Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

Synergistic Combination of AS101 and Azidothymidine against Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae

“…The checkerboard analysis revealed 60.9% (14/23), 87.1% (27/31), 100% (7/7), and 92.31% (12/13) synergetic effects in ESBL-producing E. coli, ESBL K. pneumoniae, NDM-1-producing strains, and mcr-1-positive E. coli, respectively. In another evaluation conducted in Taiwan, Chang et al reported 100% synergistic activities for both KPC-producing and non-KPC-producing colistin-resistant CRKP isolates [12]. In vivo results demonstrated an extended lifespan and decreased risk ratios in a Caenorhabditis elegans model infected by a KPC-producing colistin-resistant CRKP isolate, positive support that AZTcolistin possessed the potential for treating CRKP infections.…”

“…To this end, some β-lactam-βlactamase inhibitor combination therapies were introduced into clinical settings recently, such as meropenem-vaborbactam, imipenem-relebactam, and ceftazidime-avibactam [7][8][9][10]. Moreover, combinations of azidothymidine (AZT), an antiviral agent usually used against HIV infection, plus other agents, were also reported, including AZT-colistin and AZTfosfomycin [11][12][13]. Hu et al obtained 74 antibiotic-resistant Enterobacteriaceae strains from hospitals in 9 countries, including 23 ESBL-producing E. coli, 31 ESBL, 7 NDM-1-producing strains, and 13 mcr-1-positive E. coli [11].…”

“…Moreover, azidothymidine was reported to show synergistic activities with some clinical antimicrobial agents such as colistin and fosfomycin. [11][12][13]. Azidothymidine (AZT), a thymidine analog, possesses an antiretroviral activity and clinically treats patients with human immunodeficiency virus (HIV) infections, the acquired immunodeficiency syndrome (AIDS) [14].…”

“…Lately, studies have reported that azidothymidine combined with antibiotics produced synergistic activities against antibiotic-resistant gram-negative bacteria both in vitro and in vivo [11]. A previous study also reported that a combination of colistin and azidothymidine revealed synergistic activity against colistin-resistant CRKP clinical isolates [12]. In a phase I clinical trial for the combination of AZT and colistin, the results revealed that a dosage of 2 million IU CMS plus 100 mg AZT twice a day might be sufficient for urinary tract infections (UTIs) [15].…”

Will There Ever Be Cure for Chronic, Life-Changing Colistin-Resistant Klebsiella pneumoniae in Urinary Tract Infection?

“…Azidothymidine is an approved antiretroviral drug, and it also exhibits antibacterial activities against Enterobacteriaceae by acting on bacterial DNA synthesis (32). Previous studies demonstrated significant synergistic activities of azidothymidine for retaining therapeutic efficacies of colistin in colistin-resistant K. pneumoniae that express mcr-1, both in vitro and in vivo (33,34).…”