Evolving Shifts in Otitis Media Pathogens: Relevance to a Managed Care Organization

The microbiological landscape of acute otitismedia (AOM) has been relatively constant over thepast half century. Because of this stability, empiricmanagement of AOM was a common and efficientpractice. Recently, there has been a proportionalshift in the microbiology of AOM, bringing thechoices for empiric therapy into question. Becauseof this shift, managed care organizations shouldreview their formularies to ensure that they are structuredto include and promote the use of appropriateantibiotics. This article explores the background andevents leading up to the shift in AOM microbiology;discusses the clinical consequences and the futureimplications of the shift, such as increased costsassociated with treatment failures, its impact on newvaccines and new-onset AOM and related diseasestates, such as sinusitis; and describes why these factorsshould be considered by managed care decisionmakers in their formulary deliberations.

(Am J Manag Care. 2005;11:S192-S201)

Acute otitis media (AOM) is one of themost common pediatric infectionsand is responsible for more than onequarter of all oral antibiotic prescriptionswritten in the United States.¹Children aged7 to 24 months are most likely to developAOM.^2-4Factors associated with an increasedrisk of developing otitis mediainclude male sex, use of daycare facilities,atopy, use of pacifiers, and low socioeconomicstatus.^5,6

AOM represents a significant burden topatients, caregivers, and the healthcare system.AOM accounts for 20 million office visitsper year in the United States and isresponsible for 18% of ambulatory care visitsamong preschool children.^7,8The number ofAOM visits has increased more than 2-fold inthe last quarter of the 20th century.⁹A conservativeestimate by the Agency forHealthcare Research and Quality gauges thetotal national cost of AOM to have been$2.98 billion in 1995 dollars,⁹whereas moreaggressive estimates gauge the direct costs at$4.1 billion with a per-patient cost of $453in 1992 dollars.¹⁰Adjusting these figures to2005 dollars using the Consumer PriceIndex¹¹provides estimates of $3.82 billionand $5.7 billion, respectively, and a per-patientcost of $630. The more conservativeestimate, gathered in a study of AOM costsconducted by the Southern CaliforniaEvidence-based Practice Center, reported anestimated 70% of the direct cost of AOM and63% of the total cost was attributable toepisodes of otitis media with effusion(OME) or chronic middle ear infectionsprogressing from AOM. These figures suggestthat effective treatments for AOM andprevention of subsequent infection couldachieve significant cost savings.⁹The economicsof AOM are presented in more depthin an accompanying article in this supplement.Any practice recommendations orformulary modifications that could reduceAOM expenditures should be of interest tohealth plans.

Microbiology of AOM Pre-PCV-7

Streptococcus pneumoniae

Haemophilus influenzae

Moraxella catarrhalis

S pneumoniae

H influenzae

M catarrhalis

AOM is typically caused by 1 of 3pathogens, ,nontypeable , or.^5,12-18Although these3 pathogens are responsible for most casesof AOM, their individual incidence varies bythe type of AOM infection. In the 20 yearsbefore the release of the heptavalent pneumococcalconjugate vaccine (PCV-7), USstudies showed as the maincausative pathogen of uncomplicated AOM,associated with a median of 42% of cases(range 32%-48%); was associated with a median of 31% of cases (range 20%-37%); and was associatedwith a median of 16% of cases (range 9%-23%).^12-16

influenzae

S pneumoniae

The microbiology of recurrent and persistentAOM differs somewhat from uncomplicatedAOM. Recurrent AOM is typicallydefined as 3 or more unique cases of AOM ina 6-month period or 4 episodes in a 12-month period.^19,20Persistent AOM is typicallydefined as clinical failure within 30 daysof completion of an antibiotic course.²¹Astudy in the 1980s of the microbiology ofAOM in persistent AOM found that was the dominant pathogen, representing53% of the isolates (versus 19% for).¹⁵In the 1990s, 3 studiesdocumented a shift in the persistent AOMpopulation to as the dominantpathogen.^5,21,22

S pneumoniae

This shift was attributed to the increasein the incidence of penicillin nonsusceptible(PNSP) (Figure 1). In fact,studies performed in the United States duringthe 1990s showed that PNSP accountedfor 31% to 70% of the recoveredfrom children with recurrent or persistentAOM.^5,17,18This phenomenon wasglobal, as data from France,²³Spain,²⁴andIsrael²⁵showed that PNSP accounted for 77%to 90% of the recovered fromchildren with refractory AOM during thistime period.

