Online Medical Reference

Nontuberculous Mycobacterial Disorders

Octavian C. Ioachimescu

J. Walton Tomford

Published: August 2010

Taxonomy

Mycobacteria other than Mycobacterium leprae, M. tuberculosis, and M. bovis were identified from human sources as early as 1885, but it was not until almost 65 years later that human infection was attributed to these organisms. Between the early 1950s and 1980s, there was increasing awareness of the spectrum of disease caused by the nontuberculous mycobacteria (NTM), although the number of cases was small. In the 1980s, in the early days of HIV infection, it was recognized that M. avium complex and M. kansasii organisms commonly caused disseminated infections in patients who were severely immunocompromised. Currently, the epidemiology and clinical features of the NTM diseases are dominated by their occurrence in patients with HIV infection and, more recently, in patients on tumor necrosis factor α (TNF-α) pathway blockers. However, disease caused by this group of organisms continues to occur in persons without detectable systemic immune dysfunction (e.g., recipients of prosthetic knees, fish tank granuloma, hot tub lung).

The genus Mycobacterium is composed of more than 100 species characterized by complex lipid-rich cell walls, which confer the acid-fast staining property. Mycobacterial species were classically differentiated using cultural and biochemical properties, but genetic differences are now used for this purpose, especially 16S ribosomal RNA sequence differences. The published mycobacterial species and subspecies, which number 139 (as of January 2008), are included in the List of Prokaryotic Names with Standing in Nomenclature. The genus Mycobacterium contains two obligate pathogens, the M. tuberculosis complex and M. leprae. The M. tuberculosis complex contains several related mycobacteria (i.e., M. bovis—including bacillus Calmette-Guérin [BCG], M. africanum, M. microti, and M. cannetti), which on DNA analysis are all variants of M. tuberculosis. The other species live freely in the environment (water and soil) and are thus often termed environmental mycobacteria or nontuberculous mycobacteria; we prefer the latter term.

NTM have been called in the past “atypical” mycobacterial species or mycobacteria other than tuberculosis (MOTT). These microbes share many common properties, such as acid fastness and the ability to cause pulmonary and extrapulmonary granulomatous disorders. As a group, they comprise diverse organisms with dissimilarities in their cultural characteristics and pathogenicity to humans compared with M. tuberculosis (MTB). There are many organisms in this group capable of causing human infections. Infections caused by M. avium-intracellulare (MAI) complex became common in patients with severe HIV infection—in patients with low CD4 lymphocyte counts—or in AIDS, for which it is a disease-defining condition. NTM cause significant lung disease in individuals with structural abnormalities (e.g., patients with bronchiectasis and chronic obstructive pulmonary disease with M. kansasii infection) and in those with immunodeficiency syndromes (e.g., M. avium infection in HIV-AIDS patients).

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Classification

NTM classifications have generally not been helpful to the clinician. The most widely used classification in the past, the Runyon system, was based on microbiologic characteristics of the organisms, such as growth rate in cultures and colony pigment formation in the presence or absence of light. Familiarity with the Runyon system remains useful for presumptive laboratory identification of possible NTM pathogens; however, positive identification of NTM species is now largely based on biochemical and molecular biology techniques. Classification of NTMs based on the organ system of primary involvement (e.g., lungs, lymph nodes, disseminated, skin, and soft tissue) is more useful to the clinician and will be used hereafter (Table 1). Based on culture characteristics, NTM are subclassified into the following main groups: the slow, intermediate, and rapid growers, with varying nutritional requirements.

Table 1 Major Clinical Syndromes Associated with Nontuberculous Mycobacteria Infections
Syndrome Common Causes Less-Common Causes
Pulmonary disease (especially in adults) Mycobacterium avium-intracellulare, M. kansasii, M. abscessus Uncommon: M. fortuitum, M. malmoense, M. szulgai, M. scrofulaceum, M. smegmatis, M. simiae, M. xenopi
Rare: M. celatum, M. asiaticum, M. shimodei
Cervical and lymphadenitis (especially children) M. avium, M. intracellulare M. scrofulaceum, M. malmoense, M. abscessus, M. fortuitum
Skin and soft tissue disease M. fortuitum, M. chelonae, M. abscessus, M. marinum M. haemophilum, M. kansasi, M. smegmatis, M. ulcerans
Skeletal (bones, joints, tendons) disease M. marinum, M. avium complex, M. kansasii, M. fortuitum group, M. abscessus, M. chelonae M. haemophilum, M. scrofulaceum, M. smegmatis, M. terrae-nonchromogenicum complex
Catheter-related infections M. fortuitum, M. abscessus, M. chelonae M. mucogenicum
Disseminated infection HIV-seropositive host: M. avium, M. kansasii M. haemophilum, M. genavense, M. xenopi, M. marinum, M. simiae, M. intracellulare, M. scrofulaceum, M. fortuitum
HIV-seronegative host: M. abscessus, M. chelonae M. marinum, M. kansasii, M. haemophilum, M. fortuitum

Slow-Growing Mycobacteria

The slow-growing group includes species of mycobacteria that require usually more than 14 days of incubation for mature growth; some may require nutritional supplementation of routine mycobacterial media. The most common clinically important species found in this group include the M. avium complex (M. avium and M. intracellulare), M. kansasii, M. xenopi, M. simiae, M. szulgai, M. scrofulaceum, M. malmoense, M. terrae-nonchromogenicum complex, M. haemophilum, and M. genavense. These organisms grow best at 35° to 37° C, with the exception of M. haemophilum, which has a preference for lower temperatures (28° to 30° C) and the presence of iron, and M. xenopi, which grows optimally at 42° C. Newer isolated slow-growing species include M. celatum, M. interjectum, M. confluentis, M. triplex, M. lentiflavum, M. branderi, M. conspicuum, M. cookii, and M. asiaticum.

Intermediate-Growing Mycobacteria

The intermediate-growing group includes M. marinum and M. gordonae. These organisms are usually pigmented and require 7 to 10 days of incubation for mature growth. M. marinum has an optimal growth temperature of 30° C, whereas M. gordonae prefers 35° C. M. gordonae is seldom if ever pathogenic, except in severely immunocompromised hosts.

Rapid-Growing Mycobacteria

The rapid-growing group of organisms includes nonpigmented and pigmented species that produce mature growth on agar plates, usually within 7 to 10 days. Nonpigmented pathogenic species are mostly grouped within the M. fortuitum complex, which includes the M. fortuitum group (M. fortuitum, M. peregrinum, and M. fortuitum third biovariant complex) and the M. chelonae-abscessus group (M. chelonae, formerly M. chelonae subspecies chelonae, M. abscessus, formerly M. chelonae subspecies abscessus, and M. mucogenicum, formerly M. chelonae-like organism). M. smegmatis may be pigmented or nonpigmented.

Pigmented, rapid-growing species are difficult to identify by traditional laboratory methods. Rapid-growing pigmented species occasionally isolated in clinical disease include M. phlei, M. aurum, M. flavescens, M. neoaurum, M. vaccae, and the thermophilic species M. thermoresistible.

