Emerging Problems in the Management of Paediatric Acute Otitis Media and Other Bacterial Infections

ICSS ICSS INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Emerging Problems in the Management of Paediatric Acute Otitis Media and Other Bacterial Infections Contributions from Albert M Collier, Hyman W Fisher, Christopher Harrison, Michael R Jacobs, Craig Martin

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ICSS INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Editor-in-Chief: Dr Jack Tinker

Emerging Problems in the Management of Paediatric Acute Otitis Media and Other Bacterial Infections Contributions from Albert M Collier, Hyman W Fisher, Christopher Harrison, Michael R Jacobs, Craig Martin Containing a summary of the proceedings of a meeting held in Baltimore, Maryland, USA, in July 2006, which were published in the International Congress and Symposium Series 265: Acute Otitis Media: Translating Science into Clinical Practice (2007). These edited extracts and additional material reflect the experience and opinions of the panellists and do not necessarily reflect the opinions of the Royal Society of Medicine Press or the recommendations of Lupin Pharmaceuticals, Inc. This activity is jointly sponsored by the University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office and the Royal Society of Medicine Press. It is supported by an unrestricted educational grant from Lupin Pharmaceuticals, Inc.

INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

© 2007 Royal Society of Medicine Press Ltd Published by the Royal Society of Medicine Press Ltd 1 Wimpole Street, London W1G 0AE, UK Tel: +44 (0)20 7290 2921 Fax: +44 (0)20 7290 2929 E-mail: [email protected] Website: www.rsmpress.co.uk Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the UK Copyright Designs and Patents Act, 1988, no part of this publication may be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publishers at the UK address printed on this page. These proceedings are published by the Royal Society of Medicine Press Ltd with financial support from the sponsor. The contributors are responsible for the scientific content and for the views expressed, which are not necessarily those of the sponsor, of the editor of the series or of the volume, of the Royal Society of Medicine or of the Royal Society of Medicine Press Ltd. Distribution has been in accordance with the wishes of the sponsor but a copy is available to any fellow of the Society at a privileged price. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-1-85315-756-1 ISSN 0142-2367 Distribution in Europe and Rest of World: Marston Book Services Ltd PO Box 269 Abingdon Oxon OX14 4YN, UK Tel:+44 (0)1235 465 500 Fax: +44 (0)1235 465 555 Email: [email protected]

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INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Contents iv Contributors 1 Introduction Section 1: Management of Acute Otitis Media 2 Susceptibility and resistance of acute otitis media pathogens MICHAEL R JACOBS

8 The changing microbiology of acute otitis media CHRISTOPHER HARRISON

11 Clinical application to paediatrics ALBERT M COLLIER

Section 2: Management of Other Common Bacterial Infections 15 Therapeutic developments in the management of other common bacterial infections HYMAN W FISHER

20 Conclusion 21 University of Kentucky Medical Center: CME, CPE, CNE accreditation

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INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Contributors Dr Albert M Collier, MD PROFESSOR OF PEDIATRICS AND CHIEF OF PEDIATRIC INFECTIOUS DISEASE, UNIVERSITY OF NORTH CAROLINA MEDICAL SCHOOL, CHAPEL HILL, NORTH CAROLINA, USA

Dr Hyman W Fisher, MD, FACP LECTURER, DEPARTMENT OF COMMUNITY AND PREVENTIVE MEDICINE, MOUNT SINAI SCHOOL OF MEDICINE, NEW YORK UNIVERSITY MEDICAL CENTER, NEW YORK, USA

Dr Christopher Harrison, MD PROFESSOR OF PEDIATRICS AND PEDIATRIC INFECTIOUS DISEASES, UNIVERSITY OF MISSOURI/CHILDREN’S MERCY HOSPITAL AND CLINICS, KANSAS CITY, MISSOURI, USA

Dr Michael R Jacobs, MD, PhD, MRC PROFESSOR OF MICROBIOLOGY, CASE WESTERN UNIVERSITY AND DIRECTOR OF CLINICAL MICROBIOLOGY, UNIVERSITY HOSPITALS OF CLEVELAND, CLEVELAND, OHIO, USA

Dr Craig Martin, PharmD, BCPS CLINICAL PHARMACY SPECIALIST IN INFECTIOUS DISEASES, UNIVERSITY OF KENTUCKY MEDICAL CENTER, LEXINGTON, KENTUCKY, USA

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University of Kentucky Medical Center CME, CNE or CPE Accreditation The University of Kentucky College of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the University of Kentucky College of Medicine and the Royal Society of Medicine Press. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine designates this educational activity for a maximum of one (1.0) AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the presentations is provided solely by presenters who have been selected for presentations because of recognized expertise in their field. The University of Kentucky College of Pharmacy is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity has been assigned ACPE # 022-999-07-074-H04 and will award one (1.0) contact hours (0.1 CEUs) of continuing pharmacy education credit in states that recognize ACPE providers. Statements of credit will indicate hours and CEUs based on successful completion of a posttest (score 70% or higher) and will be issued within ten business days. The college complies with the Criteria for Quality for continuing education programming. Educational Review Systems is an approved provider of continuing education in nursing by ASNA, an accredited provider by the ANCC/Commission on Accreditation. Provider # 5-115-07-029. This program is approved for up to one (1.0) hour. Educational Review Systems is also approved for nursing continuing education by the state of California and the District of Columbia. Disclosure Statement and Information Faculty presenters of continuing education activities sponsored by the University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office are expected to disclose any real or perceived conflict of interest related to the content of their presentations.

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The University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office endorses the standards of the Accreditation Council for Continuing Medical Education and the guidelines of the Association of American Medical Colleges that the speakers at continuing medical education activities disclose relevant relationships with commercial companies whose products or services are discussed in educational presentations.