S pneumonia

influenzae

M catarrhalis

On the basis of the data available in the1980s and 1990s, managed care organizationsand public health agencies structuredempiric AOM treatment recommendationsto provide coverage for , especiallyPNSP, as the primary pathogen and and as the secondaryand tertiary pathogens, respectively.

PCV-7 Vaccine: Impact on theIncidence of AOM

In February 2000, PCV-7 was introducedin the United States and recommended forthe active immunization of infants and toddlers.²⁶Although initially recommended forthe prevention of invasive disease, PCV-7also had a favorable impact on preventinginfections by pneumococcal strains responsiblefor AOM. The 7 pneumococcal serotypesin the vaccine (4, 6B, 9V, 14, 18C,19F, and 23F) are commonly found in AOM,5 of which are PNSP strains (6B, 9V, 14, 19F,and 23F).^2,3,27,28As the efficacy of PCV-7immunization against AOM-causing serotypesbecame known, the AOM indicationwas added to the labeling of PCV-7.²⁶

Based on the assumption that 20% ofAOM cases were caused by vaccine-typeserotypes, and that the vaccine would prevent80% of those infections, Fireman et alpredicted an overall 16% reduction inAOM.²⁰Using somewhat different assumptions,Pelton and Klein estimated a 15% to20% reduction in AOM.⁴

Although these predictions were mathematicallysound, the initial clinical trials ofPCV-7 vaccination found an overall reductionof 6% to 8.9%.^19,20,29,30However, of moreinterest to health plans and payer groupswere the observed reductions in recurrentAOM and otologic surgical procedures, bothof which can be far costlier than uncomplicatedAOM. The study preformed in theNorthern California Kaiser Permanente systemobserved a 10% to 26% reduction inrecurrent AOM and a 24% reduction in tympanostomytube placement in children whoreceived the PCV-7.²⁰

Impact of PCV-7 on the Microbiologyof AOM

According to the National ImmunizationSurvey, 40.8% of US children aged 19 to 35months had at least 3 PCV-7 vaccinations in2002; this number rose to 68.1% in 2003(Figure 2).³¹A number of vaccine shortagesprevented vaccination in the full population,and many patients only received 2 doses ofPCV-7 instead of the recommended 3 to 4doses.³²Researchers found that childrenreceiving only 2 doses of PCV-7 experienceda lesser reduction in otitis visits comparedwith those receiving 3 doses (6.5% reductionversus 7.8% reduction), and children whodid not receive a third PCV-7 dose graduallylost the benefit of vaccination throughoutthe first year of life.²⁰Fortunately, this shortagewas resolved, and it is expected that themajority of the recommended pediatric populationwill receive the full complement ofPCV-7 vaccinations in the future.

S pneumoniae

H influenzae

M catarrhalis

S pneumoniae

H influenzae

S pneumoniae

H influenzae

Two studies published in 2004 haveshown that PCV-7 has had a major impacton the microbiology of AOM. The nearly 60%decrease in AOM caused by serotypes contained in the vaccine^22,30,33hasresulted in a corresponding shift in the proportionof cases caused by and.^21,22These 2 recent studies,one in rural Kentucky and another in suburbanRochester, New York, simultaneouslyreported from very different geographic andpatient population bases a significant decreasein the overall proportion of and increase in nontypable when comparing pre-and post-PCV-7 AOMmicrobiology^21,22(Figure 3). The overall proportionof decreased from48% to 31% in both studies,^21,22and nontypableincreased from 41% to56% in Kentucky²²and 38% to 57% in NewYork.²¹These studies demonstrate a significantproportional shift in the microbiologyof AOM in the pediatric population. Gram-negativepathogens accounted for about twothirds of all AOM pathogens recovered inchildren who had received 3 or 4 doses ofPCV-7.^21,22Similar shifts in AOM microbiologywere seen in Finnish studies.^30,33

H influenzae

Of additional interest was the dramaticincrease in beta-lactamase-producing. Compared with 5 years ago,beta-lactamase-producing aremore common (Figure 4). Based on theresults of the 2 recent studies by Block etal²⁹and Casey and Pichichero,²¹there was a47% to 57% increase in beta-lactamae-producingpathogens, accounting for nearly onehalf of all AOM pathogens recovered in childrenwho have received 3 to 4 doses of PCV-7. When was specifically brokenout, the rate of beta-lactamase-producingincreased by 16% to 22% inthe post-PCV-7 time period.^21,22

In addition to the PCV-7, 2 other factorsmay have contributed to the shifting microbiologyof AOM seen since the 1990s. InJanuary 1998, the Centers for DiseaseControl and Prevention (CDC) and theAmerican Academy of Pediatrics (AAP)released a set of guidelines calling for physiciansto conscientiously distinguish AOMfrom OME and to defer antibiotics forOME.³⁴It was predicted that this wouldresult in the avoidance of up to 8 millionunnecessary courses of antibiotics annually.Also, there was a pronounced decrease inthe use of chemoprophylaxis against AOMby practitioners, as the benefit of chemoprophylaxiswas deemed too small³⁵to justifyits use in an era of rising antibacterialresistance.

