Nontuberculous Mycobacteria

Author: Dr Charles L. Daley National Jewish Health 2008-07-28

Nontuberculous Mycobacteria: An Emerging Epidemic

Introduction 

Tuberculosis, one of the most recognized infections in the world, is caused by members of the Mycobacterium tuberculosis complex and can be transmitted from person to person. However, M. tuberculosis is just one of over 125 different species of mycobacteria most of which are referred to as nontuberculous mycobacteria (NTM).(1) NTM are dispersed widely in our environment and unlike tuberculosis, are not spread from person to person.  NTM are also less likely to cause disease in humans, but the frequency of NTM-related disease is increasing and in some areas of the world these infections are more common than tuberculosis. This article will review what we know about NTM, their epidemiology (where they occur and who and how many they affect), ability to cause disease, and treatment.

What are nontuberculous mycobacteria?

Nontuberculous mycobacteria (NTM) is the term used to distinguish environmental mycobacteria from Mycobacterium leprae (the cause of leprosy) and from organisms in the Mycobacterium tuberculosis complex (the cause of tuberculosis).(2) NTM are also referred to as mycobacteria other than tuberculosis (MOTT), atypical mycobacteria, and environmental mycobacteria. The latter name refers to the fact that these organisms exist in our environment and can be isolated from water and soil.
Over 125 different species of NTM have been described (http://www.bacterio.cict.fr/m/mycobacterium.html) and they are typically divided into rapidly- and slowly–growing mycobacteria based on their ability to produce visible colonies on solid culture medium at optimal conditions in more or less than seven days.(1) (Table 1)

Table 1. Some Common Slowly and Rapidly Growing NTM Reported to Cause Disease in Humans

Slowly Growing Mycobacteria	Rapidly Growing Mycobacteria
M. avium M. intracellulare M. kansasii M. malmoense M. marinum M. simiae M. szulgai M. ulcerans M. xenopi	M. abscessus M. chelonae M. fortuitum

In addition, Runyon and Timpe developed a classification system that characterizes the various species by the presence of absence of pigmentation as well as growth rate (1, 3).

• Group I - photochromogens, develop yellow or orange pigment when exposed to light; examples of photochromogens include Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium simiae. 

• Group II - scotochromogens, form orange-yellow pigment in the dark; examples include Mycobacterium gordonae, Mycobacterium szulgai and Mycobacterium scrofulaceum. 

• Group III - nonchromogens, are unpigmented; examples include M. avium complex (MAC), M. xenopi, and M. malmoense (Figure 2)

• Group IV - rapid growers, examples include M. chelonae, M. abscessus, and M. fortuitum.

NTM have several features that distinguish them from members of the M. tuberculosis complex.(1)

• The NTM display a wide range of pathogenicity (the ability to cause disease in another organism). The pathogenicity of the various NTM species varies greatly from organisms that are seldom pathogenic to humans – such as M. gordonae – to those that are almost always disease producing, such as M. kansasii.
• Unlike M. tuberculosis, the NTM are not transmissible from human to human. Instead, they are acquired from our environment, presumably through exposure to water and soil.
• Many of the pathogenic NTM are relatively drug resistant compared with M. tuberculosis and thus, they are difficult to treat with high rates of treatment failure and recurrence.

NTM – a historical perspective
NTM have been recognized since the late nineteenth century when “tuberculosis” in chickens was first described in 1868.(4) By 1890, this organism was recognized in the laboratory to be distinct from M. tuberculosis, the cause of tuberculosis. The organism that caused disease in chickens was later identified to be M. avium. Because these organisms did not cause characteristic disease when inoculated into guinea pigs, they were recognized as distinct from M. tuberculosis and were not believed to cause disease in humans.
Remarkably it was not until the 1930’s that NTM were recognized to cause disease in humans. One of the first cases of lung disease due to M. avium complex (MAC) was described in 1943 in a man with underlying silicosis (a form of lung [pulmonary] disease). By the 1950s, pulmonary disease due to NTM became more commonly recognized and accounted for approximately 1-2% of admissions to tuberculosis sanatoriums in the southeastern United States.
Interest in NTM increased when HIV infected patients began to develop disseminated infections due to various NTM species, particularly M. avium.(1) As antiretroviral drugs became available, the incidence of disseminated MAC decreased, but we are now seeing an increase in the number of cases of pulmonary disease due to NTM, particularly among postmenopausal Caucasian women. In addition there are increasingly frequent reports of NTM infections involving skin, soft tissues, and bone/joints.

