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About This Calculator
Colistin (polymyxin E) is a parenteral antibiotic used to treat severe infections caused by multidrug-resistant gram-negative bacteria. For a variety of reasons, the historical dosing of colistin has been challenged by newer pharmacokinetic analyses. This calculator uses recent pharmacokinetic modeling data and recommendations published in 2011 by Garonzik et al.2
Garonzik et al Modeling Equations 2
In one of the largest pharmacokinetic studies of colistin, Garonzik et al analyzed blood samples of 105 critically ill patients receiving a physician-selected colistin dosage regimen, administered as the prodrug, colistimethate sodium (CMS). These samples were used to develop a population pharmacokinetic model and dosing recommendations.
This calculator implements the dosing recommendations made by Garonzik et al. There are several important caveats to these recommendations:
- It is recommended for all patients to receive a CMS loading dose, followed by a maintenance dose 24 hours later
- A newer Jelliffe equation is used for patients with unstable renal function;3 the traditional Cockcroft-Gault equation is used for those with stable renal function 4
- Dosing weight should be based on either ideal body weight or actual body weight, whichever is lower
The model and resulting dosage recommendations are not reliably effective for:
- Causative pathogens with a colistin MIC ≥ 1 mg/L
- Patients with normal renal function (creatinine clearance, or CrCL, ≥ 70 mL/min/1.73 m2)
Colistin versus colistimethate sodium (CMS)
In the United States, colistin is only available in its less toxic prodrug formulation, colistimethate sodium (CMS).5 When prescribing CMS, clinicians should pay special attention to dosage units. Depending on the country and formulation, CMS may be expressed in milligrams of “colistin base activity” (CBA), International Units (IU), or, less frequently, in milligrams of the chemical CMS itself. CMS dosing in this calculator is expressed as milligrams of “colistin base activity” (CBA); however, each vial of CMS does not contain any actual colistin, simply milligrams of the chemical product, CMS. For conversion, 30 mg of CBA is equivalent to approximately 1 million IU of CMS or approximately 80 mg of the chemical product, CMS.2
CMS is slowly hydrolyzed to colistin in vivo. Because CMS is primarily renally eliminated (whereas colistin is primarily non-renally eliminated), renal function significantly influences the extent of CMS converted to colistin in vivo. Decreased renal function results in decreased CMS elimination, which leads to increased amounts of CMS available in the body for conversion to colistin and, thus, higher colistin plasma concentrations. Conversely, very good renal function leads to a smaller percentage of CMS being converted to colistin, resulting in lower colistin plasma concentrations. This complex pharmacokinetic relationship between prodrug and active moiety is one of the reasons for the current debate regarding optimal CMS dosage regimens. It also underlies the difficulty in dosing CMS in patients with normal renal function (CrCL ≥ 70 mL/min/1.73 m2) who may have low colistin plasma concentrations as a result.
Target Colistin Average Steady State Plasma Concentration (Css,avg)
A typical Css,avg target is 2 to 2.5 mg/L based on pharmacokinetic and animal models.2,6 In Garonzik et al, the median Css,avg was 2.36 mg/L (range 0.48 to 9.38 mg/L). The Css,avg should be based on the organism MIC, site, and severity of infection. Consultation with an infectious diseases specialist is strongly recommended for assistance with determination of target Css,avg.
Due to the slow conversion of CMS to colistin in vivo, it may take a few hours to days to reach target Css,avg in plasma and continuation of a maintenance regimen without a loading dose may result in accumulation of colistin plasma concentrations over time. Therefore, a loading dose of CMS is recommended.2 The maintenance regimen should be initiated 24 hours after the loading dose.
Although most organizations (CLSI, EUCAST, BSAC) set an MIC susceptibility breakpoint of ≤ 2 mg/L for most microorganisms, Garonzik et al. note their dosing recommendations may not be reliable effective for isolates with an MIC ≥ 1 mg/L.2 This is particularly a concern for patients with normal renal function (CrCL ≥ 70 mL/min/1.73 m2) who may have lower colistin plasma concentrations with the maximum daily dosage recommended in current product labeling (300 mg CBA per day or about 5 mg/kg/day).1,2
Maximum Colistin Dosing
Because of a lack of clinical data and the packaging for certain colistin products,1 Garonzik et al recommends against exceeding 300 mg CBA per day (about 5 mg/kg/day) for either the loading or maintenance doses.2
Combination Therapy with Colistin
Given colistin’s role as a last line agent for multidrug-resistant gram-negative infections, it is important to consider combination antimicrobial therapy with colistin, particularly when treating high-inoculum or deep-seated infections (e.g. pneumonia) or infections in which the colistin MIC of the causative pathogen is ≥ 1 mg/L.2,6 This is especially prudent for patients with normal renal function who may have low colistin plasma concentrations with maximally recommended CMS dosage regimens. Combination therapy may also help minimize the emergence of resistance in gram-negative isolates harboring colistin heteroresistance, e.g. Pseudomonas aeruginosa.7 Of note, clinical benefit of this strategy with colistin combination therapy has not been clearly demonstrated in the literature to date.
