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

Charalampos Antachopoulos; Anastasia Geladari; Cornelia B Landersdorfer; Eleni Volakli; Stavroula Ilia; Evangelos Gikas; Helen Gika; Maria Sdougka; Roger L Nation; Emmanuel Roilides

doi:10.1128/AAC.00002-21

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

Antimicrob Agents Chemother. 2021 May 18;65(6):e00002-21. doi: 10.1128/AAC.00002-21. Print 2021 May 18.

Authors

Affiliations

¹ Third Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece.
² Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
³ Pediatric Intensive Care Unit, Hippokration General Hospital, Thessaloniki, Greece.
⁴ Pediatric Intensive Care Unit, University of Crete, Heraklion, Greece.
⁵ Faculty of Chemistry, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Laboratory of Forensic Medicine & Toxicology, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece.
⁷ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia roger.nation@monash.edu roilides@med.auth.gr.
⁸ Third Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece roger.nation@monash.edu roilides@med.auth.gr.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intravenous
Anti-Bacterial Agents / therapeutic use
Child
Colistin* / therapeutic use
Critical Illness*
Gram-Negative Bacteria
Humans

Substances

Anti-Bacterial Agents
Colistin