BACKGROUND: High dose (70 to 90 mg/kg/day) amoxicillin is recommended as first line therapy of acute otitis media (AOM) in geographic areas where drug-resistant Streptococcus pneumoniae is prevalent. Information on the bacteriologic efficacy of high dose amoxicillin treatment for AOM is limited. OBJECTIVES: To evaluate the bacteriologic and clinical efficacy of high dose amoxicillin as first line therapy in AOM. METHODS: In a prospective study 50 culture-positive patients ages 3 to 22 months (median, 9 months; 77% <1 year) were treated with high dose amoxicillin (80 mg/kg/day three times a day for 10 days) No antibiotics were administered 72 h before enrollment. Twenty-four (48%) patients presented with their first episode of AOM. Middle ear fluid was cultured by tympanocentesis at enrollment and on Days 4 to 6 of therapy. Additional middle ear fluid cultures were obtained if clinical relapse occurred. Bacteriologic failure was defined by positive cultures on Days 4 to 6 and clinical failure by no change or worsening of AOM signs and symptoms and requirement for additional antibiotics during therapy and/or at end of therapy. Patients were followed until Day 28 +/- 2. Susceptibility to penicillin and amoxicillin was measured by E-test. RESULTS: Sixty-five organisms were recovered at enrollment: Haemophilus influenzae (38), Streptococcus pneumoniae (24), Streptococcus pyogenes (2) and Moraxella catarrhalis (1). Eighteen (75%) S. pneumoniae were nonsusceptible to penicillin (MIC > 0.1 microg/ml). All 24 S. pneumoniae isolates had amoxicillin MIC < or = 2.0 microg/ml. Thirteen (34%) of the 38 H. influenzae were beta-lactamase producers. Eradication was achieved in 41 (82%) patients for 54 of 65 (83%) pathogens: 22 of 24 (92%) S. pneumoniae, 21 of 25 (84%) beta-lactamase-negative H. influenzae, 8 of 13 (62%) beta-lactamase-positive H. influenzae, 2 of 2 S. pyogenes and 1 of 1 M. catarrhalis. Seven organisms not initially present were isolated on Days 4 to 6 in 5 patients: 3 beta-lactamase-positive H. influenzae; 1 beta-lactamase-negative H. influenzae; 2 S. pneumoniae; and 1 M. catarrhalis. In total 14 of 50 (28%) patients failed bacteriologically on Days 4 to 6 (persistence + new infection), of whom 9 (64%) had beta-lactamase-positive H. influenzae. Three (33%) of the 9 patients with bacteriologic failure (2 beta-lactamase-positive H. influenzae, 1 S. pneumoniae) failed also clinically on Days 4 to 6. CONCLUSIONS: The predominant pathogens isolated from children with AOM failing high dose amoxicillin therapy were beta-lactamase-producing organisms. Because its overall clinical efficacy is good, high dose amoxicillin is still an appropriate choice as first line empiric therapy for AOM, followed by a beta-lactamase-stable drug in the event of failure.