How does one get NTM infections?
The source of NTM infection appears to be environmental exposure; transmission from human to human has not been described.(1) Genotyping (taking the DNA fingerprint of the organism) methods have demonstrated similar patterns between isolates cultured from patients and their environments. In most cases, the source of infection has been water, although soil has also been implicated. A recent study from Japan evaluated the water from the residences of 49 patients with MAC and 43 healthy volunteers.(5) MAC was isolated from 11 samples from multiple bathroom samples but not from other sites in the home. MAC was more likely to be isolated from patient homes than the homes of the control group; in two cases, the genotype pattern matched that of the patient. Therefore, it is possible that the patients were being infected by water in their bathrooms.
NTM are dispersed widely within our environment so exposure is likely very common. MAC isolates were recovered from 42 of 108 (32%) of tested locations such as homes, hospitals, commercial buildings, and reservoirs in Los Angles, California.(1) NTM have been found in municipal water supplies or treated water supplies from 95 of 115 (83%) dialysis centers throughout the United States. In a study of 50 biofilm (the filmy layer at the pipe and water interface) samples from a variety of pipe systems in Germany, 90% of the samples contained NTM.(1)
The importance of host immunity has been demonstrated in individuals and families with mutations in the IFN-gamma/IL-12 pathway genes in whom disseminated mycobacterial infections have been reported. In a study from Japan, 170 patients with MAC lung infection were studied and of 622 siblings of these patients, three had MAC lung disease also.(1) The authors concluded that the rate of infection among the siblings was higher than previously estimated among the general population and thus suggested a genetic predisposition to disease.
In patients with HIV infection, disseminated NTM infections typically occur only after the CD4 lymphocyte (a type of white blood cell in the immune system) count falls below 50 cells/ml suggesting that specific T-cell (a type of lymphocyte) products or activities are required for mycobacterial resistance.(1) In HIV infected persons with disseminated MAC, the organisms presumably enter the body through ingestion of contaminated food or liquid and subsequently spread through the bloodstream.
There is a striking association between bronchiectasis (a disease of the breathing passages), nodular pulmonary NTM infections, and a particular body type, predominantly in postmenopausal women.(6) In the latter instance, it is not known if these women have some sort of subtle immune deficiency that predisposes them to NTM pulmonary infections or if their predisposition is related to an inability to clear their airways of mucous. This form of disease has been referred to as “Lady Windermere’s syndrome” after a character in Oscar Wilde’s play.(7)
Unlike M. tuberculosis, the NTM do not appear to live in a state of dormancy. Moreover, simply isolating NTM from a respiratory specimen may not mean that the patient has NTM-related disease. For years the term “colonization” has been used to differentiate those who have no evidence of progressive disease from those who do. For persons who were considered to be “colonized” with NTM, no treatment was given. However, we now know that many of these patients who were thought to have been “colonized”, did in fact have evidence of disease on CT scans and demonstrated slow clinical and radiographic progression. It remains difficult to distinguish colonization from active disease in many patients. When in doubt, patients should be followed carefully for several years to make sure that there infection is not progressing and in need of treatment.

Epidemiology of NTM
A substantial proportion of adults in the United States have had prior exposure to MAC. Studies that have measured skin test reactivity to antigens found in M. avium and M. intracellulare have found that over 50% of adults in the southeastern United States have been exposed to MAC (and possibly other NTM species) compared to approximately 20% in other regions of the country.(1) However, skin test reactivity does not mean that someone has an active infection but simply that their immune system has seen the antigens at some time in their life.
Microbiological survey data from state laboratories in the early 1980’s estimated a prevalence of NTM infection of 1 to 2 cases per 100,000 population.(1) A similar survey from 1993-1996 reported an annual case rate of 7 to 8 per 100,000 documenting an increase in isolation of NTM when compared to the previous survey.
The most useful information comes from studies that combine clinical and microbiologic data to provide estimates of disease rates. A recent population-based study from Ontario Province in Canada documented a prevalence of NTM infection of 14.1/100,000 by 2003.(8) The most common isolate was MAC with a prevalence of 8.4 per 100,000. This study also documented an increase in the isolation rate of several NTM species.

