Optimizing colistin dosing in acute-on-chronic liver failure patients with sepsis due to multidrug-resistant gram-negative pathogens

BACKGROUND: Acute-on-chronic liver failure (ACLF) patients with sepsis represent a special population which is highly susceptible to serious infections but remains understudied for antibiotic dose optimization. Colistin, a reserve antibiotic for multidrug-resistant Gram-negative infections, is frequently used for management of sepsis in this group of patients. There is an unmet medical need of describing dosing regimen developed using population pharmacokinetic approach in this group of patients. RESEARCH DESIGN AND METHODS: ACLF patients receiving intravenous colistin were enrolled. Population pharmacokinetic modelling was performed using nonlinear mixed-effects methods, with covariate analysis and bootstrap validation. Monte Carlo simulations were conducted to evaluate probability of target attainment (PTA) across dosing regimens and renal function strata. RESULTS: A total of 68 plasma concentrations from eligible patients admitted over two years were analysed. Colistin pharmacokinetics were adequately described by a one-compartment model, with considerable inter-individual variability. Creatinine clearance was found to be significant covariate for clearance. The probability of target attainment (PTA) for pertinent PK/PD index varied across different dosing regimens and renal function strata. CONCLUSIONS: Colistin pharmacokinetics in patients with ACLF is highly variable with creatinine clearance emerging as a significant covariate. We propose a creatinine-clearance-guided dosing regimen based on the findings of the study.