Pulmonary Medicine

Non-tuberculous Mycobacterial Infections of the Lung

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What every physician needs to know:

There are currently more than 160 identified species of non-tuberculous mycobacteria (NTM). The NTM are a widely diverse group of organisms with a broad spectrum of virulence and potential for causing disease in humans. Clinicians are faced with a steady stream of newly identified NTM species and the accompanying responsibility for determining the clinical impact of those new species. In addition, NTM lung diseases are becoming more prevalent. In this context, NTM diseases could legitimately be seen as an emerging public-health threat.

Classification:

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Are you sure your patient has a non-tuberculous mycobacterial infection of the lung? What should you expect to find?

Patients with NTM lung disease generally present radiographically in one of two ways, either characterized by upper lobe cavitary densities similar to those associated with pulmonary tuberculosis or associated with nodules and bronchiectasis (nodular/bronchiectatic disease). Patients with either type of NTM lung disease should be diagnosed using established guidelines that include symptomatic, radiographic, and microbiologic criteria.

Beware: there are other diseases that can mimic non-tuberculous mycobacterial infections of the lung.

The most important disease to exclude in patients with NTM lung disease is tuberculosis.

How and/or why did the patient develop a non-tuberculous mycobacterial infection of the lung?

The source of NTM that cause lung disease is assumed to be the environment, with increasing concern that biofilms that form in municipal water sources may be a significant source. Feazel et al. analyzed RNA gene sequences from 45 showerhead sites around the U.S. and identified sequences indicative of Mycobacterium aviumin 20 percent of showerhead swabs. A quantitative PCR with M. avium-specific primers detected M. aviumin 20 additional biofilm swab samples.

Using microbiologic techniques, Nishiuchi et al. reported the recovery of M. aviumcomplex (MAC) from residential bathrooms of patients with pulmonary MAC disease. MAC was isolated from 10 out of 371 patient residence cultures versus 1 out of 333 control households. Two patients with MAC lung disease were found to have identical sputum and bathroom MAC genotypes.

Falkinham reported that NTM was isolated from 59 percent of the water systems from households of patients with NTM lung disease; in seven households, the patient isolate and one plumbing isolate exhibited similar genotype patterns.

Two additional reports demonstrated identical genotypes of MAC isolated from plumbing and clinical MAC isolates, including one patient with conventional MAC lung infection and one with hypersensitivity-like lung disease. Lande et al. recently showed that M. avium is frequently isolated from the household plumbing of patients with M. avium lung disease, with almost 50 percent genotypic concordance between the household and clinical isolates. The Japanese have also demonstrated genotypic concordance between environmental MAC (M. avium and M. intracellulare) and clinical isolates from patients. It appears increasingly clear that, for some patients, acquisition of their NTM isolates occurred from their home environment and specifically from household plumbing.

Even in the context of this provocative data, it is still unknown how much of a risk NTM in household plumbing presents and whether municipal plumbing in general, and showerheads specifically, represent a significant or common source of NTM for the majority patients with NTM lung disease.

Bronchiectasis and pulmonary NTM infection are inextricably linked. Twenty percent of cystic fibrosis patients and 10 percent of primary ciliary dyskinesia patients have NTM recovered from respiratory specimens, which strongly suggests a predisposing alteration in airway-surface defenses caused by or associated with bronchiectasis, at least for some patients.

Kim et al. at the NIH reported a characteristic body habitus in 63 patients with NTM lung disease, but they identified no recognized immune defects, including cell-mediated dysfunction or cytokine-pathway abnormalities, in these patients. However, in this selected population, the body mass index (BMI) was significantly lower and the height significantly greater than matched controls. This group also had higher rates of scoliosis, pectus excavatum, and mitral valve prolapse. Kartalija et al. at National Jewish Health noted similar morphologic characteristics in patients with NTM lung disease.

Kim et al. noted more frequent cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations compared with a matched control population. A subsequent study from Japan also found that patients with pulmonary NTM disease have CFTR gene mutations more frequently than do those in the general population. The pathophysiologic consequences of these observations are still unclear, as there was not a consistent correlation between sweat chloride concentrations and CFTR variants. In a provocative recent study of patients with heterozygous CFTR mutations, nasal mucosal potential differences were greater in patients compared to controls, suggesting a mucosal ion transport abnormality.

