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Semi-mechanistic modeling of resistance development to β-lactam and β-lactamase-inhibitor combinations

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Abstract

The use of β-lactam (BL) and β-lactamase inhibitor (BLI) combinations, such as piperacillin-tazobactam (PIP-TAZ) is an effective strategy to combat infections by extended-spectrum β-lactamase-producing bacteria. However, in Gram-negative bacteria, resistance (both mutational and adaptive) to BL-BLI combination can still develop through multiple mechanisms. These mechanisms may include increased β-lactamase activity, reduced drug influx, and increased drug efflux. Understanding the relative contribution of these mechanisms during resistance development helps identify the most impactful mechanism to target in designing a treatment to counter BL-BLI resistance. This study used semi-mechanistic mathematical modeling in combination with antibiotic sensitivity assays to assess the potential impact of different resistance mechanisms during the development of PIP-TAZ resistance in a Klebsiella pneumoniae isolate expressing CTX-M-15 and SHV-1 β-lactamases. The mathematical models were used to evaluate the potential impact of several cellular changes as a sole mediator of PIP-TAZ resistance. Our semi-mechanistic model identified 2 out of the 13 inspected mechanisms as key resistance mechanisms that may independently support the observed magnitude of PIP-TAZ resistance, namely porin loss and efflux pump up-regulation. Simulation using the resulting models also suggested the possible adjustment of PIP-TAZ dose outside its commonly used 8:1 dosing ratio. The current study demonstrated how theory-based mechanistic models informed by experimental data can be used to support hypothesis generation regarding potential resistance mechanisms, which may guide subsequent experimental studies.

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Authors and Affiliations

  1. Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

    Sebastian T. Tandar, Linda B.S. Aulin, Eva M. J. Leemkuil, Apostolos Liakopoulos & J. G. Coen van Hasselt

  2. Department Clinical Pharmacy and Biochemistry, Freie Universität Berlin, Berlin, Germany

    Linda B.S. Aulin

  3. Department of Biology, Utrecht University, Utrecht, The Netherlands

    Apostolos Liakopoulos

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  1. Sebastian T. Tandar
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  5. J. G. Coen van Hasselt
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Contributions

ST, LA, and CH conceived the presented idea. ST and EL collected experimental results and explored different analytical angles. AL counseled the details of the strain’s resistance mechanism implementation on the model. CH supervised and evaluated the work. ST wrote the main manuscript text. All authors reviewed the manuscript.

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Correspondence to Sebastian T. Tandar or J. G. Coen van Hasselt.

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Tandar, S.T., Aulin, L.B., Leemkuil, E.M.J. et al. Semi-mechanistic modeling of resistance development to β-lactam and β-lactamase-inhibitor combinations. J Pharmacokinet Pharmacodyn 51, 199–211 (2024). https://doi.org/10.1007/s10928-023-09895-3

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