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The reduction in antimicrobial activity at high bacterial counts is a microbiological phenomenon known as the inoculum effect (IE). In a previous  in vitro  study, a significant IE was observed for polymyxin B (PMB) against a clinical isolate of  Acinetobacter baumannii , and well described by a new pharmacokinetic-pharmacodynamic model. Few  in vivo  studies have investigated the impact of inoculum size on survival or antibiotic efficacy. Therefore, our objective was to confirm the influence of inoculum size of this  A. baumannii  clinical isolate on PMB  in vivo  effect over time. Pharmacokinetics and pharmacodynamics of PMB after a single subcutaneous administration (1, 15 and 40 mg/kg) were studied in a neutropenic murine thigh infection model. The impact of  A. baumannii  inoculum size (10 5 , 10 6  and 10 7  CFU/thigh) on PMB efficacy was also evaluated.  In vivo  PMB PK was well described by a two-compartment model including saturable absorption from the subcutaneous injection site and linear elimination. The previous  in vitro  PD model was modified to adequately describe the decrease of PMB efficacy with increased inoculum size in infected mice. The IE was modeled as a decrease of 32% in the  in vivo  PMB bactericidal effect when the starting inoculum increases from 10 5  to 10 7  CFU/thigh. Although not as important as previously characterized  in vitro  an IE was confirmed  in vivo.

PKPD Modeling of the Inoculum Effect of Acinetobacter baumannii on Polymyxin B in vivo