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

Olga Lomovskaya,Kirk Nelson,Dongxu Sun,Ruslan Tsivkovski,Debora Rubio-Aparicio,Mariana Castanheira,Jeffery Loutit,Michael Dudley,Jill Lindley

doi:10.1128/aac.00210-21

Olga Lomovskaya, Kirk Nelson + Show 7 more

Open Access

https://doi.org/10.1128/aac.00210-21

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Abstract

ABSTRACTQPX7728 is an ultrabroad-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 (QPX; 8 μg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with various 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 of 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. An additional 290 selected isolates (“challenge panel”) that were either nonsusceptible 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, versus 68% to 70% for QPX-MEM and QPX-PIP and 63% to 65% for TOL-TAZ and CAZ-AVI, respectively. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ∼70% of strains versus 2% to 40% for other combinations. Increased efflux and impaired OprD had various effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varied results according to beta-lactamase production and other intrinsic resistance mechanisms.

Highlights

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases
Using large panels of clinical isolates of carbapenem-resistant Enterobacterales and Acinetobacter baumannii, we previously identified the QPX7728 concentration required to shift meropenem MICs for .90% of isolates to #8 mg/ml; this value corresponds to the meropenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint for 2 g meropenem administered as a 3-h intravenous (i.v.) infusion every 8 h
The in vitro activity of meropenem, ceftolozane, or cefepime combined with QPX7728 at 8 mg/ml was determined against the panel of 500 isolates of Pseudomonas aeruginosa that were selected to represent the MIC distributions of meropenem and ceftazidime-avibactam from the 2017 SENTRY surveillance data (“representative panel”)

Summary

Introduction

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. Due to efficient efflux activity combined with the low permeability of the outer membrane, P. aeruginosa is intrinsically resistant to a large number of marketed antibiotics [5,6,7,8]. Acquired resistance to this already limited arsenal of available antibiotics further threatens. Three novel beta-lactam (BL)–beta-lactamase inhibitor (BLI) combination products, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam, and first-in-class siderophore cephalosporin, cefiderocol, were recently approved for clinical use with activity against P. aeruginosa [14,15,16]. Ongoing research and development aiming to identify improved approaches for treatment of these pathogens is warranted

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