The purpose of the present investigation was to determine if the efficacy of
amoxicillin-
clavulanate against
penicillin-resistant Streptococcus pneumoniae could be improved by increasing the pediatric
amoxicillin unit dose (90 versus 45 mg/kg of
body weight/day) while maintaining the
clavulanate unit dose at 6.4 mg/kg/day. A rat
pneumonia model was used. In that model approximately 6 log10 CFU of one of four strains of S. pneumoniae (
amoxicillin MICs, 2 microg/ml [one strain], 4 microg/ml [two strains], and 8 microg/ml [one strain]) were instilled into the bronchi of rats.
Amoxicillin-
clavulanate was given by computer-controlled
intravenous infusion to approximate the concentrations achieved in the plasma of children following the administration of oral doses of 45/6.4 mg/kg/day or 90/6.4 mg/kg/g/day divided every 12 h or saline as a control for a total of 3 days. Infusions continued for 3 days, and 2 h after the cessation of infusion, bacterial numbers in the lungs were significantly reduced by the 90/6.4-mg/kg/day equivalent dosage for strains for which
amoxicillin MICs were 2 or 4 microg/ml. The 45/6.4-mg/kg/day equivalent dosage was fully effective only against the strain for which the
amoxicillin MIC was 2 microg/ml and had marginal efficacy against one of the two strains for which
amoxicillin MICs were 4 microg/ml. The bacterial load for the strain for which the
amoxicillin MIC was 8 microg/ml was not reduced with either dosage. These data demonstrate that regimens which achieved concentrations in plasma above the MIC for at least 34% of a 24-h dosing period resulted in significant reductions in the number of viable bacteria, indicating that the efficacy of
amoxicillin-
clavulanate can be extended to include efficacy against less susceptible strains of S. pneumoniae by increasing the
amoxicillin dose.