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Relevant relationships include receiving from a commercial company: research grants, consultant fees, honoraria, and travel or other benefits, or having a self-managed equity interest in a company. Disclosure of a relationship is not intended to suggest or condone any bias in any presentation, but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Relevant relationships exist with the following companies/organizations whose products or services may be discussed: Dr Albert M Collier MD has disclosed the following: Speakers Bureau – Abbott Pharmaceuticals; Aventis Pharmaceuticals; GlaxoSmithKline Pharmaceuticals; Lupin Pharmaceuticals; MedImmune Pharmaceuticals; Merck Pharmaceuticals; Pfizer Pharmaceuticals; Wyeth Pharmaceuticals Dr Hyman W Fisher MD: Has nothing to disclose Dr Christopher Harrison MD has disclosed the following: Research grants – Wyeth Laboratories; Sanofi-Pasteur; Astellas Inc Consultant – Abbott Pharmaceuticals; Sanofi-Aventis Pharmaceuticals; TM-Bioscience; Lupin Pharmaceuticals Speakers Bureau – Sanofi-Pasteur; Merck Inc; Abbott Pharmaceuticals Dr Michael R Jacobs MD has disclosed the following: Research grants – Abbott Pharmaceuticals; ARPIDA Pharmaceuticals; Aventis Pharmaceuticals; Basilea Pharmaceuticals; Bristol-Myers Squibb Pharmaceuticals; Bayer Pharmaceuticals; Daiichi Pharmaceuticals; Dr Reddy’s Laboratory; Eli Lilly & Co; GlaxoSmithKline Pharmaceuticals; Meji Pharmaceuticals; Ortho-McNeil Pharmaceutical; Pfizer, Inc; Rambaxy Laboratories; Roche Pharmaceuticals; TAP Pharmaceuticals; Warner-Lambert Pharmaceuticals; Wockhardt Pharmaceuticals; Wyeth Ayerst/Lederle Pharmaceuticals Consultant – Abbott Pharmaceuticals; Aventis Pharmaceuticals; Bristol-Myers Squibb Pharmaceuticals; Bayer Pharmaceuticals; GenSoft Pharmaceuticals; Lupin Pharmaceuticals; Ortho-McNeil Pharmaceutical; Sanofi-Aventis Pharmaceuticals; TAP Pharmaceuticals; Wockhardt Pharmaceuticals; Wyeth Ayerst/Lederle Pharmaceuticals Speakers Bureau – Bayer Pharmaceuticals; GlaxoSmithKline Pharmaceuticals; Ortho-McNeil Pharmaceutical Dr Craig Martin PharmD, BCPS: Research grants – Ortho-McNeil Pharmaceutical Speakers Bureau – Astellas Inc; Schering-Plough; Cubist Pharmaceuticals; Ortho-McNeil Pharmaceutical; Wyeth Pharmaceuticals

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INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Introduction Needs statement The management of common bacterial infections is a continually changing field. Much discussion surrounds the relevance of new developments in scientific understanding, as well as the most appropriate approach to the management of these troublesome conditions. Acute otitis media (AOM) in particular poses management problems because, if untreated or treated inappropriately in children younger than two years, it can lead to serious complications. Although treatment of AOM with antibiotics is not always essential in the older and non-symptomatic patient, antibiotics do resolve symptoms more often in the first four days, and, in almost half of patients, effective antibiotic therapy more rapidly resolves the problem compared with no antibiotic treatment.

Learning objectives This publication discusses the management of common bacterial infections, focusing on AOM. In July 2006, a number of physicians with differing interests in the field of AOM met to attempt to translate the science into clinical practice. Their objectives were to: ● ● ● ●

review the scientific literature specific to antibacterial resistance and susceptibility in AOM discuss the shift in pathogens that has occurred since the introduction of the pneumococcal 7-valent conjugate vaccine (PCV-7) discuss how to translate scientific data into clinical application discuss the role of other therapeutic alternatives in the current environment and their position in the treatment armamentarium.

This publication contains a summary of some of the presentations that took place during that meeting, which were published as part of the Royal Society of Medicine Press’s International Congress and Symposium Series (ICSS) – ICSS 265: Acute Otitis Media: Translating Science into Clinical Practice (2007), and also a review of treatment approaches in other common bacterial infections.

Target audience This activity is designed for general practitioners, paediatricians, nurses and pharmacists.

Release date: July 1, 2007 Expiration date: July 1, 2008 EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BY ALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Susceptibility and resistance of acute otitis media pathogens MICHAEL R JACOBS

Many physicians assume that an organism will be susceptible to an antibiotic because it has not developed resistance to that antibiotic, but this is a common misconception. In fact, the drug must have adequate pharmacokinetic characteristics to treat baseline or wild-type organisms. Furthermore, some organisms have intrinsic resistance to antibiotics, but this is often overlooked, as acquired resistance has been the focus of most research in this field.

In vitro activity To make decisions on prescribing in clinical practice, the in vitro susceptibility of a bacterium must first be measured in the laboratory. This is achieved by identifying the minimum inhibitory concentration (MIC) of the micro-organism. The MIC50 is the concentration of antibiotic needed to inhibit 50% of the strains in a population and the MIC90 the concentration needed to inhibit 90% of strains. It is important to note that these values do not indicate 50% or 90% inhibition of one strain: even when the MIC90, for example, is low, some strains may still be resistant. A population of bacteria with no acquired mechanism of resistance produces a distribution of MIC values – the baseline MIC range – which usually has one peak, similar to a bellshaped curve. When a mechanism of resistance is developing in a population of bacteria, a bimodal population, which has two peaks, is usually produced; widely separated MIC50 and MIC90 values provide a clue that this may be the case. Unfortunately, the literature usually only provides MIC50 or MIC90 values rather than the full MIC distribution. Susceptibility breakpoints are discriminatory antimicrobial concentrations that can be used to differentiate MICs into susceptible, intermediate and resistant categories.

In vivo activity The most important determinant of clinical outcome in an infectious disease, such as acute otitis media (AOM), is eradication of infection, as bacterial survival is likely to lead to clinical failure. Two factors are important in overcoming bacterial infections: host defences

EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BY ALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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MICHAEL R JACOBS

and antibiotics. Without host defences, antibiotics cannot eradicate bacteria – they kill or inhibit most of the bacteria but never eradicate the entire population. The role of an antibiotic, therefore, is to aid host defences. With respiratory tract infections (RTIs) treated on an outpatient basis, it is difficult to show whether or not antibiotics have a significant impact, as these diseases have high rates of spontaneous resolution. Most clinical outcome studies are comparative and do not include placebo arms. Unfortunately, therefore, they are unable to demonstrate the efficacy of antibiotics. Studies that determine bacterial outcome, however, can show differences between agents.

Pharmacokinetics and pharmacodynamics A drug’s pharmacokinetics (PK) consider its serum concentration profile and penetration to the site of infection, providing an indication of the drug’s fate after administration. A drug’s pharmacodynamics (PD) consider its in vivo efficacy, based on whether it produces concentration- or time-dependent killing and whether it has persistent (post-antibiotic) effects. Integration of PK and PD parameters has allowed us to predict in vivo efficacy based on in vitro susceptibility and the PK/PD interactions discussed above.

Time-dependent and concentration-dependent agents For time-dependent agents, such as β-lactams, in vivo killing does not occur until the serum concentration of unbound drug reaches the MIC. After the concentration reaches the MIC, organisms are killed until the drug concentration falls to below the MIC, and the population then increases until the next dose is given and the concentration again reaches the MIC. For concentration-dependent agents, such as macrolides and quinolones, bacterial killing begins once an inhibitory concentration is reached; this is followed by a post-antibiotic effect by which killing or inhibition continues. Only when the post-antibiotic effect stops can the bacterial population begin to increase again. Studies have shown that the drug concentration needs to be above the MIC for 40% of the dosing interval for penicillins and 50% for cephalosporins.1 The efficacy of drugs against penicillin-susceptible Streptococcus pneumoniae varies considerably, and, as spontaneous resolution occurs in about 15–20% of cases in placebo studies with S. pneumoniae, any drugs that achieve 20% eradication are no more effective than placebo, with the host defences in fact eradicating the bacteria. The situation is similar with Haemophilus influenzae, for which placebo studies show spontaneous resolution in almost 50% of cases.

