Nontuberculous Mycobacterial Infections

Written By: Sam Savage

Published Date: August 30, 2008 Last Edited: August 30, 2008

By Jarzembowski, Jason A Young, Michael B

* Context.-Nontuberculous mycobacteria include numerous acid- fast bacilli species, many of which have only recently been recognized as pathogenic. The diagnosis of mycobacterial disease is based on a combination of clinical features, microbiologic data, radiographic findings, and histopathologic studies. Objective.-To provide an overview of the clinical and pathologic aspects of nontuberculous mycobacteria infection, including diagnostic laboratory methods, classification, epidemiology, clinical presentation, and treatment.

Data Sources.-Review of the pertinent literature and published methodologies.

Conclusions.-Nontuberculous mycobacteria include numerous acid- fast bacilli species, many of which are potentially pathogenic, and are classified according to the Runyon system based on growth rates and pigment production. Their slow growth hinders cultures, which require special medium and prolonged incubation. Although such methods are still used, newer nucleic acid-based technologies (polymerase chain reaction and hybridization assays) can rapidly detect and speciate some mycobacteria-most notably, distinguishing Mycobacterium tuberculosis from other species. Infections caused by these organisms can present as a variety of clinical syndromes, not only in immunocompromised patients but also in immunocompetent hosts. Most common among these are chronic pulmonary infections, superficial lymphadenitis, soft tissue and osteoarticular infections, and disseminated disease. Treatment of nontuberculous mycobacterial infections is difficult, requiring extended courses of multidrug therapy with or without adjunctive surgical intervention. (Arch Pathol Lab Med. 2008;132:1333-1341)

Nontuberculous mycobacteria (NTM) comprise a variety of species and are responsible for a wide range of clinical syndromes. They encompass all mycobacterial species other than Mycobacterium tuberculosis complex (MTB) and Mycobacterium leprae. Nontuberculous mycobacteria have been known since the time of Robert Koch, but historically they have been overshadowed by tuberculosis and dismissed as contaminants. Their clinical significance has only been recently appreciated. With advances in molecular microbiology and knowledge of these organisms, NTM are now recognized as true pathogens and important causes of human infection.

MICROBIOLOGY

Classification

Nontuberculous mycobacteria generally are free-living organisms that are ubiquitous in the environment. Important reservoirs include water (including tap water), soil, animals, and dairy products; they can also be found as colonizers of medical equipment such as endoscopes and surgical solutions.1 Person-to-person spread has not been reported.1 More than 125 species of NTM have been identified, 2 approximately 60 of which are suspected or known to cause disease.1 Traditionally, NTM have been grouped into 4 broad categories according to the Runyon system (Table 1). In this classification, NTM are divided by growth rates and pigment production. Groups I to III are slow-growing NTM, and group IV are fast growers (ie, detectable in culture within 7 days). The slow-growing NTM are subdivided into group I photochromogens (pigment producers in the presence of light), group II scotochromogens (pigment producers in the absence of light), and group III nonchromogens. Although superseded by more modern genetic techniques, this classification system provides physicians with a clinically relevant, presumptive speciation. Clinically important species by group include Mycobacterium kansasii and M marinum (group I); Mycobacterium gordonae and M scrofulaceum (group II); Mycobacterium avium- intracellulare (MAI) and M ulcerans (group III); and Mycobacterium fortuitum, M chelonae, and M abscessus (group IV).

Laboratory Safety

Hospital-based laboratories performing a low volume of mycobacterial isolation, identification, and susceptibility testing are classified as ”low-risk” and must follow Biosafety Level 2 protocols.3 In addition to universal precautions, all specimen processing should be performed in a Class I or Class II biosafety cabinet, attempting to avoid aerosol formation during any liquid manipulations. Screening of laboratory personnel by (at least) annual purified protein derivative skin testing and appropriate postexposure clinical evaluation and testing are essential.3

Specimen Collection

As with all clinical specimens destined for microbiologic analysis, body fluids and tissue samples should be col lected in sterile, properly labeled containers and immediately transported to the laboratory.4,5 Specimens that cannot be sent within an hour or so should be refrigerated. 6,7 Although swabs have traditionally been considered unacceptable for mycobacterial work, several groups have reported adequate recovery of organisms from such samples. 8,9

