In Vitro Activity Analysis of a New Polymyxin, SPR741, Tested in Combination with Antimicrobial Agents against a Challenge Set of Enterobacteriaceae, Including Molecularly Characterized Strains

The activities of azithromycin, fusidic acid, vancomycin, doxycycline, and minocycline were evaluated alone and in combination with SPR741. A total of 202 Escherichia coli and 221 Klebsiella pneumoniae isolates were selected, and they included a genome-sequenced subset (n = 267), which was screened in silico for β-lactamase, macrolide-lincosamide-streptogramin (MLS), and tetracycline (tet) genes. Azithromycin (>16 mg/liter), fusidic acid (>64 mg/liter), vancomycin (>16 mg/liter), and SPR741 (>8 mg/liter) showed off-scale MICs when each was tested alone against all isolates. MIC_50/90 results of 0.5/8 mg/liter, 4/>32 mg/liter, 16/>16 mg/liter, 2/32 mg/liter, and 0.25/4 mg/liter were obtained for azithromycin-SPR741, fusidic acid-SPR741, vancomycin-SPR741, doxycycline-SPR741 and minocycline-SPR741, respectively, against all isolates. Overall, azithromycin-SPR741 (MIC₉₀, 2 to 4 mg/liter) and minocycline-SPR741 (MIC₉₀, 0.5 to 2 mg/liter) showed the lowest MIC₉₀ values against different subsets of E. coli isolates, except for azithromycin-SPR741 (MIC₉₀, 16 mg/liter) against the AmpC and metallo-β-lactamase subsets. In general, minocycline-SPR741 (MIC₉₀, 2 to 8 mg/liter) had the lowest MIC₉₀ against K. pneumoniae isolates producing different groups of β-lactamases. The azithromycin-SPR741 MIC (MIC_50/90, 2/32 mg/liter) was affected by MLS genes (MIC_50/90 of 0.25/2 mg/liter against isolates without MLS genes), whereas doxycycline-SPR741 (MIC_50/90, 0.5/2 versus 8/32 mg/liter) and minocycline-SPR741 (MIC_50/90, 0.25/1 versus 1/8 mg/liter) MIC results were affected when tested against isolates carrying tet genes in general. However, minocycline-SPR741 inhibited 88.2 to 92.9% of tet-positive isolates regardless of the tet gene. The azithromycin-SPR741 MIC results (MIC_50/90, 1/16 mg/liter) against isolates with enzymatic MLS mechanisms were lower than against those with ribosomal protection (MIC_50/90, 16/>32 mg/liter). SPR741 increased the in vitro activity of tested codrugs at different levels and seemed to be dependent on the species and resistance mechanisms of the respective codrug.