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J Antimicrob Chemother. 2019 Oct 26. pii: dkz437. doi: 10.1093/jac/dkz437. [Epub ahead of print]

β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill.

Author information

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, Université 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, Nîmes University Hospital, University of Montpellier, Nîmes, France.
11
Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.

Abstract

OBJECTIVES:

To determine the β-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 β-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/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 48 h 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 fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all β-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05).

CONCLUSIONS:

A β-lactam fCmin/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.

PMID:
31665353
DOI:
10.1093/jac/dkz437

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