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: | Jacqueline Bühler, Julian Schill, Birgit Schellhorn, Marilyne Bourotte, Marc Gitzinger, Christian Kemmer, Glenn E. Dale, Jonathan J Butcher, Vincent Trebosc, Valentina Lucchini, Sergio Lociuro |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Acinetobacter baumannii
Microbiology (medical) Asia Rifabutin medicine.drug_class Antibiotics Microbial Sensitivity Tests Tigecycline Microbiology 03 medical and health sciences Drug Resistance Multiple Bacterial parasitic diseases polycyclic compounds medicine AcademicSubjects/MED00740 Pharmacology (medical) Mode of action Original Research 030304 developmental biology Pharmacology 0303 health sciences biology 030306 microbiology bacterial infections and mycoses biology.organism_classification rpoB Anti-Bacterial Agents 3. Good health Europe AcademicSubjects/MED00290 Infectious Diseases Carbapenems Colistin AcademicSubjects/MED00230 Mycobacterium medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dkaa370 |
| Popis: | BackgroundRifabutin, 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.ObjectivesTo determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates.MethodsTwo 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.ResultsRifabutin 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.ConclusionsThis 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. |
| Databáze: | OpenAIRE |
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