Pharmacokinetic/pharmacodynamic targets of ß-lactams associated with bacterial killing and suppression of the resistance emergence in the hollow fiber infection model: A systematic review
Résumé
The hollow-fibre infection model (HFIM) is an in vitro model used to study pharmacokinetic/pharmacodynamic (PK/PD) interactions between antibiotics and bacteria. However, its external validity remains poorly assessed. This study aimed to identify PK/PD targets and experimental variables associated with bacterial killing and prevention of resistance emergence during β-lactam treatment in HFIM.
Methods: Systematic review of studies using HFIM and β-lactams, with literature search conducted in 4 databases, following PRISMA guidelines. After a quality assessment (modified ToxRtools scale) of the included studies, univariate and multivariate analyses identified factors associated with the prevention of resistance emergence. CART analysis determined values of PK/PD indices best predicting this outcome. Results: Of the 497 screened studies, 41 were included. A total of 367 experiments were analysed, mainly involving Pseudomonas aeruginosa (51%) and carbapenems (46%). Antibiotic exposure through minimal or steady-state free concentrations ( f C min,ss /MIC) (OR 0.78, 95% CI [0.70-0.85], P < 0.001), the initial inoculum size (OR 1.48, 95% CI [1.08-2.06], P = 0.017) and the use of a combination therapy (OR 0.33, CI [0.17-0.64], P = 0.001) remained significantly associated with resistance emergence in multivariate analysis. For carbapenems in monotherapy, the prevention of resistance emergence was likely with f C min,ss /MIC > 5.7. Conclusions: Stringent PK/PD indices thresholds were necessary to prevent resistance emergence in HFIM experiments.
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