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

Vincent H. Tam, Henrietta Abodakpi, Weiqun Wang, Kimberly R. Ledesma, Paul R. Merlau, Katrina Chan, Rachel Altman, Truc T. Tran, Michael Nikolaou, Amelia K. Sofjan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 Emax 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.

Original languageEnglish (US)
Pages (from-to)179-183
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Volume76
Issue number1
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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