Open AccessIn Vitro Activity Analysis of a New Polymyxin, SPR741, Tested in Combination with Antimicrobial Agents against a Challenge Set of Enterobacteriaceae , Including Molecularly Characterized Strains
Author(s) -
Rodrigo E. Mendes,
Paul R. Rhomberg,
Troy Lister,
Nicole Cotroneo,
Thomas Parr,
Mariana Castanheira
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00742-20
Subject(s) - microbiology and biotechnology , fusidic acid , biology , tetracycline , fosfomycin , klebsiella pneumoniae , tigecycline , antibacterial agent , antimicrobial , enterobacteriaceae , vancomycin , broth microdilution , escherichia coli , antibiotics , minimum inhibitory concentration , bacteria , staphylococcus aureus , gene , genetics , biochemistry
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 (MIC 90 , 2 to 4 mg/liter) and minocycline-SPR741 (MIC 90 , 0.5 to 2 mg/liter) showed the lowest MIC 90 values against different subsets of E. coli isolates, except for azithromycin-SPR741 (MIC 90 , 16 mg/liter) against the AmpC and metallo-β-lactamase subsets. In general, minocycline-SPR741 (MIC 90 , 2 to 8 mg/liter) had the lowest MIC 90 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.