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

ICSSEmerging 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

ICSS INTERNATIONAL CONGRESS AND SYMPOSIUM SERIES 270

ICSSEditor-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

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iii

Contents

ivContributors

1Introduction

Section 1: Management of Acute Otitis Media

2Susceptibility and resistance of acute otitis media pathogens

MICHAEL R JACOBS

8The changing microbiology of acute otitis media

CHRISTOPHER HARRISON

11Clinical application to paediatrics

ALBERT M COLLIER

Section 2: Management of Other Common Bacterial Infections

15Therapeutic developments in the management of other common

bacterial infectionsHYMAN W FISHER

20Conclusion

21University of Kentucky Medical Center:

CME, CPE, CNE accreditation


Contributors

Dr Albert M Collier, MDPROFESSOR OF PEDIATRICS AND CHIEF OF PEDIATRIC INFECTIOUS DISEASE,

UNIVERSITY OF NORTH CAROLINA MEDICAL SCHOOL, CHAPEL HILL, NORTH CAROLINA, USA

Dr Hyman W Fisher, MD, FACPLECTURER, DEPARTMENT OF COMMUNITY AND PREVENTIVE MEDICINE,

MOUNT SINAI SCHOOL OF MEDICINE, NEW YORK UNIVERSITY MEDICAL CENTER, NEW YORK, USA

Dr Christopher Harrison, MDPROFESSOR 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, MRCPROFESSOR OF MICROBIOLOGY, CASE WESTERN UNIVERSITY AND DIRECTOR OF CLINICAL

MICROBIOLOGY, UNIVERSITY HOSPITALS OF CLEVELAND, CLEVELAND, OHIO, USA

Dr Craig Martin, PharmD, BCPSCLINICAL PHARMACY SPECIALIST IN INFECTIOUS DISEASES,

UNIVERSITY OF KENTUCKY MEDICAL CENTER, LEXINGTON, KENTUCKY, USA


iv

University of Kentucky Medical CenterCME, CNE or CPE Accreditation

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Faculty presenters of continuing education activities sponsored by the University of Kentucky

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The University of Kentucky Colleges of Pharmacy and Medicine Continuing Education Office

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v

✂✂

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 com-

pany. Disclosure of a relationship is not intended to suggest or condone any bias in any presen-

tation, 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 ser-

vices 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

vi

✂✂


Introduction

Needs statement

The management of common bacterial infections is a continually changing field. Muchdiscussion surrounds the relevance of new developments in scientific understanding, as wellas the most appropriate approach to the management of these troublesome conditions.Acute otitis media (AOM) in particular poses management problems because, if untreated ortreated inappropriately in children younger than two years, it can lead to seriouscomplications. Although treatment of AOM with antibiotics is not always essential in theolder and non-symptomatic patient, antibiotics do resolve symptoms more often in the firstfour days, and, in almost half of patients, effective antibiotic therapy more rapidly resolvesthe problem compared with no antibiotic treatment.

Learning objectives

This publication discusses the management of common bacterial infections, focusing onAOM. In July 2006, a number of physicians with differing interests in the field of AOM metto 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 duringthat meeting, which were published as part of the Royal Society of Medicine Press’sInternational Congress and Symposium Series (ICSS) – ICSS 265: Acute Otitis Media:Translating Science into Clinical Practice (2007), and also a review of treatment approaches inother common bacterial infections.

Target audience

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

Release date: July 1, 2007Expiration date: July 1, 2008

1

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

Susceptibility and resistance of acute otitis

media pathogensMICHAEL R JACOBS

Many physicians assume that an organism will be susceptible to an antibiotic because it hasnot 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-typeorganisms. Furthermore, some organisms have intrinsic resistance to antibiotics, but this isoften 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 abacterium must first be measured in the laboratory. This is achieved by identifying theminimum inhibitory concentration (MIC) of the micro-organism. The MIC50 is theconcentration of antibiotic needed to inhibit 50% of the strains in a population and theMIC90 the concentration needed to inhibit 90% of strains. It is important to note that thesevalues do not indicate 50% or 90% inhibition of one strain: even when the MIC90, forexample, is low, some strains may still be resistant.

