Neurotoxicity associated with colistin methanesulfonate treatment is enhanced by concomitant sevoflurane inhalation

Abstract

Colistin methanesulfonate (CMS) is a cyclic polypeptide antibiotic with neurotoxic side effects. Sevoflurane (Sevo), an inhaled anesthetic, is known to enhance the non-depolarizing effect of neuromuscular relaxants; however, its mechanism of action is unclear. In this study, we investigated the augmentation effect of Sevo on CMS-induced neurotoxicity. We prepared a sciatic nerve-skeletal muscle stimulation model using Sprague-Dawley male rats administered CMS with or without Sevo. The muscle contraction inhibition rate was determined from electromyogram measurements. Furthermore, we simulated the pharmacokinetics of CMS and colistin using previous reports, and the relationship between the effect of muscle contraction inhibition and pharmacokinetic parameters was evaluated. We observed a dose-dependent neuromuscular inhibitory effect of Sevo under CMS administration. The 50 % inhibitory dose (ID50) values for CMS and CMS+Sevo were 167 ± 12 and 85 ± 5 mg/kg, respectively. The combination of CMS with Sevo showed a 49 % decrease in the ID50 compared with CMS alone. The simulated area under the time–concentration curve (AUC) values for CMS and colistin administration in rats at 200 mg/kg were 219 and 16.0 mg·h/L, respectively. The predicted AUC values of colistin corresponding to the ID50 at 0–45 min for CMS alone and CMS+Sevo were 12.0 and 7.0 mg·h/L, respectively. We revealed that the neurotoxic effect of CMS was enhanced by the concomitant use of Sevo. Based on the simulated AUC values, we concluded that this neurotoxic effect may also occur in clinical settings, and concomitant use of CMS and Sevo should be avoided.