Supplements Balancing Outcomes in AOM and ABS: Impact of Efficacy and Adherence and the Implications for Managed
A Review of Recommended Antibiotic Therapies With Impact on Outcomes in Acute Otitis Media and Acute Bacterial Sinusitis
Acute otitis media (AOM) and acute bacterial sinusitis (ABS) management is becoming increasingly complex, with continual changes in the pathogens responsible for these conditions. Treatment involves the selection of an efficacious agent displaying a favorable adherence profile. Although antibiotic efficacy is critical to treatment successes, therapy adherence is arguably of equal importance, because failure to adhere to even the most effective therapy can ultimately lead to clinical failure and undermine treatment efforts. The dual importance of efficacy and adherence requires additional consideration when treating pediatric infections. Managed care organizations (MCOs) are increasingly aware that a balance is needed when weighing efficacy and adherence issues with antibiotics. In one study, a health maintenance organization initiated a guideline compliance education and provider-reporting pathway program among 900 physicians, nurse practitioners, and physician assistants in Rochester, NY, resulting in increased quality of care and a reduction in pharmacy costs.1
More health plans should use provider and patient education strategies to improve provider compliance to national guidelines. Formulary redevelopment can improve care if efforts are made to evaluate emerging disease management issues, including the shifting microbiology of the organisms implicated in AOM and ABS, medication costs, and the evaluation of products with the best reported adherence. The purpose of this paper is to present the main costs of AOM and ABS, review the impact of treatment failures, and discuss the dual role of efficacy and adherence in the treatment of AOM and ABS.
Direct and Indirect Costs of AOM and ABS
The total costs of both AOM and ABS can be high. Direct AOM and ABS costs are typically based on medication use and physician visits. Annual estimates of direct AOM costs range from $1.96 billion to $4.1 billion,2,3 whereas direct sinusitis costs (as a primary diagnosis) are estimated at $1.8 billion.4 However, direct costs represent only a portion of the total economic burden of illness. Indirect costs can include the expense of care for sick children, transportation costs, the value of work time lost, baby-sitting fees, ancillary medication costs, and expenditures for treatment of adverse effects.5 Indirect costs are estimated at $1.02 billion for AOM2 and $1.6 billion for ABS.4 These significant indirect costs emphasize that AOM and ABS impose a considerable economic burden for the patient, family, or employer who is purchasing health insurance coverage in part or in full.
Impact of Treatment Failures
Treatment failure can lead to persistent or recurrent infection, which in turn leads to an increase in overall cost of care.6 Poor efficacy is in part responsible for persistent and recurrent infections, with prior antibiotic use increasing the likelihood of treatment failure by enhancing the risk of infection from resistant organisms.7,8 An incorrect diagnosis and poor adherence to therapy also contribute to poor treatment outcomes. Primary care physicians refer and ear, nose, and throat (ENT) surgeons operate on patients with persistent and recurrent infection. 9 Consequently, improved adherence to diagnostic criteria and appropriate antibiotic selection according to national treatment guidelines may improve the management of AOM and ABS.6
As discussed in the previous article, treatment success and the cost of therapy can be attributed greatly to therapy adherence.10 Adherence is influenced by factors such as tolerability, patient and caregiver preference, dosing regimen/duration of therapy, palatability, and satisfaction with therapy.5,11-16 For example, tolerability and ease of administration may increase adherence to prescribed therapy,14 and a shorter duration of therapy (ie, 5 days vs 10 days) is shown to improve therapy adherence.15 To predict the likelihood of treatment success in AOM and ABS, it is important to look at components of adherence for agents used to treat these conditions.
Benefits of Judicious Treatment Selection: Current Therapies
When selecting an agent for the treatment of AOM and ABS, the main contributors to favorable outcomesľefficacy and adherenceľshould be examined closely. Judicious antibiotic selection should positively affect the entire healthcare system. This merits review of the guideline-endorsed antibiotics (Table 1), the antibiotics not endorsed, and the rationale for the distinction between the 2 groups of drugs.
