal-appearing skin using clean or sterile techniques. Examples include excision of benign or malignant neoplasms, excision of noninflamed follicular cysts, biopsies, and most cases of Mohs’ surgery. The majority of dermatological surgery falls into this category. Under these conditions, infection rates should be less than 5%. 2. Clean-contaminated wounds (Class II). These are created on contaminated skin or any mucosal or moist intertriginous surface such as the oral cavity, upper respiratory tract, axilla, or peritoneum. The infection rate for wounds created under these circumstances should be about 10%. 3. Contaminated wounds (Class III). These wounds have visibly inflamed skin with or without the presence of nonpurulent discharge. Examples of Class III wounds might include such conditions as inflamed epidermal inclusion cysts or inflamed neoplasms. Traumatic wounds also fall into this category. The infection rate for these wounds is expected to be in the 20% to 30%. 4. Infected wounds (Class IV). These wounds contain contaminated foreign bodies, demonstrate purulent discharge, or have devitalized tissue present. Examples include ruptured cysts, active hidradenitis suppurativa, and neo-
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00096-7
338
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
plasms with visibly necrotic tissue. The infection rate for these wounds is 30% to 40% [1]. Clean (Class I) wounds do not require antibiotic prophylaxis. There are several studies in the literature supporting this assertion [2 – 5]. Baran et al published a study in the Journal of Plastic and Reconstructive Surgery looking at 1400 patients undergoing plastic surgery. Half of the group received 2 grams of a sulbactam – ampicillin intravenously prior to surgery, and the other half received normal saline. There was no significant difference in postoperative wound infection [2]. Similar studies have been performed on patients undergoing hernia repair and breast surgery. These are considered to be at least clean procedures, and in these trials no significant difference in postoperative wound infection rate was discovered between patients receiving prophylaxis and patients not receiving antibiotic prophylaxis [3,5]. Full-face laser resurfacing is a special case. Such resurfacing probably falls into the clean wound category because the operation is performed on clean skin, usually not on mucosal surfaces, and certainly not on contaminated or infected skin. It should follow, therefore, that these patients should not receive antibiotic prophylaxis. Gaspar et al addressed this issue by performing a prospective study of 31 patients undergoing full-face laser resurfacing. Seventeen patients received antibiotics whereas 14 did not receive preprocedure antibiotics. None of the 17 patients who received antibiotic prophylaxis had clinical infection, whereas 4 of the 14 patients without antibiotic coverage had evidence of infection clinically and on bacterial culture. The authors nonetheless concluded that antibiotic prophylaxis is not essential because ‘‘meticulous wound care and close clinical monitoring of patients daily with routine bacterial swabs can detect infection early.’’ Once infection is detected, early treatment can prevent adverse sequelae [6]. Manuskiatti et al discussed the need for antibiotic prophylaxis, comparing laser resurfacing to a seconddegree burn [7]. They performed a randomized control trial in which 356 patients were divided into four groups that consisted of treatment with oral ciprofloxacin, oral ketoconazole, oral fluconazole, or no prophylaxis. The highest rate of wound infection occurred in patients without antibiotic prophylaxis (8.2%) compared with patients receiving oral ciprofloxacin (4.3%). Yeast infections were seen in 1.7% of patients, none of whom were treated with an antifungal. For 7 months after the procedure, patients were randomized to intranasal mupirocin or no treat-
ment. Staphylococcal infections developing within that time period all happened in patients who were receiving mupirocin [7]. Another study was a retrospective chart review of 133 patients undergoing CO2 laser resurfacing. A significantly higher rate of infection occurred in patients who received intravenous (IV) cephalexin or oral azithromycin compared with patients who did not receive any antibiotics [8]. At the authors’ institution, The University of California at San Francisco, the authors use neither prophylactic antibiotics nor antifungals for laser resurfacing. The authors’ experience agrees with that of Gaspar—these medications can be readily and effectively initiated if and when infection is detected. The sole exception to this rule is the administration of oral antiviral drugs to patients with a history of herpes simplex virus. Such individuals receive antiviral medication on the day of the procedure and continue the chosen drug for 10 days afterwards. The use of antibiotics in clean-contaminated wounds (Class II wounds) is controversial. There have been studies published on this topic from various disciplines of medicine, including head and neck surgery, dental surgery, gastrointestinal surgery, and gynecologic surgery. Several authors believe that clean-contaminated surgery requires antibiotics, especially if saliva contaminates the wound or if the aerodigestive tract is violated [9 – 15]; however, there have been some interesting double-blind trials that did not find a difference in infection rate between patients with and without antibiotic prophylaxis in clean-contaminated procedures. A double-blind study performed by Monaco looked at the infection rate following third molar extraction. Sixty-six patients were randomized to receive 2 g of amoxicillin for 5 days starting on the day of surgery, whereas 75 patients received no antibiotics. They found no significant difference between groups with regard to infection rate, fever, pain, or swelling [16]. A randomized, controlled trial of elective laparoscopic cholecystectomy with 450 patients showed no difference in infection rate between patients treated with cefotetan 1 g IV, cefazolin 1 g IV, or IV placebo [17]. In the head and neck literature, a randomized, controlled trial was published of 438 patients who underwent major head and neck surgery that was not contaminated by saliva. These procedures included parotidectomy, thyroidectomy, or submandibular gland excision. There was no difference in infection rates between patients who received antibiotics and patients who did not [18]. In the urology literature, a randomized trial enrolled 580 patients who underwent transurethral resection for either a prostate or bladder tumor. All patients
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
received either drug or placebo 30 to 90 minutes prior to surgery. Of the patients completing the study, 3.3% of patients receiving 500 mg of ciprofloxacin, 4.8% of patients receiving 1 g of cefotaxime, and 7.0% of patients receiving placebo had postoperative bacteriuria. The placebo group had a slightly higher rate of bacteriuria, but they also had a lower rate of drug-related adverse events (3%, 6%, and 1% for ciprofloxacin, cefotaxime, and placebo, respectively) [19]. In the gynecologic literature, a randomized trial was performed on 67 healthy women who underwent endometrial curettage for metrorrhagia. One group received doxycycline 200 mg daily for 1 week while the other group did not receive any antibiotics. There was no significant difference in pelvic inflammatory disease during the postoperative follow-up period [20]. The surgical treatment of ulcers deserves special mention. This surgery probably falls into the cleancontaminated category. A prospective double-blind study of 94 patients with venous or arterial ulcers of the lower extremity found no difference in skin graft take or surgical site infection when patients were treated with antibiotics or placebo [21]. Antibiotics are not therefore necessary concomitant to surgical treatment of ulcers. Antibiotics are probably not indicated in cleancontaminated (Class II) wounds in dermatologic surgery even if the surgery site has been contaminated with saliva or there has been exposure to mucous-lined cavities. In addition, there is sufficient literature to justify avoidance of routine antibiotic prophylaxis in other anatomic areas that fall into the clean-contaminated category such as the perineum, axilla, and respiratory mucosa. Rather than expose all patients to antibiotics, it is preferable to treat infections when they arise. A patient should only be treated with prophylactic antibiotics in the case of clean-contaminated (Class II) wounds if an infection would result in significant morbidity to the patient. Other risk factors for infection, such as the patient’s overall health status and the length and complexity of surgery should be guiding factors. In contaminated wounds (Class III) and infected wounds (Class IV), antibiotics serve a therapeutic rather than a prophylactic role and should be used in these cases [1].
Antibiotic selection in cutaneous surgery In contaminated wounds (Class III) and infected wounds (Class IV), the choice of which antibiotics to use is based on the speculation of which bacteria is the causative organism. The most common bacterium
339
in the skin flora is Staphylococcus epidermidis, which comprises more than 50% of the staphylococcal species in the skin, particularly on the upper body [22]. The ability of this organism to produce serious pathology is limited. The pathogen that serves as the most common cause of wound infection is Staphylococcus aureus. S. aureus is not part of the routine resident flora, but it is present in the peritoneum in up to 20% of individuals and in the nasal passages in about 20% to 40% of individuals. Other pathogens to be considered are Streptococcus viridans, which is found in the oral cavity, and enterococci and Escherichia coli, which are found in and around the gastrointestinal and genitourinary tract. These are less common causes of cutaneous wound infection [1]. First-generation cephalosporins are a good choice for treatment of wound infections because of their excellent coverage of staphylococcal organisms, common Gram-negative organisms such as E. coli, and certain Proteus species. Cephalosporins are rapidly absorbed from the gastrointestinal tract and demonstrate good tissue penetration. Side effects are relatively few, the most common being morbilliform drug rash, eosinophilia, and fever. The crossreactivity in penicillin-allergic patients is 5% to 10%. Patients who have experienced urticarial reaction to penicillins should not receive cephalosporins. On the other hand, patients who have developed nonurticarial penicillin-induced drug eruptions can usually tolerate the cephalosporins without difficulty. Cephalexin (Keflex, Disto Products, Division of Eli Lilly Co., Indianapolis, India), cephradine (Anspor, Velosef [Teva Pharmaceuticals, Sellersville, PA]), and cefadroxil (Duricef, Bristol-Myers Squibb, Princeton, NJ) are examples of first-generation cephalosporins. Cefadroxil might have an advantage because its serum half-life (which is almost twice that of cephalexin) allows twice daily dosing. The cost of a cefadroxil 500 mg dose course is in between the cost of a cephalexin 250 mg dose and 500 mg dose courses [23,24]. Penicillins are safe antibiotics that can be used by most patients except those with hypersensitivity. The isoxazolyl penicillins, which include dicloxacillin and nafcillin, provide the best coverage because they treat b-lactamase – producing bacterial strains. These bacterial strains are often resistant to cephalosporin antibiotics. Dicloxacillin is effective against most streptococci and S. aureus. Strains of S. aureus that are resistant to methicillin are generally resistant to the isoxazolyl penicillins. Aminopenicillins, which include ampicillin and amoxicillin, have better Gramnegative coverage and coverage against enterococci and group A streptococci. Amoxicillin is the AHA’s
340
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
first choice for endocarditis prophylaxis. Amoxicillin has an advantage over ampicillin because it has better oral absorption and causes diarrhea less frequently. The aminopenicillins are, however, susceptible to degradation by b-lactamase – producing bacteria, and they are therefore not effective against most strains of S. aureus. This characteristic makes such antimicrobials less desirable for wound infections. Macrolides such as erythromycin are a good alternative for patients who are allergic to penicillin or cephalosporins. Erythromycin is effective in treating wound infections caused by streptococcal or staphylococcal species, although not as effective as penicillins. Strains of erythromycin-resistant S. aureus are increasing, so this medication should not be used when a better alternative is available. The antibiotic is one of the safest on the market. The side effects include rare hypersensitivity and dose-related gastrointestinal upset. The estolate form of erythromycin is associated with an increased risk of cholestatic jaundice in patients who are pregnant or under 12 years old. The newer macrolides, clarithromycin (Biaxin, Abbott Laboratories, Abbott Park, Illinois) and azithromycin (Zithromax, Pfizer Inc., New York, NY) offer a somewhat broader antimicrobial coverage, but at a much higher price. Clarithromycin has two to four fold greater activity against Grampositive organisms compared with erythromycin, whereas azithromycin has two to four fold less activity. The newer macrolides offer greater Gram-negative coverage than erythromycin. Quinolone antimicrobials such as ciprofloxacin possess a wide antibacterial spectrum. Not only do they have activity against many staphylococcal and streptococcal species, but they are also effective against Pseudomonas aeruginosa, E. coli, Enterobacter cloacae, Klebsiella pneumoniae, and Proteus species. Ciprofloxacin is one of the few oral agents that generally has efficacy against methicillin-resistant S. aureus. Nonetheless, ciprofloxacin is not used as a first-line agent for staphylococcal and streptococcal wound infections to keep antibiotic resistance to a minimum and because lower cost alternatives (eg, penicillins and cephalosporins) are equally good at treating these infections [23,24].
Patient risk factors Several risk factors predispose patients to wound infection. When a patient has one or more risk factors it might be appropriate to start antibiotic therapy when it otherwise might not have been considered. For example, patients with poorly controlled diabetes
mellitus are at a higher risk, and antibiotic prophylaxis can be considered [25]. Diabetes has been associated with immune system abnormalities such as defects in leukocyte mobilization [1]. Infections with S. aureus are more common and more difficult to treat in diabetics. One trial demonstrated a higher infection rate in patients who were diabetic; however, this higher rate of infection was the same in the antibiotic-treated group as the placebo-treated group [13]. The theory that diabetics are generally at an increased risk for wound infection is controversial. Studies have shown an increased risk, such as the one above, whereas others have shown no difference in risk of infection [26 – 28]. Most authors feel that a patient’s level of glucose control is a better indicator of risk than simply having diabetes. Other risk factors that predispose patients to wound infection associated with cutaneous surgery include impaired immune status, immunocompromise caused by medication such as steroids, infectious disease or cancer, malnutrition, heavy smoking, habitual alcohol use, advanced age, and long-standing medical illnesses such as chronic obstructive pulmonary disease or chronic renal failure [13,16,29]. It is often impossible to correct these risk factors; therefore, each patient deemed to be at ‘‘high risk’’ must be evaluated on a case-by-case basis to determine if prophylactic antibiotics would preclude a significant health risk. Conversely, some ‘‘high-risk’’ patients might well tolerate being treated only if or when an infection develops.
Environmental risk factors There are a number of exogenous risk factors that physicians performing cutaneous surgery can try to avoid and some exogenous factors that can help prevent wound infection. Perioperative shaving Preoperative shaving 24 hours prior to the procedure has been associated with an increased rate of infection [30]. It is important to instruct patients not to shave prior to surgery. Clipping hair has a lower risk of infection than shaving. If shaving is indicated, it is best performed at the time of surgery. Length of operation The longer the procedure, the higher the infection rate. The infection rate roughly doubles per hour of procedure [30]. During Mohs’ surgery, for example, if
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
a patient undergoes several stages and is in the office all day, the authors might consider antibiotics if any other risk factors are present. Keeping procedures as short as possible without compromising care to the patient is ideal. Preoperative showering A shower the evening before surgery with regular or antibacterial soap will reduce the rate of infection. Concomitant infections If a patient has an infection independent of the surgical site (eg, in the urinary or respiratory tract), the postoperative infection rate will be higher. It is important to identify and treat such infections at least 24 hours before skin surgery [31]. Use of sterile or clean technique In performing most cutaneous surgery, the same standards of sterility adopted for the operating room are not commonly utilized; however, the typical ‘‘clean’’ or ‘‘sterile’’ techniques used in an office setting yield an infection rate that is comparable to the rate expected from an operating room. Thus, antiseptic maneuvers such as sterile skin preparation, use of meticulously sterilized instruments, preoperative hand washing, and gloving will affect the infection rate in a positive manner [30,32]. Perioperative stay It is rare for skin surgery patients to require hospitalization. When this occurs, the duration of hospitalization is directly correlated with an increasing infection rate. This is true whether the hospital stay is before or after the surgery [33]. Thus, hospitalization should be avoided whenever possible.
Evaluating endocarditis risk Bacterial endocarditis is defined as infection of the heart lining or heart valves. In either location, this can lead to serious cardiac dysfunction. Endocarditis occurs when blood-borne organisms are deposited on abnormal valves or damaged cardiac tissue. Transient bacteremia accompanies such banal activities as dental procedures and brushing the teeth, yet endocarditis rarely intervenes. Regions of the body with greater bacterial (or yeast) colonization—such as the mouth, upper respiratory system, and gastrointes-
341
tinal or distal genitourinary tracts—are more likely to yield endocarditis when they are manipulated [34]. It follows that the most recent AHA endocarditis prophylaxis guidelines include stronger recommendations when medical procedures are performed that involve these relatively higher-risk areas. When endocarditis occurs it carries a mortality of 5% to 76%, and it is ultimately lethal in virtually all patients who do not receive prompt, adequate treatment; 40% of patients who experience endocarditis will require heart valve replacement during the ensuing 5 to 8 years [35]. There is nearly universal agreement that primary prevention of endocarditis is preferable to treatment after the fact. Nonetheless, deciding when to administer endocarditis prophylaxis remains controversial, and there are no randomized, controlled studies that conclusively prove that prophylaxis is efficient. Moreover, the majority of cases of endocarditis are not the result of medical manipulation [34 – 37]. The AHA issued new guidelines in 1997 that detail which underlying cardiac conditions require prophylactic antibiotics and for which procedures. The AHA divides cardiac conditions into three categories: high risk, moderate risk, and negligible risk. Endocarditis prophylaxis is recommended for highand moderate-risk disorders, whereas it is not recommended for negligible-risk disorders. The text box below lists entities that fall into each risk category.
Cardiac conditions associated with endocarditis (from [37]) Endocarditis prophylaxis recommended High-risk category Prosthetic cardiac valves, including bioprosthetic and homograft valves Previous bacterial endocarditis Complex cyanotic congenital heart disease (eg, single ventricle states, transposition of the great arteries, tetralogy of Fallot) Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category Most other congenital cardiac malformations (other than above and below) Acquired valvular dysfunction (eg, rheumatic heart disease)
342
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
Hypertrophic cardiomyopathy Mitral valve prolapse with valvular regurgitation or thickened leaflets Endocarditis prophylaxis not recommended Negligible-risk category (no greater risk than the general population) Isolated secundum atrial septal defect Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 mo) Previous coronary artery bypass graft surgery Mitral valve prolapse without valvular regurgitation Physiologic, functional, or innocent heart murmurs Previous Kawasaki disease without valvar dysfunction Previous rheumatic fever without valvular dysfunction Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators
procedure. He further points out that skin cannot be sterilized, and therefore the setting of the procedure— whether it be the operating room or an outpatient office setting—does not make a difference. Additionally, the author adds that bacteria found on the skin are not usually the bacteria that cause endocarditis, and bacteremia following surgery involving scrubbed skin is not likely. Even traumatic lacerations do not need antibiotic prophylaxis according to these guidelines [38]. Some physicians reading this article might be hesitant to change their practice, but other, more invasive procedures also do not require antibiotic prophylaxis regardless of the patient’s cardiac history (eg, cesarean section, sterilization procedures, implantation of cardiac defibrillators, and therapeutic abortion). There are exceptions, however. If the surgical procedure violates respiratory, oral, intestinal, or genitourinary mucosa or if it is performed on infected skin, then antibiotics are indicted in the highand moderate-risk groups (see box).
Procedures and endocarditis prophylaxis (from [37]) Endocarditis prophylaxis recommended (only for high- and moderate-risk cardiac conditions) Dental Procedures
When a patient has been placed into the high- or moderate-risk category, the clinician must determine whether or not the procedure also warrants antibiotic prophylaxis. In general, procedures involving areas of the body with a high bacterial count require prophylaxis. A detailed list of such procedures can be found in the text box below. New to the AHA recommendations is the following: ‘‘incision or biopsy of surgically scrubbed skin’’ does not require prophylaxis—even if the patient is categorized as being at high risk for endocarditis [37]. This recommendation carries significant implications for dermatological surgery. Although many dermatologists will prescribe antibiotics when the patient can be categorized as high risk, according to the AHA guidelines that practice should stop regardless of the patient’s cardiac history. Unfortunately, the guidelines do not go into much detail regarding what qualifies as surgically scrubbed skin; however, this concern was addressed in a letter to the editor that was published in The Journal of The American Medical Association [38]. In that publication, the author indicates that surgically scrubbed skin implies proper cleansing before a
Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated Respiratory tract Tonsillectomy or adenoidectomy Surgical operations that involve respiratory mucosa
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
Bronchoscopy with a rigid bronchoscope
Gastrointestinal tract Sclerotherapy for esophageal varices Esophageal stricture dilation Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa
Genitourinary tract Prostatic surgery Cystoscopy Urethral dilation
Endocarditis prophylaxis not recommended Dental Procedures Restorative dentistry (operative and prosthodontic) with or without retraction corda Local anesthetic injections (non intraligamentary) Intracanal endodontic treatment; post placement and buildup Placement of rubber dams Postoperative suture removal Placement of removable prosthodontic or orthodontic appliances Taking of oral impressions Fluoride treatments Taking of oral radiographs Orthodontic appliance adjustment Shedding of primary teeth
Respiratory tract Endotracheal intubation Bronchoscopy with a flexible bronchoscope, with or without biopsyb Tympanostomy tube insertion
343
Gastrointestinal tract Transesophageal echocardiography Endoscopy with or without gastrointestinal biopsyb Genitourinary tract Vaginal hysterectomyb Vaginal deliveryb Cesarean section Urethral catheterization (in uninfected tissue) Uterine dilatation and curettage (in uninfected tissue) Therapeutic abortion (in uninfected tissue) Sterilization procedures (in uninfected tissue) Insertion or removal of intrauterine devices (in uninfected tissue) Other Cardiac catheterization, including balloon angioplasty Implanted cardiac pacemakers, implanted defibrillators, and coronary stents Incision or biopsy of surgically scrubbed skin Circumcision a
Clinical judgment might indicate antibiotic use in selected circumstances that might create significant bleeding. b Prophylaxis is optional for high-risk patients.
Antibiotic selection in endocarditis prophylaxis When the decision is made to use prophylactic antibiotics to prevent endocarditis, they should be administered in the perioperative period. New to the 1997 AHA guidelines is the recommendation that antibiotics need only to be given once before the procedure and not again several hours later, as was suggested in the past. Antibiotics administered more than 4 hours after the procedure probably have no prophylactic benefit in dermatologic surgery. The only cases in which antibiotics are recommended after the surgery are procedures on high-risk patients invol-
344
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
ving gastrointestinal or genitourinary mucosa. The guidelines recommend that antibiotics should be given 1 to 2 hours prior to surgery and not be continued for an extended period after the surgery. Exceptions exist for procedures on infected tissue, which should follow the guidelines of treating the
infection until it has cleared. Endocarditis can develop despite appropriate perioperative antibiotics, and surgeons should be aware of the early signs of the disease (unexplained fever, chills, myalgia, arthralgia, lethargy, or malaise) following high-risk operations. Various antibiotic regimens are listed in Table 1 [37].
Table 1 Endocarditis prophylaxis for cutaneous surgery Situation
Agent
Procedures involving oral or respiratory mucosa Standard general prophylaxis Amoxicillin Unable to take oral medications
Ampicillin
Allergic to penicillin
Clindamycin or cephalexina or cefadroxila or azithromycin or clarithromycin
Allergic to penicillin and unable to take oral medications
Clindamycin or cefazolina
Procedures involving gastrointestinal or genitourinary mucosa High-risk patients Ampicillin plus gentamicin
High-risk patients allergic to ampicillin/amoxicillin
Vancomycin plus gentamicin
Moderate-risk patients
Amoxicillin or ampicillin
Moderate-risk patients allergic to ampicillin/amoxicillin
Vancomycin
Regimen Adults: 2.0 g; children: 50 mg/kg orally 1 h before procedure Adults: 2.0 g IM or IV; children: 50 mg/kg IM or IV within 30 m before procedure Adults: 600 mg; children: 20 mg/kg orally 1 h before procedure Adults: 2.0 g; children; 50 mg/kg orally 1 h before procedure Adults: 500 mg; children: 15 mg/kg orally 1 h before procedure Adults: 600 mg; children: 20 mg/kg IV within 30 m before procedure; adults: 1.0 g; children: 25 mg/kg IM or IV within 30 m before procedure
Adults: ampicillin 2.0 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed 120 mg) within 30 m of starting procedure; 6 h later, ampicillin 1 g IM/IV or amoxicillin 1 g orally; children: ampicillin 50 mg/kg IM or IV (not to exceed 2.0 g) plus gentamicin 1.5 mg/kg within 30 m of starting the procedure; 6 h later, ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally Adults: vancomycin 1.0 g IV over 1 – 2 h plus gentamicin 1.5 mg/kg IV/IM (not to exceed 120 mg); complete injection/infusion within 30 m of starting procedure; children: vancomycin 20 mg/kg IV over 1 – 2 h plus gentamicin 1.5 mg/kg IV/IM; complete injection/infusion within 30 m of starting procedure Adults: amoxicillin 2.0 g orally 1 h before procedure, or ampicillin 2.0 g IM/IV within 30 m of starting procedure; children: amoxicillin 50 mg/kg orally 1 h before procedure or ampicillin 50 mg/kg IM/IV within 30 m of starting procedure Adults: vancomycin 1.0 g IV over 1 – 2 h complete infusion within 30 m of starting procedure; children: vancomycin 20 mg/kg IV over 1 – 2 h; complete infusion within 30 m of starting procedure
Note: Total children’s dose should not exceed adult dose. Abbreviations: IV, intravenously; IM, intramuscular. a Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins. From Sadick NS. Systemic antibacterial agents. In: Wolverton SE, editor. Comprehensive dermatologic drug therapy. Philadelphia (PA): WB Saunders; 2001. p. 25 – 46.