Clinical Consequences

S pneumoniae-

In protecting patients from infection byPNSP strains, PCV-7 has reversed the trendof rising rates of resistant causing AOM that was evident throughoutthe 1990s. Indeed there has been a documentedreduction in the incidence of invasivedisease caused by PNSP^36-38and AOM.²¹Casey and Pichichero reported a 42%decrease in the proportion of PNSP in the 3years after the release of PCV-7 comparedwith a 3-year period just before the release.²¹Based on increasing PCV-7 coverage, theodds of AOM caused by vaccine-type PNSPhave been greatly reduced.

When selecting antibiotics for the empirictreatment of infectious disease, practitionersshould consider the CDC principlesfor the judicious use of antibiotics.³⁹Thefirst principle is to only prescribe an antibioticwhen it is likely to be beneficial to thepatient. To ensure this principle, the CDCguidelines for AOM recommend the use ofspecific diagnostic criteria that include thepresence of otorrhea of middle ear origin orpresence of middle ear fluid or effusion andsigns or symptoms of acute local or systemicillness.³⁹It has been recommended thatpneumatic otoscopy be used to confirm thepresence of middle ear fluid or effusion.^39,40

H influenzae

S pneumoniae

H influenzae

Once a diagnosis has been confirmed, theantibiotic selected should have activityagainst the most commonly occurringpathogens. As discussed earlier, the causativepathogens implicated in AOM havechanged; there has been an increase in beta-lactamase-producing and adecrease in resistant . Theserotypes of not containedin PCV-7 are typically susceptible to treatmentwith amoxicillin, whereas beta-lactamase-producing are typicallyresistant to amoxicillin.^41,42

influenzae

S pneumoniae

catarrhalis

H influenzae

Given the recent changes in the microbiologyof AOM, empiric treatment still focuseson the same 3 main pathogens ([including beta-lactamase-producingstrains], , and ), but the change in their frequencyand resistance patterns should betaken into consideration. As full penetrationof the PCV-7 vaccine in pediatric populationsis achieved, it is increasingly likely thatthe primary pathogen implicated in AOMwill be .²²Economic consequencesof this shift could result from anincreased number of treatment failures associatedwith inadequate coverage of theimplicated pathogens. The full effect of PCV-7 on the bacteriology of AOM will becomemore evident in the next few years. A continuedshift to is expected asvaccination with the full 4-dose recommendedschedule of PCV-7 is achieved.

Appropriate Antibiotic Selection

When faced with suspected AOM, mostclinicians treat the infection empirically.When selecting empiric therapy, providersoften make assumptions about the patientcaregiver's preferences for antibiotic therapy(dose frequency, duration of therapy, suspensiontaste, etc); these assumptions arenot always correct. In a survey comparingthe opinions of 400 parents and 100 pediatricianson antibiotics, parents selected sideeffects as the most important antibiotic factor,whereas pediatricians ranked this asleast important, selecting dosing schedule asthe most important factor.⁴³(The next articlein this supplement will explore theseissues in more depth and also addressesissues of adherence.) The Table summarizesselect oral therapies approved by the USFood and Drug Administration (FDA) for usein AOM.

Aminopenicillins.

H influenzae

Aminopenicillins (particularlyamoxicillin) have long been consideredfirst-line therapy for the treatment ofAOM. High-dose amoxicillin achieves middleear fluid concentrations that should effectivelyeradicate penicillin-susceptible, intermediate,and some nonsusceptible strains ofpneumococci.^41,44However, neither highdosenor regular-dose amoxicillin will affectbeta-lactamase-producing .⁴¹The significant presence of gram-negativeorganisms in fully PCV-7-vaccinated childrenmay make amoxicillin ineffective as anAOM treatment in populations that haverecently been treated with antibiotics.^21,22Because of its low cost and relative safety,amoxicillin is still considered first-line therapyin all major guidelines.^22,45,46However, ifthe trend toward an increased frequency ofbeta-lactamase-producing organisms continues,the decision to use amoxicillin asfirst-line therapy for AOM may need to bereconsidered.

