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Antimicrobial Agents and Chemotherapy, January 1999, p. 35-40, Vol. 43, No. 1
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.
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
*
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.
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