title: Determinants of gentamicin concentrations in critically ill patients: a population pharmacokinetic analysis.
abstract: When treating critically ill patients with gentamicin for severe infection, peak concentrations (Cmax) determine clinical efficacy and trough concentrations (Cmin) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of Cmaxis generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate Cminand gentamicin dosing intervals, but the most accurate predictor is not known. This study aimed to quantify the impact of several patient parameters on gentamicin Cmaxvalues and to determine which measure of renal function best predicts gentamicin clearance (CL). Clinical data and serum gentamicin levels were retrospectively collected from all critically ill patients treated with gentamicin at our intensive care unit between 1 January and 30 June 2011. Data were analysed using non-linear mixed-effects modelling (NONMEM v.7.1.2). A two-compartmental model was developed based on 303 gentamicin concentration-time data from 44 critically ill patients. Serum albumin levels explained 25% of interindividual variability in the volume of distribution (Vd). Creatinine clearance calculated from the creatinine concentration in a 6-h urine portion (CalcCLCr) resulted in acceptable estimation of gentamicin CL, whilst serum creatinine (SCr) and creatinine clearance estimated by the Cockcroft-Gault formula (CGCLCr) overestimated gentamicin CL and therefore underestimated Cmin. In conclusion, low albumin concentrations resulted in a larger Vdand lower Cmaxof gentamicin. These results suggest that use of a higher gentamicin starting dose in critically ill patients with hypoalbuminaemia may prevent underdosing. Urinary CalcCLCris a better predictor of Cminthan SCr or CGCLCr.
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: c.j.hodiamont@amc.nl.
authors.forename: Caspar J
authors.initials: CJ
authors.lastname: Hodiamont
authors.affiliation: Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Juffermans
authors.affiliation: Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Catherine S C
authors.initials: CS
authors.lastname: Bouman
authors.affiliation: Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Menno D
authors.initials: MD
authors.lastname: de Jong
authors.affiliation: Department of Hospital Pharmacy & Clinical Pharmacology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
authors.affiliation: Department of Hospital Pharmacy & Clinical Pharmacology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Reinier M
authors.initials: RM
authors.lastname: van Hest
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D016638:Critical Illness; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007362:Intensive Care Units; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012189:Retrospective Studies; D044967:Serum / Q000737:chemistry*; D012709:Serum Albumin / Q000032:analysis; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D012709:Serum Albumin; D003404:Creatinine
keywords: Critical illness; Gentamicin; Hypoalbuminaemia; Population pharmacokinetics; Renal function