This article will discuss how therapy adherencemay have an impact on acute otitis media (AOM)outcomes. Although the relationship between therapyadherence and treatment failures in AOM has notbeen proved beyond question, many believe thatadherence with antibiotic therapy plays a key role inpatient outcomes. Poor adherence may contribute totreatment failures; treatment failures are known toresult in poorer health outcomes, higher total costs ofcare, and an increased potential for bacterial resistance.As such, managed care organizations shouldconsider strategies for achieving better patient adherencewith antibiotic regimens for AOM.
(Am J Manag Care. 2005;11:S202-S210)
Acute otitis media (AOM) is a highlyprevalent and costly disease. WhenAOM has been diagnosed and thedecision to treat the infection with antibiotictherapy has been made, practitioners andparents should consider issues such as efficacy,therapy adherence, spectrum of activity,and health outcomes when selectingtherapy. Several agents appear to be equallyefficacious in the treatment of recurrentAOM; however, there are other factors thatdifferentiate these agents. The microbiologyof AOM is shifting, and there will be clinicalconsequences related to the selection oftherapy.1 The first-line therapy for the treatmentof uncomplicated AOM (amoxicillin) isunlikely to be affected by this shift becauseof its safety and low cost, but there arepotential implications for therapy in recurrentAOM. Although the relationship betweentherapy adherence and treatmentfailures in AOM has not been proven beyondquestion, many believe that adherence withantibiotic therapy plays a key role in patientoutcomes.2-7 Poor adherence may contributeto treatment failures; treatment failures areknown to result in poorer health outcomes,higher total costs of care, and an increasedpotential for bacterial resistance.
Direct and Indirect Costs of AOM
The total annual costs of AOM in theUnited States have been estimated to bebetween $1.4 billion and $4.1 billion.8-12 Areview of these estimates can be found inTable 1; these estimates vary based on differencesin the age ranges of the populationand estimates of disease incidence used inthe analyses. Of these estimates, the mostreliable estimate appears to have beencompleted by the Southern CaliforniaEvidence-based Practice Center. Based ondata from the 1995 National AmbulatoryMedical Care Surveys (NAMCS) and theNational Hospital Ambulatory Medical CareSurveys (NHAMCS), an estimated 5.18 millionepisodes of AOM occurred among children0 to 17 years old, resulting in a totalannual cost of $2.98 billion.8
When evaluating the total costs of AOM,it may be useful to examine the 2 componentsof total cost (direct costs and indirectcosts) separately. Direct medical costs,defined as fixed and variable costs associateddirectly with a medical condition orhealthcare intervention,13 often includecomponents such as office visit, hospitalization,medication, and surgical costs. A retrospectiveanalysis of a fee-for-serviceMedicaid program claims database led to anational estimate of $4.1 billion in directmedical costs incurred by otitis media inchildren younger than 14 years old.9 Thisanalysis also demonstrated that more than40% of national expenditures on otitismedia were generated by children between1 and 3 years old and that the largest componentof direct medical costs was officevisits. Other estimates of the total annualdirect costs of AOM in children have rangedfrom $1.3 billion to $3.2 billion.8,11,12
Whereas indirect costs attributed to illnessare often overlooked, these costs canrepresent a large percentage of total illnesscosts and can present a significant burden topatients and caregivers. As 2 wage-earnerfamilies have become the largest employeegroup in the United States,14 one parentoften has to stay home to care for a child sufferingfrom AOM, as daycare providers willnot care for a sick, febrile child.15 The valueof work time lost, transportation costs (actuallya direct cost), alternate childcare fees,ancillary medication costs (direct cost), andcharges for treatment of adverse effects(direct cost) are often included in calculationsof the indirect costs of AOM.4,16 As partof a safety and efficacy study, parents orguardians of children being treated for AOMcompleted a questionnaire 12 to 14 daysafter the first dose of antibiotic therapy. Atotal of 60% of the parents completing thesurvey worked, and, of those, 32% missed anaverage of 1.2 days of work (range 0.5-3days) because of the child's illness. Of theparents who used daycare for their children,42% of the children missed an average of 1.7days from daycare because of the illness.17In studies that have examined both directand indirect costs of AOM, it has been estimatedthat the indirect costs of AOM representbetween 9.8% and 57.1% of the totalcosts of illness.8,11,12 Further, these cost estimatesfail to account for the sizable impactthat AOM has on the quality of life of boththe child and their caregivers.18
