DIAGNOSIS AND TREATMENT OF DISEASE CAUSED BY NONTUBERCULOUS MYCOBACTERIA Tms

OFFICIAL STATEMENT OF THE AMERICAN ThORACIC SOCIETY WAS ADOPTED BY THE ATS BOARD OF DIRECTORS, MARCH 1990.

Contents Introduction Epidemiology/Pathogenesis Clinical Presentation and Diagnostic Criteria Laboratory Treatment of M kansasii Disease Treatment of M avium Complex Disease (M avium, M intracellulare, M. scrofulaceum) Treatment of Rapidly Growing Mycobacterial Disease Treatment of M. marinum Disease Treatment of Other Nontuberculous Mycobacteria Pulmonary Disease Monitoring for Drug Toxicity Summary Introduction This is the first official statement of a diagnostic and therapeutic standard that deals exclusively with the nontuberculous mycobacteria. This topic was previously covered briefly in the statement on "Diagnostic Standards and Classification of Thberculosis and other Mycobacterial Diseases," the fourteenth and most recent version of which was published in 1981. Historically, M tuberculosis, M bovis, and M leprae have caused the preponderance of human disease. However, in recent years, other mycobacteria have become more widely appreciated as potential human pathogens. Collectively, these mycobacteria have been identified by a variety of terms, including mycobacteria other than tubercle bacilli, environmental mycobacteria, "atypical" mycobacteria, and nontuberculous mycobacteria (NTM). The tremendous growth in the number and prevalence of these species, which we have elected to refer to collectively as the NTM, has prompted us to put forth this new statement. The principles of therapy and diagnosis of disease caused by M tuberculosis have been updated since the 1981 statement and now appear in two separate statements: "Treatment of Thberculosis and Thberculosis Infection in Adults and Children" (American Review of Respiratory Disease 1986;134:355-63) and "Diagnostic Standards and Classification of Thberculosis" (American Reviewof Respiratory Disease 1990; 142:725-35). Like the previous standards that dealt primarily with tuberculosis, this statement is designed as a basic guide for those professionals involved in the diagnosis and managment of disease caused by NTM. Although not prepared as an all-inclusive review, the areas of discussion have been referenced in more detail than 940

in earlier standards to allow the reader a greater opportunity to assess the scientific basis for ideas and recommendations that are put forth. Included within this statement are the first recommendations of diagnostic criteria that apply primarily to the NTM and the first American Thoracic Society (ATS)recommendations of specific therapeutic drug regimens for disease caused by M kansasii and M avium complex. It is anticipated that additional changes will occur with the NTM. More species will be recognized, additional information about treatment will be accumulated, and some concepts about these organisms may change. Until that time, this statment should supplement existing literature regarding diagnosis and therapy of these mycobacterial diseases.

Epidemiology/Pathogenesis Sources of Infection Most NTM are isolated from water and soil (1,2), but some are isolated from other sources such as house dust (3). Extensive environmental studies in the United States have shown that M avium complex grows well in natural waters, particularly in the Southeast (4). M avium complex strains with plasmids, possibly associated with virulence, have been shown to be preferentially aerosolized, providing a possible mechanism for airborne acquisition of these organisms (5). Although M avium is an important cause of disease in poultry and swine, serologic studies have not indicated that animal-to-human transmission is important in human acquisition of infection (6). It is now generally accepted that environmental sources, especially natural waters, are the reservoir for most human infections caused by M avium complex. Water is also the likely source of infection for M marinum, commonly associated with fish tanks and swimming pools (7). In contrast, M kansasii has not been recovered from soil or natural water supplies (2). It has been isolated on numerous occasions from tap water (8) and from a few domestic animals. Rapidly growing mycobacteria such as M fortuitum, M chelonae, and M. smegmatis can be readily recovered from soil and natural water supplies, and investigations of some nosocomial outbreaks caused by these species have suggested that air (9, 10), tap water (11-13), and distilled water used for dialysis (14) or preparing surgical solutions (e.g., gentian violet) (15) may serve as the source of the organisms. M xenopi has been recovered almost exclusively from water, especially from hot water taps within the hospitals where it has been associated with cases of clinical disease (16). Interestingly, the organism has not been recovered from water mains entering the hospital. However, it has been speculated that the organism enters the hospital in this man-

ner but in low numbers, then multiplies in the hospital heating tanks where the temperature is 43° to 45° C, the optimal temperature for growth of this organism (16). Presumably, aerosolization of the organism then results in infection in the susceptible host. Much less is known about the environmental epidemiology and sources of infection for the other NTM, although environmental sources of infection are likely. A good review of environmental studies is provided by Wolinsky and Rynearson (2). Much remains to be understood about the pathogenesis of NTM infection and disease in humans. Epidemiologic studies and skin test surveys "suggest that person-to-person transmission of infection is rare. It is assumed that most persons are infected by environmental NTM. Of the likely sources of infection, airborne NTM may play an important role in respiratory NTM· disease, whereas ingestion of NTM may be the source of infection for children with NTM cervicallymphadenitis and for patients with AIDS whose disseminated M avium disease may begin with gastrointestinal infection. It is not known whether NTM disease develops soon after infection or, like tuberculosis, develops after a period of latent infection. Direct inoculation with NTM organisms in the water or other material is likely the source of infection for patients with soft tissue infections.

Prevalence in Humans Although frrst observed soon after Koch's discovery of the tubercle bacillus, NTM were not widely recognized as human pathogens until the 1950swhen several large series of patients with NTM disease were reported (17-19). These patients were epidemiologically distinct from patients with tuberculosis, being older, more commonly white, and quite often with underlying chronic lung disease such as bronchiectasis, silicosis, and healed tuberculosis. Positive reactions of 10 mm or more to purified protein derivative (PPD) tuberculin were less common than among tuberculous patients, and family contacts tended to be tuberculin-negative. As reports of patients with NTM disease increased, it became apparent there was marked geographic variability both in the prevalence of disease and in the mycobacterial species responsible for disease. Most patients in the southeastern United States with NTM disease were from rural areas and had isolates of M. avium complex, whereas those in the central United States more commonly had disease caused by M kansasii (20). In addition, patients with NTM disease tended to react more strongly to skin test antigens prepared from the infecting mycobacterial species than to standard PPD-S or PPDT, antigens prepared from M tuberculosis AM REV RESPIR DIS 1990; 142:940-953

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(21). Skin test surveys using NTM antigens suggested that infection by NTM was common, especially in rural areas and in the Southeast (22). NTM disease is not reportable in the United States, and until recently reliable estimates of its incidence or prevalence have not been available. Twonational surveys in the last decade have helped to define the extent of NTM infection in the United States. The initial study based on state laboratory reports from 19791980indicated that NTM comprised approximately one-third of the 32,000 mycobacterial isolates (23). Of these, 61070 were M avium complex, 19070 were M fortuitum complex, 10070 wereM kansasii, and the remaining 10070 were other NTM potentially pathogenic for humans. A second surveillance study based on reports from tuberculosis control officers on isolates ofNTM recovered between 1981 and 1983 showed higher rates of NTM disease among nonwhites, women, and patients residing in urban areas when compared with the initial study. White males, however, continued to serveas the major diseased population (24). Using combinations of national surveillance data, the prevalenceof NTM disease has been estimated to be 1.8cases per 100,000population for the entire United States. Of this, M avium complex represents 1.1/100,000. One important category of persons with NTM diseasenot representedin the above data are patients with AIDS and disseminated NTM disease. Although tuberculosis occurs commonly in patients with dual HIV and tuberculosis infection, M avium is now recognized as one of the more common causes of opportunistic infections in patients with AIDS in the United States (25, 26). Autopsy series suggest that 30 to 50070 of patients with AIDS will have disseminated M avium complex disease at the time of their death (27). An unusual feature of the M avium complex isolates in this setting is that the majority belong to serotype 4, and more than 95070 belong to one of the M avium serotypes (especially serotypes 1, 4, and 8) (28). This suggests that M avium isolates are more virulent in the setting of HIV disease than are M intracellulare isolates and suggests that some specialvirulencefactor may be present in these serotypes. These isolates have a number of other unusual features, including the observation that most strains are pigmented (28), and almost all strains contain one or more small plasmids that are similar in their DNA content (homology) (29). Other NTM species, including M kansasii (30, 31), M scrofulaceum (30), and M xenopi (32), have also been described as a cause of disseminated NTM disease in AIDS. More than 95070 of cases, however, are due to isolates of the M avium complex (30). Clinical Presentation and Diagnostic Criteria Pulmonary Chronic pulmonary disease resembling tuber-

