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Lack of association between rrl and erm(41) mutations and clarithromycin resistance in Mycobacterium abscessus complex

Abstract

BACKGROUND

Mycobacterium abscessus complex (MABC) includes species with high resistance rates among mycobacterial pathogens. In fact, MABC infections may not respond to clarithromycin treatment, which has historically been very effective against MABC infection. Molecular markers have been proposed to detect both acquired (rrl polymorphisms) and inducible (erm(41) polymorphisms) clarithromycin resistance in MABC isolates.

OBJECTIVES

This study aimed to evaluate the susceptibility profile and molecular markers of clarithromycin resistance in MABC.

METHODS

The clarithromycin susceptibility profile was determined by broth microdilution with reads on days 3, 5, 7 and 14. Mutations in the rrl and erm(41) genes were evaluated by polymerase chain reaction (PCR) using specific primers, followed by sequencing.

FINDINGS

A total of 14 M. abscessus subsp. abscessus isolates and 28 M. abscessus subsp. massiliense isolates were evaluated, and clarithromycin resistance was observed in all isolates for up to three days of incubation. None of the 42 isolates exhibited a point mutation in the rrl gene, while all the isolates had a T28 polymorphism in the erm(41) gene. Moreover, all 28 M. abscessus subsp. massiliense isolates had a deletion in the erm(41) gene.

MAIN CONCLUSIONS

While all the MABC isolates exhibited acquired clarithromycin resistance, no isolates exhibited a point mutation in the rrl gene in this study. The M. abscessus subsp. massiliense isolates demonstrated clarithromycin resistance, which is an uncommon phenotype. The molecular data for the rrl and erm(41) genes were not consistent with the phenotypic test results of clarithromycin susceptibility, indicating a lack of correlation between molecular clarithromycin resistance markers for both acquired and inducible resistance.

Key words:
clarithromycin resistance; erm(41) gene; rrl gene; M. abscessus complex; inducible resistance; acquired resistance


Several rapidly growing mycobacteria (RGM) can cause infections in humans, most of which are caused by Mycobacterium abscessus complex (MABC), M. chelonae and M. fortuitum (Brown-Elliott et al. 2002aBrown-Elliott BA, Griffith DE, Wallace RJ. Newly described or emerging human species of nontuberculous mycobacteria. Infect Dis Clin North Am. 2002a; 16(1): 187-220., bBrown-Elliott BA, Wallace RJ. Clinical and taxonomic status of pathogenic nonpigmented or late-pigmenting rapidly growing mycobacteria. Clin Microbiol Rev. 2002b; 15(4): 716-46.). MABC is comprised of three closely related subspecies (M. abscessus subsp. abscessus, M. abscessus subsp. bolletii and M. abscessus subsp. massiliense), which are the most pathogenic and multidrug-resistant (MDR) isolates among all RGMs (Griffith et al. 2015Griffith DE, Brown-Elliott BA, Benwill JL, Wallace RJ. Mycobacterium abscessus. “Pleased to meet you, hope you guess my name…”. Ann Am Thorac Soc. 2015; 12(3): 436-9., Lee et al. 2015Lee MR, Sheng WH, Hung CC, Yu CJ, Lee LN, Hsueh PR. Mycobacterium abscessus complex infections in humans. Emerg Infect Dis. 2015; 21(9): 1638-46.). Infections due to MABC are difficult to treat (Kasperbauer & de Groote 2015Kasperbauer SH, de Groote MA. The treatment of rapidly growing mycobacterial infections. Clin Chest Med. 2015; 36(1): 67-78., Kang & Koh 2016Kang YA, Koh WJ. Antibiotic treatment for nontuberculous mycobacterial lung disease Expert Rev Respir Med. 2016; 10(5): 557-68.) because they are intrinsically resistant to not only classical antituberculosis drugs but also to most antibiotics that are currently available (Ryu et al. 2016Ryu YJ, Koh WJ, Daley CL. Diagnosis and treatment of nontuberculous mycobacterial lung disease: clinicians’ perspectives. Tuberc Respir Dis. 2016; 79(2): 74-84., Stout et al. 2016Stout JE, Koh WJ, Yew WW. Update on pulmonary disease due to non-tuberculous mycobacteria. Int J Infect Dis. 2016; 45: 123-34.).

