In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms.

Autor:	Trebosc V; BioVersys AG, Basel, Switzerland., Schellhorn B; BioVersys AG, Basel, Switzerland., Schill J; BioVersys AG, Basel, Switzerland., Lucchini V; BioVersys AG, Basel, Switzerland.; Biozentrum, University of Basel, Basel, Switzerland., Bühler J; BioVersys AG, Basel, Switzerland., Bourotte M; BioVersys SAS, Lille, France., Butcher JJ; BioVersys AG, Basel, Switzerland., Gitzinger M; BioVersys AG, Basel, Switzerland., Lociuro S; BioVersys AG, Basel, Switzerland., Kemmer C; BioVersys AG, Basel, Switzerland., Dale GE; BioVersys AG, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2020 Dec 01; Vol. 75 (12), pp. 3552-3562.
DOI:	10.1093/jac/dkaa370
Abstrakt:	Background: Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE. Objectives: To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates. Methods: Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017-19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin's mode of action and resistance mechanisms. Results: Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore-drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10-9 at rifabutin concentrations at or above 2 mg/L. Conclusions: This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver. (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)
Databáze:	MEDLINE
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