Amoxicillin/Clavulanate.

H influenzae

To combat thepresence of beta-lactamase-producingpathogens, clavulanate has been added toamoxicillin (amoxicillin/clavulanate). Traditionaldosing of amoxicillin was at 45mg/kg/day when used alone or in combinationwith clavulanate. When administered at45/6.4 mg/kg/day, amoxicillin/clavulanateachieves suboptimal eradication ratesagainst . In 2 studies, reportederadication rates were 87% and 62%.^47,48When the dose of the amoxicillin componentwas raised to the currently recommended90/6.4 mg/kg/day, eradication ratesimproved to 90% to 94%.^49,50

High-dose amoxicillin/clavulanate hasbeen recommended by the AAP and theCDC for the treatment of AOM in patientswho have failed previous therapy with amoxicillin.^45,46

Cephalosporins.

H influenzae

M catarrhalis

S pneumoniae.

A number of cephalosporinshave been approved by the FDA forthe treatment of AOM (Table), yet most ofthese agents are not considered appropriatefor empirical therapy of AOM today. Ofthose approved, 3 oral cephalosporins (cefdinir,cefpodoxime, and cefuroxime) havebeen shown to possess the best activityagainst beta-lactamase-negative and beta-lactamase-positive gram-negative pathogens(and ) as well asretaining reasonable activity against intermediate-susceptible ^22,51-57

pneumoniae

S pneumoniae

H influenzae

One cephalosporin, ceftriaxone, has beenreserved for use parenterally for patientsfailing oral therapy or those with recalcitrantor severe disease. More than 99% ofpenicillin-susceptible and intermediate isolates and 85% of penicillin-resistantisolates are susceptibleto ceftriaxone administeredparenterally.⁵⁶Ceftriaxone also achievescomplete eradication of .^58,59

The 1998 CDC guidelines recommendedthe use of cefuroxime in addition to amoxicillin/clavulanate as a treatment option forpatients failing therapy with amoxicillin.⁴⁵The 2004 AAP/American Academy ofFamily Physicians (AAFP) guidelines recommendcefdinir, cefpodoxime, and cefuroximeas the preferred cephalosporins,especially if penicillin allergy is suspected.⁴⁶Recent evidence suggests that theincidence of cross-reactivity between penicillinsand cephalosporins is less than 0.5%.⁶⁰

Macrolides.

Erythromycin is no longerrecommended for AOM because of rising levelsof macrolide resistance.⁴⁵Studies haveshown that pneumococci resistant to erythromycinare also resistant to clarithromycinand azithromycin.^61,62For this reason the1998 CDC guidelines do not recommend theiruse and the 2004 AAP/AAFP guidelines recommendtheir use only in the case of severetype I allergic reactions to penicillins.^45,46

Future Implications

Data gathered on the microbiology ofAOM between 2000 and 2003 do not yetillustrate the full effect of the PCV-7 vaccine,because a significant portion of the pediatricpopulation was not fully vaccinated duringthat time period (Figure 2).³¹Because ofshortages, many patients received only 2doses of PCV-7 instead of the recommended3 to 4 doses.³²As previously discussed, AOMprotection is not sustained through the firstyear of life without the third PCV-7 dose.²⁰Now that the PCV-7 shortage is over, it isexpected that the majority of the pediatricpopulation will receive the recommended 3to 4 PCV-7 doses. Only after this has occurredcan the full population impact of PCV on themicrobiology of AOM be assessed.

H influenzae

M catarrhalis

S pneumoniae

H influenzae

S pneumoniae

As the percentage of the pediatric populationvaccinated with PCV-7 increases, thetrends of proportional increases in nonvaccinepneumococcal serotypes and and isolated in AOM maycontinue, further shifting the microbiologyof AOM. These continued changes may wellalter the face of AOM in several ways. First,by further decreasing AOM caused by vaccine-type , AOM outcomesshould improve as suggested by the decreasesin recurrent otitis and tympanostomytube insertion after PCV-7 vaccinationobserved in Finland and the UnitedStates.^19,30,33,63Second, by increasing the ratesof AOM caused by , AOM may beassociated with less severe inflammatoryreactions and a less visually inflammatoryview at otoscopy.^64-68Acute mastoiditis is amain complication of AOM that can lead toor is associated with further complications,such as epidural, subdural, extradural, cerebellar,and periosteal abscesses, cavernousor lateral sinus vein thrombosis, bacterialmeningitis, labyrinthitis, petrositis, facialnerve palsy, and hearing loss. Acute mastoiditishas been associated more oftenwith infection by .^69-72Ashift away from as the dominantpathogen in AOM may lead to lesscomplications.

