In vivo pharmacokinetics and pharmacodynamics of ceftibuten/ledaborbactam, a novel oral beta-lactam/beta-lactamase inhibitor combination

Objectives Oral beta-lactam treatment options for MDR Enterobacterales are lacking. Ledaborbactam (formerly VNRX-5236) is a novel orally bioavailable beta-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 log(10) cfu/thigh change at 24 h relative to 0 h controls was plotted against ledaborbactam fAUC(0-24)/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 log(10) cfu/thigh. Robust growth (3.12 +/- 0.93 log(10) cfu/thigh) was achieved in untreated control mice. Growth of 2.51 +/- 1.09 log(10) cfu/thigh was observed after administration of humanized ceftibuten monotherapy. Individual isolate exposure-response relationships were strong (mean +/- SD R-2 = 0.82 +/- 0.15). The median ledaborbactam fAUC(0-24)/MIC associated with stasis was 3.59 among individual isolates and 6.92 in the composite model. Conclusions Ledaborbactam fAUC(0-24)/MIC exposures for stasis were quantified with a ceftibuten human-simulated regimen against beta-lactamase-producing Enterobacterales. This study supports the continued development of oral ceftibuten/ledaborbactam etzadroxil (formerly ceftibuten/VNRX-7145).