culosis is the most common clinical presentation associated with NTM (2). M kansasii and M avium complex are the common species affecting the lungs. Other pathogens occasionally causing pulmonary disease include M chelonae, M fortuitum, M xenopi, M malmoense, M szulgai, and M simiae. The patients are generally older adults. With rare exceptions, children do not develop this form of NTM disease (2). Signs and symptoms of NTM pulmonary disease are variable and nonspecific. They include productive cough, dyspnea, hemoptysis, malaise, and fatigue. Feverand weight loss can occur but are less common and less severe than with M tuberculosis. Evaluation is often complicated by symptoms caused by other preexisting lung diseases. These predisposing lung conditions include pneumoconiosis, previous mycobacterial diseases, chronic obstructive airwaydisease, bronchiectasis, and malignancy. There are some differences in the radiographic features of NTM lung disease compared with those produced by M. tuberculosis. NTM tend to cause thin-walled cavities with less surrounding parenchymal infiltrate, have less bronchogenic but more contigious spread of disease, are more likely to involve the apical and anterior segments of the upper lobes, and produce more marked involvement of pleura over the involved areas of the lungs. Occasionally, they may produce dense pneumonic disease or a solitary pulmonary nodule without cavitation. Basal pleural disease is not often found, and pleural effusion is rare. However, none of these findings is pathognomonic or diagnostic of NTM. There has been a great deal of interest in the availability of species-specific skin test antigens. Unfortunately, many surface antigens are shared by the different mycobacterial species, and extensive cross-reactions have occurred with PPD tuberculin and the various NTM skin test antigens studied to date. Until these antigen preparations are standardized and highly specific, skin testing with single or multiple preparations remains unhelpful in the diagnosis 0 f NTM pulmonary disease. In the absence of specific diagnostic features in the history and physical examination, the chest roentgenogram, and differential skin testing, cultural isolation of the NTM is essential for diagnosis. However, as these organisms are commonly found in nature, contamination of culture material or transient infection does occur. Thus, a single positive sputum culture does not suffice to diagnose disease. Furthermore, some patients with multiple positive sputum cultures may not need drug therapy. In some patients, the respiratory tract may be infected with the organisms without causing disease, particularly in patients with chronic respiratory disease. This condition has often been referred to as "colonization" and has been seen most often with M avium complex. It is characterized by the presence of non cavitary, stable, and usually minimal radiographic disease associated with sporadic excretion of organisms from the re-

spiratory tract. Recognition of this syndrome is important because drug therapy may not be required. For some patients, bronchial toilet with or without antimycobacterial drugs has been associated with rapid clearing of the mycobacteria from the sputum (33). Given these reservations, the diagnosis of lung disease caused by NTM is usually not difficult. In most patients, a diagnosis can be made without the need for a lung biopsy. For patients with a cavitary infiltrate on chest radiograph, definite NTM disease is considered to be present when: (1) two or more sputums (or sputum and a bronchial washing) are acid-fast bacilli smear-positive and/or result in moderate to heavy growth of NTM on culture; (2) other reasonable causes for the disease process have been excluded, e.g., fungal disease, malignancy, tuberculosis, etc.

Clinical studies have established the validity of bronchial washings as a culture source for M tuberculosis. Although similar studies have not been done for NTM, bronchial washings are considered to be more sensitive than routine expectorated sputums, but they are probably less specific for the recovery of NTM. Approximately 90070 of patients with disease caused by M kansasii and as much as 75070 of patients with disease caused byM avium complex have cavitary infiltrates, and disease will be diagnosed by these criteria (33). In the presence of a noncavitary infiltrate not known to be due to another disease,NTM lung disease is considered to be present when: (1) two or more sputums (or sputum and a bronchial washing) are AFB smear-positive and/or result in moderate to heavy growth on culture; _ (2) failure of the sputum cultures to convert to negative with either bronchial hygiene or 2 wk of specificmycobacterialdrug therapy; (3) other reasonable causes for the disease have been excluded.

Clearance of NTM other than M avium complex and M kansasii by bronchial hygiene or 2 wk of specific mycobacterial drug therapy when a colonization state rather than disease has not been studied, but this is presumed to occur. When lung disease is due to M chelonae, cavitary infiltrates are usually not present, so the majority of cases caused by this species are usually diagnosed using the above diagnostic criteria. Patients in whom the organisms appear to clear with either of the above approaches should continue to be observed for clinical symptoms and pulmonary findings, as the very chronic nature of some infections may prevent an early diagnosis even when tissue invasion is present and will eventually progress. In the patient with low numbers of organisms on sputum culture and/or concern about the presence of another disease to explain the radiographic abnormalities, a lung biopsy is often required for diagnosis. If a transbronchial, percutaneous, or open lung biopsy is

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TABLE 1 RECOMMENDED DIAGNOSTIC CRITERIA FOR PULMONARY DISEASE CAUSED BY NONTUBERCULOUS MYCOBACTERIA I. For patients with oavitary lung disease 1. Presence of two or more sputum specimens (or sputum and a bronchial washing) that are acid-fast bacilli smear-positive and/or result in moderate to heavy growth of NTM on culture 2. Other reasonable causes for the disease process have been excluded (e.g., tuberculosis, fungal disease, etc.) II. For patients with noncavitary lung disease 1. Presence of two or more sputum specimens (or sputum and a bronchial washing) that are acid-fast bacilli smear-positive and/or produce moderate to heavy growth on culture 2. If the isolate is M. kansasii or M. avium complex, failure of the sputum cultures to clear with bronchial toilet or within 2 wk of institution of specific mycobacterial drug therapy (although only studied for these two species, this criteria is probably valid for other species of NTM) 3. Other reasonable causes for the disease process have been excluded III. For patients with cavitary or noncavitary lung disease whose sputum evaluation is nondiagnostic or another disease cannot be excluded 1. A transbronchial or open lung biopsy yields the organism and shows mycobacterial histopathologic features (l.e., granulomatous inflammation, with or without acid-fast bacilli). No other criteria needed 2. A transbronchial or open lung biopsy that fails to yield the organism but shows mycobacterial histopathologic features in the absence of a prior history of other granulomatous or mycobacterial disease plus: (1) presence of two or more positive cultures of sputum or bronchial washings; (2) other reasonable causes for granulomatous disease have been excluded

performed and the biopsied tissue sample yields the organism and shows mycobacterial histopathologic changes (i,e., granulomatous inflammation with or without AFB), this by itself is sufficient to establish the diagnosis of NTM lung disease. If the lung biopsy has a negative culture (something that often happens when transbronchial biopsiesare performed because of the small size of the tissue sample) but demonstrates mycobacterial histopathologic features (in the absenceof a prior history of other granulomatous or mycobacterial disease), a diagnosis of NTM lung disease is considered to be present when: (1) two or more sputums (or sputum and a bronchial washing) are culture-positive for NTM, even if they are negative for AFB on smear and result in light growth on culture; (2) other reasonable causes for granulomatous disease have been excluded. These criteria are summarized in table 1. Lymphadenitis Infection of the submandibular, submaxillary, or cervical lymph nodes in children between 1 and 5 yr of age is the most common presentation of NTM lymphadenitis (2, 34, 35). In the absence of AIDS, adults are rarely affected by this disease (2). The disease occurs insidiously, with minimal symptoms. The involved lymph nodes are unilateral (99070) and generally not tender. The nodes may enlarge rapidly, and even rupture, with formation of sinus tracts that result in prolonged local drainage. Other nodes, especially axillary or inguinal, may be involvedoccasionally. There is typically no history of exposure to tuberculosis, and the chest radiograph is normal. Most children with NTM lymphadenitis will react to skin test antigens prepared from M. avium complex (e.g., PPD-B) (35, 36). However, efforts to produce a safe, standardized preparation of these antigens have failed to date, and thus no commercial NTM

skin test material is available. All children in this setting should be tested using PPD tuberculin. Most children tested with intermediate strength (5 TU) PPD tuberculin will have a weakly reactiveskin test (5 to 9 mm), but some children may be negative, and others may respond with 10 mm or more induration. The presumptivediagnosis of NTM lymphadenitis is based on the histopathologic appearance of the lymph node showing caseating granulomata with or without acid-fast bacilli and a negativetuberculin skin test. Failure of the node to yield M. tuberculosis provides stronger presumptive evidence for the diagnosis of NTM lymphadenitis. A simple diagnostic biopsy or incision and drainage of the involved lymph nodes should be avoided since the majority of these procedures will be followed by fistulae formation with chronic drainage (35). If the diagnosis of NTM lymphadenitis is being considered or is made at the time of surgery, total excision of the significantlyinvolvednodes, rather than excisional biopsy, is the treatment of choice for the disease because it will avoid the morbidity of chronic sinus tract formation. A definite diagnosis of NTM lymphadenitis is made by recovery of the causative organism from lymph node cultures. However, in most series, only about 50070 of exciseddiseased lymph nodes will be culture-positive (35), although in some hands the recoveryrate may be as high as 85070 (E. Wolinsky, unpublished observations). Currently, approximately 80070 of culture-positive cases are due to M. avium complex and the remainder to M. scrofulaceum (35, 37). This is a change from 20yr ago when most geographic areas reported M. scrofulaceum as the most common etiologic agent (34). At the present time in the United States, only about 10070 of cultureproved mycobacterial cervical lymphadenitis in children is due to M. tuberculosis; the remainder are due to M. avium complex and M. scrofulaceum (37). In contrast, more than

90070 of culture-proved mycobacterial lymphadenitis at any site in the adult is due to M. tuberculosis.

