Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Antimicrobial Agents and Chemotherapy - Tập 55 Số 7 - Trang 3284-3294 - 2011
Samira Merali1, Jian Li2, Visanu Thamlikitkul3, David L. Paterson4, Shmuel Shoham5, Jovan Jacob2, Fernanda P. Silveira6, Alan Forrest1, Roger L. Nation2
1School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York
2Facility for Anti-infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
3Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
4The University of Queensland Center for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Australia
5Washington Hospital Center, MedStar Clinical Research Center, Washington, DC
6Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Tóm tắt

ABSTRACT With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m 2 . Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥1.0 mg/liter.

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Thông tin xuất bản

Antimicrobial Agents and Chemotherapy

Tập 55 Số 7

3284-3294

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