Repurposing azithromycin in combination with last-line fosfomycin, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

Abstract

AbstractBackgroundNew therapeutical strategies are urgently needed against multidrug-resistant (MDR) Enterobacterales. Azithromycin is a widely prescribed antibiotic with additional immunomodulatory properties, but traditionally underused for the treatment of enterobacterial infections. We previously identified azithromycin as a potent enhancer of colistin, fosfomycin and tigecycline against Klebsiella pneumoniae ATCC 13883.ObjectivesThe aim of this work was to evaluate the antibacterial in vitro activity of azithromycin-based combinations with last-line antibiotics against an expanded panel of MDR/XDR K. pneumoniae isolates.MethodsTime-kill assays of azithromycin alone and in pair-wise combinations with fosfomycin, colistin and tigecycline were performed against a collection of 12 MDR/XDR K. pneumoniae isolates. Synergistic and bactericidal activities of azithromycin-based combinations were analyzed after 8, 24 and 48 hours of treatment, and compared with antimicrobial combinations frequently used in the clinic for the treatment of MDR Enterobacterales.ResultsSynergistic interactions were detected in 100% (12/12) for azithromycin/fosfomycin, 58.3% (7/12) for azithromycin/colistin and 75% (9/12) for azithromycin/tigecycline of the strains, showing potent killing activities. Clinical combinations currently used in the clinic showed synergy in 41.6% (5/12) for meropenem/ertapenem, 33.33% (4/12) for meropenem/colistin, 75% (9/12) for fosfomycin/colistin and 66.6% (8/12) for fosfomycin/tigecycline of the strains, with lower bactericidal efficacy.ConclusionsNovel azithromycin-based combinations with last-line MDR/XDR K. pneumoniae antibiotics were identified showing in vitro capacity to eradicate MDR/XDR K. pneumoniae. Our results provide an in vitro basis supporting azithromycin used in combinatorial treatment for MDR-related infections.