Slowly Growing Nontuberculous Mycobacteria (NTM)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has disease due to slowly growing nontuberculous mycobacteria? What should you expect to find?

Nontuberculous mycobacteria (NTM) can infect almost any organ in the body, thus, signs and symptoms will vary depending on the site of infection. In general, NTM cause four different clinical syndromes:

progressive pulmonary disease

skin and soft-tissue infection

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lymphadenitis

disseminated disease
Among the slowly growing mycobacteria (SGM), the most clinically relevant species are members of M. avium complex (MAC), M. haemophilum, M. kansasii, M. malmoense, M. marinum, M. simiae, and M. xenopi. M. avium complex includes the common pathogens M. avium, M. chimaera, and M. intracellulare. M. kansasii is the most pathogenic of the slow growers and second only to MAC as a cause of lung disease in some regions.

Symptoms

Pulmonary disease

The symptoms of pulmonary disease due to SGM are variable and nonspecific in nature. It is often difficult to determine if the symptoms are due to mycobacterial infection or the underlying lung disease, such as bronchiectasis, cystic fibrosis, or chronic obstructive pulmonary disease.

Chronic or recurring cough (70-90%), which may be productive, is one of the most common symptoms.

Other symptoms include:

Fatigue (>80%), malaise, low-grade fevers, night sweats, weight loss (<40%), chest pain, dyspnea (70%), and, occasionally, hemoptysis (<40%)
Skin, soft-tissue and bone disease

Patients report drainage or abscess formation at the site of puncture wounds or open traumatic injuries.
Lymph node disease

Patients present with enlarged, unilateral, non-tender lymph nodes, most commonly in the cervical chain.
Disseminated disease

In patients with advanced HIV infection, the clinical manifestations are protean and may be confused with other diseases. SGM can produce disseminated disease in HIV-infected patients with advanced immunosuppression.

Classic symptoms: fever (>80%), night sweats (>35%), and weight loss (>25%)

Additional symptoms: abdominal pain and diarrhea

In non-HIV infected immunocompromised patients, disseminated SGM disease may present as multiple cutaneous nodules or abscesses.

Physical findings

Pulmonary Disease

Physical findings are nonspecific and often reflect the underlying pulmonary disease.

Nodular-bronchiectatic NTM disease tends to occur in post-menopausal women, many of whom have a characteristic morphotype with a thin body habitus, kyphoscoliosis, pectus excavatum, and mitral valve prolapse.

Fibro-cavitary disease typically occurs in patients with underlying chronic obstructive pulmonary disease, thus, auscultatory findings include distant breath sounds, wheezes, and rhonchi.
Skin, soft-tissue and bone disease

Localized drainage or abscess formation occurs at the site of puncture wounds or open traumatic injuries.

Lesions may be mildly erythematous in appearance, mildly tender, and with serosanguinous drainage.
Lymph node disease

Enlarged, unilateral, non-tender lymph nodes, most commonly in the cervical chain occur.
Disseminated disease

Physical findings may include cutaneous nodules, abdominal tenderness, hepatosplenomegaly, and lymphadenopathy.

How did the patient develop disease due to slowly growing nontuberculous mycobacteria? What was the primary source from which the infection spread?

Pulmonary disease due to SGM develops after inhaling contaminated aerosols or after aspiration of contaminated foods/liquids or gastric contents. Sources that have been associated with infection include natural and treated waters, as well as soil. In most instances, the actual source of infection is not documented.

Pulmonary disease due to SGM has been associated with esophageal disorders, such as gastroesophageal reflux and achalasia; however, this does not occur as commonly as with rapidly growing mycobacteria (RGM).

Exposure to water contaminated with SGM has been associated with hypersensitivity pneumonitis and pulmonary infection.
Skin and soft-tissue infection usually follows a puncture wound or surgery.
Lymph node disease typically occurs in children 5 years of age or younger and is likely related to ingestion of the mycobacteria with direct extension to the lymph nodes.
Disseminated disease can result from entry of SGM into the blood stream via other primary sites of infection.

Recently, outbreaks of M. chimaera infection after open-heart surgery have been reported. The source of infection has been traced back to contaminated heater-cooler devices used routinely in the operating room. Aerosols from the device have been found to contain M. chimaera. Prosthetic valve endocarditis and sternal wound infections occur, often presenting with symptoms months after surgery, and dissemination to multiple organs is common. Treatment is difficult because of infection of prosthetic material, and the mortality rate is >50%.

Which individuals are at greater risk of developing disease due to slowly growing nontuberculous mycobacteria?

