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

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 aKlebsiella 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 ex perimental data can be used to support hypothesis generation regarding potential resistance mechanisms, which may guide subsequent experimental studies.
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research