H influenzae

S pneumoniae

H influenzae

M catarrhalis

The increased prevalence of nontypableand the reduced prevalence ofantibiotic-resistant in AOMbrings into question future empiric therapy.Empiric treatment of uncomplicated AOMwith amoxicillin (80-90 mg/kg/day) may beless effective in the future if the increasingrates of and as acause of AOM continues along with a correspondingincrease in the proportion of beta-lactamase-producing organisms.

Conclusion

H influenzae

Although the microbiological landscape ofAOM was relatively constant over the past30 years, the introduction of PCV-7 hascaused an abrupt alteration since its releasein the United States in 2000. This shift in thecausative pathogens of AOM can have adirect effect on empiric treatment. Just asthe decrease in vaccine-type pneumococcalserotypes left behind a proportional increasein nonvaccine-type serotypes, this shift hasalso been accompanied by a proportionalincrease in infections caused by ,bringing the risk of beta-lactamase productionto the forefront as a focus ontreatment failure. As the proportion of thepopulation vaccinated with PCV-7 increases,it is expected that this trend will continue.

influenzae

Although the economic consequences ofthe shift in AOM pathology are still beingdetermined, this shift should be consideredby managed care when structuring their formulary.The next article in this supplementwill discuss the importance of improvingAOM outcomes through proper antibioticutilization and adherence. Managed careprofessionals must ensure that the mostappropriate agents for use as empiric treatmentof AOM in the post-PCV-7 era areavailable and appropriately positioned withinhealth plan formularies to encourageproper use. Given the current trends, it isexpected that recognition of the shift in rate by practitioners and managedcare organizations may contribute tofewer AOM treatment failures, thereby containingthe direct and indirect costs attributedto AOM.

Vaccine.

1. Dagan R. Treatment of AOM: challenges in the era ofantibiotic resistance. 2001;19:S9-S16.

Pediatr Infect Dis J.

2. Block SL, Hedrick J, Harrison CJ, et al.Pneumococcal serotypes from acute otitis media in ruralKentucky. 2002;21:859-865.

Pediatr Infect Dis J.

3. Wald ER, Mason EO Jr, Bradley JS, Barson WJ,Kaplan SL. Acute otitis media caused by Streptococcuspneumoniae in children's hospitals between 1994 and1997. 2001;20:34-39.

Pediatr Infect

Dis J.

4. Pelton SI, Klein JO. The promise of immunoprophylaxisfor prevention of acute otitis media. 1999;18:926-935.

Pediatr Infect Dis J.

5. Block SL, Harrison CJ, Hedrick JA, et al. PenicillinresistantStreptococcus pneumoniae in acute otitismedia: risk factors, susceptibility patterns and antimicrobialmanagement. 1995;14:751-759.

Laryngoscope.

6. Rodriguez WJ, Schwartz RH, Akram S, Khan WN.Streptococcus pneumoniae resistant to penicillin: incidenceand potential therapeutic options. 1995;105:300-304.

N Engl J Med.

7. Berman S. Otitis media in children. 1995;332:1560-1565.

Vital Health Stat 13.

8. Freid VM, Makuc DM, Rooks RN. Ambulatory healthcare visits by children: principal diagnosis and place ofvisit. 1998;(137):1-23.

Management

of Acute Otitis Media. Evidence Report/Technology

Assessment No. 15 (Prepared by the Southern California

Evidence-based Practice Center under Contract No.

290-97-0001). AHRQ Publication No. 01-E010.

9. Marcy M, Takata G, Shekelle P, et al. Rockville, Md: Agency for Healthcare Research andQuality, 2001.

Pediatrics.

10. Bondy J, Berman S, Glazner J, Lezotte D. Directexpenditures related to otitis media diagnoses: extrapolationsfrom a pediatric Medicaid cohort. 2000;105:E72.

11. What is a dollar worth? Federal Reserve Bank ofMinneapolis. Available at: http://minneapolisfed.org/Research/data/us/calc/index.cfm. Accessed May 6, 2005.

Pediatr Infect Dis J.

12. Bluestone CD, Stephenson JS, Martin LM. Ten-yearreview of otitis media pathogens. 1992;11(suppl 8):S7-S11.

J Pediatr.

