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.
Highlights
Antimicrobial resistance (AMR) has been one of the most challenging public health problems during this era of expeditious medical advances
Colistin resistance was defined as minimum inhibitory concentrations (MICs) > 2 μg/mL, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria [19]
In agreement with a recent study [34], we found relatively low AZT MICs (0.03125–1 μg/mL) for colistin-resistant K. pneumoniae after combination with colistin, indicating that AZT could be a practical therapeutic candidate because of its clinically achievable concentrations
Summary
Antimicrobial resistance (AMR) has been one of the most challenging public health problems during this era of expeditious medical advances. Multidrug-resistant organisms (MDROs) are recognized as an imminent global threat that impose substantial medical burdens and economic costs [1]. The prevalence rates of carbapenem-resistant Enterobacteriaceae (CRE) have been increasing, especially those of Klebsiella pneumoniae and Escherichia coli [4]. Because of the limited antimicrobial options and an increased risk for horizontal transmission due to the presence of resistance genes in mobile genetic elements, the treatment and containment of CRE infections have become serious dilemmas in daily practice and in terms of infection control [5]. The phenotypic resistance to carbapenems in CRE typically originates from two main mechanisms: (1) the combined effects of β-lactamase(s) and structural mutations, and (2) the production of carbapenemases [6]. CP-K. pneumoniae (CPKP) is the most widely reported CRE species, with a much higher and increasing prevalence compared with E. coli [9]. CPKP is the most extensively studied CRE regarding treatment response to various new and old antibiotics
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