Pharmacokinetic/pharmacodynamic adequacy of polymyxin B against extensively drug-resistant Gram-negative bacteria in critically ill, general ward and cystic fibrosis patient populations

Abstract

Dose-limiting nephrotoxicity is a significant side effect of polymyxin B treatment. Only limited clinical studies describe the pharmacodynamics of polymyxin B, with little guidance existing for treatment optimisation against multidrug-resistant Gram-negative bacteria. In this study, differences in the likelihood of achieving efficacious and toxic exposures of polymyxin B for critically ill, general ward and cystic fibrosis (CF) patients were evaluated. The following dosing regimens were tested: maintenance doses of 1, 1.25, 1.5 and 2 mg/kg every 12 h (q12h); and loading doses of 2 mg/kg followed by 1.25 mg/kg q12h and 2.5 mg/kg followed by 1.5 mg/kg q12h. Patient weight notably influenced exposure and the required patient dose. To achieve an optimised exposure with minimal toxicity risk, an empirical polymyxin B dose of 2 mg/kg q12h was required for critically ill patients weighing 50 kg, whereas doses of 1.25 mg/kg q12h and 1 mg/kg q12h were required for those weighing 75 kg and 100 kg, respectively. Conversely, 2 mg/kg q12h was required for general ward patients weighing 75 kg. For general ward and CF patients weighing 50 kg, the target exposure could not be achieved with any regimen. Furthermore, the likelihood of toxicity was always high for bacteria with minimum inhibitory concentrations (MICs) of ≥2 mg/L. These findings support the use of a loading dose to increase the achievement of polymyxin B target exposures. To improve efficacy, doses should be optimised according to the patient population.