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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.
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
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:
|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:
Amputee adjustment in 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:
|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)