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
Orthopedic prosthetic devices Approximately 450,000 total joint arthroplasties are performed in the United States each year. When infection occurs, it is almost always at the time of the surgery [39]. When prosthetic joints are infected, the patient must undergo expensive revision. Antibiotic prophylaxis in patients with artificial joints who are undergoing unrelated procedures is controversial. It is not clear whether or not bacteremias resulting from other procedures can infect joints; however, the morbidity and mortality of such infections are high. Currently, there are no published guidelines on antibiotic prophylaxis in patients with orthopedic prosthetic devices undergoing cutaneous surgery. The majority of articles published in the literature deal with dental procedures and prosthetic devices. Any extrapolation of these data to cutaneous surgery can only be considered approximate and controversial. Bacteremia from cutaneous surgery is less than that following dental surgery, and the bacterial flora is different. Most total hip replacements become infected with bacteria from the incisional skin or from the respiratory, gastrointestinal, or genitourinary mucosa [40]. The most common organism infecting orthopedic joints is S. aureus, followed by S. epidermidis [40 – 43]. Infection of a joint prosthesis after the initial replacement surgery is usually from an identifiable source such as an infected wound, chronic bacteremia, or an abscess [41,44,45]. Transient bacteremia, such as that created during cutaneous surgery, is an unlikely source. The American Dental Association (ADA) and the American Academy of Orthopedic Surgeons (AAOS) issued an advisory statement in 1997 on the need for antibiotic prophylaxis to prevent hematogenous prosthetic joint infections in dental procedures. The panel decided that antibiotic prophylaxis is not indicated for patients with pins, plates, and screws, nor for most patients with total joint replacement [46]. The committee created a set of criteria that might place a patient at a higher risk of hematogenous joint infection; these criteria are listed in the text box below. The committee advises using prophylactic antibiotics in patients with these conditions who are undergoing ‘‘high-risk’’ dental procedures, including dental extractions, periodontal surgery, endodontic (root canal) instrumentation, intraligamentary local anesthetic injections, prophylactic cleaning of teeth, or implants in which bleeding is anticipated. Patients with the conditions listed in the text box below who are undergoing lower-risk procedures do not need prophylactic antibiotics.
345
Patients at potential increased risk of hematogenous total joint infection [46] Immunocompromised/immunosuppressed patients Inflammatory arthropathies (eg, rheumatoid arthritis, systemic lupus erythematosus) Disease-, drug-, or radiation-induced immunosuppression Other patients Insulin-dependent (Type 1) diabetes First 2 y following joint placement Previous prosthetic joint infections Malnourishment Hemophilia
Despite these recommendations, some authors feel that prophylactic antibiotics should not be used at all simply because a patient has a prosthetic joint. In a review of the literature, Little found a failure to associate prosthetic joint infections with transient bacteremias from invasive dental procedures. He discovered that patients in the ‘‘high-risk’’ category had the same bacteria colonization as other patients with prosthetic joint infections, indicating that infecting bacteria are from wound contamination of the original surgery or from different sites of chronic infection and unrelated to the dental procedure. He concluded that patients undergoing invasive dental procedures do not need antibiotic prophylaxis because there is no proven benefit but there are risks to giving antibiotics [39]. Another study looked at 1000 patients with joint replacements who were advised not to take prophylactic antibiotics during a 6-year follow-up period. Of these patients 224 had dental or surgical procedures. Three developed hematogenous infection, two of which had chronic skin infection and one of whom had varicose ulcers. No patients had only transient bacteremia [45]. A similar study reviewed the charts of 2693 patients with total prosthetic joints and found that only one (0.04%) late prosthetic joint infection was associated with a dental procedure. The authors note that their findings are similar to others in the literature, and they question the appropriateness of submitting 99.95% of the dental population with prosthetic joints to antibiotics to possibly prevent 0.05% of infections [41].
346
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
Table 2 The author’s recommendations for when antibiotics prophylaxis is indicated in cutaneous surgery
Healthy patient, no cardiac or orthopedic history High-risk endocarditis lesionb Moderate-risk endocarditis lesionb History of implanted orthopedic device
Clean cutaneous surgery on intact skin
Clean-contaminated surgery violating mucosa
Contaminated or infected skin
No
No
Yesa
No No No
Yes Yes Maybec
Yesa Yesa Yesa
a
Ideally, surgery should be delayed until infection is treated. As defined by the American Heart Association Guidelines listed in text box in ‘‘Evaluating endocarditis risk’’ section. c If patient is at increased risk for joint infection as outlined in text box in ‘‘Orthopedic prosthetic devices’’ section, then antibiotics are indicated; otherwise not. b
When cutaneous surgery is performed on clean skin and does not violate any mucosal membrane, it is probably safe to not give prophylactic antibiotics in patients with prosthetic joints. There are no data that directly support this assumption. A conservative approach would be to follow the guidelines listed in the text box in this section for high-risk dental procedures, especially if mucosal membranes are to be violated. Chronic cutaneous infection is much more likely to cause prosthetic joint infection, and it should be treated appropriately preoperatively.
Antibiotic choice for prophylactic prosthetic joint infection Similar to the AHA guidelines, antibiotics only need to be given in a single dose with no repeated dose several hours after the procedure. Medications recommended for high-risk patients undergoing invasive dental procedures (not specific to cutaneous surgery) include cephalexin, cephradine, amoxicillin (2 g orally 1 hour prior to dental procedure), or clindamycin (600 mg orally 1 hour prior to dental procedure if patient is allergic to penicillin) [46].
Summary Few situations in dermatologic surgery require prophylactic antibiotics. The AHA has decreased the dose for endocarditis prophylaxis from antibiotics before and after the procedure to only 1 hour prior to the procedure. In the 1997 guidelines, fewer procedures are listed as requiring antibiotics compared with prior guidelines. In fact, several authors have questioned the efficacy of prophylactic antibiotics. The sequela of endocarditis or an infected prosthetic joint are certainly serious and possibly life-threat-
ening conditions, yet this should not be a justification for using a therapy that is not proven and has potential serious side effects of its own. The authors suggest not using antibiotics on clean or clean-contaminated wounds regardless of cardiac history. Patients with prosthetic joint replacements probably do not need prophylactic antibiotics in cutaneous surgery unless mucosa is invaded; in such cases the guidelines set by the ADA and the AAOS should be followed. The authors believe that antibiotics should be reserved for contaminated or infected wounds when their application is therapeutic. Table 2 contains a summary of the authors’ recommendations for the use of antibiotics in cutaneous surgery. Each patient should be evaluated on an individual basis, and consultation with the patient’s primary physician, cardiologist, or orthopedist should be sought when the need arises.
References [1] Haas AF, Grekin RC. Antibiotic prophylaxis in dermatologic surgery. J Am Acad Dermatol 1995;32: 155 – 76. [2] Baran CN, Sensoz O, Ulusoy MG. Prophylactic antibiotics in plastic and reconstructive surgery. Plast Reconstr Surg 1999;103:1561 – 6. [3] Barreca M, Stipa F, Cardi E, et al. [Antibiotic prophylaxis in the surgical treatment of inguinal hernia: need or habit?]. Minerva Chir 2000;55:599 – 605 [in Italian]. [4] Dobay KJ, Freier DT, Albear P. The absent role of prophylactic antibiotics in low-risk patients undergoing laparoscopic cholecystectomy. Am Surg 1999;65: 226 – 8. [5] Gupta R, Sinnett D, Carpenter R, et al. Antibiotic prophylaxis for post-operative wound infection in clean elective breast surgery. Eur J Surg Oncol 2000;26: 363 – 6. [6] Gaspar Z, Vincuillo C, Elliott T. Antibiotic prophylaxis
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
for full-face laser resurfacing: is it necessary? Arch Dermatol 2001;137:313 – 5. Manuskiatti W, Fitzpatrick RE, Goldman MP, et al. Prophylactic antibiotics in patients undergoing laser resurfacing of the skin. J Am Acad Dermatol 1999; 40:77 – 84. Walia S, Alster TS. Cutaneous CO2 laser resurfacing infection rate with and without prophylactic antibiotics. Dermatol Surg 1999;25:857 – 61. Friberg D, Lundberg C. Antibiotic prophylaxis in major head and neck surgery when clean- contaminated wounds are established. Scand J Infect Dis Suppl 1990;70:87 – 90. Weber RS, Callender DL. Antibiotic prophylaxis in clean-contaminated head and neck oncologic surgery. Ann Otol Rhinol Laryngol Suppl 1992;155:16 – 20. DiPiro JT, Record KE, Schanzenbach KS, et al. Antimicrobial prophylaxis in surgery: part 1. Am J Hosp Pharm 1981;38:320 – 4. Johnson JT, Myers EN, Thearle PB, et al. Antimicrobial prophylaxis for contaminated head and neck surgery. Laryngoscope 1984;94:46 – 51. Rodrigo JP, Alvarez JC, Gomez JR, et al. Comparison of three prophylactic antibiotic regimens in clean-contaminated head and neck surgery. Head Neck 1997;19: 188 – 93. Righi M, Manfredi R, Farneti G, et al. Short-term versus long-term antimicrobial prophylaxis in oncologic head and neck surgery. Head Neck 1996;18: 399 – 404. Mustafa E, Tahsin A. Cefotaxime prophylaxis in major non-contaminated head and neck surgery: oneday vs. seven-day therapy. J Laryngol Otol 1993; 107:30 – 2. Monaco G, Staffolani C, Gatto MR, et al. Antibiotic therapy in impacted third molar surgery. Eur J Oral Sci 1999;107:437 – 41. Higgins A, London J, Charland S, et al. Prophylactic antibiotics for elective laparoscopic cholecystectomy: are they necessary? Arch Surg 1999;134:611 – 3. Johnson JT, Wagner RL. Infection following uncontaminated head and neck surgery. Arch Otolaryngol Head Neck Surg 1987;113:368 – 9. Klimberg IW, Malek GH, Cox CE, et al. Single-dose oral ciprofloxacin compared with cefotaxime and placebo for prophylaxis during transurethral surgery. J Antimicrob Chemother 1999;43(Suppl A):77 – 84. Makris N, Iatrakis G, Sakellaropoulos G, et al. The role of antibiotics after dilatation and curettage in women with metrorrhagia in the prevention of pelvic inflammatory disease. Clin Exp Obstet Gynecol 2000; 27:27 – 8. Bizer LS, Ramos S, Weiss PR. A prospective randomized double blind study of perioperative antibiotic use in the grafting of ulcers of the lower extremity. Surg Gynecol Obstet 1992;175:113 – 4. Roth RR, James WD. Microbiology of the skin: resident flora, ecology, infection. J Am Acad Dermatol 1989;20:367 – 90.
347
[23] Bruce S. Antibacterial agents. In: Wolverton SE, editor. Systemic drugs for skin disease. Philadelphia (PA): WB Saunders; 1991. p. 47 – 85. [24] Sadick NS. Systemic antibacterial agents. In: Wolverton SE, editor. Comprehensive dermatologic drug therapy. Philadelphia (PA): WB Saunders; 2001. p. 28. [25] Lazzarini L, Pellizzer G, Stecca C, et al. Postoperative infections following total knee replacement: an epidemiological study. J Chemother 2001;13:182 – 7. [26] Lilienfeld DE, Vlahov D, Tenney JH, et al. Obesity and diabetes as risk factors for postoperative wound infections after cardiac surgery. Am J Infect Control 1988; 16:3 – 6. [27] Tabet JC, Johnson JT. Wound infection in head and neck surgery: prophylaxis, etiology and management. J Otolaryngol 1990;19:197 – 200. [28] Simchen E, Shapiro M, Marin G, et al. Risk factors for post-operative wound infection in cardiac surgery patients. Infect Control 1983;4:215 – 20. [29] Noman TA, Raja’a YA, Assiraji HM, et al. Rate of wound infection after clean surgery. Saudi Med J 2001;22:58 – 60. [30] Cruse PJ, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973;107:206 – 10. [31] Valentine RJ, Weigelt JA, Dryer D, et al. Effect of remote infections on clean wound infection rates. Am J Infect Control 1986;14:64 – 7. [32] Sebben JE. Sterile technique and the prevention of wound infection in office surgery – Part I. J Dermatol Surg Oncol 1988;14:1364 – 71. [33] Nichols RL. Surgical wound infection. Am J Med 1991;91:54S – 64S. [34] Everett ED, Hirschmann JV. Transient bacteremia and endocarditis prophylaxis. A review. Medicine (Baltimore) 1977;56:61 – 77. [35] Jeserich M, Just H. [Current status of endocarditis prevention]. Z Kardiol 2001;90:385 – 93 [in German]. [36] Taubert KA, Dajani AS. Optimisation of the prevention and treatment of bacterial endocarditis. Drugs Aging 2001;18:415 – 24. [37] Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. Clin Infect Dis 1997;25: 1448 – 58. [38] Park JY. Prevention of bacterial endocarditis: American Heart Association recommendations. JAMA 1997;278:1232; discussion 1233. [39] Little JW. Patients with prosthetic joints: are they at risk when receiving invasive dental procedures? Spec Care Dentist 1997;17:153 – 60. [40] McGowan DA, Hendrey ML. Is antibiotic prophylaxis required for dental patients with joint replacements? Br Dent J 1985;158:336 – 8. [41] Jacobson JJ, Millard HD, Plezia R, et al. Dental treatment and late prosthetic joint infections. Oral Surg Oral Med Oral Pathol 1986;61:413 – 7. [42] Fitzgerald Jr RH. Infections of hip prostheses and artificial joints. Infect Dis Clin N Am 1989;3:329 – 38.
348
M.D. Babcock, R.C. Grekin / Dermatol Clin 21 (2003) 337–348
[43] Sanderson PJ. The choice between prophylactic agents for orthopaedic surgery. J Hosp Infect 1988;11(Suppl C):57 – 67. [44] Segreti J, Levin S. The role of prophylactic antibiotics in the prevention of prosthetic device infections. Infect Dis Clin N Am 1989;3:357 – 70. [45] Ainscow DA, Denham RA. The risk of haematogenous
infection in total joint replacements. J Bone Joint Surg Br 1984;66:580 – 2. [46] Anonymous. Advisory statement. Antibiotic prophylaxis for dental patients with total joint replacements. American Dental Association: American Academy of Orthopaedic Surgeons. J Am Dent Assoc 1997;128: 1004 – 8.
Dermatol Clin 21 (2003) 349 – 369
Vaccines for viral diseases with dermatologic manifestations Mathijs H. Brentjens, MS, MD, Kimberly A. Yeung-Yue, MD, Patricia C. Lee, MD, Stephen K. Tyring, MD, PhD* University of Texas Medical Branch—Galveston, Departments of Dermatology, Microbiology/Immunology and Internal Medicine , Galveston, TX, USA
Advances in immunology have led to a greater understanding of immune system function in viral diseases. Progress in genetics and molecular biology has allowed researchers to design vaccines with novel mechanisms of action such as DNA, vectored DNA, and virus-like particle (VLP) vaccines. Vaccines have also been designed to specifically target particular viral components, allowing for stimulation of various arms of the immune system as desired. Ongoing research shows promise in prophylactic and therapeutic vaccination for viral infections with cutaneous manifestations. Further studies are necessary before vaccines for herpes simplex, human papillomavirus, and HIV become commercially available. The modern concept of widespread, systematic vaccination against disease derives from the observations of Edward Jenner in his 1798 treatise Variolae Vaccinae [1]. Jenner expanded on the commonly accepted notion that those who contacted the mild disease cowpox generally would not subsequently develop the more serious disease smallpox. He demonstrated that cowpox was easily transmitted from person to person and that it effectively provided widespread protection against smallpox [2]. Vaccination against smallpox by this method became common in the nineteenth century [1]. In the 1870s, Louis Pasteur provided further impetus to the theory of vaccination by describing the attenuation of chicken cholera and how immunization with the attenuated
* Corresponding author. UTMB Center for Clinical Studies, 2060 Space Park Drive, Suite 200, Houston, TX 77058. E-mail address:
[email protected] (S.K. Tyring).
strain provided subsequent resistance to challenges with more virulent strains. Pasteur next developed an attenuated anthrax vaccine, which proved to be effective in protecting farm animals from challenge with more virulent strains of anthrax. He began vaccination in humans with an attenuated rabies virus in 1885. At the turn of the century, human vaccines consisting of killed pathogens for typhoid, cholera, and plague had become available. In the 1920s, research on chemically inactivated tetanus and diphtheria toxins (toxoids) led to another form of vaccination containing only purified proteins as opposed to whole live or killed pathogens. Vaccine research with live attenuated organisms, killed organisms, or purified proteins flourished after World War II with the development of vaccines for polio, measles, mumps, rubella, yellow fever, varicella, Japanese encephalitis, and hepatitis A, among others. Purified polysaccharides were also developed for use as vaccine candidates. Approved polysaccharide vaccines include H. influenzae type b, pneumococcal, and meningococcal vaccines. More recently, recombinant gene technology has resulted in the development of a vaccine for hepatitis B using yeast expressing the hepatitis B surface antigen (HbsAg).
Commercially available vaccines Many prophylactic vaccines now accepted as standard for disease prevention in the Unites States are directed against diseases with primary or predominant skin manifestations: the measles, mumps, and rubella vaccine (MMR); the chickenpox vaccine; and the hepatitis B vaccine. Increased awareness of
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00098-0
350
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
the potential for bioterrorism has also resulted in renewed interest in the smallpox vaccine, which has not been administered in the United States since 1972. Finally, the yellow fever vaccine is available in the United States for travelers to areas with endemic yellow fever. Measles, mumps, and rubella Measles is one of the most contagious viral infections that affect humans. Although the incidence of measles has declined worldwide since the development of an effective vaccine, it remains a significant source of morbidity and mortality. Twenty to thirty million people are infected with measles annually, and nearly 1 million people die from the disease, mostly children and infants in developing countries [3,4]. Measles virus has no animal reservoir, making it an attractive candidate for worldwide eradication. A prodrome of fever, malaise, anorexia, cough, coryza, and conjunctivitis develop 1 to 2 weeks after exposure to the measles virus. A transient morbilliform rash might also develop during this time. Koplik’s spots, irregular red spots with a central blue – white speck in the center, are pathognomonic for measles. They appear on the buccal mucosa 1 to 3 days prior to the appearance of a rash. The rash appears 3 to 4 days after onset of prodromal symptoms, beginning on the head before spreading inferiorly. Lesions consist of small blanching macules and papules that become confluent with rash progression. Fever peaks 3 to 4 days after rash onset, followed by rapid defervescence. Pulmonary involvement is common, and hepatic dysfunction might occur in older patients [4,5]. Most patients recover quickly after rash onset, but complications can occur, including pneumonia, myocarditis, and encephalitis [4]. Diagnosis is most often made on clinical grounds (eg, appearance of Koplik’s spots). Treatment for measles consists of supportive care. Prior to the development of the live attenuated measles vaccine, a formalin-inactivated measles vaccine was available; however, upon subsequent exposure to wild-type measles virus, some vaccinees developed atypical measles, which resembles Rocky Mountain spotted fever [4]. Symptoms of atypical measles include a severe prodrome followed by the appearance of a macular rash. The rash starts on the palms and soles and spreads to the trunk. Vesicles and petechiae might also appear. Pulmonary symptoms can be severe. Most often, this illness is self-limited. Increased antibody titers have been noted in patients with atypical measles and some evidence points to a causal role of delayed-type hypersensitivity [6 – 10].