Sputum is the preferred specimen for suspected pulmonary disease and is best obtained first thing in the early morning.2 Although the presence of MTB in any specimen is considered clinically significant, oral contamination from NTM is a possible source of false positivity with nonproductive efforts to induce sputum.10 For initial diagnostic purposes, specimen should be collected on 3 to 5 consecutive days; for evaluating therapeutic efficacy, specimens should be collected weekly starting 3 weeks after beginning treatment.4,11,12 Bronchoalveolar lavage fluid or bronchial washings may be submitted instead of sputum; these specimens should be collected directly into an aliquot of medium, such as Middlebrook broth.13 Gastric lavage fluid (swallowed sputum) is an acceptable surrogate for sputum in pediatric and neurologically compromised patients.14 The specimen is collected by aspiration through an orogastric or nasogastric tube and neutralized by immediately adding 100 mg sodium carbonate. False-negative results from gastric lavage specimens can occur when the stomach acid is not neutralized in a timely fashion causing degradation of mycobacteria.4 False-positive results may result from contamination by oral saprophytic mycobacterial species.10

Blood cultures can be performed using an automated system such as BACTEC (BD Diagnostic Systems, Sparks, Md) with specialized collection tubes designed to lyse cells, thereby releasing intracellular organisms. As with sputum, the first voided urine of the day gives the highest diagnostic yield. Midstream clean catch specimens should be collected in sterile containers. Stool cultures are useful for the identification of gastrointestinal disease in immunocompromised patients.15,16 Specimens should be aseptically collected and an aliquot sent to the laboratory. Fecal smears are rather insensitive (about 30%) and therefore should be cultured regardless of whether organisms are identified on the initial screen.17 Finally, tissue biopsies can be sent in parallel for histology and mycobacterial culture.

Specimen Processing

Aseptically collected specimens can be directly inoculated into appropriate medium, using a liquid sample or saline-based homogenate of sterile tissue.4,5 Potentially contaminated samples, on the other hand, pose a greater challenge. Because mycobacteria are slow growing and require extended incubation, contaminating organisms pose a greater problem than in routine bacteriology. Furthermore, mycobacteria may be lodged within viscous fluid or cellular debris, needing to be released prior to culture. Chemical and enzymatic treatment of the specimen can solve both these problems. Typically used reagents include sodium hydroxide, dithiothreitol, dilute sodium hypochlorite, and N-acetylcysteine, often used in combination; vortex mixing or physical disruption may also be useful.4,5,18 The optimal pretreatment regimen will depend on the specimen type, institutional experience, and laboratory workflow. Finally, to optimize culture sensitivity, concentration of the specimen (usually by centrifugation) prior to inoculation is recommended.19

Staining

Because culture of these relatively slow-growing organisms can take weeks, specimen smears can rapidly yield clinically relevant information. Properly performed smears are highly specific and relatively sensitive, around 50%.20,21 All mycobacteria are acid- fast bacilli, that is, they do not decolorize with acidified alcohol after staining with carbolfuchsin. This property is thought to exist due to the presence of mycolic acid in the lipid-rich bacterial cell wall. By the traditional Gram stain method, mycobacteria can occasionally stain positively (mimicking gram-variable organisms) or, more commonly, appear as unstained silhouettes against the background. As with any preparation, debris and other organisms may mimic the appearance of mycobacteria, requiring careful assessment of staining and morphologic features. At least 300 fields of a carbolfuchsin-stained smear should be thoroughly searched at high power ( x 1000) before declaring it to be negative.5,18 Fluorescently stained smears, using auraminerhodamine, highlight the organisms as orange-yellow rods against a black background and can be screened at lower magnification ( x 250) for correspondingly fewer fields (at least 30); these have become the preferred method of smear examination.2,4

Culture

Unfortunately, mycobacterial cultures are time-consuming and require specialized reagents. Lowenstein-Jensen media, an egg-based medium containing malachite green dye to inhibit growth of contaminating organisms, is the traditional solid media for culture of mycobacteria. The use of agar-based Middlebrook medium can facilitate ear ly detection of colony growth, but these plates are more expensive and outdate quickly.With either method, visible colony growth can take up to 6 weeks. With liquid media and modern culture systems (such as the BACTEC AFB or Mycobacteria Growth Indicator Tubes), growth can typically be seen in approximately 2 weeks. However, neither is 100% sensitive, and both should be used together.2,22 Although broth-based cultures are more sensitive and can yield quicker growth, solid-phase cultures allow assessment of colony morphology and longer-term storage. Although most mycobacteria grow optimally between 35 and 37[degrees]C in 5% to 10% CO2, a subset including M marinum, M ulcerans, M chelonae, and M haemophilum thrive better between 25 and 33[degrees]C. Identification and Speciation