Although single CFTR mutations do not appear to be adequate for explaining the presence of bronchiectasis and NTM lung disease in the majority of patients, a recent study by Szymanski et al. suggests that bronchiectasis may be the cumulative consequence of multiple genetic abnormalities. Again, the exact pathways by which the progression from these genetic abnormalities and how bronchiectasis develops remains unknown, but the two diseases are strongly linked and that, for many (perhaps most) NTM patients with bronchiectasis, bronchiectasis is the primary disease process and NTM infection is secondary.

As with Mycobacterium tuberculosis, tumor-necrosis factor alpha (TNF-alpha) blockers are an important and potent predisposition for NTM infections. The U.S. Food and Drug Administration (FDA) MedWatch database of NTM disease in patients who are receiving TNF-alpha blocker therapy reported that NTM infections were associated with all available (at the time) TNF-alpha blockers and that MAC was the NTM species most commonly implicated. Extrapulmonary disease was common, and 9 percent of patients had died at the time their infection was reported. Some TNF-alpha blockers are an important predisposing factor for potentially serious, even fatal, NTM infection, and they must be used with caution in patients with NTM disease. Newer “biologic” agents that are not specific TNF-alpha inhibitors have variable but generally less deleterious impact on the progression of NTM infection.

Which individuals are at greatest risk of developing a non-tuberculous mycobacterial infection of the lung?

Available data supports the contention that NTM disease is becoming more prevalent. Determining the incidence and prevalence of NTM lung disease remains problematic primarily because disease reporting is not mandatory in the U.S., and there must be an assessment of the clinical significance of individual NTM isolates, as opposed to M. tuberculosis, where each isolate is assumed to be associated with true disease. A surrogate for disease prevalence has been "isolation prevalence" for NTM species, although the clinical significance of a specific NTM isolate may be either unknown or highly unlikely.

In an insightful and provocative analysis of NTM isolation prevalence data, Iseman and Marras suggested that, while the incidence of NTM lung disease may be comparable to that of tuberculosis, the prevalence of NTM lung disease is almost certainly much higher than that of tuberculosis because of the difficulty in curing patients with NTM lung disease versus the relatively high cure rates for tuberculosis patients, and the subsequent accumulation of NTM patients who have persistent, usually indolent and sometimes incurable disease.

In a report of four large regional healthcare systems, the mean annual NTM disease prevalence was estimated to be 5.5 per 100,000, ranging from 1.7 per 100,000 in Southern Colorado to 6.7 per 100,000 in Southern California. This study suggested an annual increase in prevalence of 2.6 percent over the study period. MAC was the most common species identified in pulmonary cases (4.7 cases per 100,000 population).

In perhaps the best and most rigorous NTM prevalence study to date, Winthrop et al. took the difficult step of matching NTM isolates with the clinical history and radiographic findings of individuals from whom the NTM isolates had been obtained. The prevalence of NTM lung disease was found to be 8.6 per 100,000 overall and 20.4 per 100,000 in those 50 years of age or older over the 2005-2006 study period.

NTM disease prevalence trends in the U.S. appear to be mirrored in other parts of the world. In Queensland, Australia, where NTM disease is a reportable condition, the incidence of clinically significant disease rose from 2.2 per 100,000 in 1999 to 3.2 per 100,000 in 2005. Similarly, in Taiwan, the incidence of NTM lung disease increased from 1.26 per 100,000 in 2000 to 7.94 per 100,000 in the year 2008.

Of particular interest, the prevalence of bronchiectasis, the most important predisposition to the acquisition of NTM lung disease, was approximately 1000 cases per 100,000 population according to a recent study from the NIH.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Diagnosis of non-tuberculous mycobacteria lung disease

The NTM share an important characteristic in that they are all found in some niche (or multiple niches) in the environment, so isolation of any NTM species can be the consequence of environmental contamination, especially contamination by nonsterile (tap) water sources. Therefore, diagnostic criteria for respiratory NTM isolates remains necessary in determining which NTM isolates are clinically significant. Overall, this decision must be based on the potential virulence of the NTM isolated, the host from which the organism was isolated, and the source of the clinical specimen from which the NTM was isolated. No single set of criteria could possibly be appropriate for all NTM species.

Some NTM species, such as M. kansasiiand M. szulgai, are almost always associated with significant disease when isolated from respiratory specimens; in some cases, lung disease might be diagnosed on the basis of one positive culture for these organisms (especially M. kansasii). Conversely, some NTM, such as M. simiaeand M. fortuitum, are usually not respiratory pathogens, even if the NTM diagnostic criteria are met. Finally, some NTM species, such as M. gordonae and M. terrae complex, almost always indicate contamination of respiratory specimens.

