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Embrace Simplicity When Treating Lady WindermereEmbrace Simplicity FREE TO VIEW

Julie Jarand, MD; Stephen K. Field, MD, FCCP
Author and Funding Information

From the Division of Respirology, Department of Medicine, University of Calgary; and Tuberculosis Services, Calgary Zone, Alberta Health Services.

CORRESPONDENCE TO: Stephen K. Field, MD, FCCP, Division of Respirology, Department of Medicine, University of Calgary and Alberta Health Services, Room 1437, Health Science Centre, 3330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada; e-mail: sfield@ucalgary.ca


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):244-246. doi:10.1378/chest.14-0046
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The early reports of Mycobacterium avium complex (MAC) lung disease described a difficult-to-treat, primarily upper-lobe, fibrocavitary lung condition with radiologic features similar to those of pulmonary TB. The majority of affected patients were men with preexisting lung disease, usually COPD; previously treated TB; or an immunodeficiency.1 Prince and colleagues2 recognized that fibronodular bronchiectasis (FNB) was not an uncommon manifestation of MAC lung disease seen mostly in elderly, thin women who often were lifetime nonsmokers without preexisting lung disease.

Ideally, treatment recommendations are based on the results of multiple, or at least duplicate, adequately powered, randomized controlled trials in patients with demographics similar to those of the target population. The substantial costs of large pharmacotherapy trials generally require sponsorship by pharmaceutical firms anticipating substantial financial rewards from the marketing of new, effective drugs. These elaborate trials are costly and, in the absence of an expectation of profit, impractical to undertake for relatively uncommon conditions such as infections due to nontuberculous mycobacteria (NTM). MAC lung disease is one of these uncommon conditions that is treated with off-patent medications and requires prolonged treatment courses and follow-up. All of these factors have significantly limited treatment trials to date, and, as a result, guidelines for the treatment of NTM infections are based largely on uncontrolled case series, retrospective data, and expert opinion.

For patients with MAC presenting as FNB, the American Thoracic Society/Infectious Disease Society of America statement on the diagnosis and treatment of NTM diseases3 recommends thrice-weekly therapy with a macrolide, either clarithromycin or azithromycin (technically an azalide but with antibacterial activity similar to that of the second-generation macrolides), ethambutol, and rifampin. This recommendation is based on two relatively small, single-center, noncomparative studies that showed that thrice-weekly therapy for treatment of MAC lung disease had sputum culture conversion results similar to those of daily therapy, with lower costs and fewer adverse effects.4,5 Thrice-weekly therapy is not recommended for patients with cavitary, previously treated, and/or severe disease, based on a study that showed that these patients did worse while on intermittent therapy.6

In this issue of CHEST (see page 276), Wallace and colleagues7 report their experience with a large cohort of patients with FNB due to MAC lung disease. The patient demographics in this report are typical for the condition: thin, elderly, primarily lifetime nonsmoking women. Strengths of the report include the large size of the cohort; the fact that all patients had at least one chest CT scan to confirm the presence of FNB; the fact that only a very small number had concurrent cavitary lesions (2%); the long duration of follow-up after therapy was completed, averaging 3.5 years; and the genotyping of isolates from patients who became culture positive after converting to negative. Limitations of the report are that it was not a controlled trial, it is unclear how patients were assigned to thrice-weekly or daily therapy, no data were provided regarding radiologic or clinical response to treatment, and strict monitoring of patient adherence to therapy was lacking.

The majority of patients were treated successfully with thrice-weekly clarithromycin or azithromycin, rifampin, and ethambutol.4 The thrice-weekly regimen was better tolerated than daily therapy, and the rate of sputum culture conversion to negative was as good as in the group receiving medication daily. Sputum cultures converted to negative in 86% treated for a minimum of 12 months, both among the patients treated thrice weekly and among those who received medication daily.

