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Antimicrobial Agents and Chemotherapy, May 2002, p. 1340-1344, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1340-1344.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effects of Specific Antibodies against Streptococcus pneumoniae on Pharmacodynamic Parameters of ß-Lactams in a Mouse Sepsis Model

J. Casal,1* L. Aguilar,2 I. Jado,1 J. Yuste,1 M. J. Giménez,2 J. Prieto,3 and A. Fenoll1

Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda,1 Medical Department, GlaxoSmithKline,2 Microbiology Department, Universidad Complutense, Madrid, Spain3

Received 21 June 2001/ Returned for modification 25 November 2001/ Accepted 25 January 2002

A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of ß-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-ß-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC ({Delta}T > MICs) {approx}30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg ({approx}8 times lower), with the {Delta}T > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.

* Corresponding author. Mailing address: Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo, Km. 2, 28220 Majadahonda, Madrid, Spain. Phone: 34 91 5097975. Fax: 34 91 5097966. E-mail: jcasal{at}isciii.es.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1340-1344, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1340-1344.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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