Abstract
Abstract Background The broad spectrum BLI xeruborbactam (XER, formerly, QPX7728) can be delivered IV or orally as the isobutyryloxymethyl prodrug. The prodrug form is in clinical development in combination with ceftibuten (BUT) for oral treatment of resistant gram-negative infections. The objective of this study was to compare the in vitro potency of BUT-XER to that of other investigational oral BL/BLI combinations and tebipenem (TBP) in blinded head-to-head testing against extended beta-lactamase (ESBL) producing and carbapenem-resistant Enterobacterales (CRE). Methods A total of 980 Enterobacterales including 515 ESBL and 460 CRE, including 195 KPC-, 97 OXA-48-like- and 168 metallo beta-lactamase (MBL) producers, were susceptibility tested by reference broth microdilution against BUT-XER (at fixed 4 mg/L) and comparator BLs or BL/BLI combinations (tested at their recommended BLI concentrations). MIC testing was conducted blinded to drug identity using CLSI reference microdilution methods and controlled using approved quality control bacterial strains and ranges. Results BLI inhibitor combinations and TBP had excellent potency against ESBL isolates with MIC90 in the ≤ 0.03-0.06 mg/L range for BUT-avibactam (AVI) and BUT-XER and in 0.125-0.25 mg/L range for TBP, BUT-VNTX-6236 (VNRX) and cefpodoxime (CPD)-ETX1317 (ETX) (Table). Against KPC and OXA-48-producers, BUT-XER and BUT-AVI (MIC90 0.25-0.5 mg/L) were 4-fold more potent than BUT-VNRX and CPD-ETX (MIC90 of 1-2 mg/L); TBP was not active against these strains. BUT-XER and CPD-ETX were the most potent agents against MBL-producing strains; however, anti-MBL activity of CPD-ETX was due to intrinsic antibacterial activity of ETX. TPB, BUT-AVI and BUT-VNTX did not have any relevant activity against MBL-producing strains. Conclusion BUT-XER had the broadest antimicrobial profile, with activity against ESBL and all carbapenemase producing isolates. Its potency against ESBL-producing isolates was comparable to the carbapenem TBP. Its in vitro potency and spectrum combined with the potential of once-daily administration based on PK studies warrants further clinical development. Disclosures Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jill Lindley, BS, AbbVie: Grant/Research Support.
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