Overview of nontuberculous mycobacterial infections

INTRODUCTION — 

Nontuberculous mycobacteria (NTM) species are mycobacterial species other than those belonging to the Mycobacterium tuberculosis complex (eg, M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti) and Mycobacterium leprae. NTM are generally free-living organisms that are ubiquitous in the environment. Molecular identification techniques, including whole-genome sequencing, have identified approximately 200 NTM species [1].

An overview of NTM infection in patients without HIV will be reviewed here. The epidemiology, microbiology, pathogenesis, diagnosis, and treatment of NTM infection, as well as infection due to rapidly growing mycobacteria and M. ulcerans, are discussed separately. (See "Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections" and "Microbiology of nontuberculous mycobacteria" and "Clinical manifestations and diagnosis of nontuberculous mycobacterial pulmonary disease" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Buruli ulcer (Mycobacterium ulcerans infection)".)

NTM infections in patients with HIV and lung transplant candidates and recipients are also reviewed separately. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

SPECTRUM OF CLINICAL SYNDROMES — 

In broad terms, nontuberculous mycobacteria (NTM) can cause four clinical syndromes in humans [2,3]:

●Pulmonary disease – This especially occurs in individuals with underlying lung disease and in patients with cystic fibrosis [4]. It can also occur in individuals without previously known lung disease. Mycobacterium avium complex (MAC), Mycobacterium abscessus subsp abscessus, and Mycobacterium kansasii are the most common causes of NTM lung disease.

Other species that cause lung disease include Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium szulgai, and Mycobacterium simiae (table 1) [5]. Geography plays a prominent role in the epidemiology of NTM pulmonary disease. M. xenopi is relatively more common in Europe, Great Britain, and Canada, M. simiae is relatively more common in the Southwest United States and Israel, while M. malmoense is relatively more common in Scandinavia and Northern Europe [2,6]. (See "Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections".)

●Superficial lymphadenitis – Cervical lymph nodes are most frequently involved. This occurs primarily in children and is caused mostly by MAC, Mycobacterium scrofulaceum, and, in Northern Europe, M. malmoense and Mycobacterium haemophilum. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children" and "Nontuberculous mycobacterial lymphadenitis in children".)

●Disseminated disease in severely immunocompromised patients – This is most commonly caused by MAC and less commonly by the rapidly growing mycobacteria [RGM], eg, M. abscessus, M. fortuitum, and Mycobacterium chelonae. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

●Infection of the skin, soft tissue, bones, and joint – This is usually a consequence of direct inoculation and is caused primarily by Mycobacterium marinum and Mycobacterium ulcerans, the RGM, and other NTM species including MAC. RGM infections in this category may be nosocomial, including surgical site infections [7]. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

MYCOBACTERIUM AVIUM COMPLEX

Species within MAC — The term M. avium complex (MAC) encompasses multiple species including M. avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium arosiense, Mycobacterium marseillense, Mycobacterium timonense, Mycobacterium bouchedurhonense, Mycobacterium vulneris, and Mycobacterium yongonense. These organisms are genetically similar and generally not differentiated in the clinical microbiology laboratory. Among nontuberculous mycobacteria (NTM), MAC (specifically M. avium and M. intracellulare) is the most common cause of pulmonary disease worldwide. (See "Microbiology of nontuberculous mycobacteria".)

It is generally felt that these organisms are acquired from the environment. Mounting evidence suggests that municipal water sources may be an important source for MAC lung infections [8-10]. Unlike M. tuberculosis, there are no convincing data demonstrating human-to-human or animal-to-human transmission of MAC. (See "Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections".)

Pulmonary disease — MAC species (specifically M. avium and M. intracellulare) are the most common cause of NTM pulmonary disease worldwide. The clinical features, diagnosis, and treatment of MAC pulmonary disease are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of nontuberculous mycobacterial pulmonary disease" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

Disseminated disease — Disseminated MAC disease may complicate MAC pulmonary disease through local multiplication and entry into the bloodstream with seeding of other organs and tissues. The disease primarily occurs in severely immunocompromised patients, such as those with advanced HIV infection, hematologic malignancy, or a history of immunosuppressive therapy including therapy with tumor necrosis alpha inhibitors [11-13]. (See "Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections", section on 'Disseminated disease'.)

