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. 2023 Dec 3;12(12):1696.
doi: 10.3390/antibiotics12121696.

Impact of Beta-Lactam Target Attainment on Resistance Development in Patients with Gram-Negative Infections

Nicole F Maranchick  1   2 , Jessica Webber  3 , Mohammad H Alshaer  1   2 , Timothy W Felton  4   5 , Charles A Peloquin  1   2
Affiliations

Impact of Beta-Lactam Target Attainment on Resistance Development in Patients with Gram-Negative Infections

Nicole F Maranchick et al. Antibiotics (Basel). .

Abstract

Background: The objective was to identify associations between beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets and Gram-negative bacteria resistance emergence in patients.

Methods: Retrospective data were collected between 2016 to 2019 at the University of Florida Health-Shands Hospital in Gainesville, FL. Adult patients with two Gram-negative isolates receiving cefepime, meropenem, or piperacillin-tazobactam and who had plasma beta-lactam concentrations were included. Beta-lactam exposures and time free drug concentrations that exceeded minimum inhibitory concentrations (ƒT > MIC), four multiples of MIC (ƒT > 4× MIC), and free area under the time concentration curve to MIC (ƒAUC/MIC) were generated. Resistance emergence was defined as any increase in MIC or two-fold increase in MIC. Multiple regression analysis assessed the PK/PD parameter impact on resistance emergence.

Results: Two hundred fifty-six patients with 628 isolates were included. The median age was 58 years, and 59% were males. Cefepime was the most common beta-lactam (65%) and Pseudomonas aeruginosa the most common isolate (43%). The mean daily ƒAUC/MIC ≥ 494 was associated with any increase in MIC (p = 0.002) and two-fold increase in MIC (p = 0.004). The daily ƒAUC/MIC ≥ 494 was associated with decreased time on antibiotics (p = 0.008). P. aeruginosa was associated with any increase in MIC (OR: 6.41, 95% CI [3.34-12.28]) or 2× increase in MIC (7.08, 95% CI [3.56-14.07]).

Conclusions: ƒAUC/MIC ≥ 494 may be associated with decreased Gram-negative resistance emergence.

Keywords: beta-lactams; drug resistance; gram-negative bacteria; pharmacokinetic/pharmacodynamic.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Violin plots showing PK/PD target attainment stratified by beta-lactam. PK/PD—pharmacokinetic/pharmacodynamic; MIC—minimum inhibitory concentration; ƒT > MIC—time free drug concentrations exceed minimum inhibitory concentration; ƒT > 4× MIC—time free drug concentrations exceed four multiples of MIC.
Figure 2
Figure 2
Bar graphs showing mean (standard deviation) daily ƒAUC/MIC stratified by beta-lactam. ƒAUC/MIC—free area under the time concentration curve to minimum inhibitory concentration.
Figure 3
Figure 3
Kaplan–Meier curve for beta-lactam duration of therapy comparing patients based on ƒAUC/MIC target attainment of 494.
See this image and copyright information in PMC

References

    1. Centers for Disease Control and Prevention About Antimicrobial Resistance. [(accessed on 23 March 2023)];2022 Available online: https://www.cdc.gov/drugresistance/about.html.
    1. World Health Organization Antimicrobial Resistance: Global Report on Surveillance. 1 April 2014. [(accessed on 23 March 2023)]. Available online: https://www.who.int/publications/i/item/9789241564748.
    1. Murray C.J.L., Ikuta K.S., Sharara F., Swetschinski L., Aguilar G.R., Gray A., Han C., Bisignano C., Rao P., Wool E., et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022;399:629–655. doi: 10.1016/S0140-6736(21)02724-0. - DOI - PMC - PubMed
    1. Magiorakos A.-P., Srinivasan A., Carey R.B., Carmeli Y., Falagas M.E., Giske C.G., Harbarth S., Hindler J.F., Kahlmeter G., Olsson-Liljequist B., et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 2012;18:268–281. doi: 10.1111/j.1469-0691.2011.03570.x. - DOI - PubMed
    1. Fernandes P. Antibacterial discovery and development—The failure of success? Nat. Biotechnol. 2006;24:1497–1503. doi: 10.1038/nbt1206-1497. - DOI - PubMed

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