A population of bacteria with no acquired mechanism of resistance produces a distributionof MIC values – the baseline MIC range – which usually has one peak, similar to a bell-shaped curve. When a mechanism of resistance is developing in a population of bacteria, abimodal population, which has two peaks, is usually produced; widely separated MIC50 andMIC90 values provide a clue that this may be the case. Unfortunately, the literature usuallyonly provides MIC50 or MIC90 values rather than the full MIC distribution.

Susceptibility breakpoints are discriminatory antimicrobial concentrations that can be usedto differentiate MICs into susceptible, intermediate and resistant categories.

In vivo activity

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

2





3

MICHAEL R JACOBS

and antibiotics. Without host defences, antibiotics cannot eradicate bacteria – they kill orinhibit most of the bacteria but never eradicate the entire population. The role of anantibiotic, therefore, is to aid host defences.

With respiratory tract infections (RTIs) treated on an outpatient basis, it is difficult to showwhether or not antibiotics have a significant impact, as these diseases have high rates ofspontaneous resolution. Most clinical outcome studies are comparative and do not includeplacebo arms. Unfortunately, therefore, they are unable to demonstrate the efficacy ofantibiotics. Studies that determine bacterial outcome, however, can show differencesbetween agents.

Pharmacokinetics and pharmacodynamics

A drug’s pharmacokinetics (PK) consider its serum concentration profile and penetration tothe site of infection, providing an indication of the drug’s fate after administration. A drug’spharmacodynamics (PD) consider its in vivo efficacy, based on whether it producesconcentration- 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 basedon 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 serumconcentration 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 populationthen increases until the next dose is given and the concentration again reaches the MIC.

For concentration-dependent agents, such as macrolides and quinolones, bacterial killingbegins once an inhibitory concentration is reached; this is followed by a post-antibioticeffect by which killing or inhibition continues. Only when the post-antibiotic effect stopscan the bacterial population begin to increase again.

Studies have shown that the drug concentration needs to be above the MIC for 40% of thedosing interval for penicillins and 50% for cephalosporins.1 The efficacy of drugs againstpenicillin-susceptible Streptococcus pneumoniae varies considerably, and, as spontaneousresolution occurs in about 15–20% of cases in placebo studies with S. pneumoniae, any drugsthat achieve 20% eradication are no more effective than placebo, with the host defences infact eradicating the bacteria. The situation is similar with Haemophilus influenzae, for whichplacebo 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 clinicalsusceptibility and resistance is the free serum concentration present for 40–50% of thedosing interval. For concentration-dependent agents, the breakpoint is the unbound serum24-hour area under the curve (AUC24) divided by 30. Table 1 shows the susceptibility ofisolates at PK/PD breakpoints;2 it is important to note that these data were reported beforethe pneumococcal 7-valent conjugate vaccine (PCV-7) was introduced to the US.

SUSCEPTIBILITY AND RESISTANCE OF ACUTE OTITIS MEDIA PATHOGENS

Clinical studies

Marchant et al showed very elegantly that a comparison of the bacteriological efficacies oftheoretical drug A and theoretical drug B could be used to determine the sample size neededto distinguish between a drug with differing activities by calculating bacteriological efficacyof theoretical drug A versus B (%) against the number of patients required.3 The resultsshowed that studies that use bacteriological diagnoses and outcomes (where a repeat tap istaken after 4–6 days) need to include about 660 patients to show a difference between a drugwith 80% bacteriological efficacy and one with 90% bacteriological efficacy, but only about100 patients to show a difference between a drug with 60% bacteriological efficacy and onewith 90% bacteriological efficacy. For a study involving a bacteriological diagnosis but aclinical outcome after 7–10 days (an initial tap but clinical criteria for outcome), about 250patients are needed to distinguish between a good drug and placebo, while about 800patients are needed to distinguish between a good drug and a mediocre drug. With theweakest 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 AOMuse this last study design, but if a study includes fewer than 500 patients, it is not powered toshow 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 15mg/kg/day three times a day or 25 mg/kg/day twice a day (45–50 mg/kg/day) and serumdrug levels were measured can be used to show the application of pharmacokinetics.4 Whenthe PK/PD parameter for amoxicillin is applied (i.e. serum concentration greater than theMIC for ≥40% of the dosing interval) to these amoxicillin dosing regimens (45–50

