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.
UR - http://www.scopus.com/inward/record.url?scp=85020125949&partnerID=8YFLogxK
U2 - 10.1093/jac/dkx002
DO - 10.1093/jac/dkx002
M3 - Article
AN - SCOPUS:85020125949
SN - 0305-7453
VL - 72
SP - 1415
EP - 1420
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 5
ER -