Susceptibility breakpoints based on PK/PD parameters For time-dependent agents, the breakpoint that will differentiate between clinical susceptibility and resistance is the free serum concentration present for 40–50% of the dosing interval. For concentration-dependent agents, the breakpoint is the unbound serum 24-hour area under the curve (AUC24) divided by 30. Table 1 shows the susceptibility of isolates at PK/PD breakpoints;2 it is important to note that these data were reported before the pneumococcal 7-valent conjugate vaccine (PCV-7) was introduced to the US.

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SUSCEPTIBILITY AND RESISTANCE OF ACUTE OTITIS MEDIA PATHOGENS

Table 1 Susceptibility of isolates at pharmacokinetic/pharmocodynamic breakpoints. Adapted from Sinus and Allergy Health Partnership.2 Drug

Susceptible PK/PD breakpoint (µg/ml)

Percentage of strains susceptible at PK/PD breakpoint

S. pneumoniae Co-amoxiclav Co-amoxiclav Amoxicillin Amoxicillin Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime axetil Cefdinir Azithromycin Clindamycin* Levofloxacin Trimethoprim– sulfamethoxazole**

H. influenzae

M. catarrhalis

2† 4‡ 2† 4‡ 0.5 1 0.5 1 1 0.25 0.12 0.25 2

92 95 92 95 20 66 75 72 73 69 71 91 99

98 100 70 70 4 100 100 23 83 78 2 0 100

100 100 7 7 9 100 85 9 51 78 100 0 99

0.5†

64

78

19

*Based on NCCLS breakpoints †Based on amoxicillin at 45 mg/kg/day ‡ Based on amoxicillin at 90 mg/kg/day **Based on trimethoprim component.

Clinical studies Marchant et al showed very elegantly that a comparison of the bacteriological efficacies of theoretical drug A and theoretical drug B could be used to determine the sample size needed to distinguish between a drug with differing activities by calculating bacteriological efficacy of theoretical drug A versus B (%) against the number of patients required.3 The results showed that studies that use bacteriological diagnoses and outcomes (where a repeat tap is taken after 4–6 days) need to include about 660 patients to show a difference between a drug with 80% bacteriological efficacy and one with 90% bacteriological efficacy, but only about 100 patients to show a difference between a drug with 60% bacteriological efficacy and one with 90% bacteriological efficacy. For a study involving a bacteriological diagnosis but a clinical outcome after 7–10 days (an initial tap but clinical criteria for outcome), about 250 patients are needed to distinguish between a good drug and placebo, while about 800 patients are needed to distinguish between a good drug and a mediocre drug. With the weakest study design, where both diagnosis and outcome are judged on clinical terms only, 540 patients are needed just to distinguish a good drug from placebo. Most studies in AOM use this last study design, but if a study includes fewer than 500 patients, it is not powered to show a difference – irrespective of the efficacy of the drugs compared. The results of a study in which children were given amoxicillin orally at a dose of 15 mg/kg/day three times a day or 25 mg/kg/day twice a day (45–50 mg/kg/day) and serum drug levels were measured can be used to show the application of pharmacokinetics.4 When the PK/PD parameter for amoxicillin is applied (i.e. serum concentration greater than the MIC for ≥40% of the dosing interval) to these amoxicillin dosing regimens (45–50

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MICHAEL R JACOBS

mg/kg/day in divided doses), a serum drug concentration of 1 mg/ml was present for ≥40% of the dosing interval in 99% of subjects. A serum drug concentration of 2 mg/ml for ≥40% of the dosing interval was achieved in 82% of subjects. These results support the use of the susceptible amoxicillin breakpoint established for a dose of 45 mg/kg/day in divided doses at 2 mg/ml, while a breakpoint of 4 µg/ml can be achieved at a dose of 90 mg/kg/day in two divided doses. These data predict that isolates with MICs of up to 2 µg/ml would be eradicated by amoxicillin at 45 mg/kg/day. Indeed, Dagan et al 5 found that eradication of S. pneumoniae was achieved in most patients, with only a few failures seen at amoxicillin MICs of 2 and 4 µg/ml. Only occasional failures were found when the dose was increased to 90 mg/kg/day.6 The calculated breakpoint for azithromycin6 is 0.1 µg/ml; when organisms were resistant with MICs >0.1 µg/ml, the failure rate was about 80% – exactly the same as was found in initial placebo studies. That more failures occurred around the breakpoint with azithromycin-susceptible strains than with amoxicillin shows that azithromycin is not as effective as amoxicillin against susceptible strains. Figures 1 and 2 show bacteriological failure rates from all published studies in AOM with a bacteriological outcome obtained via tympanocentesis on day 2–6 of treatment.5–10 For H. influenzae, placebo resulted in 52% bacteriological failure, and the figures show that many agents have efficacy only as good as or even worse than placebo, with the macrolides clarithromycin, erythromycin and azithromycin, as well as cefprozil, having no activity against this organism. Cefixime and ceftriaxone are highly active against H. influenzae, with very low bacteriological failure rates. For S. pneumoniae,8,9 the failure rate for placebo is about 80%. When the results are divided into subsets of penicillin-susceptible and penicillin-non-susceptible strains, most of the cephalosporins have relatively good efficacy and amoxicillin excellent efficacy against penicillin-susceptible strains, but for penicillin-

52

Placebo Clarithromycin Erythromycin Azithromycin Cefprozil Cefaclor Cefdinir 25QD Cefuroxime Amox-clav45 Amox-clav90 Cefpodoxime Cefixime Ceftriaxone 1 dose Ceftriaxone 3 doses Gatifloxacin

80 75 67 57 37 27 17 20 4 5 7 0 0 0 0

(a)

20

40

Placebo

60

100

52 23

Susceptible

Amoxicillin 45

Resistant

63 0

Trimethoprim– sulfamethoxazole

(b)

80

50 0

20

40

60

80

Figure 1 Bacteriological failure rates in studies of AOM: H. influenzae for antibiotics excluding amoxicillin and trimethoprim–sulfamethoxazole (a); and for amoxicillin and trimethoprim–sulfamethoxazole (b).5-10

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SUSCEPTIBILITY AND RESISTANCE OF ACUTE OTITIS MEDIA PATHOGENS

81

Placebo 27

Cefixime* 17

Cefpodoxime* 8

Cefprozil*

10

Cefaclor Cefdinir 25QD

9

Cefuroxime

9

9

Ceftriaxone 1 dose 0 Ceftriaxone 3 doses 0

53 9 7 20

0

(a)

Penicillin–non-susceptible

20

10

Amox-clav45 0 Amox-clav90 0

Gatifloxacin

Penicillin–susceptible

21

10

Amoxicillin 45

62 43

40

60

80

Placebo

100

81 5

Susceptible

Azithromycin 92

Resistant

0

Trimethoprim– sulfamethoxazole

73 0

20

40

60

80

100

(b)

Figure 2 Bacteriological failure rates in studies of AOM: S. pneumoniae for antibiotics excluding azithromycin and trimethoprim–sulfamethoxazole (a); and for azithromycin and trimethoprim–sulfamethoxazole (b).5-10 *, No penicillin-non-susceptible isolates in these studies.

non-susceptible strains, many of the antibiotics show failure. This is not surprising, as penicillin-non-susceptibility also predicts non-susceptibility to oral cephalosporins. Even one-dose ceftriaxone was not adequate to treat some penicillin-non-susceptible S. pneumoniae.

