Colistin Dosing in Renally Impaired Patients
Special Feature
By Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Dr. Song reports no financial relationships relevant to this field of study.
Colistin (Ppolymyxin E) was isolated from bacillus colistinus 60 years ago and, during the 1960s, a new intravenous formulation (Coly-Mycin M Parenteral) became available for use in clinical practice.1-3 Despite widespread use of colistin during the first two decades after its introduction, the emergence of reports of serious adverse events caused this agent to fall out of favor in the medical community.4 At present, expansion of multi-drug resistant (MDR) bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Enterobacteriaceae, has resulted in renewed interest in old antimicrobial agents such as colistin.5
To date, most information available about the dosing of colistin in renally impaired patients is from studies conducted four decades ago and may not apply to patients requiring treatment at the present time.6-8 The purpose of this review is to discuss the pharmacokinetics of colistin in dialysis patients and to review dosing of this drug in renally impaired patients included in published studies.
Renal Dose Adjustment of Colistin
Two forms of colistin are distributed as commercially available products: colistin sulfate and colistimethate sodium (also known as colistin methanesulfonate, colistin sulphomethate sodium). Because of its toxicity profile, colistin sulfate is restricted to topical use; colistimethate is used for parenteral or nebulized administration.4 Numerous commercial preparations of colistimethate are available worldwide, and their differences have made evaluation of doses reported in clinical studies difficult to interpret when drug formulations were not fully described by investigators.9
Colistimethate, a polyanion at physiological pH, undergoes hydrolysis to yield a series of methanesulphonated derivatives and colistin, which is a polycation entity. Coly-Mycin M Parenteral is produced by JHP Pharmaceuticals, LLC, in the United States.10 The current FDA-approved package insert for Coly-Mycin M Parenteral states that each vial contains 150 mg of colistin base and should be given at a dose of 2.5 to 5 mg/kg/day (not to exceed 300 mg/day, based on ideal body weight) in 2-4 divided doses. Given that there is 360 mg of colistimethate per 150 mg of colistin base, this translates into a 2.4-fold higher recommended dose of the colistimethate equivalent.11
A commonly used formulation of colistimethate in Europe is Colomycin injection, produced by Dumex-Alpharma A/S (Copenhagen, Denmark). The package insert states that each million unit of the product contains 80 mg of colistimethate (12,500 units/milligram). The colistin formulation distributed by Norma Pharmaceuticals (Greece) has been reported to consist of 12,500 to 13,300 units per milligram.11
The FDA-approved package insert for Coly-Mycin states that patients with a serum creatinine of 1.3 to 1.5 mg/dL should be given 2.5 mg/kg to 3.8 mg/kg of colistin base (6-9.1 mg/kg colistimethate) daily, in two divided doses. Patients with a serum creatinine of 1.6 to 2.5 mg/dL should be given 2.5 mg/kg of colistin base (6 mg/kg colistimethate) daily, in one or two divided doses. When serum creatinine increases to 2.6 to 4.0 mg/dL, the patient should receive 1.5 mg/kg of colistin base (3.6 mg/kg colistimethate) every 36 hours. The manufacturer does not provide dosing recommendations for hemodialysis patients or for peritoneal dialysis patients.10 Renal dose adjustments of colistimethate reported in clinical trials are summarized in Table 1.
