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Antimicrobial Agents and Chemotherapy, January 1999, p. 35-40, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Efficacy of High-Dose Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniae

Gary Woodnutt* and Valerie Berry

SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania

Received 20 November 1997/Returned for modification 31 March 1998/Accepted 1 September 1998

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 µg/ml [one strain], 4 µg/ml [two strains], and 8 µg/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 µg/ml. The 45/6.4-mg/kg/day equivalent dosage was fully effective only against the strain for which the amoxicillin MIC was 2 µg/ml and had marginal efficacy against one of the two strains for which amoxicillin MICs were 4 µg/ml. The bacterial load for the strain for which the amoxicillin MIC was 8 µg/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.

* Corresponding author. Mailing address: SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Rd., P.O. Box 5089, Collegeville, PA 19426-0989. Phone: (610) 917-5567. Fax: (610) 917-7901. E-mail: Gary_Woodnutt{at}sbphrd.com.

Antimicrobial Agents and Chemotherapy, January 1999, p. 35-40, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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