title: The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study.
abstract: BACKGROUND
  Optimizing colistin dosing should translate to improved patient outcomes.
  
  
  METHODS
  We used data from 2 prospective cohort studies performed between 2006 and 2009 and between 2012 and 2015. In the latter period, a new policy of high-dose colistin (9 million international units [MIU] loading dose followed by 9 MIU daily for normal renal function) was introduced in 2 participating hospitals. We included adult inpatients with invasive infections caused by carbapenem-resistant gram-negative bacteria treated with colistin. Our primary exposure variable was colistin dose, dichotomized to high-dose vs other regimens. The primary outcome was 28-day mortality. We generated a propensity score for high-dose colistin and conducted propensity-adjusted multivariable and matched-cohort analyses for mortality.
  
  
  RESULTS
  Of 529 consecutive patients fulfilling inclusion criteria, 144 were treated with high-dose colistin and 385 with lower-dose colistin regimens. The median daily dose in the high-dose group was 9 MIU (interquartile range [IQR], 9-9) vs 4 MIU (IQR, 3-6) with other regimens. There were 50 of 144 (34.7%) deaths with high-dose colistin vs 165 of 385 (42.9%) with low-dose colistin (P = .1). The propensity-adjusted odds ratio (OR) for mortality was 1.07 (95% confidence interval [CI], .63-1.83) for high-dose colistin. Similar results were obtained when using the study period as the exposure variable, in the subgroup of bacteremic patients (n = 207) and in the propensity-matched cohort (OR, 1.11 [95% CI, .67-1.82]). Nephrotoxicity (RIFLE injury or higher; OR, 2.12 [95% CI, 1.29-3.48]; n = 396) and seizures were significantly more common with high-dose colistin.
  
  
  CONCLUSIONS
  In a large cohort, we found no association between high colistin dosing and all-cause mortality. High dosing was associated with more nephrotoxicity.
authors: Infectious Diseases Institute, Rambam Health Care Campus.|Cheryl Spencer Department of Nursing, University of Haifa.
authors: Yael Dishon
authors: YD
authors: Benattar
authors: Sackler Faculty of Medicine, Tel Aviv University.|Pharmacy Services.
authors: Muna
authors: M
authors: Omar
authors: Sackler Faculty of Medicine, Tel Aviv University.|Department of Medicine E.
authors: Oren
authors: O
authors: Zusman
authors: Sackler Faculty of Medicine, Tel Aviv University.|Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah Tikva.
authors: Dafna
authors: D
authors: Yahav
authors: Infectious Diseases Institute, Rambam Health Care Campus.|Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Yael
authors: Y
authors: Zak-Doron
authors: Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Sergey
authors: S
authors: Altunin
authors: Department of Medicine E.
authors: Michal
authors: M
authors: Elbaz
authors: Department of Medicine E.
authors: Vered
authors: V
authors: Daitch
authors: Cheryl Spencer Department of Nursing, University of Haifa.
authors: Michal
authors: M
authors: Granot
authors: Sackler Faculty of Medicine, Tel Aviv University.|Department of Medicine E.
authors: Leonard
authors: L
authors: Leibovici
authors: Infectious Diseases Institute, Rambam Health Care Campus.|Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Mical
authors: M
authors: Paul
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015780:Carbapenems / Q000494:pharmacology; D015331:Cohort Studies; D003091:Colistin / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006305:Health Status Indicators; D006801:Humans; D008297:Male; D009026:Mortality; D011446:Prospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D003091:Colistin
keywords: Acinetobacter; Klebsiella; hospital-acquired infection; multidrug resistant gram-negative bacteria; polymyxin