Summary In vitro susceptibility can be accurately interpreted on the basis of PK/PD parameters. The principles of PK and PD can be used to: ● ● ●

develop effective dosing regimens for antimicrobials develop new formulations and dosage regimens contribute to guideline recommendations

References 1.

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Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 2003: 17: 479–501.

2.

Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2000; 123(Suppl 1): S1–32.

MICHAEL R JACOBS

3.

Marchant CD, Carlin SA, Johnson CE, Shurin PA. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the ‘Pollyanna phenomenon’. J Pediatr 1992; 120: 72–7.

4.

Fonseca W, Hoppu K, Rey LC, Amaral J, Qazi S. Comparing pharmacokinetics of amoxicillin given twice or three times per day to children older than 3 months with pneumonia. Antimicrob Agents Chemother 2003; 47: 997–1001.

5.

Dagan R, Hoberman A, Johnson C et al. Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J 2001; 20: 829–37.

6.

Hoberman A, Dagan R, Leibovitz E et al. Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial acute otitis media in children. Pediatr Infect Dis J 2005; 24: 525–32.

7.

Hoberman A. Extra-strength amoxicillin/ clavulanate (A/C-ES) versus azithromycin (AZI)

for acute otitis media (Ace) in children. Abstract presented at the 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 14–17 September 2003 (Abstract G-459). 8.

Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect 2001; 7: 589–96.

9.

Arguedas A, Dagan R, Leibovitz E et al. A multicenter, open label, double tympanocentesis study of high dose cefdinir in children with acute otitis media at high risk of persistent or recurrent infection. Pediatr Infect Dis J 2006; 25: 211–18.

10.

Leibovitz E, Piglansky l, Raiz S et al. Bacteriological efficacy of gatifloxacin (GATI) in the treatment of recurrent/non-responsive acute otitis media (RNR-AOM). Abstract presented at the 41st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 16–19 December 2001 (Abstract G-1558a).

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The changing microbiology of acute otitis media CHRISTOPHER HARRISON

The three major middle ear pathogens over the years have been Streptococcus pneumoniae (pneumococcus), non-typeable Haemophilus influenzae, and Moraxella catarrhalis. As Moraxella is much less difficult to treat, the focus for choosing antimicrobials to treat acute otitis media (AOM) has been directed by resistance patterns among pneumococcus and nontypeable H. influenzae. In pneumococci, the major mechanism of antibiotic resistance (penicillin resistance caused by alterations in penicillin-binding proteins (PBPs)) also proportionally conveys resistance to the cephalosporins and increases the likelihood that the same strain contains acquired resistance to trimethoprim–sulfamethoxazole and macrolides. β-lactamase production has been the major mechanism of resistance among non-typeable H. influenzae in the USA for the last 30 years. When clinicians choose an antibiotic to treat AOM, they must have a clear understanding of the patterns of antibiotic resistance in their geographical area and the advantages or adverse effects of the candidate antibiotics. Resistance patterns in the literature can vary by the population of patients studied as well as the era in which the studies are performed. It is also important to understand that the rate of spontaneous cure of AOM depends on the pathogen, age of the patient (more commonly older than two years), immune status and function of the Eustachian tube.

Otopathogens in the 2000s – the effect of PCV-7 Pneumococcal 7-valent conjugate vaccine (PCV-7) came into universal use as part of the infant immunization schedule in the US, but not other countries, in 2000. This introduction seems to have had a striking impact on middle ear pathogens from patients failing initial antibiotic therapy. This became clear when a study from rural Kentucky and a study from suburban Rochester revealed remarkably similar results when comparing the dominant pathogens and their resistance patterns from before and after introduction of PCV-7.1,2 In the pre-vaccine era, S. pneumoniae accounted for nearly 50% of isolates (with equal numbers of middle ear isolates with high and intermediate penicillin resistance and penicillin-susceptibility) and H. influenzae for around 40%. The proportion of β-lactamaseproducing H. influenzae was higher in rural Kentucky than in suburban Rochester (about 40% vs 25–30%), although the increase in β-lactamase production seen in Rochester was still sizeable. After the vaccine was introduced, the pneumococcal contribution to AOM EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BY ALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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CHRISTOPHER HARRISON

pathogens decreased by about one-half and the H. influenzae contribution increased by about one-third. Among patients who had failed previous antibiotic therapy, non-typeable H. influenzae now made up 56% of isolates in rural Kentucky and suburban New York, and two-thirds of these produced β-lactamase. A proportional decrease was also seen in penicillin-resistant strains of S. pneumoniae in both centres. The comparability of data from these geographically distinct centres gives credence to a change to non-typeable H. influenzae as the dominant middle ear pathogen and an increase in β-lactamase-producing Haemophilus strains during this part of the post PCV-7 era. Figure 1 shows a series of isolates from patients with AOM and acute bacterial rhinosinusitis (ABRS) obtained in Louisville during 2000–05 (Harrison C, unpublished data). Prior to full implementation of PCV-7 (2000 to 2001), vaccine types predominated, including serotypes 19F, 14, 9V and 6B. Type 4 was observed in small numbers. During 2002–05, when more children had been immunized with PCV-7, serotypes 14 and 9B had disappeared, while serotypes 6B, 19F and 23F had maintained a presence, although at a lower level than before the vaccine was introduced. Serotype substitution was also observed, as non-vaccine serotypes 3, 11 and 33 became more common after introduction of the vaccine. This confirms the observation of a group in Finland that non-vaccine serotypes of S. pneumoniae might emerge to take advantage of Eustachian tube dysfunction in young children, even when they have antibody against the seven vaccine strains.3 The data from Finland did not suggest that serotypes that were crossreactive with the vaccine types would emerge; however, data from the US obtained since the introduction of PCV-7 revealed that 6A and particularly 19A had become major players

30% 25% 20% 15% 10%

2000-2 2001-1 2001-2 2002-1 2002-2 2003-1 2003-2 2004-1 2004-2 2005-1 2005-2

5%

X 23

X 6A X 6C X 18 X 18F X9 X 19 X 19A

V 9V V 14 V 18C V 19F V 23F X6

33 V4 V 6B

7

11 15

3

0%

Isolates of S. pneumoniae Figure 1 Isolates of S. pneumoniae obtained from patients with AOM and acute bacterial rhinosinusitis in Louisville, 2000–05. V designates PCV-7 types and X designates PCV-7 cross-reactive types.

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THE CHANGING MICROBIOLOGY OF ACUTE OTITIS MEDIA

among S. pneumoniae causing AOM and acute bacterial rhinosinusitis in immunized children in the Louisville area. Interestingly, in 2002, serotype 19F alone comprised almost 30% of the total AOM isolates. However, while serotype 19F had decreased by 2005, serotype 19A had increased so that 19A together with 19F comprised the same 30% of total AOM isolates. It thus seems that 19A serotype substituted sufficiently for 19F so that no real change in serogroup 19 isolates occurred. Of more concern is that 19A isolates seem to have higher levels of amoxicillin resistance than the previously commonly seen 19F strains.