13. Johnson CE, Carlin SA, Super DM, et al. Cefiximecompared with amoxicillin for treatment of acute otitismedia. 1991;119:117-122.

J Pediatr.

14. Del Beccaro MA, Mendelman PM, Inglis AF, et al.Bacteriology of acute otitis media: a new perspective.1992;120:81-84.

Pediatr Infect Dis.

15. Harrison CJ, Marks MI, Welch DF. Microbiology ofrecently treated acute otitis media compared with previouslyuntreated acute otitis media. 1985;4:641-646.

Antimicrob Agents Chemother.

16. Jacobs MR, Dagan R, Appelbaum PC, Burch DJ.Prevalence of antimicrobial-resistant pathogens in middleear fluid: multinational study of 917 children withacute otitis media. 1998;42:589-595.

Pediatr Infect Dis J.

17. Block SL, Hedrick JA, Tyler RD, Smith RA, HarrisonCJ. Microbiology of acute otitis media recently treatedwith aminopenicillins. 2001;20:1017-1021.

Pediatr Infect Dis J.

18. Duchin JS, Breiman RF, Diamond A, et al. Highprevalence of multidrug-resistant Streptococcus pneumoniaeamong children in a rural Kentucky community.1995;14:745-750.

Pediatr

Infect Dis J.

19. Black S, Shinefield H, Fireman B, et al. Efficacy,safety and immunogenicity of heptavalent pneumococcalconjugate vaccine in children. Northern CaliforniaKaiser Permanente Vaccine Study Center Group. 2000;19:187-195.

Pediatr Infect Dis J.

20. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E,Ray P. Impact of the pneumococcal conjugate vaccineon otitis media. 2003;22:10-16.

Pediatr Infect Dis J.

21. Casey JR, Pichichero ME. Changes in frequency andpathogens causing acute otitis media in 1995-2003.2004;23:824-828.

Pediatr Infect Dis J.

22. Block SL, Hedrick J, Harrison CJ, et al. Community-widevaccination with the heptavalent pneumococcalconjugate significantly alters the microbiology of acuteotitis media. 2004;23:829-833.

Pediatr Infect Dis J.

23. Gehanno P, N'Guyen L, Derriennic M, Pichon F,Goehrs JM, Berche P. Pathogens isolated during treatmentfailures in otitis. 1998;17:885-890.

Pediatr Infect Dis J.

24. del Castillo F, Baquero-Artigao F, Garcia-Perea A.Influence of recent antibiotic therapy on antimicrobialresistance of Streptococcus pneumoniae in children withacute otitis media in Spain. 1998;17:94-97.

Pediatr Infect Dis J.

25. Leibovitz E, Raiz S, Piglansky L, et al. Resistancepattern of middle ear fluid isolates in acute otitis mediarecently treated with antibiotics. 1998;17:463-469.

Physician's Desk Reference (electronic version).

26. Greenwood Village, Colo: Thomson MICROMEDEX;2005.

J Infect

Dis.

27. Dagan R, Givon-Lavi N, Shkolnik L, Yagupsky P,Fraser D. Acute otitis media caused by antibiotic-resistantStreptococcus pneumoniae in southern Israel: implicationfor immunizing with conjugate vaccines. 2000;181:1322-1329.

Clin Infect Dis.

28. Joloba ML, Windau A, Bajaksouzian S, et al.Pneumococcal conjugate vaccine serotypes ofStreptococcus pneumoniae isolates and the antimicrobialsusceptibility of such isolates in children with otitismedia. 2001;33:1489-1494.

Pediatr Res.

29. Block SL, Hedrick JA, Harrison CJ. Widespread useof conjugated pneumococcal vaccine significantlyreduces rates of AOM and antibiotic usage. Abstract#1135. 2004;55(suppl):201A.

N Engl J Med.

30. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcalconjugate vaccine against acute otitis media.2001;344:403-409.

MMWR Morb

Mortal Wkly Rep.

31. Centers for Disease Control. National, state, andurban area vaccination coverage among children aged19-35 months—United States, 2003. 2004;53:658-661.

MMWR Morb Mortal Wkly

Rep.

32. Centers for Disease Control. Updated recommendationsfor use of pneumococcal conjugate vaccine: reinstatementof the third dose. 2004;53:589-590.

Clin Infect

Dis.