Specific conditions that predispose patients to infection with SGM

There are a number of medical conditions associated with infection due to SGM. These can be divided into those associated with chronic lung conditions, immunological defects, and exposure to high burdens of organisms.
Chronic lung conditions include:

Idiopathic bronchiectasis

Cystic fibrosis

Primary ciliary dyskinesia

Allergic bronchopulmonary aspergillosis

Chronic obstructive pulmonary disease

Alpha-one antitrypsin deficiency

Pneumoconiosis

Interstitial lung disease (from any cause)

Chronic aspiration syndromes

Pulmonary alveolar proteinosis
Immunological defects include:

Human immunodeficiency virus/AIDS

Immunosuppressive drugs

Common variable immunodeficiency syndrome (CVID)

Genetic defects in interferon-γ receptors or interleukin 12
Exposure to high burdens of mycobacteria include:

Indoor hot tubs

Nosocomial exposures

Beware: there are other diseases that can mimic disease due to slowly growing nontuberculous mycobacteria:

Diseases that can mimic disease due to SGM

Pulmonary disease

Fibrocavitary disease due to NTM disease presents similarly to pulmonary tuberculosis.

Other conditions that produce fibrocavitary disease include:

Sarcoidosis

Histiocytosis X

Ankylosing spondylitis

Chronic hypersensitivity pneumonitis

Nodular bronchiectactic disease is often misdiagnosed as asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
Skin, soft tissue and bone disease can be caused by tuberculosis or other bacterial infections, such as methicillin resistant Staphylococcus aureus.
Lymph node enlargement can be due to tuberculosis, lymphoma, head and neck carcinoma, or metastatic carcinomas.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

There are no blood tests that are specific for the diagnosis of SGM infection.

Complete blood count: Patients may have anemia of chronic disease and/or lymphopenia. Eosinophilia is usually related to underlying causes of bronchiectasis (e.g., allergic bronchopulmonary aspergillosis). Immunosuppressed patients with disseminated infection may present with severe anemia.
C-reactive protein and ESR: These tests are often elevated in patients with SGM disease and may normalize with therapy.
Comprehensive metabolic panel: Some patients with severe disease have low serum protein and albumin levels. Hyponatremia can also occur in this setting because of SIADH. The alkaline phosphatase is often elevated in disseminated disease.
Serology: Because rheumatologic conditions can produce the underlying lung disease associated with SGM infection, a serologic screen should be performed, including antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-SSA/anti-SSB. For cavitary disease, ANCAs should be evaluated.
Alpha-one antitrypsin levels: Some patients with alpha-one deficiency present with primarily bronchiectasis as opposed to emphysema.
Cystic fibrosis screen: Patients should be considered for the possibility of cystic fibrosis (CF). A sweat chloride test and/or genetic screen should be considered.
Immunoglobulins: Common variable immunodeficiency (CVID) may be associated with recurrent sinopulmonary infections, including NTM pulmonary disease.
Lymphocyte enumeration: This test should be performed in anyone with disseminated mycobacterial infection.
HIV: This test should be performed in anyone with disseminated mycobacterial infection.

· Sputum specimens should be obtained on at least three separate occasions for acid-fast smear and mycobacterial culture, as well as bacterial and fungal cultures. If patients are unable to produce sputum, spontaneously specimens can be obtained via induction with hypertonic saline (3-10%). Bronchoscopy with bronchoalveolar lavage may be necessary if adequate sputum specimens are not obtainable. A positive acid fast bacillus (AFB) smear may be due to NTM disease; however, tuberculosis should be considered as the first possible diagnosis.

Results that confirm the diagnosis

· Pulmonary disease

The diagnosis of SGM pulmonary disease requires culture of respiratory specimens, such as sputum or bronchoalveolar lavage (BAL) specimens. However, simply isolating SGM from a respiratory specimen does not necessarily indicate the organism is causing disease.
The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) have published criteria to distinguish disease from “colonization” (Table I). Two positive sputum cultures are required to meet the criteria or if sputum is not available: one positive bronchoscopy specimen culture or a biopsy with an accompanying positive culture.
Current diagnostic criteria do not take into account the specific pathogen. For example, common water contaminants, such as M. gordonae, M. terrae, and M. lentiflavum, seldom produce lung disease in an immunocompetent host. However, M. kansasii and M. szulgai are almost always causing disease when isolated. In a series of studies from the Netherlands, the proportion of isolates felt to be causing disease varied (Table II).
Patients suspected of having NTM infection but who do not meet the criteria in Table I should be followed closely as disease will often progress.

Table I.

Clinical	Pulmonary symptoms such as cough weight loss, fever and
Radiographic	Nodular or cavitary opacities on chest radiograph or
	High resolution computed tomography that shows multifocal bronchiectasis with centrilobular nodules and
Microbiologic	Positive culture results from at least two sputum specimens or
	Positive culture from a bronchoalveolar lavage or washing or
	Transbronchial or other lung biopsy with compatible histopathological features and positive culture or biopsy showing mycobacterial histopathological features and one or more sputum or bronchial washings that are culture positive

Table II.