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Epidemiology

In the United States, the number of significant NTM isolates continues to increase, in parallel with a recent increase in the number of immunocompetent patients with NTM disease (primarily lung disease) and a slow decline of tuberculosis (TB). Factors that may be contributing to this increase include the following:

  • An increased number of clinical specimens submitted for acid-fast bacilli (AFB) stains and cultures
  • Improved laboratory techniques, which have made identification and isolation of NTM more rapid and accurate
  • Higher recognition of NTM disease, especially in chronic pulmonary disease and in immunocompetent patients (e.g., older women with MAI disease)

Evidence is mounting to show that the environment is the major source of human NTM infection. NTM are ubiquitous in the environment and have been isolated from water (most cases), soil, dust, domestic and wild animals, milk, and food. DNA fingerprinting techniques—restriction fragment length polymorphism analysis by pulsed field gel electrophoresis and major polymorphic tandem repeat probe sequence analysis—have been useful for epidemiologic investigation (e.g., point source epidemics). These techniques also may provide clues to pathophysiologic differences among NTM species. For example, there appears to be great genetic variability among MAI isolates from different patients and sometimes even from the same patient. In contrast, clinical M. kansasii isolates generally have similar genotypes, suggesting that most clinical isolates are clonal. This clonal nature of most clinical isolates of M. kansasii would seem unusual for environmental species such as MAI, and suggests that their colonization of environmental sites of human disease acquisition (e.g., municipal water supplies) is fairly recent and involves only select genotypes.

Unlike TB, disease caused by NTM is rarely if ever transmitted from patient to patient. Infection is acquired from the environment; pulmonary disease is probably caused by the inhalation of aerosols of water containing the mycobacteria. The incidence of disease caused by NTM is somewhat independent of that of TB, but is determined by the number, distribution, and species of NTM in the environment and the susceptibility of the human population. In regions where TB is common, only a small minority of cases of pulmonary mycobacterial disease will be caused by NTM. By contrast, in regions where TB is rare, such as rural areas of western Europe and the United States, a much higher proportion of pulmonary mycobacterial disease is caused by NTM. There are geographic variations in distribution of the species of NTM: whereas the MAI complex occurs worldwide, others, such as M. xenopi and M. malmoense, are restricted to certain regions. M. xenopi is the second most common NTM causative organism in Canada and the United Kingdom, and M. malmoense is the second most common NTM disease in Sweden and other northern European countries. M. ulcerans infections occur mostly in Australia and tropical countries. Although MAI disease has a worldwide distribution, disseminated MAI is rarely seen in people from central Africa who have AIDS, even though MAI can be recovered from that environment. One possible explanation is that those who have AIDS in Africa may die from infection with more aggressive pathogens such as M. tuberculosis before their immunosuppression becomes severe enough to develop disseminated MAI. In addition, the distribution of species varies with time, possibly as a result of environmental changes.

Immune reactions elicited by exposure to NTM have been postulated as a cause of the wide geographic variation in the protective efficacy of BCG. One possible explanation is that repeated contact with NTM leads to protective immunity equivalent to that conferred by BCG; in this case, BCG vaccination would not add any protective effect. Another explanation is that the immune response in TB is qualitatively different, eliciting protective immunity or a delayed hypersensitivity reaction, with possible disease progression. The switch between the two responses is determined by helper T cell 1 (Th1) versus helper T cell 2 (Th2) T lymphocyte selection in the immune response. A predominant Th1 response facilitates protective immunity, whereas a superimposed Th2 response seems to be associated with tissue necrosis. When given neonatally, BCG confers protection against TB inducing a Th1 response, but later in life it boosts or fails to downregulate an environmentally determined harmful Th2 component and therefore fails to protect from—and may even predispose to—active TB. A third hypothesis, supported by mouse models, is that environmental sensitization to M. avium (but not M. fortuitum and M. chelonae) prevents the multiplication of BCG in tissues, which is essential for the development of protective immunity. These hypotheses are not mutually exclusive.

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Virulence and Pathogenicity

Many questions surround the determinants of virulence of M. tuberculosis and M. leprae, and even less is known about the virulence of NTM. A mouse model has revealed three patterns of pathogenicity. After intravenous inoculation in immunocompetent mice, most tested species were found to replicate progressively in the liver and spleen; some replicated in these organs in interferon gamma (IFN-γ)-deficient mice, but not in immunocompetent mice (e.g., M. heidelbergense and M. intermedium). Others were eliminated in both types of mice (e.g., M. confluentis and M. lentiflavum). The relevance of these findings to human disease remains to be established, but they suggest that IFN-γ is not a crucial determinant of protection in all forms of mycobacterial disease. For the clinician, it is important to emphasize that NTM disease can occur in immunocompetent hosts.

There are few data on the relative virulence of NTM in humans. Although some species such as MAI and M. kansasii are recognized as pathogens, others such as M. gordonae are often isolated as nonpathogenic contaminants of the respiratory tract but only occasionally as causes of overt disease. In the presence of immunosuppression, all NTM must be regarded as potential pathogens, but some species are particularly associated with disease. For unknown reasons, HIV-positive patients are particularly prone to develop disease caused by certain genetic variants of MAI.

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Clinical Syndromes

Five major clinical syndromes have been described that are attributable to NTM (see Table 1): pulmonary disease; lymphadenitis; skin, soft tissue, and skeletal infections; catheter-related bloodstream infections; and disseminated disease, especially in persons with AIDS or severely immunocompromised hosts (e.g., individuals on high-dose corticosteroids). There is limited documentation (if any) of person-to-person transmission of NTM. Nosocomial infections and outbreaks caused by inadequate disinfection or sterilization of medical devices or environmental contamination of medications or medical devices have been described.

Pulmonary Disease

Pulmonary disease caused by NTM may occur as a component of disseminated infection, but often the disease affects only the lungs (Table 2). Four main categories of pulmonary disease can be nosologically identified. First, the disease occurs in middle-aged or older patients, usually men with a history of lung disease. Second, the disease occurs in otherwise apparently healthy persons, although some may have minor and covert immune defects. Third, the disease occurs in children with more severe immune defects or predisposing pulmonary disease, notably cystic fibrosis or severe fungal infection (e.g., invasive or semi-invasive Aspergillus disease). Fourth, the disease occurs in very immunosuppressed patients, of which HIV infection is the prevalent cause worldwide. Also, it is important to emphasize that patients with NTM diseases do not need to be isolated because of the noncontagiousness of these conditions.

Table 2 Clinical Settings for Nontuberculous Mycobacteria Lung Disease
Radiographic Disease Setting Usual Pathogen Rare Pathogen
Upper lobe cavitary Male smokers, often abusing alcohol, usually in their early 50s M. avium complex, M. kansasii
RML, lingular nodular bronchiectasis Female nonsmokers, usually older than 60 yr M. avium complex, M. abscessus M. kansasii
Localized alveolar, cavitary disease Prior granulomatous disease (usually tuberculosis) with bronchiectasis M. abscessus, M. avium complex
Not well established Adolescents with cystic fibrosis M. avium complex, M. abscessus
Reticulonodular or alveolar lower lobe disease Achalasia, chronic vomiting secondary to GI disease, exogenous lipoid pneumonia (mineral oil aspiration, etc.) M. fortuitum M. abscessus, M. avium complex, M. smegmatis
Reticulonodular disease HIV-positive hosts, patients with preexisting bronchiectasis, others M. avium complex

GI, gastrointestinal; HIV, human immunodeficiency virus; RML, right middle lobe.

Patients with Predisposing Lung Disease

Most patients are men with a history of smoking, bronchiectasis, chronic obstructive lung disease, rheumatoid lung, healed TB, or exposure to industrial dusts as a result of mining, sandblasting, or welding. Risk factors have been evaluated in South African gold miners with pulmonary mycobacterial disease. In this study,1 51 patients with disease caused by NTM and 425 with TB were similar with regard to age, education, home region, and smoking habits. Those with disease caused by NTM were more likely to have been previously treated for TB, worked longer underground, or have evidence of silicosis. Patients with disease caused by NTM were less likely to be HIV-positive (35.3%) than those with TB (48.8%), although the difference was not statistically significant. Pulmonary disease caused by M. kansasii is particularly associated with underlying lung damage such as pneumoconiosis or silicosis, which leads to slowly progressive and insidious disease in miners and other workers. This species has been recognized since 1977 as the most common cause of NTM pulmonary disease in South African gold miners. The disease occurs in both HIV-positive and HIV-negative patients, and most have had radiologic evidence of silicosis. Disease caused by M. kansasii in HIV-positive gold miners differs from that occurring in HIV-positive patients without the risks associated with mining. Thus, in miners, the disease occurs much earlier in the course of HIV infection, with CD4+ T cell counts being significantly higher, and clinically it more closely resembles the disease in HIV-negative patients. It has been noted that assessment of the clinical significance of sputum isolates of M. kansasii in this group of patients by American Thoracic Society guidelines2 is not straightforward.

