Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity

Justin R Lenhard, Visanu Thamlikitkul, Fernanda P Silveira, Samira M Garonzik, Xun Tao, Alan Forrest, Beom Soo Shin, Keith S Kaye, Jurgen B Bulitta, Roger Nation, Jian Li, Brian Tsuji

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Abstract

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii. The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactamresistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC0-24 .60 mg·h/L and Cavg of.2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactameradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.

Original languageEnglish
Pages (from-to)1415-1420
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number5
DOIs
Publication statusPublished - 2017

Cite this

Lenhard, Justin R ; Thamlikitkul, Visanu ; Silveira, Fernanda P ; Garonzik, Samira M ; Tao, Xun ; Forrest, Alan ; Shin, Beom Soo ; Kaye, Keith S ; Bulitta, Jurgen B ; Nation, Roger ; Li, Jian ; Tsuji, Brian. / Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. In: Journal of Antimicrobial Chemotherapy. 2017 ; Vol. 72, No. 5. pp. 1415-1420.
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title = "Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity",
abstract = "Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii. The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactamresistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC0-24 .60 mg·h/L and Cavg of.2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactameradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.",
author = "Lenhard, {Justin R} and Visanu Thamlikitkul and Silveira, {Fernanda P} and Garonzik, {Samira M} and Xun Tao and Alan Forrest and Shin, {Beom Soo} and Kaye, {Keith S} and Bulitta, {Jurgen B} and Roger Nation and Jian Li and Brian Tsuji",
year = "2017",
doi = "10.1093/jac/dkx002",
language = "English",
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Lenhard, JR, Thamlikitkul, V, Silveira, FP, Garonzik, SM, Tao, X, Forrest, A, Shin, BS, Kaye, KS, Bulitta, JB, Nation, R, Li, J & Tsuji, B 2017, 'Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity', Journal of Antimicrobial Chemotherapy, vol. 72, no. 5, pp. 1415-1420. https://doi.org/10.1093/jac/dkx002

Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. / Lenhard, Justin R; Thamlikitkul, Visanu; Silveira, Fernanda P; Garonzik, Samira M; Tao, Xun; Forrest, Alan; Shin, Beom Soo; Kaye, Keith S; Bulitta, Jurgen B; Nation, Roger; Li, Jian; Tsuji, Brian.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 5, 2017, p. 1415-1420.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity

AU - Lenhard, Justin R

AU - Thamlikitkul, Visanu

AU - Silveira, Fernanda P

AU - Garonzik, Samira M

AU - Tao, Xun

AU - Forrest, Alan

AU - Shin, Beom Soo

AU - Kaye, Keith S

AU - Bulitta, Jurgen B

AU - Nation, Roger

AU - Li, Jian

AU - Tsuji, Brian

PY - 2017

Y1 - 2017

N2 - Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii. The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactamresistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC0-24 .60 mg·h/L and Cavg of.2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactameradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.

AB - Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii. The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactamresistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC0-24 .60 mg·h/L and Cavg of.2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactameradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.

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U2 - 10.1093/jac/dkx002

DO - 10.1093/jac/dkx002

M3 - Article

VL - 72

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EP - 1420

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

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ER -