Summary In 1970–80, H. influenzae was at least as important as, if not more important than S. pneumoniae in AOM. Neither β-lactamase-producing H. influenzae nor penicillin-resistant S. pneumoniae were seen in clinically important numbers. In the 1980s, a gradual increase in the proportion of cases of AOM caused by S. pneumoniae was seen, and β-lactamaseproducing organisms (mostly non-typeable H. influenzae) became more important in recurrent AOM. Non-typeable β-lactamase-producing H. influenzae became the main target for therapy in patients failing previous antibiotic therapy and those patients who suffered frequent recurrences. In the 1990s, the situation changed because of the increase in penicillin-non-susceptible S. pneumoniae. S. pneumoniae therefore became the major pathogen in patients with treatment failures and frequent AOM recurrences. β-lactamaseproducing H. influenzae was still a concern, but it had dropped to second place as a cause of treatment failures when compared with penicillin-non-susceptible S. pneumoniae. Since year 2000, with the advent of universal use of PCV-7 in infancy, a decrease in the proportion of penicillin-non-susceptible S. pneumoniae was observed, and H. influenzae (particularly β-lactamase-producing H. influenzae) have become more important causes of AOM treatment failure. Despite this, it is essential to remember that S. pneumoniae is still the pathogen involved in about one-third of treatment failures and that about half of those are due to penicillin-non-susceptible S. pneumoniae.

References

10

1.

Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J 2004; 23: 824–8.

2.

Block SL, Hedrick J, Harrison CJ et al. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly

alters the microbiology of acute otitis media. Pediatr Infect Dis J 2004; 23: 829–33. 3.

Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344: 403–9.

INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Clinical application to paediatrics ALBERT M COLLIER

Relationship between immunity in the foetus and young child and respiratory illnesses The pathogenesis of acute otitis media (AOM) and the balance between host and pathogen are important in understanding the aims of treatment with antibiotics. Immunoglobulin G (IgG) is an important molecule for immunity. Figure 1 illustrates the pattern of levels of IgG in a child from conception through to the age of nine years.1 After the fourth month of foetal age, the pregnant mother begins to pass her own IgG molecules through the placenta, so that, by birth, the baby has a level of IgG greater than 100% of the mother’s. Although babies born premature and weighing <1000 g are much more likely to survive now than many years ago, they are still more susceptible to infections because, in part, they have not received the maximum amount of IgG from their mother before birth. After birth and separation from the placenta, levels of IgG decrease very rapidly, with viral antibodies remaining longer than bacterial antibodies. At about 10–11 months, all of the maternal antibodies for bacteria have disappeared. At about 7.5 months of foetal age, the foetal immune system itself begins to manufacture IgG, but the levels increase very slowly, with much maturation of the immune system occurring after birth. Not until the child is aged two years does it have a level commensurate with even 80% of that of its mother. The nadir of IgG concentration is at nine months, which, in longitudinal studies, is the time of the peak incidence of AOM and prior to conjugate (Hib) vaccine of Hib meningitis.2 Indeed, Figure 2, when compared with Figure 1, shows an inverse relation between the incidence of respiratory illnesses by age and levels of IgG antibodies by age in children, with the incidence of respiratory illnesses peaking in the second six months of life, when the mother’s antibodies are diminishing and the child’s own immune system is still maturing, with the IgG levels slowly rising.

Otopathogens Currently, the major pathogens of interest in AOM are Haemophilus influenzae and Streptococcus pneumoniae. S. pneumoniae was discovered in 1880 by Pasteur, who also disproved spontaneous generation and proved the tenet of infectious diseases – that a person must be colonized EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BY ALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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Transplacentally acquired

Endogenous production

100

Percentage of adult values

80

60 Total 40

20

0 2

3 4 5 6 7 8 9 Fetal age (months) Birth

1

2

3 4 5 Age (years)

6 7 8 9

Respiratory illnesses per child–year

Figure 1 Levels of immunoglobulin G (IgG) at different ages. Adapted with permission from Goldman and Goldblum.1

12 Total respiratory illnesses Lower respiratory illnesses

10.4 10 8

8.1

7.7 6.5

6.3 6 4.6 3.8

4 2 0

1.2

1.1

0–1/2

1/2–1

0.4 1–2

0.5 2–3

0.4 3–4

0.3 4–5

0.5 All ages

Age (years) 2

Figure 2 Frequency of respiratory illnesses by age.

with an organism before that organism can cause disease. Most often, the organism is acquired through contact with another person infected or colonized with the organism, which is important in explaining the changing epidemiology of AOM in children. In 1968 in North Carolina, for example, only 1% of children younger than five years were in day care and children had little regular contact with other children, perhaps attending Sunday school once a week during the first years of life; in 2006, however, 78% of children younger than five years were in day care and thus having regular contact with other young children. H. influenzae was discovered by Pfeiffer in 1892, when the organism was isolated from a number of patients during the influenza pandemic. In the 1930s, Dr Margaret Pittman, as a project for her PhD in microbiology at the University of Pennsylvania, Philadelphia, was asked to obtain isolates of H. influenzae from children with meningitis, to produce antisera in rabbits and to identify any different serotypes. She identified six types, which she named a–f, by making antibodies to the polysaccharides in the capsules that surrounded the

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ALBERT M COLLIER

organisms. When the antibodies were added to the isolates and observed under the microscope, each bacterial serotype could be identified by its reaction to the antisera, with the correct antisera causing the capsule to swell up. Dr John Robbins and Dr David Smith, who worked in competing laboratories, both isolated the serotype b polysaccharide, which helps the bacteria to evade phagocytosis and remain in the bloodstream long enough to reach the large joints, pericardial space and meninges. They hypothesized that administration of this polysaccharide to children at two, four and six months of age – before the peak incidence of meningitis – would encourage the children to produce antibodies against H. influenzae type b. Disappointingly, the polysaccharide did not have the desired effect, because children are unable to produce good antibodies to polysaccharide antigens until they reach the age of 18–24 months. The polysaccharide was then linked to a protein, which changed the evoked response from T-cell-independent to T-cell-dependent and resulted in the production of good antibodies against H. influenzae type b as early as two months of age. The resultant vaccine produced a reduction in cases of H. influenzae type b systemic disease from 20 000 cases a year in the US to around 100 cases in 2005. Unfortunately, as the H. influenzae that cause AOM are non-typeable, the vaccine had no effect on surface infections such as AOM. Of the 90 types of S. pneumoniae, seven serotypes were observed to predominate in invasive disease. These seven are the types conjugated to protein carriers in the pneumococcal 7valent conjugate vaccine (PCV-7). In contrast with the H. influenzae type b conjugated vaccine, the same types of S. pneumoniae included in the pneumococcal conjugated vaccine also predominate in AOM, so PCV-7 has had an effect on the incidence of mucosal surface infections such as AOM. Furthermore, a high percentage (reportedly 30–65%) of these PCV-7 strains had penicillin minimum inhibitory concentrations (MIC) >2 µg/ml. PCV-7 not only promotes production of humoral circulating antibodies, but some antibody in the form of IgG seems to reach the mucosa. The surface antibody can prevent attachment and reduce colonization, which, ultimately, prevents disease.