Disseminated disease following exposure to contaminated equipment used in cardiac surgery has also been described. (See 'M. chimaera associated with cardiac surgery' below.)

Clinical symptoms and signs — Clinically, disseminated MAC manifests as intermittent or persistent fever (>80 percent), night sweats (>35 percent), weight loss (>25 percent), with additional symptoms including fatigue, malaise, and anorexia [12]. Organ-specific symptoms and signs reflect the major sites of involvement including anemia and neutropenia from bone marrow involvement; adenopathy or hepatosplenomegaly from lymphoreticular involvement; diarrhea, abdominal pain, hepatomegaly, and elevations of liver enzymes from involvement of the gastrointestinal tract; and cough and lung infiltrates from pulmonary involvement.

Diagnosis — The diagnosis is most readily established by culture of blood for mycobacteria. It is important to note that mycobacterial blood cultures are collected in special media, different from the media used in standard bacterial blood cultures, and must be specifically requested. Mycobacterial cultures must be specifically requested so that the cultures are not discarded before there has been time to detect mycobacterial growth. Although mycobacterial growth can sometimes be detected as early as a few days after obtaining the culture, in general, mycobacterial cultures cannot be confidently deemed negative until six weeks have passed without growth.

Specimens from bone marrow, or fluid or tissue from suspected sites of involvement should also be submitted for culture and histopathology. Noncaseating granulomas on pathology are supportive of mycobacterial involvement. Bacillary forms may be visible on acid-fast staining, but their absence does not rule out the possibility of infection.

Although molecular testing has been used for epidemiological investigation, such techniques are generally not clinically available.

Management — Limited data are available to guide management of disseminated MAC in patients without HIV infection. Medical therapy typically consists of several antimycobacterial agents for at least several months. Correction of immunosuppression is also essential for an optimal response to therapy. Patients with disseminated disease may also require adjunctive surgical intervention (eg, valve replacement, joint replacement, or debridement of infected bone) for clinical cure.

For patients with macrolide-susceptible disease, a multidrug regimen similar to that used for pulmonary MAC disease (ie, a macrolide plus ethambutol plus a rifamycin) is generally used. Patients with extensive, severe, or life-threatening disease should also receive a parenteral aminoglycoside, such as amikacin, during the initial 8 to 12 weeks of therapy, although even longer periods of parenteral therapy may be required.

If the isolate is macrolide-resistant, therapy consists of ethambutol plus a rifamycin, preferably rifabutin, plus a parenteral aminoglycoside. The addition of another antimycobacterial agent, such as clofazimine, may also be of some value, although there are few data supporting its use in this setting. The fluoroquinolones have no demonstrated activity or value in this setting.

Oral agents are administered daily. Parenteral aminoglycosides (eg, amikacin) are administered three to five times weekly. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Regimen selection'.)

The optimal duration of treatment has not been established, but treatment is usually administered for at least six months. The precise duration depends on the underlying cause or predisposition for the disseminated MAC infection. As an example, for patients with easily remediable sources of MAC dissemination (ie, without a sequestered site of infection), six months of therapy may be adequate. In contrast, for patients with MAC infections in areas where antibiotic penetration is suboptimal, such as bone or joints, 12 months of therapy is likely necessary for cure. Similarly, for those patients with underlying immunosuppression, the duration of therapy depends on the severity and reversibility of the immune deficits. For patients with reversible or temporary immunosuppression, treatment duration is similar to that for patients with HIV and disseminated MAC who recover immune function (ie, at least 12 months of treatment with at least six months of immune reconstitution). For patients with persistent and severe immunosuppression, the adequate duration of therapy is not established, and may be open ended. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Duration of MAC therapy'.)

One difficult aspect of treating extra-pulmonary MAC infection is the lack of diagnostic tools to measure treatment outcome. Whereas sputum AFB cultures and chest radiographic studies are relatively easy to obtain and follow to evaluate a patient's response to therapy for pulmonary MAC disease, obtaining sequential cultures may be essentially impossible for many extra-pulmonary sites. The reliability of sequential imaging for sites such as bone and joints is also not established. (See "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults", section on 'Monitoring during therapy'.)