One frequently encountered scenario is the isolation of an NTM species from a patient who is undergoing therapy for tuberculosis. Jun et al. reported on 958 patients with tuberculosis, of whom 68 (7.1%) had NTM isolated during tuberculosis therapy. Most patients (71%) had only one positive NTM culture, and only two patients (3%), both with M. abscessusisolates, were thought to have progressive NTM disease after completion of tuberculosis therapy. The authors concluded that isolation of NTM in patients with tuberculosis was not uncommon but was rarely due to invasive or progressive NTM disease. Nevertheless, these patients required follow-up after completion of tuberculosis therapy, especially with isolation of potentially virulent NTM species.

Newer diagnostic techniques to augment the current diagnostic criteria are under investigation. One novel approach is a serologic test based on an enzyme immunoassay kit (EIA) that detects serum IgA antibody to glycopeptidolipid core antigen specific for MAC. This EIA kit appeared to be useful in identifying patients with MAC lung disease and in differentiating patients with MAC lung disease from tuberculosis patients. However, there was considerable overlap in serum IgA-antibody levels between the patient groups. In addition, the EIA test was not evaluated as a predictor of disease progression or as a guide as to which patients would require therapy. It remains to be determined where this test will fit in the overall evaluation of patients with suspected MAC lung disease.

What imaging studies will be helpful in making or excluding the diagnosis of a non-tuberculous mycobacterial infection of the lung?

Both plain chest radiography and chest CT evaluation are necessary for diagnosing NTM lung disease. Patients with NTM disease associated with cavitary consolidation can be diagnosed using plain chest radiographs, but they must be evaluated first for tuberculosis. Patients with disease characterized by nodules and bronchiectasis generally require a high resolution CT scan of the chest for diagnosis. The characteristic combination of bronchiectasis and “tree-in-bud” abnormalities is highly suggestive of NTM lung disease, but it is not diagnostic.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a non-tuberculous mycobacterial infection of the lung?

The most important non-invasive diagnostic study is sputum collection for acid-fast bacilli (AFB) analysis. The diagnosis of NTM lung disease cannot be made empirically, so isolation of an NTM from a respiratory specimen is essential for making the diagnosis. For patients unable to produce sputum spontaneously, induction of sputum with nebulized hypertonic saline is a frequently effective and important option.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a non-tuberculous mycobacterial infection of the lung?

If spontaneous or induced sputum production does not yield an NTM pathogen from a patient who is strongly suspected of having NTM lung disease, then bronchoscopy would be indicated to obtain lower respiratory secretions for AFB analysis. Whether bronchoscopically obtained specimens are significantly more effective for NTM lung disease diagnosis compared with spontaneous sputum production has not been rigorously tested.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a non-tuberculous mycobacterial infection of the lung?

If efforts to obtain respiratory secretions do not yield a diagnosis of NTM lung disease, then, in rare cases, lung biopsy, usually with bronchoscopically obtained transbronchial biopsy, may be helpful.

If you decide the patient has a non-tuberculous mycobacterial infection of the lung, how should the patient be managed?

Therapy for non-tuberculous mycobacteria lung disease

An especially frustrating problem in the management of patients with NTM diseases (pulmonary, disseminated, etc.) is that in-vitro susceptibility testing may not be a guide for effective in-vivo response to antibiotics, as it is in the therapy of tuberculosis. The most clinically vexing example is MAC, where there is evidence to support a correlation among in-vitro macrolide susceptibility and in-vitro amikacin susceptibility and in-vivo clinical response. Multiple studies have confirmed this scientific and clinically unsatisfactory paradox.

Both the Clinical and Laboratory Standard Institute and the American Thoracic Society (ATS) recommend that new MAC isolates be tested in vitro only for susceptibility to macrolides. The next iteration of these standards likely also will include amikacin in the recommendation. Understandably, clinicians still cling to in-vitro susceptibility reports for MAC isolates that list multiple agents as either "susceptible" or "resistant" based on in-vitro minimum inhibitory concentrations (MICs), even though those MICs have not been shown to correlate with in-vivo response to the antibiotics tested. Perhaps not surprisingly, there are multiple other NTM species and pathogens that share this frustrating property with MAC. There are multiple potential explanations for this treatment paradox, which might be explained by a process called "innate resistance."

