OVERVIEW: What every practitioner needs to know

Are you sure your patient has disease due to rapidly 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:

1) progressive pulmonary disease

Symptoms

Pulmonary disease

The symptoms of pulmonary disease due to RGM 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 (>90%), 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 may complain of localized drainage or abscess formation at the site of puncture wounds or open traumatic injuries.

Pain may be out of proportion to the apparent degree of inflammation.
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. RGM are uncommon causes of disseminated disease in HIV infected patients.

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

Additional symptoms include abdominal pain and diarrhea.

In non-HIV infected immunocompromised patients, disseminated RGM 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, ausculatory findings include distant breath sounds, wheezes, and rhonchi.
Skin, soft tissue and bone disease

Patients may complain of localized drainage and or abscess formation at the site of puncture wounds or open traumatic injuries.

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

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

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

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

Patients develop pulmonary disease due to RGM 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 RGM has been associated with esophageal disorders, such as gastroesophageal reflux and achalasia.

Exposure to water contaminated with RGM, such as in hot tubs, has been associated with hypersensitivity pneumonitis and pulmonary infection.
Soft-tissue infection usually follows a puncture wound or surgery.
Disseminated disease can result from entry of RGM into the blood stream via other primary sites of infection.

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

Specific conditions that predispose patients to infection with RGM

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

Chronic lung conditions

Idiopathic bronchiectasis

Cystic fibrosis

Primary ciliary dyskinesia

Allergic bronchopulmonary aspergillosis

Chronic obstructive pulmonary diseases

Alpha-one antitrypsin deficiency

Pneumoconiosis

Interstitial lung disease (from any cause)

Chronic aspiration syndrome

Pulmonary alveolar proteinosis
Immunological defects

Human immunodeficiency virus (HIV)/AIDS

Immunosuppressive drugs, including those given post-transplant

Biological anti-inflammatory agents

Common variable immunoglobulin deficiency syndrome

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

Indoor hot tubs

Nosocomial exposures

Beware: there are other diseases that can mimic disease due to rapidly growing nontluberculous mycobacteria:

Pulmonary disease

Fibrocavity disease due to RGM presents similarly to pulmonary tuberculosis

Other conditions that produce fibrocavitary disease include:

Sarcoidosis

Histiocytosis X

Ankylosing spondylitis

Chronic hypersensitive pneumonitis

Nodular bronchiectasis 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 MRSA.
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 RGM infection.

Complete blood count (CBC): Patients may have anemia of chronic disease/or lymphopenia. Eosinophilia is usually related to underlying causes of bronchiectasis (e.g., allergic bronchopulmonary aspergillosis). Disseminated infection in patients with immunosuppression may present with severe anemia.

C-reactive protein or erythrocyte sedimentation rate (ESR): These tests are often elevated in patients with RGM disease and may normalize with therapy.

Comprehensive metabolic panel: Some patients with several diseases have low serum protein and albumin levels. Hyponatremia can also occur in this setting because of syndrome of inappropriate antidiuretic hormone (SIADH). In disseminated disease, the alkaline phosphatase is often elevated.

Serology: Because rheumatologic conditions can produce the underlying lung disease associated with the RGM infection, a serologic screen should be performed, including antinuclear antibody (ANA), rheumatoid factor (RF), and anti SSA/anti-SSB. For cavitary disease, anti-neutrophil cytoplasmic antibody (ANCAs) should be elevated.

Alpha-one antitrypsin levels: Some patients with alpha-one deficiency present with primarily bronchiectasis, as opposed to emphysema.

Cystic fibrosis screening: 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 should be performed in anyone with disseminated mycobacterial infection.

HIV: This should be performed on 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 should 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 RGM pulmonary disease requires culture of respiratory specimens, such as sputum or bronchoalveolar lavage (BAL) specimens. However, simply isolating NTM 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.” 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 (Table I).

Patients suspected of having NTM infection but do not meet the criteria in Table I should be followed closely, as disease will often progress.

Approximately 25-50% of patients who grow an RGM meet ATS/IDSA criteria.

Skin, soft-tissue and bone disease

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

For RGM causing skin or soft-tissue infection, the incubation temperature of the culture should be lowered.
Disseminated disease

Blood cultures are positive in 90% of AIDS patients with disseminated Mycobacterium avium complex (MAC), a slowly growing NTM. However, the proportion of blood cultures that are positive with RGM is not known.