Prescription Antibiotic Use in AOM
A retrospective analysis using NAMCSdata documented a large increase in antimicrobialprescribing for otitis media.19Between 1980 and 1992, the number ofantibiotic prescriptions written for AOMnearly doubled from 11.9 million per year to23.6 million per year, fueled by largeincreases in the rate of amoxicillin andcephalosporin use. Among children youngerthan 15 years old, the office visit rate for otitismedia increased significantly, fromapproximately 275 visits per year to approximately425 visits per year per 1000 children(= .004). The increase in office visits forotitis media likely represents an actualincrease in the incidence of the disease,because widespread use of daycare facilitiesby infants and toddlers evolved during thisperiod.20-22
A follow-up study compared antimicrobialprescribing for the periods of 1989-1990and 1999-2000.23 In this analysis, the investigatorsdetermined that the mean annualoffice visit rate for otitis media per 1000children and adolescents younger than 15years old decreased from 428 visits per yearto 230 visits per year (<.001) between the2 time periods. Similar decreases were seenin office visits for pharyngitis and bronchitis.Overall, the mean number of antimicrobialprescriptions per year for respiratory tractinfections per 1000 children and adolescentsdecreased by 47% during the study period,from 347 prescriptions in 1989-1990 to 184prescriptions in 1999-2000 (< .001), yetthere was no change in visit-based prescribingrates for AOM.22 Decreased office visitsfor AOM can be attributed to physiciansbeing less likely to schedule follow-up visitsthe first few weeks after AOM treatmentbecause antimicrobials ceased to be recommendedfor the management of uncomplicatedAOM.23
Adherence Issues in AOM: Clinical andEconomic Impact
Adherence with antibiotic therapies isgenerally poor among adults; a survey of3600 Europeans showed that only 65% ofworking adults completed the full course ofantibiotic therapy, 87% of the patients whodiscontinued antibiotic therapy did sobecause they felt better, and more than 20%of the respondents also felt it was reasonableto save unused antibiotics for future use.2Fortunately, adult attitudes regarding antibioticprescriptions for their children are different.In the same survey, a much higherpercentage (81%) of mothers reported thattheir children completed the full course ofantibiotic therapy; similar results were seenin a survey of 400 parents and caregivers inMassachusetts.24 As parental and caregiverattitudes indicate an increased desire forantibiotic adherence among their children,antibiotics with indications for childhooddiseases (such as AOM) should possess characteristicsdesigned to improve adherencewith therapy.
Lack of adherence to antibiotic therapyfor AOM may have both clinical and economicimplications to the health plan andtheir members. As discussed earlier, somethought leaders believe that a lack of adherenceto antibiotic therapy may promotetreatment failure in otitis media.2-5 Treatmentfailure can lead to recurrent AOM,which can increase both the health burdenof illness (prolonged discomfort of the child)and the economic burden of disease (eg,through more frequent office visits, laboratoryexpenses, and procedure costs).25Further, persistent and recurrent otitismedia has been associated with serious long-termeffects in children, such as hearing lossand language impairment.26,27
The economic costs of treatment failureinclude increased doctor visits, additionaldays of work missed, and sequelae, such asotitis media with effusion and chronic middleear infection. Improved treatment adherencemay result in improved outcomesbecause of less treatment failures and recurrentdisease, which would lead to better economicoutcomes by decreasing office visits,avoiding time missed from work, anddecreasing overall healthcare costs. Increasedtreatment failures from inadequatecoverage of the implicated pathogens maybe the result of the shift in AOM microbiology.1 The economic impact of this is not fullyknown and will become more evident aschanging pathogens evolve caused byincreased and sustained use of pneumococcalconjugate vaccine.