Old TB lesions may be colonized or infected by NTM. In one study in Japan, 75% of mycobacteria isolated from sputum more than 1 year after completion of therapy for TB were NTM. The presence of such mycobacteria could lead to a false diagnosis of recurrence of TB. In some cases, disease caused by M. xenopi has been superimposed on aspergillomas in old cavities; this disease has a generally poor prognosis and response to therapy.

Immunocompetent Hosts

A number of cases, mostly caused by MAI complex, have been reported in older people, principally nonsmoking women with no other evidence of lung disease except for the associated bronchiectasis. It has been postulated that such disease in women is associated with the practice of coughing quietly and covertly, thereby suppressing the clearance of sputum. The disease has accordingly been termed Lady Windermere syndrome after the fastidious aristocrat in Oscar Wilde’s play, “Lady Windermere’s Fan.”3 We prefer not to use “Lady Windermere syndrome,” mainly because the term is not comprehensive and does not illustrate the full spectrum of the disease. If the disorder continues undetected for years, cavities develop in the lungs and respiratory failure may ensue; however, the natural history of this disorder is unpredictable. The causative organisms include MAI and M. kansasii and, less frequently, M. xenopi, M. scrofulaceum, M. szulgai, M. malmoense, M. simiae, M. celatum, and M. chelonae. A similar but less common form of pulmonary disease caused by NTM has also been reported in apparently immunocompetent men.

A bizarre characteristic of 10 previously healthy patients with diffuse pulmonary disease caused by NTM (M. avium in 9 of the 10 cases) was that they all bathed in hot tubs. Although this serious condition was termed hot tub lung, further studies are required to confirm whether the use of such tubs is an important predisposing factor.4 Although the patients described appeared clinically and immunologically normal, it is possible that they had minor immune defects. On detailed investigation, some patients with pulmonary disease caused by NTM have been found to have such defects, although it is not clear whether these were a cause or consequence of the disease.

Children

Although rare in childhood, a few cases caused by MAI, M. chelonae, and M. fortuitum have been reported in children with cystic fibrosis. Children with deteriorating lung function should be screened for NTM because therapy can, in some cases, halt the deterioration. Familial susceptibility to NTM disease, but not to M. tuberculosis, can be linked to different mutations in four genes. These mutations result in eight different clinical syndromes, all characterized by impaired cell-mediated immune responses mediated by IFN-?. Because these syndromes vary in severity and require different therapeutic strategies, identification of the underlying genetic defect is important.

Immunosuppressed Hosts

Mycobacteria, both M. tuberculosis and NTM, are common causes of lung disease in HIV-positive patients. In general, the isolation of NTM, and most notably of MAI complex, from the respiratory tract of an HIV-positive person is more likely to be clinically significant than from an HIV-negative person. Cough is a common complaint irrespective of HIV status, but HIV-positive patients are more likely to have fever. Abnormal chest radiographs are common, with HIV-positive patients being more likely to have diffuse abnormalities. In one study, a specific diagnosis was made in 20 of 25 HIV-positive patients with cavitating lung lesions.8 Bacteria, often more than one species, were the cause in 17 patients. Mycobacteria were isolated in 8 patients. Mediastinal or hilar lymphadenopathy and additional ill-defined, noncavitating, nodular opacities were seen more frequently in patients with mycobacterial pathogens.

Localized Cutaneous, Soft Tissue, and Bone Infections

Skin and Subcutaneous Diseases

Postinoculation lesions usually affect skin or subcutaneous tissues following a traumatic inoculation. This can take the form of swimming pool (or fish tank) granuloma or Buruli ulcer, the latter mainly outside the United States. Although all species of NTM have been incriminated in cutaneous NTM disease, M. marinum and rapid-growing mycobacteria most often cause localized skin infections. M. marinum causes an infection historically recognized as swimming pool or fish tank granuloma. Most infections occur 2 to 3 weeks after contact with contaminated fresh or salty water from one of these sources. The lesions are most often small violet papules on the hands and arms that may progress to shallow crusty ulcerations and scar formation. Lesions are usually singular. However, multiple ascending lesions resembling sporotrichosis (sporotrichoid disease) can occasionally occur; in our experience, the antifungal-resistant sporotrichosis is the most common presentation. Most patients are clinically healthy with a previous local hand injury that became infected while cleaning a fish tank, or patients may sustain scratches or puncture wounds from saltwater fish, shrimp, or fins contaminated with M. marinum. Diagnosis is made from culture and histologic examination of biopsy material, along with a compatible history of exposure. There is no treatment of choice for M. marinum; traditionally, the regimen has been a combination of rifampin and ethambutol or monotherapy with doxycycline, minocycline, clarithromycin, or trimethoprim-sulfamethoxazole, given for a minimum of 3 months. Clarithromycin has been used increasingly because of good clinical efficacy and minimal side effects, although published experience is limited. Because M. marinum grows better at lower temperatures, local heat can produce amelioration.

The rapid-growing species M. abscessus, M. fortuitum, and M. chelonae are probably the most common NTM involved in cases of community-acquired infections of skin and soft tissue. Localized traumatic injury, such as puncture wounds from stepping on a nail, and open lacerations or fractures are the usual scenarios. An outbreak in California was associated with contamination of a post–leg shaving solution, causing mycobacterial abscesses of the lower extremities.5 Occasionally, these infections may involve slow- growing species, including M. avium complex, M. kansasii, and M. terrae-nonchromogenicum complex.

Sporadic cases of nosocomial skin and soft tissue disease have also been described as possible point source outbreaks. These cases include infections of long-term IV or peritoneal catheters, postinjection abscesses, surgical wound infections such as those after cardiac bypass surgery, and augmentation mammaplasty. In ophthalmology, rapid-growing species may cause keratitis and corneal ulceration after surgery, as well as infection after local accidental trauma. Clustered outbreaks or pseudo-outbreaks of mycobacterial skin, soft tissue, or bone infections have been described and usually result from contaminated fluids such as ice made from tap water, water, injectable medicines, and topical skin solutions. Most of these outbreaks have involved the rapid-growing species M. fortuitum and M. abscessus. The reservoir for these outbreaks has generally been municipal or distilled (hospital) water supplies. These and other species such as M. avium complex and M. xenopi are incredibly resistant, can endure temperatures of 45° C and higher (MAI complex and M. xenopi), and may resist the activity of commonly used disinfectants.

Diagnosis of all types of skin and soft tissue infections is made by culture of specific NTM from drainage material or tissue biopsy (swabs are useless). Treatment may include amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, sulfonamides, and imipenem for the M. fortuitum group, whereas only amikacin, cefoxitin, imipenem, and clarithromycin or only amikacin, imipenem, tobramycin, and clarithromycin have activity against M. abscessus and M. chelonae, respectively. Clarithromycin is generally the first drug of choice for localized disease caused by M. fortuitum, M. chelonae, and M. abscessus, although its use in combination with at least one other drug is preferred. The duration of therapy is usually 4 to 6 months. Antituberculous agents have no efficacy against any of the rapidly growing mycobacteria other than ethambutol for M. smegmatis. Treatment of slow-growing species is similar to that for chronic lung disease, except that the duration of therapy may only be 6 to 12 months.