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 RGM requires isolation of the specific species causing the infection. RGM can be differentiated from slowly growing mycobacteria based on their rate of growth in culture. RGM typically grow within 7 days of subculture.

Species identification is critical, as the need for therapy and treatment outcomes vary by species. 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 RGM as other methods cannot reliably differentiate M. chelonae from M. abscessus and its subspecies.

Drug susceptibility testing can be performed by broth microdilution minimal inhibitory concentration (MIC) determination.

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 bronchiectasiswith centrilobular nodules
	and
Microbiologic	Positive culture results from at least two sputum specimens or
	Positive culture results from a bronchoalveolar lavage/wash or
	Transbronchial or other lung biopsy with compatible histopathologic featuresand positive culture or biopsy showing mycobacterial histopathologic featuresand one or more sputum or bronchial washings that are culture positive

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

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

HRCT usually shows bronchiectasis and centrilobular nodules.

Cavitation has been reported in 14-44% of cases with M. abscessus.
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 rapidly growing nontuberculous mycobacteria, what therapies should you initiate immediately?

Infectious disease: Consultation may be necessary if treatment is planned.
Pulmonary: Consultation may be necessary if diagnostic procedures, such as bronchoscopy, are required.
Respiratory care services: Such 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 RGM, varies depending on the particular species identified and the goals of therapy. RGM are typically resistant to many antimicrobials, so treatment outcomes are often poor.
Patients should be treated with a multidrug (≥2 drugs) regimen to prevent the emergence of resistance.

A combination of intravenous and oral antimicrobials is usually recommended for the initial phase of therapy.

Oral antibiotics (and inhaled antibiotics for pulmonary disease) should be used in the continuation phase of therapy of pulmonary disease.
Treatment regimens should be based on in vitro susceptibility results, although correlation with clinical outcomes is often suboptimal.
Mycobacterium abscessus ss. abscessus contain erm(41), which can induce macrolide resistance. Thus, although macrolides are currently recommended for treatment, it is likely they are not very active in vivo.

Mycobacterium abscessus ss. massiliense contains erm(41) with a deletion that makes it nonfunctional, thus, macrolide resistance is unlikely to be induced as with M. abscessus ss abscessus.

Clarithromycin has been shown to be a stronger inducer of erm(41) than azithromycin.

Mycobacterium fortuitum contains erm(39), which can induce macrolide resistance, thus, macrolides should not be used for treatment if other oral drugs are available.

Mycobacterium chelonae does not have an erm gene.
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 RGM species, empiric therapy is not recommended.

In patients with severe or disseminated disease, a regimen including intravenous amikacin, imipenem, and a macrolide should be initiated and modified when precise speciation is known.

Ultimately, precise species identification is necessary to determine the most appropriate treatment regimen.

M. abscessus ss. abscessus and M. abscessus ss. bolletii should be treated with intravenous amikacin and imipenem (or cefoxitin) plus any oral antimicrobials with demonstrated in vitro activity. Unfortunately, there are few oral antibiotics that have in vitro activity. These include the macolides (azithromycin and clarithromycin), linezolid, clofazimine, and, rarely, the fluoroquinolones. M. abscessus ss. abscessus contains the erm(41) gene, which results in acquired macrolide resistance when the organism is incubated in vitro with clarithromycin. Whether this is important clinically is not clear; however, one study reported significant differences in treatment outcome based on the presence or absence of a functional erm gene.

M. abscessus ss.massiliense should be treated like M. abscessus ss.abscessus; however, because this organism does not contain a functional erm(41) gene, macrolides are likely to be effective.

M. chelonae should be treated with intravenous amikacin and imipenem (the organism is resistant to cefoxitin) plus any oral antimicrobials with demonstrated in vitro activity. M. chelonae does not contain an erm gene, so macrolides should be effective.

M. fortuitum should be treated with at least two antimicrobial drugs that have in vitro activity. M. fortuitum contains erm(39) so acquired macrolide resistance is likely. Fortunately, M. fortuitum typically has in vitro activity to several oral antibiotics.

See Table II for treatment options for RGM.

2. Next list other key therapeutic modalities.

Table II.

