Abstract Background Ledaborbactam is an investigational oral β-lactamase inhibitor that restores ceftibuten's activity against strains of Enterobacterales expressing ESBLs and serine carbapenemases, offering a potential oral therapeutic option for cUTIs. Objectives To characterize the activity of ceftibuten-ledaborbactam human simulated regimens (HSRs) against β-lactamase-producing Enterobacterales in a murine urinary tract infection (UTI) model assessing infection in both the kidney and bladder. Methods Ten urogenic Enterobacterales (ceftibuten-ledaborbactam MIC ≤0.03 to 4 mg/L; ESBL, KPC, OXA-48) were assessed. Murine HSRs for oral ceftibuten (400 mg q8 h and 600 mg q12 h) alone and combined with oral ledaborbactam (400 mg q8 h and 600 mg q12 h) were developed. Activity was assessed by absolute bacterial burden (log10 cfu) in kidneys and bladders after 24 h of treatment. Results Mean (±SD) bacterial burdens in kidneys and bladders of mice at the start of dosing (0 h control) were 5.54 ± 0.22 and 2.95 ± 0.39 log10 cfu/tissue, respectively, which increased to 9 and 5.5 log10 cfu/tissue after 24 h. Ceftibuten monotherapy demonstrated similar growth compared to saline-dosed controls. Ceftibuten-ledaborbactam activity resulted in bacterial burden ranging from 3.56 to 6.44 log10 cfu/kidney for the q8 h regimen and 4.09–5.94 log10 cfu/kidney for the q12 h regimen across nine isolates with MIC ≤ 0.5 mg/L. In bladders, a bacterial burden of 2.00–3.92 log10 cfu was observed across treatment groups. As anticipated, the high MIC strain (4 mg/L), displayed only a moderate bacterial burden reduction in the kidney and bladder after treatment. Conclusion HSR exposures of ceftibuten-ledaborbactam administered q8 h and q12 h resulted in similar and marked bacterial reduction in an upper (kidney) and lower (bladder) UTI model caused by a variety of multi-drug resistant Enterobacterales.
Koenig et al. (Thu,) studied this question.
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