Nontuberculous Mycobacteria

After completing this article, the reader should be able to: Mycobacteria other than those causing tuberculosis and leprosy were not recognized to cause human disease until the 1950s. The incidence of nontuberculous mycobacterial (NTM) disease remained stable until the acquired immune deficiency syndrome (AIDS) epidemic began in the early 1980s. Since then, the prevalence of infections and number of mycobacterial species identified as pathogens have grown significantly (Table 1). This appears to be a result not only of the increased prevalence of immunocompromised patients but of the improved ability to cultivate and speciate these organisms. Buruli ulcer (M ulcerans), found most commonly among children in countries that have tropical rain forests, is the third most common mycobacterial infection worldwide after tuberculosis and leprosy. NTM infections can occur in well children and include lymphadenitis, skin ulcers, and rarely otomastoiditis and posttraumatic soft-tissue or bone infections. In immunocompromised children, NTM infections include localized, nosocomial, foreign body-associated, and disseminated infections; among children who have cystic fibrosis (CF), pneumonia occurs rarely.NTM organisms are ubiquitous and can be isolated from soil and water, including natural waters, hospital water, food products, and domestic and wild animals (Table 2). Transmission is by inhalation, ingestion, or direct contact with these environmental sources. Person-to-person transmission is rare. For children who have cervicofacial lymphadenitis, the focused age range of 1 to 5 years may be the result of ingestion followed by contact of the organism with gingival or oropharyngeal abrasions resulting from tooth eruptions or foreign bodies in the mouth.NTM infections are not reportable. Thus, incidence and prevalence figures are based on surveillance studies of state laboratory bacterial isolation reports. One such study from 1979 to 1980 indicated that M tuberculosis (MTB) accounted for two thirds and NTM for one third of isolates. Of the NTM isolates, 61% were M avium complex (MAC), 19% were M fortuitum complex, and 10% were M kansasii. A 1991 to 1992 survey demonstrated a dramatic change, with MTB representing only 26% of mycobacterial isolates and MAC accounting for more isolates than MTB. MAC accounts for more than 95% of cases of disseminated NTM disease. Disseminated MAC (DMAC) is the most common bacterial infection among patients who have AIDS; it occurs in 20% to 40% of AIDS patients. This infection undoubtedly accounts for the change in the prevalence of NTMs found in the 1991 to 1992 study.In Sweden, where NTM incidence data are available, the cumulative incidence rate among the birth cohorts born between 1975 and 1985 for extrapulmonary NTM disease in children younger than 5 years of age was 26.8/100,000.Although more than 50 species of NTM have been identified, only a small number cause infections in humans. Runyon developed the first good scheme for grouping NTM based on growth rates (Table 1) and colony pigmentation. Historically, identification of individual species has been based on a battery of biochemical tests, the results of which may not be available for more than 1 month. Most laboratories now use one of the rapid diagnostic tests. As can be seen from Table 1, the distinction between rapid- and slow-growing NTM can be made within 7 to 10 days. MTB requires 4 to 6 weeks for in vitro growth.NTM also can be grouped according to the type of clinical disease they produce (Table 1). Nosocomial infections most often are caused by the rapidly growing organisms, such as M abscessus, M chelonae, and M fortuitum.The most common manifestation of NTM infection in children is lymphadenitis (Table 3). Distinguishing MTB from NTM lymphadenitis is important because MTB infections require drug therapy and intensive public health tracking and NTM infections do not (Fig. 1). For NTM infections, the child appears well, the chest radiograph is negative, there is no history of MTB exposure, and results of purified protein derivative (PPD) skin tests of family members, when performed, usually are negative. When a 5TU skin test is placed on a child who has NTM lymphadenitis, the results are variable. There may be 5 to 9 mm induration in the infected child caused by NTM cross-reactivity with MTB. Some children have negative skin test results, and as many as 33% have induration of 10 mm or more.Complete excision of the lymph node is the treatment of choice. Lymph node tissue can be obtained when the lymph node is excised or by fine-needle aspiration. Use of the latter procedure is controversial because excision is both diagnostic and therapeutic, and there is a risk for chronic sinus tract formation. Biopsy and incision and drainage procedures should not be performed because chronic sinus tracts often result (Fig. 2).A presumptive diagnosis is based on the presence of caseating granulomas in the lymph node removed at surgery, with or without acid-fast bacilli (AFB) seen on a stain, in an otherwise well child who has a negative PPD result. The definitive diagnosis is made by