Organism	Antibiotic	Dose	Alternative
M. abscessus, sp abscessus	Azithromycin	250 mg daily	Cefoxitin 2-3 gms IV 3-4 times dailyTigecycline IV 50 mg once dailyLinezolid 600 mg once dailyMoxifloxacin 400 mg once dailyClofazimine 100 mg daily
	Imipenem	500-750 mg IV three times daily
	Amikacin	15 mg/kg/day given IV three times per week
M. abscessus, sp massiliense	Azithromycin (or clarithromycin)	250 mg daily	Cefoxitin 2-3 gms IV 3-4 times dailyTigecycline IV 50 mg once dailyLinezolid 600 mg once dailyMoxifloxacin 400 mg once dailyClofazimine 100 mg daily
	Imipenem	500-750 mg IV three times daily
	Amikacin	15 mg/kg/day given IV three times per week
M. abscessus, sp bolletii	Azithromycin	250 mg daily	Cefoxitin 2-3 gms IV 3-4 times dailyTigecycline IV 50 mg once dailyLinezolid 600 mg once dailyMoxifloxacin 400 mg once dailyClofazimine 100 mg daily
	Imipenem	500-750 mg IV three times daily
	Amikacin	15 mg/kg/day given IV three times per week
M. chelonae	Azithromycin (or clarithromycin)	250 mg daily	Tigecycline IV 50 mg once dailyLinezolid 600 mg once dailyMoxifloxacin 500 mg once dailyClofazimine 100 mg daily
	Imipenem	500-750 mg IV three times daily
	Tobramycin	8 mg/kg/day given IV three times per week
M. fortuitum	Moxifloxacin	400 mg daily	Imipenem 500-750 mg IV three times dailyCefoxitin 2-3 gms IV 3-4 times dailyTigecycline IV 50 mg once dailyLinezolid 600 mg once dailyClofazimine 100 mg daily
	Trimethoprim/sulfmethaxazole	500-750 mg IV hree times daily
	Doxycycline (or minocycline)	15 mg/kg/day given IV three times per week

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%) should be used.

Patients with gastroesophageal or swallowing disorders should have these addressed to prevent recurrent aspiration.

Controversial or 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 rapidly growing nontuberculous mycobactiera?

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

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

The expected treatment outcomes vary greatly depending on the site of infection, species causing disease, and underlying severity of disease. To date, there are no randomized clinical trials that have evaluated treatment outcomes in patients with disease due to RGM.
Pulmonary disease: In general, sustained culture conversion (≥12 months) has been reported to occur in 50-60% of patients with pulmonary disease due to M. abscessus. Three recent studies have described the treatment outcomes for pulmonary infections due to M. abscessus:

Jeon and colleagues reported treatment outcomes in 65 patients with pulmonary M. abscessus disease. Patients were treated with a standardized regimen that included 1 month of intravenous amikacin and cefoxitin (or imipenem) followed by clarithromycin, ciprofloxacin, or doxycycline for a total duration of 24 months. Treatment response rates were 83% for symptoms and 74% for HRCT. Sputum culture conversion was sustained for 12 months in 58% of the patients. Conversion was lower (17%) in those whose isolate demonstrated in vitro resistance to clarithromycin. Fourteen (22%) of the patients underwent surgical resection. Negative sputum culture conversion was achieved within a median duration of 1.5 months postoperatively and was maintained in 88% of patients with a preoperative positive culture. Toxicity was common. Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%), respectively. Drug-induced hepatoxicity occurred in 15% of patients. Ultimately, cefoxitin was discontinued in 60% of patients after a median of 22 days of treatment.

Koh and colleagues reported treatment outcomes for 64 patients with M. abscessus and 81 patients with M. massiliense lung disease. All patients were treated with the same regimen as described in the study published by Jeong and colleagues. Patients with M. massiliense lung disease were more likely to show symptomatic, radiographic, and microbiologic improvement than those with M. abscessus. Eighty-eight percent of patients with M. masiliense converted their sputum cultures to negative compared to 25% with M. abscessus.

Jarand and colleagues reported 107 patients with pulmonary M. abscessus infection. Patients were treated with individualized treatment regimens based on ATS/IDSA recommendations. Sixty-nine patients were followed for a mean of 34 months. Forty-eight percent remained culture negative for at least 12 months, 29% remained culture positive, 23% converted but relapsed, and 16% died. Twenty-two percent of the patients underwent surgical resection, and they were more likely to remain culture negative for at least 1 year (57% vs. 28%). Toxicity was common. At least one drug had to be stopped because of adverse reactions in 65% of patients. Cefoxitin and amikacin were most likely to cause adverse reactions.
Skin and Soft-tissue disease is usually cured, although surgical resection and removal of foreign bodies is often necessary.
Lymph node disease is usually cured, although surgical resection of the involved nodes may be necessary.
Disseminated NTM disease is associated with a poor prognosis. Treatment should be started as soon as disseminated disease is diagnosed.

