Effects of specific antibodies against Streptococcus pneumoniae on pharmacodynamic parameters of beta-lactams in a mouse sepsis model.
A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of beta-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-beta-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 (deltaT > MICs) approximately 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 ( approximately 8 times lower), with the deltaT > 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.
Casal
J
J
Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. jcasal@isciii.es
Aguilar
L
L
Jado
I
I
Yuste
J
J
Giménez
M J
MJ
Prieto
J
J
Fenoll
A
A
D000658:Amoxicillin / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D002439:Cefotaxime / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D047090:beta-Lactams / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D000907:Antibodies, Bacterial; D007106:Immune Sera; D047090:beta-Lactams; D000658:Amoxicillin; D002439:Cefotaxime