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Editorial |

Nontuberculous Mycobacterial Disease Therapy: Take It to the Limit One More Time FREE TO VIEW

David E. Griffith, MD, FCCP; Timothy R. Aksamit, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

aUniversity of Texas Health Science Center, Tyler, TX

bDivision of Pulmonary Disease and Critical Care Medicine, Mayo Clinic, Rochester, MN

CORRESPONDENCE TO: David E. Griffith, MD, FCCP, University of Texas Health Science Center, 11937 US Hwy 271, Tyler, TX 75708


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(6):1177-1178. doi:10.1016/j.chest.2016.07.015
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Published online

All too often we are reminded that essentially nothing about nontuberculous mycobacterial (NTM) disease is easy or simple, and the role of drug susceptibility/resistance is no exception. Many nontuberculous mycobacteria causing disease display a counterintuitive and frustrating disparity between in vitro drug susceptibility test results and in vivo response to specific antimicrobial agents. This NTM characteristic has been attributed to innate resistance factors that are frequently not reflected in the minimum inhibitory concentration of the antimicrobial agent for the organism., The inducible macrolide resistance (erm) gene in Mycobacterium abscessus subspecies abscessus is one such factor., Innate resistance is also unavoidable.

FOR RELATED ARTICLE SEE PAGE 1211

In addition, some NTM pathogens also display acquired mutational drug resistance, which is the common mechanism of acquired drug resistance most physicians know because of familiarity with TB. Acquired mutational drug resistance occurs when an antimycobacterial agent is given either as monotherapy or with inadequate companion medications and there is selection of mycobacterial isolates with naturally occurring mutations conferring resistance to the specific antimycobacterial agent. It is an unassailable truth that monotherapy with an antimycobacterial agent for active TB will result in acquired mutational resistance to that agent.

This phenomenon of acquired drug resistance occurs not only with M tuberculosis but also with M kansasii for rifamycins (rpoβ gene mutation), M avium complex with macrolides (23S ribosomal RNA gene mutation), and “M abscessus” with macrolides (23S ribosomal RNA gene mutation).,,,, While an active erm gene is the primary mechanism for in vitro “M abscessus” macrolide resistance, approximately 20% of M abscessus subspecies abscessus isolates have a mutation that inactivates the erm gene, making the isolate macrolide susceptible and significantly easier to treat. Choi et al showed that macrolide-susceptible M abscessus subspecies massiliense isolates with an inactive erm gene are significantly more likely to respond to antimycobacterial therapy including a macrolide than M abscessus subspecies abscessus isolates with an active erm gene. The clear message is that macrolide resistance, for any reason, is a significant impediment to successful therapy for disease caused by any “M abscessus” subspecies. Furthermore, even if an M abscessus subspecies abscessus fortuitously has an inactive erm gene, it is still possible to develop acquired mutational macrolide resistance. The most significant aspect of acquired mutational drug resistance is that it is preventable.

In this issue of Chest, Koh et al describe their treatment of patients with M abscessus subspecies massiliense lung disease with regimens including long-term macrolide monotherapy after an initial phase of multidrug therapy. Almost all patients treated with this protocol attained sustained microbiologic conversion, although two patients developed macrolide-resistant M abscessus subspecies massiliense infection with this strategy.

Wallace et al showed that macrolide monotherapy could be effective for treating disseminated, skin and soft tissue M chelonae infections. Mycobacterium chelonae is a rapidly growing mycobacterium similar in many respects to M abscessus species but without an active erm gene. The results were generally encouraging, although one patient developed acquired mutational macrolide resistance with this strategy, a finding not surprisingly affirmed by a later report., In spite of overall favorable results, widespread adoption of macrolide monotherapy for M chelonae disease was not achieved because of the predictable, if infrequent, emergence of acquired macrolide resistance.

In the study by Koh et al, it is gratifying that most patients had a favorable microbiologic outcome. It is also somewhat surprising that only two patients developed acquired macrolide-resistant M abscessus subspecies massiliense isolates. While the absolute number is low, for those two individuals the consequences of developing macrolide resistance are far from trivial. They have transitioned from having a mycobacterial infection that is relatively easy to treat effectively to a mycobacterial infection that is not.

At present, most US mycobacterial laboratories (1) don’t provide subspecies information about “M abscessus” isolates and (2) don’t perform macrolide preincubation of “M abscessus” isolates to determine the activity of the erm gene, thereby determining the true status of in vitro macrolide susceptibility. It is possible a physician could see a low macrolide minimum inhibitory concentration for an “M abscessus” isolate and incorrectly assume the isolate was M abscessus subspecies massiliense. If that isolate was one of the 20% of M abscessus subspecies abscessus isolates with an inactivated erm gene and true macrolide susceptibility, then macrolide monotherapy could result in acquired macrolide resistance and transition the infection to the typically difficult-to-treat M abscessus subspecies abscessus infection.

Another consideration is that coisolation of “M abscessus” with Mycobacterium avium complex (MAC) is relatively common. Macrolide monotherapy for MAC isolates is clearly a risk factor for the development of macrolide-resistant MAC lung disease, which has a demonstrably poor prognosis. At a minimum, macrolide monotherapy for “M abscessus” infections would require careful and ongoing surveillance for the presence of MAC.