Risk factors for NTM infections
Skin testing data from Palm Beach, Florida reported that 32.9% of 447 participants in a population-based random household survey had a positive reaction to M. avium sensitin.(9) Factors that predicted a positive skin test reaction included Black race, birth outside the United States, and more than six years’ cumulative and extensive exposure to soil (See paragraph below). Exposure to water, food, and pets was not associated with skin test reactivity.
Male sex, non-Hispanic Black race, and birth outside of the United States were reported as risk factors in individuals who underwent skin testing with PPD-B (M. intracellure) as part of the National Health and Nutrition Examination Surveys (NHANES).(10) Both this study and the one from Florida reported that occupations with the potential for extensive soil exposure, such as in the agricultural or construction industry, were more likely to be sensitized to M. intracellulare than persons in other occupations. 
Patients who have pulmonary disease caused by NTM often have structural lung disease such as chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, pneumoconiosis, prior tuberculosis, alveolar proteinosis, and chronic aspiration.(1,2,3)
Patients with abnormalities in the IFN-gamma or IL-12 pathways are predisposed to severe mycobacterial infections, as are patients receiving TNF-antagonist drugs. HIV infected patients who have advanced disease are at risk of developing disseminated disease.  Of note, many women with NTM infection have nodular bronchiectasis and similar body types: scoliosis (curvature of the spine), pectus excavatum (hollowed chest), mitral valve prolapse (a common heart disorder), and joint hypermobility.(6,7) The reason for this association has not been definitively determined.
After tuberculosis and leprosy, Buruli ulcer (see below for a description) is the third most common mycobacterial disease of humans.(11) Major foci of disease are usually near wetlands in tropical or subtropical areas. The highest rate of infection is in children under 15 years of age. The largest known concentration of patients is in west Africa although the disease is also found in Papua New Guinea and Australia, with a few patients reported from South America and Mexico. Recent data suggest that insects may be involved in transmission of the infection to humans. M. ulcerans has been identified in the salivary glands of a water bug (Naucoridae) and the disease has been spread from water bugs to mice.
M. marinum was first identified as a cause of disease in humans in 1954 and called “swimming pool granuloma,” but the infection is often acquired from maintaining fish tanks where the name “fish tank granuloma” is used.(1) The incidence of M. marinum infections is probably underestimated but rates of up to 0.27 cases per 100,000 persons have been reported.

How do NTM infections present clinically?
NTM infections usually cause disease in the lungs although areas outside the lungs can also be involved and the frequency of occurrence outside the lungs varies with the species of NTM. For example, M. marinum and M. ulcerans produce skin and soft tissue infections whereas MAC and M. kansasii usually involve the lung.
Pulmonary Disease
Patients who have pulmonary infections often present with chronic cough, fatigue, malaise, and weight loss.(1,2,3) In many instances, patients have been misdiagnosed as having chronic bronchitis and treated repeatedly with courses of antibiotics. Physical examination is often unrevealing, although patients with nodular bronchiectasis disease are often slender postmenopausal women who may have accompanying scoliosis, pectus excavatum, and mitral valve prolapse.
Radiographic findings suggestive of NTM infection depend on whether or not the disease is primarily fibrocavitary (has evidence of scarring and cavities (holes) like tuberculosis) or characterized by nodules and bronchiectasi. In the latter instance, chest radiograph findings are usually in the mid and lower lung fields. High resolution computed tomography (HRCT) is the most sensitive way to detect bronchiectasis and the small centrilobular nodules that are characteristic of NTM pulmonary infection.

Lymphadenopathy Disease
Children often present with infections in the lymph nodes, most often in the neck.(1) Typically, the lymph nodes enlarge slowly and without systemic symptoms. The involved lymph nodes are usually unilateral (on one side) and not tender to touch. Other lymph nodes can also be involved including those within the chest (mediastinal nodes). A contrast-enhanced CT scan can demonstrate the extent of involvement better than physical examination or plain chest radiograph (X-ray).
Skin/Soft tissue and Bone/Joint Disease
Skin and soft tissue infection usually occur after a puncture of the skin. The findings may be localized initially, but with time the infection may spread beyond the initial site of inoculation. The rapidly growing mycobacteria such as M. abscessus, M. fortuitum, and M. chelonae are a well-known cause of infection after certain medical procedures such as:

• Long-term intravenous or intraperitoneal(the area containing the abdominal organs) catheters
• Postinjection abscesses
• Infections after liposuction
•  Augmentation mammaplasty (breast enhancement)
•  Cardiac bypass surgery           
• Corneal infections after laser in situ keratomileusis (LASIK)