Two unusual species causing skin and soft tissue infections in select situations are M. ulcerans and M. haemophilum. M. ulcerans is not endemic in the United States, but is endemic in areas of Australia and tropical locations, where it is commonly known as the Buruli ulcer. This infection progresses from an itchy nodule, most often on the extremities, to a necrotic lesion that may result in severe deformity. Treatment success is common in early disease with excisional surgery, rifampin, sulfonamides, and clofazimine but, for advanced ulcerative disease, therapeutic response has generally been poor. Surgical débridement and skin grafting then become the usual therapeutic measures of choice. Studies have suggested that clarithromycin is highly active in vitro.

The second unusual species, M. haemophilum, causes cutaneous infections, primarily of the extremities, in immunosuppressed patients, especially in the setting of organ transplantation, long-term high-dose steroid use, or HIV. A review by Saubolle and coworkers has cited more than 50 cases of M. haemophilum, with almost 80% of them involving skin and soft tissue infections. Careful attention to culture technique is essential because this species requires heme or iron to grow in culture. Therapy for this species usually includes clarithromycin and rifampin or rifabutin.

Skeletal Disease: Bone, Tendon, Ligament, and Joint Diseases

Both rapid-growing and slow-growing species of NTM have been implicated in chronic granulomatous infections involving tendon sheaths, bursae, bones, and joints after direct inoculation of the pathogen through accidental trauma, surgical incisions, puncture wounds, or injections. Most patients have no underlying immune suppression, but those at high risk for pathogens such as M. chelonae and M. haemophilum are patients who are immunosuppressed. MAI complex and M. marinum have been described as causing tenosynovitis of the hand, although the rapid-growing mycobacteria, M. kansasii, and M. terrae complex (especially M. nonchromogenicum) have also been associated with a chronic type of disease. Osteomyelitis of the sternum caused by M. fortuitum and M. abscessus has also been found in clustered outbreaks and sporadic cases after cardiac surgery. Additionally, M. haemophilum has a tendency to involve bones and joints, usually with concurrent draining skin lesions and bacteremia.

Management of mycobacterial bone and soft tissue infections often requires surgical débridement for both diagnosis and therapy, especially for the closed spaces of the hand and the wrist and for patients with infected bones, such as fractured long bones or the sternum after cardiac surgery. Drug therapy for the specific pathogen is also essential.

Lymphadenitis

Lymphadenitis usually affects the cervical lymph nodes in otherwise healthy children younger than 5 years. Lymphadenitis in older persons usually indicates HIV infection or some other form of immunosuppression. Many mycobacterial species are involved. Since the early 1980s, 80% of cases of culture-positive NTM lymphadenitis in children in the United States have been caused by M. avium complex.6 The remainder of cases in Australia and the United States are caused by M. scrofulaceum, and only about 10% of cases have been caused by M. tuberculosis (this should serve as a reminder about this condition). Rarely, other species are recovered, including rapid-growing mycobacteria, M. kansasii, and M. haemophilum. This last species has a special growth requirement for hemin or iron and may present some diagnostic difficulties if iron- or hemin- supplemented media and lower temperatures (incubation at 28°-30° C) are not used. A surprising number of specimens are AFB smear-positive and culture-negative, so a presumptive diagnosis is often based on typical caseating granulomas and a negative culture for M. tuberculosis in the common clinical setting. Skin testing with purified protein derivative–Battey (PPD-B), an antigen prepared from M. avium complex, has been shown to be useful, but the antigen is unavailable except for use in experimental protocols.

Treatment of NTM cervical lymphadenitis is still evolving. Routine biopsy or incision and drainage should be avoided because these procedures often result in the formation of fistulas and chronic drainage. Fine-needle aspiration with cytology and culture has been used increasingly, with apparently few associated problems. The treatment of choice is excision of the involved nodes by an experienced surgeon. Chemotherapy seems to be of little benefit. The potential role of chemotherapy without surgery or as a supplement to surgery in complicated or recurrent disease is being considered with increasing frequency. Clarithromycin combined with ethambutol or rifabutin is the usual suggested regimen (Box 1). However, the established treatment of routine NTM cervical lymphadenitis remains surgical excision, without chemotherapy.

Box 1 Guidelines for Diagnosing NTM Pulmonary Disease
Clinical and radiologic features indicative of mycobacterial disease
AFB smear-positive and/or moderate/heavy growth of NTM on culture in two clinical specimens (e.g., sputum or BAL)
Absence of other pathogens/conditions (e.g., tuberculosis, aspergillosis)
Underlying host conditions (e.g., alcoholism, immunosuppressive conditions, chronic lung disease, cystic fibrosis, lung cancer)
Failure of clearance of the NTM in sputum within 2 weeks of initiation of antimycobacterial therapy
When sputum evaluation in cavitary or noncavitary disease is negative:
Transbronchial or open lung biopsy has histopathologic features of mycobacterial disease and grows NTM on culture
Transbronchial or open lung biopsy does not grow the organism but has histopathologic features of mycobacterial disease and other reasonable causes for granulomatous disease have been excluded

AFB, acid-fast bacilli; BAL, bronchial lavage; NTM, nontuberculous mycobacteria.



Box 2 Proposed Diagnostic Criteria for Nontuberculous Mycobacterial Pulmonary Disease
  • Compatible clinical presentation based on symptoms, radiographic findings (chest radiograph or high-resolution CT scan) and exclusion of other diagnoses
  • Collection of at least three sputum and/or bronchial washing specimens
  • One culture-positive sputum or bronchial washing that is heavily (≥2+) smear-positive or heavily (≥2+) culture-positive
or
  • One culture-positive sputum or bronchial washing associated with multiple smear-positive specimens
or
  • Multiple positive cultures (≥3) over 1 year, regardless of smear positivity
For unusual radiographic presentation or nondiagnostic sputum analysis, lung biopsy (bronchoscopy with transbronchial biopsy) demonstrating granulomatous inflammation or culture positive for NTM is required.
In questionable cases, expert consultation is required.

Catheter-Related Infections

Currently, catheter-related infections are the most common nosocomial NTM infections encountered. They are usually seen with long-term central IV catheters, but they may also occur with peritoneal or shunt catheters. The usual pathogens are rapid-growing mycobacteria. These infections may be manifested as fever, local catheter site drainage, or bacteremia or occasionally as lung infiltrates or granulomatous hepatitis. The usual treatment is catheter removal combined with pus drainage and appropriate antibiotics for 6 to 12 weeks.

Disseminated Diseases

Localized nonpulmonary lesions in the kidneys, bones, joints, and central nervous system have been described, but are exceedingly rare. Most diseases in this category are multifocal, especially to the skin, or widely disseminated. Such diseases are almost always associated with some form of congenital or acquired immune defect, including post-transplantation immunosuppressive therapy. Most cases at present occur in patients with AIDS, and most are caused by MAI.