Skin and Soft Tissue Infection The NTM species that most commonly cause infections of the skin and subcutaneous tissue are M. fortuitum, M. chelonae, M. marinum, and M. ulcerans (2). However, virtually all species of NTM have been described as a cause of cutaneous disease (2). Localized drainage or abscess formation at the site of puncture wounds (such as occurs after stepping on a nail), or after open traumatic injuries or fractures, are most often due to the rapidly growing mycobacterial species M. fortuitum or M. chelonae (38). Nosocomial disease caused by these two species is also seen. These include infections of long-term intravenous or peritoneal catheters (38, 39), postinjection abscesses,or surgicalwound infections after augmentation mammaplasty (40) or cardiac-bypass surgery (9, 10, 38). Diagnosis is made by culture of the specific pathogen from drainage material or tissue biopsy. M. marinum is the cause of "swimming pool granuloma" or "fish tank granuloma" (2). The lesions usually appear as papules on an extremity, especially on the elbows, knees, and dorsum of feet and hands, progressing subsequently to shallow ulceration and scar formation. Most lesions are solitary, although occasional "ascending" lesions develop that resemble sporotrichosis. Clinical involvement of regional nodes is absent. The oranisms may be introduced into the skin through abrasions in swimming pools and fish tanks or by scratches or puncture wounds from fish, shrimp, fins, etc. Diagnosis is made from biopsy material, histologic examination, and culture. M. ulceranscauses indolent necrotic lesions of the skin and underlying tissue in tropical areas of the world, and it has not been reported within the United States. The lesions occur most commonly in children and young adults (41). Bursae, Joints, Tendon Sheaths, Bones Chronic granulomatous infection caused by NTM may develop in tendon sheaths, bursae, joints, and bones after direct inoculation of the organisms through accidental traumas, surgical incisions, puncture wounds, or injection. M. marinum: is commonly involved in infections of the hand and wrist. M. avium complex is particularly prone to cause joint infections, although M. fortuitum, M. chelonae, M. marinum, and M. kansasii have been implicated (2). M. terrae complex (especially M. nonchromogenicum) has also been isolated from synovialtissue of the hand or wrist, and it tends to be associated with a very indolent, chronic type of disease. Occasionally, axial bones and extremities have been infected without apparent trauma and are due presumably to hematogenous infection. After open heart surgery, osteomyelitis of the sternum caused by M. chelonae or

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M. fortuitum has been described with both epidemic and sporadic disease (9, 10, 38). Disseminated Disease in Patients without AIDS Dissemination of NTM in adult patients with immunosuppression but without AIDS (e.g., renal or cardiac transplantation, leukemia, etc.) has been observed. M. avium complex (2, 42), M. kansasii (2, 43), M. chelonae (2, 38), M. scrofulaceum (2), M. fortuitum (2), and M. haemophilum (43) have all been reported to cause disease in this setting. In general, the disease caused by M. avium complex presents as a fever of unknown origin (42), whereas disease caused by M. kansasii, M. chelonae, and M. haemophilum generally presents as multiple subcutaneous nodules or abscesses that drain spontaneously (2, 43). The mortality relates directly to the type and severity of underlying disease. Lincoln and Gilbert (34) reviewed 12 cases (all fatal) of disseminated NTM disease in children. Most of the children were infected with M. avium complex, were younger than 3 yr of age, and had no apparent underlying disease. Disseminated M. avium complex disease in children may also occur in the setting of severe combined immunodeficieny syndrome (28). The isolation of organisms from sterile,closed sites such as bone marrow or blood, or from a skin biopsy (in the setting of multiple lesions), is diagnostic of the disease. Disseminated Disease in Patients with AIDS Numerous reports havedefined that mycobacterial disease is common among patients with AIDS and among persons at risk for AIDS (25). A detailed reviewof this association and other aspects of the disease are provided in the ATSposition paper "Mycobacteriosis and the Acquired Immunodeficiency Syndrome" published in 1987 (26). The most common mycobacterial species isolated from patients with AIDS in the United States is M. avium complex. However, among Haitians and inner-city minority intravenous drug abusers, M tuberculosis is more common. M avium infection in patients with AIDS almost invariably presents as disseminated disease.The usual presenting symptoms are numerous and nonspecific, with persistent or intermittent fever being the only finding present in essentially all patients. Symptoms that have been suggested as being more common in the M avium complex than in patients with other complications of AIDS include weight loss of greater than 20 pounds, anorexia, abdominal pain, and diarrhea (27). Physical and laboratory findings include fever, hepatosplenomegaly, and generalizedlymphadenopathy, including mediastinal adenopathy. Although lung cultures for M avium complex in disseminated disease are usually positive at autopsy, radiographic evidence of pulmonary involvement is rare. The significance of a positive sputum or bronchoscopic culture for M avium complex in the absence of other findings of disseminated disease is un-

known. Of concern has been that patients with evidence for localized pulmonary infection are at high risk for disseminated disease, and therapy may prevent this dissemination. Diagnosis of disseminated disease is made by culture of the organism from blood, bone marrow, and/or stool. Rarely, biopsy of other tissues such as lymph nodes, liver, etc. may be necessary to demonstrate the organism. Patients with diarrhea and malabsorption, and negative smears for acid-fast bacilli in the stool, may require a small bowelbiopsy. Histologically, granuloma formation is not usually seen, but sheets of foamy macrophage filled with acid-fast organisms are commonly found. Laboratory Because of the large number of potentially pathogenic NTM that can be encountered in the clinical laboratory, a species identification of these organisms is one of the most complex procedures performed in the mycobacteriology laboratory. For this reason, it is recommended that only the highest level iaboratory attempt it. Currently, laboratory functions that contribute to the diagnosis and management of disease caused by M tuberculosis and the NTM have been divided into three major categories of services offered. These are as follows: Level L Collection and transport of specimens; preparation and examination of smears for acid-fast bacilli. LevelIL Procedures of Level I plus isolation and identification of M tuberculosis. Level IlL All procedures of Level II plus identification of the NTM. Drug susceptibility testing is usually performed at LevelII and should be performed at Level III.

base media (commonly, Middlebrook 7HI0 or 7Hll). Specimens should be inoculated onto both types of media, with additional use of a broth medium also being useful. This can be the standard Middlebrook 7H9 broth or the radiolabeled 7H12 broth used for rapid isolation in the BACTEC system. The slowgrowing NTM produce detectable growth in 2 to 4 wk on the solid media and in 1wk with the BACTEC system. All of the currently recognized NTM pathogens will grow on these media with the exception of M. haemophilum. If this species is suspected, a commercial surface paper strip containing hemin (X factor) used for the identification of Haemophilus influenzae should be added to the surface of a 7HI0 plate (44), or hemin or ferric ammonium citrate should be incorporated into the medium. The major modification of culture techniques for recoveryof NTM speciesis the need to incubate all skin or soft tissue samples at two temperatures: 35° C and 28° to 32° C. This is because a number of the common pathogens of these tissues, including M haemophilum, M. ulcerans, M. marinum, and M. chelonae ssp. chelonae, may grow only at the lower temperatures, especially on primary isolation. Increased CO 2 concentration (5 to 10070) enhances the growth of many NTM species as it does M tuberculosis.

Identification of Nontuberculous Mycobacteria Traditional identification of NTM, as well as M. tuberculosis, has relied upon statistical probabilities of presenting a characteristic reaction pattern in a battery of biochemical tests. The niacin test was the most useful of these tests for separating NTM and M. tuberculosis as the former is usually negative, Digestion, Decontamination, and whereas isolates of M tuberculosis are posiStaining Procedures tive. Runyon devised the first good scheme Methods used for digestion and decontamifor grouping NTM based on growth rates and nation of clinical samples for recovery of M. colony pigmentation. Although species identuberculosis have also proved useful for the tification has become more sophisticated and NTM. In general, however, NTM are more the number of potential pathogens has insusceptible to killing by NaOH or other alka- creased since this scheme was introduced, the line agents commonly used for decontami- use of growth rates and colony morphology remain important early laboratory signs of nation, and for this reason, care must be taken not to exceed the recommended concenthe presence of an NTM species. Knowledge tration and time guidelines for their use. that an organism grows in less than 7 days Staining and microscopy of NTM also fol- (rapidly growing mycobacteria) or that it low the guidelines used for M tuberculosis. produces pigmentation in the presenceof light Both conventional acid-fast stains (Kinyoun (photochromogen) tellsthe physician not only or Ziehl-Neelsen) and the fluorochrome pro- that he is dealing with a species other than cedure are effective in recognizing the pres- M. tuberculosis but gives him an early clue ence of NTM in clinicalmaterial. The appearas to what the species may be. ance of NTM on microscopy is indistinguish- ' A more appropriate grouping currently for able from M tuberculosis, with the exception these organisms is based on the type of clinithat M kansasii organisms often are larger cal disease they produce: lymphadenitis, cuand have a more beaded appearance. taneous disease, disseminated disease, and pulmonary disease. Grouping of the NTM by Culture Techniques for Nontuberculous this scheme is shown in table 2. Mycobacteria Because of the extremely. slow nature of The principles and practices of culturing M traditional biochemical tests, more rapid tuberculosis have proved very effective for the methods for species identification are under NTM species. Twogeneral types of solid me- investigation, including thin-layer chromatogdia are available: egg-potato-base media raphy, gas liquid chromatography, and, more (commonly, Lowenstein-Jensen) and agar- recently, high pressure liquid chromatography,

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TABLE 2 CLASSIFICATION OF THE NONTUBERCULOUS MYCOBACTERIA RECOVERED FROM HUMANS Clinical Disease Pulmonary

Common Etiologic Species

Growth Rate

Morphologic Features*

References

Unusual Etiologic Species

2

M. avium complex

Slow (> 7 days)

Usually not pigmented

M. kansasii

Slow

Photochromogen; often large and beaded on acid-fast bacilli smear

61-63

M. simiae

94

M. che/onae subspecies abscessus

Rapid « 7 days)

