Pharmacokinetics and Pharmacodynamics of Colistin Methanesulfonate in Healthy Chinese Subjects after Multi-Dose Regimen

Colistin methanesulfonate (CMS) is an important treatment option for infections caused by carbapenem-resistant Gram-negative organisms (CROs). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) profiles and safety of CMS in Chinese subjects following a recommended dosage. A total of 12 healthy Chinese subjects received CMS injections at 2.5 mg/kg once every 12 h for 7 consecutive days. The PK/PD profiles of the active form of CMS, colistin, against CROs were analyzed with the Monte Carlo simulation method. No serious adverse events were observed. The average steady-state plasma concentrations of CMS and colistin were 4.41 +/- 0.75 mu g/mL and 1.27 +/- 0.27 mu g/mL, and the steady-state exposures (AUC(0-12,ss)) were 52.93 +/- 9.05 h center dot mu g/mL and 15.28 +/- 3.29 h center dot mu g/mL, respectively. Colistin, at its minimum inhibitory concentration (MIC) of 0.5 mu g/mL, has >90% probability to reduce CROs by >= 1 log. The PK/PD breakpoints for the >= 1 log kill were >= MIC90 for carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa, but were <= MIC50 for carbapenem-resistant Acinetobacter baumannii. The recommended dose regimen of CMS for 7 consecutive days was safe in Chinese subjects. The systemic exposure of colistin showed a high probability of being sufficient for most CROs, but was not sufficient for some carbapenem-resistant A. baumannii.