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



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/sulbactam-resistant). 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.



Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg 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/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth.



To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences and School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.|California Northstate University College of Pharmacy, Elk Grove, CA, USA.
Justin R
JR
Lenhard
Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Visanu
V
Thamlikitkul
Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Fernanda P
FP
Silveira
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences and School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.
Samira M
SM
Garonzik
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
Xun
X
Tao
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences and School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.|Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Alan
A
Forrest
School of Pharmacy, Sungkyunkwan University, Gyeonggi-do, Korea.
Beom
B
Soo Shin
Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
Keith S
KS
Kaye
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
Jürgen B
JB
Bulitta
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Roger L
RL
Nation
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Jian
J
Li
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences and School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.|Veterans Administration Western New York Healthcare System, Buffalo, NY, USA.
Brian T
BT
Tsuji
D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015780:Carbapenems / Q000494:pharmacology*; D003091:Colistin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology* / Q000627:therapeutic use; D013845:Thienamycins / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D000077731:Meropenem; D011112:Polymyxin B; D003091:Colistin