Slowly Growing Mycobacteria	Proportion that met ATS criteria
M. malmoense	32/40 (80%)
M. szulgai	11/15 (73%)
M. kansasii	12/17 (70%)
M. xenopi	21/44 (48%)
M. avium	24/59 (41%)
M. simiae	6/28 (21%)
M. intracellulare	2/16 (13%)
M. gordonae	1/48 (2%)

· Skin, soft-tissue, and bone disease

Diagnosis is confirmed by culture and histopathological examination of biopsy tissue.

· Disseminated disease

Blood cultures are positive in 90% of AIDS patients with disseminated MAC.
In non-HIV patients, diagnosis of disseminated disease can be made via blood culture, bone marrow culture, or biopsy of enlarged lymph nodes or skin nodules.
Definitive diagnosis of infection due to SGM requires isolation of the specific species causing the infection. SGM can be differentiated from rapidly growing mycobacteria (RGM) based on their rate of growth in culture. RGM typically grow within 7 days on subculture, whereas SGM take longer than 7 days to see visible colonies.
Both solid and liquid culture methods are recommended for isolation of NTM. The optimum temperature for growth for most SGM is between 28 and 37°C.
Fastidious species of SGM require supplementation of the media to enhance growth and may require a different incubation temperature.

M. haemophilum grows only on media supplemented with iron-containing compounds, such as ferric ammonium citrate, hemin, or hemoglobin. Optimum incubation temperature is 28-30°C.

M. marinum should be incubated at 28-30°C.

M. xenopi grows optimally at 45°C.

Species identification is critical, as treatment outcomes vary by species identification can be performed with high pressure liquid chromatography (HPLC), biochemically, and with molecular methods. The latter are the most accurate ways to speciate SGM.

Drug Susceptibility Testing: For SGM, no single susceptibility method is recommended for all species.

MAC: Broth-based methods with both microdilution or macrodilution methods are acceptable. Because there has been poor correlation between in vitro susceptibility results and clinical response to MAC treatment for agents other than macrolides, current recommendations are to test only clarithromycin.
M. kansasii: Only susceptibility to rifampin is recommended to be performed, unless resistance is documented, and then additional drugs should be tested (e.g., fluoroquinolones, aminoglycosides, ethambutol, sulfonamides, isoniazid, macrolides).
Other SGM: There are not specific recommendations for other SGM.

Table I. Criteria for the Diagnosis of Nontuberculous Mycobacterial Lung Infections

What imaging studies will be helpful in making or excluding the diagnosis of disease due to slowly growing nontuberculous mycobacteria?

Chest radiograph should be the first imaging study ordered when a patient is suspected of having SGM pulmonary disease. $
High resolution chest computed tomography (HRCT) is the most important imaging study, as it is the most sensitive test for identifying underlying bronchiectasis and centrilobular nodules that are suggestive of NTM disease. $$$

HRCT usually shows bronchiectasis and centrilobular nodules.

Cavitation may occur in either nodular bronchiectatic disease or fibrocavitary disease.
For skin and soft-tissue infections, a CT scan or preferably an MRI scan should be obtained. $$$

· ($ = 125-500, $$ = 500-1,000, $$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has disease due to slowly growing nontuberculous mycobacteria, what therapies should you initiate immediately?

· Infectious diseases: Consultation may be necessary if treatment is planned.

· Pulmonary: Consultation may be necessary if diagnostic procedures, such as bronchoscopy are required.

· Respiratory care services: Services are needed to address pulmonary hygiene and obtain sputum specimens, which are often induced after inhalation of hypertonic saline.

· Immunology: Consultation may be needed if an immune defect or allergic bronchopulmonary aspergillosis is suspected.

· Surgical consultation: Consultation may be necessary in selected patients with cutaneous, soft tissue, lymph node, or pulmonary disease.

Key principles of therapy

Treatment for pulmonary NTM infections, including disease caused by SGM, varies depending on the particular species identified and the goals of therapy.
Patients should be treated with a multidrug (≥3 drugs) regimen to prevent the emergence of resistance.
Optimum duration of therapy is not known, but the current recommendation is to treat for 12 months beyond the point of culture conversion to negative.
Use of in vitro susceptibility results should be used with caution given the poor correlation with clinical outcomes.

Clarithromycin should be tested for MAC isolates.

Rifampin should be tested for M. kansasii.
Surgical resection of the most involved lung segments or skin/soft tissue may be indicated in some patients, particularly those with focal disease who have failed medical therapy and/or acquired antimicrobial resistance.
Expert consultation should be obtained in most patients.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapies

Because there are many different SGM species, empiric therapy is not recommended.
In patients with severe or disseminated disease for whom a SGM is suspected, a regimen including an oral macrolide, rifamycin, and ethambutol plus intravenous amikacin should be initiated and modified when precise speciation is known.
Ultimately, precise identification is necessary to determine the most appropriate treatment regimen.

