Novel Polymyxin Combination with the Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-Producing Multidrug-Resistant Klebsiella pneumoniae

• Published in: Antimicrobial agents and chemotherapy 2019-04, Vol.63 (4)
• Main Authors: Lin, Yu-Wei, Abdul Rahim, Nusaibah, Zhao, Jinxin, Han, Mei-Ling, Yu, Heidi H, Wickremasinghe, Hasini, Chen, Ke, Wang, Jiping, Paterson, David L, Zhu, Yan, Rao, Gauri G, Zhou, Qi Tony, Forrest, Alan, Velkov, Tony, Li, Jian
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Anti-Retroviral Agents; Anti-Retroviral Agents - pharmacology; beta-Lactamases; beta-Lactamases - metabolism; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - drug effects; Drug Synergism; Female; Klebsiella pneumoniae; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - metabolism; Mice; Microbial Sensitivity Tests - methods; Pharmacology; Polymyxin B; Polymyxin B - pharmacology; Zidovudine; Zidovudine - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02176-18

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM)-producing 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 against Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An one-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 [ ] of 6 mg/liter) against BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against 02. 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 log CFU/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 log CFU/thigh lower than each monotherapy against 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.