As discussed previously, mycobacteria can be preliminarily and roughly classified by pigmentation and growth characteristics. Previously, further identification of mycobacterial species was a uniformly tedious process involving biochemical tests that could require weeks of subcultures. Most clinically important species can now be identified more rapidly via nucleic acid probes (eg, MAI and MTB) and by examining mycolic acid ester patterns via high- performance layer chromatography.23-28 The development of nonisotopically labeled DNA probes complementary to species- specific rRNA has allowed rapid identification of organisms using aliquots of broth culture or picked colonies.29-31 Many different polymerase chain reaction amplification-based assays, including the Mycobacterium Tuberculosis Direct Test (GenProbe, San Diego, Calif), the AMPLICOR MTC assay (Roche, Basel, Switzerland), and a plethora of ”homebrew” tests, have been created to detect M tuberculosis rapidly and directly from specimens.32-37 Depending on the particular assay, and specimen type and volume, reported sensitivities vary from 50% to 100% and specificity is usually greater than 95%. However, these molecular tests also detect nonviable organisms, precluding their use in proof of treatment. The polymerase chain reaction assays are best suited to rapid initial detection of infection, with the primary goal of identifying MTB to initiate prompt therapy (see reference 37 for a review of the various molecular techniques suitable for mycobacterial analysis).

Susceptibility

The antimicrobial susceptibility of MTB and rapidly growing NTM species (RGM) can be ascertained by traditional methods, such as broth dilution, Kirby-Bauer, or Etest,20,37-40 although broth-based methods are preferred.2 Unfortunately, there is little in the way of controlled trials correlating in vitro antibiotic susceptibility and clinical efficacy, with the exception of clarithromycin-based therapy for MAC and rifampin-based therapy for M kansasii.2With the exception of clarithromycin, in vitro susceptibility patterns of MAC correlate poorly with in vivo behavior; therefore, routine, broad antimicrobial susceptibility testing for MAC is not advised.38 Recommendations for initial antimicrobial susceptibility testing for other NTM species varies. Current recommendations for M kansasii and other slow-growing NTM species such as Mycobacterium malmoense, M xenopi, and M terrae complex include initial susceptibility testing to rifampin, and if rifampin resistant, testing of second-line agents such as amikacin, ciprofloxacin, clarithromycin, ethambutol, rifabutin, streptomycin, sulfonamides, and isoniazid should be done.2 For RGM (eg, M abscessus, M chelonae, M fortuitum, M smegmantis, M mucogenicum), broth microdilution antimicrobial susceptibility testing is recommended.2 There is no standard panel of antibiotic testing routinely recommended for these species. 2 However, agents that have been used to treat RGM infections have included amikacin, imipenem, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, linezolid, sulfamethoxazole, and tobramycin. Additional testing for newer agents such as linezolid, moxifloxacin, and tigecycline can be considered, although there is little clinical experience with these agents. Of note, ciprofloxacin susceptibility testing, which correlates with susceptibilities to levofloxacin and ofloxacin, may not predict susceptibilities to the newer fluoroquinolone moxifloxacin.2 No initial antimicrobial susceptibility testing for M marinum is recommended.2

HISTOPATHOLOGY

Evidence of NTM infection may be seen in sampled lung, skin, bone marrow, lymph node, mediastinum, liver, or other sites (Figure, A through C). Many patients with disseminated NTM infection, especially in the immunocompromised population, lack granulomas or stainable organisms. Mycobacteria-laden histiocytes or macrophages may be seen in lieu of well-formed granulomas, especially on acid- fast stains such as Fite or Ziehl-Neelsen. For example, MAI infection of the small bowel may show organisms within macrophages distending the lamina propria, similar to Whipple disease (Figure, B).41,42 Therefore, although stains should be routinely performed when clinical suspicion for NTM is high, absence of histologic features does not rule out infection.