Formalin-inactivated measles vaccine has not been used in the Unites States since 1967. Like measles, the rubella virus has no reservoir other than humans. The incidence of rubella (German measles) has also declined with the advent of immunization. This infection is typically milder than measles, and as many as 80% of cases are subclinical [11]. Infection occurs by way of the nasopharynx, and a transient primary viremia is followed by secondary viremia that peaks 10 to 17 days after infection. Two weeks after exposure, a mild prodrome can occur with low-grade fever, headache, conjunctivitis, sore throat, and diffuse lymphadenopathy. The rash of rubella appears 3 days later, consisting of erythematous macules and papules that start on the forehead and spread downward. Resolution of the rash usually occurs within 5 days of onset. The nonspecific nature of the infection makes clinical diagnosis difficult, and the infection is usually confirmed serologically. Although mild, primary infection with rubella in pregnant women can lead to the congenital rubella syndrome in fetuses, especially if exposure occurs in the first trimester. This syndrome results in the appearance of ‘‘blueberry muffin’’ spots in newborns, representing areas of extramedullary hematopoeisis. Severe sequelae of congenital rubella include ocular defects, hearing loss, heart defects, and mental retardation. As with measles, treatment consists largely of supportive care. Vaccine Live attenuated measles and rubella vaccines were developed independently of each other, and they have proven to be extremely effective in preventing transmission of these viruses. The first live attenuated measles vaccine approved in the United States was derived from the Edmonston strain. [12]. Since that time, several attenuated live vaccines derived from this strain have been developed. Attenuated measles virus immunization results in induction of humoral and cellular immune responses. Side effects are typically mild. The fact that measles has only one natural host makes it an ideal candidate for eradication [3,13,14]. Recent efforts at eradication have focused on geographic areas that are chronically underimmunized against measles. One recent article describing a 4-year-long vaccination campaign in Africa achieved 91% coverage in children in seven countries [15]. A dramatic reduction in measles and subsequent mortality was reported with no significant sequelae caused by vaccination. An attenuated rubella vaccine based on strain HPV-77 was approved in the Unites States in 1969 [16]. In 1979, this strain was replaced in the United
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
States by strain RA27/3. This vaccine induces cellular and immune responses, and it results in the production of rubella specific IgA secretion on mucosal surfaces, which might be responsible for protection against infection with wild strains. Duration of immunity after rubella vaccination is still debated. In 1971, measles and rubella vaccines were combined with a live attenuated mumps vaccine and approved for use in the United States as the trivalent MMR [16]. This formulation has become the dominant method of immunization in developed countries, although individual vaccinations still occur in underdeveloped countries. Although initially approved as a single vaccination, an outbreak of measles in Unites States in the late 1980s led to the recommendation of a booster vaccination, either at school entry or at 11 to 13 years of age [3,17]. One study found decreased rubella titers at 11 to 13 years, but antibody titers against measles were not significantly changed in this age group as opposed to those receiving repeat immunization at 4 to 6 years of age [17]. More recently, further outbreaks in underimmunized children led to the recommendation that a second dose of MMR be given at 4 to 6 years of age [18]. Since then, the number of measles outbreaks has declined sharply; only 86 cases were reported in 2000 [19], and 26 of these cases were acquired outside of the Unites States. Vaccination with MMR has a good safety profile; however, recent reports have associated the vaccine with several severe adverse events. It has recently been associated with the development of autism or inflammatory bowel disease in children [20 – 22]. No scientific evidence exists for establishing causality, however [23 – 27]. Finally, case reports have associated MMR vaccination with sixth nerve palsy, and a recent case – control trial demonstrated a potential increased risk for febrile seizures with no long-term consequences 8 to 14 days after immunization with MMR [28]. Current recommendations for MMR in HIV+ children suggest that they should receive MMR prior to 1 year of age, after which they apparently develop poorer immune responses to vaccination than healthy controls [29]. At least one case report describes a measles-like illness in an HIV+ child immunized with MMR at 14 months [30]. Efficacy of MMR might be decreased in transplant patients, and it is suggested in one review that MMR should be administered to transplant candidates as early as 6 months of age to ensure adequate protection [31]. Varicella zoster Varicella zoster virus (VZV) is the etiologic agent of chickenpox. The virus is extremely infectious, with
351
80% to 90% of susceptible household contacts developing clinical infection [32]. Prior to the approval of a vaccine against VZV, an estimated 3.8 million cases of chickenpox occurred yearly in the Unites States [33]. Transmission of VZV occurs by the airborne route or by direct contact. After initial infection, a latency period ensues that averages 2 weeks. During this time, the virus spreads to lymph nodes and causes a transient primary viremia. Further replication occurs, followed by a larger secondary viremia that transmits the virus to the skin. Prodromal symptoms consisting of malaise and fever can occur 1 to 2 days prior to the onset of rash. The rash initially presents as numerous erythematous macules and papules that quickly progress to vesicles, pustules, then crusts. In contrast to the vesicles caused by smallpox, the vesicles of chickenpox tend to cluster on the head and trunk with relative sparing of the extremities. Lesions of chickenpox can also be seen in all stages of development simultaneously. Rash development occurs over the course of 1 to 2 days and is accompanied by constitutional symptoms such as fever and chills. The development of new lesions typically stops with the resolution of fever. Chickenpox generally becomes more severe with increasing age. Severe disease also commonly occurs in immunocompromised individuals. Varicella pneumonia, aseptic meningitis, and cerebellar ataxia are uncommon complications of chickenpox in otherwise healthy patients. After resolution of chickenpox, VZV establishes latency in dorsal root and trigeminal ganglia. In the presence of adequate cell mediated immunity (CMI) to VZV, the virus will remain latent; however, CMI to varicella declines with time, and immunosuppression from a variety of causes can result in the reactivation of VZV in one or several ganglia. Reactivation results in the appearance of herpes zoster (also known as shingles). Skin lesions are usually preceded by a prodrome of burning, itching, pain, or tingling that might last for several days. Motor nerve involvement is also possible. The rash of herpes zoster develops in a dermatomal pattern with the appearance of numerous vesicles on an erythematous base. Lesions usually persist for 1 to 4 weeks if not treated with antiviral therapy. Recurrences of zoster are rare in immunocompetent patients. Pain and dysesthesia can persist for months after the resolution of skin lesions (postherpetic neuralgia), representing a significant source of morbidity in the elderly. Disseminated herpes zoster results from activation of VZV in multiple nerve roots, and it most often occurs in immunocompromised hosts. Chickenpox and herpes zoster can be treated with oral antiviral medications (valacyclovir, famciclovir,
352
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
or acyclovir). Severe disease might require hospitalization for supportive care and treatment with intravenous (IV) acyclovir. Vaccine An effective attenuated live varicella vaccine (OKA strain) was developed in 1974 [34]. This vaccine was originally tested in healthy children and found to be safe and effective [35]. Since that time, numerous studies have demonstrated safety, immunogenicity, and protection from infection in healthy and moderately immunosuppressed patients [36 – 39]. Varicella vaccine has demonstrated 70% to 90% protection from infection and more than 95% protection against severe VZV infection in healthy children with negligible side effects [40,41]. Several studies have evaluated vaccinees with breakthrough VZV infections [41 – 44]. These studies demonstrated that breakthrough infection after VZV immunization leads to mild disease. The attenuated OKA strain vaccine was approved in the United States in 1995 and it is recommended for all children 12 months to 12 years old as well as susceptible adults [45,46]. Surveillance data gathered after approval of the vaccine in the Unites States demonstrated a 71% to 84% decrease in varicella cases from 1995 to 2000 [47]. The long delay in United States approval for the vaccine was based on concerns about waning CMI after immunization. In theory, vaccination at a young age followed by waning immunity will lead to an older population that is at risk for primary VZV infection. While these concerns must be taken seriously, long-term followup of vaccinees has been reassuring. Asano et al [37] described a long-term follow-up of patients vaccinated against VZV. Only two vaccinees developed breakthrough infection during follow-up periods ranging from 17 years to nearly 20 years. During this time, vaccinees reported 100 contacts with VZVinfected individuals in the household, at school, or in the hospital. Two other studies demonstrated the presence of neutralizing antibodies in the vast majority of vaccinees followed for 6 to 10 years [48,49]. The overall attack rate was 3% of vaccinee exposures to VZV in one study [48]. The second study reported an annual breakthrough rate of only 0.2% to 2.3% [49]. Concerns about waning immune response after the administration of a live vaccine should also be allayed by the long-term immunogenicity of the MMR. The VZV vaccine has also been evaluated for the prevention of herpes zoster in elderly individuals with a prior history of chickenpox. Two studies evaluated immune response after a ‘‘boosting’’ vaccination with
the VZV vaccine [50,51]. The booster vaccination was well tolerated with only mild side effects in both studies. Significant increases in VZV-specific cell mediated immunity were also noted. The incidence of herpes zoster was not reduced over the course of 6 years in patients receiving booster vaccinations compared with historical controls [51]; however, shingles were typically mild and no postherpetic neuralgia was noted. A double-blind, randomized, placebo-controlled trial is currently underway to determine the ability of booster vaccinations to stimulate CMI in the elderly. Another study to evaluate the protective effect of booster vaccinations against herpes zoster in the elderly is ongoing at Veterans Administration (VA) medical centers in the United States. Early studies of the VZV vaccine in moderately immunocompromised individuals (eg, children with leukemia) demonstrated the safety and efficacy of the VZV vaccine. This result was recently confirmed in a study of 575 patients with leukemia [52]. Each patient received two doses of vaccine, resulting in a 95% seroconversion rate after the second dose. Side effects were typically mild, but 50% of patients still on chemotherapy developed a mild chickenpox-like rash. One hundred twenty three patients in this study had household contact with VZV after vaccination. Complete protection against exposure occurred in 86% of patients with just 14% developing a mild case of varicella. Safety and efficacy were assessed in children with renal transplants and in patients on hemodialysis [53]. Seventeen dialysis patients and 17 transplant patients were vaccinated, resulting in an 85% seroconversion rate and only mild vaccineassociated rashes in 10% of patients. Seventy-six percent were still seropositive at 2 years, and the breakthrough rate of varicella was 10%. No studies have directly assessed the use of the VZV vaccine in HIV+ patients; however, a study on the interactions between HIV and VZV did not find evidence that VZV infection had an adverse effect on the natural history of HIV infection in children [54]. This implies that immunization with the live VZV vaccine will not adversely affect the course of HIV infection and might be safe for use in HIV+ children with stable immune function. Hepatitis B Infection with the hepatitis B virus (HBV) remains a worldwide health problem. An estimated 350 million people are considered to be carriers who are capable of infecting others [55]. Up to 40% of chronic carriers will die of their disease, and HBV is
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
responsible for as many as 1 million deaths yearly [56,57]. Hepatitis B is blood-borne, and transmission can occur by sexual contact, intravenous drug use, occupational exposure, or vertical transmission from a carrier mother to her child. The course of hepatitis B infection is variable, and it can be divided into acute and chronic stages. A healthy carrier state is also possible after resolution of acute hepatitis. Symptoms of acute hepatitis become apparent after an incubation period of 2 to 6 months. They include slow onset of nonspecific prodromal symptoms such as fever, malaise, myalgias, and gastrointestinal difficulties. Many patients will develop jaundice. As many as 1% of those with acute hepatitis B will progress to fulminant hepatic failure [58], characterized by hepatic encephalopathy, coagulopathy, and elevated liver enzymes. Following the acute phase of infection, patients might recover completely with no evidence of viral infection or progress to chronic hepatitis. Chronic HBV infection is usually asymptomatic, although nonspecific symptoms can occur. Hepatitis B carriers are the only natural reservoir for this virus. Symptoms of acute hepatitis include a serum sickness-like syndrome characterized by urticaria, angioedema, arthropathy, lymphadenopathy, and renal dysfunction. In children, acute skin manifestations might include the Gianotti-Crosti syndrome (papular acrodermatitis of childhood). This syndrome causes an eruption of small papules on the buttocks and thighs that subsequently spreads to the arms, face, and ears with relative sparing of the trunk. Skin manifestations of chronic HBV infection include purpuric skin lesions associated with mixed cryoglobulinemia. These lesions appear as nonblanching, erythematous papules and plaques, and they can develop vesicles or bullae. Polyarteritis nodosa might also develop. Jaundice, spider nevi, palmar erythema, and purpura also develop with worsening hepatic failure. Antiviral therapy is available for chronic HBV infection. Interferon-a and lamivudine (a secondgeneration nucleoside analog) have been licensed for treatment of chronic hepatitis [59]; however, these drugs have only modest benefit in a majority of patients [59]. Combination therapy with interferons and other antiviral medications has also proven to be moderately effective. Vaccine A vaccine against HBV has been available in the United States since 1982. This vaccine contains the HBV surface antigen (HbsAg), a glycoprotein that makes up the outer envelope of HBV [60]. It has a good safety profile and confers 90% to 95% protec-
353
tion against HBV infection, eliciting humoral and cell-mediated immune responses [61]. This protein was initially derived from the plasma of asymptomatic HBV carriers. High cost, limited availability, and concerns about safety led to the development of the first recombinant vaccine approved for use in the United States. HbsAg expressed recombinantly in yeast and subsequently purified was approved as a vaccine in 1987. This vaccine was as efficacious and tolerable as the previously approved plasma-derived vaccine [62]. Recently, a bivalent vaccine consisting of the inactivated hepatitis A vaccine and HBsAg was approved for use in the United States [63,64]. Recent concerns have surfaced about the possible relationship between hepatitis vaccination and the development of autoimmune and other disorders. Hepatitis B immunization has been temporally associated with the onset of glomerulonephritis, myelitis, type 1 diabetes mellitus, multiple sclerosis, leukoencephalitis, lichen planus, pancytopenia, vasculitis, and Gianotti-Crosti syndrome [65 – 74]. Additionally, a study published in 2001 associated hepatitis B vaccination temporally with statistically significant increases in the incidence of arthritis, acute ear infection, and pharyngitis [75]. With the exception of the case study of a patient with glomerulonephritis (in which HbsAg was recovered from a kidney biopsy), these studies have not demonstrated any causal link with HBV vaccination but instead rely on temporal association with immunization. Other studies dispute the relationship between these adverse events and HBV vaccination. Although these observations merit careful observation, no scientific evidence supports a causal role of HBV vaccination in the development of these illnesses. A recent study did not support the contention that hepatitis B vaccines were positively associated with adverse events in infants [76]. Furthermore, DeStefano found no link between immunization and the onset of type 1 diabetes mellitus [68]. Gout describes a study that failed to support a causal role for hepatitis B vaccination in the development of multiple sclerosis [77]. Initially, recommendations for vaccination were aimed at high-risk patients such as health care workers, hemodialysis patients, and IV drug users. This strategy proved to be ineffective in reducing the prevalence of infection, and in 1997 the World Health Organization recommended the inclusion of the HBV vaccine in all national immunization programs [78,79]. Efforts are currently underway to extend HBV vaccination to chronically underimmunized populations [79]. Ten to twenty percent of new HBV infections occur in pediatric and adolescent patients. This
354
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
prompted the American Academy of Pediatrics to recommend universal vaccination of infants in 1992 [80]. The hepatitis vaccine is now a standard part of childhood immunization in the United States. Vertical transmission from infected mother to infant remains a source of concern. One study demonstrated that early vaccination with the HBV vaccine in combination with HBV immune globulin provided 85% protection against neonatal HBV infection after 12 months [81], which is significantly better than receiving no therapy or treatment with vaccination alone. The serologic status of the mother also affected transmission, with HbsAg positivity resulting in higher rates of infection in infants. Although the current recombinant protein vaccine provides protection to 90% to 95% of vaccinees, nonresponders remain a source of concern. New vaccines are being developed in an attempt to increase the efficacy of immunization. Two studies have tested the immunogenicity of HbsAg combined with a novel adjuvant containing alum and monophosphoryl lipid A (HbsAg/SBAS4) in humans [82,83]. This vaccine was found to be safe, and it generated stronger humoral and cell-mediated immune responses than HbsAg alone. Additionally, HbsAg/SBAS4 induced strong immune responses in nonresponders (patients who did not develop protective immunity after receiving the standard vaccine) [83]. A triple antigen vaccine employing three components of the HbsAg (Pre-S1, Pre-S2, and S antigens) has also proven to be safe and effective in stimulating host immune responses [84 – 86]. In particular, the triple antigen vaccine was more protective than HbsAg in revaccination of nonresponders. Enhanced cellular responses to the triple antigen vaccine are thought to contribute to its superior protective effect [86]. This vaccine is now approved throughout Europe [85]. Recent studies have assessed DNA vaccines in animal models [87,88]. One Phase I trial assessed the safety of a naked DNA vaccine encoding the gene for HbsAg [89]. No primary immune responses were noted in this study. Therapeutic vaccines for HBV infection have also been tested in humans. An open-label study of an HbsAg/Pre-S2/Alum vaccine in patients with chronic stable hepatitis B determined that 15 of 32 patients responded to vaccination as measured by serum HBV assays [90]. Thirteen patients had no detectable virus 3 months after the last vaccination. Other recombinant vaccines have also been assessed as therapeutic modalities [91]. Preliminary animal studies have evaluated a DNA vaccine as a therapeutic modality [91]. The HbsAg vaccine appears to be safe for use in immunocompromised patients, but response rates are
poor (25 – 70% in HIV+ individuals and 20 – 30% in transplant candidates) [31,92,93]. Early vaccine administration is urged in transplant candidates. A transient increase in HIV viral load and poor immune response in HIV-infected patients make vaccination of these patients inadvisable except for patients with high-risk exposures. Smallpox Smallpox infections are caused by the poxvirus variolae. After contact with a susceptible host, the smallpox virus replicates intensively, causing primary viremia [94]. Patients are generally asymptomatic during this period, although a mild flu-like illness might occur. Secondary viremia results in the spread of the virus to multiple organ systems, including the skin. Prior to the appearance of skin lesions, patients experience a prodromal syndrome of fever, headaches, back pain, and vomiting. A macular prodromal rash might also be present. Skin lesions manifest as discrete vesicular pocks starting on the face and spreading to the extremities [95]. With time, these lesions develop into pustules, frequently with central umbilication. Lesions subsequently scab and heal, leaving scars. Although primary clinical manifestations of smallpox infections are dermatologic, smallpox also affects other organs, including the central nervous system, resulting in encephalitis. At least 30% of unvaccinated individuals will die from this infection. No therapy is available, and treatment is only supportive. The last naturally occurring case of smallpox was identified in 1977, and the disease is now considered to be eradicated. The eradication of smallpox by vaccination with the live poxvirus, vaccinia, remains the greatest success in the history of medicine. Smallpox vaccines have not been regularly administered in the United States since 1972; however, Russia and the United States maintain stocks of variola, and the potential for using the virus as a weapon have long been realized (see, for example, Capps’ article in the American Journal of Public Health [96]). Recent terrorist attacks on the United States have refocused attention on smallpox as a potential bioterrorist weapon. Vaccine Eradication of smallpox was achieved with the live poxvirus, vaccinia. This virus induces a neutralizing immune response to smallpox that appears to provide protection from infection and might attenuate the severity of those infected with smallpox after vaccination [97 – 99]. Vaccinia infections are generally mild and self-limiting. After intradermal
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
immunization, vaccinia replicates in the skin, causing the development of a limited number of vesicles at the site of immunization. The duration of immunity is not known, although at least one study found some neutralizing antibody activity up to 30 years after vaccination in individuals who received two immunizations [100]. The resurgence of interest in smallpox vaccines has led to the discovery that the United States might not have sufficient stores of the vaccine in the event of a widespread bioterrorist attack with smallpox. Recent articles have assessed the immunogenicity of diluted vaccines. A dose-ranging study assessing the immunogenicity of smallpox vaccine diluted to 1:10 and 1:100 demonstrated significantly decreased success rates (ie, formation of vesicles at the site of immunization) compared with undiluted vaccine [101]. A follow-up study evaluated 1:5 and 1:10 dilutions. For patients who did not develop vesicles after the first immunization, a second dose was given 1 to 3 weeks later. This study showed adequate success rates in the 1:10 dilution group [102]. New vaccine candidates are also being explored [103,104]. Yellow fever virus Yellow fever viruses are flaviviruses that normally infect mosquitoes and nonhuman primates. Humans are incidental hosts who become infected after exposure to mosquitoes carrying the yellow fever virus. This disease is endemic to the tropical regions of South America and Brazil, with periodic epidemic outbreaks in these areas. As many as 200,000 persons are infected annually in these areas [105]. The disease course after infection with yellow fever virus ranges from nonspecific, transient illness to overwhelming sepsis and hemorrhagic fever [106]. After an incubation period of a few days, patients complain of fevers and chills, myalgias, and general malaise. These symptoms can last for several days before subsiding. In a small portion of these patients, symptoms return 2 to 3 days later in a much more severe form with fever, vomiting, severe jaundice, renal failure, and hemorrhagic diatheses. Jaundice results from overwhelming liver failure. One recent study found that aspartate transaminase (AST) and alanine transaminase (ALT) levels reached as high as 2766 and 660 (normal levels are typically < 40 for AST and ALT), respectively, in patients who die from the disease [107]. Renal failure likely results from direct viral injury and hypotension secondary to shock [105,108]. Finally, hemorrhagic tendencies are likely multifactorial, with liver failure and consumption of clotting
355
factors. Finally, myocardial injury is often also noted in these patients. Between 25% and 50% of patients who develop late symptoms will die [105]. Clinical diagnosis usually depends upon the presence of jaundice, history of recent exposure in an area with endemic yellow fever, and a lack of vaccination. Human response to yellow fever virus infection is largely mediated by humoral response and the development of specific protective antibodies. No medications have proven to be effective in treating yellow fever, and current management consists of supportive therapy only. Vaccine The first yellow fever virus vaccine was introduced in 1937 using an attenuated yellow fever vaccine [109]. The attenuated 17D strain vaccine has been in use since that time. It has established an excellent safety profile and is effective in preventing yellow fever. More than 400 million people have been vaccinated since the vaccine’s introduction [105]. Its use is widespread in endemic areas of South America (80 – 90% vaccine coverage) and less so in Africa (1 – 40% vaccine coverage) [105]. Current recommendations for travelers to endemic areas include vaccination once every 10 years; however, one recent study has demonstrated protective neutralizing antibody activity in nearly 75% of vaccinees 11 to 38 years after immunization [110]. The yellow fever vaccine is not recommended for transplant patients [31]. It appears to be safe for HIV+ patients with good immune function [111]; however, because the vaccine consists of live attenuated virus, extreme caution should be used in HIV patients demonstrating immune dysfunction. Elderly persons might be at risk for more frequent or severe adverse events after immunization Recent case reports have demonstrated adverse events potentially associated with use of the yellow fever vaccine. One article reported the development of severe systemic reactions somewhat atypical of yellow fever in four persons older than age 63 who had recently been immunized [112]. Three other adverse reactions more consistent with yellow fever were reported in younger patients after immunization [113,114]. All three patients died. These cases have led to recommendations that human responses and possible risk factors enhancing susceptibility to this vaccine such as age be studied more closely. Additionally, the potential for mutation of the attenuated vaccine into a more virulent one should be studied [115]. This vaccine still has an excellent safety profile, and recommendations for vaccination have not changed.