Colistin Dosing in Renal Dysfunction
Renal Dysfunction, not on Renal Replacement Therapy
Current data suggest the total daily dose of CMS should be decreased for patients with renal dysfunction. This total daily dose should be administered as 2 divided doses every 12 hours.
Intermittent Hemodialysis (IHD)
CMS and colistin are significantly removed by intermittent hemodialysis (IHD). In a recent pharmacokinetic study of 10 subjects receiving IHD, 37% of CMS and 26% of colistin were removed in one 4-hour HD session.8 This removal was via dialysate and likely adsorption to the HD membrane. Because absolute concentrations of CMS are much higher than colistin in plasma, HD removal affects CMS to a much greater extent. This removal limits the amount of CMS available for conversion to colistin in vivo. While PK data in IHD patients are currently limited, results consistently suggest the following practices: (1) timing IHD near the end of the CMS dosing interval and (2) administering a supplemental dose of CMS after IHD. This calculator assumes optimal timing of IHD and automatically incorporates supplemental dosing into the second dose on HD days. The supplemental dose is 30% of the total daily dose if administered after HD or 50% of the total daily dose if administered during the last hour of HD.
Continuous Renal Replacement Therapy (CRRT)
Removal of CMS and colistin is even more marked with continuous renal replacement therapy (CRRT) compared to IHD. Therefore, total daily doses of CMS for patient on CRRT are typically similar to patient with normal renal function. It is also suggested to administer this total daily dose as 3 divided doses every 8 hours or as 2 divided doses every 12 hours. Given the relatively high dosage regimens recommended for these patients, close monitoring and immediate dosage adjustments are warranted for patients in whom CRRT is interrupted or discontinued.
Toxicities Associated with Colistin 9
Due to its narrow therapeutic window and knowledge deficits regards its kinetic profile, all patients receiving colistin should be assessed for signs and symptoms of toxicity. Nephrotoxicity occurs commonly (20-60% of patients) and often takes the form of acute tubular necrosis. Neurotoxicity typically occurs in 7% of patients or less and often manifests as paresthesias, apnea, nausea/vomiting, and dizziness. In severe cases, however, neurotoxicity may present as myopathy, neuropathy, confusion, psychosis, or seizure.
References and Additional Reading
- Colistimethate [package insert]. Rochester (MI): JHP Pharmaceuticals; 2013. DailyMed Monograph.
- 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 Jul;55(7):3284-94. PMID 21555763.
- Jelliffe R. Estimation of creatinine clearance in patients with unstable renal function, without a urine specimen. Am J Nephrol. 2002 Jul-Aug;22(4):320-4. PMID 12169862.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. PMID 1244564.
- Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006 Sep;6(9):589-601. PMID 16931410.
- Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill?. Semin Respir Crit Care Med. 2015 Feb;36(1):126-35. PMID 25643276.
- Ly NS, Bulitta JB, Rao GG, et al. Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance. J Antimicrob Chemother. 2015 May;70(5):1434-42. PMID 25712313.
- Jitmuang A, Nation RL, Koomanachai P, et al. Extracorporeal clearance of colistin methanesulphonate and formed colistin in end-stage renal disease patients receiving intermittent haemodialysis: implications for dosing. J Antimicrob Chemother. 2015 Jun;70(6):1804-11. PMID 25698772.
- Justo JA, Bosso JA. Adverse reactions associated with systemic polymyxin therapy. Pharmacotherapy. 2015 Jan;35(1):28-33. PMID 25266910.
Julie Ann Justo, PharmD, MS, BCPS, AAHIVP
Dr. Justo is an Assistant Professor at the South Carolina College of Pharmacy who specializes in infectious diseases and HIV pharmacotherapy. She received her Doctor of Pharmacy degree from the University of Florida in 2009 and her Master of Science in Clinical and Translational Science from the University of Illinois at Chicago in 2013. She also completed a 1-year Pharmacy Practice residency in 2010 and a 3-year Infectious Diseases Pharmacotherapy Fellowship in 2013 at the University of Illinois at Chicago. Dr. Justo is a Board Certified Pharmacotherapy Specialist and a certified HIV Pharmacist through the American Academy of HIV Medicine.