The mechanism for one example of "innate resistance" was recently discovered with rapidly growing mycobacteria (RGM), including M. abscessus, and may offer a window into the complex relationship between in-vitro responses and the in-vivo effect of antibiotics on NTM in general. Macrolide antimicrobial agents act by binding to the 50S ribosomal subunit and inhibiting peptide synthesis. Erythromycin methylase (erm) genes, a diverse collection of methylases that impair binding of macrolides to ribosomes, reduce the inhibitory activity of these agents.

The primary mechanism of acquired clinically significant macrolide resistance for RGM is the presence of an inducible erm gene (erm 41). All isolates of M. abscessus and M. fortuitum, but not M. chelonae, contain an inducible erm gene. (There is also a novel erm gene in M. tuberculosis, which explains the poor response of M. tuberculosisto macrolide antibiotics.) The most interesting and frustrating aspect of this inducible gene is that, if an M. fortuitum or M. abscessus isolate is exposed to macrolide, the erm gene activity is induced with subsequent in-vivo macrolide resistance, which was likely not reflected by the initial in-vitro MIC of the organism for the macrolide. In other words, the organism in vitro may appear to be susceptible to the macrolide, but it will not respond to the macrolide in vivo.

This in-vivo macrolide resistance that does not affect the initial in-vitro MIC for macrolide has been termed "cryptic resistance." It requires that an NTM isolate be incubated with macrolide prior to determining an MIC for the macrolide and appears to represent one possible mechanism for the discrepancy between in-vitro susceptibility results and in-vivo responses for M. abscessusand M. fortuitum. While there is no erm gene in MAC, could there be other, similar inducible genes the confer in-vivo resistance to other antibiotics for MAC? It is an intriguing possibility. For the time being, however, we are still left with the vexing paradox of a general lack of correlation between in-vitro MAC susceptibility for most drugs and in-vivo response to those drugs.

Mycobacterium avium complex lung disease is associated radiographically with upper lobe fibrocavitary abnormalities, which occur primarily in men with underlying obstructive lung disease, and nodules and bronchiectasis (nodular/bronchiectatic disease), which occur primarily in women without other underlying pulmonary disease. These women are associated with a specific morphotype, including low BMI, tall stature, scoliosis, pectus excavatum, and mitral valve prolapse.

The decision to treat patients who have MAC lung disease, especially the nodular/bronchiectatic form of MAC lung disease, should be based on the potential risks and benefits of therapy for individual patients. Treatment for MAC lung disease is long and costly, and it is often associated with drug-related toxicities. Longitudinal follow-up of patients with MAC and close familiarity with their clinical course is absolutely essential for making this determination. As a rule, patients with cavitary MAC lung disease should be treated without a period of observation as they usually experience progressive clinical decline without treatment.

Clinical improvement and sputum conversion to 12 months of sputum culture negativity while on therapy are the main treatment success criteria, although these goals are not achieved for all patients. MAC treatment regimens should consist of a rifamycin (rifampicin or rifabutin), ethambutol, and a macrolide (azithromycin or clarithromycin). Therapy can be given daily or intermittently, depending on the disease type and severity. Cavitary disease and true disease relapses should be treated with daily drug dosing, as intermittent therapy yields relatively poor results in these group. For moderate to severe disease or for patients who do not respond to standard oral therapy, streptomycin or amikacin can be added to the regimen. The optimal duration for parenteral therapy is unknown.

This strategy has been shown to increase culture conversion rates but not to improve long-term outcome. There is no evidence of a beneficial role for fluoroquinolones. Clofazimine combined with ethambutol and a macrolide may provide an effective alternative for patients who do not tolerate rifamycins, although clofazimine is difficult to obtain for this indication.

A critical element in the management of patients with MAC lung disease is prevention of the emergence of macrolide resistance. In contrast to “innate resistance,” the emergence of macrolide-resistant MAC is due to a familiar and well-recognized mechanism, that is, the acquired mutational resistance similar to that which occurs during tuberculosis therapy. The most important risk factors for developing macrolide-resistant MAC are macrolide monotherapy and the combination of macrolide and fluoroquinolone without a third companion drug. While the role of in vitro susceptibility for other agents remains controversial, it is clear that the development of macrolide resistance in a MAC isolate (MIC > 16 µg/mL) is strongly associated with treatment failure and increased mortality.