Add what-if scenarios here:

What if the patient is asymptomatic?

Some patients with radiographic evidence of RGM 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?

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 RGM?

There are many different species of RGM. 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 rapidly 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 by 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 RGM are second to MAC causing 20% of all NTM related lung disease in the United States.
Organisms from the M. chelonae/abscessus group are the most common cause of lung disease due to a RGM. In the United States, the Southeastern United States from Florida to Texas appears to have the highest rate of isolation of M. abscessus.
Patients with pulmonary RGM infection are typically female, nonsmokers, and post-menopausal, although, in some areas, male patients are more common.

The incidence and prevalence of disease due to NTM have varied greatly from region to region. There are very few data that describe the incidence and prevalence due to RGM.
In a retrospective study of laboratory cultures in Oregon between 2005 and 2006, 933 patients were identified who had 1 or more 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/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 to be more common in urban areas.
In a follow-up study, all Oregon residents with 1 or more NTM isolate were identified. From a population-based subset, clinical and radiographic information was obtained. Again, approximately 50% of the patients met ATS microbiologic criteria giving a 2-year period prevalence of 8.6/100,000 persons and 20.4/100,000 persons for those 50 years of age or older within the Portland, Oregon area.
Incidence and prevalence are increasing in some areas.

Ontario, Canada (2007): The isolation prevalence of all species (excluding Mycobacterium gordonae) was 19 per 100,000 population and increased 8.5% per year from 1997. The isolation prevalence of RGM varied from 1.2 to 2.3% but did not change significantly over the study period.

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% 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 at which 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 were 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 Asian/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 Disease 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% per year).

RGM pulmonary disease occurs when a susceptible individual inhales contaminated aerosols or aspirates contaminated food/water or gastric contents.
Human disease is thought to occur by exposure to environmental sources, although the specific source is often not identified.
Transmission from human-to-human has not been demonstrated conclusively.

One study retrospectively analyzed 1,062 respiratory specimens from 214 patients with cystic fibrosis of whom 5 had 37 cultures positive for M.absessus. Pulsed field gel electrophoresis (PFGE) demonstrated that all 5 patients had unique genotype patterns documenting no transmission between patients.

Seventy-one isolates from 14 patients with cystic fibrosis, 3 non-CF patients with pulmonary disease, 1 patient with mastoiditis, 4 patients with infected wounds, and 6 environmental isolates underwent PFGE. Twenty-four patients had unique strains, whereas 4 patients had identical strains, 2 of whom were siblings with CF. They concluded that person-to-person transmission rarely occurs.

A recent report described possible interperson transmission of M.abscessus ss.massilinse in 5 patients at a CF center. Four of 5 patients had overlapping clinic visit days, but no other shared space was identified. Environmental studies of the clinic rooms, toilets, and spirometers performed 8 months after initial recovery were negative for M.abscessus.

RGM are not known to be spread from animal to human.

What pathogens are responsible for this disease?

By far, the most common RG to produce lung disease are those of the M.abscessus group followed by M.chelonae and M.fortuitum. The other RGM are rare causes of lung disease.

M. abscessus ss.abscessus

M. abscessus ss.massiliense

M. abscessus ss.bolletii

M. chelonae

M. fortuitum

M. alvei

M. boenickei

M. brumae

M. confluentis

M. elephantis

M. goodii

M. holsaticum

M. mucogenicum

M. peregrinum

M. phocaicum

M. speticum

M. thermoresistible

How do these pathogens cause disease?

NTM are environmental organisms, so exposure is common. However, progression to disease is relatively uncommon.

The pathogenicity of NTM varies widely with some species, such as M. mucogenicum, rarely causing disease and others, such as M. abscessus, frequently causing disease when isolated from a clinical specimen.
Among rapidly growing mycobacteia, the most pathogenic appear to be M. abscessus group followed by M. chelonae and M. fortuitum.
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 are inhaled or aspirated from the environment and presumably cause disease because of 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 bronchietasis and NTM infections is unknown. To date, no significant immunological defect has been described.
Skin and soft-tissue infections usually result after a puncture or other trauma. There are now numerous reports of nosocomial RGM infections occurring after surgical procedures.
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 and IL12 receptors.