Not pigmented

38, 92

M. szulgai

95

M. xenopi

Slow

Pigmented

M. malmoense

93

16, 97, 98

M. fortuitum (all three biovariants)

Lymphadenitis

Cutaneous

Disseminated

References

38, 92

M. chelonae subspecies che/onae

92

M. fortuitum (all three biovariants)

38

34, 35

M. che/onae (both subspecies)

38

34, 35, 37

M. avium complex

Slow

Usually not pigmented

M. scrofulaceum

Slow

Scotochromogen

M. kansasii

2

M. marinum

Rapid

Photochromogen; requires low temperatures (28° to 30°C) for isolation

2, 7

M. avium complex

2

M. fortuitum (all three biovariants)

Rapid

Not pigmented

38

M. kansasii

2

M. che/onae (both subspecies)

Rapid

Not pigmented

38

M. terrae

2

M. utcemns"

Slow

Usually a scotochromogen: requires low temperatures for isolation

41

M. smegmatis

84

M. avium complex

Slow

Isolates from patients with AIDS, usually pigmented (80%)

25,28, 30, 42

M. fortuitum (all three biovariants)

38

M. xenopi

32

M. kansasii

Slow

Photochromogen

31,43

M. chelonae (both subspecies)

Rapid

Not pigmented

38, 43

M. haemophilum

Slow

Not pigmented; requires hemin, often needs low temperatures and CO 2 to grow

43, 44

* Photochromogen: isolate is buff-colored in the dark but turns yellow with brief exposure to light. Scotochromogen: isolate is yellow-orange or orange-colored even when grown in the dark.

which examines the mycolic acid fingerprint patterns that appear to differ in each species of Mycobacterium (45). Twoadditional techniques for rapid identification of NTM are currently in use. These are the use of speciesspecific DNA probes and the BACTEC NAP tests. Commercial radiolabeled C2S I) DNA probes complementary to ribosomal-RNA have been approved for use in identifying isolates of M tuberculosis, M avium, and M intracellulare. They appear to be highly sensitive and specific, and they can provide species identification using a culture from broth or agar within 4 h. The radiometric culture system (BACTEC) can be used to differentiate between M tuberculosis and NTM using a selective growth inhibitor called NAP (p-nitro-a-acetylaminol3-hydroxypropiophenone) (46). This compound, at a concentration of 5 ug/ml, inhibits the growth of M tuberculosis complex but not NTM. The average time for the NAP test

is 5 days. However, a species identification schema other than the use of the DNA probes for NTM has not been worked out for use with the BACTEC, and such identification must depend on one of the previously discussed methods. Distinction between M avium and M intracellulareis not possible biochemically, and serotyping is the traditional method used to separate the species. Because of limited availability of typing sera and other problems, serotyping has been available only as a research tool in a few laboratories. The newly developed DNA probes, however, provide a rapid, reliable, and readily available method for separation of these two species. At present, this distinction is not known to have any clinical relevance for human pulmonary disease. This does not appear to be true with disseminated disease in AIDS where most isolates have been M avium. Serotyping of M avium complex isolates is currently available

as a research or epidemiologic tool only at the National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado, and the Mycobacterial Section, Centers for Disease Control, Atlanta, Georgia.

Drug Susceptibility Testing Susceptibility testing of the NTM does not utilize a system that, on clinical or laboratory grounds, has been shown to be optimal for these organisms, but rather, for convenience, the organisms have been tested using the same method, the same drugs, and the same critical concentrations of these drugs as are used for M tuberculosis. Although the current system works well for M tuberculosis, it has not been generally helpful in clinical management of disease caused by NTM. A number of reasons seem to be responsible for the latter finding. There appears to be little variation in drug susceptibility among most species of NTM using the current single-

945

AMERICAN THORACIC SOCIETY

TABLE 3

M tuberculosis and has a high degree of over-

STANDARD DRUG PATTERNS OF THE COMMONLY PATHOGENIC NONTUBERCULOUS MYCOBACTERIA USING THE CURRENT DRUG CONCENTRATIONS RECOMMENDED FOR M. tuberculosis

all agreement with the much slower proportion method in agar. Some disagreementshave occurred, most commonly with ethambutol and to a lesser degree with isoniazid. With the NTM, however, both M avium complex (49, 50) and (for some drugs) M kansasii usually have lower minimum inhibitory capacities in broth than in agar, so there has been a relatively poor agreement between the methods when tested against these species using the same critical concentrations. For the pathogenic rapidly growing mycobacteria M fortuitum, M chelonae, M smegmatis, and, occasionally, other species such as the M. chelonae-like organisms, routine susceptibility testing to antimicrobial agents such as amikacin, doxycycline, and the sulfonamides should be performed on all clinically significant isolates. This is because there are numerous subgroups within the two major species of rapidly growing mycobacteria, each of which has a different drug pattern, and some drugs exhibit variable inhibitory activity even within the same subgroup (51). The best studied method of susceptibility testing has been broth microdilution minimum inhibitory concentration determination using cation-supplemented Mueller-Hinton broth (51), although other methods such as agar disk elution (52) may be more practical when only small numbers of isolates are tested. When and how isolates of the M. avium complex should be subjected to susceptibility testing by other than the standard antituberculosis methods remains controversial. It is possible that the use of higher drug concentrations than are used for M tuberculosis (e.g., 50r 10 ug/ml of rifampin or 10 ug/ml of streptomycin) or determination of minimum inhibitory concentrations may be helpful in predicting clinical response as many isolates are susceptible to higher drug concentrations. One recent study of 75 patients showed that responders to drug therapy were more likely to receivedrugs to which their isolate was susceptible in vitro (using high concentrations) than were nonresponders (mean, 2.4 drugs versus 1.4 drugs; p < 0.001) (47). Combination drug studies have shown substantial synergism,particularly betweenrifampin and ethambutol, and, to a lesser extent, between rifampin and ethionamide or streptomycin (53, 54). Antagonistic drug interactions, although far less common, have been reported. The meaning of these in vitro findings and how to relate to them to the testing of individual clinical isolates have yet to be determined in clinical trials. Severalexperimentaldrugs havebeen shown to be active in vitro against NTM, and clinical studies of these agents are being conducted. These include drugs such as rifabutin (ansamycin, LM427) (M avium complex) (48, 55), and ofloxacin (M fortuitum, M kansasiii (48, 56).Additional drugs have been approved by the Food and Drug Administration for uses other than against NTM. The in vivo activity and the clinical use of these agents for the NTM are still under investigation. These in-

Species M. M. M. M. M.

kansasii marinum avium complex fortuitum chelonae

Susceptible RMP,EMB RMP, EMB None None

Resistant

Intermediate *

PZA INH, PZA INH, RMP, SM, PZA INH, RMP, EMB SM, PZA

INH, SM SM Cycloserine, EMB Capreomycin

Definition of abbreviations: RMP = rifampin; EMS = ethambutol; 8M = streptomycin; PZA = pyrazinamide; INH = isoniazid. * Partial resistance (1 to 10%) is usually seen, but some isolates may be reported as either susceptible or resistant.

drug concentrations used in most laboratories, so that drug patterns are predictable (see table 3). Isolates of M. marinum and M. kansasii are susceptible to concentrations of rifampin and ethambutol used in tests with M. tuberculosis. Although variation in susceptibilities is seen when higher single-drug concentrations are tested against isolates of the M. avium complex (47), they are almost always resistant to the relatively low drug concentrations currently used for testing M. tuberculosis: isoniazid, 0.2 and 1.0 ug/rnl; rifampin, 1.0 ug/ml; streptomycin, 2.0 ug/ml; ethambutol, 5.0 ug/ml; pyrazinamide, 50 J,1g/ ml; capreomycin, 10 ug/rnl; ethionamide, 5.0 ug/ml; cycloserine, 30 ug/ml, In 155 M. avium complex strains tested at these drug concentrations at the Centers for Disease Control, susceptibility to the individual drugs ranged from zero to 70/0 (48). Isolates of M. fortuitum and M. chelonaeare invariably resistant to these concentrations of antituberculosis drugs, and these drugs have never been shown to be therapeutically efficacious for treatment of disease caused by these two species. Because of these factors, routine susceptibility testing to the antituberculosis agents,

as currently performed using the abovementioned criticalconcentrations, does not provide useful clinicalinformation and should not be routinely performed for four species of the NTM: M. marinum, M. avium complex, M. fortuitum, and M. chelonae. For the last two species,the rapidly growing mycobacteria, testing to antituberculosis agents under any circumstancesshould be discontinued. For the other species, special circumstances might warrant standard susceptibility testing. Situations in which susceptibility testing using the standard antituberculosis methodology should be performed include the following: (1) All initial isolates of M. kansasii to rifampin in which prior drug therapy cannot be excluded or the history of a patient's prior drug therapy is not available. (2) Cases of M. kansasii disease in which sputum fails to convert after 4 months of rifampin-containing regimens or cases of relapse (i,e., smears and/or cultures become positive after apparent successfulsputum con-

version or treatment). Although wild strains are initially susceptible, acquired resistance to rifampin and ethambutol has been documented with this species and is readily detectable by current methods. (3) Recoveryof an infrequently isolated species of NTM that appears to be clinically significant, but for which drug therapy and knowledge of susceptibility patterns, is limited. This would include such speciesas M szulgai, M. malmoense, M haemophilum, M. xenopi, etc. (4) Smear-positive samples in a clinical setting suspicious for tuberculosis. Direct susceptibilities should be performed on these samples, as the major pathogen likely to be encountered in any laboratory is still M

tuberculosis. (5) Cases of M marinuminfection in which there has been a failureto respond to rifampincontaining regimens or a microbiologic relapse. (Resistance to rifampin in this setting, however, has not been reported.)

These recommendations should not be interpreted as meaning that susceptibility testing has no clinical value for M. avium complex. It does mean that the use of the current single low drug concentrations designed for routine antituberculosis testing has no clinical value.

