title: Augmented renal clearance, low β-lactam concentrations and clinical outcomes in the critically ill: an observational prospective cohort study.
abstract: Whilst augmented renal clearance (ARC) is associated with reduced β-lactam plasma concentrations, its impact on clinical outcomes is unclear. This single-centre prospective, observational, cohort study included non-pregnant, critically ill patients aged 18-60 years with presumed severe infection treated with imipenem, meropenem, piperacillin/tazobactam or cefepime and with creatinine clearance (CL(Cr)) ≥60 mL/min. Peak, intermediate and trough levels of β-lactams were drawn on Days 1-3 and 5. Concentrations were deemed 'subthreshold' if they did not meet EUCAST-defined non-species-related breakpoints. Primary and secondary endpoints were clinical response 28 days after inclusion, and ARC prevalence (CL(Cr)≥130 mL/min) and subthreshold and undetectable concentrations, respectively. Logistic regression was used to evaluate associations between ARC, antibiotic concentrations and clinical failure. From 2010 to 2013, 100 patients were enrolled (mean age, 45 years; median CL(Cr) at inclusion, 144.1 mL/min). ARC was present in 64 (64%) of the patients. Most patients received imipenem/cilastatin (54%). Moreover, 86% and 27% of patients had at least one subthreshold or undetectable trough level, respectively. Among imipenem and piperacillin trough levels, 77% and 61% were subthreshold, respectively, but intermediate levels of both antibiotics were largely above threshold. ARC strongly predicted undetectable trough concentrations (OR=3.3, 95% CI 1.11-9.94). A link between ARC and clinical failure (18/98; 18%) was not observed. ARC and subthreshold β-lactam antibiotic concentrations were widespread but were not associated with clinical failure. Larger studies are necessary to determine whether standard dosing regimens in the presence of ARC impact negatively on clinical outcome and antibiotic resistance.
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland. Electronic address: angela.huttner@hcuge.ch.
authors: Angela
authors: A
authors: Huttner
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Elodie
authors: E
authors: Von Dach
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Adriana
authors: A
authors: Renzoni
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Benedikt D
authors: BD
authors: Huttner
authors: University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Mathieu
authors: M
authors: Affaticati
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Leonardo
authors: L
authors: Pagani
authors: Division of Pharmacology, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Yousef
authors: Y
authors: Daali
authors: Division of Critical Care Medicine, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Jerôme
authors: J
authors: Pugin
authors: Department of Laboratory Medicine, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Abderrahim
authors: A
authors: Karmime
authors: Department of Laboratory Medicine, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Marc
authors: M
authors: Fathi
authors: Division of Infectious Diseases, Geneva University Hospitals and Medical School, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Daniel
authors: D
authors: Lew
authors: Infection Control Programme, Geneva University Hospitals and Faculty of Medicine, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 4, Switzerland.
authors: Stephan
authors: S
authors: Harbarth
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams
keywords: Antibacterial agents; Augmented renal clearance; Carbapenems; Critically ill; Therapeutic drug monitoring; β-Lactam antibiotics