Skin infections have also occurred in the legs after foot-baths. These infections are referred to as furunculosis and result when someone soaks their feet in contaminated foot-baths while undergoing a pedicure. Most of these infections have been due to rapidly growing mycobacteria.
NTM have also been implicated as causes of osteomyelitis (bone infection) and infections of joints. These infections usually result from a traumatic puncture, surgery, or injection of steroids into joints or bursae. Chronic granulomatous infections of the hand are commonly due to M. marinum and MAC although several NTM have been implicated as a cause of tenosynovitis (inflammation of the sheath around the tendon).
There are two species of NTM, M. marinum and M. ulcerans, which have a predilection for skin and soft tissue infections. M. marinum causes chronic skin and soft tissue infections that appear as papules (a small solid bump on the skin) on an extremity (arms and hands, legs and feet) and slowly progress to shallow ulcer formation and scarring.(1) Most lesions are solitary, but ascending spread up the extremity can also occur. Infections involve the upper extremity in 95% of patients and may spread to deeper structures, including bone. The lesions usually occur on the hands and fingers in aquarium owners; the lesions appear on elbows, knees and feet in swimming-pool related cases. Lesions first appear after approximately two to four weeks of incubation.
M. ulcerans produces the condition known as Buruli ulcer.(1) The organism produces mostly painless, necrotic (dead tissue) ulcers of the skin and underlying soft tissues. (http://www.who.int/buruli/photos/en/index.html) The severe necrosis results from a myolactone that is produced by M. ulcerans. Lesions are usually single and begin as a nonulcerative lesion just beneath the skin that is painless and nontender. After approximately one to two months the lesion may ulcerate.
Disseminated Disease
Disseminated infections (infections that spread beyond one location) are most commonly associated with severe forms of immunosuppression such as advanced HIV disease. Over 90% of reported disseminated infection in HIV infected patients are due to MAC and almost all of these are due to M. avium.(1) M. kansasii is the second most common cause of disseminated disease in HIV infected patients. Patients with advanced HIV disease typically complain of fever, night sweats, abdominal pain, diarrhea, and weight loss. In non HIV-infected patients, fever of unknown origin is a common presentation.
How are NTM infections diagnosed?
The first step is diagnosing an NTM infection is to suspect that it might be the underlying cause of the symptoms or radiographic findings. Chronic cough (lasting >3 weeks), fatigue, night sweats, and weight loss should make clinicians consider mycobacterial infections and the possible cause of the symptoms. In the case of pulmonary infections, a chest radiograph, or more likely, a HRCT, will be the first clue that an NTM infection is present. Respiratory specimens should be obtained and sent for mycobacterial culture. Even after an NTM has been isolated and identified, the patient may not have disease because NTM can be isolated transiently from respiratory specimens. In order to assist clinicians with the difficult task of trying to determine if a given NTM species is causing disease in a patient the American Thoracic Society developed a set of criteria that utilized clinical, radiographic, and microbiologic parameters. (Table 2)

Table 2.  Clinical, radiographic, and microbiologic criteria for diagnosing nontuberculous mycobacterial lung disease.

CLINICAL	Compatible pulmonary symptoms and
RADIOGRAPHIC	Nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules and
	Appropriate exclusion of other diagnoses and
MICROBIOLOGIC	Positive culture results from at least two separate expectorated sputum samples. If results are nondiagnostic, consider repeat sputum AFB smears and cultures or
	Positive culture result from at least one bronchial wash or lavage or
	Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM.

Adapted from (1)

The bacteriological diagnosis of NTM is based on isolation of these organisms from diagnostic specimens using standard culture techniques. All cultures should include both solid and broth media for detection of mycobacteria. Most NTM organisms grow between 28° and 37°C although some species grow best outside of this temperature range. For example, NTM that have a predilection for skin and soft tissue infections, such as M. marinum and M. ulcerans, grow best at lower temperatures. Most NTM grow within two to three weeks on subculture, although rapidly growing mycobacteria usually grow within seven days of subculture and M. ulcerans and M. genavense may require at least eight to 12 weeks to detect growth.

Identification of specific species of NTM is important because of the variation in antimicrobial susceptibility and treatment options. NTM can be categorized by their growth rate, pigmentation, and biochemical profiles, although these characteristics are not specific enough for final identification. The modern clinical laboratory includes a large variety of rapid methods for mycobacterial identification including nucleic acid probes, polymerase chain reaction and other amplification methods, high-performance liquid chromatography (HPLC), and nucleic acid sequencing.

