title: Selection of Resistance to Clarithromycin in Mycobacterium abscessus Subspecies.
abstract: Mycobacterium abscessus is an emerging pathogen against which clarithromycin is the main drug used. Clinical failures are commonly observed and were first attributed to acquired mutations in rrl encoding 23S rRNA but were then attributed to the intrinsic production of the erm(41) 23S RNA methylase. Since strains of M. abscessus were recently distributed into subspecies and erm(41) sequevars, we investigated acquired clarithromycin resistance mechanisms in mutants selected in vitro from four representative strains. Mutants were sequenced for rrl, erm(41), whiB, rpIV, and rplD and studied for seven antibiotic MICs. For mutants obtained from strain M. abscessus subsp. abscessus erm(41) T28 sequevar and strain M. abscessus subsp. bolletii, which are both known to produce effective methylase, rrl was mutated in only 19% (4/21) and 32.5% (13/40) of mutants, respectively, at position 2058 (A2058C, A2058G) or position 2059 (A2059C, A2059G). No mutations were observed in any of the other genes studied, and resistance to other antibiotics (amikacin, cefoxitin, imipenem, tigecycline, linezolid, and ciprofloxacin) was mainly unchanged. For M. abscessus subsp. abscessus erm(41) C28 sequevar and M. abscessus subsp. massiliense, not producing effective methylase, 100% (26/26) and 97.5% (39/40) of mutants had rrl mutations at position 2058 (A2058C, A2058G, A2058T) or position 2059 (A2059C, A2059G). The remaining M. abscessus subsp. massiliense mutant showed an 18-bp repeat insertion in rpIV, encoding the L22 protein. Our results showed that acquisition of clarithromycin resistance is 100% mediated by structural 50S ribosomal subunit mutations for M. abscessus subsp. abscessus erm(41) C28 and M. abscessus subsp. massiliense, whereas it is less common for M. abscessus subsp. abscessus erm(41) T28 sequevar and M. abscessus subsp. bolletii, where other mechanisms may be responsible for failure.
authors: APHP, Hôpitaux universitaires Lariboisière-Saint Louis, Service de Bactériologie, Paris, France.|IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.|Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.
authors: Faiza
authors: F
authors: Mougari
authors: IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.|Université des sciences et de la technologie Houari Boumadienne, Algiers, Algeria.
authors: Feriel
authors: F
authors: Bouziane
authors: IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Flora
authors: F
authors: Crockett
authors: Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.
authors: Rachid
authors: R
authors: Nessar
authors: IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Françoise
authors: F
authors: Chau
authors: Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.|APHP, Hôpital Pitié-Salpêtrière, Bactériologie-Hygiène, F-75013, Paris, France; Sorbonne Universités, UPMC Université Paris, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bacteriology), Paris, France.
authors: Nicolas
authors: N
authors: Veziris
authors: EA3647-EPIM, UFR des Sciences de La Santé, Université de Versailles St. Quentin, Montigny le Bretonneux, Atelier de Bioinformatique, ISYEB, UMR 7205, Paris, France.
authors: Guillaume
authors: G
authors: Sapriel
authors: APHP, Hôpitaux universitaires Lariboisière-Saint Louis, Service de Bactériologie, Paris, France.|IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.|Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.
authors: Laurent
authors: L
authors: Raskine
authors: APHP, Hôpitaux universitaires Lariboisière-Saint Louis, Service de Bactériologie, Paris, France emmannuelle.cambau@lrb.aphp.fr.|IAME, UMR 1137, INSERM, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.|Centre National de Référence des Mycobactéries et Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France.
authors: Emmanuelle
authors: E
authors: Cambau
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002440:Cefoxitin / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D017291:Clarithromycin / Q000494:pharmacology*; D015378:Imipenem / Q000494:pharmacology; D000069349:Linezolid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009161:Mycobacterium / Q000187:drug effects* / Q000235:genetics; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D002440:Cefoxitin; D000078304:Tigecycline; D015378:Imipenem; D000583:Amikacin; D008911:Minocycline; D017291:Clarithromycin; D000069349:Linezolid
keywords: ARN23S; Mycobacterium abscessus; antibiotic resistance; clarithromycin; resistant mutants; rrl