356
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
Vaccines currently under study Advances in genetics and immunology have opened new avenues of research for vaccine candidates. Vaccines using DNA, conjugated proteins, or conjugated polysaccharides to enhance immunogenicity and new vaccines using recombinant proteins are currently undergoing clinical trials. Different vectors such as viruses and bacteria are also being evaluated for vaccine administration. These new vaccines are being assessed for prophylaxis and therapy in a wide variety of diseases, including infections and malignancies. New vaccine candidates that have not yet approved for use in humans target diseases with cutaneous manifestations. These include vaccines against herpes simplex virus (HSV), human papillomavirus (HPV), and HIV infections, which have demonstrated potential for future prophylactic and therapeutic uses. Clinical trials are already underway for some of these candidates. Herpes simplex viruses 1 and 2 HSV infections result in a variety of diseases. The most frequent manifestations include herpes labialis (cold sores, most often caused by herpes simplex type I) and herpes genitalis (most often caused by herpes simplex type II). Other manifestations include neonatal herpes, herpes encephalitis, herpetic whitlow, herpes gladiatorum, erythema multiforme, and eczema herpeticum. Clinical manifestations of herpes infection include a prodrome of burning, pain, itching, or tingling followed by the appearance of papules, vesicles, or pustules on an erythematous base. Primary infection is typically the most severe. After resolution of the primary infection, however, the virus persists in neural ganglion cells. Reactivation of the virus results in periodic recurrences of clinical manifestations. Transmission of HSV is accomplished by close personal contact with infected body fluids such as saliva, semen, and vesicular fluid. Most often, transmission occurs during periods when the patient is asymptomatic (asymptomatic viral shedding). More than 85% of the world’s population is seropositive for HSV-I, reflecting the overwhelming prevalence of herpes labialis [116]. Genital herpes is one of the most common sexually transmitted diseases in the world. Recent prevalence estimates of exposure to HSV-II in the United States have ranged as high as 22% in the period of 1988 to 1994, a 30% increase over the prevalence from 1976 to 1980 [117]. There is no cure for herpes infections. Currently approved treatment modalities are limited to episodic
or suppressive therapy with antiviral medications such as acyclovir, valacyclovir, penciclovir, and famciclovir. Foscarnet is indicated for rare cases of acyclovir-resistant HSV. Vaccines The increasing prevalence of herpes genitalis has led to a strong interest in the development of prophylactic or therapeutic vaccines against HSV, especially HSV-II. None of these treatments are currently approved by the Food and Drug Administration (FDA), but at least three vaccine strategies are currently being explored. The disabled infection single cycle (DISC) vaccine containing a herpes virus incapable of producing infectious virions has been studied in clinical trials as a preventative and therapeutic vaccine. Recombinant subunit vaccines consisting of viral proteins with an immunogenic adjuvant are also undergoing preliminary clinical trials. Finally, DNA vaccines using HSV DNA plasmids containing a limited number of HSV genes are being developed for clinical trials. The DISC vaccine consists of live HSV that has been genetically engineered, resulting in the deletion of the glycoprotein gH gene [118]. In the absence of glycoprotein gH, HSV is incapable of producing new infectious virions. After the virion enters a target cell and replicates, the copies of the virus are incapable of infecting other cells. This vaccine has proven to be well tolerated and immunogenic in Phase I trials, stimulating humoral and cell-mediated immune responses [119,120]. Human trials have not yet demonstrated a therapeutic effect, however. A trial evaluating the vaccine’s prophylactic efficacy in humans has been performed, but results have not yet been published. Recombinant vaccines against HSV consisting of two HSV envelope glycoproteins (gB and gD) have also been studied. These proteins lack the same level of immunogenicity as live attenuated vaccines; however, the addition of an adjuvant can serve to enhance the T-cell immune response. Clinical trials have been undertaken to evaluate at least four subunit vaccine candidates employing different adjuvants. One vaccine candidate combined a truncated recombinant HSV gD (gD2) protein with an aluminum hydroxide (alum) adjuvant [121]. This vaccine generated a modest immune response in humans and it was marginally protective. The same protein was later combined with a muramyl tripeptide adjuvant; however, this vaccine had an unacceptable reactogenicity profile [118]. Another vaccine candidate has combined recombinant gD2 and gB2 proteins with MF59 (containing polysorbate 80, squalene, and sorbitan
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
trioleate) [122]. The reactogenicity profile was acceptable, but the vaccine lacked therapeutic efficacy for recurrent genital herpes [123]. When examined for prophylactic efficacy in two studies, it appeared to be protective within the first 5 months after vaccination, but not in the long-term [124]. There was a gender-specific effect offering marginal protection for women but no protection for men. This vaccine also lacked the ability to prevent symptomatic infection or reduce the severity of genital herpes outbreaks [122]. Finally, a recombinant gD2 vaccine with a monophosphoryl lipid A adjuvant has recently been tested in human trials [118]. This vaccine has demonstrated a trend toward reduction of HSV-II acquisition, but only in women who are HSV-I and HSV-II seronegative (double seronegative women) prior to vaccination [125]. It also demonstrated a statistically significant reduction in genital herpes symptoms for double seronegative women who were immunized and subsequently seroconverted to HSV-II positivity. The vaccine was not efficacious in either men or HSV-I – positive women. Trials are currently being planned to furher evaluate the vaccine’s efficacy in double seronegative women and to determine the mechanism of action, which is thought to be related to local immunity induced by cervical secretions containing antibodies and cellular factors against HSV-II. Finally, vaccines employing DNA plasmids that encode a limited number of HSV-II proteins are now also under study. In theory, plasmids consisting of genes encoding for gB or gD will generate proteins that can be directed to different locations (cytoplasm, plasma membranes, or extracellular spaces), thereby stimulating different levels of both cellular and humoral immune responses [126,127]. Animal studies have demonstrated protection against challenge with HSV in guinea pigs and mice [128 – 132], and at least one phase I trial is underway to evaluate a gD2 DNA vaccine [118]. Human papillomaviruses To date, more than 100 types of human papillomavirus (HPV) have been identified [133]. They are responsible for a wide spectrum of benign and malignant clinical diseases. Benign lesions include verruca vulgaris, plantar warts, condyloma acuminata (genital warts), and papillomas of the oropharynx and upper respiratory tract. More importantly, HPV have also been associated with various cutaneous and mucosal malignancies, including squamous cell carcinomas, anogenital cancers, and cervical cancer. The potential for malignant transformation after HPV
357
infection depends largely on HPV type and whether that type has been classified as low risk or high risk. The mechanism of action by which high-risk HPV types induce carcinogenesis is not fully understood. Viral DNA integration into the host genome and the resultant loss of transcriptional control over oncogenic HPV genes might play a large role [134 – 136]. Cervical cancer is the seventh most common cancer worldwide and the third most common in women [137]. The widespread use of the Papanicolaou smear in industrialized countries has resulted in a significant reduction of cervical cancer, but epidemiologic projections still estimate 12,800 new cases and 4,600 deaths in the United States in 2000 [138]. Infection with high-risk HPV types have been demonstrated in all stages of cervical dysplasia, and the contributing role of HPV infection in cervical cancer is unquestioned. Human papillomavirus DNA has been found in more than 99.7% of cervical cancer specimens according to one recent study [139]. Various high-risk HPV types have been identified in premalignant and malignant cervical lesions, but types 16 and 18 are most common. The vast majority of HPV infections, both high and low risk, will resolve spontaneously. If needed, treatment modalities for clinically apparent HPV infections include physical ablation (surgical excision, cryotherapy, chemical ablation, and laser therapy), the antiviral cidofovir, and medications designed to stimulate human immune responses such as interferons and imiquimod. Cervical dysplasia can be treated with conization, loop electrocautery excision procedures, cryotherapy, and laser ablation. Vaccines There are currently no FDA-approved vaccines against HPV. The high worldwide incidence of cervical cancer (500,000 cases in 2001) and the lack of easy access to regular preventive health care—especially in underdeveloped countries—make such a vaccine highly desirable. Most vaccines currently under study have targeted HPV types 16 and 18, which are responsible for the large majority of cervical cancers. As with HSV vaccine studies, a variety of modalities are being tested as prophylactic and therapeutic candidates. Vaccination strategies for HPV include the use of recombinant HPV proteins, protein peptides, virus-like particles (VLPs), DNA plasmids employing viral and bacterial vectors, and DNA vaccines. Recombinant proteins show promise as prophylactic vaccine candidates. One recent study employing a pentameric recombinant canine oncogenic papillomavirus L1 protein has demonstrated protec-
358
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
tion from oral viral challenges in dogs [140]. Another study has evaluated a fusion protein consisting of HPV 16 L2E6E7 that exhibited cell-mediated and humoral immune responses in animals [141]. Prophylactic studies with peptide sequences stimulate both humoral and cell-mediated immune responses; however, most recent studies using peptide vaccines have concentrated on therapeutic vaccinations (see below). One study found a strong humoral immune response to a synthetic peptide containing polymerized epitopes of the HPV 16 E7 protein [142]. Virus-like particles (VLPs) are noninfectious particles that display epitopes that are conformationally equivalent to HPV protein epitopes. These particles have been extensively studied and are capable of producing strong immune responses in vitro and in animal models and in humans [143 – 145]. Immune responses involve cell-mediated immunity and humoral immunity, depending on whether the constructs are developed with late (structural) L1 and L2 proteins or early (nonstructural) E6 and E7 proteins [143,144,146,147]. Humoral immunity is thought to play a larger role in preventing HPV transmission; therefore, prophylactic vaccines have concentrated on VLPs composed of L1 and L2. Phase I and II trials have demonstrated the immunogenicity and safety of an HPV 16 L1 VLP [144,148]. At least one prophylactic Phase III study of the L1 VLP is underway. HPV type 11 L1 VLPs have also been assessed in women and demonstrate strong serum immune responses [149]. Finally, there is evidence in animal models that an HPV 11 VLP demonstrates systemic and mucosal antibody responses after oral administration in mice [150]. A follow-up study also demonstrated systemic and mucosal humoral immunity in mice vaccinated with L1 VLPs from HPV types 16 and 18 when combined with Escherichia coli heatlabile enterotoxins [151]. Viral and bacterial vector vaccines have been evaluated for prophylactic immunization against HPV. Three studies have assessed recombinant salmonella vaccines, two expressing HPV 16 L1 VLPs and one using HPV 16 E6 and E7 gene products [152 – 154]. These vaccines were found to provoke HPV-specific immune responses in animal models. Earlier efforts led to the development of a recombinant vaccinia virus expressing the HPV 16 L1 gene [155]. This vaccine demonstrated antibody responses specific to L1 in mice. DNA plasmid vaccine candidates have been developed relatively recently. These vaccines appear to be promising, but they have not been extensively studied yet. One vaccine employing a DNA plasmid
that encodes for HPV 16 L1 has recently been evaluated in animal models after oral and parenteral administration [156]. This study found similar humoral responses with intramuscular, subcutaneous, and oral routes of administration. Mucosal IgA antibody specific to L1 was also observed, and orally administered DNA vaccine demonstrated the strongest response. Cell-mediated immunity was not stimulated to the degree that was expected. Another DNA trial demonstrated that HPV 16 L1 plasmids stimulate a larger immune response when RNA coding sequences are changed [157]. An enhanced expression of gene products improves immunogenicity, resulting in increased amounts of VLPs in cells. Mucosal immunity might be important in the development of a prophylactic vaccine. Schreckenberger et al used an HPV 6bL1 DNA vaccine in rabbits [158] and found that vaginal immunization resulted in mucosal IgA responses specific to 6bL1 VLPs. Moreover, this response was prolonged; IgA was detected up to 14 weeks after the first immunization, and it was capable of viral neutralizing activity. Therapeutic vaccines have been studied for HPVinduced benign and malignant lesions. Phase I and II trails evaluating the benefit of therapeutic vaccination for genital warts with a recombinant HPV 6 L2E7 protein have been performed [159,160]. This vaccine was safe and generated humoral and cell-mediated immune responses. Five of 25 subjects enrolled in the Phase II trial had complete wart clearance within 8 weeks. Several animal and in vitro studies have been performed to assess recombinant proteins employing immunogenic adjuvants for use as therapeutic vaccines [143,161]. These studies concluded that HPV proteins are promising therapeutic vaccine candidates because they induce strong CD8 immunity independently of CD4 T cell function. Chimeric VLPs consisting of early and late gene products have also been studied in vitro and in animal models [162,163], stimulating enhanced antigen presentation, increased T-cell responses, and lysis in vitro while also providing protection from tumor challenge in mice. Vectored vaccines have been evaluated for therapy against HPV-induced tumors. One Phase I/II study has been performed in patients with late-stage cervical cancer using a vaccinia vector expressing HPV 16 and 18 E6 and E7 proteins [164]. Vaccination with this modified virus was safe, and three of eight patients enrolled developed HPV-specific antibody responses. One of three evaluable patients also developed a cytotoxic T lymphocyte (CTL) response to HPV. Clinical responses were not specifically assessed in this study. Listeria monocytogenes has been genetically altered to express or secrete HPV
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
type 16 E7 proteins [165]. Both vaccines demonstrated strong CTL responses in mice, and the secretory E7 protein proved to be capable of reducing tumor size. HPV type 16 E5 protein delivered by an adenovirus vector has been assessed as a therapeutic vaccine candidate in animal models [166]. When given to animals with E5-expressing tumors, this vaccine is capable of reducing growth through stimulation of a CTL response independently of CD4 cell response. He et al have developed a recombinant vaccine with an adenovirus vector that expresses either E6 or E7 HPV gene products [146]. They demonstrated protection from tumor challenge in animal models. Plasmid DNA vaccines might provide therapeutic benefit in the treatment of HPV-induced tumors. A DNA construct consisting of HPV 16 E7 protein with four epitopes rearranged in the DNA sequence was constructed to assess antitumorigenic response in animal studies [167]. The rearrangement of epitopes was necessitated by concern that a plasmid expressing native E7 could promote oncogenesis by itself. It demonstrated high levels of CTL activity in mice and was able to protect against challenge from E7 positive tumor cells. Other studies have also assessed the use of mutated E7 DNA plasmids for therapeutic vaccinations against HPV [168,169]. Finally, one study evaluated a combination of an HPV 16 E7 DNA vaccine followed by immunization with a recombinant vaccinia virus expressing HPV 16 E7 antigen [170]. This prime-boost strategy generated a strong CTL response in an animal model, although E7 specific CD4 activity was not enhanced. HIV Recent prevalence estimates from the WHO suggest that there are 40 million cases of HIV infection worldwide. Five million new cases were identified in 2001 [171]. In the United States, recent prevalence estimates of HIV infection range from 800,000 to 900,000 individuals, with 40,000 new infections diagnosed yearly [172 – 174]. AIDS remains one of the most common causes of death in the world, especially in underdeveloped countries, where access to effective antiretroviral medications is limited. About 3 million people died from AIDS in 2001, and AIDS is now the leading cause of death in subSaharan Africa [171]. Infection with HIV can lead to a wide variety of skin lesions. Dermatologic manifestations of HIV are of clinical importance because they might be the first indication of infection with HIV. They might also appear as an early indication of more serious sys-
359
temic infections. Dermatologic manifestations of HIV can be divided into infectious, noninfectious, and malignant lesions. Patients with HIV or AIDS are susceptible to common infectious diseases with cutaneous manifestations. In the presence of immune dysfunction, however, the incidence of these infections might be much higher and the course of disease more severe. Individuals infected with HIV also develop cutaneous lesions that are not typically found in immunocompetent patients (see Porras or Aftergut for reviews on the cutaneous manifestations of HIV and AIDS) [175,176]. Skin lesions associated with HIV infection include the acute exanthem of HIV, which is associated with acute retroviral infection. This condition might pass unnoticed by the patient or physician. Some patients might develop a morbilliform rash involving the trunk and upper extremities that is associated with constitutional symptoms such as fever, malaise, myalgias, and diarrhea. The exanthem typically develops within 2 to 4 weeks of HIV infection and lasts for about 1 week [177 – 179]. Other noninfectious skin manifestations of HIV include seborrheic dermatitis, Reiter’s syndrome, eosinophilic folliculitis, xerotic and atopic dermatitis, chronic urticaria, and porphyria cutanea tarda. Finally, HIV+ patients demonstrate more frequent cutaneous reactions to medications, usually presenting as fine, red macules and papules located primarily on the trunk [180,181]. HIV-infected individuals develop malignancies with cutaneous manifestations such as Bowenoid papulosis, verrucous carcinomas, cutaneous lymphomas, and Kaposi’s sarcoma at a much higher rate than individuals who are immunocompetent. These neoplastic diseases are frequently associated with viral infections, as with verrucous carcinomas, Bowenoid papulosis (both associated with HPV infection), and Kaposi’s sarcoma (associated with HHV-8 infections). Treatment for HIV infection is currently limited to the use of four classes of antiretroviral medications: non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, and protease inhibitors. Combination therapy with these medications, called highly active antiretroviral therapy (HAART), has proven to be successful in treating HIV infections and prolonging the time before onset of AIDS symptoms; however, problems exist with this regimen. Inherent instability in the HIV genome results in frequent mutations, often leading to therapy resistance, especially in those who are noncompliant with their medications. Furthermore, HAART is
360
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
extremely expensive and is not widely available in underdeveloped countries. Vaccines The devastating impact of the HIV epidemic has led to the development of numerous vaccine candidates employing different methods of stimulating immune responses. Categories of prophylactic HIV vaccine candidates include recombinant protein vaccines using immunogenic adjuvants, viral vectors expressing recombinant HIV proteins (live vector constructs), and live attenuated vaccines. Ongoing research focuses on new vaccination strategies, with two different vaccines being given sequentially (prime-boost vaccination). Vaccines are also being tested for use as therapeutic agents in patients who are already infected with HIV. Vaccines for HIV must stimulate both humoral and cell-mediated immune responses. In fact, cell-mediated responses might be more important in controlling HIV infection and transmission than humoral immunity [182]. No vaccines for HIV have yet been approved by the FDA, but two candidates are undergoing Phase III trails, and another Phase III study is being planned. Other vaccines are in earlier stages of development. Vaccine studies involving HIV are too numerous for the scope of this paper, so only recent developments will be discussed in more depth. Recombinant vaccines employing HIV proteins with immunogenic adjuvants have been studied extensively for HIV. Both vaccine candidates in the ongoing Phase III trials employ recombinant gp120 proteins with an alum adjuvant. The study in Thailand employs proteins from HIV subtypes B and E, whereas the trial in the United States and Europe uses gp120 from two B subtypes. These trials are ongoing. Earlier studies demonstrated protective immunity in chimpanzees and a modest neutralizing antibody response in humans [183 – 186]. Although the vaccine demonstrated an acceptable safety profile, the immune response was not sufficient in Phase II trials to protect against subsequent HIV infection [187]. Among other recombinant protein-adjuvant vaccines under study, a recombinant peptide mimicking a sequence from HIV gp120 was recently assessed in a Phase I trial. This vaccine was given in a prime-boost manner. The peptide was first administered orally with the hope of eliciting an IgA immune response on mucosal surfaces. It was subsequently administered by way of intramuscular injection with an alum adjuvant. Animal trials previously showed good immune responses to this vaccine when given by either mucosal or parenteral routes [188 – 190]. Fur-
thermore, this vaccine was immunogenic in humans when given intramuscularly [191]. Although no severe adverse reactions were noted, this trial demonstrated a poor immune response to the orally administered vaccine [192]. Other Phase I and II trials assessing recombinant proteins include vaccines targeting gp160, gp120, env 2 to 3 (an envelope protein of HIV), and a multivalent peptide vaccine targeting the V3 loop of gp120 [193 – 200]. A more recent strategy involves using defective or attenuated viruses as vectors for HIV plasmids to stimulate humoral and cell-mediated immune responses [200 – 202]. Phase III trials have not yet been conducted, but animal and preliminary human studies are promising. Multiple viral vectors have been studied, including vaccinia virus, canarypox virus, adenovirus, alphaviruses (Venezuelan equine encephalitis and sindbis virus), and rhabdoviruses [201,203,204]. Poxviruses have been most widely studied as vectors for prophylactic HIV immunization. Although vaccinia has shown promise as an HIV vector, recent studies have focused more on canarypox because this virus has an extremely limited capacity to replicate and cause disease in humans [205]. A canarypox vector containing an HIV gp160 envelope gene has demonstrated strong cell-mediated and neutralizing antibody activity in Phase I trials [206]. Another canarypox vector vaccine containing genes encoding HIV gp120, gag, and pol proteins has demonstrated a stronger CTL response [207,208]. Finally, a canarypox vaccine containing genes encoding gp120, transmembrane gp41, gag, pro, nef, and pol has shown durable CTL responses when given in conjunction with a recombinant gp120 vaccine [209]. A canarypox vaccine in conjunction with the recombinant gp120 vaccine is scheduled for Phase III trials using a prime-boost strategy [210,211]. Adenoviruses have also attracted attention as viral vectors for prophylactic HIV vaccines. Replicationincompetent adenoviruses containing the HIV env gene have demonstrated strong CTL and humoral immune responses in mice, especially when used after priming with a DNA vaccine [212]. A Phase I clinical trial has begun using a replication-incompetent adenovirus vaccine containing the HIV gag gene. Adeno-associated virus (AAV) has also been used as a vector for HIV vaccination. One recent study evaluated the immune response of mice to an AAV vector expressing HIV env, tat, and rev genes [213]. This study revealed that this vaccine elicits serum IgG and mucosal IgA antibodies to HIV as well as a strong cell-mediated immune response.
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
As with virus-vectored vaccines, DNA vaccines have been developed with the goal of stimulating humoral and cell-mediated immunity. Animal studies have shown promise for this modality in stimulating cell-mediated immunity to HIV [214]. These vaccines might prove useful for HIV prophylaxis, especially in conjunction with other vaccine candidates that stimulate a stronger humoral immune response. No prophylactic DNA vaccines against HIV are currently undergoing Phase III trials. One Phase I trial has demonstrated transient cell-mediated and chemokine responses in healthy subjects vaccinated with a DNA construct consisting of HIV env and rev genes [215]. Another DNA vaccine employing a plasmid containing the gag gene is also being developed, and it shows promise for inducing a strong cell-mediated immune response in animal models [216]. Finally, animal models demonstrated enhanced immunogenicity when genes encoding IL-8, VIP-10, RANTES, and other chemokines were inserted into DNA plasmids containing HIV env and gag/pol genes [217]. Barouch et al examined a combination of genes encoding IL-2 and the Fc portion of IgG combined with the HIV gag gene [218]. This vaccine demonstrated strong and enduring CTL immunogenicity and appeared to offer protection against progression of disease after challenge with a chimeric virus encoding simian immunodeficiency virus and HIV genes. HIV vaccines have also been investigated as therapeutic modalities. Therapeutic vaccinations with recombinant HIV proteins and HIV-related peptides have been disappointing. Some studies suggest an immune response to vaccination in a few HIV+ individuals, but none have demonstrated a therapeutic effect [219 – 224]. A canarypox virus has been evaluated as a therapeutic vaccine for HIV infection in asymptomatic individuals [225]. Patients in this study were started on HAART within 120 days of diagnosis, and they received a recombinant canarypox-vectored vaccine expressing gp120 and other HIV proteins. They were simultaneously vaccinated with recombinant gp160. The trial demonstrated cellular and humoral immune responses after immunization, but clinical efficacy was not assessed [225]. HIV DNA vaccines have been assessed as therapeutic modalities for HIV-infected patients. Although demonstrated as safe and effective for asymptomatic HIV+ patients, DNA vaccines have not had a significant impact against HIV and have had inconsistent cellular immune responses [226,227]. A gp120-depleted, inactivated HIV immunogen has been studied in HIV+ patients. This study demonstrated that the vaccine was well tolerated and generated an antibody-mediated immune
361
response in HIV+ patients. Clinical assessments were not done [228].
Summary Vaccines against infectious diseases have been available since the 1800s, when an immunization strategy against smallpox developed by Jenner gained wide acceptance [1]. Until recently, the only vaccination strategies available involved the use of protein-based, whole killed, and attenuated live virus vaccines. These strategies have led to the development of effective vaccines against a variety of diseases with primary or prominent cutaneous manifestations. Effective and safe vaccines now used worldwide include those directed against measles and rubella (now commonly used together with a mumps vaccine as the trivalent MMR), chickenpox, and hepatitis B. The eradication of naturally occurring smallpox remains one of the greatest successes in the history of modern medicine, but stockpiles of live smallpox exist in the United States and Russia. Renewed interest in the smallpox vaccine reflects concerns about a possible bioterrorist threat using this virus. Yellow fever is a hemorrhagic virus endemic to tropical areas of South America and Africa. An effective vaccine for this virus has existed since 1937, and it is used widely in endemic areas of South America, and to a lesser extent in Africa. This vaccine is recommended once every 10 years for people who are traveling to endemic areas. Advances in immunology have led to a greater understanding of immune system function in viral diseases. Progress in genetics and molecular biology has allowed researchers to design vaccines with novel mechanisms of action (eg, DNA, vector, and VLP vaccines). Vaccines have also been designed to specifically target particular viral components, allowing for stimulation of various arms of the immune system as desired. Ongoing research shows promise in prophylactic and therapeutic vaccination for viral infections with cutaneous manifestations. Further studies are necessary before vaccines for HSV, HPV, and HIV become commercially available.
References [1] Hilleman MR. Vaccines in historic evolution and perspective: a narrative of vaccine discoveries. J Hum Virol 2000;3:63 – 76. [2] Plotkin SA, Plotkin SL. A short history of vaccination. In: Plotkin SA, Orenstein WA, Plotkin SA, et al,
362
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13] [14]
[15]
[16]
[17]
[18]
[19]
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 editors. Vaccines. Philadelphia (PA): WB Saunders; 1999. p. 1 – 12. Orenstein WA, Strebel PM, Papania M, et al. Measles eradication: is it in our future? Am J Public Health 2000;90:1521 – 5. Oxman MN. Measles virus. In: Richman DD, Whitley RJ, Hayden FG, et al, editors. Clinical virology. Washington DC: ASM Press; 2002. p. 791 – 828. Shalev-Zimels H, Weizman Z, Lotan C, et al. Extent of measles hepatitis in various ages. Hepatology 1988;8:1138 – 9. Fulginiti VA, Eller JJ, Downie AW, et al. Altered reactivity to measles virus. Atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 1967;202:1075 – 80. Lennon RG, Isacson P, Rosales T, et al. Skin tests with measles and poliomyelitis vaccines in recipients of inactivated measles virus vaccine. Delayed dermal hypersensitivity. JAMA 1967;200:275 – 80. Krause PJ, Cherry JD, Naiditch MJ, et al. Revaccination of previous recipients of killed measles vaccine: clinical and immunologic studies. J Pediatr 1978;93: 565 – 71. Nieburg PI, D’Angelo LJ, Herrmann KL. Measles in patients suspected of having Rocky Mountain spotted fever. JAMA 1980;244:808 – 9. Annunziato D, Kaplan MH, Hall WW, et al. Atypical measles syndrome: pathologic and serologic findings. Pediatrics 1982;70:203 – 9. Horstmann DM. Rubella. In: Evans AS, editor. Viral infections is humans. Epidemiology and control. New York (NY): Plenum; 1976. p. 409 – 27. Redd SC, Markowitz LE, Katz SL. Measles vaccine. In: Plotkin SA, Orenstein WA, Plotkin SA, et al, editors. Vaccines. Philadelphia (PA): WB Saunders; 1999. p. 222 – 66. World Health Organization. Executive summary. Geneva, Switzerland: World Health Organization; 1989. Centers for Disease Control and Prevention. Advances in global measles control and elimination: summary of the international meeting. MMWR CDC Surveill Summ 1998;47:1 – 23. Biellik R, Madema S, Taole A, et al. First 5 years of measles elimination in southern Africa: 1996 – 2000. Lancet 2002;359:1564 – 8. Plotkin SA. Rubella vaccine. In: Plotkin SA, Orenstein WA, Plotkin SA, et al, editors. Vaccines. Philadelphia (PA): WB Saunders; 1999. p. 409 – 39. Johnson CE, Kumar ML, Whitwell JK, et al. Antibody persistence after primary measles-mumps-rubella vaccine and response to a second dose given at four to six vs. eleven to thirteen years. Pediatr Infect Dis J 1996;15:687 – 92. American Academy of Pediatrics. Committee on Infectious Diseases. Age for routine administration of the second dose of measles-mumps-rubella vaccine. Pediatrics 1998;101:129 – 33. Centers for Disease Control and Prevention. Measles—United States, 2000. MMWR 2002;51:120 – 3.
[20] Wakefield AJ, Murch SH, Anthony A, et al. Ileallymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637 – 41. [21] Kawashima H, Mori T, Kashiwagi Y, et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci 2000;45: 723 – 9. [22] Walker-Smith J. Autism, bowel inflammation, and measles. Lancet 2002;359:705 – 6. [23] Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353:2026 – 9. [24] Afzal MA, Minor PD, Schild GC. Clinical safety issues of measles, mumps and rubella vaccines. Bull World Health Organ 2000;78:199 – 204. [25] Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001;285:1183 – 5. [26] Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a causal association. Vaccine 2001;19:3632 – 5. [27] Fombonne E, Chakrabarti S. No evidence for a new variant of measles-mumps-rubella – induced autism. Pediatrics 2001;108:E58. [28] McCormick A, Dinakaran S, Bhola R, et al. Recurrent sixth nerve palsy following measles mumps rubella vaccination. Eye 2001;15:356 – 7. [29] Rudy BJ, Rutstein RM, Pinto-Martin J. Responses to measles immunization in children infected with human immunodeficiency virus. J Pediatr 1994;125: 72 – 4. [30] Goon P, Cohen B, Jin L, et al. MMR vaccine in HIVinfected children – potential hazards? Vaccine 2001; 19:3816 – 9. [31] Burroughs MH. Immunization in transplant patients. Pediatr Infect Dis J 2002;21:158 – 60. [32] Ross AH, Lencher E, Reitman G. Modification of chickenpox in family contacts by administration of gamma globulin. N Engl J Med 1962;267:369 – 76. [33] Gershon AA, Silverstein SJ. Varicella zoster virus. In: Richman DD, Whitley RJ, Hayden FG, et al, editors. Clinical virology. Washington DC: ASM Press; 2002. p. 413 – 32. [34] Gershon AA, Takahashi M, White CJ. Varicella vaccine. In: Plotkin SA, Orenstein WA, Plotkin SA, et al, editors. Vaccines. Philadelphia (PA): WB Saunders; 1999. p. 475 – 507. [35] White CJ. Varicella-zoster virus vaccine. Clin Infect Dis 1997;24:753 – 63. [36] Andre FE. Worldwide experience with the Okastrain live varicella vaccine. Postgrad Med J 1985; 61:113 – 20. [37] Asano Y, Suga S, Yoshikawa T, et al. Experience and reason: twenty-year follow-up of protective immunity of the Oka strain live varicella vaccine. Pediatrics 1994;94:524 – 6.