The commercially available AccuProbe technology (Gen-Probe, San Diego, CA) is currently recommended for identification of M. tuberculosis complex, M. avium complex (as well as M. avium and M. intracellulare separately), M. kansasii, and M. gordonae.

HPLC, which analyzes the chromatographic profile of the mycolic acids extracted from the bacterial cell wall, is a highly sensitive method that can detect specific chromatographic patterns representing 73 mycobacterial species. A much broader range of species can be reliably identified by combining information from the HPLC test results with other data, such as growth requirements, growth rate, colonial morphology (form and structure), and pigmentation.

Identification of mycobacteria by 16S ribosomal DNA sequencing provides more accurate determination of the species (MicroSec 500 16S rDNA Bacterial Sequencing Kit system from Applied Biosystems, Foster City, CA). This procedure involves amplification of a fragment of 16S ribosomal DNA. The species identification is based on a comparison between the sequences obtained and those in the libraries of already known species. The supplies for the test and the libraries are commercially available in an automated format

Unlike with tuberculosis, the in vitro results do not correlate well with clinical outcomes for some mycobacterial species. This has resulted in continued controversy regarding the clinical usefulness of drug susceptibility testing in the management of patients with NTM.
There is no single susceptibility method or choice of drugs that is recommended for all species of NTM. At a minimum, initial isolates of MAC should be tested to the macrolide antibiotic clarithromycin, as should isolates from treatment failures and relapses, those who have taken macrolides previously, and AIDS patients who develop bacteremia on macrolide prophylaxis. Testing of other drugs may be useful when trying to select additional drugs for treatment of patients with MAC, especially in patients who are failing therapy, have relapsed, or who have macrolide-resistant disease. M. kansasii should be tested to rifampin as resistance to rifampin is associated with treatment failure/relapse.

Broth microdilution minimum inhibitory concentration (the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism) determination for susceptibility testing is recommended for rapidly growing mycobacteria and inclusion of the following drugs is recommended: amikacin, kanamycin, tobramycin, imipenem, doxycycline, clarithromycin, azithromycin, trimethoprim/sulfamethoxazole, amoxicillin clavulanate, cefoxitin, ciprofloxacin, moxifloxacin, tigecycline and linezolid.

Buruli ulcer is often diagnosed and treated based on clinical findings in endemic areas. Four laboratory confirmatory methods are commonly used.(12)

• Direct smear examination – Swabs from ulcers or smears from tissue biopsies can be examined under a microscope to try to identify the organism. Unfortunately, the sensitivity of this method is low (approximately 40%).
• Culture of M. ulcerans – Culture takes about six to eight weeks or more and the sensitivity is only 20-60%.
• Polymerase chain reaction (PCR) – Results can be obtained within two days and has a high sensitivity of about 98%.
• Histopathology – This method requires that a biopsy be performed and has a sensitivity of 90%.

How are NTM infections treated?
General Concepts
Treatment of NTM infections is usually more complicated than treatment of tuberculosis. The drugs, frequency of administration, and duration of therapy will vary depending on the species of NTM causing the disease, site of infection, and extent of disease.
Antimycobacterial Drugs
Some antituberculosis drugs are also active against some NTM species. However, treatment of most NTM species also requires the use of antibiotics that are not typically used to treat tuberculosis. These drugs are listed in Table 3.

Table 3.  Drugs and dosages used to treat nontuberculous mycobacterial infections in adults.

Drug	Daily Dose (max)	Three times/week Dose (max)
Oral drugs
Isoniazid	5 mg/kg/day (300 mg)	15 mg/kg/day (900 mg)
Rifampin	10 mg/kg/day (600 mg)	10 mg/kg/day (600 mg)
Rifabutin	5 mg/kg/day (300 mg)	5 mg/kg/day (300 mg)
Ethambutol	15-20 mg/kg/day	20-35 mg/kg/day
Azithromycin	250 mg/day	500-600 mg/day
Clarithromycin	500-1000 mg/day	1000 mg/day
Doxycycline	100 mg/day (100 mg)	--
Trimethoprim-sulfamethoxazole	160 mg trimethoprim/800 mg sulfamethoxazole twice daily	--
Ciprofloxacin	500-750 mg twice daily	--
Moxifloxacin	400 mg/day (400 mg)	--
Linezolid	600 mg once or twice daily	--
Parenteral drugs
Tobramycin	4-7 mg/kg/day IV	--
Streptomycin	10-15 mg/kg/day (1 g) IV or IM	15-20 mg/kg (1.5) IV or IM
Amikacin/ kanamycin	10-15 mg/kg/day (1 g) IV or IM	15-20 mg/kg (1.5) IV or IM
Cefoxitin	100-200 mg/kg (12g/day) in divided doses IV	--
Imipenem	500-1000 mg 2-3 times/day IV	--
Tigecycline	50 mg twice daily IV	--