4

Table 1 Susceptibility of isolates at pharmacokinetic/pharmocodynamic breakpoints. Adapted from Sinus and

Allergy Health Partnership.2

Drug Susceptible PK/PD Percentage of strains susceptible at PK/PD breakpoint

breakpoint (µg/ml)

S. pneumoniae H. influenzae M. catarrhalis

Co-amoxiclav 2† 92 98 100

Co-amoxiclav 4‡ 95 100 100

Amoxicillin 2† 92 70 7

Amoxicillin 4‡ 95 70 7

Cefaclor 0.5 20 4 9

Cefixime 1 66 100 100

Cefpodoxime 0.5 75 100 85

Cefprozil 1 72 23 9

Cefuroxime axetil 1 73 83 51

Cefdinir 0.25 69 78 78

Azithromycin 0.12 71 2 100

Clindamycin* 0.25 91 0 0

Levofloxacin 2 99 100 99

Trimethoprim–

sulfamethoxazole** 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.

5

MICHAEL R JACOBS

52

80

75

67

57

37

27

17

20

4

5

7

0

0

0

0 20 40 60 80 100

Placebo

Clarithromycin

Erythromycin

Azithromycin

Cefprozil

Cefaclor

Cefdinir 25QD

Cefuroxime

Amox-clav45

Amox-clav90

Cefpodoxime

Cefixime

Ceftriaxone 1 dose

Ceftriaxone 3 doses

Gatifloxacin

(a)

(b)

52

63

50

806040200

Placebo

Amoxicillin 45

Trimethoprim–

sulfamethoxazole

23

0

Susceptible

Resistant

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

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 thesusceptible amoxicillin breakpoint established for a dose of 45 mg/kg/day in divided doses at2 mg/ml, while a breakpoint of 4 µg/ml can be achieved at a dose of 90 mg/kg/day in twodivided doses. These data predict that isolates with MICs of up to 2 µg/ml would beeradicated 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 MICsof 2 and 4 µg/ml. Only occasional failures were found when the dose was increased to 90mg/kg/day.6 The calculated breakpoint for azithromycin6 is 0.1 µg/ml; when organismswere resistant with MICs >0.1 µg/ml, the failure rate was about 80% – exactly the same aswas found in initial placebo studies. That more failures occurred around the breakpoint withazithromycin-susceptible strains than with amoxicillin shows that azithromycin is not aseffective as amoxicillin against susceptible strains.

Figures 1 and 2 show bacteriological failure rates from all published studies in AOM with abacteriological 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 manyagents have efficacy only as good as or even worse than placebo, with the macrolidesclarithromycin, erythromycin and azithromycin, as well as cefprozil, having no activityagainst this organism. Cefixime and ceftriaxone are highly active against H. influenzae, withvery low bacteriological failure rates. For S. pneumoniae,8,9 the failure rate for placebo isabout 80%. When the results are divided into subsets of penicillin-susceptible andpenicillin-non-susceptible strains, most of the cephalosporins have relatively good efficacyand amoxicillin excellent efficacy against penicillin-susceptible strains, but for penicillin-

SUSCEPTIBILITY AND RESISTANCE OF ACUTE OTITIS MEDIA PATHOGENS

non-susceptible strains, many of the antibiotics show failure. This is not surprising, aspenicillin-non-susceptibility also predicts non-susceptibility to oral cephalosporins. Evenone-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. Theprinciples 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

6

Placebo

Cefprozil*

Cefaclor

Cefdinir 25QD

Cefuroxime

Amox-clav45

Amoxicillin 45

Amox-clav90

Cefpodoxime*

Cefixime*

Ceftriaxone 1 dose

Ceftriaxone 3 doses

Gatifloxacin

(a)

(b)

81

92

73

100806040200

81

27

17

8

10

962

43

219

1020

1000

0

0

9

9

7

0 20 40 60 80 100

Placebo

Azithromycin

Trimethoprim–

sulfamethoxazole

5

0

53

Susceptible

Resistant

Penicillin–susceptible

Penicillin–non-susceptible

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.