M. chimaera associated with cardiac surgery — Mycobacterium chimaera is a MAC species that has generally been thought to have relatively low virulence, at least as a pulmonary pathogen. Two prolonged outbreaks of M. chimaera prosthetic valve infections and associated disseminated infection, in which the source was determined through epidemiologic and molecular analysis to be the heater-cooler unit used for cardiac bypass procedures, were first described in 2015 in Europe and the United States [14,15], and subsequent clusters have been reported elsewhere [16,17]. Molecular testing further suggested that the source of contamination of the implicated heater-cooler devices (Stockert 3T) was the manufacturing facility itself [18]. In the United States, the Food and Drug Administration and Centers for Disease Control and Prevention have made several recommendations to try to lower the risk of additional infections [19,20]. These include removing from service any Stockert 3T heater-cooler device that has tested positive for M. chimaera or that has been associated with known M. chimaera infections, replacing accessories and connectors that were used with such devices, and refraining from using any 3T heater-cooler device manufactured before September 2014 except in emergent situations when no other device is available. These infections can also be avoided by physically removing heater-cooler devices from the operating room. Testing of devices to identify contamination is not recommended because of technical challenges and a high rate of false-negative tests.

Although the risk is low, providers of patients who have undergone cardiac surgery should be aware of the possibility of M. chimaera infection if they develop signs and symptoms compatible with disseminated mycobacterial disease (eg, persistent fever, night sweats, weight loss). The majority of the patients described in the outbreaks presented with prosthetic valve endocarditis accompanied by other signs of disseminated disease including ocular emboli, bony involvement (eg, vertebral osteomyelitis), splenomegaly, pancytopenia, hepatitis, and renal impairment [14,15,17,21]. Other cases have involved surgical site infection. Patients presented months to years following the surgical procedure. Patients who have a presentation compatible with disseminated M. chimaera infection should have several mycobacterial blood cultures; depending on the clinical presentation, specimens from other sites should also be collected for microbiological and pathological testing [22]. (See 'Clinical symptoms and signs' above and 'Diagnosis' above.)

Treatment of the prosthetic valve and disseminated M. chimaera infections requires combined medical and surgical approaches. M. chimaera appears to be similar to other MAC species with regard to antibiotic responses and should be treated with the same macrolide-based regimens as other MAC species such as M. avium and M. intracellulare. However, similar to other MAC species, treatment success is not guaranteed with macrolide-based therapy. (See 'Management' above.)

This outbreak is unusual from many perspectives but especially with regards to the causative organism, which had traditionally been thought of as having low virulence. There is also no precedent for a similar outbreak of nosocomial mycobacterial prosthetic valve endocarditis. The reason that this pathogen has manifest now with this clinical presentation is unknown. Nevertheless, the relatively rapid identification of an unusual pathogen as the cause of a nosocomial outbreak and the identification of the environmental source of the infecting organism is a testament to the utility of molecular epidemiologic techniques for mycobacteria [23].

MYCOBACTERIUM KANSASII — 

Unlike other NTM, M. kansasii has never been found in soil or natural water supplies but has been recovered consistently from tap water in cities where M. kansasii is endemic. Thus, there appears to be an association between clinical disease and potable water supplies. (See "Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections", section on 'Environmental sources'.)

M. kansasii usually presents as lung disease that is nearly identical to tuberculosis, although fever may be less common [24]. The clinical features and diagnosis of M. kansasii pulmonary infection are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of nontuberculous mycobacterial pulmonary disease".)

Disseminated infection is a rare complication that occurs in immunocompromised hosts such as those with HIV infection. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV", section on 'Mycobacterium kansasii'.)

RAPIDLY GROWING MYCOBACTERIA — 

Rapidly growing mycobacteria (RGM) include three clinically relevant species: M. abscessus (including three subspecies: abscessus, massiliense, and bolletii), M. fortuitum, and M. chelonae (table 1). The RGM are environmental organisms found worldwide that usually grow in culture in less than one week following initial isolation, and may sometimes grow on standard microbiologic media (rather than requiring special mycobacterial media). Pulmonary disease due to rapidly growing mycobacteria (RGM) is predominantly due to M. abscessus subsp abscessus and subsp massiliense and, less commonly, subsp bolletii. M. fortuitum and M. chelonae are rarely associated with lung disease. This is discussed in detail separately. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Pulmonary infection'.)