Methods of resting Susceptibilitytesting of NTM to the antituberculosis agents can be performed using the standard methodology used for M. tuberculosis. This usually includes the use of 7HI0 agar and the modified method of proportions whereby resistance is defined as growth on the drug-containing quadrant of more than 1% of the number of colonies that grow on the drug-free control quadrant. Details of this method are included in the ATSstatement "Diagnostic Standards and Classification of Tuberculosis,"and a similar description willsoon be available as a preliminary standard by the National Committee for Clinical Laboratory Standards. The use of the broth radiometric method (BACTEC; Johnson Laboratories, Towson, MD), which measures 14 C0 2 production from labeled palmitic acid, has proved useful with

946 elude ciprofloxacin (M fortuitum, M avium complex, and M kansasiii (52, 57), clofazamine (M avium complex andM chelonae) (58), imipenem (M. fortuitum and M. chelonae) (51),and sulfonamides and trimethoprim/sulfamethoxazole (M. kansasii, M marinum) (52, 59). Susceptibility testing of

with pulmonary disease should receive drug therapy. There have been no randomized controlled trials of treatment for disease caused by M kansasii, comparing one drug regimen with another or with no drug treatment at all. There have been, however, several retrospective and these agents is and should be limited to ma- prospective studies of various treatment regjor clinical and research laboratories. imens (61, 62, 64-66) that have given us a good basis for drug therapy recommendations. Earlier reports of treatment with antimycobacTreatment of M. kansas;; Disease terial drugs in the prerifampin period were Introduction disappointing when compared with the much Disease caused by M. kansasii is one of the higher success rates achieved in treating tuberculosis with these same drugs. The sputum two most common NTM pulmonary diseases conversion rates at 6 months ranged from 52 affecting humans. It tends to occur in geographic clusters and affects primarily adult to 81070, and relapse rates of approximately 10070 were seen in patients achieving an iniwhite men, but it can affect patients of any sex, race, or age. Pulmonary disease is the tial response (61, 64). Surgical resection was often recommended to achieve better initial most frequent clinical presentation. The orcontrol and to prevent relapse. The advanganism frequently exhibits a beaded or crossbarred appearance on acid-fast stain and tage of the addition of surgery was never established, however (64). produces rough buff-colored colonies that deWith the advent of rifampin, the picture velop a yellowish pigmentation because of the deposition of beta-carotene crystals after ex- changed considerably for the better. Four months sputum conversion rates with rifamposure to light. Disease-producing strains are pin-containing regimens were 100070 in 180pausually highly catalase-positive. Only one tients from three studies (61, 62, 65). There serotype of M. kansasii has been identified. Untreated strains of M kansasii are suswere two treatment failure cases, however (an ceptible to rifampin, isoniazid, ethambutol, incidence of 1.1070). These patients converted ethionamide, streptomycin, and cycloserine their sputa, but they became culture positive again while still receiving therapy. Both had at concentrations readily achievable in the serum with usual therapeutic doses (60,61). Bebeen treated with isoniazid, rifampin, and cause the concentrations of drugs used in susethambutol, and both failures were associatceptibility testing were chosen for their useed with the development of rifampin resisfulness with M. tuberculosis and because M tance (61). Long-term relapse rates with rikansasii is less susceptible to these drugs, some fampin also appear to be very low, with only isolates of the latter species may be reported one relapse recorded among 134 patients resistant to isoniazid at 0.2 or 1 ug/ml and (0.8070) with long-term follow-up in three to streptomycin at 2 ug/ml, These isolates are studies (61, 62, 66). Surgery is now considsusceptible to slightly higher drug concentraered to have no role in the management . of tions (60), and laboratory reports of resistance routine cases of pulmonary disease. The current recommendation for treatment to the low concentrations of these two drugs of pulmonary disease caused by M kansasii have no clinical or therapeutic significance is the regimen of isoniazid (300 mg), rifamas long as a rifampin regimen is being used (62). Thus, when clinically indicated, isoniazid pin (600 mg), and ethambutol (15 mg/kg) given daily for 18 months. In patients who are and/or streptomycin should be used against M kansasii regardless of the in vitro suscep- unable to tolerate isoniazid, rifampin and ethambutol with or without streptomycin for tibility results. M kansasii is also susceptible in vitro to erythromycin, sulfamethoxazole, the first 3 months would seem reasonable, but this has not been established by clinical trials amikacin, and rifabutin, although there is (see below). Pyrazinamide is unacceptable as limited information on the clinical usefulness of these drugs (59). Isolates are usually resisan alternate or third drug for M kansasii as all isolates are resistant. tant to achievable serum levels of p-aminoThe use of intermittent drug regimens or salicylic acid, capreomycin, and pyrazinamide. short-course treatment has not been adequateAcquired resistance to rifampin, ethambutol, ly studied to permit its recommendation. One and isoniazid has been demonstrated in isostudy of 40 patients did demonstrate that the lates from treatment failure cases (59, 61), and addition of intermittent streptomycin 1 g twice resistance to the first two agents is reliably weekly for the first 3 months to the previousdemonstrated by current M tuberculosis susly recommended three-drug regimen given for ceptibility test methods. 12 months resulted in apparent cure of all but one patient (65). A trial of low dose ethamTreatment butol (15 mg/kg) and rifampin given for 9 The natural history of pulmonary disease months sponsored by the British Medical Recaused by M. kansasii in patients receiving search Council is ongoing with promising no drug treatment has been assessed (63). In results (67), but the final study has not been general, this has shown persistence of spupublished. tum positivity and progression of clinical and In patients whose organisms have become radiographic disease. On this basis, patients resistant to rifampin as a result of previous

AMERICAN THORACIC SOCIETY

therapy, a regimen consisting of daily high dose isoniazid (900 mg), pyridoxine (50 mg), high dose ethambutol (25 mg/kg), and sulfamethoxazole (3.0 mg) for 18to 24 months has been under investigation. The oral therapy has been combined with daily or five times per week streptomycin or amikacin for 2 to 3 months followed by intermittent streptomycin or amikacin for a total of at least 6 months. Preliminary results with this regimen described sputum conversion in seven of eight patients (88070) after a mean of 10 wk (59). For treatment of extrapulmonary disease, the regimen of antimycobacterial drugs should be the same as for pulmonary disease. Disseminated disease has been described in patients with AIDS, and it is the second most common NTM-producing disseminated disease in this setting (30). Of the cases detailed in the literature, most have been fatal (31). It is unknown at present if drugs should be prescribed differently or for a longer period of time than for patients without AIDS. The previous position paper of the ATS, "Mycobacteriosis and the Acquired Immunodeficiency Syndrome," published in 1987, recommended the current standard three-drug regimen with some consideration for the addition of streptomycin 1 g twice weekly for the first 3 months (26). In the treatment of lymph node disease in children, excision of all accessible nodes at the time of the initial biopsy should be done since the probabilities are that the etiologic agent is a TNM other than M kansasii for which excision is the indicated treatment.

Treatment of M. avium Complex Disease (M. evtum, M. intracellulare, M. scrofulaceum) Introduction The early experience with medical treatment of M. avium complex disease was disappointing, and the best outcomes were in those patients subjected to resectional surgery. Despite significant progress in the therapy of tuberculosis, there have been no similar advances in the treatment of M. avium complex disease. No controlled clinical trials in this disease have been conducted, and treatment recommendations have been based largely on empiric data. Therapy is limited by the absence of antimicrobial agents with low toxicity and a good in vivo therapeutic index against the organism. Most of the first-line antimycobacterial drugs with good in vitro activity against M tuberculosis have 10 to 100 times less activity against M avium complex isolates. This diminished activity is believed to result from the lipophilic cell wall, which prevents drug penetration (68). The drugs with the best in vitro activity are second-line drugs, such as cycloserine and ethionamide, which have much more toxicity than the first-line drugs do.

Pulmonary Disease The natural history of M avium complex lung

947

AMERICAN THORACIC SOCIETY

disease is unpredictable. Some patients maintain a stable clinical and radiographic picture for years, whereas others have a steady progression of their disease. For most patients, especially those with noncavitary disease, a period of observation of at least several months may be needed to assess the contribution of M avium complex disease to the overall clinical picture. During this time, patients should receive therapy for underlying pulmonary disease,if present (e.g.,bronchodilators, broad-spectrum antibiotics, smoking cessation), and have sputum cultures taken on a regular basis (e.g.,everymonth). Patients with a stable clinical picture and minimal symptoms, and those whose sputum clears with nonspecific therapy, should continue to be observed. For patients with significant symptoms and advanced or progressive radiographic disease, an observation period is not needed to establish the need for therapy. Drug therapy for M avium complex disease involves multiple drugs, and because of this, the risk of drug toxicities is relatively high. The therapeutic regimens are less well established, and the development of new drugs such as the fluorinated quinolones may result in changes in therapy recommendations. For these reasons, the treatment of M avium complex disease may best be served by physicians experienced in pulmonary or mycobacterial diseases. Initial therapy for patients with M avium complex disease for whom treatment is indicated should consist of the four-drug regimen of isoniazid (300mg), rifampin (600 mg), and ethambutol (25 mg/kg for the first 2 months, then 15mg/kg), with streptomycin for the initial 3 to 6 months of therapy. The optimal dose or duration of therapy for streptomycin has not been established. Daily therapy of five times per week is the preferred initial streptomycin therapy for patients with normal renal function (serum creatinine) and who are younger than 70 yr of age. The exact dose will depend on the patient's age and weight. This should be given five times per week for 6 to 12 wk, usually until some response to therapy is evident. At this point, the patient should be changed to intermittent therapy, again related to age and weight, for an additional 3 to 4 months. The patient and physician should be alert to signs and symptoms of streptomycin toxicity, and these may prevent completion of the full course of therapy. Suggested doses of streptomycin based on patient age and weight is shown in table 4. This four-drug regimen should be given regardless of susceptibility tests, which willlikely show resistance to all these agents. The optimal length of drug therapy for M avium complex is unknown. The usual recommendation is that patients will be treated for 18 to 24 months and for at least 12months after sputum culture conversion. This recommendation is based on empiric data, in part, drawing from the early experiencein treating tuberculosis. This four-drug regimen has not been proved by comparative trials. There are, however, multiple rationales for its use.