The treatment of M. abscessus lung disease remains difficult. Jeon et al. recently reported the results of therapy for a series of 69 patients with M. abscessus lung disease. While hospitalized, these patients were treated with a regimen consisting of an initial 1-month of parenteral therapy with amikacin and cefoxitin in combination with oral medications that included clarithromycin, ciprofloxacin, and doxycycline for a median of 24 months. Forty-seven of the 69 patients (68%) converted sputum to negative with a median time to sputum conversion of 1 month. Nine of these 47 patients (19%) relapsed after a median of 12months. Sputum conversion with macrolide resistant strains occurred in 27 percent of patients vs. 71 percent with macrolide-susceptible strains. Relapse occurred in 100 percent of patients with macrolide-resistant strains.

These sputum conversion rates are surprising given the in-vitro susceptibility pattern of M. abscessus previously reported, with 0 percent isolates susceptible in vitro to fluoroquinolones, less than 5 percent isolates susceptible in vitro to doxycycline, and the relatively short period of parenteral therapy. The likely explanation for the surprisingly good outcomes by Jeon et al. is that the majority of their patients appear to have been infected by M. abscessus subspecies massiliense, which does not have an active erm gene and is therefore susceptible to macrolide both in vitro and in vivo.

Using a more traditional approach, Jarand et al. reported a retrospective analysis of treatment outcomes for 107 patients with M. abscessus pulmonary disease. Antibiotic treatment was individualized based on drug susceptibility results and patient tolerance. Sixteen antibiotics were used in 42 combinations for an average of 4.6 drugs per patient over the course of therapy, with a median of 6 IV antibiotic months. In the majority of patients, at least one drug was stopped, usually amikacin or cefoxitin, because of side effects or toxicity. Twenty-four patients had surgery in addition to medical therapy. Forty-nine patients converted sputum cultures to negative, but 16 relapsed. There were significantly more surgical patients than medical patients who culture-converted, and 17 (15.9%) deaths occurred in the study population.

For unclear reasons, M. abscessus subspecies massiliense is a rare cause of lung disease in the United States but relatively common in Korea, which likely explains the significant differences in treatment outcomes between the two studies cited above. Overall, the optimal therapy for M. abscessus lung disease remains elusive.

The treatment of RGM pulmonary disease is highly dependent on the species isolated, the source of the RGM species isolated, and the presence of inducible resistance genes for macrolides. Park et al. reported that only 26 of 182 patients with M. fortuitum respiratory isolates had more than one positive respiratory culture. After a mean follow-up period of 12 months, no patients were noted to have progressive pulmonary disease attributed to M. fortuitum, and no patients had persistently positive cultures for M. fortuitum.

It is clear that M. fortuitum is a low-grade pathogen that infrequently causes progressive pulmonary disease and usually does not require specific antibiotic therapy. Clinicians should be careful when evaluating the clinical significance of M. fortuitum respiratory isolates, be confident about the diagnosis, base therapy on in-vitro susceptibility, use at least two agents with in-vitro activity against the clinical M. fortuitum isolate, treat for at least 12 months of negative sputum cultures while on therapy (as is recommended for other non-tuberculous respiratory isolates), and avoid macrolides if an inducible erm gene can be demonstrated for a specific M. fortuitum isolate.

M. kansasiiremains the most easily treatable of the NTM pulmonary pathogens. As opposed to most other NTM, there is a good correlation between in-vitro susceptibilities and in-vivo response for a variety of antimicrobial agents, including rifamycins, ethambutol, fluoroquinolones, and macrolides.

The British Thoracic Society (BTS) performed a prospective study of 106 patients with M. malmoense lung disease over a 5-year period. The result of 2 years of treatment with rifampin plus ethambutol was equivalent that of rifampin, ethambutol, and isoniazid; although only 53 percent of patients were alive at 5 years, 44 of the original 106 patients (42%) were cured of the infection. In a follow-up study, the BTS randomly assigned 167 patients with M. malmoense lung disease to clarithromycin, rifampin, and ethambutol; or ciprofloxacin, rifampin, and ethambutol. Overall response rates were low, but the group receiving clarithromycin had slightly better clinical response and lower mortality.

In an uncontrolled retrospective study of 136 patients with M. xenopi pulmonary infection, the absence of treatment was associated with a poor prognosis; median survival was 10 months in untreated patients compared with 32 months in treated patients. Combination therapy with a rifamycin-containing regimen was associated with improved survival rates. These outcomes were not adjusted for comorbidities, so the difference in survival rate cannot be definitively attributed to treatment. In a similar study from the Netherlands, several treatment regimens were used in 49 patients with M. xenopi lung disease, but no specific drug combination showed consistently superior results.