Adapted from (1)
IV – intravenously, IM - intramuscularly
Treatment Regimens
Treatment of pulmonary infections
Mycobacterium avium complex
The treatment of pulmonary disease due to MAC will vary depending on whether or not cavities (holes) are present in the lung and whether the patient has been treated previously for MAC. The usual treatment regimen includes a macrolide antibiotic (azithromycin or clarithromycin), ethambutol, and a rifamycin (rifabutin or rifampin).(1) When there is evidence of cavities or extensive disease on the chest radiograph, an injectable drug like amikacin or streptomycin is usually given for several months. Cure rates have varied considerably from 55% TO 85%. The current recommendations for the treatment of pulmonary MAC are listed in Table 4.

Table 4. Currently recommended treatment regimens for pulmonary MAC disease.

Type of Disease	Regimen
Nodular/bronchiectatic disease	clarithromycin 1000 mg tiw or azithromycin 500-600 mg tiw and
	ethambutol 25 mg/kg tiw and
	rifampin 600 mg tiw
Cavitary disease	clarithromycin 500-1000 mg/day or azithromycin 250-300 mg/day and
	ethambutol 15 mg/kg daily and
	rifampin 450-600 mg daily and
	streptomycin or amikacin 15 mg/kg tiw
Advance or Previously Treated	clarithromycin 500-1000 mg/day or azithromycin 250-300 mg/day and
	ethambutol 15 mg/kg daily and
	rifabutin 150-300 mg daily or rifampin 450-600 mg daily and
	streptomycin or amikacin 15 mg/kg tiw

Adapted from (1)

tiw – three times per week

Mycobacterium kansasii

Mycobacterium kansasii is treated much like tuberculosis. The usual treatment regimen includes isoniazid, rifampin, and ethambutol given daily.(1) Pyrazinamide, the fourth drug in the standard four-drug regimen for the treatment of tuberculosis, is not effective against M. kansasii. Cure rates are over 95%, similar to tuberculosis. Other drugs that have activity against M. kansasii include the macrolides, fluoroquinolones, and trimethoprim-sulfamethoxazole. These drugs may be used when the infecting strain is resistant to the standard three-drug combination or when intolerance to one of the drugs occurs.

Mycobacterium malmoense

Pulmonary infections due to M. malmoense may be difficult to treat and the optimal treatment regimen is not known. Drug susceptibility test results do not correlate well with clinical outcomes. Currently, a regimen that includes isoniazid, rifampin, ethambutol with or without fluoroquinolones, and macrolides is recommended by the ATS.(1) A randomized clinical trial conducted by the British Thoracic Society compared rifampin and ethambutol to rifampin, ethambutol, and isonizid in patients with pulmonary disease due to M. malmoense and reported similar outcomes for the two regimens.(13) Although the initial clinical response to therapy was good, approximately one-third of the patients were dead after 5 years of follow-up (most deaths were not due to M. malmoense infection). At the end of five years only 42% of the patients were cured.

Mycobacterium simiae

Because of high rates of drug resistance, M. simiae is difficult to treat. The optimum regimen and duration of therapy is not known. According to the American Thoracic Society, a regimen that includes a macrolide, moxifloxacin, and trimethoprim/sulfamethoxazole may be successful.(1)

Mycobacterium szulgai

M. szulgai is susceptible to most antituberculosis drugs. Treatment with a standard anti-tuberculosis regimen has been known to be successful. Because there is activity of the fluoroquinolones and macrolides to M. szulgai, a regimen including isoniazid, rifampin, and ethambutol plus a fluoroquinolone or macrolide should be associated with good response.