Recommended Treatment Regimens by Species

M. avium complex should be treated with an oral macrolide (azithromycin or clarithromycin), rifamycin (rifampin or rifabutin), and ethambutol. These recommendations are based on randomized clinical trials and several observational studies.

Cavitary disease: Daily therapy should be given, and use of intravenous aminoglycoside (streptomycin or amikacin) is strongly recommended.

Nodular bronchiectasis disease without cavitation: Intermittent or daily therapy is possible. An aminoglycoside is not recommended, unless there is extensive disease, macrolide resistance, or treatment failure.
M. haemophilum should be treated with a regimen that includes at least three agents with likely in vitro activity, such as macrolides, rifamycins, fluoroquinolones, and amikacin. All isolates are resistant to ethambutol.
M. kansasii should be treated with a regimen that includes isoniazid, rifampin, and ethambutol given daily or three times per week. An aminoglycoside should be considered for advanced cavitary disease Substitution of a macrolide for isoniazid had been associated with good outcomes. These recommendations are based on a randomized trial and observational studies.
M. malmoense should be treated with a MAC regimen. A fluroquinolone can be substituted. These recommendations are based on two randomized clinical trials and observational studies.
M. marinum should be treated with two active agents for approximately 2 months after resolution of the lesions, typically 3-4 months in total. Agents typically active in vitro include rifamycins, macrolides, ethambutol, sulfonamides, and susceptible or intermediately susceptible to doxycycline and minocycline. Deep tissue infection, particularly hand infections, may require surgical debridement. These recommendations are based on observational studies.
M. simiae should be treated with a MAC regimen, and an aminoglycoside should be considered for cavitary disease. Recent reports have described in vitro synergy with clofazimine and amikacin.
M. xenopi should be treated with a MAC regimen with addition or substitution of a higher generation fluoroquinolone. An aminoglycoside should be considered for cavitary disease or the acute infiltrative form of disease. These recommendations are based on two randomized clinical trials, observational studies, and systematic review.

See Table III, Table IV, Recommended Treatment Regimens by Species.

Table III.

Organism	Antibiotic	Dose	Alternative
M. marinum	Azithromycin	250 mg daily	Clarithromycin 1000 mg dailyRifampin 600 mg dailyRifabutin 300 mg dailyMoxifloxacin 400 mg dailyTrimethoprim-sulfamethoxazole DS twice dailyDoxycycline 100 mg twice dailyMinocycline 100 mg daily
M. marinum	Ethambutol	15 mg/kg per day
M. simiae	Azithromycin	250 mg daily	Clarithromycin 1000 mg dailyRifabutin 300 mg dailyMoxifloxacin 400 mg dailyClofazimine 100 mg daily
	Rifampin	600 mg daily
	Ethambutol	15 mg/kg /day per day
M. xenopi	Azithromycin	250 mg daily	Clarithromycin 1000 mg dailyRifabutin 300 mg dailyMoxifloxacin 400 mg dailyClofazimine 100 mg daily
	Rifampin	600 mg daily
	Ethambutol	15 mg/kg/day per day 15 mg/kg/day per day

Table IV.

Organism	Antibiotic	Dose	Alternative
M. avium complex (non cavitary)	Azithromycin	500 mg three times per week	Clarithromycin 1000 mg three times per weekRifabutin 300 mg three times per weekMoxifloxacin 400 mg dailyClofazimine 100 mg daily
	Rifampin	600 mg three times per week
	Ethambutol	25 mg/kg per day three times per week
M. avium complex (cavitary)	Azithromycin	250 mg daily	Clarithromycin 1000 mg dailyRifabutin 300 mg dailyClofazimine 100 mg daily
	Amikacin	600 mg daily
	Rifampin	15 mg/kg/day per day
	Ethambutol	15 mg/kg/day IV three times per week
M. haemophilum	Azithromycin	250 mg daily	Rifabutin 300 mg dailyMoxifloxacin 400 mg dailyAmikacin 15mg/kg/day three times weekly
	Rifampin	600 mg daily
	Ciprofloxacin	500 mg twice daily
M. kansasii	Isoniazid	300 mg daily	Azithromycin 250 mg dailyClarithromycin 1000 mg dailyMoxifloxacin 400 mg once dailyClofazimine 100 mg dailyTrimethoprim/sulfamethaxazole DS twice daily
	Rifampin	600 mg daily
	Ethambutol	15 mg/kg per day
M. malmoense	Azithromycin	250 mg daily	Clarithromycin 1000 mg dailyRifabutin 300 mg dailyMoxifloxacin 400 mg dailyClofazimine 100 mg daily
	Azithromycin	600 mg daily
	Rifampin	15 mg/kg/day per day
	Ethambutol	15 mg/kg/day IV three times per week

Treatment of Disseminated MAC in HIV infected Patients

Patients should be treated with at least two active drugs to provide more rapid clearance of the mycobacteria from the blood and prevent acquisition of drug resistance.
Drugs with activity that have been studied include the macrolides (clarithromycin and azithromycin), rifabutin, ethambutol, and the aminoglycosides.
Clarithromycin versus azithromycin: Clarithromycin at 500 mg twice daily is preferred over azithromycin 600 mg daily based on data from a clinical trial showing a higher frequency of elimination of MAC from blood and more rapid clearance. However, azithromycin may be substituted if there are concerns for drug interactions or intolerance.
Note: There are drug-drug interactions with the use of clarithromycin and rifabutin in combination. The rifabutin serum drug concentration increases, and the clarithromycin level decreases. The increased rifabutin level has been associated with uveitis.