33. Kilpi T, Ahman H, Jokinen J, et al. Protective efficacyof a second pneumococcal conjugate vaccine againstpneumococcal acute otitis media in infants and children:randomized, controlled trial of a 7-valent pneumococcalpolysaccharide-meningococcal outer membrane proteincomplex conjugate vaccine in 1666 children. 2003;37:1155-1164.

Nurse Pract.

34. Dowell SF, Butler JC, Giebink GS. Acute otitismedia: management and surveillance in an era of pneumococcalresistance. Drug-Resistant StreptococcusPneumoniae Therapeutic Working Group. 1999;24(suppl 10):1-9.

JAMA.

35. Williams RL, Chalmers TC, Stange KC, ChalmersFT, Bowlin SJ. Use of antibiotics in preventing recurrentacute otitis media and in treating otitis media with effusion.A meta-analytic attempt to resolve the brouhaha.1993;270:1344-1351.

N Engl J

Med.

36. Whitney CG, Farley MM, Hadler J, et al. Decline ininvasive pneumococcal disease after the introduction ofprotein-polysaccharide conjugate vaccine. 2003;348:1737-1746.

Pediatr Infect

Dis J.

37. Black S, Shinefield H, Baxter R, et al. Postlicensuresurveillance for pneumococcal invasive disease after useof heptavalent pneumococcal conjugate vaccine inNorthern California Kaiser Permanente. 2004;23:485-489.

N Engl J

Med.

38. Klugman KP, Madhi SA, Huebner RE, et al. A trialof a 9-valent pneumococcal conjugate vaccine in childrenwith and those without HIV infection. 2003;349:1341-1348.

Pediatrics.

39. Dowell SF, Marcy SM, Philips WR, Gerber MA,Schwartz B. Otitis media—principles of judicious use ofantimicrobial agents. 1998;101(suppl):165-171.

Pediatrics.

40. Garbutt J, Jeffe DB, Shackelford P. Diagnosis andtreatment of acute otitis media: an assessment.2003;112:143-149.

Antimicrob Agents Chemother.

41. Lister PD, Pong A, Chartrand SA, Sanders CC.Rationale behind high-dose amoxicillin therapy for acuteotitis media due to penicillin-nonsusceptible pneumococci:support from in vitro pharmacodynamic studies.1997;41:1926-1932.

Pediatr Infect Dis J.

42. Piglansky L, Leibovitz E, Raiz S, et al. Bacteriologicand clinical efficacy of high dose amoxicillin for therapyof acute otitis media in children. 2003;22:405-413.

Pediatrics.

43. Palmer DA, Bauchner H. Parents' and physicians'views on antibiotics. 1997;99:E6.

Pediatr Infect Dis J.

44. Seikel K, Shelton S, McCracken GH Jr. Middle earfluid concentrations of amoxicillin after large dosages inchildren with acute otitis media. 1997;16:710-711.

Pediatr Infect Dis J.

45. Dowell SF, Butler JC, Giebink GS, et al. Acute otitismedia: management and surveillance in an era of pneumococcalresistance—a report from the Drug-resistantStreptococcus Pneumoniae Therapeutic Working Group.1999;18:1-9.

Pediatrics.

46. American Academy of Pediatrics Subcommittee onManagement. Diagnosis and management of acute otitismedia. 2004;113:1451-1465.

Pediatr Infect Dis J.

47. Dagan R, Johnson CE, McLinn S, et al. Bacteriologicand clinical efficacy of amoxicillin/clavulanate vs.azithromycin in acute otitis media. 2000;19:95-104.

Pediatr.

48. Patel JA, Reisner B, Vizirinia N, Owen M,Chonmaitree T, Howie V. Bacteriologic failure of amoxicillin-clavulanate in treatment of acute otitis mediacaused by nontypeable Haemophilus influenzae. 1995;126:799-806.

Pediatr Infect Dis J.

49. Dagan R, Hoberman A, Johnson C, et al.Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media.2001;20:829-837.

Pedatr Infec Dis J.

50. Hoberman A, Dagan R, Leibovitz E, et al. Largedosage amoxicillin/clavulanate, compared withazithromycin, for the treatment of bacterial acute otitismedia in children. 2005;24:525-532.

Clin Infect Dis.

51. Howie VM. Eradication of bacterial pathogens frommiddle ear infections. 1992;14(suppl2):209-211.

J Infect Dis.

52. Dagan R, Abramson O, Leibovitz E, et al.Bacteriologic response to oral cephalosporins: areestablished susceptibility breakpoints appropriate inthe case of acute otitis media? 1997;176:1253-1259.

Int J Antimicrob

Agents.

