Severe infusion-related adverse events and renal failure in patients receiving high-dose intravenous polymyxin B [PublishAheadOfPrint]

Very high doses of polymyxin B (PMB) have been addressed in in vitro experiments against carbapenem-resistant Gram-negative bacilli as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. This is a retrospective cohort study assessing patients receiving >3mg/kg/day or a total dose ≥250mg/day of PMB. The main outcomes were severe infusion-related adverse event according to Common Terminology Criteria for Adverse Criteria and renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 were included for analysis of infusion-related events. The mean PMB dose was 3.61±0.97mg/kg/day (median total dose/day=268 mg). Severe infusion-related adverse events occurred in two patients determining an incidence of 0.9% (95% Confidence Interval, 0.2-3.2): one was classified as a life-threatening and one as severe adverse effect. Renal failure was analyzed in 115 patients: 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]). Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Our data suggest that high dose schemes have acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patients' outcomes and minimize the emergence of PMB resistance.

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