The effects of combining fosfomycin with various antimicrobial agents were evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate the following 30 Gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and 20 Enterobacteriaceae isolates. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with β-lactams. Two isolates of Pseudomonas aeruginosa, 2 of Klebsiella pneumoniae, and 1 of the A. baumannii-A. calcoaceticus species complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.

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.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

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BackgroundMultidrug resistance (MDR) among Gram-negative (GN) organisms and the limited active therapeutic options against these pathogens are matters of worldwide concern. Polymyxins are cationic peptides that act on the bacterial cell membrane and have good activity against GN organisms, including MDR strains. We evaluated the activity of QPX9003, a novel polymyxin analog with an improved safety profile over current polymyxins, against a large collection of resistant GN isolates collected worldwide.MethodsSusceptibility testing was performed by reference microbroth dilution against 2,518 GN organisms for QPX9003, colistin (COL), levofloxacin, tigecycline, gentamicin, amikacin, meropenem, cefepime, piperacillin–tazobactam, and ceftazidime–avibactam. Isolates included 1,000 Pseudomonas aeruginosa (PSA) enriched for MDR, 503 carbapenem-resistant Acinetobacter baumannii (CRAB), and 1,105 Enterobacterales (ENT).ResultsQPX9003 had potent activity against PSA isolates enriched for resistance against β-lactam/β-lactamase inhibitor combinations and was 4-fold more potent than COL (MIC50/90, 0.25/0.25 mg/L vs. MIC50/90 of 1/1 mg/L). QPX9003 was also more potent than COL against the panel of CRAB with MIC50/90 of 0.125/1 mg/L and 0.5/4 for QPX9003 and COL, respectively. QPX9003 had a modal MIC of 0.06 mg/L against a large collection of ENT isolates resistant to cephalosporins and/or carbapenems (MIC50/90, 0.06/16 mg/L). QPX9003 activity was identical against 508 carbapenem-resistant Enterobacterales (CRE; MIC50/90, 0.06/16 mg/L) isolates and 511 Klebsiella pneumoniae isolates (MIC50/90, 0.06/16 mg/L) in this collection. Escherichia coli isolates were considerably more sensitive to QPX9003 (MIC50/90, 0.06/0.12 mg/L) compared with K. pneumoniae isolates. Activity of QPX9003 and COL was similar against ENT. Other comparator agents had limited activity against PSA, CRAB, and CRE isolates.ConclusionQPX9003 had activity against this collection of highly resistant GN isolates and was particularly active against the PSA and CRAB isolates. QPX9003 is a promising new-generation polymyxin agent. Disclosures All authors: No reported disclosures.