Current treatment recommendations

Begin with a three-drug regimen, including clarithromycin 500 mg twice daily, ethambutol 15 mg/kg/day, and rifabutin 300 mg daily if the patient is not on an antiretroviral regimen. If the patient is receiving a protease inhibitor, dosage adjustments must be made.
Begin a two-drug regimen, including clarithromycin 500 mg twice daily and ethambutol 15 mg/kg/day if the patient is receiving a protease inhibitor. Rifabutin may be added for patients with a high bacillary load and/or advanced immunosuppression.
Duration: Patients should be treated for a minimum of 12 months. Therapy should be life-long in patients without immune reconstitution.
Discontinuation of therapy: The United States Public Health Service and IDSA recommend that patients receive at least 12 months of anti-MAC therapy plus 6 months of immune reconstitution.

Adjunctive Therapy

· Antiretroviral therapy is critical for the treatment of HIV infection. Current recommendations are to initiate ART in treatment naïve patients 2 weeks after starting anti-MAC therapy to decrease the risk of complications related to the immune reconstitution syndrome and overlapping drug toxicities.

2. Next list other key therapeutic modalities.

Patients with underlying bronchiectasis should be trained in proper airway hygiene:

Airway hygiene should include, at minimum, the use of a flutter or positive expiratory pressure value.
Additional benefit may be obtained with use of a vibratory vest.

· Inhaled hypertonic saline (7%) has been shown to improve pulmonary function.

Controversial evolving therapies

The use of immune adjuvants, such as interferon-gamma, remains controversial. Currently, interferon-gamma should be administered only when patients have documented immunological defects that would be expected to respond to treatment. Expert immunological consultation is advised.

What complications could arise as a consequence of disease due to slowly growing nontuberculous mycobacteria?

What should you tell the family about the patient’s prognosis?

Hemoptysis: Patients with SGM pulmonary infections may develop hemoptysis.
Concurrent or recurrent infections with other bacteria, such as Pseudomonas aeruginosa, are common.
Aspergillosis: Similarly, colonization with Aspergillus species is common.

Add what-if scenarios here:

· What if the patient is asymptomatic?

o Some patients with radiographic evidence of SGM disease have no symptoms at the time of diagnosis. The decision to treat or not treat varies based on a number of factors, such as the specific species isolated, presence of co-morbidities, extent of disease, and overall goals of therapy.

· What if the patient suffers drug-related adverse reactions?

o Adverse reactions are common with the multidrug regimens used to treat RGM infections. If a drug must be stopped, it is important to identify a substitute drug.

· What if I have never heard of this species of SGM?

o There are many different species of SGM, and, fortunately, most rarely, if ever, cause human disease. In such cases, it is strongly recommended that expert consultation be obtained.

How do you contract disease due to slowly growing nontuberculous mycobacteria and how frequent is this disease?

NTM are widely distributed in the environment with high rates of isolation worldwide.

Organisms can be found in soil and water, including both natural and treated water sources.
Human disease is thought to occur through exposure to environmental sources, although the specific source is often not identified.