In the setting of advanced HIV infection, most disseminated NTM disease is caused by M. avium. However, other NTM, including M. kansasii, M. genavense, M. intracellulare, M. haemophilum, M. simiae, M. celatum, M. malmoense, M. marinum, and rapid- growing mycobacteria, have also been cited. In the absence of HIV infection, cases of disseminated MAI complex are rare. Disseminated infections by other NTM species in non-AIDS patients, such as organ transplant recipients or patients receiving chronic steroids, have occurred in all age groups, almost exclusively in immunosuppressed patients. The most commonly reported physical findings in disseminated M. avium infection include fever, weight loss, skin lesions, and enlargement of organs of the reticuloendothelial system. Although anemia often occurs with a hematocrit lower than 25%, and one third of patients with disseminated M. avium infection have elevated alkaline phosphatase levels, laboratory studies and chest radiographs are not usually conclusive in establishing the diagnosis of disseminated NTM disease. The usual method of diagnosis is mycobacterial blood cultures in patients with AIDS or, in other patients, by skin biopsy. The diagnosis of disseminated M. avium is rare in HIV-infected patients with more than 100 CD4+ lymphocytes. Also, patients with hairy cell leukemia seem to be particularly susceptible to MAI infections.7

Disseminated M. kansasii is the second most frequent cause of disseminated NTM disease. Pulmonary and cutaneous manifestations have occurred in patients with chronic lymphocytic leukemia, after organ transplantation, and in those infected by HIV. One study has reported five patients with disseminated M. kansasii infection, including three patients with pulmonary and extrapulmonary involvement and two patients with exclusive extrapulmonary involvement. All patients had CD4+ lymphocyte counts less than 200 cells/?L. The most common clinical manifestation was pulmonary disease with thin-walled cavitary lesions.

The incidence of disseminated M. avium infection can be reduced by the use of prophylactic antimicrobials. Rifabutin, 300 mg daily, clarithromycin, 500 mg twice daily, and azithromycin, 1200 mg weekly either alone or in combination with rifabutin, have all been shown in controlled trials to be effective as prophylactic agents for the prevention of M. avium–disseminated disease and are recommended in patients with a CD4+ cell count lower than 75 cells/?L, even when levels improve with HIV therapy.

The diagnosis of central nervous system involvement by NTM is difficult, and therefore it is extremely important to suspect the diagnosis on the basis of the clinical setting. Nontuberculous mycobacteria are rarely found on routine AFB smear analysis of cerebrospinal fluid (CSF), so a positive AFB culture is usually required to make the diagnosis. The CSF in NTM disease usually shows an elevated white blood cell count with a neutrophilic or lymphocytic predominance. CSF protein and glucose levels may vary widely, from within normal limits to far outside the normal range.

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Diagnosis

Because there are no typical clinical features of NTM disease, diagnosis depends on having a high index of suspicion. Signs and symptoms of NTM pulmonary disease are variable and nonspecific and include chronic cough, sputum production, and fatigue. Malaise, dyspnea, fever, hemoptysis, and weight loss can also occur, usually with advanced disease, but are less common than with tuberculosis.

Although some differences in radiologic features between TB and diseases caused by NTM-and even between different species of NTM-have been described, there is so much overlap in these features that a radiologic determination of the cause is not possible in the individual patient (see Table 2). A radiologic feature noted in some cases was described as a cluster of homogeneous shadows 1 cm across, surrounding a translucent zone, with line shadows radiating from each lesion. Some patients, notably nonsmokers with no other evidence of lung disease, tend to have nodular lesions localized to the middle lobe or the lingula. When MAI causes chest disease in immunocompetent individuals, there are three categories of chest radiograph patterns seen in clinical practice.

The most common appearance is similar to that of apical postprimary TB, with or without cavities. It is not possible to differentiate this disease from TB, although the cavities have been described as being thinner and smaller. Somewhat common are patchy nodular opacities in any zone of the lung, which on computed tomography (CT) scanning are shown to be associated with local bronchiectasis. Least common is the isolated pulmonary nodule. Mediastinal lymphadenopathy and pleural effusion are also rare, especially in MAI infections. Bizarre and rapidly changing radiologic appearances are seen in patients with AIDS and other immunosuppressive disorders. Chest radiographs may appear normal in up to one third of AIDS patients with NTM pulmonary disease. As with TB, diffuse appearances and lymph node enlargement are more common than in immunocompetent persons and cavitation is less common.

Nontuberculous mycobacterial disease is characterized histopathologically by the presence of caseating and noncaseating granulomatous inflammation, epithelial histiocytes, and occasional giant cells. NTM infection cannot be differentiated definitively histopathologically from tuberculosis. Poorly formed granulomas with histiocytic reactions are more commonly reported in immunodeficient patients, especially those who have AIDS, but they can be seen in immunocompetent patients because not all NTM stimulate granuloma formation equally well. Dimorphic granuloma or the absence of caseating necrosis does not rule out TB nor is this specific for NTM disease, because immune status can modulate the pathologic response.

Definitive diagnosis is made by mycobacteriologic examination, preferably from tissue or aspirated specimens. All mycobacteria are acid-fast and the fluorochrome method (auramine stain) is preferred for microscopic recognition of NTM in clinical samples, although it is important to remember that using only fluorochrome stains, several mycobacterial species can be missed. The appearance of NTM by microscopy is sometimes indistinguishable from that of M. tuberculosis, and therefore confirmation of the presence of NTM still requires cultures. Cultures should be inoculated onto one or more solid media (e.g., Löwenstein-Jensen or Middlebrook 7H10 or 7H11) and into a liquid medium as well, given the more rapid recovery of all mycobacteria in broth systems such as the BACTEC system. All skin or soft tissue samples should be incubated at 95° F (35° C) and at 82.4° to 89.6° F (28° to 32° C), because a number of pathogens that infect these tissues, including M. haemophilum and M. marinum, may grow much better at lower temperatures.

As a consequence of the demand for more rapid diagnosis of M. tuberculosis, identification of NTM increasingly focuses on the use of rapid diagnostic systems: high-performance liquid chromatography, which assesses the patterns of long-chain fatty acids (mycolic acids) found in different NTM species, and genetic methods, such as polymerase chain reaction–restriction fragment length polymorphism analysis of a 439-base pair fragment of the 65-kD heat shock protein gene and genetic probes. Commercial genetic probes for mycobacterial RNA are currently available for the identification of M. tuberculosis complex, M. avium, M. intracellulare, M. gordonae, and M. kansasii. For some of the newer species, such as M. genavense, M. cookii, and M. triplex, high-performance liquid chromatography, 16S ribosomal DNA sequencing, or both are important or essential to make a species identification. Traditional biochemical testing to determine carbohydrate uptake and other standard mycobacterial tests such as arylsulfatase, nitrate reduction, and iron uptake provide alternative, although slower, methods for identification of slow-growing and rapid-growing NTM. For epidemiologic studies, standard biochemical and susceptibility tests have been useful in initial strain comparison for most outbreaks involving NTM, although the latter are rare. Molecular methods such as Southern hybridization with repetitive elements, arbitrarily primed polymerase chain reaction, and pulsed-field gel electrophoresis (DNA fingerprinting) of NTM are now the standard for definitive strain comparison of NTM outbreaks.

Most clinical and public health laboratories now use one or more rapid diagnostic methods for mycobacterial species identification, including high-performance liquid chromatography and commercial DNA probes, which are available for identifying isolates of M. tuberculosis, M. gordonae, M. kansasii, M. avium, and M. intracellulare. These probes are highly sensitive and specific and can provide species identification using a culture directly from the broth medium.

Various skin test reagents have been prepared from various species of NTM, including purified protein derivative (PPD-A) from M. avium and PPD-B from M. intracellulare; however, they are not specific, lack standardization and are not clinically useful in the diagnosis of NTM disease. The use of NTM skin test reagents is currently confined to epidemiologic studies and is not available at this time for clinical use in the United States.

