Multidrug-resistant (MDR) Enterobacteriales
infections have become an urgent global threat to public health. The aim of this study was to evaluate the efficacy of
zidovudine-
amikacin combination
therapy in vitro and in vivo. Molecular characteristics and antibiotic resistance profiles of 53
amikacin-resistant MDR, extensively
drug-resistant (XDR), or pan-
drug-resistant (PDR) clinical isolates were examined via PCR and susceptibility testing. Checkerboard assays were performed for these 53 isolates to assess in vitro synergistic effects of the
zidovudine-
amikacin combination, and static time-kill experiments were performed for four XDR or PDR Enterobacteriales isolates. A Galleria mellonella model and a rat
tissue cage infection model were established to assess in vivo synergistic effects. The aac(6')-Ib gene was detected in 25 (47.2%) isolates, followed by armA in 5 (9.4%) isolates, rmtB in 27 (50.9%) isolates, and rmtC in 3 (5.8%) isolates. Checkerboard assays showed the synergy of this combination against 38 (71.7%) isolates. The time-kill assays further confirmed that
zidovudine strongly synergized with
amikacin against four XDR or PDR Enterobacteriales isolates. The Galleria mellonella model study showed that the survival benefit of
zidovudine-
amikacin combination
therapy was significantly better than that of monotherapy for those four Enterobacteriales isolates. Furthermore, the rat
tissue cage infection model study showed that
zidovudine-
amikacin combination
therapy displayed more potent bactericidal activity than monotherapy after 3 and 7 days of treatment for the above four isolates. Our data support the idea that the
zidovudine-
amikacin combination could be a plausible alternative
therapy against
infections with
amikacin-resistant MDR Enterobacteriales, especially with XDR and PDR Enterobacteriales. IMPORTANCE Our study revealed for the first time that the
zidovudine-
amikacin combination shows a significant bactericidal effect against
amikacin-resistant MDR, XDR, and PDR Enterobacteriales. Second, using in vitro and in vivo approaches, our study showed that
zidovudine strongly synergized with
amikacin against
amikacin-resistant MDR Enterobacteriales isolates. Most importantly, with regard to survival benefit, pharmacokinetics, and bactericidal effects, our in vivo experiment demonstrated the effectiveness of
zidovudine-
amikacin.