Special Feature

Colistimethate: Risk of Serious or Fatal Medication Error

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, is Associate Editor for Infectious Disease Alert.

Dr. Song reports no financial relationship to this field of study.

The National Medication Error Reporting Program (operated by the Institute for Safe Medication Practices [ISMP]) recently issued an alert on the potential risk of medication errors associated with dosing colistimethate for injection.1 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.2

Colistin (polymyxin 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.3-5 Despite widespread use of colistimethate 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.6 At present, expansion of multi-drug resistant bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Enterobacteriaceae has resulted in renewed interest in old antimicrobial agents such as colistimethate.7

The National Medication Error Reporting Program's alert highlighted a recent case in which the prescribing physician mistakenly ordered a dose of colistimethate approximately 2.5 times in excess of the usual recommended dose.1 The pharmacists and nurses failed to recognize the dosing error; the patient developed acute renal failure, along with other complications, and died. DeRyke and associates reported key findings from their retrospective cohort study of adult patients who received a minimum of 48 hours of intravenous colistimethate for injection.8 Ten of 30 patients received doses that were calculated based on actual body weight, instead of ideal body weight. The risk for developing nephrotoxicity was approximately 13 times higher in patients who received doses based on actual body weight compared with patients who received normal or low-normal doses (P = 0.005).

The purpose of this article is to discuss dosing formulations of commercially available colistimethate, and to provide dosing recommendations for patients with deviations in ideal body weight, along with recommending dosing in renally impaired patients.

Colistin Formulations

Two forms of colistin are distributed as commercially available products: colistin sulfate and colistimethate sodium (also known as colistin methanesulfate and colistin sulphomethate sodium). Because of its toxicity profile, colistin sulfate is restricted to topical use; colistimethate is used for parenteral or nebulized administration.6

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.9 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 2.5-5 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.10

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 units of the product contain 80 mg of colistimethate (12,500 units/mg). The colistin formulation distributed by Norma Pharmaceuticals (Greece) has been reported to consist of 12,500-13,300 units/mg.10

Dosing Recommendations: Minimizing Risk for Error

The FDA-approved package insert for Coly-Mycin states that patients with a serum creatinine of 1.3-1.5 mg/dL should be given 2.5-3.8 mg/kg of colistin base (6-9.1 mg/kg colistimethate) daily, in two divided doses. Patients with a serum creatinine of 1.6-2.5 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 2.6-4.0 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.9

A previously published article in Infectious Disease Alert summarized dosing recommendations in renally impaired patients.11 Renal dose adjustments of colistimethate recommended by Marchand et al, Li et al, and Curtis et al are summarized in Table 1.12-14 In addition, dose adjustments of colistimethate in patients with deviations in ideal body weight also can be found in Table 1.15-17

Conclusion

Based on the ambiguity of product nomenclature and the complexity of dosing colistimethate in special populations, the following guidelines should be considered by health care professionals:

  • Restrict the ordering of coli-stimethate to Infectious Disease Consult Services
  • Orders for colistimethate for injection should be written as colistin in terms of base activity, with doses ranging from 2.5 to 5.0 mg/kg/day (divided in 2-4 doses) in patients with normal renal function. Ideal body weight should be used for calculating the dose of colistimethate in obese patients.
  • Refer to the FDA-approved package insert for reducing doses of colistimethate in renally impaired patients.
  • If the order is written as "colistimethate" or "colistimethate sodium," the ordering physician should be contacted to verify the order in terms of colistin base.
  • Patients receiving colistimethate for injection should be monitored for changes in renal function and the appropriateness of dosage should be assessed periodically during treatment.

