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

• Published in: Frontiers in pharmacology Vol. 13; p. 842921
• Main Authors: Chauzy, Alexia, Akrong, Grace, Aranzana-Climent, Vincent, Moreau, Jérémy, Prouvensier, Laure, Mirfendereski, Hélène, Buyck, Julien M, Couet, William, Marchand, Sandrine
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers 16-03-2022; Frontiers Media S.A
• Subjects: Acinetobacter baumannii; in vivo; inoculum effect; Life Sciences; modelling; Pharmaceutical sciences; Pharmacology; PKPD; polymyxin B (PMB); Acinetobacter baumannii; PKPD; in vivo; polymyxin B (PMB); inoculum effect; modelling
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2022.842921

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