One major problem in the diagnosis of pulmonary disease caused by NTM is to establish the clinical significance of these organisms isolated from sputum and other pulmonary specimens by culture or detected by nucleic acid-based techniques. There are no absolute criteria for distinguishing true pulmonary disease caused by NTM from contamination or colonization, but the American Thoracic Society and the British Thoracic Society have issued similar guidelines for reaching a diagnosis, which may be summarized as follows (Boxes 1 and 2):

  • Compatible chest radiograph or CT appearance, including infiltrates, multiple nodules, multifocal bronchial disease, and cavities
  • Compatible clinical symptoms
  • Exclusion of other causes of the symptoms and radiologic signs, including TB
  • Three sputum specimens positive on culture within a 12-month period or two culture-positive specimens if they are also positive for acid-fast bacilli on microscopic examination
  • Heavy growth on culture and AFB seen on microscopic examination of one specimen of bronchial washings
  • Isolation of mycobacteria from a sterile site, including lung tissue obtained by transbronchial biopsy or open lung biopsy

It should, however, be noted that these diagnostic criteria were developed principally with respect to disease caused by the common pathogens for MAI, such as M. kansasii, and M. abscessus. Further clinical experience is required to evaluate the relevance of these criteria to the less frequent, and possibly less pathogenic, NTM. Additionally, as outlined below, these criteria are of limited value in determining the significance of isolates of NTM from certain high-risk groups, such as miners with silicosis.

Bronchial washing of segments draining areas with nodular opacities on a CT scan is useful in the differentiation of causative from casual isolates of MAI and for making a diagnosis when sputum is negative on culture or the patient is incapable of producing sputum. In addition, bronchial washing is more likely to aid in the diagnosis than transbronchial biopsy, even though the latter reveals characteristic granuloma formation.

The presence of an obvious cause of immunosuppression, such as HIV infection, does not per se indicate that an isolated NTM is causing the disease. In a study based on the clinical, bacteriologic, and radiographic diagnostic criteria advocated by the American Thoracic Society, MAI isolates were only considered clinically significant in 7 of 46 HIV-positive patients and 1 of 34 HIV-negative patients.8 The diagnostic problems are further illustrated by a study in a Dutch TB center where NTM were isolated from 27 patients (25 HIV-negative and 2 HIV-positive patients) but were only considered to be pathogenic in 14 patients. The detection of NTM led to unnecessary or inappropriate treatment (including treatment for TB) in 17 of the patients, and a diagnosis of malignant disease was delayed in 2 patients.

Special Considerations

M. avium-intracellulare Complex Infection

MAI complex is the most common cause of NTM lung disease. In most U.S. patients, MAI lung disease is caused by M. intracellulare; in other geographic areas, M. avium infection is equally common. Lung disease caused by MAI has traditionally been diagnosed in middle-aged or older white men, usually with a history of cigarette smoking and underlying lung disease, such as chronic obstructive pulmonary disease (COPD), previous tuberculosis, pneumoconiosis, or bronchiectasis. Most of these patients have cavitary changes on chest imaging. This form of disease can be aggressive and causes extensive lung destruction. In our experience, these patients should also be screened for Nocardia or Aspergillus coinfections.

It is now clear that MAI lung disease has a more heterogeneous clinical presentation, in particular in older female nonsmokers who have no known underlying lung disease.9 These patients present radiographically with midlung and lower lung field disease characterized by a combination of discrete, small (<5 mm) pulmonary nodules and accompanying bronchiectasis, abnormalities that are especially apparent with high-resolution CT scanning of the chest. Because this form of disease is radiographically atypical for mycobacterial disease, diagnosis may be delayed, even in patients who have persistent cough and progressive radiographic abnormalities. Disease progression is usually indolent; however, this form of MAI lung disease can be associated with significant morbidity and mortality.

It has also become apparent that patients with noncavitary MAI lung disease who are infected by one MAI genotype can be reinfected by another MAI genotype (i.e., polyclonal infections are possible). These patients would previously have been considered treatment failures, but in fact they are actually reinfected by new MAI strains. This phenomenon complicates the evaluation of a patient who has successfully completed therapy but has sputum that again becomes culture-positive for MAI.

M. kansasii Infection

M. kansasii produces pulmonary disease that most closely parallels clinical disease caused by M. tuberculosis. Patients with M. kansasii lung disease are characteristically older men from urban environments who are cigarette smokers with one or more underlying pulmonary diseases, including COPD, previous TB, bronchiectasis, or pneumoconiosis.10 The radiographic findings are similar to those of re-activated pulmonary TB, with an upper lobe predilection and cavitation in approximately 90% of patients. Some patients with noncavitary disease, similar to those with MAI lung disease, have also been identified with M. kansasii disease. Once isolated, M. kansasii should not be considered a colonizer; a pulmonology or infectious disease consultation should be obtained in this setting.

M. abscessus Infection

Patients who have M. abscessus lung disease are typically older nonsmoking females with no known underlying or predisposing lung disease.11 This disease clinically and radiographically most closely resembles noncavitary (nodular bronchiectatic) pulmonary MAI disease. M. abscessus and MAI are occasionally isolated concurrently or consecutively in some patients.

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Treatment

Treatment of NTM infections is not as simple or dependent on in vitro drug susceptibilities as the treatment of TB; some familiarity with the treatment details for each NTM is necessary.2 Because of the duration of therapy required and the potential toxicity of the medications, not all patients with NTM lung disease will benefit from therapy. For some patients, the treatment is in essence worse than the disease. Older patients who have few symptoms and minimal or slowly progressive disease, or have severe comorbid conditions and limited life expectancy, may not benefit from drug therapy directed at some NTM pathogens, especially MAI. These patients should be selected to receive treatment only after careful evaluation.

Treatment recommendations for NTM diseases in immunocompetent and immunocompromised hosts will probably continue to evolve as new agents with activity against NTM are introduced. The introduction of agents such as clarithromycin, azithromycin, and rifabutin has dramatically improved the treatment outcomes for some NTM infections. The treatment of NTM infections is complicated by the observation that response to therapy for some NTM infections does not correlate with in vitro drug susceptibilities, especially to antituberculous drugs. For example, clinical response to multidrug antimycobacterial regimens for M. kansasii correlates only with in vitro susceptibility to rifampin (rifampicin). Response of MAI disease to antimycobacterial drug regimens in the past frequently had no correlation with in vitro drug susceptibilities. In contrast, there is a strong correlation between successful treatment of NTM infections, including MAI infection, with clarithromycin and azithromycin and the in vitro macrolide susceptibility of the specific NTM. Patients with pulmonary or disseminated MAI infection resistant to macrolides will not respond favorably to macrolide-containing regimens.12, 13 Macrolide monotherapy for disseminated or pulmonary MAI disease is associated with a genetic mutation conferring resistance to macrolides and should therefore be avoided.14

Recommendations for treating NTM pulmonary disease are given in Table 3. Patients undergoing therapy for NTM pulmonary disease require frequent follow-ups to evaluate symptomatic and objective response to therapy and medication toxicity, and to collect specimens for AFB analysis.