1. 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).

7

8

The changing microbiology of acute

otitis mediaCHRISTOPHER HARRISON

The three major middle ear pathogens over the years have been Streptococcus pneumoniae(pneumococcus), non-typeable Haemophilus influenzae, and Moraxella catarrhalis. AsMoraxella is much less difficult to treat, the focus for choosing antimicrobials to treat acuteotitis media (AOM) has been directed by resistance patterns among pneumococcus and non-typeable H. influenzae. In pneumococci, the major mechanism of antibiotic resistance(penicillin resistance caused by alterations in penicillin-binding proteins (PBPs)) alsoproportionally conveys resistance to the cephalosporins and increases the likelihood that thesame 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 ofthe patterns of antibiotic resistance in their geographical area and the advantages or adverseeffects of the candidate antibiotics. Resistance patterns in the literature can vary by thepopulation of patients studied as well as the era in which the studies are performed. It is alsoimportant to understand that the rate of spontaneous cure of AOM depends on thepathogen, age of the patient (more commonly older than two years), immune status andfunction 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 theinfant immunization schedule in the US, but not other countries, in 2000. This introductionseems to have had a striking impact on middle ear pathogens from patients failing initialantibiotic therapy. This became clear when a study from rural Kentucky and a study fromsuburban Rochester revealed remarkably similar results when comparing the dominantpathogens 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 equalnumbers of middle ear isolates with high and intermediate penicillin resistance andpenicillin-susceptibility) and H. influenzae for around 40%. The proportion of β-lactamase-producing H. influenzae was higher in rural Kentucky than in suburban Rochester (about40% vs 25–30%), although the increase in β-lactamase production seen in Rochester wasstill sizeable. After the vaccine was introduced, the pneumococcal contribution to AOM





9

CHRISTOPHER HARRISON

pathogens decreased by about one-half and the H. influenzae contribution increased byabout one-third. Among patients who had failed previous antibiotic therapy, non-typeableH. influenzae now made up 56% of isolates in rural Kentucky and suburban New York, andtwo-thirds of these produced β-lactamase. A proportional decrease was also seen inpenicillin-resistant strains of S. pneumoniae in both centres. The comparability of data fromthese 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-producingHaemophilus 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 fullimplementation of PCV-7 (2000 to 2001), vaccine types predominated, including serotypes19F, 14, 9V and 6B. Type 4 was observed in small numbers. During 2002–05, when morechildren had been immunized with PCV-7, serotypes 14 and 9B had disappeared, whileserotypes 6B, 19F and 23F had maintained a presence, although at a lower level than beforethe vaccine was introduced.

Serotype substitution was also observed, as non-vaccine serotypes 3, 11 and 33 became morecommon after introduction of the vaccine. This confirms the observation of a group inFinland that non-vaccine serotypes of S. pneumoniae might emerge to take advantage ofEustachian tube dysfunction in young children, even when they have antibody against theseven vaccine strains.3 The data from Finland did not suggest that serotypes that were cross-reactive with the vaccine types would emerge; however, data from the US obtained since theintroduction of PCV-7 revealed that 6A and particularly 19A had become major players

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X 2

3

2000-22001-12001-22002-12002-22003-12003-22004-12004-22005-1

2005-2

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.

