Association between Colistin Dose and Microbiologic Outcomes Lama H. Nazer BCPS Clinical Pharmacy Specialist - Critical Care King Hussein Cancer Center - Amman, Jordan Colistin is a bactericidal polymyxin antibiotic that is used for the treatment of multi-drug resistant gram-negative bacteria (GNB). Despite the increased use of colistin over the last decade, the optimal dosing regimen remains unclear. Recently, a retrospective cohort study by Vicari et al.[SUP]1 [/SUP]evaluated the association between colistin dose and microbiological eradication rate. All patients with a blood culture positive for carbapenem-resistant GNB, who received intravenous colistin for at least 72 hours between the years 2005 and 2010, were included. The primary objective was to determine if the colistin dose (mg of colistin base activity (CBA)/kg/day) independently predicted microbiological recovery at day 7 of treatment. In addition, the study evaluated the association between colistin dose and 7-day mortality, 28-day mortality, and acute kidney insufficiency. During the study period, 67 patients were included, and 7-day microbiological success was reported in 52 patients (68%). The median colistin dose was higher in patients who achieved 7-day microbiological success and higher in survivors at day 7 (2.9 vs 1.5 mg/kg/day; p=0.011) and (2.7 vs 1.5 mg/kg/day), respectively. However, there was no association between colistin dose and 28-day mortality. Acute kidney injury was reported in 27 patients (36%); according to the RIFLE criteria, 10 patients met criteria for risk, 7 patients met criteria for injury, and 10 patients met criteria for failure. The development of nephrotoxicity was associated with higher colistin doses (3.8 vs 1.6 mg/kg/day, p<0.001). The study had several limitations such as: the retrospective design, not adjusting for the patients’ fluid status and other nephrotoxic medications, the initiation of colistin therapy about 3 days after the cultures were drawn, and the administration of lower colistin doses in patients with renal failure. Nevertheless, this study provides valuable information regarding dosing of colistin. The association between higher colistin doses and improved outcomes reported by Vicari et al. are supported by previous studies. A large retrospective study of 258 patients reported a decrease in mortality associated with increased daily colistin dose, with the percent mortality associated with 3 million IU (100 CBA), 6 million IU (200 CBA), and 9 million IU (300 CBA) being 38.6%, 27.8%, and 21.7%, respectively.[SUP]2[/SUP] Another study suggested that the administration of a loading dose of colistin, 9 million IU (300 CBA), followed by 4.5 million IU (150 CBA) every 12 hours achieved higher cure rate (82%) than previously reported.[SUP]3[/SUP] Furthermore, pharmacokinetic studies suggested that the currently administered doses may not achieve the desired colistin levels.[SUP]4,5 [/SUP] The currently available evidence suggests that high colistin doses may be needed for the treatment of multi-drug resistant GNB. Further research is needed to determine the optimal dosing regimen for colistin that would provide maximal benefit, while minimizes the risk of nephrotoxicity. [TABLE] [TR] [TD="class: contentReference"]References [/TD] [/TR] [TR] [TD="class: contentBody"]1. Vicari G, Bauer SR, Neuner EA, et al. Association between colistin dose and microbiologic outcomes in patients with multi-drug resistant gram-negative bacteremia. Clin Infect Dis 2012;Oct 22 [Epub ahead of print]. [PMID: 23090926] [Full Text][/TD] [/TR] [TR] [TD="class: contentBody"]2. Falagas ME, Rafailidis PI, Ioannidou E, et al. Colistin therapy for microbiologically documented multi-drug resistant gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 2012;35:194-99. [PMID: 20006471] [Full Text][/TD] [/TR] [TR] [TD="class: contentBody"]3. Dalfino L, Puntillo F, Mosca A, et al. High dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012;54:1720-26. [PMID: 22423120] [Full Text][/TD] [/TR] [TR] [TD="class: contentBody"]4. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother 2009;53:3430-36. [PMID: 19433570] [Full Text][/TD] [/TR] [TR] [TD="class: contentBody"]5. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother 2011;55:3284-94. [PMID: 21555763] [Full Text][/TD] [/TR] [/TABLE] My take - 3mg/kg/day appears to be a safe dose for Colistin in Multi-Drug resistant, Gram Negative Bacteria.