EPIDEMIOLOGY

The true prevalence of infection with NTM is unknown. Noncomprehensive, national survey data of mycobacterial isolates from the 1970s and 1980s estimate the rate of NTM infection at 1.8 cases per 100 000 in the United States.43,44 This number likely underestimates the current prevalence of NTM infection. More recent data have shown an increase in the number and distribution of mycobacterial infections. In contrast to the previously mentioned studies in which two thirds of mycobacterial isolates were MTB, a Centers for Disease Control and Prevention survey found that 74% of mycobacterial isolates in 1991 to 1992 were NTM despite an overall increase in the number of MTB isolates.45,46 This rise in NTM infections has been attributed to an increased recognition of NTM clinical syndromes and the emergence of the immunocompromised patient, particularly patients with human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) but also those immunosuppressed for other reasons such as organ transplantation.47

Nontuberculous mycobacterium are more commonly isolated from young adults and elderly patients.45 It is thought that this reflects the predilection for disseminated and pulmonary NTM disease in these age groups, respectively. 47 Disseminated disease is most often seen in HIV/ AIDS, which predominantly afflicts a younger population, and chronic pulmonary NTM syndromes are more common among the elderly.

Mycobacterium avium-intracellulare is the most commonly encountered NTM in the United States. National surveys from the early 1980s found 61% of NTM isolates were MAI, 19% were M fortuitum complex, and 10% were M kansasii.43,44 From this same data, it was estimated that the prevalence of MAI infection was 1.1 cases per 100 000.43,44 As noted previously, these surveys were performed prior to the HIV/AIDS era and likely underestimate the prevalence of MAI infection. Reported rates of disseminated NTM infection in HIV/AIDS patients range from 5% to 40%,48-50 of which 96% were MAI.49

Nontuberculous mycobacteria infections vary geographically by species. For example, MAI is found worldwide but rarely causes disseminated infection in HIV/AIDS patients in Africa.47 Mycobacterium kansasii tends to be clustered in the central United States, and species rarely seen in the United States such as M xenopi and M malmoense are major pathogens in Canada/Britain and Scandinavia, respectively. 47

CLINICAL FEATURES

The spectrum of clinical infections caused by NTM varies widely and defies easy review. However, it can be divided into several broad categories: chronic pulmonary infections, superficial lymphadenitis, soft tissue and osteoarticular infections, disseminated disease, and iatrogenic infections.

Pulmonary Infections

Chronic pulmonary infections are among the most common clinical manifestations of NTM disease. The NTM species most often associated with pulmonary disease in the United States is MAI followed by M kansasii.2 Less commonly reported organisms include M abscessus, M fortuitum, M szulgai, M simiae, M xenopi, M malmoense, M celatum, M asiaticum, and M shimoidei.2 As stated previously, the distribution of species causing disease varies geographically. For example, M xenopi, which is rarely found in the United States, is the second most commonly isolated organism in Canada and Europe.2

The clinical presentation with NTM-related pulmonary infection can be quite varied. Chronic cough is nearly universal, but fevers, malaise, weight loss, dyspnea, and hemoptysis are much more variable.2 Affected individuals typically are not severely immunocompromised. However, those with underlying lung pathology such as chronic obstructive pulmonary disease, bronchiectasis, prior MTB, cystic fibrosis, other pneumoconiosis, treatment with tumor necrosis factor inhibitors, or certain body habiti (eg, pectus excavatum or scoliosis, particularly in postmenopausal women) are at risk, although infection in individuals without risk factors is well reported.2

The clinical spectrum of pulmonary disease is quite variable as well. Both M xenopi and MAI have been reported to cause disease similar to MTB. Upper lobe involvement and cavitary lesions can be seen, particularly with M kansasii in which up to 90% of patients will have cavitary disease.46,47 Patients with this type of MTB- like lung involvement typically are middle-aged to elderly men with a history of smoking or underlying lung disease as noted previously.46,47 Pulmonary infiltrates without cavitation has also been reported. Affected individuals typically have bronchiectasis, such as can be seen in older individuals with a history of MTB or patients with cystic fibrosis. 2,46,51,52 A more unusual presentation of MAI is the socalled Lady Windemere syndrome.53 This syndrome is seen in elderly women without preexisting pulmonary conditions or a history of tobacco abuse. The typical clin ical scenario is of interstitial pulmonary infiltrates, often starting in dependent regions of the right middle lobe or lingula, with an absence of cavitation or hilar lymphadenopathy. 53 Mycobacterium avium-intracellulare has also been reported to cause solitary pulmonary nodules in the absence of other symptoms,46,52 and a newly described syndrome has been reported of hypersensitivity pneumonitis typically related to exposure to MAI in aerosolized household water, that is ”hot tub lung.” 54,55 Another hypersensitivity pneumonitis- like syndrome, presumably related to exposure to organic metal- working compounds, may also be seen.2 Isolated pulmonary disease has been the exception rather than the rule in HIV/AIDS. However, most reports of HIV-associated MAI disease are from an era prior to effective HIV therapy. With the development of highly active antiretroviral therapy and the ability to reconstitute CD4+ T-cell- based immune function, localized MAI disease in HIV/AIDS patients may become more frequent. The radiographic findings seen with NTM pulmonary infections are variable.2 Plain radiography can reveal cavitary lesions, frank parenchymal or interstitial infiltrates, bronchiectasis, volume loss, or solitary or multiple pulmonary nodules or be relatively unremarkable.46,56 Because of superior resolution, high-resolution computed tomography of the chest is now recommended if plain chest radiography does not reveal fibrocavitary disease.2 The pattern of lung lesions does not reliably distinguish between NTM species.

