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

<span class="paragraphSection"><strong>Objectives:</strong> The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant <span style="font-style:italic;">Acinetobacter baumannii</span>. The objectives of the current investigation were to define the <span style="font-style:italic;">in vitro</span> emergence of polymyxin resistance and identify a combination regimen capable of eradicating <span style="font-style:italic;">A. baumannii</span> with no apparent drug susceptibilities.<strong>Methods:</strong> Two clonally related, paired, <span style="font-style:italic;">A. baumannii</span> isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an <span style="font-style:italic;">A. baumannii</span> 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.<strong>Results:</strong> Despite achieving colistin steady-state targets of an AUC_0–24 >60 mg·h/L and <span style="font-style:italic;">C</span>_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 <span style="font-style:italic;">A. baumannii</span> by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth.<strong>Conclusions:</strong> To combat polymyxin-resistant <span style="font-style:italic;">A. baumannii</span>, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.</span>

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