Evolution of the spectrum of otopathogens In the 1970s, S. pneumoniae and H. influenzae were common in children with AOM, but there was no penicillin resistance in S. pneumoniae and minimal β-lactamase-positive H. influenzae.3–5 In the 1980s, a gradual increase was seen in S. pneumoniae and about 25% of non-typeable H. influenzae were β-lactamase-positive, which were the main pathogens seen in patients with treatment failure or recurrence.6 In the 1990s, there was an increase in penicillin-non-susceptible S. pneumoniae, which became the major pathogen in failures and recurrences; β-lactamase-positive H. influenzae remained an issue, but were less important than penicillin-non-susceptible S. pneumoniae.7–9 The 2000s have seen the conjugated vaccine effect, in which there has been a decrease in the numbers of penicillin-nonsusceptible S. pneumoniae, although with more of an effect with the intermediate than resistant S. pneumoniae.10,11 A study by Casey and Pichichero highlights this gradual shift in incidence of pathogens found in cases of persistent AOM and treatment failures (Figure 3). In 1995–97, S. pneumoniae was the dominant organism, with H. influenzae having a lesser role. By 1998–2000, around the time that the pneumococcal vaccine was introduced, the number of cases caused by each pathogen were comparable, but by 2001–03, H. influenzae was the dominant organism and S. pneumoniae the minor contributor.12 Increases have been seen in β-lactamase-positive H. influenzae, which, again, is the major pathogen in treatment failures and recurrences.10,11 It is important to note, however, that penicillin-non-susceptible S. pneumoniae have not been completely eradicated, as recent serotype substitution may be

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Percentage

60

S. pneumoniae p ⫽ 0.017 H. influenzae p ⫽ 0.012

50

40

30 1995–97

1998–2000

2001–03

Figure 3 Shift in incidence of pathogens found in persistent acute otitis media and treatment failures. Reproduced from Casey and Pichichero.12

occurring.13,14 Protection from the vaccine is thus not 100% and it only protects against the types in the vaccine. It is time to consider adding conjugated type 19A polysaccharide to the pneumococcal vaccine.

References 1.

Goldman AS, Goldblum RM. Primary deficiencies in humoral immunity. Pediatr Clin North Am 1977; 24: 277–91.

2.

Collier AM, Henderson FW. Respiratory disease in infants and toddlers. In: Cryer D, Harms T, eds. Infants and Toddlers in Out-of-Home Care. Baltimore: Paul Brookes Publishing, 2000; 163–77.

3.

4.

5.

14

Howie VM, Ploussard JH. Efficacy of fixed combination antibiotics versus separate components in otitis media. Effectiveness of erythromycin estrolate, triple sulfonamide, ampicillin, erythromycin estolate–triple sulfonamide, and placebo in 280 patients with acute otitis media under two and one-half years of age. Clin Pediatr (Phila) 1972; 11: 205–14. Leibovtiz E, Jacobs MR, Dagan R. Haemophilus influenzae: a significant pathogen in acute otitis media. Pediatr Infect Dis J 2004; 23: 1142–52. Schwartz R, Rodriguez W, Khan W, Ross S. The increasing incidence of ampicillin-resistant Haemophilus influenzae. A cause of otitis media. JAMA 1978; 239: 320–3.

6.

Bluestone CD, Stephenson JS, Martin LM. Tenyear review of otitis media pathogens. Pediatr Infect Dis J 1992; 11: S7–11.

7.

Harrison CJ, Chartrand SA, Pichichero ME. Microbiology and clinical aspects of a trial of once daily cefixime vs twice daily cefaclor for treatment of AOM in infants and children. Pediatr Infect Dis J 1993; 12: 62–9.

8.

Gooch WM, III, Blair E, Puopolo A et al. Clinical comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of pediatric patients with AOME. Clin Ther 1995; 17: 838–51.

9.

Pichichero ME, McLinn S, Aronovitz G et al. Cefprozil treatment of persistent and recurrent AOM. Pediatr Infect Dis J 1997; 16: 471–8.

10.

Block SL, Hedrick JA et al. Five-day twice daily cefdinir therapy for AOM: microbiologic and clinical efficacy. Pediatr Infect Dis J 2000; 19: S153–8.

11.

Hoberman A, Dagan R, Leibovitz E et al. Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial AOM in children. Pediatr Infect Dis J 2005; 24: 525–32.

12.

Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J 2004; 23: 824–8.

13.

Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344: 403–9.

14.

Farrell D. Emergence and spread of multiresistant Streptococcus pneumoniae serotype 19A clone in USA: focus on the pediatric population. Abstract presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 27–30 September 2006.

INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

Therapeutic developments in the management of other common bacterial infections HYMAN W FISHER

The management of bacterial infections requires constant re-evaluation of the resistance to antibiotics of the bacteria that typically cause them. Susceptibility and resistance patterns of the pathogens found in acute otitis media (AOM) and the subsequent problems arising in the management of this condition are discussed in other articles in this publication. This article considers how changes have been occurring in the antibiotic therapy of other commonly encountered infections, including uncomplicated urinary tract infections (UTIs), pharyngitis, tonsillitis, acute bronchitis, acute exacerbations of chronic bronchitis, acute bacterial rhinosinusitis, and uncomplicated cervical and urethral gonorrhoea.

Uncomplicated urinary tract infections Uncomplicated UTIs continue to be a common problem, and treatment of these infections has become more difficult because of the rising levels of resistance to commonly used antibiotics.1,2 The 1999 guideline of the Infectious Diseases Society of America recommends a 3-day course of trimethoprim plus sulfamethoxazole (TMP-SMZ) as standard therapy for acute cystitis if the community resistance among uropathogens is <20%.3 The resistance of Escherichia coli to TMP-SMZ has been increasing and is in the range of 20% or higher in some parts of the US and other countries; this has led to the testing of alternative agents, including b-lactams and fluoroquinolones, for the treatment of uncomplicated UTIs.3–5 A 2004 Swedish study of the distribution of and antimicrobial resistance in urinary tract pathogens, primarily E. coli, in children ⱕ2 years of age and adults 18 to 50 years of age, over a period of 12 years found that E. coli was the most common pathogen in both age groups. E. coli resistance to ampicillin and trimethoprim was higher in children than in adults and increased over time in both age groups, while resistance to fluoroquinolones was higher in adults than in children, but also increased over time in both groups. It was concluded that the steadily increasing and now high E. coli resistance levels in children to ampicillin and trimethoprim rendered empirical therapy with these drugs doubtful.6

EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BY ALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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A randomized, prospective, multicentre study in Israel compared once-daily oral cefixime (8 mg/kg) with twice daily oral TMP-SMZ (8/40 mg/kg/day) in the treatment of acute UTIs in children aged 6 months to 13 years. All Gram-negative organisms were susceptible to cefixime and 85% were susceptible to TMP-SMZ. It was concluded that the efficacy and safety of cefixime administered once daily compared favourably with TMP-SMZ administered twice daily for acute uncomplicated UTIs in children.7 In a South African randomized study of acute uncomplicated UTIs in 528 patients who received cefixime 400 mg once daily, cefixime 200 mg twice daily, or TMP-SMZ two tablets twice daily for 10 days, cefixime 200 mg twice daily was found to be an effective and safe alternative to TMP-SMZ.4 In a double-blind, randomized study of uncomplicated cystitis in Israeli women, it was found that a 3-day regimen of 400 mg cefixime administered once daily was as efficient as a 3-day regimen of 200 mg ofloxacin administered twice a day.8

Pharyngitis and tonsillitis Although penicillin has in the past been the primary agent recommended for the treatment of tonsillo-pharyngitis caused by group A b-haemolytic streptococci (GABHS), there has been, since the early 1980s, an increase in GABHS infections not cured by penicillin treatment, and this has led to the testing of alternative antibiotics. A meta-analysis of randomized controlled trials comparing a cephalosporin versus penicillin in the treatment of bacteriologically confirmed GABHS tonsillo-pharyngitis included 35 trials involving 7125 children. The overall summary odds ratios for both bacteriological and clinical cure rates significantly favoured cephalosporins compared with penicillin, with the individual cephalosporins cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil, cefixime, ceftibuten and cefdinir showing superior bacteriological cure rates. This metaanalysis indicates that the likelihood of bacteriological and clinical success in GABHS tonsillo-pharyngitis is significantly greater if an oral cephalosporin is prescribed, compared with oral penicillin.9 Although cephalosporins are in general active against Streptococcus pyogenes and are therefore of value in the treatment of tonsillo-pharyngitis, they have not yet been shown to prevent rheumatic fever.10

Acute bronchitis and acute exacerbations of chronic bronchitis Acute bronchitis and acute exacerbations of chronic bronchitis are frequently caused by Streptococcus pneumoniae and Haemophilus influenzae – organisms that are becoming more resistant to narrow-spectrum b-lactams such as penicillin and amoxicillin. Extendedspectrum cephalosporins are among the antibiotics that retain activity against many resistant strains of these organisms. Comparative trials have shown that the clinical and bacteriological efficacy of cefixime 200–400 mg daily administered as a single dose or in two divided doses is comparable with that of cefaclor, amoxicillin, or amoxicillin/clavulanic acid in acute lower RTIs. Cefixime is considered a suitable alternative to cefaclor or amoxicillin in acute lower RTIs.11

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HYMAN W FISHER

A multicentre trial involving 167 patients in Germany compared a 5-day course of cefixime 400 mg/day with a standard 10-day course of the same daily dose of cefixime in the treatment of acute exacerbations of chronic bronchitis, and found that the 5-day course of therapy was equivalent in efficacy to the standard 10-day course, and may offer cost advantages.12

Acute bacterial rhinosinusitis The most common bacterial species isolated from the maxillary sinuses of patients with acute bacterial rhinosinusitis are S. pneumoniae, H. influenzae, and Moraxella (Branhamella) catarrhalis, the latter being more common in children. Other streptococcal species, anaerobic bacteria, and Staphylococcus aureus cause a small percentage of cases.13 Bacterial resistance is a growing problem in the treatment of rhinosinusitis. Approximately 25% of S. pneumoniae strains are penicillin-resistant and about 30% of H. influenzae and essentially all M. catarrhalis isolates produce b-lactamases. Resistance of H. influenzae to TMP-SMZ is also common.14 Treatment of acute maxillary sinusitis (AMS) with amoxicillin has been reported to render S. pneumoniae and H. influenzae in recurrences resistant not only to amoxicillin but also to other antibiotics.14 A study in the US of the antimicrobial susceptibility of organisms isolated from the nasopharynx of 70 children presenting with AMS or maxillary sinusitis that recurred after amoxicillin therapy (RMS) found that treatment of AMS with amoxicillin increases the development of resistance of S. pneumoniae and H. influenzae isolates found subsequently, relative to treatment with co-amoxiclav, TMP-SMZ, cefprozil, cefuroxime axetil, cefdinir, cefixime or azithromycin. After amoxicillin therapy, resistance to cefprozil was present in 5% of AMS and 15% of RMS, to cefuroxime axetil in 5% and 10%, to cefdinir in 5% and 15%, and to cefixime in 11% and 30%, respectively. The Sinus and Allergy Health Partnership, in the 2004 update of its 2000 treatment guidelines for acute bacterial rhinosinusitis, recommends a respiratory fluoroquinolone or high-dose amoxicillin/clavulanate for initial therapy of adults with moderate acute bacterial rhinosinusitis or with mild disease who have received antibiotics in the previous 4–6 weeks. Alternative recommendations include parenteral ceftriaxone or combination therapy with high-dose amoxicillin or clindamycin plus cefixime, or high-dose amoxicillin or clindamycin plus rifampin.13 Support for the use of combination therapy consisting of ampicillin plus cefixime comes from in vitro studies showing synergy of these two agents against S. pneumoniae, including penicillin-resistant strains.15,16

Uncomplicated cervical or urethral gonorrhoea The Centers for Disease Control and Prevention (CDC) updated its guidelines for the treatment of gonorrhoea in April 2007 due to widespread resistance to the fluoroquinolones (increasing from 0.6% in 2001 to 6.7% in 2006 in the US). In some cities the increases reported were more dramatic (e.g. Philadelphia rose from 1% in 2004 to 27% in 2006). The recommended treatment alternatives for gonorrhoea include oral cefixime and intramuscular ceftriaxone, these being the only two cephalosporin compounds recommended by the CDC.17 Oral cefixime and intramuscular ceftriaxone are also the only recommended

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alternative first-line agents for the treatment of gonorrhoea in the UK. The general use of ciprofloxacin as first-line treatment stopped when resistance to it increased to >9% in 2002.18 The French Agency for Health Product Safety recommends presumptive, simultaneous treatment for both Neisseria gonorrhoeae and Chlamydia trachomatis in cases of uncomplicated urethritis and cervicitis. For presumptive gonorrhoea, the Agency suggests a single dose of cefixime (oral), ceftriaxone (intramuscular or intravenous), spectinomycin (intramuscular) or ciprofloxacin (oral).19

Summary Bacteria that cause common infections in children and adults are becoming increasingly resistant to antibiotics, especially to b-lactam antibiotics. Extended-spectrum cephalosporins provide broad-spectrum coverage of Gram-positive and Gram-negative organisms associated with many of the bacterial infections commonly encountered in clinical practice, including uncomplicated urinary tract infections, AOM, pharyngitis, tonsillitis, acute bronchitis, acute exacerbations of chronic bronchitis, acute sinusitis, and uncomplicated gonorrhoea. These agents are important options in the therapeutic armamentarium for such infections, particularly in this era of increasing antimicrobial resistance and dwindling treatment choices.

References 1.