In fact, clarithromycin has become the drug of choice for infections caused by MABC, and it was the treatment mainstay until induced resistance was described (Griffith et al. 2007Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175(4): 367-416., Nash et al. 2009Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009; 53(4): 1367-76.). Inducible resistance is believed to be mainly related to the capacity of some MABC subspecies to encode a functional erythromycin ribosomal methylase gene, erm(41), which modifies the binding site for macrolide antibiotics, resulting in inducible macrolide resistance (Bastian et al. 2011Bastian S, Veziris N, Roux AL, Brossier F, Gaillard JL, Jarlier V, et al. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother. 2011; 55(2): 775-81., Maurer et al. 2014Maurer FP, Castelberg C, Quiblier C, Böttger EC, Somoskövi A. Erm(41) dependent inducible resistance to azithromycin and clarithromycin in clinical isolates of Mycobacterium abscessus. J Antimicrob Chemother. 2014; 69(6): 1559-63.). Because resistance to clarithromycin is increasing, its use as a monotherapy for treatment is not recommended, and it should instead be combined with other drugs (Kasperbauer & de Groote 2015Kasperbauer SH, de Groote MA. The treatment of rapidly growing mycobacterial infections. Clin Chest Med. 2015; 36(1): 67-78.). Additionally, sequence analysis of the erm(41) gene allowed for the identification of M. abscessus subspecies (Griffith et al. 2015Griffith DE, Brown-Elliott BA, Benwill JL, Wallace RJ. Mycobacterium abscessus. “Pleased to meet you, hope you guess my name…”. Ann Am Thorac Soc. 2015; 12(3): 436-9.).

Acquired resistance to clarithromycin is related to point mutations in a region of the rrl gene encoding the peptidyltransferase domain of 23S rRNA (Nash et al. 2009Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009; 53(4): 1367-76.). The main molecular mechanism of clarithromycin-acquired resistance reportedly occurs through adenine point mutations at either position 2058 (A2058G) or position A2059 in the 23S rRNA gene (Maurer et al. 2012Maurer FP, Rüegger V, Ritter C, Bloemberg GV, Böttger EC. Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41). J Antimicrob Chemother. 2012; 67(11): 2606-11.).

Phenotypic tests (susceptibility profile) revealed that acquired resistance can be detected for up to five days of incubation of the MABC with clarithromycin, while inducible resistance requires prolonged incubation (14 days of incubation) (Bastian et al. 2011Bastian S, Veziris N, Roux AL, Brossier F, Gaillard JL, Jarlier V, et al. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother. 2011; 55(2): 775-81.).

The aim of this study was to evaluate correlation between the susceptibility profile and the molecular mechanisms of clarithromycin resistance in MABC.

MATERIALS AND METHODS

A total of 42 isolates from a previous surveillance study (Nunes et al. 2014Nunes LDS, Baethgen LF, Ribeiro MO, Cardoso CM, de Paris F, de David SM, et al. Outbreaks due to Mycobacterium abscessus sub-sp. bolletii in southern Brazil: persistence of a single clone from 2007 to 2011. J Med Microbiol. 2014; 63(10): 1288-93.) of samples from different sources collected between 2007 and 2013 were used in this study. The susceptibility profile was determined by broth microdilution following the guidelines of the Clinical and Laboratory Standards Institute [CLSI document M24-A2 (CLSI 2011CLSI - Clinical and Laboratory Standards Institute. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes; Approved standard - Second edition. CLSI document M24-A2. Wayne: Clinical and Laboratory Standards Institute; 2011.)] with readings on days three, five, seven and 14. Point mutations in the rrl gene were evaluated by polymerase chain reaction (PCR) amplification with primers 18 (AGT CGG GAC CTA AGG CGA G) and 21 (TTC CCG CTT AGA TGC TTT CAG) (Meier et al. 1994Meier A, Kirschner P, Springer B, Steingrube V, Brown B, Wallace R, et al. Identification of mutations in 23S rRNA gene of clarithromycin resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994; 38(2): 381-4.). Polymorphisms in the erm(41) gene were evaluated with primers ERM1f (CGC CAA CGA GCA GCT CG) (Bastian et al. 2011Bastian S, Veziris N, Roux AL, Brossier F, Gaillard JL, Jarlier V, et al. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother. 2011; 55(2): 775-81.) and MC823 (GAC TTC CCC GCA CCG ATT CCA C) (Nash et al. 2009Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009; 53(4): 1367-76.) using the following steps: 94°C for 5 min, 40 cycles of 94°C for 1 min, 64°C for 1 min and 72°C for 1 min, and 72°C for 10 min. M. abscessus ATCC 19977 was used as quality control.

