Colistin Dosing May Be Wrong for HD Patients

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BOSTON—Colistin is a treatment option for infections caused by multidrug resistant gram negative organisms. New findings presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, however, suggest that available dosing guidelines for this agent may be inappropriate for patients receiving intermittent hemodialysis (HD).

“You need relatively high doses for these subjects,” said study investigator Samira Garonzik, PharmD, a pharmacometrics research fellow at the University of Buffalo in Buffalo, N.Y. “The other important thing that is very relevant for patients on dialysis is that you need about a 25% increase in the dose on a dialysis day if the drug is dosed during the last 30 minutes of dialysis, 15%-20% if dosed after the end of dialysis.”

Colistin treatment usually involves intravenous (IV) administration of the prodrug Colistin methanesulfonate (CMS), which is then hydrolyzed into the active form, colistin. The drug has been available since 1959, but there are very few pharmacokinetic data to guide appropriate CMS dosage selection in critically ill patients or those with significant end-organ dysfunction.

Dr. Garonzik and her coworkers looked at the dosing of this agent in four HD patients and five patients with severe liver disease who were on the liver transplant waiting list. All patients received colistin as a single IV dose of CMS 2.5 mg/kg. For the HD patients, CMS was dosed over 30 minutes at the start of HD. Plasma was sampled at several time points over a 24-hour period (seven samples per patient). During HD, simultaneous arterial and venous plasma samples were collected. The study was designed to analyze how this agent is removed during dialysis and what type of supplemental dosing may be required on dialysis days. 

When CMS is dosed during dialysis, the HD patients required longer to convert the prodrug into colistin. This was not the case with the liver disease patients. The researchers observed a fourfold difference in colistin clearance between the hepatic and renal groups, which translated into the need for threefold higher dosing in the liver disease group compared with the HD patients. In simulations, the investigators found that larger doses were required in the liver disease patients to achieve optimal levels of colistin, and these doses could put these patients at increased risk of nephrotoxicity.

The package insert does not have dosing information for patients on renal replacement therapy. The findings of the new study show that the colistin doses recommended in the package insert would be too low for these patients, she said.

“If colistin is used correctly, I think it can reduce morbidity and mortality,” Dr. Garonzik said. “I do not think that it is being used 100% correctly right now. There are no new drugs that treat the organisms that colistin is used for. So we are going back to a 51-year-old agent that is extremely toxic, and we don't know how best to use it, however we feel that it can best be utilized as part of a combination of active agents for the highest likelihood of efficacy”

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