Czaja CA, Hooton TM. Update on acute uncomplicated urinary tract infection in women. Postgrad Med 2006; 119: 39–45.

2.

Wagenlehner FM, Naber KG. Treatment of bacterial urinary tract infections: presence and future. Eur Urol 2006; 49: 235–44.

3.

4.

5.

6.

18

Warren JW, Abrutyn E, Hebel JR et al. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999; 29: 745–58. Levenstein J, Summerfield PJ, Fourie S et al. Comparison of cefixime and co-trimoxazole in acute uncomplicated urinary tract infection. A double-blind general practice study. S Afr Med J 1986; 70: 455–60. Le TP, Miller LG. Empirical therapy for uncomplicated urinary tract infections in an era of increasing antimicrobial resistance: a decision and cost analysis. Clin Infect Dis 2001; 33: 615–21. Abelson SK, Osterlund A, Kahlmeter G. Antimicrobial resistance in Escherichia coli in urine samples from children and adults: a 12 year analysis. Acta Paediatr 2004; 93: 487–91.

7.

Dagan R, Einhorn M, Lang R et al. Once daily cefixime compared with twice daily trimethoprim/ sulfamethoxazole for treatment of urinary tract infection in infants and children. Pediatr Infect Dis J 1992; 11: 198–203.

8.

Raz R, Rottensterich E, Leshem Y, Tabenkin H. Double-blind study comparing 3-day regimens of cefixime and ofloxacin in treatment of uncomplicated urinary tract infections in women. Antimicrob Agents Chemother 1994; 38: 1176–7.

9.

Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children. Pediatrics 2004; 113: 866–82.

10.

Chambers ST, Murdoch DR, Pearce MJ. Clinical and economic considerations in the use of thirdgeneration oral cephalosporins. Pharmacoeconomics 1995; 7: 416–27.

11.

Brogden RN, Campoli-Richards DM. Cefixime. A review of its antibacterial activity. Pharmacokinetic properties and therapeutic potential. Drugs 1989; 38: 524–50.

12.

Lorenz J. Comparison of 5-day and 10-day cefixime in the treatment of acute exacerbation of chronic bronchitis. Chemotherapy 1998; 44 (Suppl 1): 15–8.

HYMAN W FISHER

13.

Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2000; 123 (Suppl 1): S1–32.

14.

Brook I, Gober AE. Antimicrobial resistance in the nasopharyngeal flora of children with acute maxillary sinusitis and maxillary sinusitis recurring after amoxicillin therapy. J Antimicrob Chemother 2004; 53: 399–402.

15.

Jones RN, Johnson DM. Combinations of orally administered beta-lactams to maximize spectrum and activity against drug-resistant respiratory tract pathogens: I. Synergy studies of amoxicillin and cefixime with Streptococcus pneumoniae. Diagn Microbiol Infect Dis 1998; 31: 373–6.

16.

Matsumoto Y. Combination cefixime/amoxicillin against penicillin-resistant Streptococcus pneumoniae infection. Chemotherapy 1998; 44 (Suppl 1): 6–9.

17.

Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted disease treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep 2007; 56: 332–6.

18.

Ison CA, Mouton JW, Jones K et al. Which cephalosporin for gonorrhoea? Sex Transm Infect 2004; 80: 386–8.

19.

French Agency for Health Product Safety. Antibiotherapy applied to uncomplicated urethritis and cervicitis. Med Mal Infect 2006; 36: 27–35.

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Conclusion The bacterial aetiology of common infections is changing and evolving, and this is particularly evident with the spectrum of pathogens changing in response to, for example, immunization practices such as the introduction of the pneumococcal 7-valent conjugate vaccine (PCV-7). The existing recommendations for the management of AOM have some limitations, and while high-dose amoxicillin certainly should be used initially, as per the AAP/AAFP’s guideline,1 physicians need to cover the emergence of resistant organisms, particularly Streptococcus pneumoniae and Haemophilus influenzae, in patients failing antibiotic therapy. Microbiological data suggest that cefixime has distinct advantages in specific settings, such as the treatment of AOM where first-line therapy may be failing due to b-lactamase-producing H. influenzae. Furthermore, a prescription of combination amoxicillin and cefixime oral suspension would bring economic implications in terms of reducing the number of follow-up visits. Clinical studies and evaluation will add credence to this approach.

Reference 1.

American Academy of Pediatrics/American Academy of Family Physicians Subcommittee on Management of Acute otitis Media. Clinical Practice Guideline. Diagnosis and Management

of Acute Otitis Media. Leawood, KS. American Academy of Pediatrics/American Academy of Family Physicians, 2004. Available at: www.aafp.org.

EMERGING PROBLEMS IN THE MANAGEMENT OF PAEDIATRIC ACUTE OTITIS MEDIA AND OTHER BACTERIAL INFECTIONS. EDITED BYALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007 INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES NO 270 PUBLISHED BY THE ROYAL SOCIETY OF MEDICINE PRESS LIMITED

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University of Kentucky Medical Center Emerging Problems in the Management of Paediatric Acute Otitis Media and Other Bacterial Infections (XEN07247) 1. It is common knowledge that pathogens that have not developed resistance to an antibiotic will be susceptible to that antibiotic. True 䡺

False 䡺

2. Studies have shown that to be effective the drug concentration for cephalosporins needs to be above the MIC for what percentage of the dosing interval? a. 15–20% c. 40% b. 25% d. 50% 3. Marchant et al showed that to differentiate between a drug with 60% bacteriological efficacy and one with 90% a clinical study using both bacteriological diagnoses and outcomes would require how many patients? a. 100 c. 540 b. 250 d. 660 4. Non-typeable b-lactamase producing H.influenzae remains as the major pathogen in patients with treatment failures and frequent AOM recurrences. True 䡺

False 䡺

5. The polysaccharide-protein linked vaccine that has resulted in a marked reduction in cases of H. influenzae type b systemic disease is proving to be equally effective in the treatment of AOM. True 䡺

False 䡺

6. The rate of spontaneous cure of AOM depends upon which of the following: a. the pathogen c. the patient’s immune status b. the age of the patient d. all of the above 7. Comparative trials have shown that cefixime is a suitable alternative to which of the following in the treatment of acute, uncomplicated urinary tract infections? a. trimethoprim plus sulfamethoxazole c. both of the above b. amoxicillin 8. According to the results of a meta-analysis of trials comparing a cephalosporin against penicillin in cases of bacteriologically confirmed tonsillo-pharyngitis due to group A betahaemolytic streptococci in children, the likelihood of bacteriological and clinical success is significantly greater with a penicillin than with a cephalosporin. True 䡺

False 䡺

9. According to a multicenter trial conducted in Germany, the standard 10-day course of cefixime 400 mg/day may be shortened to how many days of the same dose of cefixime and still have the same efficacy in the treatment of acute exacerbations of chronic bronchitis? a. 3 days c. 7 days b. 5 days

22

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10. Which of the following pathogens commonly implicated in bacterial rhinosinusitis is/are presenting a problem due to an increasing number of strains producing b-lactamases? a. S. pneumoniae c. M. catarrhalis b. H. influenzae d. All of the above