A new pharmacokinetically enhanced formulation of amoxicillin-clavulanate (2,000 mg of amoxicillin/125 mg of clavulanate twice a day; ratio 16:1) has been designed, with sustained-release technology, to allow coverage of bacterial strains with amoxicillin-clavulanic acid MICs of at least 4/2 mug/ml. The bacteriological efficacy of amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was compared in a rat model of respiratory tract infection versus four other amoxicillin-clavulanate formulations: 8:1 three times a day (1,000/125 mg), 7:1 three times a day (875/125 mg), 7:1 twice a day (875/125 mg), and 4:1 three times a day (500/125 mg); levofloxacin (500 mg once a day); and azithromycin (1,000 mg on day 1 followed thereafter by 500 mg once a day). Bacterial strains included Streptococcus pneumoniae, with amoxicillin-clavulanic acid MICs of 2/1 (one strain), 4/2, or 8/4 microg/ml (three strains each), and Haemophilus influenzae, one beta-lactamase-positive strain and one beta-lactamase-negative, ampicillin-resistant strain. Animals were infected by intrabronchial instillation. Antibacterial treatment commenced 24 h postinfection, with doses delivered by computer-controlled intravenous infusion to approximate the concentrations achieved in human plasma following oral administration. Plasma concentrations in the rat corresponded closely with target human concentrations for all antimicrobials tested. Amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was effective against all S. pneumoniae strains tested, including those with amoxicillin-clavulanic acid MICs of up to 8/4 microg/ml and against beta-lactamase-producing and beta-lactamase-negative ampicillin-resistant H. influenzae. These results demonstrate the bacteriological efficacy of pharmacokinetically enhanced amoxicillin-clavulanate 2,000/125 mg twice a day (ratio 16:1) against S. pneumoniae with amoxicillin-clavulanic acid MICs of at least 4/2 microg/ml and support clavulanate 125 mg twice a day as sufficient to protect against beta-lactamase in this rat model.