Although pulmonary M. szulgai disease is rare, M. szulgai isolates are usually clinically significant. Disease occurs most often in patients with underlying lung disease. In a study of 12 patients treated for M. szulgai infection, patients responded well to multiple treatment regimens, usually including rifampin, ethambutol, and either clarithromycin or ciprofloxacin. Patients with M. szulgai lung disease appear more likely to respond to therapy than do patients with M. malmoense, M. xenopi, or M. simiae infection.

When it is isolated in clinical samples, M. simiae is more often a contaminant than a true pathogen, but it is extremely difficult to treat when it is a true pathogen, and there are no predictably effective drug combinations for treating it.

What is the prognosis for patients managed in the recommended ways?

Two recently published studies (one from the United States and one from Korea) have shown that the majority of patients with nodular/bronchiectatic MAC lung disease experience sputum conversion with standard three-drug macrolide-based therapy. Unfortunately, these patients also experience frequent microbiologic recurrences, usually due to new (reinfection) MAC isolates. These findings strongly suggest that individual episodes of MAC infection can be treated successfully but that patients with bronchiectasis and NTM lung disease are likely vulnerable to multiple episodes of NTM lung infection. The impact of nodular/bronchiectatic MAC lung disease on longevity is not clear; however, it is quite clear that there is increased mortality for patients with cavitary NTM lung disease caused by any NTM pathogen.

What other considerations exist for patients with non-tuberculous mycobacterial infections of the lung?

Non-tuberculous mycobacterial lung diseases are encountered with increasing frequency by clinicians in the United States and other parts of the world. In the United States the prevalence of NTM lung disease exceeds that of tuberculosis; NTM lung disease an important public-health threat. The recognition and diagnosis of NTM lung diseases may be improved, perhaps as a result of increased familiarity, but reliable and effective treatment of NTM, especially MAC, remains problematic. It is still frustrating and scientifically unsatisfying that NTM generally do not respond to antimicrobials based on in-vitro susceptibility testing. Recent insights into molecular mechanisms of in-vivo drug resistance in RGM may provide clues to this poorly understood and vexing process.

Patients with NTM lung disease invariably have respiratory comorbidities, specifically bronchiectasis and/or chronic obstructive lung disease. Optimal management of these disorders will greatly impact patient symptoms and quality of life. It is sometimes difficult to know with certainty if a patient’s symptoms are due to underlying lung disease such as bronchiectasis or chronic obstructive pulmonary disease or due to progressive NTM disease, which places additional pressure on the clinician to keep the underlying lung diseases as well compensated as possible so that changes in the NTM lung infection can be readily recognized and appropriately attributed.

What’s the evidence?

Griffith, DE, Aksamit, T, Brown-Elliott, BA. "An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases". Am J Respir Crit Care Med. vol. 175. 2007. pp. 367-416.

(The most recent comprehensive review of nontuberculous mycobacteria (NTM) available and the best single source document for NTM treatment recommendations.)

Feazel, LM, Baumgartner, LK, Peterson, KL. "Opportunistic pathogens enriched in showerhead biofilms". Proc Natl Acad Sci U S A. vol. 106. 2009. pp. 16393-99.

(A provocative study that supports the contention that municipal and household water systems are important sources for NTM that cause human disease.)

Nishiuchi, Y, Maekura, R, Kitada, S, Tamaru, A, Taguri, T, Kira, Y. "The recovery of Mycobacteriumavium-intracellulare complex (MAC) from the residential bathrooms of patients with pulmonary MAC". Clin Infect Dis. vol. 45. 2007. pp. 347-51.

(Another provocative study implicating municipal and household water systems as sources of NTM respiratory pathogens.)

Falkinham, JO. "Nontuberculous mycobacteria from household plumbing of patients with nontuberculous mycobacteria disease". Emerg Infect Dis. vol. 17. 2011. pp. 419-24.

(Another provocative study implicating municipal and household water systems as a source of NTM respiratory pathogens.)

Kim, RD, Greenberg, DE, Ehrmantraut, ME. "Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome". Am J Respir Crit Care Med. vol. 178. 2008. pp. 1066-74.

(This interesting study in a select referral population suggests a characteristic phenotype for patients with NTM disease associated with nodules and bronchiectasis, as well as a higher than expected incidence of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations.)

Kartalija, M, Ovrutsky, AR, Bryan, CL. "Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes". Am J Respir Crit Care Med. vol. 187. 2013. pp. 197-205.

(This study reproduces the findings of a distinct morphologic phenotype for NTM patients with nodular/bronchiectatic disease.)