Nontuberculous mycobacteria pulmonary infection can be diagnosed via a combination of clinical, radiographic, bacteriologic, and histologic criteria as proposed by the American Thoracic Society and the Infectious Disease Society of America (Table 2).2 These guidelines apply to both HIV-positive and immunocompetent hosts. Briefly, the diagnosis of NTM lung disease requires appropriate symptomatology, radiographic evidence of pulmonary involvement (eg, infiltrates, nodules, or cavities on plain radiography or high- resolution computed tomography findings of multifocal bronchiectasis and/or small nodules), positive cultures or suggestive histologic findings, and exclusion of other diagnoses.2 Semiquantitative reporting of acid-fast bacilli smear positivity, which was part of the 1997 American Thoracic Society guidelines,46 is no longer recommended.

Treatment of NTM pulmonary infection can be difficult and involves prolonged courses of multiple antimycobacterial agents. The approach to treatment and the choice of medication varies according to the NTM species isolated. For MAI, current recommendations are for a minimum of 3 drugs. The backbone of any regimen should be a macrolide, either clarithromycin or azithromycin, which are the most effective agents for MAI, combined with a second or third agent to prevent the emergence of macrolide resistance.2 Monotherapy with clarithromycin or azithromycin has been shown to be clinically efficacious but should not be used as resistance and eventual treatment failure has been shown to develop when a macrolide is used alone.57,58 Treatment guidelines for MAI pulmonary disease vary with severity of disease.2 For initial therapy of nodular/bronchiectatic disease, the recommendations are clarithromycin 1000 mg 3 times a week or azithromycin 500 to 600 mg 3 times a week combined with ethambutol 25 mg/kg 3 times a week and rifampin 600 mg 3 times a week. For cavitary disease, clarithromycin 500 to 1000 mg per day or azithromycin 250 to 300 mg per day, ethambutol 15 mg/kg per day, rifampin 450 to 600 mg per day, with or without parenteral amikacin or streptomycin is recommended, whereas for severe or previously treated disease, the previous with parenteral aminoglycoside for the first 2 to 3 months is recommended. American Thoracic Society guidelines recommend obtaining sputum cultures monthly while on therapy. As a general rule, most patients treated with a macrolide- based regimen should improve within 3 to 6 months and convert their sputum to culture negative within 12 months.2 The role of surgical therapy is limited as MAI pulmonary disease tends to be a multifocal process but may be important for select individuals.2

Treatment of pulmonary disease resulting from M kansasii also involves a multidrug regimen, the backbone of which is rifampin. The current recommendation is a combination of isoniazid (300 mg per day), rifampin (600 mg per day), and ethambutol (15 mg/kg per day) until the sputum cultures remain negative for 12 months.2 Mycobacterium fortuitum is typically susceptible to fluoroquinolones, doxycycline, minocycline, sulfonamides, linezolid, and tigecycline, and 2-drug regimens until 12 months of negative sputum cultures are likely to be effective.2,46,59-61 Mycobacterium fortuitum typically tests sensitive to macrolides as well, although the recent discovery that this species carries the erythromycin methylase gene erm raises the possibility of inducible macrolide resistance.2 Pulmonary disease with M abscessus is more common than M fortuitum and much more difficult to treat. Antibiotic options are limited to clarithromycin and intravenous agents such as amikacin, cefoxitin, and possibly imipenem.2 The toxicity of these intravenous medications can be significant because of the prolonged length of therapy needed for probable cure. The newer fluoroquinolones, linezolid, and telithromycin do not have reliable activity against M abscessus but may be second-line options.2,59,61 Recent studies have found the novel glycylcycline tigecycline has excellent activity against the RGM, including M abscessus.60 Whether this will translate into clinical efficacy is unknown, but tigecycline is generally well tolerated and may provide another option for long- term therapy of M abscessus.