Factors Affecting Adherence
Adherence to antimicrobial therapy andhealth outcomes can be influenced by factorssuch as tolerability, dosing schedule,duration of therapy, and the preferences ofpatients and caregivers (including palatability,satisfaction with therapy, and prescriptioncost or copayment level).28
Assuming all else is equal,antibiotic tolerability and ease of administrationare the primary considerations in theantibiotic selection process. Contemplationof these items can increase adherence toprescribed therapy.29 If the child experiencesadverse drug events, such as vomiting,nausea, or diarrhea, they are less likely totake the antibiotic, and their parents orcaregivers will be less likely to administerit.29 This can prolong the duration of illnessand the length of time a parent would haveto stay home to care for the child.
The various antibiotics indicated fortreatment of AOM have different tolerabilityprofiles. In a study by Block et al, 425 patientsaged 6 months to 6 years old with nonrefractoryAOM were randomized to a 5-daycourse of cefdinir treatment (14 mg/kg, dividedtwice daily) or a 10-day course of amoxicillin/clavulanate treatment (45/6.4 mg/kg,divided twice daily).30 In this trial, 24% ofsubjects receiving cefdinir experienced adrug-related adverse event, significantly lessthan the 38% of subjects receiving amoxicillin/clavulanate (< .002), and fewer subjectsreceiving cefdinir discontinued therapybecause of drug-related adverse events (0.5%)than subjects receiving amoxicillin/clavulanate(1.9%). A study of 388 caregivers byCifaldi et al examining the same agents,doses, and duration of therapies for thetreatment of AOM as Block et al found ahigher percentage of amoxicillin/clavulanatepatients with vomiting compared with cefdinir(16% vs 8%; = .016), and more parentsof children in the cefdinir groupreported that their child took 100% of theirmedication (68% vs 53%; = .005).17
Numerous studies have examined the useof azithromycin in AOM. In a study byArrieta et al,31 300 patients 6 months to 6years of age with recurrent or persistent AOMwere randomized to receive either high-doseazithromycin (20 mg/kg once daily) for 3days or high-dose amoxicillin/clavulanate(amoxicillin/clavulanate 45/6.4 mg/kg, dividedtwice daily plus amoxicillin 45 mg/kg,divided twice daily) for 10 days. Rates oftreatment-related adverse events were notstatistically different between azithromycinand amoxicillin/clavulanate (32% vs 42%;= .095), although the incidence of diarrheawas significantly lower in the azithromycingroup (30% vs 44%; = .045). Parent-reportedcompliance with therapy (defined as>80% of the prescribed regimen) was 99% forazithromycin and 93% for amoxicillin/clavulanate(= .018). In another trial, a comparisonof 5 days of therapy with azithromycin(10 mg/kg on day 1, 5 mg/kg on days 2-5) orcefdinir (7 mg/kg twice daily) in 357 childrenbetween the ages of 6 months and 6 yearsrevealed no difference between agents in theincidence of adverse events.32 Parent-reportedcompliance with therapy (defined as >80%of the prescribed regimen) was 99% for boththe azithromycin and cefdinir groups.
Dosing Schedule and Duration of
Agents recommended for the treatmentof AOM by the American Academy ofPediatrics33 can be divided by once-andtwice-daily dosing regimens (Table 2). As ageneral rule, compliance with antimicrobialtherapy is better when the patient requiresfewer doses per day.34 A meta-analysis ofinterventions designed to improve therapyadherence showed that dosing schedulechanges can improve adherence an averageof 12% + 8%.35
Agents recommended for the treatment ofAOM by the American Academy of Pediatrics33can also be sorted by those requiringa duration of therapy of 5 or fewer days andthose requiring 7 to 10 days of use (Table 3).Evidence has demonstrated that antibioticregimens of short duration can be effectivefor the treatment of AOM. A 5-day course oftherapy is appropriate for older children, asthere is a high rate of resolution and curewith 3 to 5 days of therapy.29,36,37 In 1997, acomprehensive review of 27 efficacy trials(6932 patients) comparing shorter andlonger courses of treatment for AOM in childrenfound that 3 to 5 days of therapy wasas effective as 10 days of treatment.36 Morerecent studies have demonstrated the efficacyof shorter courses of antibiotic therapycompared with regimens of longerduration.30,31
The duration of antibiotic therapy canalso impact therapy compliance. In a studyby Steele et al,38 a group of 86 healthcarepersonnel was asked to rate the palatabilityof 11 antibiotic suspensions for children incategories of appearance, smell, texture,taste, and aftertaste. Once scored, the participantswere asked to adjust their palatabilityscores once the product's cost,treatment duration, and dosing interval wasmade known. The analysis showed that theantibiotics with a 5-day duration of therapywere rated more favorably than antibioticswith a 10-day duration of therapy. Further,duration of therapy was considered by theevaluators to be more important than dosinginterval, except for those antibiotics dosed 3to 4 times per day.38
Patient and Caregiver Preferences.