Genetic profiling of the two genes was performed by partial sequencing using the ABI 3500 Genetic Analyser with 50-cm capillaries and the POP7 polymer (Applied Biosystems, Thermo Fisher Scientific, Califórnia, EUA). PCR products were labelled with 3.2 pmol of specific primers and 1 μL of the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems) in a final volume of 10 μL. Sequence alignment was performed using the program Biological Sequence Alignment Editor - BioEdit 7.2-5. Homology analysis was performed by comparing the consensus sequences obtained for each isolate with those deposited in GenBank using the BLAST algorithm (Basic Local Alignment Search Tool, http://www.ncbi.nlm.nih.gov/BLAST). The erm(41) sequences of M. abscessus subsp. Abscessus T28 sequevar ATCC19977 (GenBank accession number HQ127365) and M. abscessus subsp. Massiliense CIP108297 (GenBank HQ127368) were used as references. This study was approved by the Ethics Committee of “Grupo de Pesquisa e Pós-Graduação (GPPG)” of “Hospital de Clínicas de Porto Alegre” (reference number CAAE: 35684114.5.0000.5327).

RESULTS

A total of 14 isolates belonging to M. abscessus subsp. Abscessus and 28 isolates belonging to M. abscessus subsp. Massiliense were identified by analysing the erm(41) gene.

Clarithromycin resistance was observed in all the isolates for up to three days of incubation.

For all the isolates, PCR yielded amplicons of the expected size (1500 bp) for the rrl gene; however, none of the 42 isolates exhibited point mutations at positions 2058 or 2059 in the peptidyltransferase region of 23S rRNA (rrl gene), which is the gene related to acquired clarithromycin resistance. For the erm(41) gene, the PCR reactions generated fragments of 764 bp for M. abscessus subsp. Abscessus and smaller amplicons (~250 bp) for all the M. abscessus subsp. Massiliense isolates. These isolates also presented the T/C polymorphism at the 28th nucleotide of erm(41), corresponding to a tryptophan at the 10th codon. Moreover, all M. abscessus subsp. massiliense isolates had a deletion in erm(41) compared to the reference sequence.

Interestingly, point mutations were identified at other positions in the erm(41), gene but they did not correspond to amino acid alteration (silent mutations) (Table).

TABLE
Positions of nucleotide substitutions in erm(41) gene

DISCUSSION

Widespread use of macrolides in clinical medical care has created favourable conditions for the selection of resistant RGM isolates (Bailey et al. 2008Bailey M, Chettiath T, Mankin AS. Induction of erm (C) expression by noninducing antibiotics. Antimicrob Agents Chemother. 2008; 52(3): 866-74.). The two main mechanisms of macrolide resistance are drug-efflux pumps and modification of ribosomal drug target sites via erm methylase expression (Nessar et al. 2012Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother. 2012; 67(4): 810-8.). This modified erm prevents binding of the antibiotic to the ribosome by mono- or di-methylation, which disturbs the shape and chemical makeup of the drug binding site, thereby reducing the affinity of the macrolide to the ribosome (Douthwaite et al. 2005Douthwaite S, Fourmy D, Yoshizawa S. Nucleotide methylations in rRNA that confer resistance to ribosome-targeting antibiotics. In: H Grosjean, editor. Topics in current genetics. Vol. 12. New York: Springer Verlag; 2005. p. 285-309., Mougari et al. 2016bMougari F, Bouziane F, Crockett F, Nessar R, Chau F, Veziris N, et al. Selection of resistance to clarithromycin with regard to the 2 subspecies in Mycobacterium abscessus. Antimicrob Agents Chemother. 2016b; 61(1): e00943-16.). Erm expression is highly regulated, as it is induced in the presence of macrolides; however, its expression is not favourable for the cell because it is associated with significant fitness costs (Brierley 2013Brierley I. Macrolide-induced ribosomal frameshifting: a new route to antibiotic resistance. Molecular Cell. 2013; 52(5): 613-5.).

