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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)199-211
JournalJournal of pharmacokinetics and pharmacodynamics
Publication statusPublished - 26 Nov 2023


  • Antimicrobial resistance
  • Klebsiella pneumoniae
  • Piperacillin-Tazobactam
  • Semi-mechanistic model


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