Prediction of in-vivo efficacy by in-vitro early bactericidal activity with oral beta-lactams, in a dose-ranging immunocompetent mouse sepsis model, using strains of Streptococcus pneumoniae with decreasing susceptibilities to penicillin

Killing curves and a sepsis model were performed with Streptococcus pneumon iae strains (MICs of penicillin = 0.01, 1, 2 and 4 mg/L) to assess the in v ivo effect of in vitro early bactericidal activity. Optimal bactericidal co ncentration (OBC) was defined as the minimal concentration needed to obtain the maximal bactericidal activity during the sampling time for colony coun ting in killing curves, Animals were treated with amoxycillin, cefuroxime o r cefpodoxime every 8 h for 48 h, with doses ranging from 2.5 to 50 mg/kg. ED100 (minimal antibiotic dose obtaining a 100% survival) was used as effic acy endpoint. C-max/MIC, AUC/MIC and DeltaT > MIC did not accurately predic t efficacy against the most resistant strains, DeltaT > OBC being the most predictive efficacy parameter indicating the in vivo effect of early bacter icidal activity. Lower DeltaT >OBC Values for amoxycilin vs oral cehalospor ins were needed for efficacy. The higher early bactericidal activity of amo xycillin may explain its higher in vivo efficacy.