Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins?

The polymyxins (colistin and polymyxin B) have emerged over the past 20 years as essential antibacterial agents that often are the only remaining active class against troublesome multidrug-resistant Gram-negative bacilli such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The utility of this class is limited by its dose-dependent nephrotoxicity, which can occur in more than one-half of patients receiving therapy with either agent. Strategies are urgently needed to optimise the use of this class of agents to ensure optimal activity while minimising the treatment-limiting nephrotoxicity. This review will focus on risk factors for polymyxin-associated nephrotoxicity, potential strategies for limiting this exposure-dependent toxicity and, finally, unknowns and future research directions pertinent to this topic.

In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy.

Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P = 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P = 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P = 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P = 0.04). In a matched analysis based on the risk factors identified (n = 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P = 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.