There have been several reports of isolation of the same species and genotype pattern in home water supplies (i.e., shower, hot tubs) as that isolated from the patient. A recent study evaluated the home water supplies of 37 patients with NTM pulmonary disease and reported isolation of the same species and genotype in 7 patients. Isolation of NTM was less common in residences in which the hot water temperature was greater than or equal to 125°F, and there was a trend for lower isolation frequency in well water compared to treated water.
In most studies, M. avium complex is the most common cause of NTM related lung disease. The second most common cause varies from study to study with M. kansasii being reported to be the second most common cause of NTM lung disease in the United States. However, recent studies have reported that M. abscessus is second to MAC, causing up to 20% of all NTM related lung disease in the United States.
Accurate data on the incidence and prevalence of SGM infections are lacking from most countries, because the disease is not reportable.
The incidence and prevalence of disease due to SGM have varied greatly from region to region.
In a retrospective study of laboratory cultures in Oregon between 2005 and 2006, 933 patients were identified who had greater than or equal to 1 NTM isolate. Approximately one-half of the patients met ATS criteria for disease, which gave an annualized prevalence of 7.2 cases per 100,000 persons. Pulmonary cases predominated with a rate of 5.6 cases per 100,000 persons followed by skin/soft-tissue cases (0.9 cases per 100,000). Pulmonary disease prevalence was significantly higher in women than men (6.4 vs. 4.7 cases per 100,000 persons) and was highest in those 50 years of age or older (15.5/100,000 persons). Disease appeared more commonly in urban areas.
In a follow-up study, all Oregon residents with greater than or equal to 1 NTM isolate were identified. From a population-based subset, clinical and radiographic information was obtained. Again, approximately one-half of the patients met ATS microbiologic criteria, giving an overall 2-year period prevalence of 8.6 per 100,000 persons and 20.4 per 100,000 persons for those 50 years of age within the Portland, Oregon area.
U.S. Medicare Beneficiaries: A nationally representative 5% sample of Medicare Part B beneficiaries was analyzed between 1997 and 2007. The annual prevalence significantly increased from 20 to 47 per 100,000 persons (8.2% per year). The period prevalence was 112 cases per 100,000 persons, although the prevalence was two-old higher among Asians/Pacific Islanders than among whites. Western states had the highest prevalence of 149 cases per 100,000 with Hawaii having the highest prevalence of 396 per 100,000 persons. Other high prevalence areas included the Southeastern United States.
Khan and colleagues demonstrated that an increase in skin test reactivity to M. intracelluare derived antigens between 1971-1972 (11.2%) and 1999-2000 (16.6%). Most of the increase was seen in foreign-born persons.

Change of Incidence and Prevalence Over Time

Ontario, Canada (2007): The isolation prevalence of all species (excluding M. gordonae) was 19 per 100,000 population and increased 8.5% per year from 1997.
Four Integrated Health Care Delivery Systems in the United States (2004-2006): 28,687 samples from 7,940 patients were included in the analysis. Fifty percent were defined as possible cases (≤1 isolate), and 47% were defined as definite cases (≥ 2 isolates). The average annual site-specific prevalence of NTM lung disease ranged from 1.4 to 6.6 per 100,000 persons. Prevalence was 1.1- to 1.6-fold higher among women than men. The prevalence of NTM lung disease was increasing significantly at the two sites where trends were studied: 2.6% per year among women and 2.9% among men. Among persons 60 years of age or older, annual prevalence increased from 19.6 per 100,000 during 1994-1996 to 26.7 per 100,000 during 2004-2006.
U.S. Medicare Beneficiaries: A nationally representative 5% sample of Medicare Part B beneficiaries was analyzed between 1997 and 2007. The annual prevalence significantly increased from 20 to 47 per 100,000 persons or 8.2% per year. The period prevalence was 112 cases per 100,000 persons, although the prevalence was two-fold higher among Asians/Pacific Islanders than among whites. Western states had the highest prevalence of 149 cases per 100,000 with Hawaii having the highest prevalence of 396 per 100,000 persons. Other high prevalence areas included the Southeastern United States.
Hospitalized Persons in the United States (1998-2005): Records were reviewed of hospitalized patients who had a NTM International Classification of Diseases Code of 031.0 in 11 states. Pulmonary NTM hospitalizations increased significantly with age among both genders. Annual prevalence increased significantly among men and women in Florida (3.2% and 6.5%) and among women in New York (4.6%/year).
NTM infections are reportable in Queensland, Australia. The incidence of cases rose from 2.2 per 100,000 population in 1999 to 3.2 per 100,000 in 2005. The pattern of disease changed from predominantly cavitary disease in middle-aged men who smoke to fibronodular disease in elderly women. Most of the increase could be attributable to M. intracellulare.
SGM pulmonary disease occurs when a susceptible individual inhales contaminated aerosols or aspirates contaminated food/water or gastric content
Human disease is thought to occur through exposure to environmental sources, although the specific source is often not identified.
Transmission from human-to-human has not been demonstrated conclusively.
Although SGM have been isolated from several different animal species, they are not known to be spread from animals to humans.

What pathogens are responsible for this disease?

By far the most common SGM to produce lung disease are those of the M. avium complex, followed by M. kansasii, M. malmoense, and M. xenopi. The other SGM are rare causes of lung disease.

M. arupense

M. asiaticum

M. avium

M. branderi

M. celatum

M. chimaera

M. florentinum

M. heckeshornense

M. intermedium

M. interjectum

M. intracellulare

M. kansasii

M. kubicae

M. lentiflavum

M. malmoense

M. palustre

M. saskatchewanse

M. scrofulacewm

M. shimodei

M. simiae

M. szulgai

M. triplex

M. xenopi

How do these pathogens cause disease due to slow growing nontuberculous mycobacteria?

