Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales

Antonello, Roberta Maria; Bella, Stefano Di; Betts, Jonathan W.; Ragione, Roberto La; Bressan, Raffaela; Principe, Luigi; Morabito, Stefano; Gigliucci, Federica; Tozzoli, Rosangela; Busetti, Marina; Knezevich, Anna; Furlanis, Linda; Fontana, Francesco; Luzzaro, Francesco; Luzzati, Roberto; Lagatolla, Cristina

doi:10.1016/j.ijantimicag.2021.106362

Cited by 23 publications

(28 citation statements)

References 43 publications

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“…In our study, MICs of zidovudine ranged from 0.25 to ≥64 mg/L, which are in accordance with similar studies (16,17,19,20). We observed potent bactericidal activities of the combinations against most strains at zidovudine concentrations below 1 mg/L with the exception of A-6 strain for which the effective zidovudine concentration in combinations was 4 mg/ml (Figure S2), which still would be below C max expected at daily doses of 600 mg (17). Pharmacokinetics and safety of zidovudine plus colistin combination antimicrobial therapy was evaluated in a clinical trial (48,49).…”

Section: Discussionsupporting

confidence: 93%

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Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

Gómara-Lomero

López-Calleja

Rezusta

et al. 2022

Preprint

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Drug repurposing is a novel strategy for the development of new therapies against antibiotic-resistant bacteria. Zidovudine, an antiviral largely used in the HIV-therapy, exerts antibacterial activity against Gram-negative bacteria. Zidovudine was identified in a previous drug repurposing synergy screening as fosfomycin enhancer against Klebsiella pneumoniae ATCC 13883. Our aim was to evaluate the antibacterial in vitro activity of zidovudine-based combinations with last-line antibiotics against MDR/XDR K. pneumoniae isolates. We validated the zidovudine/fosfomycin combination against a collection of 12 MDR K. pneumoniae isolates by the checkerboard assay (CBA). In addition, we performed time-kill assays (TKA) to analyze synergistic and bactericidal activities of zidovudine paired combinations with fosfomycin, ceftazidime-avibactam, colistin and tigecycline. These were compared with frequent clinical combinations in the treatment of MDR Enterobacteriaceae. The potential of the triple zidovudine/fosfomycin/colistin was also assessed by TKA. CBA synergy confirmation rate between zidovudine/fosfomycin was 83.33%. TKA yielded synergy confirmation rates of 83.3% for zidovudine/ceftazidime-avibactam, 75% for zidovudine/fosfomycin, 75% for zidovudine/colistin and 66.6% for zidovudine/tigecycline with potent killing activities. Frequent clinical combinations displayed synergy rates of 41.6% for meropenem/ertapenem, 33.33% for meropenem/colistin, 75% for fosfomycin/colistin and 66.6% for fosfomycin/tigecycline with lower bactericidal efficacy than zidovudine-based combinations. The triple zidovudine/fosfomycin/colistin combination exhibited activities similar to fosfomycin/colistin and fosfomycin/zidovudine. As conclusion, zidovudine is an effective partner in in vitro combinations with existing antibiotics against MDR K. pneumoniae, especially with ceftazidime-avibactam, fosfomycin or colistin. Further studies are needed to elucidate the clinical potential of zidovudine as a repurposed drug in the antibacterial therapy.

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Section: Discussionsupporting

confidence: 93%

“…Toxicity and the emergence of resistant strains were the main drawbacks limiting the development of zidovudine-based antibacterial therapies. More recently, in vitro studies explored the synergistic activity of zidovudine in combination with known antibiotics (16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

Gómara-Lomero

López-Calleja

Rezusta

et al. 2022

Preprint

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“…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. In a separate work, fosfomycin was noticed to have synergistic effects with AZT against 16 CRKP isolates, with the FICI of 87.5% isolates (14/16) ≤ 0.5 [13]. In vivo, the larvae of Galleria mellonella were infected by KPC-producing or NDM-producing CRKP isolate and treated with AZT-fosfomycin combination therapy.…”

Section: Discussionmentioning

confidence: 98%

“…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].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Sung

Hung

et al. 2021

Pathogens

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Owing to the over usage of carbapenems, carbapenem resistance has become a vital threat worldwide, and, thus, the World Health Organization announced the carbapenem-resistant Enterobacteriaceae (CRE) as the critical priority for antibiotic development in 2017. In the current situation, combination therapy would be one solution against CRE. Azidothymidine (AZT), a thymidine analog, has demonstrated its synergistically antibacterial activities with other antibiotics. The unexpected antimicrobial activity of the immunomodulator ammonium trichloro(dioxoethylene-o,o’)tellurate (AS101) has been reported against carbapenem-resistant Klebsiella pneumoniae (CRKP). Here, we sought to investigate the synergistic activity between AS101 and AZT against 12 CRKP clinical isolates. According to the gene detection results, the blaOXA-1 (7/12, 58.3%), blaDHA (7/12, 58.3%), and blaKPC (7/12, 58.3%) genes were the most prevalent ESBL, AmpC, and carbapenemase genes, respectively. The checkerboard analysis demonstrated the remarkable synergism between AS101 and AZT, with the observable decrease in the MIC value for two agents and the fractional inhibitory concentration (FIC) index ≤0.5 in all strains. Hence, the combination of AS101 and azidothymidine could be a potential treatment option against CRKP for drug development.

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Medical Importance of ESKAPE Pathogens

Salim,

Mohan,

Forgia

et al. 2024

ESKAPE Pathogens

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Zidovudine in synergistic combination with fosfomycin: an in vitro and in vivo evaluation against multidrug-resistant Enterobacterales

Cited by 23 publications

References 43 publications

Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

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

Medical Importance of ESKAPE Pathogens

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