b-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill Gloria Wong 1,2 *, Fabio Taccone 3 , Paola Villois 3 , Marc H. Scheetz 4–6 , Nathaniel J. Rhodes 4–6 , Scott Briscoe 7 , Brett McWhinney 7 , Maria Nunez-Nunez 8 , Jacobus Ungerer 7,9 , Jeffrey Lipman 1,2,10 and Jason A. Roberts 1,2,10,11 1 UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia; 2 Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia; 3 Department of Intensive Care, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium; 4 Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA; 5 Department of Pharmacy Practice and Pharmacometrics Center of Excellence, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA; 6 Department of Pharmacology, College of Graduate Studies, Midwestern University, Chicago College of Pharmacy, Downers Grove, IL, USA; 7 Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia; 8 Department of Pharmacy and Department of Infectious Diseases, University Hospital San Cecilio, Granada, Spain; 9 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia; 10 Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nı ˆmes University Hospital, University of Montpellier, Nı ˆmes, France; 11 Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia *Corresponding author. E-mail: gloria.wong@alumni.utoronto.ca Received 22 May 2019; returned 5 July 2019; revised 17 September 2019; accepted 25 September 2019 Objectives: To determine the b-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. Patients and methods: Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with b-lactams were collected from two databases. Free minimum concentrations (fC min ) of aztreonam, cefe- pime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were inter- preted in relation to the measured MIC for targeted bacteria (fC min /MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. Results: Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fC min /MIC 1 and fC min /MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fC min /MIC >1.3 for all b-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fC min /MIC >4.95 for meropenem, aztreonam or ceftriaxone (pre- dicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). Conclusions: A b-lactam fC min /MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target. Introduction Gram-negative bloodstream infections (BSIs) are associated with a high burden in critically ill patients, with mortality rates common- ly exceeding 15%. 1,2 Emergence of resistant bacteria associated with ineffective initial therapy is an additional challenge faced by clinicians. b-Lactam antibiotics, with broad-spectrum activity against Gram-negative bacteria, are commonly used in this setting. The efficacy of b-lactams is closely correlated with the percent- age of time where the unbound (or free) drug concentration remains above the MIC for the targeted bacteria (%fT >MIC ). Early in vitro and animal studies suggest that, depending on the subclass of b-lactam, a pharmacokinetic/pharmacodynamic (PK/PD) index of at least 30%–60% fT >MIC is required for bactericidal effect; how- ever, trough (minimum) antibiotic concentrations up to 5–6% MIC (fC min /MIC >5) have been associated with improved clinical VC The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 429 J Antimicrob Chemother 2020; 75: 429–433 doi:10.1093/jac/dkz437 Advance Access publication 26 October 2019 Downloaded from https://academic.oup.com/jac/article/75/2/429/5607718 by guest on 26 February 2023