10

THE CHANGING MICROBIOLOGY OF ACUTE OTITIS MEDIA

among S. pneumoniae causing AOM and acute bacterial rhinosinusitis in immunized childrenin the Louisville area. Interestingly, in 2002, serotype 19F alone comprised almost 30% ofthe total AOM isolates. However, while serotype 19F had decreased by 2005, serotype 19Ahad increased so that 19A together with 19F comprised the same 30% of total AOMisolates. It thus seems that 19A serotype substituted sufficiently for 19F so that no realchange in serogroup 19 isolates occurred. Of more concern is that 19A isolates seem to havehigher 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 inthe proportion of cases of AOM caused by S. pneumoniae was seen, and β-lactamase-producing organisms (mostly non-typeable H. influenzae) became more important inrecurrent AOM. Non-typeable β-lactamase-producing H. influenzae became the main targetfor therapy in patients failing previous antibiotic therapy and those patients who sufferedfrequent recurrences. In the 1990s, the situation changed because of the increase inpenicillin-non-susceptible S. pneumoniae. S. pneumoniae therefore became the majorpathogen in patients with treatment failures and frequent AOM recurrences. β-lactamase-producing H. influenzae was still a concern, but it had dropped to second place as a cause oftreatment failures when compared with penicillin-non-susceptible S. pneumoniae. Since year2000, with the advent of universal use of PCV-7 in infancy, a decrease in the proportion ofpenicillin-non-susceptible S. pneumoniae was observed, and H. influenzae (particularlyβ-lactamase-producing H. influenzae) have become more important causes of AOMtreatment failure. Despite this, it is essential to remember that S. pneumoniae is still thepathogen involved in about one-third of treatment failures and that about half of those aredue to penicillin-non-susceptible S. pneumoniae.

References

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.

11

Clinical application to paediatricsALBERT M COLLIER

Relationship between immunity in the foetus and young child andrespiratory illnesses

The pathogenesis of acute otitis media (AOM) and the balance between host and pathogenare 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 ofIgG in a child from conception through to the age of nine years.1 After the fourth month offoetal 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. Althoughbabies born premature and weighing <1000 g are much more likely to survive now thanmany years ago, they are still more susceptible to infections because, in part, they have notreceived the maximum amount of IgG from their mother before birth. After birth andseparation from the placenta, levels of IgG decrease very rapidly, with viral antibodiesremaining longer than bacterial antibodies. At about 10–11 months, all of the maternalantibodies for bacteria have disappeared.

At about 7.5 months of foetal age, the foetal immune system itself begins to manufactureIgG, but the levels increase very slowly, with much maturation of the immune systemoccurring after birth. Not until the child is aged two years does it have a levelcommensurate with even 80% of that of its mother. The nadir of IgG concentration is atnine months, which, in longitudinal studies, is the time of the peak incidence of AOM andprior to conjugate (Hib) vaccine of Hib meningitis.2 Indeed, Figure 2, when compared withFigure 1, shows an inverse relation between the incidence of respiratory illnesses by age andlevels of IgG antibodies by age in children, with the incidence of respiratory illnessespeaking in the second six months of life, when the mother’s antibodies are diminishing andthe 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 andStreptococcus pneumoniae.

S. pneumoniae was discovered in 1880 by Pasteur, who also disproved spontaneousgeneration and proved the tenet of infectious diseases – that a person must be colonized





12

CLINICAL APPLICATION TO PAEDIATRICS

with an organism before that organism can cause disease. Most often, the organism isacquired 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 inNorth Carolina, for example, only 1% of children younger than five years were in day careand children had little regular contact with other children, perhaps attending Sunday schoolonce a week during the first years of life; in 2006, however, 78% of children younger thanfive 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 anumber of patients during the influenza pandemic. In the 1930s, Dr Margaret Pittman, as aproject for her PhD in microbiology at the University of Pennsylvania, Philadelphia, wasasked to obtain isolates of H. influenzae from children with meningitis, to produce antiserain rabbits and to identify any different serotypes. She identified six types, which she nameda–f, by making antibodies to the polysaccharides in the capsules that surrounded the

2 3 4 5 6 7 8 9

Age (years)Fetal age (months)

100

Transplacentally acquired Endogenous production

Total

80

60

40

20

0

Perc

enta

ge o

f adult v

alu

es

Birth

1 2 3 4 5 6 7 8 9

0–1/20

2

4

6

8

10

8.1

1.2 1.10.4 0.5 0.4 0.3 0.5

10.4

7.7

6.3

4.63.8

Total respiratory illnesses

Lower respiratory illnesses

Re

sp

ira

tory

ill

ne

sse

s p

er

chil

d–y

ea

r

6.5

12

1/2–1 1–2 2–3

Age (years)

3–4 4–5 All ages

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

Goldblum.1

Figure 2 Frequency of respiratory illnesses by age.2

13

ALBERT M COLLIER

organisms. When the antibodies were added to the isolates and observed under themicroscope, each bacterial serotype could be identified by its reaction to the antisera, withthe correct antisera causing the capsule to swell up.

Dr John Robbins and Dr David Smith, who worked in competing laboratories, both isolatedthe serotype b polysaccharide, which helps the bacteria to evade phagocytosis and remain inthe 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 sixmonths of age – before the peak incidence of meningitis – would encourage the children toproduce antibodies against H. influenzae type b. Disappointingly, the polysaccharide did nothave the desired effect, because children are unable to produce good antibodies topolysaccharide antigens until they reach the age of 18–24 months. The polysaccharide wasthen linked to a protein, which changed the evoked response from T-cell-independent toT-cell-dependent and resulted in the production of good antibodies against H. influenzaetype b as early as two months of age. The resultant vaccine produced a reduction in cases ofH. influenzae type b systemic disease from 20 000 cases a year in the US to around 100 casesin 2005. Unfortunately, as the H. influenzae that cause AOM are non-typeable, the vaccinehad no effect on surface infections such as AOM.

Of the 90 types of S. pneumoniae, seven serotypes were observed to predominate in invasivedisease. These seven are the types conjugated to protein carriers in the pneumococcal 7-valent conjugate vaccine (PCV-7). In contrast with the H. influenzae type b conjugatedvaccine, the same types of S. pneumoniae included in the pneumococcal conjugated vaccinealso predominate in AOM, so PCV-7 has had an effect on the incidence of mucosal surfaceinfections such as AOM. Furthermore, a high percentage (reportedly 30–65%) of thesePCV-7 strains had penicillin minimum inhibitory concentrations (MIC) >2 µg/ml. PCV-7not only promotes production of humoral circulating antibodies, but some antibody in theform of IgG seems to reach the mucosa. The surface antibody can prevent attachment andreduce 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, butthere 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% ofnon-typeable H. influenzae were β-lactamase-positive, which were the main pathogens seenin patients with treatment failure or recurrence.6 In the 1990s, there was an increase inpenicillin-non-susceptible S. pneumoniae, which became the major pathogen in failures andrecurrences; β-lactamase-positive H. influenzae remained an issue, but were less importantthan penicillin-non-susceptible S. pneumoniae.7–9 The 2000s have seen the conjugatedvaccine effect, in which there has been a decrease in the numbers of penicillin-non-susceptible S. pneumoniae, although with more of an effect with the intermediate thanresistant S. pneumoniae.10,11 A study by Casey and Pichichero highlights this gradual shift inincidence 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 lesserrole. By 1998–2000, around the time that the pneumococcal vaccine was introduced, thenumber of cases caused by each pathogen were comparable, but by 2001–03, H. influenzaewas the dominant organism and S. pneumoniae the minor contributor.12 Increases have beenseen in β-lactamase-positive H. influenzae, which, again, is the major pathogen in treatmentfailures and recurrences.10,11 It is important to note, however, that penicillin-non-susceptibleS. pneumoniae have not been completely eradicated, as recent serotype substitution may be

14

CLINICAL APPLICATION TO PAEDIATRICS

1995–97

30

40

50

60

Pe

rce

nta

ge

1998–2000 2001–03

S. pneumoniae

p � 0.017

H. influenzae

p � 0.012

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

from Casey and Pichichero.12

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. 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.

4. Leibovtiz E, Jacobs MR, Dagan R. Haemophilus

influenzae: a significant pathogen in acute otitis

media. Pediatr Infect Dis J 2004; 23: 1142–52.

