# The pharmacodynamics of polymyxin B in Acinetobacter baumannii in murine thigh and lung infection models

## TL;DR

This study examines how polymyxin B works against Acinetobacter baumannii in mouse models of thigh and lung infections, finding it effective in the thigh but not the lung.

## Contribution

The study identifies pharmacodynamic targets for polymyxin B in thigh infections and highlights limitations in lung infections and standard dosing.

## Key findings

- Polymyxin B achieved 2-log10 bacterial kill in thigh infections but not in lung infections for most strains.
- Standard human dosing of polymyxin B may not reach effective targets and could be toxic.
- Pharmacodynamic targets for polymyxin B in thigh infections correlate with fAUC/MIC values of 2.1 to 4.0.

## Abstract

Polymyxin B has been used for many years to treat Acinetobacter baumannii, but little is known about its pharmacodynamics (PD). We aimed to describe the PD of polymyxin B in treating A. baumannii infections.

Using the murine neutropenic thigh and lung infection models we determined the magnitude of the pharmacokinetic (PK)/PD index correlating with efficacy for eight A. baumannii strains. PD was analysed using the Emax model to determine PD targets. Using published human PK data the PTAs were calculated.

In the thigh infection model, stasis, 1-log10 and 2-log10 kill were reached for all strains. Median (range) fAUC/MIC (area under the unbound concentration–time curve divided by the MIC) targets for stasis, 1-log10 kill and 2-log10 kill were 2.1 (1.0–11), 2.9 (1.0–15) and 4.0 (1.1–20), respectively. In contrast, in the lung model, 2-log10 kill was reached in 2/8 strains only, and there was insufficient killing at tolerated exposures to determine PD fAUC/MIC targets. For the standard human dosing regimen, PTAs derived from the thigh model were inadequate at the USCAST (United States Committee on Antimicrobial Susceptibility Testing) clinical breakpoint and a protein binding of 90%.

Whereas polymyxin B treatment had good efficacy in the murine thigh infection model, in the lung infection model its effect was limited. PD targets, with MICs of circulating A. baumannii isolates of ≤2 mg/L, are not reached with a standard human dosing regimen and will probably exceed threshold values for toxicity. These data suggest that the efficacy of polymyxin B as monotherapy for A. baumannii infections is questionable.