title: Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.
abstract: Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.
authors.affiliation: 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece iliaskaraiskos@gmail.com.
authors.forename: Ilias
authors.identifier: http://orcid.org/0000-0002-2226-0239
authors.initials: I
authors.lastname: Karaiskos
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
authors.affiliation: 1st Department of Respiratory Diseases-Intensive Care Unit, Sotiria Hospital, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Pontikis
authors.affiliation: Clinical Pharmacist, Hygeia General Hospital, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ioannidis
authors.affiliation: 1st Department of Respiratory Diseases-Intensive Care Unit, Sotiria Hospital, Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Tsagkari
authors.affiliation: 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece.
authors.forename: Lamprini
authors.initials: L
authors.lastname: Galani
authors.affiliation: 1st Department of Respiratory Diseases-Intensive Care Unit, Sotiria Hospital, Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kostakou
authors.affiliation: 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece.
authors.forename: Fotini
authors.initials: F
authors.lastname: Baziaka
authors.affiliation: Intensive Care Unit, Hygeia General Hospital, Athens, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Paskalis
authors.affiliation: 1st Department of Respiratory Diseases-Intensive Care Unit, Sotiria Hospital, Greece.
authors.forename: Antonia
authors.initials: A
authors.lastname: Koutsoukou
authors.affiliation: 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Giamarellou
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003091:Colistin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; C004691:colistinmethanesulfonic acid; D003091:Colistin