Lymphadenitis

Localized lymph node infection is the most common presentation of NTM disease in children.2 The most commonly affected lymph node chains are in the head and neck, particularly the anterior cervical chain but also the submandibular, submaxillary, and preauricular lymph nodes.1,2,46 Occasionally, mediastinal lymph nodes can be involved.1 The usual presentation is of painless swelling of one or more lymph nodes in a regional distribution without systemic symptoms.2 It is unilateral in 95% of cases and can result in chronic, draining fistulae to the skin.1,2,46

The peak incidence occurs in children ages 1 to 5 years.2 Lymphadenitis is uncommon in adults with the exception of HIV- infected patients in the post-highly active antiretroviral therapy era.62 Historically, NTM disease, overwhelmingly because of MAI, in HIV-infected individuals was almost uniformly a disseminated process. With the advent of effective antiretroviral therapy, lymphadenitis as part of the syndrome of immune reconstitution can be seen. Usually found in HIV-infected individuals with severe CD4+ lymphopenia and preexisting subclinical MAI infection, this syndrome presents as a constellation of fevers, leukocytosis, and lymphadenitis (cervical, thoracic, and/or abdominal) that can be seen with initiation of highly active antiretroviral therapy.62

The most common species found in lymphadenitis in children is MAI, which is found in approximately 80% of culture-positive cases.1,2,46 Mycobacterium scrofulaceum, the most common cause in the 1970s, is the second most commonly isolated species in the United States.1,2,46 Other species that have been reported to cause NTM lymphadenitis include the RGM, M malmoense, M kansasii,Mhaemophilum, M interjectum, M palustre, M tusciae, M heidelbergense, M elephantis, M lentiflavum, and M bohemicum.1 Approximately 10% of mycobacterial lymphadenitis in children is because of MTB. In contrast, more than 90% of cases in adults is because of MTB.2

Diagnosis of NTM lymphadenitis hinges on either positive culture for NTM or suggestive histopathology coupled with a negative evaluation of MTB. All persons should receive a purified protein derivative test to evaluate for MTB. Most individuals will have a mild ( 10 mm) reaction because of cross-reactivity between MTB and NTM proteins, but induration greater than 10 mm has been reported in nearly one third of children with NTM lymphadenitis.46 Lymph node tissue can be obtained either by fine-needle aspiration or excision of the involved lymph nodes.2 Classic histopathologic findings include caseating granulomata.2 Acid-fast bacilli may or may not be seen, and positive tissue cultures for NTM can be obtained in 50% to 80% of cases.2

Surgical removal without antimycobacterial therapy is the cornerstone of treatment of NTM lymphadenitis, in contrast to MTB- related lymphadenitis for which antibiotic therapy is paramount.2 This approach is curative in more than 90% of cases in children. It must be emphasized that complete excision of affected lymph nodes and not simple incision and drainage must be performed, because the latter approach frequently results in fistula formation and persistent disease. Antimycobacterial-based therapy should be reserved for those with recurrent disease or for whom surgical therapy is impractical, and the choice of antibiotics will depend on the NTM species isolated.2

Disseminated Disease

Disseminated NTM disease is most commonly found in patients with advanced HIV disease, particularly those with CD4+ cell counts less than 50 cells per L.2 More than 95% of disseminated NTM disease in HIV patients is because of MAI.2 Other NTM species reported to cause disseminated disease in HIV patients include M chelonae, M abscessus, M xenopi, M conspicuum, M gordonae, M kansasii, M genavense, M haemophilum, M fortuitum,Mmarinum, M simiae, M scrofulaceum, M celatum, M malmoense, M triplex, and M lentiflavum.1,46,47 The most common symptoms of disseminated NTM disease in HIV patients are fevers, night sweats, and weight loss.2 Diarrhea and abdominal pain are also frequently reported with MAI. Physical examination findings typically are nonspecific, although hepatosplenomegaly can be seen. Mycobacteria chelonae, M abscessus, and M haemophilum may present with diffuse subcutaneous nodules and abscesses, and disease withMkansasii is usually associated with pulmonary involvement.47 Laboratory findings are also nonspecific but may reveal severe anemia and an elevated alkaline phosphatase in MAI disease.2 Disseminated disease in non-HIV patients are usually found in those with severe immunosuppression from other conditions, such as organ transplantation, hematologic malignancies, and chronic steroid use.2,46,63,64 Nontuberculous mycobacteria infections have also been reported in individuals receiving therapy with tumor necrosis factor- alpha antagonists such as infliximab and etanercept.63,64 Reported NTM species from disseminated NTM disease in non-HIV patients include MAI, M kansasii, M chelonae, M abscessus, and M haemophilum.2 As a rule, MAI disease in immunocompromised, non-HIV patients also presents as fevers without localizing signs, whereas other NTM species will present with subcutaneous nodules or abscesses.2