isolation of NTM in culture. Currently there are no available United States Food and Drug Administration-approved skin testing reagents for NTM.The causative organisms and descriptions of NTM cutaneous and soft-tissue infections in children are summarized in Table 4: Rapidly growing mycobacteria are a rare cause of otomastoiditis in children. Otomastoiditis caused by NTM is characterized by chronic otorrhea in children who have tympanotomy tubes or a chronic perforation, with abundant granulation tissue, in a setting of repeated use of antibiotics or frequent topical corticosteroid or aminoglycoside drops. M chelonae, M abscessus, and M fortuitum all have been reported to cause this syndrome. In one ear-nose-throat practice, 17 patients who had perforations of the tympanic membrane had chronic otorrhea caused by M chelonae. A case-control study identified different methods of instrument sterilization between this office and a second office that had no such infections. The source of infection in patients who have tympanotomy tubes and chronic perforations probably is tap water or natural water following bathing or swimming. In the case of the ear-nose and throat office, repeated ear examinations and suctioning with inadequately sterilized instruments was held responsible for the infections, based on the identity of the isolates.Many of the rapidly growing NTM isolates associated with otomastoiditis have been highly resistant to the aminoglycosides. This is most likely a consequence of repeated use of topical aminoglycoside otic preparations. Susceptibility testing is necessary for each of these isolates because antimycobacterial susceptibility patterns vary greatly (Table 5).Genetic susceptibilities to disseminated mycobacterial infections have been described in children. In most cases, the defect was related to decreased interferon gamma production or absent lymphocyte surface receptors for interferon gamma. Thus, interferon gamma appears to play a central role in protection against NTM. Administration of interferon gamma and antimycobacterial drugs has provided some support for affected children.The incidence of DMAC in HIV-infected children is 10% to 40%. It may disseminate to any organ, but most commonly it involves the lungs, liver, spleen, gastrointestinal tract, skeletal system, and skin. Common presenting features include recurrent fever, failure to thrive, night sweats, abdominal pain, and neutropenia. Unlike adults, children may develop DMAC with CD4-positive T-cell counts of greater than 100 cells/mm3. DMAC usually is associated with the end stages of AIDS and reduced survival. Therapy improves survival, but cure is difficult, and many patients require lifelong treatment.Children, other than those who have CF, rarely develop chronic pulmonary disease with NTM. Similarly, in adults, underlying lung disease almost always precedes NTM infection, and in adults, it is the most common localized form of NTM.Among children who have CF, it is very difficult to distinguish NTM colonization from disease without a tissue biopsy. Diagnosis is based on three positive sputum cultures and symptoms of infection. Unfortunately, repeated sputum cultures positive for NTM do not correlate well with invasive disease in autopsy studies. Decisions regarding antimycobacterial therapy must be made carefully and with consultation because drug regimens are complex, toxicity is significant, and cure is rare.The laboratory should be notified when an NTM infection is suspected because special techniques are needed for optimal recovery and identification of these organisms.Examination of clinical material should include conventional stains used to identify AFB such as the periodic acid-Schiff (PAS) stain or the basic fuchsin method (Kinyoun stain), as well as the preferred fluorochrome method (auramine-rhodamine stain).Rapid diagnostic tests include high-performance liquid chromatography (HPLC), the neutrophil activating protein (NAP) test, DNA probes, and polymerase chain reaction (PCR). HPLC can distinguish mycolic acid fingerprint patterns, which differ among species. Nonradiolabeled DNA probes, complementary to ribosomal RNA, are available. They are highly sensitive and specific and can be used on organisms from a broth culture. MTB can be distinguished from NTM by NAP, a compound that inhibits the growth of MTB but not of NTM.The spectrum of available antimycobacterial agents and relative susceptibilities by species are summarized in Table 5. Standardized testing conditions for antimycobacterial agents and NTM organisms in many cases have not been established or correlated with disease outcome and treatment. Thus, the American Thoracic Society has made several important recommendations: When indicated, antimycobacterial agents usually are used for long periods of time and in combination. Potential toxicities are summarized in Table 6.Excisional surgery without chemotherapy is the preferred treatment because the success rate (cure) is 95% when surgery is performed early in the disease course. Chemotherapy may be helpful for patients who have established sinus tracts, for those at high risk for facial nerve damage