Adverse effects, regimen modification, or both occurred in only a minority of patients treated thrice weekly, whereas most patients treated with the daily regimen required some modification of their regimen.4 As seen in previous treatment trials, but of obvious concern, is that a proportion of patients failed to convert to negative (in this study, 14%) or relapsed while on therapy. None had macrolide-resistant MAC, and none developed macrolide-resistance during treatment. Adherence was not monitored and may explain some of the treatment failures. Another possibility is that the dosing was insufficient to achieve adequate drug levels, either because of inadequate drug absorption from the gut or the effect of rifampin on macrolide serum levels.8

One of the acknowledged limitations of the treatment of MAC lung disease is that a significant number of patients, in this study 48%, develop recurrence of infection after successful therapy. There is very limited literature regarding the proportion of patients who become reinfected and also require retreatment (ie, progressive clinical symptoms and radiologic changes). The organism is ubiquitous and is present in drinking water; earth, particularly potting soils with a high peat content; and dust.9 After successful treatment, patients have ongoing exposure to the organism and presumably the immune or respiratory susceptibility that led to infection in the first place persists.10,11 It is not surprising that patients remain vulnerable to reinfection. In this report, just under one-half developed recurrent infection during an average follow-up period of 3.5 years. Genotyping demonstrated that the majority (approximately 75%) of isolates from patients with recurrent infection were different strains from those isolated prior to successful treatment, consistent with patients being reinfected rather than experiencing relapse of their initial infection.7 These findings are similar to those of a previous study published by these authors.12 The clinical implications of genotyping are still under investigation because research, thus far, has not shown an association with clinical characteristics or disease progression.13

The favorable outcomes in a large cohort of patients treated according to the American Thoracic Society/Infectious Disease Society of America guidelines are their best available endorsement. Both daily and thrice-weekly therapy are recommended by the guidelines and resulted in sputum conversion-to-negative rates of approximately 85%. Lao Tzu’s dictum to “embrace simplicity” applies to patient adherence. The simpler a regimen, the more likely patients will be able to adhere to it. The report by Wallace and colleagues7 represents an important advance reassuring physicians that the simpler thrice-weekly regimen is as effective as daily therapy yet much better tolerated and undoubtedly less expensive for patients with FNB. As suggested previously, these results should not be extrapolated to patients with cavitary disease. The high reinfection rate within the 3.5 years following treatment emphasizes the importance of the recommendation for ongoing surveillance of these patients after successful treatment.

References

Crow HE, King CT, Smith CE, Corpe RF, Stergus I. A limited clinical, pathologic, and epidemiologic study of patients with pulmonary lesions associated with atypical acid-fast bacilli in the sputum. Am Rev Tuberc. 1957;75(2):199-222. [PubMed]
 
Prince DS, Peterson DD, Steiner RM, et al. Infection withMycobacterium aviumcomplex in patients without predisposing conditions. New Engl J Med. 1989;321(13):863-868. [CrossRef] [PubMed]
 
Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [published correction appears inAm J Respir Crit Care Med. 2007;175(7):744-5]. Am J Respir Crit Care Med. 2007;175(4):367-416. [CrossRef] [PubMed]
 
Griffith DE, Brown BA, Murphy DT, Girard WM, Couch L, Wallace RJ Jr. Initial (6-month) results of three-times-weekly azithromycin in treatment regimens forMycobacterium aviumcomplex lung disease in human immunodeficiency virus-negative patients. J Infect Dis. 1998;178(1):121-126. [CrossRef] [PubMed]
 
Griffith DE, Brown BA, Cegielski P, Murphy DT, Wallace RJ Jr. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due toMycobacterium aviumcomplex. Clin Infect Dis. 2000;30(2):288-292. [CrossRef] [PubMed]
 
Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment ofMycobacterium aviumcomplex lung disease. Am J Respir Crit Care Med. 2006;173(11):1283-1289. [CrossRef] [PubMed]
 
Wallace RJ Jr, Brown-Elliott BA, McNulty S, et al. Macrolide/azalide therapy for nodular/bronchiectaticMycobacterium aviumcomplex lung disease. Chest. 2014;146(2):276-282.
 
van Ingen J, Egelund EF, Levin A, et al. The pharmacokinetics and pharmacodynamics of pulmonaryMycobacterium aviumcomplex disease treatment. Am J Respir Crit Care Med. 2012;186(6):559-565. [CrossRef] [PubMed]
 