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 [38] Ngai AL, Staehle BO, Kuter BJ, et al. Safety and immunogenicity of one vs. two injections of Oka/ Merck varicella vaccine in healthy children. Pediatr Infect Dis J 1996;15:49 – 54. [39] Vazquez M, LaRussa PS, Gershon AA, et al. The effectiveness of the varicella vaccine in clinical practice. N Engl J Med 2001;344:955 – 60. [40] Weibel RE, Neff BJ, Kuter BJ, et al. Live attenuated varicella virus vaccine. Efficacy trial in healthy children. N Engl J Med 1984;310:1409 – 15. [41] Kuter BJ, Weibel RE, Guess HA, et al. Oka/Merck varicella vaccine in healthy children: final report of a 2-year efficacy study and 7-year follow-up studies. Vaccine 1991;9:643 – 7. [42] Johnson C, Rome LP, Stancin T, et al. Humoral immunity and clinical reinfections following varicella vaccine in healthy children. Pediatrics 1989;84: 418 – 21. [43] Bernstein HH, Rothstein EP, Watson BM, et al. Clinical survey of natural varicella compared with breakthrough varicella after immunization with live attenuated Oka/Merck varicella vaccine. Pediatrics 1993;92:833 – 7. [44] Watson BM, Piercy SA, Plotkin SA, et al. Modified chickenpox in children immunized with the Oka/ Merck varicella vaccine. Pediatrics 1993;91:17 – 22. [45] American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for the use of live attenuated varicella vaccine. Pediatrics 1995;95: 791 – 6. [46] Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1996;45:1 – 36. [47] Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995 – 2000. JAMA 2002;287: 606 – 11. [48] Asano Y, Nagai T, Miyata T, et al. Long-term protective immunity of recipients of the OKA strain of live varicella vaccine. Pediatrics 1985;75:667 – 71. [49] Vessey SJ, Chan CY, Kuter BJ, et al. Childhood vaccination against varicella: persistence of antibody, duration of protection, and vaccine efficacy. J Pediatr 2001;139:297 – 304. [50] Berger R, Trannoy E, Hollander G, et al. A dose-response study of a live attenuated varicella-zoster virus (Oka strain) vaccine administered to adults 55 years of age and older. J Infect Dis 1998;178 (Suppl 1):S99 – 103. [51] Levin MJ, Barber D, Goldblatt E, et al. Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis 1998;178(Suppl 1):S109 – 12. [52] LaRussa P, Steinberg S, Gershon AA. Varicella vaccine for immunocompromised children: results of collaborative studies in the United States and Canada. J Infect Dis 1996;174(Suppl 3):S320 – 3.
363
[53] Zamora I, Simon JM, Da Silva ME, et al. Attenuated varicella virus vaccine in children with renal transplants. Pediatr Nephrol 1994;8:190 – 2. [54] Gershon AA, Mervish N, LaRussa P, et al. Varicellazoster virus infection in children with underlying human immunodeficiency virus infection. J Infect Dis 1997;176:1496 – 500. [55] Purcell RH. The discovery of the hepatitis viruses. Gastroenterology 1993;104:955 – 63. [56] Beasley RP. Hepatitis virus as the etiologic agent in hepatocellular carcinoma. Hepatology 1983;2: 22S – 6S. [57] The World Health Report. Fighting disease, fostering development. Geneva, Switzerland: World Health Organization; 1996. [58] Befeler AS, Di Bisceglie AM. Hepatitis B. Infect Dis Clin N Am 2000;14:617 – 32. [59] Zuckerman JN, Zuckerman AJ. Current topics in hepatitis B. J Infect 2000;41:130 – 6. [60] Mahoney FJ, Kane M. Hepatitis B vaccine. In: Plotkin SA, Orenstein WA, Plotkin SA, et al, editors. Vaccines. Philadelphia (PA): WB Saunders; 1999. p. 158 – 82. [61] Suzuki T, Yamauchi K, Kuwata T, et al. Characterization of hepatitis B virus surface antigen-specific CD4+ T cells in hepatitis B vaccine non-responders. J Gastroenterol Hepatol 2001;16:898 – 903. [62] Lai CL, Wong BC, Yeoh EK, et al. Five-year followup of a prospective randomized trial of hepatitis B recombinant DNA yeast vaccine vs. plasma-derived vaccine in children: immunogenicity and anamnestic responses. Hepatology 1993;18:763 – 7. [63] FDA approval for a combined hepatitis A and B vaccine. MMWR Morb Mortal Wkly Rep 2001;50: 806 – 7. [64] Abraham B, Baine Y, De-Clercq N, et al. Magnitude and quality of antibody response to a combination hepatitis A and hepatitis B vaccine. Antiviral Res 2002;53:63 – 73. [65] Shapiro E, Kopicky J. Comment on the article ‘‘Can immunization precipitate connective tissue disease? Report of 5 cases of systemic lupus erythematosus and review of the literature’’. Semin Arthritis Rheum 2000;30:215 – 6. [66] Al-Khenaizan S. Lichen planus occurring after hepatitis B vaccination: a new case. J Am Acad Dermatol 2001;45:614 – 5. [67] Ashok Shenoy K, Prabha Adhikari MR, Chakrapani M, et al. Pancytopenia after recombinant hepatitis B vaccine—an Indian case report. Br J Haematol 2001; 114:955. [68] DeStefano F, Mullooly JP, Okoro CA, et al. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001;108:E112. [69] Karaali-Savrun F, Altintas A, Saip S, et al. Hepatitis B vaccine related-myelitis? Eur J Neurol 2001;8: 711 – 5. [70] Konstantinou D, Paschalis C, Maraziotis T, et al. Two episodes of leukoencephalitis associated with re-
364
[71]
[72] [73]
[74]
[75]
[76]
[77] [78] [79]
[80] [81]
[82]
[83]
[84]
[85]
[86]
[87] [88]
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 combinant hepatitis B vaccination in a single patient. Clin Infect Dis 2001;33:1772 – 3. Sindern E, Schroder JM, Krismann M, Malin JP. Inflammatory polyradiculoneuropathy with spinal cord involvement and lethal [correction of letal] outcome after hepatitis B vaccination. J Neurol Sci 2001; 186:81 – 5. Tay YK. Gianotti-Crosti syndrome following immunization. Pediatr Dermatol 2001;18:262. Zaas A, Scheel P, Venbrux A, et al. Large artery vasculitis following recombinant hepatitis B vaccination: 2 cases. J Rheumatol 2001;28:1116 – 20. Pennesi M, Torre G, Del Santo M, et al. Glomerulonephritis after recombinant hepatitis B vaccine. Pediatr Infect Dis J 2002;21:172 – 3. Fisher MA, Eklund SA, James SA, et al. Adverse events associated with hepatitis B vaccine in U.S. children less than six years of age, 1993 and 1994. Ann Epidemiol 2001;11:13 – 21. Lewis E, Shinefield HR, Woodruff BA, et al. Safety of neonatal hepatitis B vaccine administration. Pediatr Infect Dis J 2001;20:1049 – 54. Gout O. Vaccinations and multiple sclerosis. Neurol Sci 2001;22:151 – 4. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733 – 45. Safary A, Beck J. Vaccination against hepatitis B: current challenges for Asian countries and future directions. J Gastroenterol Hepatol 2000;15:396 – 401. Ott MJ, Aruda M. Hepatitis B vaccine. J Pediatr Health Care 1999;13:211 – 6. Sehgal A, Gupta I, Sehgal R, et al. Hepatitis B vaccine alone or in combination with anti-HBs immunoglobulin in the perinatal prophylaxis of babies born to HBsAg carrier mothers. Acta Virol 1992;36:359 – 66. Thoelen S, Van Damme P, Mathei C, et al. Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system. Vaccine 1998;16: 708 – 14. Thoelen S, De Clercq N, Tornieporth N. A prophylactic hepatitis B vaccine with a novel adjuvant system. Vaccine 2001;19:2400 – 3. Zuckerman JN, Sabin C, Craig FM, et al. Immune response to a new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose-response study. BMJ 1997;314:329 – 33. Young MD, Rosenthal MH, Dickson B, et al. A multicenter controlled study of rapid hepatitis B vaccination using a novel triple antigen recombinant vaccine. Vaccine 2001;19:3437 – 43. Zuckerman JN, Zuckerman AJ, Symington I, et al. Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines. Hepatology 2001;34:798 – 802. Koff RS. Hepatitis vaccines. Infect Dis Clin N Am 2001;15:83 – 95. Schirmbeck R, Reimann J. Revealing the potential of DNA-based vaccination: lessons learned from the
[89]
[90]
[91]
[92] [93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103] [104] [105] [106]
hepatitis B virus surface antigen. Biol Chem 2001; 382:543 – 52. Tacket CO, Roy MJ, Widera G, et al. Phase 1 safety and immune response studies of a DNA vaccine encoding hepatitis B surface antigen delivered by a gene delivery device. Vaccine 1999;17:2826 – 9. Pol S. Immunotherapy of chronic hepatitis B by anti HBV vaccine. Biomed Pharmacother 1995;49: 105 – 9. Michel ML, Pol S, Brechot C, Tiollais P. Immunotherapy of chronic hepatitis B by anti HBV vaccine: from present to future. Vaccine 2001;19: 2395 – 9. Rousseau MC, Moreau J, Delmont J. Vaccination and HIV: a review. Vaccine 2000;18:825 – 31. Castells L, Esteban R. Hepatitis B vaccination in liver transplant candidates. Eur J Gastroenterol Hepatol 2001;13:359 – 61. Fulginiti VA. Smallpox and complications of smallpox vaccination. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, et al, editors. Dermatology in general medicine. New York, NY: McGraw-Hill; 1993. p. 2596 – 602. Cross Jr JT, Altemeier III WA. A pediatrician’s view. Skin manifestations of bioterrorism. Pediatr Ann 2000;29:7 – 9. Capps L, Vermund SH, Johnsen C. Smallpox and biological warfare: the case for abandoning vaccination of military personnel. Am J Public Health 1986;76:1229 – 31. Downie AW, McCarthy K. The antibody response in man following infection with virsuses of the pox group. III. Antibody response in smallpox. J Hyg (Lond) 1958;56:479 – 87. Kempe CH, Bowles C, Meiklejohn G, et al. The use of vaccinia hyperimmune gamma-globulin in the prophylaxis of smallpox. Bull World Health Organ 1961;25:41 – 8. Benenson AS. Smallpox. In: Evans AS, editor. Viral infections of humans: epidemiology and control. New York (NY): Plenum Medical Books; 1982. p. 541 – 68. el-Ad B, Roth Y, Winder A, et al. The persistence of neutralizing antibodies after revaccination against smallpox. J Infect Dis 1990;161:446 – 8. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med 2002;346:1265 – 74. Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. N Engl J Med 2002; 346:1275 – 80. Cimons M. US dilutes smallpox vaccine supplies. Nat Med 2001;7:1265. Kerr C. Yellow fever vaccine arrives. Trends Microbiol 2001;9:528. Monath TP. Yellow fever: an update. Lancet Infect Dis 2001;1:11 – 20. Kerr JA. The clinical aspects and diagnosis of yellow fever. In: Strode GK, editor. Yellow fever. New York (NY): McGraw-Hill; 1951. p. 629 – 40.
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 [107] Oudart JL, Rey M. [Proteinuria, proteinaemia, and serum transaminase activity in 23 confirmed cases of yellow fever]. Bull World Health Organ 1970;42: 95 – 102 [in French]. [108] Monath TP, Brinker KR, Chandler FW, et al. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am J Trop Med Hyg 1981;30:431 – 43. [109] Theiler M, Smith HH. The use of yellow fever modified by in vitro cultivation for human immunization. J Exp Med 1937;65:787 – 800. [110] Niedrig M, Lademann M, Emmerich P, et al. Assessment of IgG antibodies against yellow fever virus after vaccination with 17D by different assays: neutralization test, haemagglutination inhibition test, immunofluorescence assay and ELISA. Trop Med Int Health 1999;4:867 – 71. [111] Receveur MC, Thiebaut R, Vedy S, et al. Yellow fever vaccination of human immunodeficiency virus-infected patients: report of 2 cases. Clin Infect Dis 2000;31:E7 – 8. [112] Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D – 204 yellow fever vaccination: a report of four cases. Lancet 2001;358:98 – 104. [113] Chan RC, Penney DJ, Little D, et al. Hepatitis and death following vaccination with 17D – 204 yellow fever vaccine. Lancet 2001;358:121 – 2. [114] Vasconcelos PF, Luna EJ, Galler R, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001;358:91 – 7. [115] Marianneau P, Georges-Courbot M, Deubel V. Rarity of adverse effects after 17D yellow-fever vaccination. Lancet 2001;358:84 – 5. [116] Yeung-Yue KA, Brentjens MH, Lee PC, Tyring SK. Herpes Simplex viruses 1 and 2. Dermatol Clin 2002; 20:249 – 66. [117] Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105 – 11. [118] Stanberry LR, Cunningham AL, Mindel A, et al. Prospects for control of herpes simplex virus disease through immunization. Clin Infect Dis 2000;30: 549 – 66. [119] McLean CS, Ni Challanain D, Duncan I, et al. Induction of a protective immune response by mucosal vaccination with a DISC HSV-1 vaccine. Vaccine 1996;14:987 – 92. [120] Boursnell ME, Entwisle C, Blakeley D, et al. A genetically inactivated herpes simplex virus type 2 (HSV-2) vaccine provides effective protection against primary and recurrent HSV-2 disease. J Infect Dis 1997;175:16 – 25. [121] Straus SE, Corey L, Burke RL, et al. Placebo-controlled trial of vaccination with recombinant glycoprotein D of herpes simplex virus type 2 for imunotherapy of genital herpes. Lancet 1994;343:1460 – 3.
365
[122] Langenberg AG, Burke RL, Adair SF, et al. A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity [corrected]. Ann Intern Med 1995;122:889 – 98. [123] Straus SE, Wald A, Kost RG, et al. Immunotherapy of recurrent genital herpes with recombinant herpes simplex virus type 2 glycoproteins D and B: results of a placebo-controlled vaccine trial. J Infect Dis 1997; 176:1129 – 34. [124] Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA 1999;282: 331 – 40. [125] Stephenson J. Genital herpes vaccine shows limited promise. JAMA 2000;284:1913 – 4. [126] Higgins TJ, Herold KM, Arnold RL, et al. Plasmid DNA-expressed secreted and nonsecreted forms of herpes simplex virus glycoprotein D2 induce different types of immune responses. J Infect Dis 2000;182: 1311 – 20. [127] Strasser JE, Arnold RL, Pachuk C, et al. Herpes simplex virus DNA vaccine efficacy: effect of glycoprotein D plasmid constructs. J Infect Dis 2000;182: 1304 – 10. [128] Bourne N, Milligan GN, Schleiss MR, et al. DNA immunization confers protective immunity on mice challenged intravaginally with herpes simplex virus type 2. Vaccine 1996;14:1230 – 4. [129] Bourne N, Stanberry LR, Bernstein DI, et al. DNA immunization against experimental genital herpes simplex virus infection. J Infect Dis 1996;173: 800 – 7. [130] McClements WL, Armstrong ME, Keys RD, et al. Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease. Proc Natl Acad Sci USA 1996;93:11414 – 20. [131] Rouse BT, Nair S, Rouse RJ, et al. DNA vaccines and immunity to herpes simplex virus. Curr Top Microbiol Immunol 1998;226:69 – 78. [132] Bernstein DI, Tepe ER, Mester JC, et al. Effects of DNA immunization formulated with bupivacaine in murine and guinea pig models of genital herpes simplex virus infection. Vaccine 1999;17: 1964 – 9. [133] Gharizadeh B, Kalantari M, Garcia CA, et al. Typing of human papillomavirus by pyrosequencing. Lab Invest 2001;81:673 – 9. [134] Szarka K, Veress G, Juhasz A, et al. Integration status of virus DNA and p53 codon 72 polymorphism in human papillomavirus type 16 positive cervical cancers. Anticancer Res 2000;20:2161 – 7. [135] Thorland EC, Myers SL, Persing DH, et al. Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res 2000;60:5916 – 21. [136] Kalantari M, Blennow E, Hagmar B, et al. Physical
366
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145] [146]
[147]
[148]
[149]
[150]
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 state of HPV16 and chromosomal mapping of the integrated form in cervical carcinomas. Diagn Mol Pathol 2001;10:46 – 54. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993;54:594 – 606. Lawson H, Henson R, Bobo J, et al. Implementing recommendations for the early detection of breast and cervical cancer among low-income women. MMWR 2000;49:37 – 55. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189: 12 – 9. Yuan H, Estes PA, Chen Y, et al. Immunization with a pentameric L1 fusion protein protects against papillomavirus infection. J Virol 2001;75:7848 – 53. van der Burg SH, Kwappenberg KM, O’Neill T, et al. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine 2001;19:3652 – 60. Tindle RW, Croft S, Herd K, et al. A vaccine conjugate of ‘‘ISCAR’’ immunocarrier and peptide epitopes of the E7 cervical cancer-associated protein of human papillomavirus type 16 elicits specific Th1and Th2-type responses in immunized mice in the absence of oil-based adjuvants. Clin Exp Immunol 1995;101:265 – 71. Chu NR, Wu HB, Wu T, et al. Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 2000;121:216 – 25. Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001;93:284 – 92. Schiller J, Lowy D. Papillomavirus-like particle vaccines. J Natl Cancer Inst Monogr 2000;28:50 – 4. He Z, Wlazlo AP, Kowalczyk DW, et al. Viral recombinant vaccines to the E6 and E7 antigens of HPV-16. Virology 2000;270:146 – 61. Pastrana DV, Vass WC, Lowy DR, et al. NHPV16 VLP vaccine induces human antibodies that neutralize divergent variants of HPV16. Virology 2001;279: 361 – 9. Bosch FX, Rohan T, Schneider A, et al. Papillomavirus research update: highlights of the Barcelona HPV 2000 international papillomavirus conference. J Clin Pathol 2001;54:163 – 75. Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human papillomavirus type 11 (HPV-11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: correlation with competitive radioimmunoassay titer. J Infect Dis 2001; 184:1183 – 6. Rose RC, Lane C, Wilson S, et al. Oral vaccination of
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
mice with human papillomavirus virus-like particles induces systemic virus-neutralizing antibodies. Vaccine 1999;17:2129 – 35. Gerber S, Lane C, Brown DM, et al. Human papillomavirus virus-like particles are efficient oral immunogens when coadministered with Escherichia coli heat-labile enterotoxin mutant R192G or CpG DNA. J Virol 2001;75:4752 – 60. Krul MR, Tijhaar EJ, Kleijne JA, et al. Induction of an antibody response in mice against human papillomavirus (HPV) type 16 after immunization with HPV recombinant Salmonella strains. Cancer Immunol Immunother 1996;43:44 – 8. Nardelli-Haefliger D, Roden RB, Benyacoub J, et al. Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice. Infect Immun 1997;65:3328 – 36. Revaz V, Benyacoub J, Kast WM, et al. Mucosal vaccination with a recombinant Salmonella typhimurium expressing human papillomavirus type 16 (HPV16) L1 virus-like particles (VLPs) or HPV16 VLPs purified from insect cells inhibits the growth of HPV16-expressing tumor cells in mice. Virology 2001;279:354 – 60. Zhou J, Crawford L, McLean L, et al. Increased antibody responses to human papillomavirus type 16 L1 protein expressed by recombinant vaccinia virus lacking serine protease inhibitor genes. J Gen Virol 1990;71:2185 – 90. Rocha-Zavaleta L, Alejandre JE, Garcia-Carranca A. Parenteral and oral immunization with a plasmid DNA expressing the human papillomavirus 16 – L1 gene induces systemic and mucosal antibodies and cytotoxic T lymphocyte responses. J Med Virol 2002;66:86 – 95. Leder C, Kleinschmidt JA, Wiethe C, Muller M. Enhancement of capsid gene expression: preparing the human papillomavirus type 16 major structural gene L1 for DNA vaccination purposes. J Virol 2001;75: 9201 – 9. Schreckenberger C, Sethupathi P, Kanjanahaluethai A, et al. Induction of an HPV 6bL1-specific mucosal IgA response by DNA immunization. Vaccine 2000; 19:227 – 33. Lacey CJ, Thompson HS, Monteiro EF, et al. Phase IIa safety and immunogenicity of a therapeutic vaccine, TA-GW, in persons with genital warts. J Infect Dis 1999;179:612 – 8. Thompson HS, Davies ML, Holding FP, et al. Phase I safety and antigenicity of TA-GW: a recombinant HPV6 L2E7 vaccine for the treatment of genital warts. Vaccine 1999;17:40 – 9. Hariharan K, Braslawsky G, Barnett RS, et al. Tumor regression in mice following vaccination with human papillomavirus E7 recombinant protein in PROVAX. Int J Oncol 1998;12:1229 – 35. Greenstone HL, Nieland JD, de Visser KE, et al. Chimeric papillomavirus virus-like particles elicit
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
antitumor immunity against the E7 oncoprotein in an HPV16 tumor model. Proc Natl Acad Sci USA 1998;95:1800 – 5. Kaufmann AM, Nieland J, Schinz M, et al. HPV16 L1E7 chimeric virus-like particles induce specific HLA-restricted T cells in humans after in vitro vaccination. Int J Cancer 2001;92:285 – 93. Borysiewicz LK, Fiander A, Nimako M, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet 1996; 347:1523 – 7. Gunn GR, Zubair A, Peters C, et al. Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J Immunol 2001;167:6471 – 9. Liu DW, Tsao YP, Hsieh CH, et al. Induction of CD8 T cells by vaccination with recombinant adenovirus expressing human papillomavirus type 16 E5 gene reduces tumor growth. J Virol 2000;74: 9083 – 9. Osen W, Peiler T, Ohlschlager P, et al. A DNA vaccine based on a shuffled E7 oncogene of the human papillomavirus type 16 (HPV 16) induces E7-specific cytotoxic T cells but lacks transforming activity. Vaccine 2001;19:4276 – 86. Shi W, Bu P, Liu J, et al. Human papillomavirus type 16 E7 DNA vaccine: mutation in the open reading frame of E7 enhances specific cytotoxic T-lymphocyte induction and antitumor activity. J Virol 1999;73:7877 – 81. Smahel M, Sima P, Ludvikova V, et al. Modified HPV16 E7 genes as DNA vaccine against E7-containing oncogenic cells. Virology 2001;281:231 – 8. Chen CH, Wang TL, Hung CF, et al. Boosting with recombinant vaccinia increases HPV-16 E7-specific T cell precursor frequencies of HPV-16 E7-expressing DNA vaccines. Vaccine 2000;18:2015 – 22. World Health Organization. AIDS epidemic update. Geneva, Switzerland: World Health Organization; December 2001. Centers for Disease Control and Prevention. HIV prevention strategic plan through 2005. Atlanta, GA: Centers for Disease Control and Prevention; January, 2001. Centers for Disease Control and Prevention. HIV and AIDS—United States, 1981 – 2001. MMWR 2001;50:430 – 4. Fleming PL, Byers RH, Sweeney PA, et al. HIV prevalence in the United States, 2000 [abstract 11]. Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 24 – 28, 2002. Porras B, Costner M, Friedman-Kien AE, et al. Update on cutaneous manifestations of HIV infection. Med Clin N Am 1998;82:1033 – 80.