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

RGM infections can involve any organ system, particularly in immunocompromised individuals. Patients’ medical history and medications should be reviewed to determine if they are immunocompromised.

A history of lymph node enlargement, particularly cervical enlargement, may be due to RGM infection.
Complaints of cutaneous lesions, either singly or multiple, may be due to RGM cutaneous disease or disseminated disease. The patient should be questioned regarding recent trauma or invasive medical procedures.

Lymphadenopathy, particularly cervical lymphadenopathy, can be a manifestation of RGM 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. M. abscessus is known to contain this antigen as well, but no studies have been published to date regarding the test performance for this RGM.

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

RGM 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 Bacillus Calmette-Guerin (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.

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

Bange, FC, Brown, BA, Smaczny, C, Wallace Jr, RJ, Bottger, EC. “Lack of transmission of Mycobacterium abscessus among patients with cystic fibrosis attending a single clinic”. Clin Infect Dis. vol. 32. 2011. pp. 1648-50. (This study reported no evidence of transmission of Mycobacterium abscessus within a single cystic fibrosis clinic. The authors used pulsed field gel electrophoresis to examine the spread of M. abcessus within the clinic, but they noted that all of the isolates were unique and, thus, transmission could not be documented.)

Choi, GE, Shin, SJ, Won, CJ. “Macrolide treatment for and infection and inducible resistance”. Am J Respir Crit Care Med. 2012. (This study compared treatment efficacies of clarithromycin and azithromycin and determined the correlation between efficacy and induced erm (41) expression in experimental models of M. abscessus and M. massiliense. Clarithromycin induced greater erm(41) expression and, thus, higher macrolide resistance than azithromcyin.)

Griffith, DE, Aksamit, T, Brown-Elliott, B. “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.)

Jarand, J, Levin, A, Zhang, L, Huitt, G, Mitchell, JD, Daley, CL. “Clinical and microbiological outcomes in patients receiving treatment for pulmonary disease”. Clin Infect Dis. vol. 52. 2011. pp. 565-71. (One hundred seven patients were treated with individualized regimens following ATS recommendations: 23% of the patients relapsed and 16% died. Of those who underwent surgical resection, 57% remained culture negative for at least 1 year.)

Jeon, K, Kwon, OJ, Lee, NY. “Antibiotic treatment of lung disease”. Am J Respir Crit Care Med. vol. 180. 2009. pp. 896-902. (Sixty-five patients were treated with a 24-month standardized regimen, including clarithromycin, ciprofloxacin, doxycycline, plus 1 month of intravenous cefoxitin (or imipenem) and amikacin. Sputum conversion occurred in 58% of the patient. Drug induced toxicity was very common. Cefoxitin had to be discontinued in 60% of patients.)

Jonsson, BE, Gilljam, M, Lindblad, A, Ridell, M, Wold, AE, Welinder-Olsson, C. “Molecular epidemiology of Mycobacterium abscessus, with focus on cystic fibrosis”. J Clin Microbiol. vol. 45. 2007. pp. 1497-504. (This study reported the possible person to person spread of Mycobacterium abscessus ssp massiliense in a cystic fibrosis clinic. Four out of five patients had overlapping clinic visits but no direct contact with each other. The environmental evaluation took place 8 months after the presumed transmission.)

Koh, WJ, Jeon, K, Lee, NY. “Clinical significance of differentiation of from “. Am J. Respir Crit Care Med. vol. 183. 2011. pp. 405-11. (This study compared treatment outcomes using a standardized regimen in patients with M. abscessus and M. massiliense. Patients with M. massiliense infection had higher rates of culture conversion than M. abscessus patients (88% vs. 25%). M. massiliense isolates had a deletion in the erm(41) gene making it nonfunctional.)

DRG CODES and expected length of stay

031.0 Pulmonary Mycobacteria, all species

031.1 Cutaneous Mycobacteria, all species

031.8 Other Spec. Mycobacteria

031.2 Disseminated Mycobacteria, all species

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Rapidly Growing Nontuberculous Mycobacteria (NTM)