Amoxicillin. Amoxicillin is the mainstay of treatment for AOM and ABS and is currently recommended as first-line therapy in both of these conditions.17,18 Amoxicillin is effective against Streptococcus pneumoniae, including penicillin nonsusceptible S pneumoniae (PNSP) when administered in off-label high dosages (eg, 80-100 mg/kg per day in children and 1.5 g twice daily in adults). However, amoxicillin is ineffective against ├č-lactamase-producing pathogens.19,20 The clinical efficacy of amoxicillin is well established, based on trials conducted from as long as 30 years ago.17,20
Although amoxicillin is an acceptable drug for eradicating ├č-lactamase-negative Haemophilus influenzae, it is no better than a placebo against ├č-lactamase-positive H influenzae.20 The release of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 and its widespread use by 2004 gradually led to a documented shift in the microbiology of persistent/recurrent AOM in the pediatric population (Figure).21,22 This shift likely occurred in ABS because both diseases involve the same pathogens. Even adult AOM and ABS likely have experienced a pathogen shift because of a herd immunity effect of PCV7. A decrease in PNSP strains from PCV7 vaccine use alluded to H influenzae as the pathogen most likely responsible for AOM and ABS infection. H influenzae has also become more resistant to antibiotics over the years by acquiring the ability to produce ├č-lactamase. This shift in microbiology allegedly occurring in both AOM and ABS should be considered when evaluating the antimicrobial efficacy of amoxicillin.
Amoxicillin is well tolerated and has favorable taste scores in suspension for- mulation for pediatric patients.15 Interestingly, a recent willingness-to-pay study in AOM patients evaluating compliance (defined as having no missed doses) and adherence (defined as taking medication on time) reported that amoxicillin therapy had the poorest ratings (75% and 59%, compliance and adherence, respectively), significantly lower than amoxicillin/clavulanate (85% and 66%), azithromycin (91% and 79%), cefprozil (71% and 64%), and clarithromycin (78% and 65%).23 Amoxicillin had the lowest tolerability rate,24 and its taste did not appear to impact compliance. Poor compliance could be the result of the dosage frequency in the study (3 times daily) or the prescribing regimen of 7 to 10 days.
Amoxicillin/clavulanate. The addition of clavulanate to amoxicillin provides the combination product with additional activity against b-lactamase-producing pathogens. As with amoxicillin, extra-strength amoxicillin/ clavulanate (90/6.4 mg/kg/day) has shown high bacterial eradication rates for PNSP of 90% and 94% in 2 studies.25,26 Based on its efficacy, extra-strength amoxicillin/clavulanate is recommended for the second-line treatment of uncomplicated AOM, first-line therapy for persistent/recurrent AOM, and first-line treatment for mild, moderate, or severe ABS.7,17,18
Tolerability of amoxicillin/clavulanate is problematic. In many head-to-head trials against other AOM and ABS treatments (including cefdinir, cefprozil, and cefuroxime), the adverse event rate for amoxicillin/ clavulanate exceeds that of the comparator agent.27-34 In most of these studies, gastrointestinal effects (such as diarrhea) are the most frequently reported adverse event of amoxicillin/clavulanate therapy.
The data related to amoxicillin/clavulanate's palatability is also not favorable. A series of 6 randomized, single-blind, crossover trials compared the taste and smell of oral antibiotic suspensions in children. Amoxicillin/clavulanate was consistently significantly inferior in taste and smell acceptance compared with cefdinir, another guideline-endorsed drug in both the single- and multi-center studies.35
Cefpodoxime. The third-generation cephalosporin cefpodoxime is one of the recommended agents for AOM and ABS. Its efficacy in AOM is demonstrated in noninferiority trials versus standard-strength amoxicillin/clavulanate, cefaclor, cefixime, and amoxicillin.36-40 In these trials, clinical response or clinical cure rates were similar in 2 trials of cefpodoxime and cefaclor (success rates of 93.6% and 95% vs 91.6% and 90%, respectively; P = NS)37,38 and a single trial with cefixime (clinical cure rate 56% vs 54%; P = NS).39 Trial results comparing cefpodoxime and standard-strength amoxicillin/ clavulanate have conflicted; and in one trial, the clinical cure rate of twice-daily cefpodoxime (68%) did not differ from that of 3-times-daily standard-strength amoxicillin/ clavulanate (65%; P = .57),36 whereas a similar trial demonstrated a difference in clinical cure rates between treatments favoring cefpodoxime (60% vs 40%; P = .003).40 Cefpodoxime was also compared with amoxicillin in the treatment of ABS and was equivalent with clinical response rates of 96% and 91%, respectively.41
In the trials, cefpodoxime had a similar adverse event profile to amoxicillin, cefaclor, cefixime, and regular-strength amoxicillin/ clavulanate,36,37,39-41 with gastrointestinal and dermatological adverse events most frequently reported.36
Adherence to once-daily cefpodoxime can be improved over amoxicillin or amoxicillin/ clavulanate from differences in dosing regimen (once-or twice-daily cefpodoxime vs 2- to 3-times-daily amoxicillin or amoxicillin/ clavulanate), although no difference in adherence was noted in 1 head-to-head trial.40 Palatability may play a key role in determining adherence with cefopdoxime for children. One blinded taste study measuring 12 antibiotic suspensions by smell, texture, taste, aftertaste, and overall acceptance found cefpodoxime significantly inferior in aftertaste to comparators.12