Mycobacterium xenopi

The optimum treatment regimen and duration of therapy is not known. As with some other NTM species, there is poor correlation between in vitro drug susceptibility test results and clinical outcomes.  Most patients are treated with a “MAC regimen” that includes a macrolide, rifamycin, and ethambutol.(1) Bacteriologic response may be enhanced by addition of a fluoroquinolone and, as with MAC, an injectable agent should be considered in patients with cavitary disease. Cure rates are low and mortality high, reflecting the typically severe underlying pulmonary disease. In a recent study from the Netherlands, antimycobacterial treated was reported to have cured 11 of 19 (58%) patients who met the current ATS definition of disease.(14) Treatment failure occurred in four (21%) patients and another four died.

Rapidly Growing Mycobacteria

The rapid growers are typically resistant to most anti-tuberculosis drugs so other antibiotics may be needed.

Mycobacterium abscessus

M. abscessus is resistant to many antibiotics and thus is very difficult to treat. In general, long-term cure of patients with pulmonary disease due to M. abscessus is usually not achievable.(1) M. abscessus is usually susceptible to the macrolides (azithromycin and clarithromycin), imipenem, cefoxitin, amikacin, tigecycline and occasionally linezolid. Unfortunately, only the macrolides and linezolid are available in an oral formulation. Current recommendations are to provide periodic drug administration of multidrug therapy including a macrolide (oral), and one or more parenteral (intravenous or intramuscular injection) agents such as amikacin, cefoxitin, or imipenem for four to six months to help control symptoms and prevent progression. Therapy can be provided at home or infusion centers depending on insurance coverage. Surgical resection of the infected portion of the lung should be considered for select patients but only after a period of intensive antimicrobial therapy and only if performed by an experienced surgeon.

Mycobacterium chelonae

M. chelonae is usually susceptible to tobramycin, macrolides, linezolid, imipenem, amikacin and may demonstrate susceptibility to fluoroquinolones and doxycycline.(1) Isolates are usually resistant to cefoxitin. Treatment should consist of at least two drugs to which there has been demonstrated in vitro drug susceptibility and the duration should be for at least 12 months of culture negativity.

Mycobacterium fortuitum

Among the more common rapid growers, M. fortuitum is usually the most susceptible to antibiotics. M. fortuitum isolates are usually susceptible to newer macrolides, fluoroquinolones, doxycycline, minocycline, sulfonamides, cefoxitin, and imipenem.(1) Most patients can be cured with a regimen that includes at least two agents with in vitro activity for at least 12 months of culture negativity.

Treatment of Skin, Soft Tissue, and Bone/joint Infections

A combination of multidrug chemotherapy plus surgical excision is usually successful for treatment of MAC infections of the skin and soft tissues. The optimal duration of therapy is not known but should probably be six to 12 months in duration. For serious infections caused by rapidly growing mycobacteria, a newer macrolide should be combined with a parenteral medication (amikacin, cefoxitin, or imipenem) or perhaps another oral agent in the case of infection due to M. fortuitum. Therapy should continue for a minimum of four months for skin infections and at least six months for bone infections. Surgery is generally indicated for extensive disease and removal of foreign objects such as breast implants, percutaneous catheters, and joint prostheses is necessary.

Mycobacterium marinum

Infections caused by M. marinum can be treated with two active agents for one to two months after resolution of the lesions; this typically takes three to four months in total.(1) Excellent outcomes have been reported with treatment with clarithromycin and ethambutol or clarithromycin and rifampin. Surgical treatment may be needed for infections that involve closed spaces of the hand or in antibiotic treatment failures.

Mycobacterium ulcerans

Buruli ulcer is a disfiguring infection that can be difficult to treat. By the time of clinical presentation, patients have often suffered significant disfigurement and scarring. The World Health Organization currently recommends a combination of rifampin and streptomycin/amikacin for eight weeks as a first-line treatment for all forms of active disease.(12) Surgery should be performed to remove necrotic tissue, cover skin defects, and correct deformities. In some settings, pre-ulcerative lesions may be excised. Continuous local heating of the involved area promotes healing.

Treatment of Disseminated Infections

Treatment of disseminated MAC infections in HIV infected patients should include: clarithromycin 500 mg twice daily, or; azithromycin 500 mg daily, and ethambutol 15 mg/kg daily with our without rifabutin 300 mg daily.(1) Treatment should be continued indefinitely or until immune restoration is achieved by antiretroviral therapy. MAC treatment can be stopped for patients who are asymptomatic and have achieved a CD4 lymphocyte count of over 100 cells/ml for at least 12 months.(1)

Are NTM infections preventable?

