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

August 1, 2005
Michael E. Pichichero, MD

Supplements and Featured Publications, Emerging Issues in the Treatment of Acute Otitis Media: Implications for Managed Care, Volume 11, Issue 6 Suppl

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.1 Children aged7 to 24 months are most likely to developAOM.2-4 Factors 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.7,8 The number ofAOM visits has increased more than 2-fold inthe last quarter of the 20th century.9 A conservativeestimate by the Agency forHealthcare Research and Quality gauges thetotal national cost of AOM to have been$2.98 billion in 1995 dollars,9 whereas moreaggressive estimates gauge the direct costs at$4.1 billion with a per-patient cost of $453in 1992 dollars.10 Adjusting these figures to2005 dollars using the Consumer PriceIndex11 provides 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.9 The 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.5,12-18 Although 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

H

influenzae

S pneumoniae

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.19,20 Persistent AOM is typicallydefined as clinical failure within 30 daysof completion of an antibiotic course.21 Astudy in the 1980s of the microbiology ofAOM in persistent AOM found that was the dominant pathogen, representing53% of the isolates (versus 19% for).15 In the 1990s, 3 studiesdocumented a shift in the persistent AOMpopulation to as the dominantpathogen.5,21,22

S pneumoniae

S pneumoniae

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.5,17,18 This phenomenon wasglobal, as data from France,23 Spain,24 andIsrael25 showed that PNSP accounted for 77%to 90% of the recovered fromchildren with refractory AOM during thistime period.

S pneumonia

H

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.26 Although 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).2,3,27,28 As 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.20 Using 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%.19,20,29,30 However, 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).31 A 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.32 Researchers 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.20 Fortunately, 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 vaccine22,30,33 hasresulted in a corresponding shift in the proportionof cases caused by and.21,22 These 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 AOMmicrobiology21,22 (Figure 3). The overall proportionof decreased from48% to 31% in both studies,21,22 and nontypableincreased from 41% to56% in Kentucky22 and 38% to 57% in NewYork.21 These 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-7.21,22 Similar shifts in AOM microbiologywere seen in Finnish studies.30,33

H influenzae

H influenzae

H influenzae

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 etal29 and Casey and Pichichero,21 there 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.34 It 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 small35 to 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 PNSP36-38 and 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.39 Thefirst 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.39 It has been recommended thatpneumatic otoscopy be used to confirm thepresence of middle ear fluid or effusion.39,40

H influenzae

S pneumoniae

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

H

influenzae

S pneumoniae

M

catarrhalis

H influenzae

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 .22 Economic 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.41,44 However, 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.22,45,46 However, 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

S

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.56 Ceftriaxone 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.46 Recent 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.45 Studies haveshown that pneumococci resistant to erythromycinare also resistant to clarithromycinand azithromycin.61,62 For 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).31 Because ofshortages, many patients received only 2doses of PCV-7 instead of the recommended3 to 4 doses.32 As 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

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.19,30,33,63 Second, by increasing the ratesof AOM caused by , AOM may beassociated with less severe inflammatoryreactions and a less visually inflammatoryview at otoscopy.64-68 Acute 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 .69-72 Ashift 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.

H

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.

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