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Antimicrobial Agents and Chemotherapy, November 2004, p. 4144-4147, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4144-4147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effects of Amoxicillin Subinhibitory Concentrations on the Cross-Protection Developed by Pneumococcal Antibodies in Mouse Sepsis Caused by an Amoxicillin-Resistant Serotype 6B Streptococcus pneumoniae Strain

D. Tarragó,¹ L. Aguilar,² M. J. Giménez,² A. Fenoll,¹ and J. Casal^1*

Centro Nacional de Microbiología, Instituto de Salud Carlos III,¹ Medical Department, GlaxoSmithKline, Madrid, Spain²

Received 4 December 2003/ Returned for modification 20 April 2004/ Accepted 5 July 2004

A model of mouse sepsis caused by a serotype 6B Streptococcus pneumoniae strain (amoxicillin MIC of 8 µg/ml) was developed to investigate the therapeutic effect of an amoxicillin dose (3.12 mg/kg of body weight three times daily for 48 h) producing, over the whole treatment period, subinhibitory concentrations in serum (peak concentration [C_max]: 6.1 µg/ml) in animals that prior to infection had been passively immunized with a 6B or 23F hyperimmune serum (obtained by immunization with a whole-cell heat-inactivated inoculum and diluted to produce no protective effect by itself). Mortality in nonimmunized animals treated with antibiotic (3.12 mg/kg) was 90%, and mortality in animals immunized but not treated with the antibiotic was 100%. Antibiotic treatment in immunized animals produced mortality rates 20% when the hyperimmune serum was used, thus showing cross-protection and synergism (defined as the situation in which there is no response to the single agents [no differences versus placebo] while the combination exhibits significant activity) with subinhibitory concentrations of the antibiotic. The presence of antipneumococcal antibodies allowed antibiotic efficacy with negligible values of pharmacodynamic parameters (C_max/MIC ratio of <1 and thus a null value for the time that serum levels exceed the MIC). This in vivo synergism offers a potential therapeutic strategy against resistant strains.

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* Corresponding author. Mailing address: Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo Km.2, 28220 Majadahonda, Madrid, Spain. Phone: 34 918223616. Fax: 34 915097966. E-mail: jcasal{at}isciii.es.

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Antimicrobial Agents and Chemotherapy, November 2004, p. 4144-4147, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4144-4147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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