title: Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?
abstract: BACKGROUND
  The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations.
  
  
  METHODS
  Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min).
  
  
  RESULTS
  For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations.
  
  
  CONCLUSIONS
  The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints.
  
  
  BACKGROUND
  NCT00235690.
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, State University of New York.
authors.forename: Samira M
authors.initials: SM
authors.lastname: Garonzik
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 and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Visanu
authors.initials: V
authors.lastname: Thamlikitkul
authors.affiliation: 4th Department of Internal Medicine, University of Athens, Medical School, Greece.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: University of Queensland Center for Clinical Research, Royal Brisbane and Women's Hospital, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Departments of Pathology and Paediatrics and School of Molecular and Biomedical Sciences, University of Adelaide, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Turnidge
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh Medical Center, Pennsylvania.
authors.forename: Fernanda P
authors.initials: FP
authors.lastname: Silveira
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003091:Colistin / Q000008:administration & dosage* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014481:United States; D055815:Young Adult
chemical_list: D003091:Colistin
keywords: clinical breakpoints; intravenous colistin; plasma colistin concentrations achieved; therapeutic implications; updated FDA- and EMA-approved dosing suggestions