(1) In vitro and in vivo studies have demonstrated some activity of all of these agents at achievable serum levels (especially for ethambutol, rifampin, and streptomycin), with much greater activity (synergy) when the same drugs are used in combination (53, 54). (2) These drugs (with the exception of daily high dose streptomycin) are generally well tolerated, even by the elderly population who usually get M avium complex disease. (3) Finally, several uncontrolled clinical trials using this regimen have shown an initial sputum conversion rate in untreated patients of approximately 80070 (69, 70). This regimen would also provide adequate coverage should the disease prove to be tuberculosis. Patients should either be given no antituberculosis drugs or should be given the four-drug regimen based on the clinical setting and needs. Therapy with lesser regimens, especially isoniazid and rifampin only, is discouraged. If patients are unable to tolerate one of these medicines, an alternative drug such as cycloserine or ethionamide should be considered. Acid-fast bacilli smears and cultures of sputum should be obtained monthly during the early part of therapy to assess response. Unfortunately, these are not as specific an indicator of response as those done for patients with tuberculosis. Most patients who respond to therapy will develop negative acid-fast bacilli smears and cultures. Occasional cultures containing small numbers of M avium complex may occur after sputum conversion and should not be interpreted as indicative of treatment failure or relapse. Definite relapses while still receiving therapy or after discontinuation of therapy are common, however, and have averaged 20070 or higher, even with the recommended four-drug regimen (69). Patients who fail to convert their sputum cultures after 12 months of therapy should be reassessed. In general, their standard therapy should be discontinued. Some patients will remain stable without therapy, despite persistently positive sputa. For patients who have failed while receiving conventional therapy and have clearly progressive, symptomatic disease, another drug regimen will be necessary. Subsequent drug therapy in these patients is complex and involves drugs with much higher incidences of side effects and toxicity. Such

therapy should be undertaken only under the guidance of health care workers experienced in handling these patients and their drugs. Intensive therapy with multiple drugs, including cycloserine (250 mg twice a day), ethionamide (250 mg twice a day, then increased to three times a day as tolerated), and prolonged use of streptomycin (three to five times per week) is recommended. Other drugs with potential use in this setting include clofazamine and ciprofloxacin. Although associated with a high incidence of side effects, a fiveor six-drug regimen including these drugs has resulted in a majority of patients clearing their sputa of M avium complex organisms (71). Monitoring of patients for toxicity given the number of drugs and the older age of these patients is essential. This willinclude monitoring of visual acuity and red-green color discrimination (ethambutol), central nervous system (cycloserine), liver (isoniazid, rifampin, and ethionamide), kidney (streptomycin), and auditory and vestibular function (streptomycin). Details of this monitoring is provided in the section on monitoring for drug toxicity below and in table 5. Patients whose disease is localized to one lobe of the lung and who can tolerate resectional surgery should also be considered for surgery, especially if there has been poor response to therapy with drugs alone. Several series of patients treated by surgical resection have suggested that the prognosis is better for these patients than for those treated medically (73, 74). Unfortunately, the bilateral nature of the disease, the age of the patients, and the frequent underlying chronic lung disease have limited the number of patients who are good candidates for surgery. One category of patient for whom surgery is the only necessary therapy is the patient who has had a resected solitary pulmonary nodule that provesto be due to M avium complex (75). Such patients who have no other evidence of disease and apparently normal immunologic mechanisms require no further therapy. Lymphadenitis Excisional surgery without chemotherapy is the recommended treatment for children with NTM cervical lymphadenitis, including those with disease caused by M avium complex and M scrofulaceum (29, 76, 77). The successrate

TABLE 4 SUGGESTED DOSES OF STREPTOMYCIN RELATIVE TO AGE AND WEIGHT IN PATIENTS WITH NORMAL SERUM CREATININE* Weight and Age

Initial Therapyt

Maintenance Therapy;

~

1 g 5x/wk 500 mg 5x/wk 750 mg 2x/wk

1 9 3x/wk 750 mg 2x/wk 750 mg 2x/wk

50 kg and

~

50 yr yr

< 50 kg or> 50-70 age> 70 yr

* These doses have not been established as optimal by clinical trials. The reduced doses with age reflect the reduced renal function and increased risk of toxicity with streptomycin seen in patients older than 50 yr of age. t For the first 6 to 12 wk of therapy as tolerated. For subsequent therapy as tolerated.

*

Streptomycin, amikacin

Rifampin

Ethambutol

Isoniazid

Drug

Clinical symptoms

Clinical symptoms; platelet count, serum creatinine as indicated

"Flulike" syndrome, thrombocytopenia, renal failure associated with intermittent therapy

Hypersensitivity (fever, rash, eosinophilia) (streptomycin)

Monitor clinical status and appropriate serum levels when possible

Increased hepatic metabolism of numerous agents, including birth control pills, ketoconazole, quinidine, prednisone, oral hypoglycemics (sulfonylureas), digitalis, methadone, and warfarin

Periodic serum creatinines; periodic amikacin serum levels

Clinical symptoms; SGOT or SGPT determinations based on symptoms

Hepatitis

Renal toxicity

Clinical symptoms

Hypersensitivity (fever, rash)

Clinical symptoms including changes in hearing, ability to walk, dizziness; periodic hearing tests in high risk patients or those with auditory/ vestibular symptoms; periodic amikacin serum levels

Clinical symptoms

Gastrointestinal disturbance (nausea, vomiting)

Vestibular/auditory toxicity (dizziness, vertigo, ataxia, tinnitus, hearing loss)

None

Orange discoloration of secretions and urine; staining of soft contact lenses

Monitor serum levels

Increased serum levels of phenytoin (Dilantin@)

Clinical symptoms

Peripheral neuropathy (related to pyridoxine deficiency) Clinical symptoms; periodic testing for red/green color discrimination; periodic testing visual acuity (at least monthly if receiving 25 mg/kg per day)

Clinical symptoms; periodic SGOT or SGPT determinations, especially in first 3 months of therapy

Optic neuritis (loss of red/green color discrimination, loss of visual acuity)

Clinical symptoms

Hepatitis

Monitoring Procedures

Hypersensitivity (fever, rash)

Major Side Effects/Toxicity

Sulfonamides, trimethoprim/ sulfamethoxazole

Tetracyclines (doxycycllne, minocycline)

Cefoxitin

Ciprofloxacin

Cycloserine

Ethionamide

Drug

Periodic'blood counts

Periodic blood counts Clinical symptoms Periodic blood counts Clinical symptoms

Hematologic (anemia, leukopenia)

Hematologic (leukopenia, anemia, thrombocytopenia) Hypersensitivity (fever, rash, Stevens-Johnson syndrome)

Clinical symptoms Central nervous system (dizziness, vertigo) (minocycline)

Gastrointestinal disturbance (nausea, vomiting, diarrhea)

Clinical symptoms

Clinical symptoms Cutaneous (photosensitivity, rash, hyperpigmentation)

Gastrointestinal disturbance (nausea, vomiting, diarrhea)

Hematologic (anemia, leukopenia)

Clinical symptoms

Clinical symptoms

Central nervous system (headache, insomnia) Hypersensitivity (fever, rash, eosinophilia)

Clinical symptoms

Clinical symptoms; assessment of mental status

Gastrointestinal disturbance (nausea, vomiting, diarrhea)

Clinical symptoms

Peripheral neuropathy

Clinical symptoms

Central nervous system (anxiety, depression, altered behavior)

Central nervous system (depression, altered behavior, confusion, anxiety, psychosis, seizures)

Clinical symptoms; periodic SGOT or SGPT determinations

Clinical symptoms

Monitoring Procedures

Hepatitis

Gastrointestinal disturbance (anorexia, nausea, vomiting, abdominal pain, diarrhea)

Major Side Effects/Toxicity

TABLE 5 CONTINUED

TABLE 5

SIDE EFFECTS AND TOXICITIES OF DRUGS USED FOR THERAPY OF NONTUBERCULOUS MYCOBACTERIAL DISEASE



CD

~

9

8

tn

n

~

o

::z:

-f

z~

m :u

:..

Q)

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AMERICAN THORACIC SOCIETY

with this procedure is about 95010 (29). Incisional biopsy or the use of antituberculosis drugs alone is frequently followed by persistence of clinical disease, including sinus tract formation and chronic drainage, and should be avoided (29, 76, 77). For children with recurrent disease, a second surgical procedure is usually performed. A multiple drug regimen such as is used for pulmonary disease should be considered only in the patient with recurrence of disease after two or more surgical resections. A special problem is created by the child who has granulomatous disease with or without acid-fast bacilli on examination of the excised lymph nodes, and whose PPD tuberculin skin test is positive. A course of antituberculosis therapy while awaiting the results of the lymph node culture is reasonable, especially when there are any risk factors for tuberculosis (positive family history, foreignborn child, etc.), In the situation where the cultures fail to yield any mycobacteria, antituberculosis therapy should be discontinued unless there are significant risk factors for tuberculosis.

