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.
A model of mouse sepsis caused by a serotype 6B Streptococcus pneumoniae strain (amoxicillin MIC of 8 microg/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 microg/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.
Tarragó
D
D
Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo Km.2, 28220 Majadahonda, Madrid, Spain.
Aguilar
L
L
Giménez
M J
MJ
Fenoll
A
A
Casal
J
J
D000658:Amoxicillin / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000502:physiology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D010403:Penicillin Resistance; D010406:Penicillins / Q000494:pharmacology*; D018805:Sepsis / Q000097:blood / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology*; D016019:Survival Analysis
D000907:Antibodies, Bacterial; D010406:Penicillins; D000658:Amoxicillin