Table 1: Renal Dose Adjustment of Intravenous Colistin in Clinical Studies |
||||
Reference |
Number of Patients |
Pathogens |
Conditions Treated |
Colistin Dose |
Trottier et al.12 |
30 |
Acinetobacter baumannii (100%) |
Initial site of infection from BAL (70%); blood (20%) |
Product used: Coly-Mycin (colistin base). CrCl > 50 mL/min: 2 mg/kg IV Q12h; CrCl 10-50 mL/min: 2 mg/kg IV Q 24h; CrCl < 10 mL/min: 2 mg/kg IV Q36h; dialysis patients received 1 mg/kg post-dialysis. |
Reina et al.13 |
55 |
Acinetobacter baumannii (65%); P. aeruginosa (35%) |
Ventilator-associated pneumonia (53%); primary bacteremia (16%); urinary tract infection (18%); other infections (13%) |
Product not specified; used colistimethate sodium from Laboratory Bristol-Myers Squibb (Argentina). Serum creatinine (SCr) < 1.2 mg/dL: 5 mg/kg (maximum, 300 mg/day) divided in three doses; SCr 1.3-1.5 mg/dL: 2.5-3.8 mg/kg/d (divided in two doses); SCr 1.6-2.5 mg/dL: 2.5 mg/kg/d in 1-2 divided doses; SCr ≥ 2.6 mg/dl: 1.5 mg/kg every 36h; hemodialysis patients received 1 mg/kg/day |
Levin et al.14 |
59 |
Acinetobacter baumannii (65%); P. aeruginosa (35%) |
Pneumonia (33%); urinary tract infection (20%); primary bacteremia (15%); central nervous system infection (8%); peritonitis (7%); catheter-related (7%); surgical site (7%); otitis media (2%) |
Product used: Coly-Mycin or Colistimethate Sodium from Bellon (Rhone-Poulenc Rorer, France). Dose of IV Colistin Base: SCr < 1. 3 mg/dl, 2.5-5.0 mg/kg/day divided in 2-3 doses (maximum of 300 mg/day); SCr 1.3-1.5 mg/dL, daily dose of 2.5-5.0 mg/kg; SCr 1.6-2.5 mg/dL, 2.5 mg/kg daily; SCr > 2.5 mg/dL, 1.0-1.5 mg/kg daily. |
Michalopoulos et al.15 |
43 |
P. aeruginosa (81%); Acinetobacter baumannii (19%) |
Intensive Care Unit setting. Pneumonia (72%); bacteremia (33%); urinary tract infection (5%); catheter-related (7%); surgical wound infection (5%); sinusitis (2%) |
Product used: Colomycin or Colistimethate Sodium from Norma (13,333 units/mg; Athens, Greece). SCr ≤ 1.2 mg/dL, 240 mg colistimethate every 8 hours; SCr 1.3-1.5 mg/dL, 240 mg colistimethate every 12 hours; SCr 1.6-2.5 mg/dL, 240 mg colistimethate every 24 hours; SCr ≥ 2.6 mg/dL, 240 mg colistimethate every 36 hours; hemodialysis patients received 80 mg colistimethate after each dialysis session. |
Falagas et al.16 |
17 |
P. aeruginosa (60%); Acinetobacter baumannii (25%); Klebsiella pneumonia (10%) |
Pneumonia (68%); urinary tract infection (11%); meningitis (11%); bacteremia (5%); surgical site infection (5%) |
Product used: Colomycin or Colistimethate Sodium from Norma (Athens, Greece). SCr 1.3-1.5 mg/dL, 160 mg colistimethate every 12 hours; SCr 1.6-2.5 mg/dL, 160 mg colistimethate every 24 hours; SCr ≥ 2.6 mg/dL, 160 mg colistimethate every 36 hours; dialysis patients received 80 mg colistimethate after each dialysis session. |
Garnacho-Montero et al.17 |
21 |
Acinetobacter baumannii (100%) |
Ventilator-associated pneumonia (100%) |
Product used: Colistimethate Sodium from Bellon (Rhone-Poulenc Rorer, France). SCr < 1. 2 mg/dL, 2.5-5.0 mg/kg/day divided in three doses; SCr 1.2-1.5 mg/dL, daily dose of 2.5-3.8 mg/kg (two divided doses); SCr 1.6-2.5 mg/dL, 2.0 mg/kg daily; SCr > 2.5 mg/dl, 1.5 mg/kg every 48 hours. |
Linden et al.18 |
23 |
P. aeruginosa (100%) |
Pneumonia (78%); bacteremia (35%); wound infection (13%); intra-abdominal (26%) |
Product used: Coly-Mycin (colistin base). SCr 1.6-2.5 mg/dL, Coly-Mycin 5 mg/kg/d (2 divided doses); SCr 2.6-4.0 mg/dl, Coly-Mycin 2.5 mg/kg IV Q 24h; SCr > 4.0 mg/dL or hemodialysis patients received 1 mg/kg Coly-Mycin daily. |
