Impact of inoculum effect on in vitro activity of intermittent and continuous piperacillin-tazobactam infusion against ESBL-producing Escherichia coli in a hollow-fiber infection model.

Authors

Marion Giry, Charles Baulier, Fabien Lamoureux, Manuel Etienne, Nicolas Nessi, François Gravey, Kévin Alexandre

Published in

Microbiology spectrum. Pages e0145726. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Use of piperacillin-tazobactam (TZP) in the treatment of severe extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) infections is controversial. Two features may explain treatment failures: the inoculum effect and suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment, particularly in critically ill patients. To study the combined impact of the inoculum effect and a PK/PD optimization on the in vitro efficacy of TZP against ESBL-EC infections. Five-day hollow-fiber infection model simulating TZP pharmacokinetics in critically ill patients was performed: two TZP infusion regimens (4/0.5 g q6h over 30 min, and 16/2 g q24h continuous infusion), three ESBL-EC clinical strains: 1146 (bla_CTX-M-15, MIC = 2 mg/L), 3383 (bla_CTX-M-15 + bla_TEM-1, MIC = 4 mg/L), and 2262 (bla_CTX-M-15 + bla_OXA-1, MIC = 8 mg/L), and two initial inocula (5 and 7 log₁₀ CFU/mL). Intermittent infusion was associated with systematic bacterial regrowth within 24 h, consistent with failure to reach the 100%fT >4× MIC threshold. Continuous infusion resulted in undetectable bacterial count for the strains 3383 (MIC = 4 mg/L, low inoculum) and 1146 (MIC = 2 mg/L, low and high inocula). For strain 3383, the inoculum effect was demonstrated by total bacterial killing in continuous infusion with low inoculum, whereas early regrowth (>10 log₁₀ CFU/mL) with resistance emergence (MIC > 256 mg/L) was observed with high inoculum. Strain 2262 (MIC = 8 mg/L) exhibited systematic treatment failure regardless of infusion mode or inoculum size. Continuous infusion of TZP may be considered as a carbapenem-sparing agent in ESBL-EC infection with a TZP MIC ≤ 2 mg/L regardless of inoculum, or a TZP MIC of 4 mg/L at low inoculum. TZP should not be used for strains with an MIC of 8 mg/L or suspected OXA-1 co-production, irrespective of the infusion mode.
Infections caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli represent a growing therapeutic challenge, particularly in critically ill patients. Carbapenems remain the reference treatment, but their overuse drives resistance emergence. Piperacillin-tazobactam is a potential carbapenem-sparing agent, but its clinical efficacy remains debated, partly due to the inoculum effect (a reduction in antibiotic activity at high bacterial densities) and suboptimal dosing regimens. Using a hollow-fiber infection model simulating the pharmacokinetics of critically ill patients, this study demonstrates that continuous infusion of piperacillin-tazobactam can overcome the inoculum effect under specific conditions, defined by the MIC of the infecting strain and the estimated bacterial density. These findings support a stratified approach to piperacillin-tazobactam use in severe ESBL-producing E. coli infections, based on MIC, inoculum size, and β-lactamase profile, and may help clinicians identify patients who could safely receive piperacillin-tazobactam instead of a carbapenem.

PMID:
42867252
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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