Dosing of colistin-back to basic PK/PD

Abstract

The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging data can be used to inform design of optimal dosage regimens. Recent data suggest the current dosage regimens of CMS are suboptimal in many critically ill patients.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

FIG. 1

Relationships for P. aeruginosa ATCC 27853 between the log10 CFU per thigh at 24 h and the PK/PD indices (A) fAUC/MIC, (B) fCmax/MIC and (C) fT>MIC. Each symbol represents the mean datum per mouse from two thighs. R2 is the coefficient of determination. The dotted line represents the mean bacterial burden in thighs at the start of treatment. Reproduced from Dudhani et al. [32] with permission.

FIG. 2

Observed individual concentrations of CMS (Panels A and B) and formed colistin (Panels C and D) in plasma of critically-ill patients after the administration of the first (Panels A and C; fourteen patients) and fourth (Panels B and D; 12 patients) dose of CMS. Reproduced from Plachouras et al.[17] with permission.