SGM are environmental organisms so exposure is common. However, progression to disease is relatively uncommon given the ubiquitous nature of NTM.
The pathogenicity of SGM varies widely with some species, such as M. gordonae, rarely causing disease and others, such as M. kansasii, almost always causing disease when isolated from a clinical specimen.
Pulmonary disease commonly occurs in the setting of underlying lung disease, such as cystic fibrosis, non-cystic fibrosis bronchiectasis, chronic obstructive lung disease, prior tuberculosis, pneumoconiosis, alveolar proteinosis, and esophageal disorders. NTM or inhaled or aspirated from the environment can presumably cause disease due to a lack of normal airway clearance mechanisms.
Women with nodular bronchiectasis and NTM pulmonary infections often have a specific morphotype characterized by lean body habitus, scoliosis, pectus excavatum, and mitral valve prolapse. Why these women develop bronchiectasis and NTM infections is unknown. To date, no significant immunological defect has been described.
HIV infected patients develop disseminated NTM disease in the setting of advanced immunosuppression. For example, disseminated MAC typically occurs when the CD4 lymphocyte count is lower than 50 cells/ul.
Several immunological defects have been described in patients with disseminated disease. These include defects in interferon gamma receptors and IL-12.

What other clinical manifestations may help me to diagnose and manage disease due to slowly growing nontuberculous mycobacteria?

NTM infections can involve organ system, particularly in immunocompromised individuals. A patient’s medical history and medications should be reviewed to determine if he or she is immunocompromised.

A history of lymph node enlargement, particularly cervical enlargement, may be due to NTM infection.
Complaints of cutaneous lesions, either singly or multiply, may be due to NTM cutaneous disease or disseminated disease. The patient should be questioned regarding recent trauma or invasive medical procedures. In the case of M. marinum, the patient should be asked about exposure to fish tanks, fishing, etc.
Lymphadenopathy, particularly cervical lymphadenopathy, can be a manifestation of SGM disease.
Cutaneous lesions can be a result of focal infection due to a puncture in the skin or after an invasive procedure.
Multiple diffusely scattered cutaneous lesions may be a result of disseminated disease in an immunocompromised host.

What other additional laboratory findings may be ordered?

A serological assay that detects IgA antibody to glycopeptidolipid core antigen is currently available in Japan (Tauns). This assay was reported to have a sensitivity of 84.3% and specificity of 100% for detection of MAC pulmonary disease.

How can disease due to slowly growing nontuberculous mycobacteria be prevented?

SGM are environmental organisms found in soil and water. To minimize exposure to potentially contaminated soil and water, an individual would need to:

Avoid hot tubs, particularly indoor tubs

Avoid swimming pools, particularly indoor pools

Avoid exposure to large amounts of dust and dirt
Vaccination with BCG has been associated with lower rates of NTM infection. However, BCG is not currently recommended to prevent NTM infection.
To avoid nosocomial infections, tap water should be avoided during medical procedures.

Prevention of Disseminated MAC in HIV Infected Patient

Placebo controlled trials have demonstrated that the incidence of MAC and associated mortality can be reduced when using clarithromycin, azithromycin, or rifabutin as a prophylactic agent.

· Preferred Drug: Clarithromycin 500 mg twice daily and azithromycin 1200 mg once weekly are superior to rifabutin.

· Initiation of prophylaxis: Current recommendations are to begin prophylactic therapy with one of the above regimens when the CD4 count falls to less than 50 cells/mm3.

· Discontinuation of prophylaxis: Prophylactic therapy can be stopped 3 months after patients attain a CD4 count greater than100 cells/mm3. This recommendation is supported by two clinical trials.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Ahn, CH, Lowell, JR, Ahn, SS, Ahn, S, Hurst, GA. “Chemotherapy for pulmonary disease due to Mycobacterium kansasii: efficacies of some individual drugs”. Rev Infect Dis. vol. 3. 1981. pp. 1028-34. (An evaluation of 256 patients with pulmonary M. kansasii infection. All of the 115 patients who received treatment that included rifampin had sputum conversion within 4 months. However, for regimens that did not include rifampin, 127 (90%) of 141 had conversion (p<0.01). There were no relapses reported in those who received rifampin versus 4/59 (7%) who did not receive rifampin.)

Ahn, CH, Lowell, JR, Ahn, SS, Ahn, SI, Hurst, GA. “Short-course chemotherapy for pulmonary disease caused by Mycobacterium kansasii”. Am Rev Respir Dis. vol. 128. 1983. pp. 1048-50. (Forty patients with pulmonary M. kansasii were treated with rifampin, isoniazid, and ethambutol for 12 months (plus streptomycin twice weekly for the first 3 months): 1/40 (2.5%) relapsed 6 months after completion of therapy.)

“First randomised trial of treatments for pulmonary disease caused by , and in HIV negative patients: rifampicin, ethambutol, and isoniazid versus rifampicin and ethambutol”. Thorax. vol. 56. 2001. pp. 167-72. (Two hundred and twenty-three patients were randomized to treatment with rifampin and ethambutol (RE) versus rifampin, ethambutol, and isoniazid. There was no correlation between in vitro resistance and treatment failure or relapse. M. xenopi was associated with the highest mortality (57%), MAC was the most difficult to eradicate, and M. malmoense had the best outcomes (42% alive at 5 years).)