Localized (Nonpulmonary) Disease For adult patients with extrapulmonary, localized M avium complex disease, a combination of excisional surgery (or surgical debridement) and chemotherapy is usually performed. Whether a four-drug regimen alone in this setting would be adequate is not known. Disseminated Disease The response to the treatment of disseminated M avium complex disease in immunosuppressed patients likely depends upon the degree of immunosuppression, the extent of mycobacterial disease, and the therapeutic regimen. Most patients without AIDS appear to respond to multiple-drug regimens such as are recommended for pulmonary disease. However, the response and long-term prognosis of patients with AIDS have been generally poor, as disseminated M avium complex disease occurs as a late opportunistic infection in severely immunosuppressed patients (25). The natural history of disseminated M avium disease in AIDS and its contribution to AIDS-related morbidity and mortality have not been well defined. In one study of 102 patients with AIDS and prior Pneumocystis carinii pneumonia, there was no difference in survival between patients infected with M avium complex and those without (78). However, a 1989 review of more than 1,000 patients with AIDS and disseminated NTM disease reported to the Centers for Disease Control revealed these patients to have a much shorter survival (median, 7.4 months) than did 33,000 patients with AIDS without disseminated NTM disease (median, 13.3 months; p < 0.0001) (30). The results of the latter study are controversial (79), and the impact of dissemianted M avium complex disease on survival in AIDS remains uncertain. Initial results of drug therapy in these patients, including those who received rifabu-

tin and clofazamine, were poor. In one study, 24 of 26 patients treated with a variety of regimens remained bacteremic. However, the follow-up of these patients was only 6 wk (25). Subsequent studies with longer follow-up suggest that perhaps 50010 of patients treated with multidrug regimens for at least 3 months will develop negative blood cultures (79-81). It is unclear at present whether this apparent poor bacteriologic response reflects the importance of the host immune system to bacteriologic response, the usual lack of bactericidal activity of the commonly used drugs against M avium complex (82), the poor inhibitory activity of the drugs and/or inability of the patients to tolerate optimal multidrug regimens, or just the huge organism burden and too short a survival to measure a microbiologic response given the above factors. However, multiple-drug therapy that includes ethambutol, rifampin (or rifabutin), clofazamine, and an injectable aminoglycoside has clearly resulted in symptomatic and clinical improvement in most (80, 81, 83) but not all (79) patients. Other drugs used in this setting include daily isoniazid, cycloserine, and ciprofloxacin. Amikacin (7.5 to 10.0 mg/kg once a day) 5 to 7 days per week has often been used in place of streptomycin because it can be given intravenously and serum levels are easily obtained, with the two drugs apparently having comparable in vitro activity. Thus, multiple-drug regimens similar to those recommended for pulmonary disease caused by M avium complex in the patient without AIDS appear to offer the best therapeutic potential in this setting, with the possible addition or substitution of clofazamine and amikacin for the standard drugs. However, recommendation of specific drug regimens and duration of therapy for disseminated M avium complex disease in AIDS cannot be made at the present time and must await further clinical studies.

Treatment of Rapidly Growing Mycobacterial Disease Introduction Disease caused by the rapidly growing mycobacteria (ROM) has come to be recognized as relatively common, especially cutaneous disease, in selected areas of the United States. The southeastern United States from Oeorgia to Texas appears to be the major endemic area, although disease has been reported from all over the United States. Most clinical disease is sporadic and community acquired, although nosocomial epidemics or clustered cases have been reported (11, 12, 14, 15) and the association of wound infections after augmentation mammaplasty (40) and cardiac surgery (9, 10, 13) is well recognized. The majority of clinical disease (more than 90010) is due to two species of ROM: M fortuitum and M chelonae (formerly M cheloneii (38). Three biovariants are recognized within M fortuitum and two subspecies in M chelonae, some of which may eventually attain species status. M smegmatis (84), M

thermoresistible (85), the unclassified organisms known as the M chelonae-like organisms (86), and rarely chromogenic ROM (87, 88) may also occasionally be responsible for human disease. M fortuitum and M chelonae are resistant to the first-line antituberculosis agents, but they are susceptible (primarily M fortuitum) to a number of traditional antibacterial agents (51). Isolates of M fortuitum are susceptible to amikacin (100010), ciprofloxacin (100010), sulfonamides (100010), cefoxitin (90010), imipenem (100010), and doxycycline (40010). Isolates of M chelonae subspecies abscessus are susceptible to amikacin (90010), cefoxitin (90010), and occasionally erythromycin (30010). Isolates of M chelonae subspecies chelonae are susceptible to amikacin (80010), tobramycin (100010), erythromycin (80010), and doxycycline (25010). Cutaneous Diseases Clinical disease caused by the ROM usually follows accidental trauma or surgery in a variety of clinical settings (31). Some minor infections will resolve spontaneously or after surgical debridement. However, several studies of postinjection abscesses in which no therapy was given revealed disease that persisted in most patients for 8 to 12 months before spontaneously resolving. In two outbreaks of sternal wound infections caused by M chelonae in the era when little was known of chemotherapy for these organisms, approximately one-third of the patients died of uncontrolled infection (9, 10). With drug therapy or combined surgical and medical therapy, a better. result is clearly evident when compared with these historical control practices. No controlled clinical trials of treatment for disease caused by M fortuitum or M chelonae have ever been performed, comparing one form of treatment with another or with no drug treatment at all. However, susceptibility studies have demonstrated excellent in vitro activity of drugs such as amikacin, ciprofloxacin, and doxycycline (the latter two for M fortuitum) (51), and several studies of patients with cutaneous disease treated on the basis of in vitro susceptibilities have shown good results (84, 89, 90). On the basis of these studies, guidelines have been suggested for drug therapy of nonpulmonary disease caused by the ROM (91). Because of variable drug susceptibility both between species and even within species and subgroups (51), susceptibility testing of all clinically significant isolates is essential for good patient management. The first-line antituberculosis drugs (isoniazid, rifampin, pyrazinamide, etc.) have no role in the therapy of rapidly growing mycobacterial disease, with the possible exception of M. smegmatis, which is susceptible to ethambutol (84). For serious disease caused by all subgroups except M chelonae subspecies chelonae, intravenous amikacin (average 400 mg twice a day to provide serum levelsin the low 20 ug/ml range) plus intravenously administered high

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dose cefoxitin (12g/day) is recommended for initial therapy (2 to 4 wk) until clinical improvement is evident. Routine monitoring of renal function, eighth nerve function, and white blood cell counts (for the beta lactam) should be done on all patients receiving this drug regimen. If the organisms are susceptible to oral agents, therapy can be switched to one or more of these agents (e.g., doxycycline 100 mg twice a day, sulfamethoxazole 1 g three times a day, or ciprofloxacin 500 mg twice a day). For serious disease, a minimum of 3 months of therapy is necessary to provide a high likelihood of cure. For bone infections, 6 months of therapy is recommended. For infections with M chelonaewhereoral therapy is not possible, the morbidity of the infection untreated must be matched against the risk and cost of therapy. For less serious disease, therapy can often await the availability of susceptibility results. Surgery is generally indicated with extensivedisease,abscess formation, or where drug therapy is difficult. Removal of foreign bodies such as breast implants, percutaneous catheters, etc. is important if not essential to recovery.

Pulmonary Disease Lung disease caused by the ROM is much less common than cutaneous disease and is the least common of the lung diseases caused by NTM. Several features of'the disease distinguish it from lung disease caused by other NTM species. The majority of patients are female, nonsmokers, and have no underlying lung disease. Almost all patients are Caucasian and older than 50 yr of age, with the average patient in his or her sixties (92). The usual presenting symptom is cough, often misdiagnosed for months or even years as bronchitis or bronchiectasis. Fever, night sweats, and weight loss occur, but they are much less common than with M tuberculosis. The chest radiograph usually shows patchy, reticulonodular, or mixed interstitial-alveolar infiltrates. Cavitation is seen in only about 25070 of cases (92). The presence of a typical presentation in an elderly patient with no underlying lung disease, a compatible chest radiograph, and multiple positive sputa is sufficient to make a diagnosis. The presence of other diseases, unusual features, etc. may require a lung biopsy to be certain of the diagnosis. The natural history of this disease is not established, although in many patients it appears to be a slowly progressive disease, and some patients show little radiographic change over years. Because the majority of cases are caused by M chelonae subspecies abscessus, therapy with oral antimicrobials is not possible because these isolates are usually susceptible only to amikacin, cefoxitin, and imipenem (51). For these patients, symptomatic care and observation is recommended. For patients infected with M fortuitum or an M. chelonae susceptible to erythromycin, attempts at cure with drug therapy should be attempted. The role of surgicalresection is not established

