title: Efficacy of high-dose amoxicillin-clavulanate against experimental respiratory tract infections caused by strains of Streptococcus pneumoniae.
abstract: 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania 19426-0989, USA. Gary_Woodnutt@sbphrd.com
authors.forename: G
authors.initials: G
authors.lastname: Woodnutt
authors.forename: V
authors.initials: V
authors.lastname: Berry
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D011008:Pneumococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D019980:Amoxicillin-Potassium Clavulanate Combination