Disseminated MAI can rarely present as single or multiple tuberculomas that mimic a neoplastic process. This syndrome of mycobacterial spindle cell pseudotumors is usually seen in patients with advanced AIDS, although it has also been reported in individuals immunocompromised for other reasons.65-71 As the name suggests, these lesions histologically are composed of expansile aggregates of proliferative spindle cells and epithelioid histiocytes that resemble a mesenchymal neoplasm.65-71 Mycobacterial spindle cell pseudotumors have been reported to involve lymph nodes, bone marrow, intestine, skin, lungs, retroperitoneum, and the brain, where they can resemble MTB tuberculomas or meningiomas.65-71

Diagnosis of disseminated NTM disease is made by positive culture from a normally sterile site such as blood or bone marrow. For those with cutaneous lesions, positive culture from skin biopsy in the appropriate clinical setting is also diagnostic. The sensitivity of blood culture in disseminated MAI disease in HIV patients is 90%.2

Treatment of disseminated NTM disease is based on multidrug therapy. Antimycobacterial regimens are similar to those recommended for NTM pulmonary disease.2 For MAI, macrolide-based therapy (clarithromycin or azithromycin) plus rifabutin and ethambutol is recommended. For those with severe symptoms, amikacin or streptomycin may be added for initial induction therapy. The use of rifabutin in HIV patients may be complicated by drug interactions with protease inhibitors and, to a lesser extent, efavirenz.72,73 Rifabutin enhances the metabolism of protease inhibitors, and protease inhibitors inhibit the metabolism of rifabutin.2,46,73 Pharmokinetic studies indicate that alternative dosing regimens of rifabutin, such as every other day administration, may allow patients to maintain therapeutic levels of protease inhibitors.46,72

Soft Tissue and Skeletal Infections

The spectrum of NTM-related soft tissue and skeletal infections (STSIs) is broad and ranges from chronically draining, localized abscesses or nodules to tenosynovitis to frank osteomyelitis. Soft tissue and skeletal infection usually arises as the result of direct inoculation such as penetrating trauma or soilage of open wounds and fractures. Infection can also be introduced iatrogenically, and NTM have been reported to cause infections following intravenous and peritoneal catheters, shunts, intramuscular injections, cosmetic surgery procedures, laser in situ keratomileusis procedures, and postsurgical wounds.1,2,46 The presentation of NTM STSI is typically indolent, and the clinical course variable. Minor cutaneous infections may resolve spontaneously during the course of 8 to 12 months.46 However, more serious disease, such as osteomyelitis, will likely progress over time.

The RGM species M abscessus, M fortuitum, and M chelonae are the most common species to cause STSI, although other species are associated with certain clinical syndromes. 2 Mycobacterium fortuitum has been noted to cause localized STSI is immunocompetent individuals, whereas patients with M chelonae and M haemophilum infection are typically immunosuppressed.1 Mycobacterium abscessus has been reported to cause localized STSI disease in both immunocompetent and immunocompromised persons.1 Mycobacterium marinum, MAI, M kansasii, and M terrae complex have been noted to cause chronic granulomatous infections of tendon sheaths, bursa, joints, and bone in addition to M abscessus, M fortuitum, and M chelonae.2 Mycobacterium marinum causes a peculiar clinical condition termed swimming pool granuloma or fish tank granuloma. This is typically seen in individuals who have had exposure to some type of marine environment (eg, fish, crustaceans, fish tanks) and presents as granulomatous lesions, usually on portions of the extremities prone to abrasions.1 The lesions usually begin as papules that then ulcerate and scar.1,46 Disease is often localized, but some patients can develop a nodular lymphangiitis similar to sporotrichosis. 1,46 Mycobacterium ulcerans causes a syndrome of chronic, necrotic skin lesions of the extremities called Buruli ulcer.2 This is usually seen in the tropics and Australia and starts as a pruritic nodule that eventually degenerates into a large, irregular, undermined ulcer.1,46,47

