Optimizing pharmacokinetics/pharmacodynamics of b-lactam/b-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria

Objectives: Reduced in vitro b-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of b-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a b-lactamase inhibitor. We evaluated different b-lactam/b-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. Methods: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating b-lactamase inhibitor (tazobactam or avibactam) concentrations on b-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid E_max model. The effect of various dosing regimens of b-lactam/b-lactamase inhibitor combinations was predicted using %T_>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. Results: A concentration-dependent reduction in b-lactam MIC was observed (r² ≥0.93). Regrowth could be suppressed in all six experiments using %T_>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. Conclusions: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected b-lactam/b-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.