367
[176] Aftergut K, Cockerell CJ. Update on the cutaneous manifestations of HIV infection. Clinical and pathologic features. Dermatol Clin 1999;17:445 – 71. [177] Tindall B, Barker S, Donovan B, et al. Characterization of the acute clinical illness associated with human immunodeficiency virus infection. Arch Intern Med 1988;148:945 – 9. [178] Rabeneck L, Popovic M, Gartner S, et al. Acute HIV infection presenting with painful swallowing and esophageal ulcers. JAMA 1990;263:2318 – 22. [179] Sinicco A, Palestro G, Caramello P, et al. Acute HIV-1 infection: clinical and biological study of 12 patients. J Acquir Immune Defic Syndr 1990;3:260 – 5. [180] Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions to trimethoprim – sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:495 – 9. [181] Coopman SA, Johnson RA, Platt R, et al. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993;328:1670 – 4. [182] McMichael A. T cell responses and viral escape. Cell 1998;93:673 – 6. [183] Berman PW, Gregory TJ, Riddle L, et al. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. Nature 1990;345:622 – 5. [184] Belshe RB, Graham BS, Keefer MC, et al. Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1, NIAID AIDS Vaccine Clinical Trials Network. JAMA 1994;272:475 – 80. [185] Berman PW, Murthy KK, Wrin T, et al. Protection of MN-rgp120-immunized chimpanzees from heterologous infection with a primary isolate of human immunodeficiency virus type 1. J Infect Dis 1996;173: 52 – 9. [186] Lee SA, Orque R, Escarpe PA, et al. Vaccine-induced antibodies to the native, oligomeric envelope glycoproteins of primary HIV-1 isolates. Vaccine 2001;20: 563 – 76. [187] Connor RI, Korber BT, Graham BS, et al. Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines. J Virol 1998;72:1552 – 76. [188] Michalek SM, Eldridge JH, Curtiss R, et al. Antigen delivery systems: new approaches to mucosal immuniztion. In: Ogra PL, Mestecky J, Lamm ME, et al, editors. Handbook of mucosal immunology. New York (NY): Academic Press; 1994. p. 373 – 90. [189] Duncan JD, Gilley RM, Schafer DP, et al. Poly (lactide-co-glycolide) microecapsulation of vaccines for mucosal immuniztion. In: Kiyono H, Ogra PL, McGhee JR, et al, editors. Mucosal vaccines. San Diego (CA): Academic Press; 1996. p. 159 – 73. [190] Michalek SM, O’Hagan DT, Gould-Fogerite S, et al. Antigen delivery systems: nonliving microparticls, liposomes, cochleates, and ISCOMS. In: Ogra PL, Mestecky J, Lamm ME, et al, editors. Mucosal im-
368
[191]
[192]
[193]
[194]
[195]
[196]
[197]
[198]
[199]
[200]
[201]
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369 munology. New York (NY): Academic Press; 1999. p. 759 – 78. Gorse GJ, Keefer MC, Belshe RB, et al. A dose-ranging study of a prototype synthetic HIV-1MN V3 branched peptide vaccine. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. J Infect Dis 1996;173:330 – 9. Lambert JS, Keefer M, Mulligan MJ, et al. A Phase I safety and immunogenicity trial of UBI microparticulate monovalent HIV-1 MN oral peptide immunogen with parenteral boost in HIV-1 seronegative human subjects. Vaccine 2001;19:3033 – 42. Dolin R, Graham BS, Greenberg SB, et al. The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network. Ann Intern Med 1991;114:119 – 27. Belshe RB, Clements ML, Dolin R, et al. Safety and immunogenicity of a fully glycosylated recombinant gp160 human immunodeficiency virus type 1 vaccine in subjects at low risk of infection. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group Network. J Infect Dis 1993;168: 1387 – 95. Schwartz DH, Gorse G, Clements ML, et al. Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine. Lancet 1993;342:69 – 73. Gorse GJ, Schwartz DH, Graham BS, et al. HIV-1 recombinant gp160 vaccine given in accelerated dose schedules. NIAID AIDS Vaccine Clinical Trials Network. Clin Exp Immunol 1994;98:178 – 84. Keefer MC, Graham BS, Belshe RB, et al. Studies of high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses 1994;10:1713 – 23. Graham BS, Keefer MC, McElrath MJ, et al. Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med 1996;125: 270 – 9. Keefer MC, Graham BS, McElrath MJ, et al. Safety and immunogenicity of Env 2 – 3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine Evaluation Group. AIDS Res Hum Retroviruses 1996;12:683 – 93. Gorse GJ, McElrath MJ, Matthews TJ, et al. Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. Vaccine 1998;16:493 – 506. Ourmanov I, Brown CR, Moss B, et al. Comparative efficacy of recombinant modified vaccinia virus Ankara expressing simian immunodeficiency virus (SIV)
[202]
[203]
[204]
[205] [206]
[207]
[208]
[209]
[210] [211] [212]
[213]
[214] [215]
Gag-Pol and/or Env in macaques challenged with pathogenic SIV. J Virol 2000;74:2740 – 51. Seth A, Ourmanov I, Schmitz JE, et al. Immunization with a modified vaccinia virus expressing simian immunodeficiency virus (SIV) Gag-Pol primes for an anamnestic Gag-specific cytotoxic T-lymphocyte response and is associated with reduction of viremia after SIV challenge. J Virol 2000;74:2502 – 9. Davis NL, Caley IJ, Brown KW, et al. Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. J Virol 2000;74:371 – 8. McGettigan JP, Sarma S, Orenstein JM, et al. Expression and immunogenicity of human immunodeficiency virus type 1 Gag expressed by a replicationcompetent rhabdovirus-based vaccine vector. J Virol 2001;75:8724 – 32. Taylor J, Paoletti E. Fowlpox virus as a vector in nonavian species. Vaccine 1988;6:466 – 8. Clements-Mann ML, Weinhold K, Matthews TJ, et al. Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group. J Infect Dis 1998;177: 1230 – 46. Belshe RB, Gorse GJ, Mulligan MJ, et al. Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers, NIAID AIDS Vaccine Evaluation Group. AIDS 1998;12:2407 – 15. The aids evaluation group 022 protocol team. Cellular and humoral immune responses to a canarypox vaccine containing human immunodeficiency virus type 1 Env, Gag, and Pro in combination with rgp120. J Infect Dis 2001;183:563 – 70. Evans TG, Keefer MC, Weinhold KJ, et al. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis 1999;180:290 – 8. Cohen J. AIDS research. Debate begins over new vaccine trials. Science 2001;293:1973. Cohen J. Disappointing data scuttle plans for largescale AIDS vaccine trial. Science 2002;295:1616 – 7. Yoshida T, Okuda K, Xin KQ, et al. Activation of HIV-1-specific immune responses to an HIV-1 vaccine constructed from a replication-defective adenovirus vector using various combinations of immunization protocols. Clin Exp Immunol 2001; 124:445 – 52. Xin KQ, Urabe M, Yang J, et al. A novel recombinant adeno-associated virus vaccine induces a long-term humoral immune response to human immunodeficiency virus. Hum Gene Ther 2001;12:1047 – 61. Barouch DH, Letvin NL. DNA vaccination for HIV-1 and SIV. Intervirology 2000;43:282 – 7. Boyer JD, Cohen AD, Vogt S, et al. Vaccination of
M.H. Brentjens et al. / Dermatol Clin 21 (2003) 349–369
[216]
[217] [218]
[219]
[220]
[221]
[222]
seronegative volunteers with a human immunodeficiency virus type 1 env/rev DNA vaccine induces antigen-specific proliferation and lymphocyte production of beta-chemokines. J Infect Dis 2000;181: 476 – 83. zur Megede J, Chen MC, Doe B, et al. Increased expression and immunogenicity of sequence-modified human immunodeficiency virus type 1 gag gene. J Virol 2000;74:2628 – 35. Boyer JD, Kim J, Ugen K, et al. HIV-1 DNA vaccines and chemokines. Vaccine 1999;17(Suppl 2):S53 – 64. Barouch DH, Santra S, Schmitz JE, et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 2000;290:486 – 92. Schwander S, Opravil M, Luthy R, et al. Phase I/II vaccination study of recombinant peptide F46 corresponding to the HIV-1 transmembrane protein coupled with 2.4 dinitrophenyl (DNP) Ficoll. Infection 1994;22:86 – 91. Eron Jr JJ, Ashby MA, Giordano MF, et al. Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection. Lancet 1996;348:1547 – 51. Pontesilli O, Guerra EC, Ammassari A, et al. Phase II controlled trial of post-exposure immunization with recombinant gp160 versus antiretroviral therapy in asymptomatic HIV-1-infected adults. VaxSyn Protocol Team. AIDS 1998;12:473 – 80. Goebel FD, Mannhalter JW, Belshe RB, et al. Recombinant gp160 as a therapeutic vaccine for HIVinfection: results of a large randomized, controlled
[223]
[224]
[225]
[226]
[227]
[228]
369
trial. European Multinational IMMUNO AIDS Vaccine Study Group. AIDS 1999;13:1461 – 8. Pinto LA, Berzofsky JA, Fowke KR, et al. HIVspecific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients. AIDS 1999;13:2003 – 12. Schooley RT, Spino C, Kuritzkes D, et al. Two doubleblinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214. J Infect Dis 2000;182:1357 – 64. Jin X, Ramanathan Jr M, Barsoum S, et al. Safety and immunogenicity of ALVAC vCP1452 and recombinant gp160 in newly human immunodeficiency virus type 1-infected patients treated with prolonged highly active antiretroviral therapy. J Virol 2002;76: 2206 – 16. MacGregor RR, Boyer JD, Ugen KE, et al. First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. J Infect Dis 1998;178: 92 – 100. Calarota SA, Leandersson AC, Bratt G, et al. Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment. J Immunol 1999;163: 2330 – 8. Limsuwan A, Churdboonchart V, Moss RB, et al. Safety and immunogenicity of REMUNE in HIVinfected Thai subjects. Vaccine 1998;16:142 – 9.
Dermatol Clin 21 (2003) 371 – 387
Current Therapy
Wound healing A multidisciplinary approach for dermatologists Eliot N. Mostow, MD, MPHa,b,* b
a Northeast Ohio University College, School of Medicine, 4209 St. Rt. 44, Rootstown, OH 44272, USA Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4290, USA
Over the last 8 years, an active multidisciplinary wound clinic was developed with specialists in dermatology, vascular surgery, plastic surgery, and orthopedic surgery along with nurses with special interest in wound care. Each of our backgrounds and training has been incorporated into the clinic. In this review are some of the ‘‘pearls’’ I have found useful to treat patients with a general review of wound care literature. Recognizing the limitations of any review, interested readers are encouraged to attend wound care courses [1] and begin a reading program that might include chapters in a major texts from dermatology, surgery, or specifically wound care [2]. The multidisciplinary approach to wound care has been described [3 – 6], but the ‘‘process’’ involved in creating a multidisciplinary program will be addressed further. The bulk of this review focuses on the diagnosis and treatment of chronic wounds with an emphasis on treatment options and protocols to consider when following patients. Acute surgical wounds are also addressed because they are part of the average practitioner’s daily routine.
Wound care: the extent of the problem The most common chronic ulcers in the United States are lower extremity ulcers related to venous insufficiency, with diabetic (neuropathic) ulcers of the
foot and pressure (decubitus) ulcers on any body part constituting the bulk of other chronic ulcers. The morbidity associated with these ulcers includes pain, odor, infection, sepsis (with mortality risk), and amputation (most common in diabetics, with estimates of 10 – 15% of diabetics developing foot ulcers [7] with up to 60,000 amputations performed annually on diabetics and 40% of all amputees being diabetics [8]). The prevalence of pressure ulcers in hospitalized patients varies from 3% to 11%, with the higher rates in intensive care unit patients [9 – 13]. Chronic wounds are more likely and problematic in aging patients. One study showed that 85% of leg ulcer patients were 65 years or older [14]. Still, there are no reliable population-based sources for incidence and prevalence data. A recent survey of 12,000 Swedish inhabitants aged 50 to 89 years included some examinations to validate patient reports of leg ulcers [15]. There was a high false-positive reported rate (43%), but the point prevalence of open leg ulcers was 0.63% of the total population (95% confidence interval 0.54 – 0.72). The year 2000 United States Census data show that there are about 25 million Americans aged 65 and older [16]. If the Swedish estimate of 0.63% point prevalence was applied to the 1999 estimate of 272 million Americans, there would be 1.72 million people with open leg ulcers.
Multidisciplinary wound care: why do it?
* 157 West Cedar Street, Suite 101, Akron, OH 44307. E-mail address:
[email protected]
Better patient care is the best reason to adopt a multidisciplinary approach to wound care. If a central clinic for wound care is created, then the physician –
0733-8635/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0733-8635(02)00100-6
372
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
patient encounter becomes more focused and efficient, more products can stocked in one place, and multispecialty collaboration becomes easier. One pragmatic advantage is the reduction of patients with oozing wounds in the general office patient mix, which often leads to improved quality-of-life for your staff and other patients. It is also possible, if the clinic is located in a hospital setting, that the hospital can bill a facility fee that covers some of the costs of dressings and time associated with these patients.
The largest and most well known is group is Curative (http://www.curative.com), which had 148 centers at the end of 1997. Other companies are also available (see http://www.woundcareresources. com). While I am not specifically in this business, I have had groups come visit the clinic with the intent of streamlining their organizational development process.
Developing a multidisciplinary wound clinic: the four Ps Who should do it? Anyone who already sees a fair number of wounds (or wants to see more) is a good candidate for joining or creating a multidisciplinary wound healing clinic. Except for dermatologists filling their practice with cosmetic patients, most clinicians still like a mix of challenging patients in their patient workload. The development of a multidisciplinary clinic is enhanced if one likes or is willing to work with other physicians, nurses, and hospital administrators.
How to begin Start by identifying goals in targeting patients with chronic wounds: Efficient clinic for chronic wound patient care High level of patient satisfaction Time efficiency for these patients, whose
mobility is often compromised Intellectual satisfaction Interspecialty collaboration Become an ‘‘expert’’ on a topic
For clinicians who want assistance, there are companies that will come to you and create the infrastructure for a wound clinic with the notion that ‘‘if you build it, they will come’’ [17]. The problem with this approach is that it discounts the importance of a committed mix of physicians from important specialty backgrounds. If the supposition is that a protocol-driven approach can work for most wounds (and it certainly can for some), then it really does not matter as much who is following the protocol. My experience with corporate-driven wound care clinics is that they do not necessarily build a ‘‘crew’’ of nurses, committed physicians, ancillary staff, and hospital administration, all of which are important pieces of an effective organization.
The four Ps refer to people, places, products, and protocols. This is the framework I suggest for organizing a multidisciplinary wound clinic. Before attempting to create a multidisciplinary wound clinic, I suggest utilizing a checklist to identify individuals with expertise in specific areas. See Table 1 for suggestions of individuals and items that are important to a multidisciplinary wound clinic.
Measurement Whether the wound is acute or chronic, accurate measurement ensures that progress (or lack thereof) can be monitored and documented. Sutured surgical sites are generally measured postoperatively for coding and documentation purposes. After electrodessication and curettage, the final wound size is often measured as well. Measurement techniques have been reviewed previously [18], and whatever method is chosen, it must be reasonable for the clinician and staff to perform. Some advanced methods of wound measurement are most practical for the research setting (eg, image analysis [19]), although some software programs provide measurements based upon tracings of digital photographs [20, 21]. My group has not chosen any particular software or digital measurement method at this point because of issues related to cost and concern for the longevity of the companies selling these products. I rely on the length, width, and depth measurements and photographs (as described herein). Ulcers should be measured using the longest diameter as the length, with the width recorded as the longest measure possible perpendicular to the diameter. This might appear to be obvious to some, but there are centers in which people are trained to measure wounds relative to the head-to-toe axis of the body. I studied this issue, asking individuals to measure artificial wounds on a prosthetic leg by (1) their usual
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
373
Table 1 Checklist for creating a wound clinic The Four Ps (people, place, products, protocols) People (identify core practitioners to run the clinic and others to assist as needed): Dermatologya Plastic surgeryb Orthopedic surgeryc Vascular surgeryd Podiatrye Nursing staff with WOCN certificationf Infectious diseaseg Endocrinologyh Internist/family medicinei Pedorthist/orthotist j Nurse practitionerk Hospital administration supportl Practice managerm Place Central location convenient to all interested physicians Easy access, preferably ground floor with wide halls and doors to accommodate wheelchairs and gurneys Space for medical records and other office functions with attention to staffing needs Space for billing and collection of copays as needed Power examination tables that can lower for access and raise for exams and procedures Computers and internet access for medline searches and other relevant searches or functions. We have a TelewoundTM program for receiving and relaying digital photographs as needed to assist in remote evaluation of wounds. We use Verisign (Verisign World Headquarters, Mountain View, CA) e-mail security ‘‘certificates’’ to forward photographs to the most appropriate physician (http://www.verisign.com). Protocols See text Products See text a The dermatologist sees all types of ulcers, with a focus on venous insufficiency ulcers and pyoderma gangrenosum, potential malignancies, immunobullous disorders, and wounds that might benefit from Apligraf or Dermagraft, maggot debridement, or general skin care related to psoriasis or other papulosquamous diseases. b We have two plastic surgeons. They provide special expertise in flaps (sometimes muscle flaps) for decubitus ulcers and skin grafts as needed for venous insufficiency ulcers. They handle and triage all wound types. c Especially those with interests and specialty training in foot and ankle surgery. Most amputations, when needed, are performed by our orthopedic surgeons. d Our vascular surgeon evaluates patients with impaired circulation (we order noninvasive arterial Doppler studies when peripheral pulses cannot be palpated or easily heard with a handheld Doppler) for potential surgical intervention. e Podiatrists coordinate wound clinics in many areas. We have our orthopedic surgeons, so we utilize the podiatrist for foot and ankle ulcers that do not require surgical intervention. f WOCN: Wound, Ostomy, and Continence Nursing certification (see http://www.wocn.org) g Infectious disease specialists utilized for difficult infections and to coordinate home or inpatient intravenous therapy as needed. h Many diabetics are not managed closely. We encourage better control to improve wound healing. i Many patients have multiple medical problems. Sometimes they do not have a dedicated primary care physician, and we always try to facilitate that relationship when possible. j These individuals are trained to provide custom shoes and other orthopedic appliances that can be essential to offloading pressure and limiting movement as appropriate. See http://www.cpeds.org. k As our clinic got busier, we trained and utilized a nurse practitioner to provide more continuity of care through the week (each of our core physicians attends the Wound Clinic one-half day per week) for inpatient consults and outpatient visits as needed. We are beginning to build a nursing home outreach program that will also involve our nurse practitioner. l We have been fortunate to have interested and supportive individuals in our local hospital administration to assist in defining space, nursing staff, and appropriate supplies as needed. m If choosing a model similar to ours (with a core group of physicians forming a separate ‘‘wound care’’ corporation) someone will need to be identified to manage credentialing, billing, and staffing issues as needed.
374
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
method, (2) the body axis method, and (3) the longest diameter method. The longest diameter and longest perpendicular proved to be most reproducible methods [22]. I use photographs for visual comparisons and have used both Polaroid (Polaroid Corporation, Waltham, MA) and digital photographs (especially for the telemedicine follow-up program) depending upon the site and resources. The deepest depth is often measured with a wooded applicator stick into the deepest section of the wound. I do not generally calculate surface area, although ulcer area has been shown to be predictive of complete healing [23 – 26]. The most recent article by Phillips et al suggests that with a baseline ulcer area of less than 5 cm2, healing occurred in 72% of patients. For patients with ulcers larger than 5 cm2, healing occurred in 40%.
Acute versus chronic wounds An acute wound is created then progresses through the well-defined phases of an inflammatory response, granulation tissue formation, and remodeling. The strength of the scar is generally 30% of normal in 3 weeks, 60% in 6 weeks, at 90% in 6 months [27]. Chronic wounds result when some part of this normal process is delayed. Many acute wounds heal well no matter what care is given. We all remember the scrapes and cuts we have gotten, ignored, then realized the area healed well after a few days. Still, we take the science we know from wound healing research and apply these principles to general wound care to improve the cosmetic result, achieve a more rapid healing rate, and prevent complications such as infection, contact dermatitis from the topical agent chosen, or a wound in which delayed healing results in a chronic wound.
Acute wound management in clinical practice Every day the dermatologist creates wounds through biopsies, cryosurgery, and specific excisional surgeries with suture closures. Instructions related to the suture-closed surgical site vary depending upon the size or type of closure used (ie, simple, layered, flap, or graft). The end result should be a healed wound that had no infection and no contact dermatitis from the recommended medications. There are many approaches to achieving this goal, but there are few data based upon randomized trials and only a few reviews of topical antibiotics and other agents [28,29]. Many people use topical antibiotics on areas postsurgically, but one randomized, controlled trial com-
pared effects of white petrolatum versus Bacitracin (Fougera and Co., Melville, NY) ointment on the incidence of wound infection, contact dermatitis, and healing characteristics [30]. In that study, 95% of patients who were initially enrolled were evaluable, with 440 patients in the white petrolatum group and 444 in the Bacitracin group. Thirteen patients developed postprocedure infection (1.5%), nine (2.0%) in the white petrolatum group versus four (0.9%) in the Bacitracin group (95% confidence interval for difference, 0.4 – 2.7%; P = 0.37). Eight infections (1.8%) in the white petrolatum group were caused by Staphylococcus aureus versus none in the Bacitracin group ( P = 0.004). No patient in the white petrolatum group developed allergic contact dermatitis versus four patients (0.9%) in the Bacitracin group ( P = 0.12). Additionally, there were no clinically significant differences in healing between the treatment groups on day 1 ( P = 0.98), day 7 ( P = 0.86), or day 28 ( P = 0.28) after the procedure. The authors concluded that white petrolatum is a safe, effective wound care ointment for ambulatory surgery. In comparison with Bacitracin, white petrolatum possesses an equally low infection rate and minimal risk for induction of allergy. The second common wound created by dermatologists is the ‘‘shave’’ or ‘‘tangential’’ removal of skin for biopsy, deep transverse excision, or Mohs’ surgery layer. These techniques result in a wound that should heal by secondary intention and will generally take longer to heal than a sutured wound. The reason for choosing a transverse removal might be a better ultimate scar (some body areas, such as scapular region commonly result in stretched scars when sutured). This sometimes large elliptical scar is often less appealing than the round scar from a transverse removal (in discussing treatment options with the patients, I tell them that the sutured wound looks better quickly and requires less care overall, but the transverse wound will often look better in 6 months) [31]. Wounds on convex surfaces tend to heal with better cosmetic results using secondary intention healing (the convex areas of the nose, eye, ear and temple carry the acronym of the NEET areas) [32]. Postoperative wound care for wounds to heal by secondary intention appears to be partly driven by science, but it is also largely left to the ‘‘art’’ of medicine, passed from teacher to student and varying based upon experience and perhaps perceived cost and benefit. For those who use antibiotic ointments, most dermatologists appear to favor Polysporin (Pfizer, Inc., New York, NY) or Bacitracin ointments. Neomycin-containing ointments are specifically avoided because of the increased potential for allergic
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
contact sensitivity and sensitization of the neomycin compared to Bacitracin zinc or Polysporin (polymyxin B sulfate 10,000 units and Bacitracin zinc 50 units). Two excellent reviews of topical antimicrobials are noted: one a general review [33] and a classic chapter in Fisher’s contact dermatitis text [34]. From these reviews and others [28,35], the following points are noted: 1. Neomycin sensitivity has been found in 30% of patients with stasis ulcers, 15% of patients with chronic otitis externa, and 5% of patients who have various chronic eczematous conditions. 2. Neomycin-sensitive patients might also react with Bacitracin. Although they are chemically dissimilar, this might represent a co-sensitization, because the most popular over-the-counter neomycin ointment, Neosporin (Pfizer, Inc., New York, NY) ointment, contains polymyxin B sulfate, Bacitracin zinc, and neomycin sulfate. 3. Neomycin is found in a number of ointments without the ‘‘Neo’’ in the name, especially those listed generically as ‘‘triple antibiotic’’ ointments. 4. Alternatives for patients who are sensitive to neomycin include mupirocin (Bactroban GlaxoSmithKline, Research Triangle Park, NC) ointment or cream, erythromycin topicals or povidine – iodine ointment (Betadine ointment The Perdue Frederick Co., Stamford, CT). 5. Caution is indicated for products named ‘‘Betadine’’ because products labeled ‘‘Betadine, First Aid Antibiotics Plus Moisturizer’’ and ‘‘Betadine Plus’’ contain polymyxin B sulfate. 6. Bacitracin is also rare contact sensitizer (this appears more commonly in Finland for some reason), although there are a few reports of anaphylactic shock related to this agent (it usually occurs in patients with prior exposures who had noted pruritus and edema previously). 7. If Bacitracin alone is desired, the patient must be instructed to get only that product, because a search for Bacitracin in online pharmacies often turns up only products with polymyxin B or neomycin. In my office, I usually dress a wound to heal by secondary intention with Bacitracin and gauze or an adhesive with nonadherent gauze (eg, Telfa-covered gauze [The Kendall Co., Mansfield, MA], Band Aid [Johnson & Johnson, New Brunswick, NJ], or other similar product). For any wound that might create serous drainage, gauze rather than Telfa is used with the instruction for the patient to wash it off so it does
375
not hurt as much when removing it. I give the patient a small foil packet of Bacitracin zinc ointment (Fougera brand [Fougera and Co., Melville, NY], 1/32 g; cost per unit about 8 cents) and instruct them to remove our dressing the next day, wash with soap and water, redress it with the Bacitracin until that runs, out then use petrolatum (I tell them ‘‘Vaseline [Chesebrough Ponds USA Co., Greenwich, CT]’’ because most Americans know that name over instructions to get ‘‘petrolatum’’). I specifically tell patients that ‘‘our mothers taught us wrong; a moist wound heals better than a dry wound,’’ encouraging them to use the Bacitracin then petrolatum as instructed. Some physicians instruct patients to use hydrogen peroxide, although there is controversy on its use. Hydrogen peroxide works well to remove crust and superficial dried debris from wounds, and it is probably harmless for occasional use on closed wounds, but it is known to have an inhibitory effect on fibroblasts and microcirculation, which might impair healing [33]. Postoperative care for sutured wounds is also a balance of art and science, but the care is generally more forgiving because the wound should be closed at the onset and the goal is rapid progression to normal tensile strength and minimal observable scarring. Suture removal is also important, with times as short as 3 to 5 days for thin skin on the face to 10 to 14 days on the back for a primarily closed wound. In areas of high tension and little concern about the scar (postamputation scars), the sutures or staples are sometimes left in for 3 to 4 weeks. Otherwise, many of the principles of wound care are the same as for secondary intention healing. The main difference, however, is that these closed wounds that just need an optimal environment for wound healing. Thus, while antibiotic ointments or petrolatum and dressing changes are reasonable, these wounds can also be covered with synthetic dressings such as hydrocolloids (eg, Duoderm [ConvaTec Professional Services, Princeton, NJ], Cutinova Hydro [Smith & Nephew, London, UK] and others) or thin-film semipermeable dressings (eg, Tegaderm [3M, St. Paul, MN], OpSite [Smith & Nephew, London, UK], Cutifilm [Beiersdorf AG, Hamburg, Germany]). Some film dressings have moisture vapor transport rates that are not conducive to sutured wounds, but the products mentioned above are all excellent choices. An excellent review of moist wound healing has been published that provides more details regarding the established science and additional specific uses [36]. The use of a hydrocolloid dressing over a plain gut sutured wound has been reported to be an excellent, cost effective choice in closure and dressing [37].
