Pharmacodynamic Target Attainment of Oral β-Lactams for the Empiric Treatment of Acute Otitis Media in Children

Abstract

To determine the probability of oral beta-lactam regimens achieving bactericidal pharmacodynamic exposure against pathogens causing acute otitis media (AOM) given contemporary prevalence and resistance rates. A 5000-patient Monte Carlo simulation was used to recreate steady-state concentration-time profiles for oral drug administration regimens of amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime in a population of 12.5-month-old children. The percent of simulated children in whom free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the drug administration interval (50% fT>MIC) were achieved was determined; 180 middle ear fluid isolates (56 Haemophilus influenzae and 124 Streptococcus pneumoniae) collected during the 2004 Global Respiratory Antimicrobial Surveillance Project (GRASP) were used. The cumulative fraction of response (CFR) was calculated and weighted against the prevalence of organisms causing AOM extrapolated from the literature. The contribution of a 'Pollyanna phenomenon' for each organism was also incorporated to estimate clinical effectiveness. Against S. pneumoniae isolates, amoxicillin 30 mg/kg every 8 hours (84.7%) achieved the greatest CFR followed by amoxicillin/clavulanic acid and the other amoxicillin-based regimens. Against H. influenzae isolates, cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid each achieved a CFR of >90%. When weighted by the prevalence of AOM-causing pathogens, CFR was highest for cefpodoxime (87.5%), amoxicillin/clavulanic acid (85.7%), and amoxicillin 30 mg/kg every 8 hours (70.8%). The contribution of a 'Pollyanna phenomenon' increased the probability of clinical effectiveness for all agents, with amoxicillin/clavulanic acid (90.2%) and cefpodoxime (90.1%) having the highest weighted CFR. Based on the recent epidemiologic and resistance profiles of S. pneumoniae and H. influenzae, amoxicillin/clavulanic acid (45 mg/kg every 12 hours) and cefpodoxime (5 mg/kg every 12 hours) provide the greatest likelihood of achieving optimal pharmacodynamic exposures empirically in children with AOM.