TY - JOUR
TI - Population pharmacokinetics and outcomes of critically ill pediatric patients treated with intravenous colistin at higher than recommended doses
AU - Antachopoulos, C.
AU - Geladari, A.
AU - Landersdorfer, C.B.
AU - Volakli, E.
AU - Ilia, S.
AU - Gikas, E.
AU - Gika, H.
AU - Sdougka, M.
AU - Nation, R.L.
AU - Roilides, E.
JO - Antimicrobial Agents and Chemotherapy
PY - 2021
VL - 65
TODO - 6
SP - null
PB - American Society for Microbiology
SN - 0066-4804, 1098-6596
TODO - 10.1128/AAC.00002-21
TODO - colistimethate;  colistin;  antiinfective agent;  colistin, adolescent;  Article;  body weight;  child;  clinical article;  clinical outcome;  creatinine clearance;  critically ill patient;  drug blood level;  electrospray;  female;  Gram negative bacterium;  human;  infant;  male;  priority journal;  systemic inflammatory response syndrome;  tandem mass spectrometry;  treatment outcome;  ultra performance liquid chromatography;  critical illness;  intravenous drug administration, Administration, Intravenous;  Anti-Bacterial Agents;  Child;  Colistin;  Critical Illness;  Gram-Negative Bacteria;  Humans
TODO - 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 (Css,avg) ranged from 1.11 to 8.47 mg/liter (median, 2.92 mg/liter). Ten patients had Css,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 Css,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. Copyright © 2021 American Society for Microbiology. All Rights Reserved.
ER -