Novel polymyxin combination with the antiretroviral zidovudine exerts synergistic killing against Ndm-producing multidrug-resistant klebsiella pneumoniae

Yu-Wei Lin, Nusaibah Abdul Rahim, Jinxin Zhao, Mei-Ling Han, Heidi H. Yu, Hasini Wickremasinghe, Ke Chen, Jiping Wang, David L. Paterson, Yan Zhu, Gauri G. Rao, Qi Tony Zhou, Alan Forrest, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-lactamase (NDM)-producing Klebsiella 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 against K. pneumoniae. Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An in vitro 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 [C max ] of 6 mg/liter) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 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 10 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 10 CFU/thigh lower than each monotherapy against K. pneumoniae 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

Original languageEnglish
Article numbere02176-18
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Drug repurposing
  • Klebsiella pneumoniae
  • Polymyxins
  • Zidovudine

Cite this

Lin, Yu-Wei ; Rahim, Nusaibah Abdul ; 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. / Novel polymyxin combination with the antiretroviral zidovudine exerts synergistic killing against Ndm-producing multidrug-resistant klebsiella pneumoniae. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 4.
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title = "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-lactamase (NDM)-producing Klebsiella 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 against K. pneumoniae. Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An in vitro 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 [C max ] of 6 mg/liter) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 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 10 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 10 CFU/thigh lower than each monotherapy against K. pneumoniae 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.",
keywords = "Drug repurposing, Klebsiella pneumoniae, Polymyxins, Zidovudine",
author = "Yu-Wei Lin and Rahim, {Nusaibah Abdul} and Jinxin Zhao and Mei-Ling Han and Yu, {Heidi H.} and Hasini Wickremasinghe and Ke Chen and Jiping Wang and Paterson, {David L.} and Yan Zhu and Rao, {Gauri G.} and Zhou, {Qi Tony} and Alan Forrest and Tony Velkov and Jian Li",
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Novel polymyxin combination with the antiretroviral zidovudine exerts synergistic killing against Ndm-producing multidrug-resistant klebsiella pneumoniae. / Lin, Yu-Wei; Rahim, Nusaibah Abdul; 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.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 4, e02176-18, 01.04.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Novel polymyxin combination with the antiretroviral zidovudine exerts synergistic killing against Ndm-producing multidrug-resistant klebsiella pneumoniae

AU - Lin, Yu-Wei

AU - Rahim, Nusaibah Abdul

AU - Zhao, Jinxin

AU - Han, Mei-Ling

AU - Yu, Heidi H.

AU - Wickremasinghe, Hasini

AU - Chen, Ke

AU - Wang, Jiping

AU - Paterson, David L.

AU - Zhu, Yan

AU - Rao, Gauri G.

AU - Zhou, Qi Tony

AU - Forrest, Alan

AU - Velkov, Tony

AU - Li, Jian

PY - 2019/4/1

Y1 - 2019/4/1

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AB - Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-lactamase (NDM)-producing Klebsiella 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 against K. pneumoniae. Three isolates were evaluated in static time-kill studies (0 to 64 mg/liter) over 48 h. An in vitro 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 [C max ] of 6 mg/liter) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 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 10 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 10 CFU/thigh lower than each monotherapy against K. pneumoniae 02. Overall, the polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

KW - Drug repurposing

KW - Klebsiella pneumoniae

KW - Polymyxins

KW - Zidovudine

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