Falkinham JO III. Ecology of nontuberculous mycobacteria—where do human infections come from? Semin Respir Crit Care Med. 2013;34(1):95-102. [CrossRef] [PubMed]
 
Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected withMycobacterium aviumcomplex. J Infect Dis. 2001;183(3):478-484. [CrossRef] [PubMed]
 
Safdar A, White DA, Stover D, Armstrong D, Murray HW. Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis. Am J Med. 2002;113(9):756-759. [CrossRef] [PubMed]
 
Wallace RJ Jr, Zhang Y, Brown-Elliott BA, et al. Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis. J Infect Dis. 2002;186(2):266-273. [CrossRef] [PubMed]
 
Kim SY, Lee ST, Jeong BH, et al. Clinical significance of mycobacterial genotyping inMycobacterium aviumlung disease in Korea. Int J Tuberc Lung Dis. 2012;16(10):1393-1399. [CrossRef] [PubMed]
 

Figures

Tables

References

Crow HE, King CT, Smith CE, Corpe RF, Stergus I. A limited clinical, pathologic, and epidemiologic study of patients with pulmonary lesions associated with atypical acid-fast bacilli in the sputum. Am Rev Tuberc. 1957;75(2):199-222. [PubMed]
 
Prince DS, Peterson DD, Steiner RM, et al. Infection withMycobacterium aviumcomplex in patients without predisposing conditions. New Engl J Med. 1989;321(13):863-868. [CrossRef] [PubMed]
 
Griffith DE, Aksamit T, Brown-Elliott BA, et al; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [published correction appears inAm J Respir Crit Care Med. 2007;175(7):744-5]. Am J Respir Crit Care Med. 2007;175(4):367-416. [CrossRef] [PubMed]
 
Griffith DE, Brown BA, Murphy DT, Girard WM, Couch L, Wallace RJ Jr. Initial (6-month) results of three-times-weekly azithromycin in treatment regimens forMycobacterium aviumcomplex lung disease in human immunodeficiency virus-negative patients. J Infect Dis. 1998;178(1):121-126. [CrossRef] [PubMed]
 
Griffith DE, Brown BA, Cegielski P, Murphy DT, Wallace RJ Jr. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due toMycobacterium aviumcomplex. Clin Infect Dis. 2000;30(2):288-292. [CrossRef] [PubMed]
 
Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment ofMycobacterium aviumcomplex lung disease. Am J Respir Crit Care Med. 2006;173(11):1283-1289. [CrossRef] [PubMed]
 
Wallace RJ Jr, Brown-Elliott BA, McNulty S, et al. Macrolide/azalide therapy for nodular/bronchiectaticMycobacterium aviumcomplex lung disease. Chest. 2014;146(2):276-282.
 
van Ingen J, Egelund EF, Levin A, et al. The pharmacokinetics and pharmacodynamics of pulmonaryMycobacterium aviumcomplex disease treatment. Am J Respir Crit Care Med. 2012;186(6):559-565. [CrossRef] [PubMed]
 
Falkinham JO III. Ecology of nontuberculous mycobacteria—where do human infections come from? Semin Respir Crit Care Med. 2013;34(1):95-102. [CrossRef] [PubMed]
 
Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected withMycobacterium aviumcomplex. J Infect Dis. 2001;183(3):478-484. [CrossRef] [PubMed]
 
Safdar A, White DA, Stover D, Armstrong D, Murray HW. Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis. Am J Med. 2002;113(9):756-759. [CrossRef] [PubMed]
 
Wallace RJ Jr, Zhang Y, Brown-Elliott BA, et al. Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis. J Infect Dis. 2002;186(2):266-273. [CrossRef] [PubMed]
 
Kim SY, Lee ST, Jeong BH, et al. Clinical significance of mycobacterial genotyping inMycobacterium aviumlung disease in Korea. Int J Tuberc Lung Dis. 2012;16(10):1393-1399. [CrossRef] [PubMed]
 
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