Evaluation of Antimicrobial Effects of a New Polymyxin Molecule (SPR741) When Tested in Combination with a Series of β-Lactam Agents Against a Challenge Set of Gram-Negative Pathogens

Abstract

The antimicrobial activities of several β-lactam agents were tested by broth microdilution alone and in combination with a new polymyxin analog, SPR741 (at a fixed concentration of 8 mg/L), against a challenge set of clinical isolates (202 Escherichia coli and 221 Klebsiella pneumoniae isolates). Using Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility criteria for each partner antibiotic, mecillinam–SPR741, temocillin–SPR741, and piperacillin–tazobactam–SPR741 combinations had susceptibility rates higher (85.6–100.0%) than the respective agents tested alone (47.5–88.7%) against extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae. Temocillin–SPR741 (97.8% susceptible) had MIC₅₀ (minimum inhibitory concentration) and MIC₉₀ results of 0.5 and 2 mg/L, respectively, against K. pneumoniae carbapenemase (KPC)-producing E. coli, 8- to 16-fold lower than temocillin alone (MIC_50/90, 8/16 mg/L; 65.2% susceptible). The mecillinam MIC₅₀/MIC₉₀ results dropped to 1/4 mg/L (from 128/>256 mg/L when tested alone) against metallo-β-lactamase (MBL)-producing E. coli. These MICs for mecillinam–SPR741 resulted in a susceptibility rate of 96.9% versus 9.4% for mecillinam. In general, a decrease in MICs for β-lactams (MIC₉₀, >32 mg/L) in the presence of SPR741 was not observed against KPC-, MBL- or OXA-48-like-producing K. pneumoniae. These study results indicate that some agents had a significant increase in in vitro activity in the presence of SPR741 and could become potential strategic options for treating serious infections caused by multidrug-resistant Enterobacteriaceae.