As noted above, disseminated NTM disease usually occurs in the immunosuppressed host. Perhaps surprisingly, M. abscessus is not an important pathogen in patients with HIV. However, in 2000, a previously unrecognized clinical entity of disseminated infection following lymphadenitis was reported in a group of 19 patients from northeast Thailand without HIV [25]. A follow-up report from this region in 2007 described 129 patients with chronic lymphadenitis and subsequent progressive involvement of other organs (eg, skin and soft tissue, lung, bone and joint, liver); 99 of 129 cases involved RGM [26]. Almost half of the patients also had other opportunistic infections, consistent with an underlying T-cell defect. In a subsequent study that included patients in Thailand and Taiwan who did not have HIV but had disseminated NTM (with both slow and rapidly growing species) or other opportunistic infections, the majority had neutralizing anti-interferon gamma autoantibodies [27]. There are only rare patients with a similar syndrome reported in the United States or Western Europe. Evaluation for neutralizing anti-interferon gamma autoantibodies should be performed in patients with disseminated NTM disease and no apparent predisposing risk factor.

RGM occasionally cause skin and soft tissue infections. This is discussed in detail separately. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Skin and soft tissue infection'.)

OTHER NONTUBERCULOUS MYCOBACTERIA

Mycobacterium marinum — Although infection with M. marinum is uncommon, the epidemiology of M. marinum disease is distinctive from the species described above. The natural habitat of M. marinum is aquatic, as the name suggests. It is found in fresh and salt water, including marine organisms, swimming pools, and fish tanks.

M. marinum causes cutaneous disease as a consequence of exposure to water, usually in the context of a minor abrasion, laceration, puncture wound, or bite wound. Skin infections can occur from putting one's hand into a contaminated fish tank, resulting in the condition called fish tank granuloma [28]. In a series of 63 cases from France, 84 percent were linked to fish tank exposure [29]. A similar epidemiologic pattern has been found in the United States, along with the recognition that M. marinum may cause a positive tuberculin skin test [30].

A 50-year epidemic of chronic progressive skin disease among residents of Satowan, in the Federated States of Micronesia, began after World War II [31]. In a case-control study, risk factors for disease were taro farming, which is done in standing water that reaches ankle height, and contact with water-filled World War II-era bomb craters. Histopathology of nine skin lesions demonstrated suppurative granulomatous inflammation and nontuberculous mycobacteria DNA was detected by polymerase chain reaction in seven of nine specimens. The two samples that were able to be sequenced had 95 and 87 percent identity to M. marinum.

Mycobacterium xenopi — M. xenopi is a slow-growing nontuberculous mycobacterium that is an opportunistic and nosocomial pathogen. It is an uncommon pathogen that most frequently causes pulmonary infection.

Its survival in water systems and resistance to common disinfectants enable M. xenopi to contaminate laboratory samples and medical devices such as bronchoscopes, thus causing healthcare-acquired pseudoinfections and laboratory contamination. In a retrospective review of 136 cases of M. xenopi infection seen over a 20 year period in France, three types of pulmonary disease were observed that varied with the host: acute infiltrates in immunocompromised hosts, solitary nodular disease in immunocompetent hosts, and cavitary disease in patients with preexisting lung disease [32]. A report from the Netherlands suggests a predominance of M. xenopi infections in males with preexisting lung disease [33]. A study from Great Britain suggests an unusually high mortality rate in such patients for unclear reasons [34].

The most common extrapulmonary sites are bone and joints. Fifty-eight cases of nosocomial spinal infection occurred in healthy patients following percutaneous nucleotomy for lower back pain or sciatica [35,36]. The outbreak stemmed from the practice of rinsing the surgical instruments with tap water. There were also seven cases of M. xenopi arthritis following invasive surgical procedures [37].

Mycobacterium haemophilum — M. haemophilum is slow-growing nontuberculous mycobacterium that is thought to live in water [38]. It has a predilection for causing skin and soft tissue infections, particularly in immunocompromised hosts because it grows at 30°C [39]. It is the second most common cause of cervical lymphadenitis in children [40], and has been reported rarely to cause lymphadenitis in immunocompetent adults [41].

