Colistin pediatric dose

To the EditorMesini et al reported plasma concentrations of colistin in 7 pediatric patients [aged 46 days to 13 years] who were receiving intravenously the inactive prodrug colistimethate; across all patients, plasma colistin concentrations were measured on 13 occasions [1]. That report has been the subject of critical appraisal by Magréault et al [2], who expressed substantial concerns about the magnitude of the plasma colistin concentrations reported and the pharmacokinetic analysis conducted by Mesini and coworkers. I agree with Magréault et al and amplify their comments. I have very substantial concerns about the dosing recommendations implicitly presented in the report of Mesini and coworkers.

In the study of Mesini et al plasma concentrations of colistin [the active and nephrotoxic entity formed from colistimethate] were determined at the end of a 1-hour infusion of the prodrug [the authors referred to this colistin concentration as Cmax] and just before the next infusion [so-called Cmin] [1]. The reported median plasma colistin Cmax and Cmin values across the 13 occasions were 9.4 mg/L [range, 4.318.9 mg/L] and 1.7 mg/L [range, 0.43.0 mg/L], respectively. It is unfortunate and worrying that Mesini et al did not compare their measured concentrations with those reported for pediatric patients by other authors [3, 4]. Antachopoulos et al reported serum concentrations of colistin immediately before and 30 minutes after a 20-minute infusion of colistimethate on 5 occasions in 3 patients [age, 1.5 months to 14 years] [3]. When the concentrations reported by Antachopoulos and coworkers are normalized to the maintenance dose employed by Mesini et al [150000 U/kg/day], the median plasma colistin concentrations just after and before a colistimethate short-term infusion were 1.20 mg/L [range, 0.731.68 mg/L] and 0.60 mg/L [range, 0.481.53 mg/L], respectively. It is immediately evident that, especially at early times in a dose interval, the colistin concentrations reported by Mesini et al are substantially higher than those reported by Antachopoulos and coworkers. From the pharmacokinetic analysis arising from a single-dose study in 7 critically ill patients 150000 U/kg/day may be required in pediatric patients [3, 4]; this may be expected to be most applicable to patients without renal impairment. Daily doses higher than this level appear to be generally well tolerated, even when administered for a prolonged treatment course [3, 12].

Because of the likely overestimation of plasma colistin concentrations in the study of Mesini et al [1]. very substantial caution is required in any consideration given to applying the reported findings to dosing of pediatric patients. Underdosing may decrease the probability of achieving efficacious concentrations and increase the likelihood of emergence of resistance.

Note

Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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