1263. Assessment of Cefepime (FEP)-Taniborbactam (TAN) Human Exposures to Suppress the Emergence of Resistance among Serine (SBL)- and Metallo-β-Lactamase (MBL)-Producing Gram-Negative Bacteria (GNB) in a Hollow Fiber Infection Model (HFIM)

Abstract

Background

FEP-TAN (FTB) efficacy and safety are currently being evaluated in a Phase 3 trial (NCT03840148). TAN, a boronic acid-based β-lactamase inhibitor, restores susceptibility to FEP when resistance is driven by SBL or MBL (ie, NDM, VIM). This in vitro study assessed whether clinical FTB exposures suppress treatment-emergent resistance in pathogenic Enterobacterales and Pseudomonas aeruginosa.

Methods

Bioreactors (C2011, FiberCell) were inoculated with clinical GNB strains (N=6) using highly concentrated log phase cultures (> 10⁸ CFU). Syringe pumps supplied humanized exposures of FEP (2 g), FTB (2 g/0.5 g), ceftazidime-avibactam (CZA, 2 g/0.5 g), each as 2 h infusions q8h, or meropenem-vaborbactam (MEV, 2 g/2 g q8h, 3 h infusion) for 7 days. Exposures were confirmed by UPLC-MS/MS for all agents. Subpopulations with elevated FTB MICs (4x) were monitored with drug-supplemented agar. CZA or MEV served as positive or negative controls for selected strains. Samples, serially removed from bioreactors, were saline-washed prior to quantitative culture to prevent drug carryover.

Results

All strains grew rapidly in the presence of FEP (Figure 1), consistent with resistance by broth microdilution (BMD, Table 1). With the addition of TAN, there was extensive killing of the total bacterial populations by FTB, and subpopulations with elevated FTB MICs were never recovered. Like FTB against Klebsiella pneumoniae (KP) BAA-1705, CZA initially decreased the inoculum to the lower limit of detection, but unlike FTB, allowed regrowth to 3.7 log₁₀ CFU/mL by day 7. The first dose of FTB was bactericidal against VIM+ and NDM+ KP strains while regrowth occurred prior to 8 h of MEV and CZA challenge, respectively. Notably, early failure of MEV is discordant with susceptibility by BMD (MIC= 4 µg/mL). By day 7, FTB sterilized an OXA-48+ KP strain that when challenged by MEV, grew to 9.8 log₁₀ CFU/ml at 24 h.

Figure 1. Bacterial burdens observed in the HFIM when treated with FEP alone or FEP+TAN (FTB)

Table 1. Characterization of strains assessed in the HFIM; minimum inhibitory concentration (MIC) values for treatments not assessed are included in parentheses.

Conclusion

In a 7-day HFIM with humanized exposures and high initial inoculums, FTB provided sustained bactericidal activity against multidrug-resistant Enterobacterales and P. aeruginosa strains harboring a diversity of β-lactamases and suppressed growth of resistant subpopulations. These data are crucial to inform understanding of the potential role for FTB in GNB infections and future clinical studies.

Disclosures

Lindsay M. Avery, PharmD, Venatorx Pharmaceuticals (Employee, Shareholder) Salvador Vernacchio, BS, Venatorx Pharmaceuticals (Employee, Shareholder) Lisa McLaughlin, BS, Venatorx Pharmaceuticals (Employee, Shareholder) Luigi Xerri, PhD, Venatorx Pharmaceuticals (Employee, Shareholder) Greg Moeck, PhD, Venatorx Pharmaceuticals (Employee, Shareholder) Daniel Pevear, PhD, Venatorx Pharmaceuticals (Employee, Shareholder)