5. 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. Ten-

year 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.

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

References

Therapeutic developments in the

management of other common

bacterial infectionsHYMAN W FISHER

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

Uncomplicated urinary tract infections

Uncomplicated UTIs continue to be a common problem, and treatment of these infectionshas become more difficult because of the rising levels of resistance to commonly usedantibiotics.1,2

The 1999 guideline of the Infectious Diseases Society of America recommends a 3-daycourse of trimethoprim plus sulfamethoxazole (TMP-SMZ) as standard therapy for acutecystitis if the community resistance among uropathogens is <20%.3 The resistance ofEscherichia coli to TMP-SMZ has been increasing and is in the range of 20% or higher insome 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 tractpathogens, primarily E. coli, in children �2 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 agegroups. E. coli resistance to ampicillin and trimethoprim was higher in children than inadults and increased over time in both age groups, while resistance to fluoroquinolones washigher in adults than in children, but also increased over time in both groups. It wasconcluded that the steadily increasing and now high E. coli resistance levels in children toampicillin and trimethoprim rendered empirical therapy with these drugs doubtful.6





15

MANAGEMENT OF OTHER COMMON BACTERIAL INFECTIONS

A randomized, prospective, multicentre study in Israel compared once-daily oral cefixime (8mg/kg) with twice daily oral TMP-SMZ (8/40 mg/kg/day) in the treatment of acute UTIsin children aged 6 months to 13 years. All Gram-negative organisms were susceptible tocefixime and 85% were susceptible to TMP-SMZ. It was concluded that the efficacy andsafety of cefixime administered once daily compared favourably with TMP-SMZadministered twice daily for acute uncomplicated UTIs in children.7

In a South African randomized study of acute uncomplicated UTIs in 528 patients whoreceived cefixime 400 mg once daily, cefixime 200 mg twice daily, or TMP-SMZ two tabletstwice daily for 10 days, cefixime 200 mg twice daily was found to be an effective and safealternative to TMP-SMZ.4

In a double-blind, randomized study of uncomplicated cystitis in Israeli women, it wasfound that a 3-day regimen of 400 mg cefixime administered once daily was as efficient as a3-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 treatmentof tonsillo-pharyngitis caused by group A b-haemolytic streptococci (GABHS), there hasbeen, since the early 1980s, an increase in GABHS infections not cured by penicillintreatment, and this has led to the testing of alternative antibiotics.

A meta-analysis of randomized controlled trials comparing a cephalosporin versus penicillinin the treatment of bacteriologically confirmed GABHS tonsillo-pharyngitis included 35trials involving 7125 children. The overall summary odds ratios for both bacteriological andclinical cure rates significantly favoured cephalosporins compared with penicillin, with theindividual cephalosporins cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil,cefixime, ceftibuten and cefdinir showing superior bacteriological cure rates. This meta-analysis indicates that the likelihood of bacteriological and clinical success in GABHStonsillo-pharyngitis is significantly greater if an oral cephalosporin is prescribed, comparedwith oral penicillin.9

Although cephalosporins are in general active against Streptococcus pyogenes and are thereforeof value in the treatment of tonsillo-pharyngitis, they have not yet been shown to preventrheumatic fever.10

Acute bronchitis and acute exacerbations of chronic bronchitis

Acute bronchitis and acute exacerbations of chronic bronchitis are frequently caused byStreptococcus pneumoniae and Haemophilus influenzae – organisms that are becoming moreresistant to narrow-spectrum b-lactams such as penicillin and amoxicillin. Extended-spectrum cephalosporins are among the antibiotics that retain activity against many resistantstrains of these organisms.

