| Autor: |
Fratoni, Andrew J, Avery, Lindsay M, Nicolau, David P, Asempa, Tomefa E |
| Předmět: |
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| Zdroj: |
Journal of Antimicrobial Chemotherapy (JAC); Jan2023, Vol. 78 Issue 1, p93-100, 8p |
| Abstrakt: |
Objectives Oral β-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable β-lactamase inhibitor that restores ceftibuten activity against Ambler Class A-, C- and D-producing Enterobacterales. We assessed the ledaborbactam exposure needed to produce bacteriostasis against ceftibuten-resistant Enterobacterales in the presence of humanized ceftibuten exposures in the neutropenic murine thigh infection model. Methods Twelve ceftibuten-resistant clinical isolates (six Klebsiella pneumoniae , five Escherichia coli and one Enterobacter cloacae) were utilized. Ceftibuten/ledaborbactam MICs ranged from 0.12 to 2 mg/L (ledaborbactam fixed at 4 mg/L). A ceftibuten murine dosing regimen mimicking ceftibuten 600 mg q12h human exposure was developed and administered alone and in combination with escalating exposures of ledaborbactam. The log10 cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam f AUC0–24/MIC and the Hill equation was used to determine exposures associated with bacteriostasis. Results The mean ± SD 0 h bacterial burden was 5.96 ± 0.24 log10 cfu/thigh. Robust growth (3.12 ± 0.93 log10 cfu/thigh) was achieved in untreated control mice. Growth of 2.51 ± 1.09 log10 cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure–response relationships were strong (mean ± SD R2 = 0.82 ± 0.15). The median ledaborbactam f AUC0–24/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model. Conclusions Ledaborbactam f AUC0–24/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against β-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145). [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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