Gelofusine ameliorates colistin-induced nephrotoxicity [PublishAheadOfPrint]

Colistin therapy is used as the last-line of defence against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side-effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulphate (14 mg/kg x 6 doses every 2 h; accumulated dose 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300 or 600 mg/kg x 6). At 2 and 20 h after the last colsitin dose, mice were euthanized and severity of renal alteration was examined histologically. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin only group. The impact of co-administered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine co-dosing did not alter the pharmacokinetics of colistin in rats, however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

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