The diagnosis of NTM STSI can be made on the basis of histology and cultures. Treatment of NTM STSI often involves a combination of antibiotics and surgical excisions. As mentioned previously, minor cutaneous disease can often resolve without treatment. However, this can be a prolonged process, and surgical treatment likely can accelerate resolution of disease. For osteoarticular infections, surgical excision of infected tissue should be performed when feasible.2 When prosthetic material is involved, its removal should be considered mandatory as NTM infection in such a setting is unlikely to resolve with antibiotic therapy alone.46

For STSI caused by MAI, antimicrobial therapy should be a multidrug regimen with a macrolide base as recommended previously.46 The optimal length of therapy is unknown but likely can be shorter than for pulmonary or disseminated disease; current recommendations are for 6 to 12 months.46 Clarithromycin, rifampin, sulfas, and clofazimine have all been used to good effect, provided disease is not advanced.1 Drug therapy for RGM species is more problematic because of a lack of clinical trials and the toxicity of antibiotics known to be effective for RGM. Soft tissue and skeletal infection with M fortuitum and M chelonae should be treated for a minimum of 4 months.2 For bone infections, a minimum of 6 months is recommended. Expert opinion for M marinum recommends 2-agent therapy (a macrolide plus rifampin or ethambutol) for 1 to 2 months after symptoms resolve; surgical debridement may be indicated for deep structure infection.2 Catheter-related infections can be treated with a 6- to 12- week course of multiple antibiotics provided that the device is removed.1 The recommended length of therapy for slow-growing NTM species is 6 to 12 months.

CONCLUSION

Nontuberculous mycobacteria are a diverse group of mycobacterial species that cause a wide range of human disease. The spectrum of clinical infections caused by these organisms varies from minor, self-limited cutaneous disease to life-threatening widespread infection that may have no effective therapy. Historically thought to cause disease only in immunocompromised individuals, NTM are now recognized as major pathogens in immunocompetent individuals as well. Nontuberculous mycobacteria disease can be broadly grouped into pulmonary infections, lymphadenitis, disseminated disease, and STSI and typically present as indolent processes in both immunocompetent and immunocompromised patients. The most important pathogenic NTM species is MAI, which causes the bulk of pulmonary and disseminated disease in the United States and can rarely masquerade as a neoplastic process. The diagnosis of NTM disease is based on a combination of clinical features, microbiologic data, radiographic findings, and histopathologic studies. Treatment of NTM infection is difficult and requires long courses of multidrug therapy with or without adjunctive surgical intervention. For most NTM species, macrolide-based drug regimens are an effective option, although treatment failure and resistance may develop. RGM, especially M abscessus, pose a particular therapeutic challenge because of a lack of effective and well-tolerated antimycobacterial agents. However, the development of new antibiotics such as tigecycline with excellent activity against RGM may offer more successful and safe treatment options.

Table 2. American Thoracic Society/Infectious Disease Society of America Guidelines for Diagnostic Criteria for Pulmonary Infection With Nontuberculous Mycobacteria (NTM)*

Clinical

1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules, AND

2. Appropriate exclusion of other diagnoses (eg, tuberculosis)

Microbiologic

1. Positive culture results from at least 2 separate expectorated sputum samples. If the results from (1) are nondiagnostic, consider repeat sputum AFB smears and cultures, OR

2. Positive culture result from at least 1 bronchial wash or lavage, OR

3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM. 4. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination.

5. Patients who are suspected of having NTM lung disease but do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded.

6. Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients.

* Reprinted from Griffith et al2 with permission from the American Thoracic Society. AFB indicates acid-fast bacilli.

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Jason A. Jarzembowski, MD, PhD; Michael B. Young, MD

Accepted for publication February 27, 2008.

From the Departments of Pathology, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee (Dr Jarzembowski); and Internal Medicine, Division of Infectious Diseases, University of Kentucky, Lexington (Dr Young).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Jason A. Jarzembowski, MD, PhD, Department of Pathology, Children’s Hospital of Wisconsin, 9000 W Wisconsin Ave, Milwaukee, WI 53201 (e-mail: [email protected]).

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