Nash et al. (2009)Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009; 53(4): 1367-76. and Kim et al. (2010)Kim HY, Kim BJ, Kook Y, Yun YJ, Shin JH, Kim BJ, et al. Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribossome methyltransferase gene (erm) and clarithromycin susceptibility patterns. Microbiol Immunol. 2010; 54(6): 347-53. investigated several isolates of the M. abscessus complex and found that M. abscessus subsp. massiliense was susceptible to clarithromycin, while the susceptibility profile of M. abscessus subsp. abscessus was variable. Conversely, we found a high percentage of M. abscessus subsp. massiliense isolates that exhibited clarithromycin resistance, which was also reported by Mougari et al. (2016b)Mougari F, Bouziane F, Crockett F, Nessar R, Chau F, Veziris N, et al. Selection of resistance to clarithromycin with regard to the 2 subspecies in Mycobacterium abscessus. Antimicrob Agents Chemother. 2016b; 61(1): e00943-16.. This susceptibility profile difference may be related to local or regional characteristics of MABC isolates. It should be noted that most of the isolates used in our study belonged to the same clone (data not shown), although they were originated from several outbreaks in different cities in southern Brazil (Nunes et al. 2014Nunes LDS, Baethgen LF, Ribeiro MO, Cardoso CM, de Paris F, de David SM, et al. Outbreaks due to Mycobacterium abscessus sub-sp. bolletii in southern Brazil: persistence of a single clone from 2007 to 2011. J Med Microbiol. 2014; 63(10): 1288-93.).

Molecular profiles of the MABC isolates established by Nash et al. (2009)Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae. Antimicrob Agents Chemother. 2009; 53(4): 1367-76. and Kim et al. (2010)Kim HY, Kim BJ, Kook Y, Yun YJ, Shin JH, Kim BJ, et al. Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribossome methyltransferase gene (erm) and clarithromycin susceptibility patterns. Microbiol Immunol. 2010; 54(6): 347-53. revealed the T28 polymorphism of erm(41) to be related to resistance and the C28 polymorphism to be related to susceptibility. Therefore, the T28 polymorphism in M. abscessus subsp. abscessus could be considered a clarithromycin resistance marker. In our study, all 14 isolates of M. abscessus subsp. abscessus exhibited a T28 polymorphism. It should be noted that in the study by Kim et al. (2010)Kim HY, Kim BJ, Kook Y, Yun YJ, Shin JH, Kim BJ, et al. Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribossome methyltransferase gene (erm) and clarithromycin susceptibility patterns. Microbiol Immunol. 2010; 54(6): 347-53., no prolonged incubation periods were evaluated (microdilution reads were made on the 5th day of incubation).

Regarding M. abscessus subsp. massiliense, the T28 polymorphism is not necessarily related to clarithromycin inducible resistance, as position 28 is located upstream of the deletion that leads to resistance. However, several M. abscessus subsp. massiliense isolates with a functional erm(41) gene have been reported (Gray et al. 2014Gray TJ, Kong F, Jelfs P, Sintchenko V, Chen SC. Improved identification of rapidly growing mycobacteria by a 16S-23S internal transcribed spacer region PCR and capillary gel electrophoresis. PLoS ONE. 2014; 9(7): e102290.). Moreover, two M. abscessus subsp. massiliense isolates with a functional erm(41) gene showing inducible clarithromycin resistance after 14 days have been described (Shallom et al. 2013Shallom SJ, Gardina PJ, Myers TG, Sebastian Y, Conville P, Calhoun LB, et al. New rapid scheme for distinguishing the subspecies of the Mycobacterium abscessus group and identifying Mycobacterium massiliense isolates with inducible clarithromycin resistance. J Clin Microbiol. 2013; 51(9): 2943-9.).

Regarding the molecular basis of acquired resistance, sequencing of the rrl gene showed an absence of mutations (wild type) at positions 2058 and 2059 of 23S rRNA in all the isolates analysed in this study. However, we found isolates that exhibited resistance for up to three days of incubation, indicating that another molecular mechanism may be involved in acquired resistance. Although rrl wild-type isolates resistant to clarithromycin are not an usual finding, Maurer et al. (2012)Maurer FP, Rüegger V, Ritter C, Bloemberg GV, Böttger EC. Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41). J Antimicrob Chemother. 2012; 67(11): 2606-11. described the presence of resistant isolates with no mutations in the rrl gene in the MABC. Therefore, mutations solely in 23S rRNA cannot be used as a marker for acquired resistance to clarithromycin.

Because Esteban et al. (2009)Esteban J, Martín-de-Hijas NZ, García-Almeida D, Bodas-Sánchez A, Gadea I, Fernández-Roblas R. Prevalence of erm methylase genes in clinical isolates of nonpigmented, rapidly growing mycobacteria. Clin Microbiol Infect. 2009; 15(10): 919-23. demonstrated low minimum inhibitory concentration (MIC) for erm(41)-positive isolates and high MIC for erm(41)-negative isolates, presence of the erm(41) gene is not necessarily correlated with clarithromycin resistance (higher MIC).