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. (This document represents the official recommendations of the ATS and IDSA.)

Griffith, DE, Brown, BA, Cegielski, P, Murphy, DT, Wallace, RJ. “Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to complex”. Clin Infect Dis. vol. 30. 2000. pp. 288-92. (A prospective non-comparative study using clarithromycin, rifabutin, and ethambutol administered three times weekly. Fifty-nine patients were enrolled, but 20% were lost to follow-up and 10% had intolerance to clarithromycin. Of the 41 patients who completed 6 months of therapy, 78% culture converted. Adverse reactions to rifabutin were common requiring a dose reduction or stopping 41% of the patients.)

Griffith, DE, Brown, BA, Murphy, DT, Girard, WM, Couch, L., Wallace, RJ. “Initial (6-month) results of three-times weekly azithromycin in treatment for complex lung disease in human immunodeficiency virus negative patients”. J Infect Dis. vol. 178. 1998. pp. 121-6. (Two consecutive open label prospective trials using intermittent azithromcyin (600 mg) were reported. Regimen A included three times weekly azithromycin, dialy ethambutol, daily rifabutin, and twice weekly streptomycin. Regimen B included the same drugs, but all given three times weekly, except for streptomycin, which was given twice weekly as with Regimen A. Culture conversion at 6 months 74% of those receiving Regimen A and 62% of those receiving Regimen B.)

Griffith, DE, Brown-Elliott, BA, Wallace, RJ. “Thrice-weekly clarithromycin-containing regimen for treatment of lung disease: results of a preliminary study”. Clin Infect Dis. vol. 37. 2003. pp. 1178-82. (Prospective evaluation in 18 patients with M. kansasii lung infection. All patients that continued treatment (4 lost to follow-up) were cured.)

Hoefsloot, W, van Ingen, J, de Lange, WC, Dekhuijzen, PN, Boeree, MJ, van Soolingen, D. “Clinical relevance of isolation in The Netherlands”. Eur Respir J. vol. 34. 2009. pp. 926-31. (Retrospective review of 51 patients with M. malmoense infection (78% pulmonary). A good outcome was reported in 70% with pulmonary disease and 73% with extrapulmonary disease using different treatment regimens.)

Jenkins, PA, Campbell, IA. “Pulmonary disease caused by in HIV negative patients: five year follow-up of patients receiving standardized treatment”. Respir Med. vol. 97. 2003. pp. 439-44. (Forty-two patients were randomized to receive rifampin and ethambutol versus rifampin, ethambutol, and isoniazid. Patients had relatively extensive disease with 81% having cavitation and usually large cavities. Mortality was high (69%) but usually due to other causes. The failure of treatment and relapse was 12%.)

Jenkins, PA, Campbell, IA, Banks, J. “Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunistic mycobacterial lung diseases and an assessment of immunotherapy”. Thorax. vol. 63. 2008. pp. 627-34. (Three hundred and seventy-one patients (170 MAC, 167 M. malmoense, 34 M. xenopi) were enrolled in a randomized study comparing rifampin and ethambutol with either ciprofloxacin or clarithromycin. All-cause mortality was high in both groups (44% clari and 43% cipro) with more side effects with cipro than clari. Patients with MAC and M. xenopi were more likely to have a poor outcome than those with M. malmoense but with no difference between treatment arms.)

Lam, PK, Griffith, DE, Aksamit, TR. “Factors related to response to intermitten treatment of complex lung disease”. Amer J Respir Crit Care Med. vol. 173. 2006. pp. 1283-9. (A prospective non-comparative trial of three times weekly therapy, including clarithromycin, ethambutol, and rifampin. Ninety-one HIV-negative patients with moderate to severe pulmonary MAC were enrolled. Three times weekly therapy was less effective in patient with cavitary disease than noncavitary disease: cavitary disease increased the time for culture response by 4.0 times.)

“Pulmonary disease caused by in HIV negative patients: 5-year follow-up of patients receiving standardized treatment”. Eur Respir J. vol. 21. 2003. pp. 478-82. (One hundred and six patients were randomized to rifampin and ethambutol (RE) vs. rifampin, ethambutol, and isoniazid (REH). Sixty percent of the patients were AFB smear positive, and 74% had cavitation present. There were three failures and eight relapses. Fifty-nine percent of the patients were alive at 5 years, of whom 42% were considered cured.)

Sax, H, Bloemberg, G, Hasse, B. “Prolonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery”. Clin Infect Dis. vol. 61. 2015. pp. 67-75.

DRG CODES and expected length of stay

031.0 Pulmonary Mycobacteria, all species

031.1 Cutaneous Mycobacteria, all species

031.8 Other species Mycobacteria

031.2 Disseminated Mycobacteria, all species

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