title: Dosing guidance for intravenous colistin in critically-ill patients.
abstract: Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large inter-patient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2mg/L.
  
  
  
  Plasma concentration-time data from 214 adult critically-ill patients (creatinine clearance 0-236mL/min; 29 receiving renal replacement therapy (RRT)) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based upon the relationship between the dose of colistimethate that would be needed to achieve a desired Css,avgand creatinine clearance. The increase in colistin clearance when patients were on RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg≥2 and <30% for Css,avg≥4mg/L.
  
  
  
  When algorithm doses were applied back to individual patients not on RRT (including patients prescribed intermittent dialysis on a non-dialysis day), >80% of patients with creatinine clearance <80mL/min achieved Css,avg≥2mg/L; but for patients with creatinine clearance ≥80mL/min target attainment was <40%, even with the maximum allowed daily dose of 360mg colistin base activity. For patients receiving RRT, target attainment rates were >80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg≥4mg/L.
  
  
  
  The project has generated clinician-friendly dosing algorithms and pointed to circumstances where intravenous monotherapy may be inadequate.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY.
authors.forename: Samira M
authors.initials: SM
authors.lastname: Garonzik
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Visanu
authors.initials: V
authors.lastname: Thamlikitkul
authors.affiliation: 4 Department of Internal Medicine, University of Athens, Medical School, Greece.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: The University of Queensland Center for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Fernanda P
authors.initials: FP
authors.lastname: Silveira
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003091:Colistin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D017410:Practice Guidelines as Topic; D017582:Renal Replacement Therapy; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D003091:Colistin
keywords: Intravenous colistin; critically-ill patients; dosing guidance; influence of renal impairment and renal replacement modalities; population pharmacokinetics