53. Brook I. Use of oral cephalosporins in the treatmentof acute otitis media in children. 2004;24:18-23.

Antimicrob Agents Chemother.

54. Jacobs MR, Bajaksouzian S, Zilles A, Lin G,Pankuch GA, Appelbaum PC. Susceptibilities ofStreptococcus pneumoniae and Haemophilus influenzaeto 10 oral antimicrobial agents based on pharmacodynamicparameters: 1997 U.S. Surveillance Study.1999;43:1901-1908.

Clin Microbiol Infect.

55. Jacobs MR. Optimisation of antimicrobial therapyusing pharmacokinetic and pharmacodynamic parameters.2001;7:589-596.

Clin Lab

Med.

56. Jacobs MR, Bajaksouzian S, Windau A, et al.Susceptibility of Streptococcus pneumoniae,Haemophilus influenzae, and Moraxella catarrhalis to 17oral antimicrobial agents based on pharmacodynamicparameters: 1998-2001 US Surveillance Study. 2004;24:503-530.

Pediatr Infect Dis J.

57. Klein JO. Microbiologic efficacy of antibacterialdrugs for acute otitis media. 1993;12:973-975.

Pediatr Infect Dis J.

58. Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologicefficacy of a three-day intramuscular ceftriaxone regimenin nonresponsive acute otitis media. 1998;17:1126-1131.

Pediatr

Infect Dis J.

59. Leibovitz E, Piglansky L, Raiz S, Press J, LeibermanA, Dagan R. Bacteriologic and clinical efficacy of oneday vs. three day intramuscular ceftriaxone for treatmentof nonresponsive acute otitis media in children. 2000;19:1040-1045.

Pediatrics.

60. Pichichero ME. A review of evidence supportingthe American Academy of Pediatrics recommendationfor prescribing cephalosporin antibiotics forpenicillin-allergic patients. 2005;115:1048-1057.

Antimicrob Agents

Chemother.

61. Ednie LM, Visalli MA, Jacobs MR, Appelbaum PC.Comparative activities of clarithromycin, erythromycin,and azithromycin against penicillin-susceptible andpenicillin-resistant pneumococci. 1996;40:1950-1952.

Performance standards for antimicrobial

susceptibility tests (M100-S8).

62. National Committee for Clinical LaboratoryStandards. Villanova, Pa: NationalCommittee for Clinical Laboratory Standards, 1998.

Pediatr Infect Dis J.

63. Olson LC, Jackson MA. Only the pneumococcus.1999;18:849-850.

Pediatr Infect Dis J.

64. Rodriguez WJ, Schwartz RH. Streptococcus pneumoniaecauses otitis media with higher fever and moreredness of tympanic membranes than Haemophilusinfluenzae or Moraxella catarrhalis. 1999;18:942-944.

Pediatrics.

65. Heikkinen T, Ghaffar F, Okorodudu AO, ChonmaitreeT. Serum interleukin-6 in bacterial and nonbacterial acuteotitis media. 1998;102:296-299.

Pediatr Infect

Dis J.

66. Broides A, Leibovitz E, Dagan R, et al. Cytology ofmiddle ear fluid during acute otitis media. 2002;21:57-61.

Pediatr Infect Dis J.

67. McCormick DP, Lim-Melia E, Saeed K, BaldwinCD, Chonmaitree T. Otitis media: can clinical findingspredict bacterial or viral etiology? 2000;19:256-258.

Pediatr Infect Dis J.

68. Leibovitz E, Satran R, Piglansky L, et al. Can acuteotitis media caused by Haemophilus influenzae be distinguishedfrom that caused by Streptococcus pneumoniae?2003;22:509-515.

Pediatr Infect Dis J.

69. Bahadori RS, Schwartz RH, Ziai M. Acute mastoiditisin children: an increase in frequency in NorthernVirginia. 2000;19:212-215.

Pediatr Infect Dis J.

70. Katz A, Leibovitz E, Greenberg D, et al. Acute mastoiditisin Southern Israel: a twelve year retrospectivestudy (1990 through 2001). 2003;22:878-882.

Int J

Pediatr Otorhinolaryngol.

71. Luntz M, Brodsky A, Nusem S, et al. Acute mastoiditis—the antibiotic era: a multicenter study. 2001;57:1-9.

Int J Pediatr Otorhinolaryngol.

72. Tarantino V, D'Agostino R, Taborelli G, MelagranaA, Porcu A, Stura M. Acute mastoiditis: a 10 year retrospectivestudy. 2002;66:143-148.