Clinical efficacy and pharmacokinetics of colistimethate sodium and colistin in critically ill patients in an Indian hospital with high endemic rates of multidrug-resistant Gram-negative bacterial infections: A prospective observational study

Background: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacody-namic (PD) data to guide dosing. Aim: To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function. Materials and Methods: Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium - at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later - were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Results: Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 1.1 mg/L (1.75-5.14) and 2.37 1.2 mg/L (1.52-5.54) for 'cure' and 'failure' groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 +/- 1.3 mg/L and 1.78 +/- 1.1 mg/L in 'cure' and 'failure' groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD. Conclusions: Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing. (c) 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).