Bienvenu, T, Sermet-Gaudelus, I, Burgel, PR, Hubert, D, Crestani, B, Bassinet, L. "Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis". Am J Respir Crit Care Med. vol. 181. 2010. pp. 1078-84.

(This study presents a possible mechanism whereby patients with single (heterozygous) CFTR mutations may develop bronchiectasis without frank cystic fibrosis.)

Winthrop, KL, Chang, E, Yamashita, S. "Nontuberculous mycobacteria infections and antitumor necrosis factor-alpha therapy". Emerg Infect Dis. vol. 15. 2009. pp. 1556-61.

(This paper summarizes the reported association between TNF-alpha inhibitor therapy and NTM disease.)

Winthrop, KL, McNelley, E, Kendall, B, Marshall-Olson, A, Morris, C, Cassidy, M. "Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease". Am J Respir Crit Care Med. vol. 182. 2010. pp. 977-82.

(The best study so far corroborating the widely held view that NTM lung disease is more common than tuberculosis and increasing in frequency, especially among older women.)

Jun, HJ, Jeon, K, Um, SW. "Nontuberculous mycobacteria isolated during the treatment of pulmonary tuberculosis". Respir Med. vol. 103. 2009. pp. 1936-40.

(An analysis of the significance of NTM respiratory isolates obtained during the course of tuberculosis therapy.)

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. vol. 53. 2009. pp. 1367-76.

(Groundbreaking work that provides some insight into the mechanisms for the discrepancy between in vitro antibiotic susceptibility and the in vivo response to that antibiotic.)

Griffith, DE, Brown-Elliott, BA, Langsjoen, B, Zhang, Y, Pan, X, Girard, W. "Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease". Am J Respir Crit Care Med. vol. 174. 2006. pp. 928-34.

(A study demonstrating the potentially dire consequences for patients who develop Mycobacterium avium complex isolates that are macrolide-resistant.)

"Clinical and Laboratory Standards Institute". Interpretive criteria for identification of bacteria and fungi by DNA target sequencing: Approved guideline. 2011.

(These consensus guidelines recommend that MAC isolates should be tested for in vitro susceptibility only to macrolides. Guidelines will likely be modified to include amikacin as well.)

Wallace, RJ, Brown-Elliott, BA, McNulty, S. "Macrolide/azalide therapy for nodular/bronchiectatic: Mycobacterium avium complex lung disease". Chest. vol. 146. 2014. pp. 276-82.

(This study evaluated 180 patients with nodular bronchiectatic MAC lung disease who were treated with macrolide-based regimens. Eight-four percent of patients obtained sputum AFB culture conversion with a regimen including macrolide, ethambutol, and rifamycin. Most patients did not tolerate daily therapy but were able to tolerate three times weekly medication administration. Microbiological recurrence was common and most frequently due to new MAC genotypes. No patient developed macrolide resistance on the three-drug macrolide-based regimen.)

Jeong, BH, Jeon, K, Park, HY. "Intermittent antibiotic therapy for nodular bronchiectatic Mycobacterium avium complex lung disease". Am J Respir Crit Care Med. vol. 191. 2015. pp. 96-103.

(A second study showing the effectiveness of three times weekly therapy with macrolide, ethambutol and rifamycin for nodular/bronchiectatic MAC lung disease).

Brown-Elliott, BA, Iakhiaeva, E, Griffith, DE. "In vitro activity of amikacin against isolates of Mycobacterium avium complex with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in treated isolates". J Clin Microbiol. vol. 51. 2013. pp. 3389-94.

(The first study to show a correlation between MAC in vitro susceptibility to a drug and in vivo response to that drug.)

Kobashi, Y, Yoshida, K, Miyashita, N. "Relationship between clinical efficacy of treatment of pulmonary Mycobacterium avium complex disease and drug-sensitivity testing of Mycobacterium avium complex isolates". J Infect Chemother. vol. 12. 2006. pp. 195-202.

(One of many studies that has failed to show a correlation between MAC in vitro susceptibility to rifampin, ethambutol and streptomycin.)

van Ingen, J, Boeree, MJ, van Soolingen, D. "Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria". Drug Resist Updat. vol. 15. 2012. pp. 149-61.

(An excellent overall review of NTM innate resistance mechanisms. Of particular note, the M. abscessus subsp abscessus genome includes multiple features other than just the erm gene such as an additional erm-like gene, multiple efflux pumps, an aminoglycoside 2′-N-acetyltransferase, and 12 homologs of aminoglycoside phosphotransferases.)

van Ingen, J, Egelund, EF, Levin, A. "The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment". Am J Respir Crit Care Med. vol. 186. 2012. pp. 559-65.

