Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae
Abstract:Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producingKlebsiella pneumoniae. However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine againstK. pneumoniae. Three isolates were evaluated in static time-kill stud… Show more
“…We demonstrated the evident synergy between AZT and colistin using the checkerboard method ( Table 4 ) and nematode killing assay ( Table 5 ). The synergistic activity of polymyxins and AZT among E. coli and K. pneumoniae carrying various resistance mechanisms ( Table 6 ) has been reported in several previous studies [ 32 , 33 , 34 , 35 ]. The most commonly investigated resistance genotypes are mcr1 and bla NDM-1 .…”
Section: Discussionsupporting
confidence: 58%
“…Given that colistin lyses GNB by permeabilizing the outer membrane, it is hypothesized that this mechanism allows AZT to enter the cell at increased intracellular drug concentrations [ 38 ]. Lin et al demonstrated that higher polymyxin B concentrations could increase outer membrane permeability, with simultaneous decreases in AZT MIC [ 33 ]. In addition, AZT can synergize with colistin by exerting a shared outer membrane disrupting effect [ 38 ].…”
Section: Discussionmentioning
confidence: 99%
“…Although AZT appears to be important in the combined treatment of MDROs, the rapid emergence of stable high-level AZT resistance in Enterobacteriaceae has been well documented, which appears to be related to the loss of thymidine kinase activity [ 30 , 43 ]. Lin et al demonstrated that the combination of polymyxin B and AZT has superior antimicrobial efficacy and minimizes the emergence of resistance to polymyxins [ 33 ]. The two-drug combination significantly increased bacterial killing and remained synergistic for up to 48 h in their study.…”
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.
“…We demonstrated the evident synergy between AZT and colistin using the checkerboard method ( Table 4 ) and nematode killing assay ( Table 5 ). The synergistic activity of polymyxins and AZT among E. coli and K. pneumoniae carrying various resistance mechanisms ( Table 6 ) has been reported in several previous studies [ 32 , 33 , 34 , 35 ]. The most commonly investigated resistance genotypes are mcr1 and bla NDM-1 .…”
Section: Discussionsupporting
confidence: 58%
“…Given that colistin lyses GNB by permeabilizing the outer membrane, it is hypothesized that this mechanism allows AZT to enter the cell at increased intracellular drug concentrations [ 38 ]. Lin et al demonstrated that higher polymyxin B concentrations could increase outer membrane permeability, with simultaneous decreases in AZT MIC [ 33 ]. In addition, AZT can synergize with colistin by exerting a shared outer membrane disrupting effect [ 38 ].…”
Section: Discussionmentioning
confidence: 99%
“…Although AZT appears to be important in the combined treatment of MDROs, the rapid emergence of stable high-level AZT resistance in Enterobacteriaceae has been well documented, which appears to be related to the loss of thymidine kinase activity [ 30 , 43 ]. Lin et al demonstrated that the combination of polymyxin B and AZT has superior antimicrobial efficacy and minimizes the emergence of resistance to polymyxins [ 33 ]. The two-drug combination significantly increased bacterial killing and remained synergistic for up to 48 h in their study.…”
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.
“…Furthermore, AZT-resistant E. coli and Salmonella were recovered from patients receiving AZT treatment for HIV infection (89,90). Recently, and in light of growing AMR, the antimicrobial properties of AZT have been explored (68)(69)(70)(71)73).…”
Antimicrobial-resistant (AMR) infections pose a serious risk to human and animal health. A major factor contributing to this global crisis is the sharing of resistance genes between different bacteria via plasmids. The WHO lists Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, producing extended-spectrum β-lactamases (ESBL) and carbapenemases as “critical” priorities for new drug development. These resistance genes are most often shared via plasmid transfer. However, finding methods to prevent resistance gene sharing has been hampered by the lack of screening systems for medium-/high-throughput approaches. Here, we have used an ESBL-producing plasmid, pCT, and a carbapenemase-producing plasmid, pKpQIL, in two different Gram-negative bacteria, E. coli and K. pneumoniae. Using these critical resistance-pathogen combinations, we developed an assay using fluorescent proteins, flow cytometry, and confocal microscopy to assess plasmid transmission inhibition within bacterial populations in a medium-throughput manner. Three compounds with some reports of antiplasmid properties were tested; chlorpromazine reduced transmission of both plasmids and linoleic acid reduced transmission of pCT. We screened the Prestwick library of over 1,200 FDA-approved drugs/compounds. From this, we found two nucleoside analogue drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduced plasmid transmission (AZT, e.g., at 0.25 μg/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plasmid transmission was reduced by concentrations of the drugs which are below peak serum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids.
IMPORTANCE More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-based system to search for drugs that will stop bacteria from sharing resistance genes. We uncovered a new role for two drugs used to treat HIV and show that they are able to prevent the sharing of two different types of resistance genes in two unique bacterial strains. This work lays the foundation for future work to reduce the prevalence of resistant infections.
“…Notably, the combination of chlorpromazine with the antifungal amphotericin B was synergistic against Cryptococcus neoformans [32] . Our laboratory previously demonstrated that the antibacterial effect of polymyxin B is synergistic in combination with non-antibiotic drugs such as closantel, ivacaftor, tamoxifen, raloxifene, toremifene, mitotane, and zidovudine [27] , [28] , [29] , [30] , [33] , [34] , [35] . The focus of the present study was to evaluate the antibacterial synergy of phenothiazine neuroleptic drugs in combination with polymyxin B against a range of polymyxin resistant and susceptible Gram-negative isolates and investigate potential antimicrobial mode of action using untargeted metabolomics and scanning and transmission electron microscopy.…”
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