Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria
| Autor: | Katrina Chan, Amelia K. Sofjan, Kimberly R. Ledesma, Truc T. Tran, Henrietta Abodakpi, Rachel Altman, Weiqun Wang, Michael Nikolaou, Paul R. Merlau, Vincent H. Tam |
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| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
Lactams Avibactam Population Ceftazidime Microbial Sensitivity Tests Pharmacology Tazobactam beta-Lactamases chemistry.chemical_compound Pharmacokinetics In vivo medicine polycyclic compounds Pharmacology (medical) education Original Research education.field_of_study Bacteria biochemical phenomena metabolism and nutrition Anti-Bacterial Agents Infectious Diseases chemistry Pharmacodynamics beta-Lactamase Inhibitors medicine.drug Piperacillin |
| Zdroj: | J Antimicrob Chemother |
| ISSN: | 1460-2091 |
| Popis: | ObjectivesReduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria.MethodsThree clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-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.ResultsA concentration-dependent reduction in β-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.ConclusionsA dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-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. |
| Databáze: | OpenAIRE |
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