Dose-limiting nephrotoxicity is a marked side effect of polymyxin B. Only limited clinical studies describe the pharmacodynamics of polymyxin B with little guidance existing for treatment optimization against multidrug-resistant gram-negative pathogens.
Herein, we evaluated the differences in likelihood of achieving efficacious and toxic exposures of polymyxin B for critically ill, general ward, and cystic fibrosis patients. The following dosing regimens were tested: maintenance dose (1, 1.25, and 1.5 mg/kg/12 h) and loading doses (2 mg/kg followed by 1.25 mg/kg/12 h; and 2.5 mg/kg followed by 1.5 mg/kg/12 h).
Patient weight notably influence exposure and the required patient dose. To achieve an optimized exposure with minimal toxicity risk, an empirical polymyxin B dose of 2 mg/kg/12 h was required for critically ill patients weighing 50 kg, whereas doses of 1.25 and 1 mg/kg/12 h were required for those weighing 75 and 100 kg, respectively. Conversely, 2 mg/kg/12 h was required for general ward patients weighing 75 kg. For general ward and cystic fibrosis patients weighing 50 kg, the target exposure could not be achieved with any regimen. Further, the likelihood of toxicity was always high for bacteria with minimum inhibitory concentrations ≥ 2 mg/L.
Our findings support the use of a loading dose to increase the achievement of polymyxin B target exposures. To improve efficacy, doses should be optimized according to the patient population.

Copyright © 2020. Published by Elsevier B.V.