Patientand caregiver preferences play animportant factor in compliance with therapyand therapy outcomes and should not beoverlooked by physicians and managed careplans when prescribing therapy or makingformulary decisions. However, prescribersmay have incorrect assumptions about theimportance that caregivers place on differentantibiotic factors. A survey of 400 parentsand 100 pediatricians was conducted todetermine parents' opinions on antibioticsand to compare the results with the opinionsof pediatricians.24 When asked to choose 2 of5 antibiotic factors (cost, dosing schedule,side effects, strength/effectiveness, or taste)that they considered to be most important,parents selected side effects (82%) twice asfrequently as any other factor. When askedto choose 2 of the same 5 antibiotic factorsthat they felt parents considered to be mostimportant, physicians selected dosingschedule (63%) most frequently, and rankedside effects least important (15%).24 Evidenceof this disconnect between caregiversand physicians should spur physicians tospeak to caregivers and patients about theirpreferences regarding antibiotic therapy, inparticular medication palatability, satisfactionwith past therapy, and medication cost.
In pediatric patients, theonly motivation to take an antibiotic forAOM may be the taste of the suspension,39,40and compliance with therapy can be predicatedon taste.38 Although many physiciansfeel this is true based on clinical experience,some historical evidence suggests thatpalatability may be a minor issue because itrelates to compliance in the pediatric population.41,42 However, more recent evidencefailed to find taste differences in the pediatricpopulation and children based on age,concluding that taste is well developed inearly therapy.40 If a better-tasting productimproves adherence, a product with a moreexpensive acquisition cost could be justifiedas cost effective.40
Numerous studies have been conductedto evaluate the taste of medications in children(Table 4).40,43-47 A series of 6 randomized,single-blind, crossover trials comparedthe palatability of cefdinir with the oral suspensionsof amoxicillin/clavulanate, cefprozil,and azithromycin.46 The study groupconsisted of 715 healthy children 4 to 8years of age, who rated the taste and smell ofthe suspensions on a smile-face scale. Fortaste acceptance, cefdinir was rated as significantlybetter than amoxicillin/clavulanate,cefprozil, and azithromycin. A totalof 85% of subjects rated cefdinir as tastinggood or really good, compared with 63% ofsubjects for the comparator products. Forsmell acceptance, cefdinir was rated significantlybetter than amoxicillin/clavulanateand azithromycin and was rated equivalentto cefprozil. The authors concluded that cefdiniris a palatable and well-accepted suspension,supporting its use in pediatricpatients with infection.46
An open-label study was conducted withmore than 12 000 children younger than 12years of age with infections treated on anoutpatient basis.47 These children received 1of 10 antibiotics, and after administrationtheir caregivers filled out a questionnaire inwhich the taste of the antibiotic was gradedon a 5-category scale (very unpleasant tovery pleasant). Of the 10 antibiotics examined,only loracarbef, cefdinir, and cefiximewere rated as very pleasant, pleasant, or okayby more than 80% of patients; alternately,the agents clarithromycin, cefuroxime, andcefpodoxime were rated as unpleasant orvery unpleasant by 50% or more of patients.47
Smaller palatability studies (20-50 subjectseach) of antibiotic suspensions in healthychildren have had various results. Two differentstudies examined the taste of antibioticsuspensions effective against beta-lactamase-producing bacteria; one found cefiximeto have a higher taste score than azithromycin,cefprozil, and amoxicillin/clavulanate,45whereas the other found that azithromycinhad a higher taste score than amoxicillin/clavulanate, erythromycin, ethylsuccinate/sulfisoxazole, and clarithromycin.43 A studyof antibiotic suspensions commonly used forskin infections found cloxacillin to have significantlylower taste scores than cephalexin,erythromycin, and fusidic acid.44
Managed care plans may wish to considerthe palatability of antibiotic suspensionswhen making formulary decisions. Evidencefrom large studies of children suggests thatagents such as cefdinir, loracarbef, andcefixime may be more palatable than comparatorantibiotic suspensions. The improvedpalatability of these agents mayimprove therapy adherence, leading toimproved clinical and economic outcomesfor both patients and the health plan.