References

  1. Institute for Safe Medication Practices. National Alert Issued: Dosing Confusion with Colistimethate for Injection. Available at: www.ismp.org/pressroom/PR20110629.pdf. Accessed July 9, 2011.
  2. Li J, et al. Colistin: The re-emerging antibiotic for multidrug resistant gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601.
  3. Taylor G, Allison H. "Colomycin" — Laboratory and clinical investigations. BMJ 1962;2:161-163.
  4. Cox CE, Harrison LH. Intravenous sodium colistimethate therapy of urinary-tract infections: Pharmacological and bacteriological studies. Antimicrob Agents Chemother 1970;10:296-302.
  5. Baines RD, Rifkind D. Intravenous administration of sodium colistimethate. JAMA 1964;190:278-281.
  6. Falagas ME, Kasiakou SK. Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Crit Care 2006;10:R27-40.
  7. 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.
  8. DeRyke CA, et al. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother 2010;54:4503-4505.
  9. Colistin Base (Coly-Mycin®) prescribing information. Rochester, MI: JHP Pharmaceuticals LLC; February 2011.
  10. Landman D, et al. Polymyxins revisited. Clin Microbiol Rev 2008;21:449-465.
  11. Song JC. Colistin dosing in renally impaired patients. Infectious Dis Alert 2010;29:135-138.
  12. Marchand S, et al. Removal of colistin during intermittent haemodialysis in two critically ill patients. J Antimicrob Chemother 2010;65:1836-1837.
  13. 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.
  14. 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.
  15. Shikora SA, et al; American Society for Parenteral and Enteral Nutrition, eds. Nutritional Considerations in the Intensive Care Unit: Science, Rationale and Practice. Dubuque, IA: Kendall/Hunt Publishing Company; 2002.
  16. Escott-Stump S. Nutrition and Diagnosis-Related Care. 5th ed. Philadelphia, PA: Williams and Wilkins; 2002.
  17. Holcombe BJ, et al; American Society for Parenteral and Enteral Nutrition, eds. The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, IA: Kendall/ Hunt Publishing Company; 2000.
Table 1. Dosing of Colistimethate for Injection.
Generic name Colistin base
Brand name (United States) Coly-Mycin®
Other names cited in literature Colomycin (Dumex-Alpharma A/S, Copenhagen, Denmark);
Colistimethate Sodium (Colistin Sulphomethate Sodium)
Differences between products Coly-Mycin (Colistin base) contains 150 mg colistin base per vial
• 150 mg colistin base = 360 mg colistimethate sodium
• 1 million units Colomycin = 80 mg colistimethate sodium
Coly-Mycin dose if SCr < 1.3 mg/dL 2.5-5.0 mg/kg/day of colistin base (divided in 2-4 doses),
based on ideal body weight (IBW) (see explanation below)
Calculation of IBW Female: 45.5 kg + 2.3 (# inches above 60 inches)
Male: 50 kg + 2.3 (# inches above 60 inches)
Note: If a patient weighs less than IBW, use actual body weight.
Deviations in IBW15-17

Disability adjustment in IBW:
• Subtract 5%-10% from IBW for paraplegia
• Subtract 10%-15% from IBW for quadriplegia

Amputee adjustment in IBW:
• Entire leg and foot: Subtract 18.5% from IBW
• Above the knee: Subtract 13% from IBW
• Below the knee: Subtract 6% from IBW
• Foot: Subtract 1.8% from IBW
• Entire arm and hand: Subtract 6.5% from IBW
• Forearm and hand: Subtract 3% from IBW

Coly-Mycin dose if SCr ≥ 1.3 mg/dL SCr 1.3-1.5 mg/dL: 2.5-3.8 mg/kg/day (divided BID)
SCr 1.6-2.5 mg/dL: 2.5 mg/kg/day (divided BID)
SCr 2.6-4.0 mg/dL: 1.5 mg/kg Q 36 hours
Coly-Mycin dose in intermittent hemodialysis12 Limited data, but Marchand et al recommended:
67 mg Colistin base (equivalent to 2 million units of Colomycin) IV Q 12 hours
Coly-Mycin dose in continuous veno-venous hemodiafiltration13

Limited data, but Li et al recommended:
2-3 mg/kg Colistin base IV Q 12 hours based on IBW

Coly-Mycin dose in peritoneal dialysis14 Limited data, but Curtis et al recommended:
2-3 mg/kg colistimethate IV Q 72 hours (divide by 2.4 to obtain equivalent Colistin base dose)