Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Abstract

<b>Introduction:</b> Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting. <b>Methods:</b> A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant <i>K. pneumoniae</i> (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP. <b>Results:</b> Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. C_max and C_min following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUC_{ss,24 h} was 79.6 ± 25.0 mg h/L and C_ss,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly. <b>Conclusion:</b> This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.