Dosing of colistin in hemodialysis patients has varied in published reports. Michalopoulos and colleagues used a dose of Colomycin 3 million units (240 mg colistimethate; 100 mg colistin base) IV every 36 hours in patients with serum creatinine levels of 2.6 mg/dL or higher, and administered 1 million units (80 mg colistimethate; 33.3 mg colistin base) post-dialysis.15 Similarly, Falagas and colleagues used Colomycin 2 million units (160 mg colistimethate; 66.7 mg colistin base) IV every 36 hours in patients with serum creatinine levels of 2.6 mg/dL or higher, and used a post-dialysis dose of 1 million units of this agent in hemodialysis patients.16 A daily dose of 1 mg/kg Coly-Mycin was administered to hemodialysis patients enrolled in a study conducted by Linden and colleagues.18
Recently, a case report of two patients highlighted the possibility of dosing colistin more frequently in patients receiving intermittent hemodialysis.19 Marchand et al reported the use of more frequent dosing of colistimethate in two male patients with acute renal failure who presented with pulmonary infection caused by MDR gram-negative bacteria susceptible to this antibiotic. The patients received intermittent hemodialysis (Gambro, AK 200), with a blood flow setting of 300 mL/minute and dialysis effluent at 500 mL/minute for four hours, using a 1.6 m2 B3 polymethylmethacrylate membrane (Toray Industries, Tokyo, Japan). The first patient received 1 million units of colistimethate (80 mg colistimethate, 33.3 mg colistin base) every 48 hours, with hemodialysis sessions occurring every 48 hours. The second patient received 2 million units of colistimethate (160 mg colistimethate; 66.7 mg colistin base) every 12 hours, and received hemodialysis on a daily basis.
Marchand et al discovered that a dosing regimen of 1 million units every 48 hours resulted in sub-therapeutic pre-dialysis levels of colistimethate. The first patient had a pre-dialysis colistin plasma concentration of 0.45 mg/L, which was far below the European Committee on Antimicrobial Susceptibility Testing minimum inhibitory concentration (MIC) breakpoint of 2 mg/liter. Consequently, a higher dose of colistimethate was administered to the second patient. The second patient did exhibit pre-dialysis colistin plasma concentrations close to the MIC breakpoint of 2 mg/L. The time-averaged dialysis clearances of colistin and colistimethate were approximately 134-140 mL/minute and 90 mL/minute, respectively. Because intermittent hemodialysis removed a significant quantity of colistin and colistimethate, Marchand et al recommended a dose of colistimethate 160 mg (colistin base 66.7 mg) every 12 hours in patients receiving intermittent hemodialysis.
Li and colleagues reported a case of a 53-year-old female (ideal body weight, 61 kg) who required colistin therapy for a new MDR Pseudomonas aeruginosa strain isolated in endotracheal aspirate.20 The patient received continuous venovenous hemodiafiltration (CVVHDF) with 1 L/hour of dialysate and 2 L/hour of post-dilution replacement fluid, yielding 3 L/hour of dialysis effluent; an extracorporeal circuit containing a hospital AN69HF hemofilter was used and the blood flow was set at 200 mL/minute. The patient received intravenous Coly-Mycin 2.5 mg/kg (colistin base; colistimethate equivalent, 6 mg/kg) every 48 hours. The MIC of colistin against the P. aeruginosa isolate from the patient was 1.0 mg/L; the concentrations of colistin in plasma were below the MIC for 42 hours of the 48-hour dosing interval. Consequently, Li et al suggested that a dose of intravenous colistin base 2-3 mg/kg (colistimethate 4.8-7.2 mg/kg) every 12 hours would have been more appropriate for their patient.