Table 3 Treatment Recommendations for Select Nontuberculous Mycobacteria Causing Lung and Disseminated Disease
NTM Suggested Drug Regimen Duration of Therapy Comments
MAI Clarithromycin, 1 g or azithromycin, 600 mg MWF plus rifabutin, 300 mg or rifampin, 600 mg MWF plus ethambutol, 25 mg/kg MWF 12 mo of sputum AFB culture negativity for pulmonary disease, or lifetime therapy for disseminated disease, unless immune status restored Clarithromycin or azithromycin-not as monotherapy; surgical resection if limited pulmonary disease; streptomycin for 2-3 mo, 500-1000 mg IM MWF or amikacin, 400 mg IV daily for severe disease; rifampin contraindicated with protease inhibitors (consider rifabutin 150 mg/day with indinavir)
M. kansasii (rifampin susceptible in vitro) Rifampin, 600 mg/day plus INH, 300 mg/day plus ethambutol, 25 mg/kg/day for 2 mo and then 15 mg/kg/day 18 mo and 12 mo of sputum AFB culture negativity for pulmonary disease or lifetime therapy for disseminated disease unless immune status restored Add streptomycin, 500-1000 mg im MWF or clarithromycin, 1 g/day initially (2-3 mo) for advanced disease; treatment success with this regimen dependent on in vitro rifampin susceptibility; PZA not effective
M. kansasii (rifampin resistant in vitro or patient on protease inhibitor) Clarithromycin, 0.5 g q12 h plus ethambutol, 25 mg/kg/day for 2 mo and then 15 mg/kg/day plus INH, 900 mg/day (B6 50 mg/day) plus sulfamethoxazole, 1.0 g PO q8 h plus streptomycin, 500-1000 mg IM MWF (initial 2-3 mo) 12 mo of sputum AFB culture negativity for pulmonary disease or lifetime therapy for disseminated disease, unless immune status restored In vitro rifampin resistance occurs as consequence of treatment failure (noncompliance) for rifampin-susceptible M. kansasii lung disease; rifabutin, 150 mg/day can be used with indinavir (see text for other options in AIDS patients)
M. abscessus Clarithromycin, 1 g/day or azithromycin, 500 mg MWF ± cefoxitin, imipenem, amikacin 12 mo of sputum AFB culture negativity No drug regimen of proven efficacy; surgical resection of limited pulmonary disease most effective therapy; first-line antituberculosis drugs not useful
M. fortuitum Two agents, including ofloxacin, 800 mg/day or ciprofloxacin, 1500 mg/day, doxycycline 100 mg q12 h, sulfamethoxazole, 1 g q8 h, clarithromycin, 0.5 g q12 h 6 mo Therapy based on in vitro antibiotic susceptibility; only 50% of M. fortuitum isolates susceptible to clarithromycin; for severe disease, amikacin, 400 mg/day IV or cefoxitin, 12 g/day IV, until favorable clinical response; first-line antituberculosis drugs not useful
M. chelonae Clarithromycin, 1 g/day 6 mo Macrolide monotherapy effective

Other NTM respiratory pathogens that likely would respond to macrolide-containing regimens: M. xenopi, M. malmoense, M. simiae, M. szulgai.

Other disseminated NTM pathogens that likely would respond to macrolide-containing regimens: M. gordonae, M. haemophilum, M. genavense.

AFB, acid-fast bacilli; INH, isoniazid; PZA, pyrazinamide; MWF, Monday, Wednesday, and Friday; NTM, nontuberculous mycobacteria.

Serial sputum AFB analysis is the most important element of disease monitoring. The sputum analysis is a critical measure of medication efficacy and may provide evidence for treatment failure, which may be caused by the emergence of selective drug resistance, disease relapse or reinfection. Additionally, the duration of therapy for some patients is determined by how long their sputum is AFB-culture negative while on therapy. Patients who have NTM lung disease should not be placed on therapy for extended periods without repeated sputum AFB evaluation. Although periodic chest radiographs are also helpful, the chest radiograph is likely to improve only slowly.

Drug treatment is not successful for all patients with NTM lung disease. Surgical resection of limited disease remains an important option, although surgical morbidity and mortality dictate that the surgical approach should be undertaken only by surgeons experienced with mycobacterial disease and after careful preoperative selection.15, 16 Other approaches, such as cytokine therapy (especially IFN-γ), are promising but remain investigational. Unfortunately, since clarithromycin and azithromycin have become available, there have been few new drugs introduced with activity against NTM. Linezolid, a new oxazolidinone, has in vitro activity against some NTM species, including M. abscessus, M. chelonae, and MAI, but this is not consistent or predictable for all isolates. Linezolid, currently an expensive drug, is also associated with frequent and severe side effects, such as anemia, peripheral neuropathy, and optic neuritis. Clearly, better antimycobacterial agents for the treatment of NTM infections are needed.

Recommendations for treating disseminated NTM disease in AIDS patients are listed in Table 4. Treatment of disseminated MAI, as well as other NTM pathogens such as M. kansasii, results in clinical and bacteriologic improvements as well as increased survival. Treatment of these infections has been complicated by the introduction of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV infection, which interact with rifamycins. There are several options for treating disseminated NTM disease for patients who are also undergoing therapy for HIV infection. One strategy is the use of three nucleoside reverse transcriptase inhibitors (NRTIs) as initial therapy for HIV disease, which would allow the use of rifampin in a multidrug regimen for disseminated NTM infection. Efavirenz, with appropriate dosage adjustment (800 mg/day if used with rifampin), can also be added to a multidrug HIV treatment regimen that contains NRTIs, and the patient could still receive a rifampin-containing regimen for NTM disease. For patients receiving the PIs indinavir, nelfinavir, and amprenavir or the NNRTIs nevirapine and evafirenz, rifabutin could be used instead of rifampin in the NTM treatment regimen. A strategy for boosting PI levels by giving ritonavir has been developed, which might also allow concomitant administration of rifampin with the PIs, but dose adjustments are still required. Clearly, the treatment of NTM disease in HIV-infected patients can be complicated. Inappropriate combinations of drugs may result in treatment failure of one or both infections as well as significant drug-related toxicity. Physicians who do not routinely treat HIV-infected patients or are not familiar with the drugs involved should seek expert consultation for the management of these patients. Effective regimens for prophylaxis against disseminated MAI are outlined in Table 4. The successful treatment of NTM central nervous system (CNS) diseases is difficult because of the relative antibiotic resistance of the organisms, the poor CNS penetration of important agents, such as clarithromycin, and the usually far advanced underlying disease of the host. One useful adjunctive therapeutic strategy would be to taper corticosteroids or lower the level of immunosuppression, if feasible.

Table 4 Prophylactic Agents Against Disseminated Mycobacterium avium-intracellulare (MAI) Complex Lung Disease in AIDS Patients
Regimen Dosage Comments
Rifabutin 300 mg/day Rifamycin (rifampin) resistance can emerge with rifabutin monotherapy in patients with occult active tuberculosis; not compatible with some protease inhibitors
Clarithromycin 1 g/day Well tolerated; clarithromycin resistance will emerge if monotherapy used for active disseminated MAI infection
Azithromycin 1.2 g/wk Well tolerated; macrolide (clarithromycin) resistance will emerge if monotherapy used for active disseminated MAI infection
Azithromycin plus rifabutin 1.2 g/wk plus 300 mg/day Very effective prophylaxis regimen; high incidence of rifabutin toxicity

Treatment of skin and soft tissue infections caused by M. fortuitum, M. abscessus, or M. chelonae unrelated to disseminated disease involves regimens similar to those recommended for pulmonary or disseminated disease (Table 5).17, 18 Surgical débridement is important for extensive or poorly responsive disease. As a rule, M. marinum seems to be the exception among NTM in the sense that it does not develop resistance to monotherapy and it is easier to treat.

Table 5 Frequently Used Treatment Regimens for Common Nontuberculous Mycobacteria
Pathogen Disease Drug Daily Adult Dosage Duration of Therapy
M. avium complex Pulmonary Clarithromycin plus 500 mg bid Until culture-negative for 12 mo
Ethambutol plus 15 mg/kg
Rifampin or 600 mg
Rifabutin 150-300 mg
Disseminated, HIV-positive Clarithromycin plus 500 mg bid For life (?)
Ethambutol plus 15 mg/kg
Rifabutin (?) 300 mg
Lymphadenitis, children Surgical excision
Clarithromycin (?) plus
Rifabutin (?) or
Ethambutol
M. kansasii Pulmonary
United States Isoniazid plus 300 mg 18 mo, culture-negative for at least 12 mo
Rifampin plus 600 mg
Ethambutol 15 mg/kg
United Kingdom Rifampin plus 600 mg 9-12 mo
Ethambutol 15 mg/kg
Disseminated Same as pulmonary
HIV-positive Same as pulmonary (United States) but replace rifampin with rifabutin or clarithromycin 150 mg500 mg bid Same as pulmonary (United States)
M. abscessus Pulmonary Amikacin IV plus 15 mg/kg (see text) 2 wk (designed to improve, not cure)
Cefoxitin IV plus 12 g/day 6 mo
Clarithromycin 500 mg bid 6 mo
Cutaneous localized Clarithromycin 500 mg bid
Disseminated or extensive cutaneous Same three drugs as above
M. marinum Cutaneous Clarithromycin or 500 mg bid 3-mo minimum for all regimens
Minocycline or 100 mg bid
Rifampin plus 600 mg
Ethambutol 15 mg/kg

Several regimens administered for 3 months are effecti ve for the treatment of M. marinum infection, including clarithromycin, 500 mg twice daily; doxycycline, 100 mg twice daily; trimethoprim-sulfamethoxazole (co-trimoxazole), 160/800 mg twice daily; and rifampin, 600 mg/day, plus ethambutol, 15 mg/kg/day.

