Murepavadin activity tested against contemporary (2016-17) clinical isolates of XDR Pseudomonas aeruginosa

Abstract

Background: Murepavadin (POL7080) represents the first member of a novel class of outer membrane proteintargeting antibiotics. Murepavadin acts by binding to LPS transport protein D and is being developed for the treatment of hospital-acquired and ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Objectives: To evaluate the antimicrobial activity of murepavadin against XDR P. aeruginosa. Methods: A total of 785 clinical isolates of XDR P. aeruginosa were collected in 2016-17 through the SENTRY Antimicrobial Surveillance Program from 34 medical centres in 21 European nations (n=353) and 75 medical centres in North America (n=432). Isolates were categorized as XDR when susceptible (CLSI) to ≤2 of the following antimicrobial classes: antipseudomonal cephalosporins, carbapenems, broad-spectrum penicillin/ β-lactamase inhibitor combinations, fluoroquinolones, aminoglycosides and polymyxins. Susceptibility testing was performed by the reference broth microdilution method and EUCAST and CLSI interpretative criteria were applied. Results: Murepavadin (MIC50/90, 0.12/0.25 mg/L) inhibited 96.7% of isolates at ≤0.5 mg/L and was 8-fold more active than colistin (MIC50/90, 1/2 mg/L). Only seven isolates (0.9%) exhibited murepavadin MIC values .4 mg/L. Colistin (MIC50/90, 1/2 mg/L; 93.6% susceptible) was the most active comparator, followed by ceftolozane/tazobactam (MIC50/90, 2/>32 mg/L; 70.6% susceptible) and tobramycin (MIC50/90, 8/>8 mg/L; 47.5% susceptible). Murepavadin remained active against isolates that were non-susceptible to colistin (n=50; MIC50/90, 0.25/ 0.25 mg/L), ceftolozane/tazobactam (n=231; MIC50/90, 0.12/0.25 mg/L) and/or tobramycin (n=412; MIC50/90, 0.12/0.25 mg/L). Conclusions: Murepavadin exhibited potent activity against a large collection of clinical XDR P. aeruginosa isolates from Europe and North America, including isolates that were non-susceptible to colistin, ceftolozane/tazobactam and/or tobramycin.