(Drug-drug interactions that are an inevitable part of standard MAC therapy result in unfavorable pharmacokinetic and pharmacodynamics for the individual agents in the regimen. There is not a demonstrated correlation between these unfavorable indices and treatment outcome.)

Adjemian, J, Prevots, DR, Gallagher, J. "Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease". Ann Am Thorac Soc. vol. 11. 2014. pp. 9-16.

(In this survey of U.S. physicians, it was found that published treatment guidelines for MAC are rarely followed.)

Field, SK, Cowie, RL. "Treatment of Mycobacterium avium-intracellulare complex lung disease with a macrolide, ethambutol, and clofazimine". Chest. vol. 124. 2003. pp. 1482-6.

(Limited data suggests that for patients who do not tolerate rifamycins, clofazimine may provide an effective alternative, combined with ethambutol and a macrolide.)

Yu, JA, Pomerantz, M, Bishop, A. "Lady Windermere revisited: treatment with thoracoscopic lobectomy/segmentectomy for right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial disease". Eur J Cardiothorac Surg. vol. 40. 2011. pp. 671-5.

(This is a review of 134 patients with bronchiectasis of the right middle lobe and lingula who underwent 172 operations. Morbidity was noted in 12 patients (7%) during the postoperative period with no operative mortality. Culture negativity was achieved in 84 percent postoperatively (92/110) while 16 percent had not converted their sputum postoperatively.)

Andrejak, C, Lescure, FX, Pukenyte, E. "Mycobacterium xenopi pulmonary infections: a multicentric retrospective study of 136 cases in north-east France". Thorax. vol. 64. 2009. pp. 291-6.

(In this retrospective study of 136 patients with M. xenopi pulmonary infection, the absence of treatment was associated with a poor prognosis; median survival was 10 months in untreated patients compared with 32 months in treated patients. Combination therapy with a rifamycin-containing regimen was associated with improved survival.)

van Ingen, J, Boeree, MJ, de Lange, WC. "Mycobacterium xenopi clinical relevance and determinants, the Netherlands". Emerg Infect Dis. vol. 14. 2008. pp. 385-9.

(In this study from the Netherlands, multiple different treatment regimens were used in 49 patients with M. xenopi lung disease, but no specific drug combination showed consistently superior results.)

van Ingen, J, Boeree, MJ, Dekhuijzen, PN, van Soolingen, D. "Clinical relevance of Mycobacterium simiae in pulmonary samples". Eur Respir J. vol. 31. 2008. pp. 106-9.

(M. simiae, when isolated in clinical samples, is more often a contaminant than a true pathogen. When it is a true pathogen, however, it is extremely difficult to treat effectively. To date, there are no predictably effective drug combinations for treating M. simiae.)

Jarand, J, Levin, A, Zhang, L. "Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease". Clin Infect Dis. vol. 52. 2011. pp. 565-71.

(This is a retrospective analysis of treatment outcomes for 107 patients with M. abscessus pulmonary disease. Sixteen different antibiotics were used in 42 different combinations for an average of 4.6 drugs per patient over the course of therapy with a median of 6 intravenous antibiotic months. Forty-nine patients converted sputum cultures to negative, but 16 relapsed. There were significantly more surgical patients who culture-converted compared with medical patients.)

Jeon, K, Kwon, OJ, Lee, NY. "Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients". Am J Respir Crit Care Med. vol. 180. 2009. pp. 896-902.

(This is a study of antibiotic treatment for 65 patients with M. abscessus lung disease. Patients were initially hospitalized and treated with 4 weeks of parenteral amikacin and cefoxitin in combination with clarithromycin, ciprofloxacin, and doxycycline. Sputum conversion and maintenance of negative sputum cultures for more than 12 months were achieved in 58 percent patients. Surgical resection was performed in 22 percent of patients. Seven (88%) of eight patients with preoperative culture-positive sputum achieved and maintained culture negativity postoperatively.)

Szymanski, EP, Leung, JM, Fowler, CJ. "Pulmonary nontuberculous mycobacterial infection: a multisystem multigenic disease". Am J Respir Crit Care Med. vol. 192. 2015. pp. 618-28.

(An elegant study demonstrating the multigenic influences on the development of bronchiectasis as well as supporting the role of bronchiectasis as primary for patients with bronchiectasis and NTM disease.)
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