Comparative trials have shown that the clinical and bacteriological efficacy of cefixime200–400 mg daily administered as a single dose or in two divided doses is comparable withthat of cefaclor, amoxicillin, or amoxicillin/clavulanic acid in acute lower RTIs. Cefixime isconsidered a suitable alternative to cefaclor or amoxicillin in acute lower RTIs.11

16

17

HYMAN W FISHER

A multicentre trial involving 167 patients in Germany compared a 5-day course of cefixime400 mg/day with a standard 10-day course of the same daily dose of cefixime in thetreatment of acute exacerbations of chronic bronchitis, and found that the 5-day course oftherapy was equivalent in efficacy to the standard 10-day course, and may offer costadvantages.12

Acute bacterial rhinosinusitis

The most common bacterial species isolated from the maxillary sinuses of patients withacute 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 Bacterialresistance 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 allM. catarrhalis isolates produce b-lactamases. Resistance of H. influenzae to TMP-SMZ isalso 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 otherantibiotics.14 A study in the US of the antimicrobial susceptibility of organisms isolated fromthe nasopharynx of 70 children presenting with AMS or maxillary sinusitis that recurred afteramoxicillin therapy (RMS) found that treatment of AMS with amoxicillin increases thedevelopment 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 treatmentguidelines for acute bacterial rhinosinusitis, recommends a respiratory fluoroquinolone orhigh-dose amoxicillin/clavulanate for initial therapy of adults with moderate acute bacterialrhinosinusitis or with mild disease who have received antibiotics in the previous 4–6 weeks.Alternative recommendations include parenteral ceftriaxone or combination therapy withhigh-dose amoxicillin or clindamycin plus cefixime, or high-dose amoxicillin or clindamycinplus rifampin.13

Support for the use of combination therapy consisting of ampicillin plus cefixime comesfrom in vitro studies showing synergy of these two agents against S. pneumoniae, includingpenicillin-resistant strains.15,16

Uncomplicated cervical or urethral gonorrhoea

The Centers for Disease Control and Prevention (CDC) updated its guidelines for thetreatment 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 increasesreported were more dramatic (e.g. Philadelphia rose from 1% in 2004 to 27% in 2006). Therecommended treatment alternatives for gonorrhoea include oral cefixime and intra-muscular ceftriaxone, these being the only two cephalosporin compounds recommended bythe CDC.17 Oral cefixime and intramuscular ceftriaxone are also the only recommended

MANAGEMENT OF OTHER COMMON BACTERIAL INFECTIONS

alternative first-line agents for the treatment of gonorrhoea in the UK. The general use ofciprofloxacin as first-line treatment stopped when resistance to it increased to >9% in2002.18

The French Agency for Health Product Safety recommends presumptive, simultaneoustreatment for both Neisseria gonorrhoeae and Chlamydia trachomatis in cases of uncomplicatedurethritis and cervicitis. For presumptive gonorrhoea, the Agency suggests a single dose ofcefixime (oral), ceftriaxone (intramuscular or intravenous), spectinomycin (intramuscular) orciprofloxacin (oral).19

Summary

Bacteria that cause common infections in children and adults are becoming increasinglyresistant to antibiotics, especially to b-lactam antibiotics. Extended-spectrum cephalosporinsprovide broad-spectrum coverage of Gram-positive and Gram-negative organismsassociated with many of the bacterial infections commonly encountered in clinical practice,including uncomplicated urinary tract infections, AOM, pharyngitis, tonsillitis, acutebronchitis, acute exacerbations of chronic bronchitis, acute sinusitis, and uncomplicatedgonorrhoea. These agents are important options in the therapeutic armamentarium for suchinfections, particularly in this era of increasing antimicrobial resistance and dwindlingtreatment choices.

References

18

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. 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.

4. 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.

5. 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.

6. 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 third-

generation 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.

19

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: fluoro-

quinolones no longer recommended for treat-

ment 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.

HYMAN W FISHER

Conclusion

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

Reference


EDITED BYALBERT M COLLIER, HYMAN W FISHER, CHRISTOPHER HARRISON, MICHAEL R JACOBS, CRAIG MARTIN, 2007


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.


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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 � False �

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 effi-

cacy 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 � False �

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 � False �

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 fol-

lowing 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 beta-

haemolytic streptococci in children, the likelihood of bacteriological and clinical success is

significantly greater with a penicillin than with a cephalosporin.

True � False �

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

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

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