Satisfaction with Therapy.
Parental satisfactionwith therapy can play a role in therapyselection and adherence.28,48 In a study byCifaldi et al, caregivers of 388 patients aged 6months to 6 years with nonrefractory AOMwere surveyed 12 to 14 days after the start ofa 5-day course of cefdinir treatment (14mg/kg, divided twice daily) or a 10-day courseof amoxicillin/clavulanate treatment (45/6.4mg/kg, divided twice daily).17 The questionnaireincluded 4 questions to assess satisfactionwith therapy: questions about generalsatisfaction and whether the parents woulduse the medication again, and questionsabout ease of use and taste. Although therewas no difference between the cefdinir andamoxicillin/clavulanate groups in overall satisfactionand willingness to use the medicationagain, parents whose children receivedcefdinir rated ease of use and taste significantlyhigher than parents of children whoreceived amoxicillin/clavulanate (Table 5).
In the previously described open-labelstudy of more than 12 000 children by Steeleet al,47 parents and caregivers were asked torate their satisfaction with 1 of the 10 studyantibiotics on a 5-category scale (extremelysatisfied to extremely dissatisfied). Of the10 antibiotics examined, 9 achieved scoresof extremely satisfied or satisfied at least80% of the time, with only cefuroximereceiving less than 80% (65.2%). Further,only 2 agents, clarithromycin and cefuroxime,had 10% or more of the parents ratetheir satisfaction with therapy as dissatisfiedor extremely dissatisfied. The poor parentsatisfaction scores with cefuroxime wereattributed to the agent's poor taste and ahigher overall failure rate.47
Prescription Cost/Copayment Level.
Thecost of a prescription can be an importantfactor in determining patient adherencewith therapy. Numerous analyses havedetermined that higher prescription costs orcopayment levels are associated with loweradherence to therapy.49-52 Costs can play aneven larger role in patient adherence forfamilies that do not have health insuranceplans with outpatient prescription coverage.
Physicians often consider antibiotic costwhen prescribing therapy for AOM,4 which inaddition to treatment guidelines promotingits use,33,53 might account for the continueduse of amoxicillin as first-line therapy.Physicians participating in an antibiotic suspensionpalatability study38 were asked toreevaluate each product once the cost of acourse of therapy was made known tothem. The palatability of trimethoprim/sulfamethoxazolewas particularly judged to bemore acceptable based on the relatively lowcost of the product. Alternatively, the palatabilityscores of ciprofloxacin and amoxicillin/clavulanate declined precipitously oncethe relatively high costs of those productswere considered, whereas the taste perceptionsof loracarbef, cefdinir, and cefiximemaintained their top ranking after adjustmentswere made for cost. A lower cost productcan be far more expensive in the long runif the patient refuses to adhere to the prescribedregimen because of the taste.
AOM is a highly prevalent and costly diseaseto young children and their parents,health plans, and society. As the shift inAOM pathogens continues, it will be importantto analyze any further increase in costsrelated to treatment failures caused by inadequatecoverage of the implicated pathogens.In addition, other factors that mayaffect AOM health outcomes, such as therapyadherence, should be considered.Nonadherence to antibiotic therapy for AOMmay increase the risk of treatment failure,which is known to lead to poorer health outcomesand increased costs of care. Factorscontributing to poor adherence include poortolerability, inconvenient dosing regimens,prolonged treatment regimens, and the preferencesof patients and caregivers.
Managed care organizations should considerstrategies for achieving better patientadherence with antibiotic regimens forAOM. These strategies may include providingplan practitioners with appropriate educationalmaterials (treatment guidelines,prescribing guidelines, etc) to ensure properantibiotic utilization and selection, andsecuring both antibiotics shown to be palatableto a pediatric population and antibioticswith less frequent dosing and shortenedtreatment durations available on the formulary.These steps may lead to improved clinicaloutcomes for patients and improvedeconomic outcomes for patients, their caregivers,and the health plan.
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