Surgical débridement may be necessary for extensive disease. Complete surgical excision is the standard treatment for NTM lymphadenitis and is usually curative.17, 19 Antimycobacterial therapy is seldom necessary, except for those patients who are immunocompromised. Regimens that contain the newer macrolides are effective for eradicating disease in patients who are unable to have surgery or who undergo incomplete excision of MAI lymphadenitis.20

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Summary

  • Although less important than tuberculosis, nontuberculous mycobacterial disorders represent a significant morbidity, especially in HIV-infected patients.
  • The latest advances in diagnosis and treatment have made the nontuberculous mycobacterial diseases considerably more amenable to diagnosis, treatment, and even cure.

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Suggested Readings

  • Ahn CH, Lowell JR, Onstad GD, et al: A demographic study of disease due to Mycobacterium kansasii or M. intracellulare-avium in Texas. Chest 1979;75:120–125.
  • Bennett C, Vardiman J, Golomb H: Disseminated atypical mycobacterial infection in patients with hairy cell leukemia. Am J Med 1986;80:891–896.
  • Berger C, Pfyffer GE, Nadal D: Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin. J Pediatr 1996;128:383–386.
  • Chaisson RE, Benson CA, Dube MP, et al: Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Ann Intern Med 1994;121:905–911.
  • Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med 1997;156(2 Pt 2):S1–S25.
  • Griffith DE, Girard WM, Wallace RJ Jr: Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients. Am Rev Respir Dis 1993;147:1271–1278.
  • Khoor A, Leslie KO, Tazelaar HD, et al: Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001;115:755–762.
  • Lai KK, Stottmeier KD, Sherman IH, McCabe WR: Mycobacterial cervical lymphadenopathy. Relation of etiologic agents to age. JAMA 1984;251:1286–1288.
  • Meier A, Heifets L, Wallace RJ Jr, et al: Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: Observation of multiple 23S rDNA mutations in a clonal population. J Infect Dis 1996;174:354–360.
  • Parrot RG, Grosset JH: Post-surgical outcome of 57 patients with Mycobacterium xenopi pulmonary infection. Tubercle 1988;69:47–55.
  • Pomerantz M, Brown JM: Surgery in the treatment of multidrug-resistant tuberculosis. Clin Chest Med 1997;18:123–130.
  • Prince DS, Peterson DD, Steiner RM, et al: Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989;321:863–868.
  • Raju B, Schluger NW: Significance of respiratory isolates of Mycobacterium avium complex in HIV-positive and HIV-negative patients. Int J Infect Dis 2000;4:134–139.
  • Reich JM, Johnson RE: Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992;101:1605–1609.
  • Saubolle MA, Kiehn TE, White MH, et al: Mycobacterium haemophilum: Microbiology and expanding clinical and geographic spectra of disease in humans. Clin Microbiol Rev 1996;9:435–437.
  • Schaad UB, Votteler TP, McCracken GH Jr, Nelson JD: Management of atypical mycobacterial lymphadenitis in childhood: A review based on 380 cases. J Pediatr 1979;95:356–360.
  • Sonnenberg P, Murray J, Glynn JR, et al: Risk factors for pulmonary disease due to culture-positive M. tuberculosis or nontuberculous mycobacteria in South African gold miners. Eur Respir J 2000;15:291–296.
  • Wallace RJ Jr: The clinical presentation, diagnosis, and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonae. Clin Chest Med 1989;10:419–429.
  • Wallace RJ Jr, Brown BA, Griffith DE, et al: Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am J Respir Crit Care Med 1994;149:1335–1341.
  • Wallace RJ Jr, Tanner D, Brennan PJ, Brown BA: Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993;119:482–486.
  • Winthrop KL, Abrams M, Yakrus M, et al: An outbreak of mycobacterial furunculosis associated with foot baths at a nail salon. N Engl J Med 2002;346:1366–1371.

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References

  1. Sonnenberg P, Murray J, Glynn JR, et al: Risk factors for pulmonary disease due to culture-positive M. tuberculosis or nontuberculous mycobacteria in South African gold miners. Eur Respir J 2000;15:291–296.
  2. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med 1997;156(2 Pt 2):S1–S25.
  3. Reich JM, Johnson RE: Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest 1992;101:1605–1609.
  4. Khoor A, Leslie KO, Tazelaar HD, et al: Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001;115:755–762.
  5. Winthrop KL, Abrams M, Yakrus M, et al: An outbreak of mycobacterial furunculosis associated with foot baths at a nail salon. N Engl J Med 2002;346:1366–1371.
  6. Lai KK, Stottmeier KD, Sherman IH, McCabe WR: Mycobacterial cervical lymphadenopathy. Relation of etiologic agents to age. JAMA 1984;251:1286–1288.
  7. Bennett C, Vardiman J, Golomb H: Disseminated atypical mycobacterial infection in patients with hairy cell leukemia. Am J Med 1986;80:891–896.
  8. Raju B, Schluger NW: Significance of respiratory isolates of Mycobacterium avium complex in HIV-positive and HIV-negative patients. Int J Infect Dis 2000;4:134–139.
  9. Prince DS, Peterson DD, Steiner RM, et al: Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989;321:863–868.
  10. Ahn CH, Lowell JR, Onstad GD, et al: A demographic study of disease due to Mycobacterium kansasii or M. intracellulare-avium in Texas. Chest 1979;75:120–125.
  11. Griffith DE, Girard WM, Wallace RJ Jr: Clinical features of pulmonary disease caused by rapidly growing mycobacteria. An analysis of 154 patients. Am Rev Respir Dis 1993;147:1271–1278.
  12. Wallace RJ Jr, Brown BA, Griffith DE, et al: Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am J Respir Crit Care Med 1994;149:1335–1341.
  13. Chaisson RE, Benson CA, Dube MP, et al: Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Ann Intern Med 1994;121:905–911.
  14. Meier A, Heifets L, Wallace RJ Jr, et al: Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: Observation of multiple 23S rDNA mutations in a clonal population. J Infect Dis 1996;174:354–360.
  15. Pomerantz M, Brown JM: Surgery in the treatment of multidrug-resistant tuberculosis. Clin Chest Med 1997;18:123–130.
  16. Parrot RG, Grosset JH: Post-surgical outcome of 57 patients with Mycobacterium xenopi pulmonary infection. Tubercle 1988;69:47–55.
  17. Wallace RJ Jr: The clinical presentation, diagnosis, and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonae. Clin Chest Med 1989;10:419–429.
  18. Wallace RJ Jr, Tanner D, Brennan PJ, Brown BA: Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 1993;119:482–486.
  19. Schaad UB, Votteler TP, McCracken GH Jr, Nelson JD: Management of atypical mycobacterial lymphadenitis in childhood: A review based on 380 cases. J Pediatr 1979;95:356–360.
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