Pharmacokinetics of colistin in patients with multi-drug resistant Gram-negative bacterial infections

AIM: This study aimed to characterize the first-dose and steady-state pharmacokinetic parameters of colistin in critically-ill patients. BACKGROUND: Increased prevalence of multidrug resistant Gram-negative bacterial infections among critically-ill patients has revived the use of colistin. There is a dire need to characterize the pharmacokinetics of colistin to find out the dosing required to achieve the optimal pharmacokinetic/pharmacodynamic(PK/PD) indices such as Cmax/MIC and AUC/MIC to ensure maximum efficacy and safety. METHODS: In this prospective observational pharmacokinetic study, we studied the first dose and steady state pharmacokinetics of colistin in 16 critically ill patients who received a loading dose of 9 million IU of colistimethate sodium (CMS), followed by maintenance dose of either 4.5 million IU twice daily (n=9) or 3 million IU thrice daily (n=7). Plasma levels of colistin were estimated using LC-MS/MS and pharmacokinetic parameters were estimated using non-compartmental model. RESULTS: We observed a wide inter-individual variability in the pharmacokinetic parameters of colistin. No significant difference was seen in the steady state pharmacokinetic parameters between two different maintenance dosing regimens. Clinical resolution was seen in 8 (50%)patients, nephrotoxicity in 6 (37.5%)patients and bacteriological eradication following repeat culture was seen in 6 (37.5%)patients. PK/PD indices such as AUC/MIC and Cmax/MIC was higher in patients with clinical resolution and bacteriological eradication but this was not statistically significant. CONCLUSION: The lower rates of clinical and microbiological efficacy, and occurrence of adverse events such as nephrotoxicity mandates the need for therapeutic drug monitoring of colistin and individualization of CMS dose for achieving optimal outcome.