title: Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Complex.
abstract: OBJECTIVE
  Clarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram.
  
  
  METHODS
  Clinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days.
  
  
  RESULTS
  We classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance.
  
  
  CONCLUSIONS
  Most clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired mutation at position 2057 of rrl gene, conferring medium-low clarithromycin constitutive resistance.
authors.affiliation: Departament de Genètica i Microbiologia, Universitat Autònoma de Barcelona, Edifici C 08193, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Rubio
authors.affiliation: Servei de Microbiologia, Fundació de Gestió de l'Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 89, 08026, Barcelona, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: March
authors.affiliation: Servei de Microbiologia, Fundació de Gestió de l'Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 89, 08026, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garrigó
authors.affiliation: Servei de Microbiologia, Fundació de Gestió de l'Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 89, 08026, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Servei de Microbiologia, Fundació de Gestió de l'Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 89, 08026, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Español
authors.affiliation: Departament de Genètica i Microbiologia, Universitat Autònoma de Barcelona, Edifici C 08193, Bellaterra (Cerdanyola del Vallès), Spain; Servei de Microbiologia, Fundació de Gestió de l'Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 89, 08026, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Coll
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017291:Clarithromycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005798:Genes, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy / Q000382:microbiology*; D009170:Nontuberculous Mycobacteria / Q000187:drug effects / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D017291:Clarithromycin