title: New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale.
abstract: Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.
authors.affiliation: INSERM U1070, Poitiers, France Université de Poitiers, Poitiers, France.
authors.forename: N
authors.initials: N
authors.lastname: Grégoire
authors.affiliation: INSERM U1070, Poitiers, France Université de Poitiers, Poitiers, France CHU Poitiers, Poitiers, France.
authors.forename: O
authors.initials: O
authors.lastname: Mimoz
authors.affiliation: Hôpital Lariboisière, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Mégarbane
authors.affiliation: INSERM CIC 0203, Université Rennes 1, Rennes, France IAME, UMR 1137, INSERM, Paris, France IAME, UMR 1137, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Comets
authors.affiliation: CHU Poitiers, Poitiers, France.
authors.forename: D
authors.initials: D
authors.lastname: Chatelier
authors.affiliation: Hôpital Bichat, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Lasocki
authors.affiliation: Hôpital Hôtel Dieu, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Gauzit
authors.affiliation: CHU Poitiers, Poitiers, France.
authors.forename: D
authors.initials: D
authors.lastname: Balayn
authors.affiliation: INSERM U1070, Poitiers, France CHU Poitiers, Poitiers, France.
authors.forename: P
authors.initials: P
authors.lastname: Gobin
authors.affiliation: INSERM U1070, Poitiers, France Université de Poitiers, Poitiers, France CHU Poitiers, Poitiers, France.
authors.forename: S
authors.initials: S
authors.lastname: Marchand
authors.affiliation: INSERM U1070, Poitiers, France Université de Poitiers, Poitiers, France CHU Poitiers, Poitiers, France william.couet@univ-poitiers.fr.
authors.forename: W
authors.initials: W
authors.lastname: Couet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D003091:Colistin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016638:Critical Illness; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D016905:Gram-Negative Bacterial Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged
chemical_list: D000900:Anti-Bacterial Agents; C004691:colistinmethanesulfonic acid; D003091:Colistin