Population Pharmacokinetics and Outcomes of Critically Ill Pediatric Patients Treated with Intravenous Colistin at Higher Than Recommended Doses

Abstract

Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations that are frequently <2 mg/liter. We conducted a population PK study in 17 critically ill patients 3 months to 13.75 years (median, 3.3 years) old who received CMS for infections caused by carbapenem-resistant Gram-negative bacteria. CMS was dosed at 200,000 IU/kg/day (6.6 mg colistin base activity [CBA]/kg/day; 6 patients), 300,000 IU/kg/day (9.9 mg CBA/kg/day; 10 patients), and 350,000 IU/kg/day (11.6 mg CBA/kg/day; 1 patient). Plasma colistin concentrations were determined using ultraperformance liquid chromatography combined with electrospray ionization-tandem mass spectrometry. Colistin PK was described by a one-compartment disposition model, including creatinine clearance, body weight, and the presence or absence of systemic inflammatory response syndrome (SIRS) as covariates (P < 0.05 for each). The average colistin plasma steady-state concentration (C_ss,avg) ranged from 1.11 to 8.47 mg/liter (median, 2.92 mg/liter). Ten patients had C_ss,avg of ≥2 mg/liter. The presence of SIRS was associated with decreased apparent clearance of colistin (47.8% of that without SIRS). The relationship between the number of milligrams of CBA per day needed to achieve each 1 mg/liter of plasma colistin C_ss,avg and creatinine clearance (in milliliters per minute) was described by linear regression with different slopes for patients with and without SIRS. Nephrotoxicity, probably unrelated to colistin, was observed in one patient. In conclusion, administration of CMS at the above doses improved exposure and was well tolerated. Apparent clearance of colistin was influenced by creatinine clearance and the presence or absence of SIRS.

Keywords: children; colistin; creatinine clearance; population pharmacokinetics; systemic inflammatory response syndrome.

FIG 1

Relationships between the daily dose of colistin base activity (CBA), expressed as milligrams per day (A) and as milligrams per kilogram per day (B), needed for each 1 mg/liter of the average steady-state plasma concentration of colistin (C_ss,avg) and creatinine clearance (in milliliters per minute). In panel A, data for patients with SIRS (filled symbols; R² = 0.81) and without SIRS (empty symbols; R² = 0.74) were regressed separately.