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Higher target attainment for B-lactam antibiotics in patients with Gram-negative bloodstream infections when four times actual minimum inhibitory concentrations and epidemiological cutoff values are applied compared to clinical breakpoints

Areskog Lejbman, Ilja LU ; Torisson, Gustav LU orcid ; Resman, Fredrik LU and Sjövall, Fredrik LU orcid (2025) In European Journal of Clinical Microbiology and Infectious Diseases 44(5). p.1129-1137
Abstract
Introduction
Beta-lactam antibiotics are essential in the treatment of Gram-negative bloodstream infections. The effect of beta-lactam antibiotics depends on the time of unbound antibiotic concentration above the minimal inhibitory concentration (MIC). An antibiotic concentration above MIC during the whole dosing interval (100% ƒT > MIC) has been suggested as a target for severe infections. The aim of the present study was to compare target attainment using targets derived from known MICs with standard generic targets.

Methods
In this prospective, single-center study, adult patients with Gram-negative bloodstream infection treated with cefotaxime, piperacillin/tazobactam or meropenem were eligible for... (More)
Introduction
Beta-lactam antibiotics are essential in the treatment of Gram-negative bloodstream infections. The effect of beta-lactam antibiotics depends on the time of unbound antibiotic concentration above the minimal inhibitory concentration (MIC). An antibiotic concentration above MIC during the whole dosing interval (100% ƒT > MIC) has been suggested as a target for severe infections. The aim of the present study was to compare target attainment using targets derived from known MICs with standard generic targets.

Methods
In this prospective, single-center study, adult patients with Gram-negative bloodstream infection treated with cefotaxime, piperacillin/tazobactam or meropenem were eligible for inclusion. Trough antibiotic concentrations were collected during a single dosing interval and actual MIC values for the antimicrobial agent against the infecting isolate were obtained using E-tests. Epidemiological cut off values, ECOFFs, were applied from European Committee on Antimicrobial Susceptibility Testing, EUCAST, tables for isolates within the wild-type distribution. Antibiotic concentrations were measured using Liquid Chromatography tandem Mass Spectrometry. Free concentrations were estimated based on total concentrations. Two targets based on actual MICs were assessed: free trough concentrations above (1) four times the actual MIC (100% ƒT > 4MIC) or above (2) the ECOFF (100% ƒT > ECOFF). Proportions of target attainment for the MIC-based targets were compared with attainment using clinical breakpoints or PK/PD breakpoints. Treatment response was defined as clinical resolution at day 7 (No persisting signs or symptoms of infection).

Results
We included 98 patients with a median age of 72 years. The most common microbiological finding was Escherichia coli (63%) followed by Klebsiella pneumoniae (12%). Of all patients, 77/98 patients (79%) attained 100% ƒT > 4MIC and 80/98 (82%) attained 100% ƒT > ECOFF, compared with 57/98 (58%) using 100% ƒT > EUCAST clinical breakpoints. Clinical resolution at day 7 was significantly associated with target attainment applying the target 100% ƒT > 4MIC (p = 0.013), but this was not the case when 100% ƒT > ECOFF was applied (p = 0.50).

Conclusions
In our material, higher target attainment rates were seen using targets derived from actual MICs, compared to EUCAST clinical breakpoints. Attaining 100% ƒT > 4MIC was associated with resolution of infection, but the latter finding should be interpreted cautiously. (Less)
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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Beta-lactam antibiotics, Gram-negative bacteremia, Sepsis, MIC, ECOFFs, EUCAST clinical breakpoints, PK/PD
in
European Journal of Clinical Microbiology and Infectious Diseases
volume
44
issue
5
pages
1129 - 1137
publisher
Springer Science and Business Media B.V.
external identifiers
  • scopus:85218704856
  • pmid:39992534
ISSN
1435-4373
DOI
10.1007/s10096-025-05068-x
language
English
LU publication?
yes
id
c6f9cb14-e5f0-476e-aa4d-c86c42ecfd55
date added to LUP
2025-02-24 17:10:52
date last changed
2025-10-14 09:36:08
@article{c6f9cb14-e5f0-476e-aa4d-c86c42ecfd55,
  abstract     = {{<b>Introduction</b><br/>Beta-lactam antibiotics are essential in the treatment of Gram-negative bloodstream infections. The effect of beta-lactam antibiotics depends on the time of unbound antibiotic concentration above the minimal inhibitory concentration (MIC). An antibiotic concentration above MIC during the whole dosing interval (100% ƒT &gt; MIC) has been suggested as a target for severe infections. The aim of the present study was to compare target attainment using targets derived from known MICs with standard generic targets.<br/><br/><b>Methods</b><br/>In this prospective, single-center study, adult patients with Gram-negative bloodstream infection treated with cefotaxime, piperacillin/tazobactam or meropenem were eligible for inclusion. Trough antibiotic concentrations were collected during a single dosing interval and actual MIC values for the antimicrobial agent against the infecting isolate were obtained using E-tests. Epidemiological cut off values, ECOFFs, were applied from European Committee on Antimicrobial Susceptibility Testing, EUCAST, tables for isolates within the wild-type distribution. Antibiotic concentrations were measured using Liquid Chromatography tandem Mass Spectrometry. Free concentrations were estimated based on total concentrations. Two targets based on actual MICs were assessed: free trough concentrations above (1) four times the actual MIC (100% ƒT &gt; 4MIC) or above (2) the ECOFF (100% ƒT &gt; ECOFF). Proportions of target attainment for the MIC-based targets were compared with attainment using clinical breakpoints or PK/PD breakpoints. Treatment response was defined as clinical resolution at day 7 (No persisting signs or symptoms of infection).<br/><br/><b>Results</b><br/>We included 98 patients with a median age of 72 years. The most common microbiological finding was Escherichia coli (63%) followed by Klebsiella pneumoniae (12%). Of all patients, 77/98 patients (79%) attained 100% ƒT &gt; 4MIC and 80/98 (82%) attained 100% ƒT &gt; ECOFF, compared with 57/98 (58%) using 100% ƒT &gt; EUCAST clinical breakpoints. Clinical resolution at day 7 was significantly associated with target attainment applying the target 100% ƒT &gt; 4MIC (p = 0.013), but this was not the case when 100% ƒT &gt; ECOFF was applied (p = 0.50).<br/><br/><b>Conclusions</b><br/>In our material, higher target attainment rates were seen using targets derived from actual MICs, compared to EUCAST clinical breakpoints. Attaining 100% ƒT &gt; 4MIC was associated with resolution of infection, but the latter finding should be interpreted cautiously.}},
  author       = {{Areskog Lejbman, Ilja and Torisson, Gustav and Resman, Fredrik and Sjövall, Fredrik}},
  issn         = {{1435-4373}},
  keywords     = {{Beta-lactam antibiotics; Gram-negative bacteremia; Sepsis; MIC; ECOFFs; EUCAST clinical breakpoints; PK/PD}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{5}},
  pages        = {{1129--1137}},
  publisher    = {{Springer Science and Business Media B.V.}},
  series       = {{European Journal of Clinical Microbiology and Infectious Diseases}},
  title        = {{Higher target attainment for B-lactam antibiotics in patients with Gram-negative bloodstream infections when four times actual minimum inhibitory concentrations and epidemiological cutoff values are applied compared to clinical breakpoints}},
  url          = {{http://dx.doi.org/10.1007/s10096-025-05068-x}},
  doi          = {{10.1007/s10096-025-05068-x}},
  volume       = {{44}},
  year         = {{2025}},
}