In Vitro Activity of the Ultrabroad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa

Abstract

QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase producing Enterobacterales and Acinetobacter spp. In this study we evaluated the in vitro activity of QPX7728 (8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with varying beta-lactam resistance mechanisms. Seven-hundred-ninety clinical isolates were included in this study; 500 isolates, termed a “representative panel”, were selected to be representative the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data (representative panel). An additional 290 selected isolates (“challenge panel”), that were either non-susceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was >90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in ∼90% and ∼80% of strains, respectively, vs 68-70% for QPX-MEM and QPX-PIP and 63-65% for TOL-TAZ and CAZ-AVI. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ∼70% of strains vs 2-40% for other combinations. Increased efflux and impaired OprD had varying effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varying results according to the beta-lactamase production and other intrinsic resistance mechanisms.

Efficacy and In Vitro Activity of Novel Antibiotics for Infections With Carbapenem-Resistant Gram-Negative Pathogens

“…These data indicate that QPX7728 administered in combination with different β−lactam antibiotics may have utility in treating bacterial infections due to carbapenem-resistant K. pneumoniae ( Sabet et al., 2020 ). Further, QPX7728, in combination with cephalosporins or carbapenems, including meropenem, was found to have excellent activity against CRE-producing serine or MBL ( Nelson et al., 2020 ; Lomovskaya et al., 2021 ).…”

QPX7728, An Ultra-Broad-Spectrum B-Lactamase Inhibitor for Intravenous and Oral Therapy: Overview of Biochemical and Microbiological Characteristics

“…The study described by Lomovskaya et al (2021) investigated the impact of QPX7728 on potency of meropenem, cefepime and ceftolozane against two panels of P. aeruginosa . The first panel consisted of 500 isolates that were selected to mirror MIC distributions of β-lactams and BL/BLI combinations observed in recent global surveillance studies.…”

“…Second, the inhibitory potency of QPX7728 for a particular β-lactamase. Finally, the impact of non- β-lactamase mediated β-lactam resistance mechanisms such as increased efflux by MexAB-OprM or inactivation of OprD on both the inhibitor and β-lactam will also impact activity ( Lomovskaya et al, 2021 ).…”

“…Studies with isogenic strains demonstrated that various combinations of non- β-lactamase-mediated intrinsic mechanisms such as increased efflux by MexAB-OprM or inactivation of a carbapenem-specific porin OprD may raise the MICs of some β-lactams to or above their susceptibility breakpoints ( Lomovskaya et al, 2021 ). The combination of QPX7728 plus ceftolozane is the most potent combination against MBL-negative strains of Pseudomonas aeruginosa since neither drug is a substrate of efflux nor is affected by inactivation of OprD.…”

“…*: % inhibited at the following concentrations: meropenem: ≤ 8 µg/ml; QPX7728/meropenem: ≤ 8 µg/ml with QPX7728 at 8 µg/ml; ceftolozane: ≤ 4 µg/ml; QPX7728/ceftolozane: ≤ 4 µg/ml with QPX7728 at 8 µg/ml; ceftolozane-tazobactam: ≤ 4/4 µg/ml; cefepime: ≤ 8 µg/ml; QPX7728/cefepime: ≤ 8 µg/ml with QPX7728 at 8 µg/ml; ceftazidime-avibactam: ≤ 8/4 µg/ml; piperacillin-tazobactam: ≤ 16 µ g/ml. Data fromLomovskaya et al (2021).…”