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most patients with respiratory isolates of this species do not have disease. Most isolates are resistant to first-line antimycobacterial drugs, and response to chemotherapy has been variTreatment of M. marinum Disease A number of treatment modalities have been able (99). For patients with disseminated or used for cutaneous disease caused by M. mar- progressive pulmonary disease in need of inum (2, 7). These include simple observa- treatment, initial therapy may be started with tion for minor lesions, surgical excision, the the four-drug regimen recommended for M. use of antituberculosis therapy, and the use avium complex, modified as needed using of single antibiotic agents. By standard sus- results of susceptibility tests. M. szulgai is a slowly growing, pigmented ceptibility testing, these isolates are susceptiMycobacterium that has been associated with ble to rifampin and ethambutol, intermediskin, joint, lymphatic, pulmonary, and disate to streptomycin, and resistant to isonia(100). When isolated from seminated disease zid and pyrazinamide. Isolates are also humans, it should be considered pathogenic. susceptible to sulfonamides or trimethoprimsulfamethoxazole, and susceptible or inter- Through 1986, only 24 cases of disease were reported in the English literature. The organmediate to doxycycline and minocycline. Acceptable treatment regimens include ism is usually susceptible to rifampin and minocycline or doxycycline at 100 mg twice higher concentrations of isoniazid, streptomya day (93, 94), trimethoprim-sulfametho- cin, and ethambutol. Enhanced activity of rixazole at 160/800 mg twice a day (95), or ri- fampin, ethambutol, and streptomycin when fampin (600 mg) plus ethambutol (15mg/kg) used in combination has been shown in vitro daily (96), with each regimen being given a (101). Most patients treated with these drugs minimum of 3 months. Rifampin alone has respond to therapy. Relatively uncommon in the United States, also been recommended, but little experience with this regimen has been reported (97). The M xenopi has been reported as a common rate of clinical response is quite variable, and cause of slowly progressive NTM pulmonary a minimum of 3 wk of therapy should be giv- disease in western Europe. In southeast Enen before considering that the patient may gland, it is the most common NTM recovnot be responding. Surgical debridement may ered in the laboratory and has been since 1977 also be important, especially for disease in- (102).Disseminated disease and joint disease volving the closed spaces of the hand or dis- caused by this organism have also been reportease that responds poorly to drug therapy (7, ed. In vitro susceptibilityto antimycobacterial 96). If a lesion is excised surgically, many cli- agents is variable, although enhanced drug nicians would provide drug coverage during activity has been shown when the combinathe perioperative period. It is not clear if tion of rifampin and streptomycin has been longer durations of drug treatment after sur- used (101). Although some investigators have reported success with surgical therapy simigery offer any additional advantage. lar to that used for selected patients with M avium complex disease, others have had disTreatment of Other Nontuberculous appointing results. Results with drug therapy Mycobacteria Pulmonary Disease alone have also shown variable results. For Although most species of NTM have been most patients, initial therapy should consist reported to cause pulmonary disease, there of isoniazid, rifampin, and ethambutol with are only four additional species that merit or without initial streptomycin. Patients who consideration. Because of the small number fail at therapy or who relapse after compleof reported cases and/or absence of therapeu- tion of treatment might be considered for surtic trials or treatment of disease caused by gery (16, 103, 104). these species, only limited recommendations on choice of drug therapy can be made at presMonitoring for Drug Toxicity ent. In most cases, if there has been satisfactory clinicaland bacteriologic response to che- Monitoring of patients who are being treated motherapy, a treatment period of 18 to 24 for NTM disease for drug toxicity is important given the number and type of drugs used months is recommended. M malmoense is a slowly growing, non- and the older age of these patients. This will pigmented NTM species that causes pulmo- include monitoring, of visual acuity and rednary disease. Although uncommon in the green color discrimination (ethambutol), cenUnited States, it has been increasingly recog- tral nervous system (cycloserine, ciprofloxanized in England, Wales, and northern Eu- cin, ethionamide), liver (isoniazid, rifampin, rope. Most isolates are susceptible to etham- ethionamide), kidney (streptomycin, amikabutol, and many are susceptible to rifampin cin), auditory and vestibular function (strepand streptomycin. The four-drug regimen tomycin, amikacin), and hematologic (sulrecommended for therapy of M avium com- fonamides, tetracyclines, cefoxitin). For the aminoglycosides, this monitoring plex has resulted in clinical and bacteriologic should include careful questioning about balresponses in the majority of cases (98). M simiae is a slowlygrowing, nonpigment- ance, ability to walk (especially in the dark), ed Mycobacterium that may be confused with symptoms of tinnitus or dizziness, and hearM tuberculosis, as it is the only NTM that ing to check for signs of toxicity. A baseline is niacin-positive. It is an uncommon cause blood urea nitrogen and creatinine should be of pulmonary and disseminated infection, and obtained, with alteration of the streptomycin and often not possible because of the presence of bilateral disease.

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dose if these are abnormal. Periodic monitoring of renal function is recommended for high risk patients reciving daily or five times a week therapy, patients older than 50 yr of age, and patients with any impairment of renal function. A baseline hearing test should also be obtained, especially in high risk patients, and then repeated if signs or symptoms of VIII nerve toxicity appear. For cycloserine, careful attention should be made to signs of central nervous system toxicity, which may include seizures, lethargy, depression, alterations in personality, and even suicidal ideations. Because toxicity with this drug relates primarily to excessive serum levels of the drug (> 40 ug/ml), patients with central nervous system symptoms or abnormal baseline renal function should have attempts made at serum level determinations. Unfortunately, such tests are not available in most clinics and are rarely available in a timely fashion to help with decisions on dosing. If serum levels are not available, physicians should remember that the drug is excreted by the kidney, and high serum levels tend to occur in the elderly or in the presence of renal failure. A lower dose (e.g., 250 mg twice a day) is often given in this setting, and discontinuation of the drug may be necessary if central nervous system symptoms occur and one cannot monitor serum levels. Given that isoniazid toxicity is higher in the older population, some patients would get a baseline SGOT, and then repeat this determination at 2,4, and 8 wk and thereafter during therapy as clinically indicated. Other treatment recommendations are the same as those for patients with tuberculosis (see the ATS Statement on "Treatment of Tuberculosis and Tuberculosis Infections in Children and Adults" [72]). The incidence of gastrointestinal side effects such as nausea, vomiting, abdominal pain, and cramps is almost prohibitive with ethionamide. This can be minimized by starting with a 250 mg single dose and then slowly increasing the dose. In the older patient, limiting the total dose to 500 mg may help reduce toxicity. A good review of side effects and toxicities experienced at the National Jewish Hospital with ethionamide and cycloserine is provided in a study by Lester (105). A review of major side effects and monitoring procedures is also listed in table 5.

Summary Diagnostic Criteria of Nontuberculous Mycobacterial Lung Disease I. For patients with a cavitary infiltrate: 1. Two or more sputums or bronchial washings that are acid-fast bacilli smear positive and/or produce moderate to heavy growth on culture. 2. Exclusion of other reasonable causes for the disease. II. For patients with a noncavitary infiltrate: 1. Two or more sputums or bronchial washings that are acid-fast bacilli smear posi-

tive and/or produce moderate to heavy growth on culture. 2. The isolate is Mycobacterium avium complex or M kansasii and cannot be cleared from the sputum with either bronchial hygieneor 2 wk of drug therapy. 3. Exclusion of other reasonable causes for the disease. III. For patients with a cavitary or noncavitary infiltrate whose sputum evaluations are nondiagnostic or another disease cannot be excluded: 1. Lung biopsy yields a NTM. 2. The biopsy shows mycobacterial histopathologic features (i.e., granulomatous inflammation) and two or more sputums are positive for a NTM even in low numbers.

Laboratory 1. Current methods of specimen staining and culture used for M tuberculosisare acceptable for NTM except for the need for lower incubation temperatures for some cutaneous pathogens and the addition of hemin to culture media for M haemophilum. 2. Routine susceptibility testing of the antituberculosis drugs using standard critical concentrations is no longer recommended for isolates of M avium complex. 3. Efforts to develop better test methods or drug concentrations to predict microbiologic responses to therapy for M avium complex are needed. 4. Susceptibility testing of the rapidly growing mycobacteria (M fortuitum, M chelonae) to the antituberculosis agents should no longer be performed. Clinically significant isolates should be tested against multiple other drugs that include amikacin and doxycycline.

Treatment of Non tubercu10 us Mycobacteria Disease 1. An 18- to 24-month regimen of daily isoniazid (300 mg), rifampin (600 mg), and ethambutol (15 mg/kg) is recommended for pulmonary disease caused by M kansasii. 2. A 24-month regimen of daily isoniazid (300 mg), rifampin (600 mg), and ethambutol (25 rug/kg for 2 months, then 15 mg/kg) is recommended for therapy of M avium complex lung disease. Streptomycin should also be given five times per week for the first 6 to 12 wk and two to three times per week for an additional3 months as tolerated. This recommendation is based on results of limited noncomparative clinical studies and a consensus of clinical experts. 3. NTM cervical lymphadenitis can be treated by surgical excision alone with a 95070 cure rate. 4. Therapy of nonpulmonary disease caused by M fortuitum and M chelonae should include drugs such as amikacin and cefoxitin for serious disease and other drugs for lesser disease based on in vitro susceptibilities.

5. There is inadequate information to make specific recommendations for therapy of disseminated M avium complex disease in patients with AIDS and lung disease caused by M chelonae, M xenopi, M szulgai, and M simiae.

This statement was prepared by an ad hoc committee of the Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections. Members ofthe committee were: RICHARD

J.

WALLACE JR., M.D., Chairman RICHARD O'BRIEN, M.D. JEFFREY

GLASSROfH, M.D. M.D. ASIM DUTT, M.D.

JAMES RALEIGH,

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Diagnosis and treatment of disease caused by nontuberculous mycobacteria.

DIAGNOSIS AND TREATMENT OF DISEASE CAUSED BY NONTUBERCULOUS MYCOBACTERIA Tms OFFICIAL STATEMENT OF THE AMERICAN ThORACIC SOCIETY WAS ADOPTED BY THE A...
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