376
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
Chronic wound management products and protocols Chronic wound management depends upon a focused attempt to achieve success (defined as wound closure). If the wound is not improving, then alternative or adjunctive dressings or treatments must be considered and implemented. It is not unusual for a patient to respond simply to the addition of compression therapy, keeping all other variables in treatment the same. Additional modifiable factors include smoking cessation, improvement in diabetic control, effective offloading, and pressure reduction as needed. When there is a team approach, or when the patient with a wound is approached in a more holistic fashion, the multidimensional wound will often start responding. The approach to the patient with a chronic wound (ie, a wound not getting smaller over time) should include the following, with studies and clinical ‘‘pearls’’ added where possible: 1. Define the etiology when possible [18]. 2. Consider first the common causes such as venous insufficiency, arterial insufficiency, diabetic neuropathy (and pressure), and pressure necrosis (decubitus ulcers). 3. On leg ulcers, make sure a pulse is truly palpable distally (dorsalis pedis or posterior tibial). 4. If there is any question regarding blood flow, obtain noninvasive arterial Doppler studies. These studies should include waveform tracings and ankle – brachial indices (ABI). The ABI is a ratio of the ankle arterial pressure to the brachial arterial pressure. A value of 0.9 to 1.1 is normal. Claudication starts to occur as the ABI falls below 0.7. An ABI 0.7 or greater is felt to be compatible with healing, and it is reasonable for applying compression bandages. Diabetics sometimes have falsely elevated ABIs because of calcification of vessels, so the waveforms are helpful to ‘‘visualize’’ diminished flow pressures in the face of a normal ABI. 5. If the common causes of chronic ulcer are not applicable or the underlying wound with that diagnosis is not responding, consider additional diagnoses such as vasculitis, pyoderma gangrenosum, panniculitis, malignances (primary cutaneous, lymphomas, metastases), infections (including bacterial, fungal, mycobacterial, and [less likely] viral causes), factitial, emboli, antiphospholipid antibody syndrome, cryoglobulinemia, sickle cell dis-
ease, and necrobiosis lipoidica diabeticorum. Most of these diagnoses can be made with biopsy, serology, or clinical picture. 6. Address the underlying cause of the chronic wound. 7. Compression: because the most common cause of chronic leg ulcers is venous insufficiency and compression therapy has been demonstrated to be important and effective to improve healing of venous leg ulcers in randomized clinical studies as reviewed by the evidence-based Cochrane Wounds Group [38,39], emphasis must be made to get the patient to comply with recommendations. 8. Compression therapy can be ordered easily, but compliance is a bigger issue. The simple answer is to have at least one (and preferably more) nurses and other staff available to work with patients, counsel them on the importance of compression therapy, and make sure they are physically able to use the given stocking, wrap, or other compression dressing. This is one of many reasons to see patients at (or send them to) a specialized wound care clinic. 9. Tubigrip (ConvaTec Professional Services, Princeton, NJ) cotton stocking ‘‘bandages’’ are one of the most common outer dressings applied in our clinic. They are often doubled over to provide increased pressure. This is an easy cotton ‘‘stocking’’ for the patient to pull over dressings on a leg of almost any size (the Tubigrip stockings come in many sizes). They are washable, and though they lose elasticity over time, they are inexpensive enough that replacement is not a major issue. 10. Unna boots are the classic compression wrap for venous leg ulcers because they are inexpensive and provide a fairly comforting wrap with zinc oxide paste and elastic bandages. These bandages tend to lose their compression over the week they are generally left on, so my center and many others have moved to multilayer compression wraps (Profore [Smith & Nephew, London, UK] and Dynaflex [Dyna-Flex International, Anaheim, CA] are two common brands). These wraps appear to be able to maintain pressures over the course of a week better than Unna boots, which start off elastic then become rigid. Some of these (eg, Surepress [ConvaTec Professional Services, Princeton, NJ], Setopress [ConvaTec Professional Services, Princeton, NJ]) have geometric guides to help the patient or caregiver
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
11.
12.
13.
14.
apply them for uniform pressure while wrapping the leg. One of our favorite single-layer wraps is the Depuy (DePuy International, Leeds, UK) compression wrap, which is essentially an extra-wide ace wrap. No compression is indicated if there is poor peripheral circulation. If a pulse cannot be palpated (perhaps because of edema), then make sure it can be heard with a Doppler, or order other noninvasive vascular studies as noted above to document/assess blood flow. The other relatively common issue is patients with heart failure and peripheral edema; sometimes such patients are unstable enough that compressing the fluid out of their legs appears to put them in worse heart failure. Arterial blood flow issues: consultation with a vascular surgeon can be critical to assess the potential for surgical intervention to increase blood flow if that factor is considered to be relevant to the healing of a given wound or limb preservation. The vascular surgeon can help determine the need for angiographic studies and help make the judgments needed regarding the success rates of various treatment options. Medical interventions might also include pentoxyphylline (Trental, Aventis Pharmaceuticals, Inc., Kansas City, MO) and cilostazol (Pletal, Otsuka America Pharmaceutical, Inc., Rockville, MD) to decrease platelet aggregation. Pentoxifylline and its metabolites decrease blood viscosity, thereby increasing flow through vessels with impaired flow. A review of randomized trials per the Cochrane Library protocols showed that pentoxifylline was more effective than placebo in terms of complete healing or significant improvement (relative risk for healing with pentoxifylline compared with placebo was 1.41, 95% confidence interval 1.19 to 1.66). Pentoxifylline and compression was more effective than placebo and compression (relative risk for healing with pentoxifylline was 1.30, 95% confidence interval 1.10 to 1.54) [40]. Cilostazol is a phosphodiesterase inhibitor that reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, Adenosine diphosphate (ADP), collagen, arachidonic acid, epinephrine, and shear stress. Plasma lipids tend to respond favorably to cilostazol, with a reduction in triglycerides and an elevation in High Density Lipoprotein (HDL) cholesterol. Cilostazol is contraindi-
15.
16.
17.
18.
377
cated in patients with congestive heart failure of any severity. There are no significant studies regarding ulcers and cilostazol. The usual dose is 100 mg twice daily. Neuropathy: approximately 7% or 8% of NIDDM patients have neuropathy at the time of diagnosis; this increases to 50% after 25 years of Non-Insulin Dependent Diabetes Mellitus (NIDDM or Type II Diabetes) [41]. Symptomatic, potentially disabling neuropathy affects nearly 50% of diabetic patients. It is usually symmetrical, but it can be focal, and it often involves the autonomic nervous system as well. The prevalence of symmetrical neuropathy is similar in type 1 and type 2 diabetes, whereas focal neuropathy is more common in older type 2 diabetes patients. Because it is a heterogeneous collection of clinical syndromes, multiple pathogenetic factors are probably involved [42]. Neuropathy should be documented using either a Semmes-Weinstein 10 g monofilament examination (SWME) or vibration by the on – off method [43]. One study looked at the positive predictive value of these tests compared with the gold standard of nerve conduction studies and found that these demonstrated acceptable diagnostic performance characteristics in terms of high sensitivity and specificity, total number of correctly predicted cases, and receiver – operating characteristic curves [44]. Annual screening with either the SWME or vibration by the on – off method ought to be routine in the primary care and diabetes clinics. Pressure relief in neuropathy: the appropriate use of devices and shoe modification for the relief of pressure points is important [45, 46]. The evaluation starts with evaluating the foot and the shoe to assess issues that might relate to the footwear. The ulcer site is obvious, but look for callous formation to indicate pressure points. Develop a relationship with an orthotist or pedorthist (often the same person) that you can trust. They will work with you to choose or design the proper shoes and other devices necessary to relieve pressure. Sometimes the recommendation will simply be for the patient to get crutches or a wheelchair and avoid putting weight on their affected foot. Offloading or pressure relief with compliance to recommendations cannot be overemphasized. The entry of a patient into a multidisciplinary wound clinic and utilization of the multi-
378
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
19.
20.
21.
22.
23.
disciplinary approach has been associated with a 50% reduction in amputations [47]. Pressure ulcer relief: mattresses and pads. This is often a difficult area to understand, although the principle is simple. If there is a skin problem that is presumably related to pressure, make adjustments to improve the situation. More attention to turning in nonambulatory patients, and attention to pressure relief in mattress pads and mattresses are crucial. The specific mattresses to get will vary depending upon vendors in your area, so those details will not be as helpful as working with a trusted vendor and having resources to guide the selection [48, 49]. Wound measurement and documentation is crucial to monitor improvement or worsening of the ulcer. Sometimes wounds enlarge when the environment of the ulcer is changing (ie, healthier granulation tissue is replacing fibrinous change in the base of an ulcer), so photographs or accurate descriptions are also important. Recent data have supported the use of ulcer size, duration, and percentage change in wound area to determine the risk of chronicity. Some of these papers are reviewed in this article. For those who prefer the simplest approach, the admonishment is simply to change treatment plans if things are not getting better over 1 to 2 weeks of a given therapeutic plan. One study by Marolis et al looked at risk factors associated with the failure of a venous leg ulcer (VLU) to heal [26]. That study was a retrospective cohort study of 260 VLU patients who received 24 weeks of compression therapy. Thirty-five percent of patients failed to heal. The risk factor for failure to heal were wound area (OR 1.19 or 19% increased risk for not healing for each cm2 surface area), duration in months (OR 1.09), 50% or more fibrin on wound (OR 3.42), a history of venous ligation or stripping (OR 2.91), and and ABI less than 0.8 (OR 9.25). Surface area calculations might not be necessary for every practice that cares for patients with wounds, but the implication of initial ulcer size carrying risk is important. Another paper by the same group [38] developed a simple scoring model to identify patients who were less likely to heal with compression alone at 24 weeks. The simplest model gave one point for wounds greater than
5 cm2 and one point if the wound was greater than 6 months old. Two datasets were reviewed (development and validation datasets). The data showed ulcers healing in 93% of patients with a score of zero but only 13% in patients with a score of two (development dataset). In the validation dataset, the results were 95% and 13%, respectively. This information can be used to determine which patients deserve more than simple compression to achieve wound closure at 24 weeks of therapy. 24. Yet another paper by the same group looked at the percentage change in wound area of VLUs as a predictor of wounds that were unlikely to heal at 24 weeks. The authors conducted a cohort study based upon an existing dataset (the control arm of a previous study) with 104 patients [50]. The rate of healing (area healed per week) did not predict failure to heal at 24 weeks, but the percentage change in area from baseline to week 4 of treatment provided the best combination of positive and negative predictive values. A wound that increased greater than 3% in the first 4 weeks had a 68% probability of failing to heal at 24 weeks. A wound that increased less than 3% in the first 4 weeks had a 75% probability of healing at 24 weeks.
Wound dressings to consider when the current plan is not working Silver-impregnated dressings are becoming popular, and they offer an excellent way to kill bacteria without antibiotics while still providing a moist environment for wound healing. Some of these products include Acticoat (Smith & Nephew, London, UK) [51], Arglaes (Medline Industries, Mundelein, IL) [52], AcryDerm Silver (Acrymed, Portland, OR) [53] and Silveron (Silveron Consumer Products, Stowe, VT) [54]. Silveron is made by a small company and claims to make their ‘‘thermo-electrically conducting fabric that is ‘plated’ (coated) with a high purity flexible metallic silver, which is released ion by ion.’’ Silver must be in the Ag+ (nonmetallic, ionic form) to work. The silver we normally think of exists in a nonionic form. The action of silver on bacteria provides broad-spectrum coverage, including action against methicillin-resistant S. aureus and vancomycin-resistant enterococci. Silver affects cell wall syn-
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
379
Small intestinal submucosa from pigs has been utilized in a unique wound healing ‘‘dressing’’ called Oasis (Cook Surgical, Bloomington, IN). Oasis is simple to use and appears to act as a ‘‘scaffolding’’ of collagen to stimulate wound healing in chronic (and possibly acute) wounds [58,59]. There have even been suggestions that growth factor molecules might survive the processing and play a role in the healing process [60]. It is an excellent product to consider because it is relatively inexpensive, easy to handle, safe, and appears to have a sound scientific basis for wound healing. It is difficult to compare with other biologic dressings because this unique product became available without the same rigorous randomized trials that were performed with other somewhat similar biological ‘‘dressings’’ (eg, Apligraf [Novartis Pharmaceuticals Corporation, East Hanover, NJ] and Dermagraft [Smith & Nephew, London, UK]).
tional treatment. There should be no exposed bone or tendon. In the pivotal trial for diabetic foot ulcers, the median time to closure was 65 days with Apligraf versus 90 days with conventional therapy ( P = 0.0026). In addition, 92% of the ulcers remained closed at 6 months versus 83% in the control group (not statistically significant). Apligraf use has been well described. It is relatively easy to obtain and learn to use [61 – 65]. Apligraf should be considered a part of any wound treatment protocol, perhaps sooner rather than later, when all economic factors are considered [66]. In this study, which modeled costs based upon data, the model estimated the annual medical cost of managing patients with hard-to-heal venous leg ulcers to be $20,041 for patients treated with Apligraf and $27,493 for patients treated with Unna’s boot. In addition, treatment with Apligraf led to approximately three more months in the healed state per person per year than did treatment with Unna’s boot. Because patients treated with Apligraf experienced improved healing compared with patients who were treated with compression therapy using Unna’s boot, they required fewer months of treatment for unhealed ulcers, which resulted in lower overall treatment costs.
Apligraf
Dermagraft
Apligraf has been available for several years. It is a valuable addition to wound care treatment options, and it has shown improved healing over conventional therapy in venous insufficiency ulcers and diabetic neuropathic ulcers. Apligraf is cultured human skin, epidermis and dermis, delivered ‘‘fresh’’ on a culture media to be placed on a patient’s ulcer. Apligraf is bilayered living skin ‘‘dressing’’ that contains no Langerhans cells, melanocytes, macrophages, lymphocytes, hair, or blood vessels. Cytokines that have been identified include interleukin, platelet-derived growth factor, tumor necrosis factor, vascular – endothelial growth factor, and fibroblast growth factor. The skin, which was cultured from human foreskin, has undergone extensive viral and genetic testing. In the pivotal trial, it was more effective than compression therapy alone in closing VLUs that were present for more than 1 year by 8 weeks (32% versus 10%) and by 24 weeks (47% versus 19%). It is U.S. Food and Drug Administration (FDA) indicated for VLUs that have been present for more than 1 month that have failed response to conventional treatment. More recently, the FDA granted approval for treatment of diabetic foot ulcers that have been present for more than 3 weeks that have failed response to conven-
Dermagraft is a human fibroblast-derived dermal substitute that was developed by Advanced Tissue Sciences (La Jolla, CA). It is similar to Apligraf in that it is a cultured product from human cell lines, but it only has dermal components and cytotines. The differences in the two products in terms of efficacy remain to be seen because there are no trials comparing the two at present. It was approved for sale in the United States in October 2001 for the treatment of diabetic foot ulcers, and it will be sold and marketed by Smith and Nephew in the Unites States [67]. Dermagraft has been available in Canada for more than 2 years, and there are a number of studies describing its successful use [68 – 73]. The pivotal study for Dermagraft showed greater median percent closure at 12 weeks compared with conventional therapy. The treated group was 1.7 times more likely to heal than the control group at any given time during the study ( P = 0.044 with the two-sided Cox proportional hazards model). The study patients were apparently not required to use offloading as often as might be normally recommended (patients reported that they were ambulatory an average of 8 hours per day), suggesting perhaps even greater benefit if offloading is also utilized.
thesis, ribosome activity, membrane transport, and transcription in bacteria. It also has activity against yeast and fungi [55 – 57].
Oasis
380
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
Debridement Surgical debridement Debridement is well established and perhaps important for providing an optimal environment for closure in wounds [74 – 78]. The issue of caution, however, is to make sure there is adequate blood supply before creating more wounds that might not heal and to make sure the diagnosis is not pyoderma gangrenosum or a malignancy that might be adversely affected by the debridement (ie, progression of the ulcer or hastening metastasis in squamous cell carcinoma). Surgical debridement is the time to obtain tissue for histopathologic review or culture. Enzymatic debridement Chemical or enzymatic debridement is commonly used when the patient cannot tolerate or refuses surgical debridement. It has the advantage of working daily while the patient is either at home or in another care facility [76,78 – 81]. Chemical debridement is slower and less aggressive than surgical debridement. Depending upon the thickness of the eschar or fibrinous material to be debrided, crosshatching of the surface might speed the process. I have found the most success with minimal damage to normal skin using collagenase (Santyl, Biospecifics Technologies Corp., Lynbrook, NY) and papain – urea (Accuzyme and Panafil, Healthpoint, Ltd., Fort Worth, TX). I find that Accuzyme is the most effective of the three, but it is sometimes more painful for the patient. Panafil has
Fig. 2. Maggots after ‘‘feeding’’ for 48 hours.
a chlorophyllin copper complex that creates a unique green color to the ointment. It is less painful to the patient, and it is included to promote of granulation tissue, control local inflammation, and reduce wound odors [82]. Fibrinolysin (Elase, Pfizer, Inc., New York, NY) was popular for some time, but it appeared to cause more damage to normal skin and does not appear to be available in the Unites States. These agents are generally applied daily and covered with gauze, and they can be used for a several weeks as needed. Trypsin, an enzymatic debriding agent in a wound care product Granulex (castor oil, balsum of peru, and trypsin) is available (Bertek Pharmaceuticals, Morgantown, WV), but the concentration is not sufficient to be an effective agent when that is the primary goal [83]. Maggot debridement Maggots have had a historical and resurgent role in debridement for wound healing [84 – 86]. Mag-
Fig. 1. Heel ulcer before maggots placed.
Fig. 3. Heel ulcer immediately after maggots removed.
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
gots are fly larvae that can be applied to a wound for debridement of necrotic tissue. It is not clear why the maggots spare the normal tissue, but they are able to do so and effectively work in deep and irregular wounds that are otherwise difficult to address with surgical debridement. In addition to the stimulation of host healing through debridement and resultant cytokine release, the maggots are known to secrete calcium salts and other antimicrobial agents. I have effectively used maggots multiple times on a diabetic patient with a heel ulcer that was failing to respond to conventional therapy. Figures 1 – 3 demonstrate the effectiveness of maggot debridement. All of my initial training came from reading and from the excellent guidance and source of sterile maggots in the Unites States, Dr. Richard Sherman [87 – 95]. Warming therapy Warming therapy has been promoted to be effective by stimulating local blood supply and providing a moist environment to stimulate wound healing [96]. There is a proprietary product called Warm-Up (Arizant, Inc., Eden Prairie, MN) that has been demonstrated to show benefit in small studies. A pressure ulcer study showed 15 wounds closed and average 61% with treatment versus 6 wounds closing an average 19% without treatment [97]. A second study in venous leg ulcers studied 17 patients with 31 wounds with an average wound duration of 4.4 years (failing ‘‘standard’’ care) [98]. There was improvement in 14 of 17 patients during the 2-week inpatient trial, and 8 of 17 patients healed completely after discharge. There was one recurrence during an 18-month follow-up period. Our clinic has tried Warm-Up therapy in one patient to date with promising results. Tender Wet Tender Wet (Elder House, Andheri [W], Mumbai, India) is a polyacrylate gel dressing pad that is designed to maintain a moist wound environment and produce a ‘‘rinsing effect’’ continuously for 24 hours. The concept is that proteins get absorbed into the gel pad and the Ringer’s solution released (added to ‘‘activate’’ the dressing) contributes to the stimulation of cell proliferation during the granulation phase of healing. Dry necrosis and hardened secreted tissue are softened, detached, and absorbed into the gel structure. My experience with the product has been largely positive, with improving wounds and decreased pain.
381
Vacuum assisted closure (VAC) treatments VAC treatments appear to be popular in some regions, and some people who use them demonstrate impressive results. The concept with these machines and dressings is that subatmospheric pressure ( 125 mmHg) is induced to help pull the wound edges together and remove fluids, apparently stimulating granulation tissue [99 – 104]. There is clearly a learning curve with these devices, but there might be wounds—especially deep decubitus ulcers—in which this is an ideal therapy. There is one report of toxic shock syndrome associated with the VAC device, but the overall significance of this is not clear [105]. Other ointments Antibiotic ointments were discussed under the acute wound section of this article. It is worth mentioning a few other agents that I have found helpful. As previously mentioned, plain white petrolatum is often as effective as Bacitracin in postoperative wound care. I commonly recommend Aquaphor (Beiersdorf AG, Hamburg, Germany) or Aquaphor Healing Ointment to patients with superficial wounds. The active ingredients are petrolatum, mineral oil, ceresin, and lanolin alcohol (panthenol, glycerin, and bisabolol are added to the Healing Ointment preparation). Bisabolol (an herbal preparation in Aquaphor), which is derived from chamomile, supposedly has anti-inflammatory properties that could be important in wound healing, but there are no studies supporting or refuting this idea. Lanolin is occasionally associated with allergic contact dermatitis, although the company has suggested that theirs is a modified lanolin and the incidence is somehow decreased. I rarely have problems with the product in terms of dermatitis. The healing ointment is about three times the cost of the ‘‘original’’ ointment per ounce. A&D ointment (Shering-Plough Health Care, Kenilworth, NJ), which is often found in the ‘‘diaper rash’’ section of a store, can be found in a number of preparations. There is some suggestion that the vitamin A and D ointments might be helpful in wound healing [106 – 108]. Although its role in wound healing is not well established, it is a benign topical therapy to prevent drying of a wound, and it is relatively inexpensive. Because it is available in many forms, it is probably worthwhile to direct patients to one that they can get at al local store and one whose ingredients you prefer. Vitamins A and D are available as a cream, Clocream Skin Cream (Lee Pharmaceuticals, South
382
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
El Monte, CA) and multiple ointment forms. The ointments include A&D (with lanolin and petrolatum; Shering-Plough Health Care), Desitin (with zinc oxide 40% in a petrolatum – lanolin base; Pfizer, Inc., New York, NY), A&D Original Ointment (petrolatum 53.4%, lanolin 15.5%, cod liver oil [contains vitamins A and D], fragrance, light mineral oil, microcrystalline wax, and paraffin; Schering-Plough Health Care), A&D Ointment with zinc oxide (dimethicone 1%, zinc oxide 10%, aloe extract, benzyl alcohol, cod liver oil, fragrance, glyceryl oleate, light mineral oil, ozokerite, paraffin, propylene glycol, sorbitol, synthetic beeswax, and water; Schering-Plough Health Care), and Fougera A&D ointment (vitamin A: 1750 U/g; vitamin D: 175 U/g in a lanolin – petroleum ointment base).
Less common wound healing issues Pyoderma gangrenosum is a diagnosis of exclusion [109 – 112]. Sometimes it has the classic presentation of the painful, rapidly expanding ulcer that perhaps started as a purpuric pustule. The edges are violaceous and undermined, and the patient has usually been started on antibiotics without benefit. Other times the presentation is not as clear, and this inflammatory ulcer persists for months, considered to be either infectious or secondary to venous insufficiency. A biopsy can assist in ruling out malignancy and vasculitis and atypical infections as needed, then the patient can be started on prednisone or cyclosporine depending upon risk factors, severity, and previous responses to treatment. Prednisone is the standard of care, but cyclosporine has advantages in diabetic patients. Peristomal pyogenic granuloma is a challenging condition [113 – 116]. Because inflammatory bowel disease is a known association with pyogenic granuloma, some patients will eventually have colostomy or ileostomy placements. An unfortunate group of these patients will develop peristomal ulcerations with classic signs and symptoms of pyoderma gangrenosum. It is imperative to work in conjunction with the patient, caregivers, and ostomy nurse to consider alternative pouch devices (some are better at reducing pressure and sealing the area from leakage). I have tried various routines to help these patients, including prednisone, cyclosporine, intermittent intralesional triamcinolone, and clobetasol 0.05% gel applied after a warm most cloth to the area, then left to dry then the pouch is placed.