In this study, point mutations in the erm(41) gene were evidenced, but this exchange of nucleotides did not lead to amino acid alteration. According to Brown-Elliott et al. (2015)Brown-Elliott BA, Vasireddy S, Vasireddy R, Iakhiaeva E, Howard ST, Nash K, et al. Utility of sequencing the erm(41) gene in isolates of Mycobacterium abscessus subsp. abscessus with low and intermediate clarithromycin MICs. J Clin Microbiol. 2015; 53(4): 1211-5., only the T28C substitution resulted in loss of erm(41) gene function, and no other nucleotide substitution is known to be associated with macrolide susceptibility. This finding disagrees with that of the Kim et al. (2016)Kim SY, Shin SJ, Jeong BH, Koh WJ. Successful antibiotic treatment of pulmonary disease caused by Mycobacterium abscessus sub-sp. abscessus with C-to-T mutation at position 19 in erm(41) gene: case report. BMC Infect Dis. 2016; 16: 207. study, which demonstrated that M. abscessus subsp. abscessus has a C-to-T mutation at position 19 (C19 → T), which leads to an Arg → stop codon mutation at codon seven of the erm(41) gene and results in loss of erm(41) gene function.

The main finding of our study was the high number of M. abscessus complex isolates with resistance to clarithromycin that did not correlate with mutations in the rrl gene. Therefore, the results of erm(41) and rrl sequencing should not be considered fully concordant with phenotypic clarithromycin susceptibility tests.

  • Financial support: CNPq (168206/2014-5), FIPE/HCPA (14-0668).

ACKNOWLEDGEMENTS

To the staff from the “Seção de Micobactérias do IPB/ LACEN-FEPPS, Laboratório de Micobactérias”, for processing the samples and for managing the cultures.