M. haemophilum was identified as the cause of an outbreak of skin and soft tissue infection and cervical lymphadenitis in 12 immunocompetent individuals, which occurred in the setting of application of permanent makeup to the eyebrows performed by a single makeup artist in Switzerland [42].

M. haemophilum is difficult to isolate because it requires special media and conditions (incubation at 30°C) for growth. (See "Microbiology of nontuberculous mycobacteria", section on 'Infrequent or difficult to culture NTM'.)

Mycobacterium simiae — M. simiae is a rare cause of chronic lung disease; it can also cause disseminated infection [43]. Only a minority of M. simiae respiratory isolates obtained from immunocompetent individuals are clinically relevant, making interpretation of the clinical significance of M. simiae isolates difficult [44]. Interpreting the clinical significance of M. simiae isolates is especially important due to the extreme difficulty effectively treating true M. simiae lung disease.

M. simiae has been isolated in the Southwestern United States and in other areas of the world such as Israel, Cuba, and Western Europe [3,44].

Mycobacterium szulgai — M. szulgai is an uncommon cause chronic lung disease, although when isolated, it is usually associated with clinically significant disease [43]. M. szulgai has been recovered from environmental sources and infection is usually associated with preexisting pulmonary conditions such as chronic obstructive lung disease or healed tuberculosis [45].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria".)

SUMMARY

●Species overview – Nontuberculous mycobacteria (NTM) species are mycobacterial species other than those belonging to the Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM are generally free-living organisms that are ubiquitous in the environment. (See 'Introduction' above.)

•MAC species – Mycobacterium avium complex (MAC) encompasses multiple species including Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera. MAC species are genetically similar and generally not differentiated in the clinical microbiology laboratory. They are the most common cause of pulmonary disease worldwide. (See 'Mycobacterium avium complex' above.)

•Rapidly growing species – Rapidly growing mycobacteria (RGM) include three clinically relevant species: Mycobacterium abscessus (including three subspecies: abscessus, massiliense, and bolletii), Mycobacterium fortuitum, and Mycobacterium chelonae. Pulmonary disease due to RGM is predominantly due to M. abscessus. (See 'Rapidly growing mycobacteria' above.)

•Mycobacterium kansasii – M. kansasii usually presents as lung disease that is nearly identical to tuberculosis. Unlike other NTM, M. kansasii has never been found in soil or natural water supplies, but has been recovered consistently from tap water in cities where M. kansasii is endemic. (See 'Mycobacterium kansasii' above.)

•Other NTM species – Other species that are uncommon causes of lung disease include Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium szulgai, and Mycobacterium simiae; their prevalence varies by geography. Mycobacterium marinum and Mycobacterium haemophilum cause skin and soft tissue infections. (See 'Other nontuberculous mycobacteria' above.)

●Clinical syndromes – In general, NTM causes four clinical syndromes (see 'Spectrum of clinical syndromes' above):

•Pulmonary disease – This is the most common clinical manifestation of NTM infection and is caused primarily by MAC, M. abscessus subsp abscessus, and Mycobacterium kansasii. Symptoms are variable and nonspecific include cough (productive or dry), fatigue, malaise, weakness, dyspnea, chest discomfort, and occasionally hemoptysis. The two major clinical presentations are nodular/bronchiectatic disease and cavitary disease. (See 'Pulmonary disease' above.)

•Superficial lymphadenitis – Cervical lymph nodes are most frequently involved. This occurs primarily in children and is caused mostly by MAC, Mycobacterium scrofulaceum, and, in Northern Europe, M. malmoense and M. haemophilum. (See "Nontuberculous mycobacterial lymphadenitis in children".)

•Disseminated disease – This most commonly occurs in immunocompromised individuals and is most commonly caused by MAC. Symptoms include persistent fever, night sweats, and weight loss, as well as organ-specific symptoms at seeded sites of infection. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

•Infection of the skin, soft tissue, bones, and joint – This is usually a consequence of direct inoculation and is caused primarily by M. marinum and Mycobacterium ulcerans, the RGM, and other NTM species including MAC. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)