Dosing recommendations for peritoneal dialysis patients are even less clear, given that studies were conducted four decades ago in this population.6,7 Curtis et al described the pharmacokinetics of colistin in three peritoneal dialysis patients (weight range, 50-60 kg) who received colistimethate 2-3 mg/kg during dialysis.6 The investigators used Dialaflex solution and 2 L exchanges with 30-minute equilibration periods. The patients exhibited a mean peritoneal clearance of 9.8 mL/minute, showing poor clearance of colistin during peritoneal dialysis. Curtis et al proposed a dose of 2-3 mg/kg colistimethate (0.8-1.2 mg/kg colistin base) given intravenously every 72 hours for peritoneal dialysis patients.
Conclusion
Colistin has not been studied extensively in renally impaired patients, especially those requiring hemodialysis or peritoneal dialysis. In light of these limitations, the following recommendations can be made:
- Patients with impaired renal function who do not require hemodialysis or peritoneal dialysis should be dosed according to the package insert for Coly-Mycin (colistin base).
- Because of its propensity to cause neurotoxic and nephrotoxic effects,10 patients should be closely monitored such that appropriate dosing adjustments can be made if renal function declines.
- Clinicians should consider more frequent dosing (every 12 hours instead of every 36-48 hours) of Coly-Mycin in patients requiring intermittent hemodialysis or CVVHDF.
References
- Taylor G, Allison H. "Colomycin" Laboratory and clinical investigations. BMJ. 1962;2:161-163.
- Cox CE, Harrison LH. Intravenous sodium colistimethate therapy of urinary-tract infections: Pharmacological and bacteriological studies. Antimicrob Agents Chemother. 1970;10:296-302.
- Baines RD, Rifkind D. Intravenous administration of sodium colistimethate. JAMA. 1964;190:278-281.
- Falagas ME, Kasiakou SK. Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Crit Care. 2006;10:R27-R40.
- Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005; 40:1333-1341.
- Curtis JR, Eastwood JB. Colistin sulphomethate sodium administration in the presence of severe renal failure and during haemodialysis and peritoneal dialysis. BMJ. 1968; 1:484-485.
- Goodwin NJ, Friedman EA. The effects of renal impairment, peritoneal dialysis, and hemodialysis on serum sodium colistimethate levels. Ann Intern Med. 1968;68: 984-994.
- MacKay DN, Kaye D. Sodium colistimethate dosage in renal failure. Ann Intern Med. 1968;69:639-641.
- Li J, et al. Colistin: The re-emerging antibiotic for mutidrug resistant gram-negative bacterial infections. Lancet Infect Dis. 2006;6:589-601.
- Colistin Base (Coly-Mycinâ) prescribing information. Rochester, MI: JHP Pharmaceuticals LLC; 2009 February.
- Landman D, et al. Polymyxins revisited. Clin Microbiol Rev. 2008;21:449-465.
- Trottier V, et al. Outcomes of Acinetobacter baumannii infection in critically ill burned patients. J Burn Care Res. 2007;28:248-254.
- Reina R, et al. Safety and efficacy of colistin in Acinetobacter and Pseudomonas infections: A prospective cohort study. Intensive Care Med. 2005;31:1058-1065.
- Levin AS, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis. 1999;28:1008-1011.
- Michalopoulos AS, et al. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: The renaissance of an old antibiotic. Clin Microbiol Infect. 2005;11:115-121.
- Falagas ME, et al. Toxicity after prolonged (more than four weeks) administration of intravenous colistin. BMC Infect Dis. 2005;5:1.
- Garnacho-Montero J, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: A comparison with imipenem-susceptible VAP. Clin Infect Dis. 2003;36: 1111-1118.
- Linden PK, et al. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2003;37:E154-E160.
- Marchand S, et al. Removal of colistin during intermittent haemodialysis in two critically ill patients. J Antimicrob Chemother. doi: 10.1093/jac/dkq185.
- Li J, et al. Pharmacokinetics of colistin methanesulfonate and colistin in a critically ill patient receiving continuous venovenous hemodiafiltration. Antimicrob Agents Chemother. 2005;49:4814-4815.
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