REFERENCES

  • Bailey M, Chettiath T, Mankin AS. Induction of erm (C) expression by noninducing antibiotics. Antimicrob Agents Chemother. 2008; 52(3): 866-74.
  • Bastian S, Veziris N, Roux AL, Brossier F, Gaillard JL, Jarlier V, et al. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother. 2011; 55(2): 775-81.
  • Brierley I. Macrolide-induced ribosomal frameshifting: a new route to antibiotic resistance. Molecular Cell. 2013; 52(5): 613-5.
  • Brown-Elliott BA, Griffith DE, Wallace RJ. Newly described or emerging human species of nontuberculous mycobacteria. Infect Dis Clin North Am. 2002a; 16(1): 187-220.
  • Brown-Elliott BA, Vasireddy S, Vasireddy R, Iakhiaeva E, Howard ST, Nash K, et al. Utility of sequencing the erm(41) gene in isolates of Mycobacterium abscessus subsp. abscessus with low and intermediate clarithromycin MICs. J Clin Microbiol. 2015; 53(4): 1211-5.
  • Brown-Elliott BA, Wallace RJ. Clinical and taxonomic status of pathogenic nonpigmented or late-pigmenting rapidly growing mycobacteria. Clin Microbiol Rev. 2002b; 15(4): 716-46.
  • CLSI - Clinical and Laboratory Standards Institute. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes; Approved standard - Second edition. CLSI document M24-A2. Wayne: Clinical and Laboratory Standards Institute; 2011.
  • Douthwaite S, Fourmy D, Yoshizawa S. Nucleotide methylations in rRNA that confer resistance to ribosome-targeting antibiotics. In: H Grosjean, editor. Topics in current genetics. Vol. 12. New York: Springer Verlag; 2005. p. 285-309.
  • Esteban J, Martín-de-Hijas NZ, García-Almeida D, Bodas-Sánchez A, Gadea I, Fernández-Roblas R. Prevalence of erm methylase genes in clinical isolates of nonpigmented, rapidly growing mycobacteria. Clin Microbiol Infect. 2009; 15(10): 919-23.
  • Gray TJ, Kong F, Jelfs P, Sintchenko V, Chen SC. Improved identification of rapidly growing mycobacteria by a 16S-23S internal transcribed spacer region PCR and capillary gel electrophoresis. PLoS ONE. 2014; 9(7): e102290.
  • Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175(4): 367-416.
  • Griffith DE, Brown-Elliott BA, Benwill JL, Wallace RJ. Mycobacterium abscessus. “Pleased to meet you, hope you guess my name…”. Ann Am Thorac Soc. 2015; 12(3): 436-9.
  • Kang YA, Koh WJ. Antibiotic treatment for nontuberculous mycobacterial lung disease Expert Rev Respir Med. 2016; 10(5): 557-68.
  • Kasperbauer SH, de Groote MA. The treatment of rapidly growing mycobacterial infections. Clin Chest Med. 2015; 36(1): 67-78.
  • Kim HY, Kim BJ, Kook Y, Yun YJ, Shin JH, Kim BJ, et al. Mycobacterium massiliense is differentiated from Mycobacterium abscessus and Mycobacterium bolletii by erythromycin ribossome methyltransferase gene (erm) and clarithromycin susceptibility patterns. Microbiol Immunol. 2010; 54(6): 347-53.
  • Kim SY, Shin SJ, Jeong BH, Koh WJ. Successful antibiotic treatment of pulmonary disease caused by Mycobacterium abscessus sub-sp. abscessus with C-to-T mutation at position 19 in erm(41) gene: case report. BMC Infect Dis. 2016; 16: 207.
  • Lee MR, Sheng WH, Hung CC, Yu CJ, Lee LN, Hsueh PR. Mycobacterium abscessus complex infections in humans. Emerg Infect Dis. 2015; 21(9): 1638-46.
  • Maurer FP, Castelberg C, Quiblier C, Böttger EC, Somoskövi A. Erm(41) dependent inducible resistance to azithromycin and clarithromycin in clinical isolates of Mycobacterium abscessus J Antimicrob Chemother. 2014; 69(6): 1559-63.
  • Maurer FP, Rüegger V, Ritter C, Bloemberg GV, Böttger EC. Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41). J Antimicrob Chemother. 2012; 67(11): 2606-11.
  • Meier A, Kirschner P, Springer B, Steingrube V, Brown B, Wallace R, et al. Identification of mutations in 23S rRNA gene of clarithromycin resistant Mycobacterium intracellulare Antimicrob Agents Chemother. 1994; 38(2): 381-4.
  • Mougari F, Amarsy R, Veziris N, Bastian S, Brossier F, Berçot B, et al. Standardized interpretation of antibiotic susceptibility testing and resistance genotyping for Mycobacterium abscessus with regard to subspecies and erm41 sequevar. J Antimicrob Chemother. 2016a; 71(8): 2208-12.
  • Mougari F, Bouziane F, Crockett F, Nessar R, Chau F, Veziris N, et al. Selection of resistance to clarithromycin with regard to the 2 subspecies in Mycobacterium abscessus Antimicrob Agents Chemother. 2016b; 61(1): e00943-16.
  • Nash KA, Brown-Elliott BA, Wallace RJ. A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae Antimicrob Agents Chemother. 2009; 53(4): 1367-76.
  • Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother. 2012; 67(4): 810-8.
  • Nunes LDS, Baethgen LF, Ribeiro MO, Cardoso CM, de Paris F, de David SM, et al. Outbreaks due to Mycobacterium abscessus sub-sp. bolletii in southern Brazil: persistence of a single clone from 2007 to 2011. J Med Microbiol. 2014; 63(10): 1288-93.
  • Ryu YJ, Koh WJ, Daley CL. Diagnosis and treatment of nontuberculous mycobacterial lung disease: clinicians’ perspectives. Tuberc Respir Dis. 2016; 79(2): 74-84.
  • Shallom SJ, Gardina PJ, Myers TG, Sebastian Y, Conville P, Calhoun LB, et al. New rapid scheme for distinguishing the subspecies of the Mycobacterium abscessus group and identifying Mycobacterium massiliense isolates with inducible clarithromycin resistance. J Clin Microbiol. 2013; 51(9): 2943-9.
  • Stout JE, Koh WJ, Yew WW. Update on pulmonary disease due to non-tuberculous mycobacteria. Int J Infect Dis. 2016; 45: 123-34.

Publication Dates

  • Publication in this collection
    Nov 2017

History

  • Received
    24 Feb 2017
  • Accepted
    06 June 2017
Instituto Oswaldo Cruz, Ministério da Saúde Av. Brasil, 4365 - Pavilhão Mourisco, Manguinhos, 21040-900 Rio de Janeiro RJ Brazil, Tel.: (55 21) 2562-1222, Fax: (55 21) 2562 1220 - Rio de Janeiro - RJ - Brazil
E-mail: memorias@fiocruz.br