if the lymph node were excised, and for children who have intraparotid adenitis that would require partial resection of the parotid gland. Clarithromycin monotherapy or clarithromycin plus rifabutin or ethambutol, or both are the preferred regimens. The length of treatment ranges from 3 to 6 months, but the optimal duration is not known.The incidence of lymphadenitis caused by NTM is much greater than that caused by MTB. Antituberculosis treatment should be started for children who have lymphadenitis and a PPD reaction of ≥15 mm of induration. It also should be initiated under these conditions if there has been contact with an adult who has tuberculosis, if the family refuses surgical excision, if incisional or spontaneous drainage persists after surgery, or until MTB is isolated from the patient and a definitive diagnosis is established.Therapy consists of complete, and if necessary, repeated surgical excision of infected tissue, removal of foreign material, and long-term antibiotic administration. Several weeks of intravenous therapy followed by 3 to 6 months of oral therapy may be necessary. Intravenous therapy with amikacin and cefoxitin or imipenem followed by clarithromycin has been successful. Susceptibilities should be obtained initially and during therapy if resolution is slower than anticipated to detect the presence of resistant organisms that may develop during therapy. Some authors recommend adding clarithromycin to the initial regimen in anticipation of amikacin resistance.Extensive surgical debridement, including catheter and foreign body removal, is the first and most important step of therapy after the diagnosis has been established or strongly suspected. Adjunctive antimicrobial therapy should be administered intravenously initially for extensive, deep-seated, or chronic infection or for infection in the immunocompromised patient. Oral antibiotics may be sufficient for localized infections. Antimycobacterial susceptibility testing should be performed. The combination of amikacin and cefoxitin is used most often as initial therapy for 2 to 4 weeks until susceptibilities are known. For oral therapy, clarithromycin, trimethoprim-sulfamethoxazole (TMP-SMX), doxycycline, or ciprofloxacin may be sufficient. Chronic or extensive infections may require 3 to 6 months of therapy. Deep-seated infections, such as arthritis or tenosynovitis, may require 9 to 12 months of therapy.Most granulomas heal spontaneously over several months. For more extensive lesions, debridement and systemic antibiotics for 4 to 12 weeks may be necessary. Doxycycline, TMP-SMX, rifampin, or ethambutol have been used. Corticosteroid injection into the lesions has been associated with a poor prognosis.Wide surgical excision with or without skin grafting is necessary. Systemic therapy with TMP-SMX, minocycline, rifampin, or dapsone has been used for recalcitrant cases. Combinations of streptomycin plus dapsone with or without ethambutol also have been used for up to 2 weeks after wound healing. Infections with this species do not respond well to drug therapy.The most common causes of NTM pulmonary infection in CF are MAC and M kansasii. MAC requires a three- to five-drug regimen, as described for disseminated infections. M kansasii is susceptible to most antituberculous drugs. A regimen of isoniazid, rifampin, and ethambutol is suggested.In the setting of HIV infection or other immunocompromising conditions, clarithromycin has shown consistent activity against MAC and no interaction with zidovudine or didanosine administered for HIV therapy. To prevent the emergence of resistance and to reduce the number of organisms as quickly as possible, at least two drugs should be used. Ethambutol is usually the second drug selected. Many clinicians favor three-drug therapy. Other drugs that can be considered include clofazimine, rifabutin, rifampin, ciprofloxacin, and amikacin. Rifabutin induces the cytochrome P-450 system, which metabolizes protease inhibitors. Clofazimine or a quinolone could be used, but may not be as active as amikacin. Isoniazid and pyrizinamide have no activity against MAC. TMP-SMX has significant in vitro activity but needs further study before it can be recommended for use. Antiretroviral therapy should be aggressive to reduce the degree of immunodeficiency. Consultation may help in selection of a third drug.For patients with AIDS, antimycobacterial drugs frequently are associated with adverse effects, and therapeutic changes often are required. Monitoring for drug toxicity is important because drug combinations usually are used for long periods of time (Table 6).Clarithromycin monotherapy is more than 69% effective as prophylaxis for DMAC in adult AIDS patients who have clarithromycin-susceptible isolates. However, life expectancy is reduced once clarithromycin-resistant DMAC develops. Rifabutin also is active as monotherapy, but it cannot be used with protease inhibitors. Drug resistance has not been a problem with rifabutin monotherapy. MTB should be identified before rifabutin is administered because it has some activity against MTB, and MTB drug resistance could develop during monotherapy.