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 studies (0 to 64 mg/liter) over 48 h. Anin vitroone-compartment pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/liter as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve maximum concentration of drug in broth [Cmax] of 6 mg/liter) againstK. pneumoniaeBM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model againstK. pneumoniae02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥4 log10CFU/ml) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥3 log10CFU/thigh lower than each monotherapy againstK. pneumoniae02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

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

“…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 .…”

“…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 ].…”

“…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.…”

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

“…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).…”

Polymyxin B combinations with FDA-approved non-antibiotic phenothiazine drugs targeting multi-drug resistance of Gram-negative pathogens

“…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.…”