PKPD Modeling of the Inoculum Effect of on Polymyxin B .

The reduction in antimicrobial activity at high bacterial counts is a microbiological phenomenon known as the inoculum effect (IE). In a previous study, a significant IE was observed for polymyxin B (PMB) against a clinical isolate of , and well described by a new pharmacokinetic-pharmacodynamic model. Few 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 clinical isolate on PMB 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 inoculum size (10, 10 and 10 CFU/thigh) on PMB efficacy was also evaluated. PMB PK was well described by a two-compartment model including saturable absorption from the subcutaneous injection site and linear elimination. The previous 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 PMB bactericidal effect when the starting inoculum increases from 10 to 10 CFU/thigh. Although not as important as previously characterized an IE was confirmed