Prevention of community acquired pulmonary infections remains difficult. The organisms have been isolated in tap water and water distribution systems, may tolerate high water temperatures, and are resistant to our typical decontamination methods. Therefore, it is not clear how to best decrease our environmental exposure to these hardy organisms. However, in health care settings – where these infections have been associated with contamination of water sources, biologicals, and multidose vials – specific steps can be taken to prevent the use of tap water to wash wounds or equipment and to avoid the use of multi-dose vials for injections.

Prophylactic (preventive) therapy for NTM is only recommended in the setting of advanced HIV disease. Preventive therapy for disseminated MAC is recommended for HIV infected patients with fewer than 50 CD4 lymphocytes/ml.(1) Azithromycin, 1200 mg once weekly is the preferred agent but alternative regimens include clarithromycin, 500 mg twice daily or rifabutin, 300 mg daily. Primary prophylaxis can be discontinued when patients have responded to antiretroviral therapy with an increase in CD4 cell count to more than 100 cells/ml for more than three months. Prophylaxis should be reintroduced if the cell count falls to less than 50 to 100 cells/ml.

Is there a vaccine against NTM infections?

There is no vaccine available for the treatment or prevention of NTM. However, reports from Sweden and the Czech Republic suggest that the vaccine for tuberculosis, Bacille Calmette-Guerin (BCG), has some protection against NTM infection; NTM lymphadenitis was less common in BCG vaccinated than non-vaccinated children. In addition, BCG may have some protective effective against Buruli ulcer.

More information

Books

Clinics in Chest Medicine. Lung Disease Due to Nontuberculous Mycobacterial Infections. Eds Antonino Catanzaro and Charles L. Daley. September 2002. W. B. Saunders Company, Philadelphia PA.

Web resources

MedlinePlus, http://medlineplus.gov

World Health Organization, http://www.who.int/buruli/photos/en/index.html

The NTM Handbook: A Guide for Patients with Nontuberculous Mycobacterial Infections Including MAC,

http://www.ntmhandbook.com/index.htm

List of Different Mycobacterial Species, http://www.bacterio.cict.fr/m/mycobacterium.html

American Thoracic Society, www.thoracic.org

NTM Information and Research (NTMIR), www.ntminfo.com

National Jewish Medical and Research Center, www.nationaljewish.org

The University of Texas Health Center at Tyler, www.maclungdisease.org

References

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2.             Field SK, Cowie RL. Lung disease due to the more common nontuberculous mycobacteria. Chest 2006;129:1653-1672.

3.             Field SK, Fisher D, Cowie RL. Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest 2004;126:566-581.

4.             Wallace R. History of MAC. (www.maclungdisease.org)

5.             Nishiuchi Y, Maekura R, Kitada S, et al. The recovery of Mycobacterium avium-intracellulare complex (MAC) from residential bathrooms of patients with pulmonary MAC. CID 2007;45:347-351.

6.             Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis: thoracic anomalies associated with pulmonary disease caused by Mycobacterium avium complex. Am Rev Respir Dis 1991;144:914.

7.             Prince DS, Peterson DD, Steiner RM, Gottlieb JI, Scott R, Israel HL, Figueroa WG, Fish JE. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989;321:863.

8.             Marras TK, Chedore P, Ying AM, Jamieson F. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997-2003. Thorax 2007;62:661-666.

9.             Reed C, von Reyn F, Chamblee S, et al. Environmental risk factors for infection with Mycobacterium avium complex. Am J Epidemiol 2006;164:32-40.

10.          Khan K, Wang J, Marras TK. Nontuberculous mycobacterial sensitization in the United States. Am J Respir Crit Care Med 2007;126:306-313.

11.          Van der Werf TS, Stienstra Y, Johnson RC, Phillips R, Adjei O, Fleischer B, Wansbrough-Jones MH, Johnson PD, Portaels F, van der Graaf WT, et al. Mycobacterium ulcerans disease. Bull World Health Organ 2005;83:785-791.

12.          World Health Organization. Buruli Ulcer Fact Sheet. 2006.

13.          The Research Committee of the British Thoracic Society. Pulmonary disease caused by M. malmoense in HIV negative patients: 5-year follow-up of patients receiving standardized treatment. Eur Respir J 2003;21:478-482.

14.          Van Ingen J, Boeree MJ, de Lange WCM, et al. Mycobacterium xenopi clinical relevance and determinants, the Netherlands. Emerg Infect Dis 2008;14:385-389.