Orthopedic perspective Orthopedic surgeons can play an important role for patients with chronic wounds. They are involved in caring for diabetic patients with Charcot foot deformities, and many of these patients develop neuropathic diabetic foot ulcers. Because diabetics with foot ulcers are more likely to require amputation of that leg, the orthopedic surgeon can be involved in preventing or delaying this outcome [117]. When and if the time comes for amputation (ie, pain, infection, or risk of serious infection), the orthopedic surgeon and patient are already familiar with each other. Offloading pressure in a patient with a neuropathic ulcer is important. As mentioned elsewhere, looking at the shoes is the first common-sense place to begin. The other crucial issue is to assess the vascular supply. Do not let yourself be fooled about a distal pulse (dorsalis pedis or posterior tibial). If they are unequivocally present, then you have saved the patient additional tests. If they are not palpable and there is not an impending severe problem (eg, gangrene, necrosis), the next step is to document the arterial flow with noninvasive Doppler studies. As for osteomyelitis issues, it is well known that exposed bone almost always correlates with osteomyelitis. The gold standard for osteomyelitis diagnosis and treatment is a bone biopsy for culture. If that is not appropriate for a given patient because of procedure risk or other factors, empiric treatment can begin based upon the examination, or preferably with supporting evidence such as radiograph, radionuclear bone scans, or a gaddalinium MRI.
Plastic surgery perspective Our plastic surgeons address the concerns of many patients with decubitus ulcers. Some of these patients are quite debilitated; their ulcers can be the cause of their death if infection takes over and leads to sepsis. The plastic surgeon’s skills are essential when it comes to flaps and grafts, which sometimes used on these patients. Extensive surgical debridements are also required occasionally, and these are largely accomplished by the plastic surgeons. Venous leg ulcers can often be effectively treated with skin grafts. Apligraf, Dermagraft, and many other old and new medical treatments exist, but sometimes a split-thickness skin graft is the best choice. Our team approach means that a patient is rarely pushed into just the options that a given
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
physician feels most comfortable using. We all see patients on different days in the same clinic, so we can share the same record with photographs and notes. The patient is never charged an additional consultation, and the care is efficient and coordinated.
383
statistical aberrations in healing rates, the focus can change from cure to palliation and reduced risk of and monitoring for infection.
Nurse practitioner perspective Vascular surgery perspective I have one vascular surgeon on my team who specializes in peripheral vascular surgery. His assistance is invaluable in the triage and treatment of our patients with ulcers that are related to vascular ischemia. When surgical correction of the problem is appropriate, he follows the progression of the wound with the unified wound care medical record then returns the patient to the clinic and inpatient consultation service postoperatively. In addition to surgical skills and vascular evaluation expertise, our vascular surgeon is a resource for assistance with the medical management of these difficult patients.
My group has utilized a nurse practitioner to be the unifying clinical eyes in the clinic and inpatient service. She is present everyday, whereas each member of my group comes to the wound clinic just onehalf day per week. She has become skilled at the diagnosis and treatment of chronic wounds and general skin care. If she ever chose to leave, the group would have to find a replacement because her function has become important to the quality care we offer patients.
Ostomy and wound care nursing perspective Podiatry perspective Podiatrists have coordinated wound clinics in many areas of the country, and they certainly have expertise in the care of the lower leg and foot. My group has added a podiatrist recently to the core group of physicians, and she is making a great contribution to general foot care with expertise in nails, debridement, and shoe and footwear issues.
Dermatology perspective Because this article has been written for a dermatology-focused publication, the justification for dermatologists in wound clinics might not be relevant. Still, for those using this reference to consider their own mix of expertise for a wound ‘‘team,’’ the benefits will follow. The dermatologist assists with the medical care of ulcers of all types with an emphasis on skin care of the surrounding (and other) skin, biopsies to address potential malignancies, vasculitis, and infections. Apligraf and Dermagraft placements are delegated to the dermatologist in our group, mostly because of the perfect timing of Wednesday clinics. Maggot debridement therapy was started with our dermatologist and one of the orthopedic surgeons, but it is now carried on by our nurse practitioner. Sometimes the dermatologist gets the most chronic ulcer cases because they might not be candidates for any surgical procedures. Other than
These are nurses who have obtained specialty training in wounds, ostomy, and continence nursing. Historically, many of these nurses started with training in ostomy care, but their field and literature expanded to focus on wound care. This was important because many physicians took little interest in dressing choices, and nurses led the doctors in many areas. In my clinic, we try to have a collaborative relationship with the nurses. We really try to work as a team to provide care to patients that is affordable, physically reasonable, and effective. The nurses spend a great deal of time on education with our patients, especially with respect to dressing changes and compression. I believe that attention to patients increases compliance and healing rates significantly.
Summary This article has provided a review of common and some less common approaches to wound healing. Chronic wound healing is one of the more challenging areas of medicine, with a nice balance of the science and art of medicine. An evidence-based, patient-centered approach can be used to effectively improve the care of many difficult to heal ulcers in often frustrated patients. The multidisciplinary wound clinic concept can work to improve the outcomes of patients with leg ulcers.
384
E.N. Mostow / Dermatol Clin 21 (2003) 371–387
References [1] http://www.woundcarenet.com/ (Advances in Skin and Wound Care) or http://www.woundheal. org (Wound Healing Society) or http://www.wound caresymposium.com/ (Symposium on Advanced Wound Care). [2] Krasner KD, Kane D, editors. Chronic wound care. A clinical source book for heathcare professionals. 2nd edition. Health Management Pubns; 1997. [3] Steed DL, Edington H, Moosa HH, Webster MW. Organization and development of a university multidisciplinary wound care clinic. Surgery 1993;114: 775 – 8, discussion 778 – 9. [4] Gottrup F, Holstein P, Jorgensen B, Lohmann M, Karlsmar T. A new concept of a multidisciplinary wound healing center and a national expert function of wound healing. Arch Surg 2001;136: 765 – 72. [5] Valdes A, Angderson C, Giner JJ. A multidisciplinary, therapy-based, team approach for efficient and effective wound healing: a retrospective study. Ostomy/Wound Management 1999;45:30 – 6. [6] Ratliff C, Rodeheaver G. The chronic wound care clinic: ‘‘one-stop shopping’’. J Wound Ostomy Continence Nurs 1995;22:77 – 80. [7] Levin M. Diabetic foot ulcers: pathogenesis and management. JET Nurs 1993;20:191 – 8. [8] Miller III OF. Essentials of pressure ulcer treatment. The diabetic experience. J Dermatol Surg Oncol 1993; 19:759 – 63. [9] Allman RM, Laprade CA, Noel LB, Walker JM, Moorer CA, Dear MR, et al. Pressure sores among hospitalized patients. Ann Intern Med 1986;105: 337 – 42. [10] Allman RM, Walker JM, Hart MK, Laprade CA, Noel LB, Smith CR. Air-fluidized beds or conventional therapy for pressure sores. A randomized trial. Ann Intern Med 1987;107:641 – 8. [11] Guralnik JM, Harris TB, White LR, CornoniHuntley JC. Occurrence and predictors of pressure sores in the National Health and Nutrition Examination survey follow-up. J Am Geriatr Soc 1988;36: 807 – 12. [12] Powell JW. Increasing acuity of nursing home patients and the prevalence of pressure ulcers: a ten year comparison. Decubitus 1989;2:56 – 8. [13] Smith DM, Winsemius DK, Besdine RW. Pressure sores in the elderly: can this outcome be improved? J Gen Intern Med 1991;6:81 – 93. [14] Nelzen O, Bergqvist D, Lindhagen A, Hallbook T. Chronic leg ulcers: an underestimated problem in primary health care among elderly patients. J Epidemiol Community Health 1991;45:184 – 7. [15] Nelzen O, Bergqvist D, Lindhagen A. The prevalence of chronic lower-limb ulceration has been underestimated: results of a validated population questionnaire. Br J Surg 1996;83:255 – 8. [16] US Census Bureau. Profile of general demographic
[17] [18] [19]
[20]
[21] [22]
[23]
[24]
[25]
[26]
[27]
[28] [29]
[30]
[31]
[32] [33] [34]
characteristics for the United States: 2000 (Table DP-1). Washington, DC: U.S. Census Bureau; 2000. Robinson PA, director. Field of Dreams. 1989. Mostow E. Diagnosis and classification of chronic wounds. Clin Dermatol 1994;12:3 – 9. Bon FX, et al. Quantitative and kinetic evolution of wound healing through image analysis. IEEE Trans Med Imaging 2000;19:767 – 72. Zebrick G. Wound Imager 2.0. 1950 Old Cuthbert Road, Suite L, Cherry Hill, NJ 08034: Med-Data Systems, Inc. Colletti P. Wound Expert. 336 Fourth Avenue Suite 602, Pittsburgh, PA 15222: Net Health Systems, Inc. Bryant JL, Brooks TL, Schmidt B, Mostow EN. Reliability of wound measuring techniques in an outpatient wound center. Ostomy Wound Manage 2001; 47:44 – 51. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. Journal of the American Academy of Dermatology 2000; 43:627 – 30. Stewart A, Leaper DJ. Treatment of chronic ulcers in the community: a comparison of Scherinsorb and Iodosorb. Phlebology 1987;2:115 – 21. Kikta MJ, Schuler JJ, Meyer JP, Durham JR, EldrupJorgensen J, Schwarcz TH, et al. A prospective randomized trial of Unna’s boots vs hydroactive dressings in the treatment of venous stasis ulcers. J Vasc Surg 1988;7:478 – 83. Margolis DJ, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol 1999;135:920 – 6. Kane D. Wound healing and wound management. In: Krasner D, editor. Chronic wound care. 2nd edition. Wayne (PA): Health Management Publications, Inc; 1997. p. 1 – 4. Thakur N. Topical ointments and wound healing. J Fam Pract 1997;44:26 – 7. O’Meara SM, Cullum NA, Majid M, Sheldon TA. Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 2001;88:4 – 21. Smack DP, Harrington AC, Dunn C, Howard RS, Szkutnik AJ, Krivda SJ, et al. Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs bacitracin ointment. A randomized controlled trial. JAMA 1996;276:972 – 7. Ellner KM, Goldberg LH, Sperber J. Comparison of cosmesis following healing by surgical closure and second intention. J Dermatol Surg Oncol 1987;13: 1016 – 20. Zitelli J. Wound healing by secondary intention. J Am Acad Dermatol 1983;9:407 – 15. Kaye ET. Topical antibacterial agents. Infect Dis Clin N Am 2000;14:321 – 39. Rietschel RL, Fowler JF, Fisher AA. Reactions to topical antimicrobials, Chapter 13. In: Rietschel RL, Fowler JF, Fisher AA, editors. Fisher’s contact dermatitis. 4th edition. Baltimore (MD): Lippincott, Williams & Wilkins; 1995. p. 205 – 24.
E.N. Mostow / Dermatol Clin 21 (2003) 371–387 [35] Geronemus RG, Mertz PM, Eaglstein WH. Wound healing. The effects of topical antimicrobial agents. Arch Dermatol 1979;115:1311 – 4. [36] Eaglstein W. Moist wound healing with occlusive dressings: a clinical focus. Dermatol Surg 2001;27: 175 – 81. [37] Siegel DM, Sun DK, Artman N. Surgical pearl: a novel cost-effective approach to wound closure and dressings. J Am Acad Dermatol 1996;34:673 – 5. [38] Margolis DJ, Berlin JA, Strom BL. Which venous leg ulcers will heal with limb compression bandages? Am J Med 2000;109:15 – 9. [39] Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2000;(3):CD000265. [40] Jull AB, Waters J, Arroll B. Oral pentoxifylline for treatment of venous leg ulcers. J Tissue Viability 2000 Oct;10(4):161. [41] Partanen J, et al. Natural history of peripheral neuropathy in patients with non – insulin-dependent diabetes mellitus. N Engl J Med 1995;333:89 – 94. [42] Sherwin R. Diabetes mellitus—part II. In: Goldman BJ, editor. Cecil textbook of medicine. Philadelphia (PA): WB Saunders; 2000. p. 1282 – 4. [43] Mayfield J, Sugarman J. The use of the Semmes-Weinstein monofilament and other threshold tests for preventing foot ulceration and amputation in persons with diabetes. Journal of Family Practice 2000;49:S17 – 29. [44] Olaleye D, Perkins BA, Bril V. Evaluation of three screening tests and a risk assessment model for diagnosing peripheral neuropathy in the diabetes clinic. Diabetes Res Clin Pract 2001;54:115 – 28. [45] Catanzariti A, Haverstock BD, Grossman JP, et al. Off-loading techniques in the treatment of diabetic plantar neuropathic foot ulceration. Adv Wound Care 1999;12:452 – 8. [46] Inlow S, Kalla T, Rahman J. Downloading plantar foot pressures in the diabetic patient. Ostomy/Wound Management 1999;45:28 – 38, quiz 39 – 40. [47] Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev 2000;16(Suppl 1): S75 – 83. [48] Maklebust J. An update on horizontal patient support surfaces. Ostomy/Wound Management 1999;45: 70S – 7S, quiz 78S – 9S. [49] van Rijswijk L, Braden BJ. Pressure ulcer patient and wound assessment: an AHCPR clinical practice guideline update. Ostomy/Wound Management 1999; 45:56S – 67S,quiz 68S – 9S. [50] Kantor J, Margolis D. A multicentre study of percentage change in venous leg ulcer area as a prognostic index of healing at 24 weeks. Br J Dermatol 2000; 142:960 – 4. [51] Nephew S.A. Smith & Nephew marketing a Westaim Biomadical product. 15 Adam Street, London WC2N 6LA UK: Smith & Nephew, Corporate HQ. [52] Medline Industries. 1 Medline Place, Mundelein, IL 60060: Medline Industries, Inc.
385
[53] AcryMed. 12232 SW Garden Place, Portland, OR 92773: AcryMed. [54] Silveron. 4780 Mountain Road, Stowe, VT 05672: Silveron Consumer Products. [55] Tredget EE, Shankowsky HA, Groeneveld A, Burrell R. A matched-pair, randomized study evaluating the efficacy and safety of Acticoat silver-coated dressing for the treatment of burn wounds. J Burn Care Rehabil 1998;19:531 – 7. [56] Yin HQ, Langford R, Burrell RE. Comparative evaluation of the antimicrobial activity of ACTICOAT antimicrobial barrier dressing. J Burn Care Rehabil 1999;20:195 – 200. [57] Innes ME, Umraw N, Fish JS, Gomez M, Cartotto RC. The use of silver coated dressings on donor site wounds: a prospective, controlled matched pair study. Burns 2001;27:621 – 7. [58] Prevel CD, Eppley BL, Summerlin DJ, Sidner R, Jackson JR, McCarty M, et al. Small intestinal submucosa: utilization as a wound dressing in fullthickness rodent wounds. Ann Plast Surg 1995;35: 381 – 8. [59] Prevel CD, Eppley BL, Summerlin DJ, Sidner R, Jackson JR, McCarty M, et al. Small intestinal submucosa: utilization for repair of rodent abdominal wall defects. Ann Plast Surg 1995;35:374 – 80. [60] Voytik-Harbin SL, Brightman AO, Kraine MR, Waisner B, Badylak SF. Identification of extractable growth factors from small intestinal submucosa. J Cell Biochem 1997;67:478 – 91. [61] Falanga V. Apligraf treatment of venous ulcers and other chronic wounds. J Dermatol 1998;25:812 – 7. [62] Kirsner RS. The use of Apligraf in acute wounds. J Dermatol 1998;25:805 – 11. [63] Trent JF, Kirsner RS. Tissue engineered skin: Apligraf, a bi-layered living skin equivalent. Int J Clin Pract 1998;52:408 – 13. [64] Dolynchuk K, Hull P, Guenther L, Sibbald RG, Brassard A, Cooling M, et al. The role of Apligraf in the treatment of venous leg ulcers. Ostomy/Wound Management 1999;45:34 – 43. [65] Bello YM, Falabella AF, Eaglstein WH. Tissueengineered skin. Current status in wound healing. Am J Clin Dermatol 2001;2:305 – 13. [66] Schonfeld WH, Villa KF, Fastenau JM, Mazonson PD, Falanga V. An economic assessment of Apligraf (Graftskin) for the treatment of hard-to-heal venous leg ulcers. Wound Repair Regen 2000;8:251 – 7. [67] Nicholls H. FDA approves Dermagraft for diabetic foot ulcers. Trends Endocrinol Metab 2001;12:433. [68] Gentzkow GD, Iwasaki SD, Hershon KS, Mengel M, Prendergast JJ, Ricotta JJ, et al. Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996;19:350 – 4. [69] Edmonds ME, Foster AV, McColgan M. ‘‘Dermagraft’’: a new treatment for diabetic foot ulcers. Diabet Med 1997;14:1010 – 1. [70] Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treat-
386
[71]
[72] [73]
[74]
[75] [76] [77]
[78]
[79]
[80]
[81]
[82] [83]
[84]
[85]
[86]
[87]
[88]
[89]
E.N. Mostow / Dermatol Clin 21 (2003) 371–387 ment of diabetic foot ulcers. Artif Organs 1997;21: 1203 – 10. Bowering CK. Dermagraft in the treatment of diabetic foot ulcers. J Cutan Med Surg 1998;3(Suppl 1): S1 – 32. Eaglstein WH. Dermagraft treatment of diabetic ulcers. J Dermatol 1998;25:803 – 4. Grey JE, Lowe G, Bale S, Harding KG. The use of cultured dermis in the treatment of diabetic foot ulcers. J Wound Care 1998;7:324 – 5. Williams C. The management of patients with venous leg ulcers: new guidelines. British Journal of Nursing 1999;8:489 – 95. Vowden K, Vowden P. Wound debridement, part 2: sharp techniques. J Wound Care 1999;8:291 – 4. Vowden KR, Vowden P. Wound debridement, part 1: non-sharp techniques. J Wound Care 1999;8:237 – 40. Cervo F, Cruz A, Posillico J. Pressure ulcers. Analysis of guidelines for treatment and management. Geriatrics 2000;55:55 – 60, quiz 62. Thomas D. Prevention and treatment of pressure ulcers: what works? What doesn’t? Clev Clin J Med 2001;68:704 – 22. Salcido R. Enzymatic debridement: a tried and tested method. Adv Skin Wound Care 2000 May – Jun;13 (3 Pt 1):92. Falabella AF, Carson P, Eaglstein WH, Falanga V. The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity. Journal of the American Academy of Dermatology 1998;39:737 – 40. Sinclair RD, Ryan TJ. Proteolytic enzymes in wound healing: the role of enzymatic debridement. Australas J Dermatol 1994;35:35 – 41. Smith LW. The present status of topical chlorophyll therapy. New York J Med 1955;55:2041. Kennedy KL, Tritch DL. Debridement. In: Krasner KD, editor. Chronic wound care. 2nd edition. Wayne (PA): Health Management Publications; 1997. p. 227 – 34. Mumcuoglu KY, Ingber A, Gilead L, Stessman J, Friedmann R, Schulman H, et al. Maggot therapy for the treatment of intractable wounds. Int J Dermatol 1999;38:623 – 7. Thomas S, Andrews A, Jones M, Church J. Maggots are useful in treating infected or necrotic wounds. Brit Med J (Clinical Research Edition) 1999;318:807 – 8. Wollina U, Karte K, Herold C, Looks A. Biosurgery in wound healing—the renaissance of maggot therapy. Journal of the European Academy of Dermatology and Venereology 2000;14:285 – 9. Sherman RA, Pechter EA. Maggot therapy: a review of the therapeutic applications of fly larvae in human medicine, especially for treating osteomyelitis. Med Vet Entomol 1988;2:225 – 30. Sherman RA, My-Tien Tran JM. A simple, sterile food source for rearing the larvae of Lucilia sericata (Diptera: Calliphoridae). Med Vet Entomol 1995;9:393 – 8. Stoddard SR, Sherman RA, Mason BE, Pelsang DJ,
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
Sherman RM. Maggot debridement therapy. An alternative treatment for nonhealing ulcers. J Am Podiatr Med Assoc 1995;85:218 – 21. Sherman RA, Tran JM, Sullivan R. Maggot therapy for venous stasis ulcers. Arch Dermatol 1996;132: 254 – 6. Sherman RA, Wyle FA. Low-cost, low-maintenance rearing of maggots in hospitals, clinics, and schools. Am J Trop Med Hyg 1996;54:38 – 41. Sherman RA. A new dressing design for use with maggot therapy. Plast Reconstr Surg 1997;100: 451 – 6. Sherman RA, Hall MJ, Thomas S. Medicinal maggots: an ancient remedy for some contemporary afflictions. Annu Rev Entomol 2000;45:55 – 81. Sherman RA, Sherman J, Gilead L, Lipo M, Mumcuoglu KY. Maggot debridement therapy in outpatients. Arch Phys Med Rehabil 2001;82:1226 – 9. Sherman RA. Maggot therapy project home page. http://www.ucihs.uci.edu/com/pathology/sherman/ home_pg.htm. Scott EM, Leaper DJ, Clark M, Kelly PJ. Effects of warming therapy on pressure ulcers—a randomized trial. AORN Journal 2001;73:921 – 38. Kloth LC, Berman JE, Dumit-Minkel S, Sutton CH, Papanek PE, Wurzel J. Effects of a normothermic dressing on pressure ulcer healing. Adv Skin Wound Care 2000;13:69 – 74. Santilli SM, Valusek PA, Robinson C. Use of a noncontact radiant heat bandage for the treatment of chronic venous stasis ulcers. Adv Wound Care 1999; 12:89 – 93. Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann Plast Surg 1997;38:553 – 62. Hartnett JM. Use of vacuum-assisted wound closure in three chronic wounds. J Wound Ostomy Continence Nurs 1998;25:281 – 90. Evans D, Land L. Topical negative pressure for treating chronic wounds: a systematic review. Brit J Plast Surg 2001;54:238 – 42. Hersh RE, Kaza AK, Long SM, Fiser SM, Drake DB, Tribble CG. A technique for the treatment of sternal infections using the vacuum assisted closure device. Heart Surg Forum 2001;4:211 – 5. DeFranzo AJ, Argenta LC, Marks MW, Molnar JA, David LR, Webb LX, et al. The use of vacuumassisted closure therapy for the treatment of lowerextremity wounds with exposed bone. Plast Reconstr Surg 2001;108:1184 – 91. Brown KM, Harper FV, Aston WJ, O’Keefe PA, Cameron CR. Vacuum-assisted closure in the treatment of a 9-year-old child with severe and multiple dog bite injuries of the thorax. Ann Thorac Surg 2001; 72:1409 – 10. Gwan-Nulla DN, Casal RS. Toxic shock syndrome associated with the use of the vacuum-assisted closure device. Ann Plast Surg 2001;47:552 – 4.
E.N. Mostow / Dermatol Clin 21 (2003) 371–387 [106] Prutkin L. Wound healing and vitamin A acid. Acta Derm Venereol 1972;52:489 – 92. [107] Tumberello J. Using vitamin A&D ointment for wounds. Oncol Nurs Forum 1995 Jul;22(6):989. [108] Terkelsen LH, Eskild-Jensen A, Kjeldsen H, Barker JH, Hjortdal VE. Topical application of cod liver oil ointment accelerates wound healing: an experimental study in wounds in the ears of hairless mice. Scand J Plast Reconstr Surg Hand Surg 2000;34:15 – 20. [109] Umezawa Y, Oyake S, Oh-i T, Nagae T, Ishimaru S. A case of pyoderma gangrenosum on the stump of an amputated right leg. J Dermatol 2000;27:529 – 32. [110] Blitz NM, Rudikoff D. Pyoderma gangrenosum. Mt Sinai J Med 2001;68:287 – 97. [111] Wines N, Wines M, Ryman W. Review article— understanding pyoderma gangrenosum: a review. MedGenMed 2001 Jun 27;3(3):6. [112] Mokni M, Phillips TJ. Management of pyoderma
[113]
[114]
[115] [116]
[117]
387
gangrenosum. Hosp Pract (Office Edition) 2001;36: 40 – 4. Lyon CC, Stapleton M, Smith AJ, Griffiths CE, Beck MH. Topical sucralfate in the management of peristomal skin disease: an open study. Clin Exp Dermatol 2000;25:584 – 8. Sheldon DG, Sawchuk LL, Kozarek RA, Thirlby RC. Twenty cases of peristomal pyoderma gangrenosum: diagnostic implications and management. Arch Surg 2000;135:564 – 8, discussion 568 – 9. Warner BW. Peristomal pyoderma gangrenosum. Gastroenterology 2000;119:873 – 4. Hughes AP, Jackson JM, Callen JP. Clinical features and treatment of peristomal pyoderma gangrenosum. JAMA 2000;284:1546 – 8. Frykberg R. Epidemiology of the diabetic foot: ulcerations and amputations. Advances in Wound Care 1999;12:139 – 41.