We enthusiastically applaud and acknowledge the prolific and consistently excellent work done by the group in South Korea, but we cannot endorse the widespread adoption of macrolide monotherapy for M abscessus subspecies massiliense or for macrolide-susceptible M abscessus subspecies abscessus. In our view, the risk-to-benefit balance of this approach does not favor macrolide monotherapy even though the majority of patients in this study were adequately treated. The significant increase in treatment difficulty between macrolide-susceptible and macrolide-resistant M abscessus subspecies massiliense isolates is prohibitive for adopting a monotherapy approach.

It could be argued that there is risk for developing macrolide resistance with any “M abscessus” treatment regimen, but that risk is usually not an inevitable consequence of the treatment strategy. While TB analogies with NTM infections are fraught with caveats, it would be unacceptable for any drug-susceptible TB treatment regimen to result predictably in even a very low percentage of patients with multidrug-resistant TB. Pushing the limits on minimizing the number of drugs required to treat any mycobacterial pathogen entails risk and in this instance we do not believe that risk is acceptable.

References

Brown-Elliott B.A. .Nash K.A. .Wallace R.J. Jr.. Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clin Microbiol Rev. 2012;25:545-582 [PubMed]journal. [CrossRef] [PubMed]
 
van Ingen J. .Boeree M.J. .van Soolingen D. .Mouton J.W. . Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat. 2012;15:149-161 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Aksamit T. .Brown-Elliott B.A. .et al ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Diseases Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [review] [published correction appears in Am J Respir Crit Care Med. 2007;175(7):744-745]. Am J Respir Crit Care Med. 2007;175:367-416 [PubMed]journal. [CrossRef] [PubMed]
 
Rubio M. .March F. .Garrigó M. .Moreno C. .Español M. .Coll P. . Inducible and acquired clarithromycin resistance in the Mycobacterium abscessus complex. PLoS One. 2015;10:e0140166- [PubMed]journal. [CrossRef] [PubMed]
 
Brown-Elliott B.A. .Vasireddy S. .Vasireddy R. .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;53:1211-1215 [PubMed]journal. [CrossRef] [PubMed]
 
Choi G.E. .Shin S.J. .Won C.J. .et al Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance. Am J Respir Crit Care Med. 2012;186:917-925 [PubMed]journal. [CrossRef] [PubMed]
 
Koh W.J. .Jeong B.H. .Jeon K. .et al Oral macrolide therapy following short-term combination antibiotic treatment of Mycobacterium massiliense lung disease. Chest. 2016;150:1211-1221 [PubMed]journal. [CrossRef]
 
Wallace R.J. Jr..Tanner D. .Brennan P.J. .Brown B.A. . Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med. 1993;119:482-486 [PubMed]journal. [CrossRef] [PubMed]
 
Tebas P. .Sultan F. .Wallace R.J. Jr..Fraser V. . Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient. Clin Infect Dis. 1995;20:443-444 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Philley J.V. .Brown-Elliott B.A. .et al The significance of Mycobacterium abscessus subspecies abscessus isolation during Mycobacterium avium complex lung disease therapy. Chest. 2015;147:1369-1375 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Brown-Elliott B.A. .Langsjoen B. .et al Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006;174:928-934 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

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References

Brown-Elliott B.A. .Nash K.A. .Wallace R.J. Jr.. Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clin Microbiol Rev. 2012;25:545-582 [PubMed]journal. [CrossRef] [PubMed]
 
van Ingen J. .Boeree M.J. .van Soolingen D. .Mouton J.W. . Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat. 2012;15:149-161 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Aksamit T. .Brown-Elliott B.A. .et al ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Diseases Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [review] [published correction appears in Am J Respir Crit Care Med. 2007;175(7):744-745]. Am J Respir Crit Care Med. 2007;175:367-416 [PubMed]journal. [CrossRef] [PubMed]
 
Rubio M. .March F. .Garrigó M. .Moreno C. .Español M. .Coll P. . Inducible and acquired clarithromycin resistance in the Mycobacterium abscessus complex. PLoS One. 2015;10:e0140166- [PubMed]journal. [CrossRef] [PubMed]
 
Brown-Elliott B.A. .Vasireddy S. .Vasireddy R. .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;53:1211-1215 [PubMed]journal. [CrossRef] [PubMed]
 
Choi G.E. .Shin S.J. .Won C.J. .et al Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance. Am J Respir Crit Care Med. 2012;186:917-925 [PubMed]journal. [CrossRef] [PubMed]
 
Koh W.J. .Jeong B.H. .Jeon K. .et al Oral macrolide therapy following short-term combination antibiotic treatment of Mycobacterium massiliense lung disease. Chest. 2016;150:1211-1221 [PubMed]journal. [CrossRef]
 
Wallace R.J. Jr..Tanner D. .Brennan P.J. .Brown B.A. . Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med. 1993;119:482-486 [PubMed]journal. [CrossRef] [PubMed]
 
Tebas P. .Sultan F. .Wallace R.J. Jr..Fraser V. . Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient. Clin Infect Dis. 1995;20:443-444 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Philley J.V. .Brown-Elliott B.A. .et al The significance of Mycobacterium abscessus subspecies abscessus isolation during Mycobacterium avium complex lung disease therapy. Chest. 2015;147:1369-1375 [PubMed]journal. [CrossRef] [PubMed]
 
Griffith D.E. .Brown-Elliott B.A. .Langsjoen B. .et al Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2006;174:928-934 [PubMed]journal. [CrossRef] [PubMed]
 
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