title: A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients.
abstract: De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum β-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n = 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium mieke.carlier@ugent.be.
authors.forename: Mieke
authors.initials: M
authors.lastname: Carlier
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Stove
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Alain G
authors.initials: AG
authors.lastname: Verstraete
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: De Waele
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy*; D047090:beta-Lactams / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams