Yohei Doi

Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates (n = 526) were more frequently susceptible to these agents than isolates from other countries (n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases (n = 157) were less frequently susceptible than isolates without carbapenemases (n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%-52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.

The development of novel therapeutic approaches to combat infections that stem from extensively drug-resistant (XDR) gram-negative bacteria remains an area of significant unmet need. One such approach is the use of antibiotic adjuvants. Currently, colistin (polymyxin E) is used as the antibiotic of last resort for the treatment of XDR gram-negative bacterial infections. However, resistance to this antibiotic is on the rise. We previously reported that IMD-0354 (an IκB kinase-β inhibitor) and related salicylanilide adjuvants overcome colistin resistance in several gram-negative pathogens. However, this scaffold exhibits unfavorable eukaryotic toxicity, thought to arise from the salicyl moiety. Herein, we investigate the structure-activity relationship (SAR) of second-generation m-hydroxybenzanilide analogs of IMD-0354, to uncover compounds with reduced eukaryotic toxicity and IκB kinase-β inhibitory properties, while maintaining colistin adjuvant activity. We have identified new leads that lower the colistin minimum inhibitory concentration (MIC) upwards of 2048-fold against highly colistin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. In particular, NDM-622 exhibits reduced HepG2 toxicity compared to IMD-0354, with an IC50 of 125 ± 8.0 μM (59.4 ± 3.8 μg/mL) and a therapeutic index of ≥50. In a murine peritonitis model using a highly a colistin-resistant K. pneumoniae strain, NDM-622 and colistin together effect a decrease in colony forming units (CFUs) compared to treatment with colistin alone or vehicle controls. Preliminary mechanism-of-action (MoA) studies suggest that m-hydroxybenzanilides, including NDM-622, likely act via a mechanism distinct from IMD-0354.