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

Abstract

Background: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (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 sodiumat a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours laterwere 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 AE 1.1 mg/L (1.75-5.14) and 2.37 AE 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 AE 1.3 mg/L and 1.78 AE 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.

Population Pharmacokinetics of Colistin Methanesulfonate Sodium and Colistin in Critically Ill Patients: A Systematic Review

“…A total of nine studies reported a maximum concentration (C max ) value of CMS and/or colistin after single-dose intravenous administration of CMS [2,3,5,[9][10][11][12]21,22]. Of the reported articles, five studies reported C max values of CMS and/or colistin after application of a loading dose [2,3,5,10,22]. In the single-dose study by Karvanen et al [21], patients receiving 2 MIU of CMS reported CMS C max value of 6.9 mg/L.…”

“…Colistin’s pharmacokinetics and clinical application have been studied extensively in the past. Unfortunately, studies have found inter- and intra-individual variability in the pharmacokinetics of colistin, resulting in extremely varied plasma concentrations following the same dosage schedule [ 2 , 3 , 4 , 5 ]. In vivo, CMS has complex pharmacokinetics and variable bioconversion, particularly in patients with varying degrees of renal function [ 2 , 6 ].…”

“…More investigations on the pharmacokinetics of CMS and colistin in critically ill patients, as well as their relationship to clinical efficacy and renal function, have recently been published [ 2 , 4 , 5 ]. Clinical failure has been linked to subtherapeutic colistin concentrations [ 5 ], although high colistin exposure has not been linked to longer survival [ 2 ]. Many studies have linked a high colistin concentration to acute renal damage [ 2 , 4 ].…”

Antimicrobial Stewardship and Its Impact on the Changing Epidemiology of Polymyxin Use in a South Indian Healthcare Setting

“…The available guidelines highlight the need for a mandatory loading dose on the initiation of polymyxins to ensure that optimal steady state concentrations are attained as early as possible [ 9 , 24 ]. A recent colistin pharmacokinetic study from India highlighted that decreased steady state concentrations correlated with lower clinical efficacy [ 25 ]. However, the practice of an appropriate loading dose was extremely low in our setting.…”

Mapping the Implementation of a Clinical Pharmacist-Driven Antimicrobial Stewardship Programme at a Tertiary Care Centre in South India

“…Recognising the gap in local population data for evaluating pharmacokinetic and pharmacodynamics parameters of antimicrobials, including colistin, the AMS team decided to broaden the responsibilities of the clinical pharmacist and appointed an additional clinical pharmacist (S Sudhir) to the AMS team. This allowed for the gathering of local population data to develop bespoke dosing schedules for antimicrobials such as colistin, allowing for more population-targeted guidelines [ 21 ]. The AMS team, led by the clinical pharmacists and approved by the microbiologist, expanded on the existing hospital antibiogram to develop department and body fluid-specific antibiograms.…”