AMERICAN JOURNAL OF Respiratory and Critical Care Medicine August 1997 Volume 156, Number 2, Part 2

Supplement: American Thoracic Society Diagnosis and Treatment of Disease Caused by Nontuberculous Mycobacteria

Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections, American Thoracic Society CONTENTS

August 1997 Volume 156 Number 2 Part 2

SUPPLEMENT: AMERICAN THORACIC SOCIETY-DIAGNOSIS AND TREATMENT OF DISEASE CAUSED BY NONTUBERCULOUS MYCOBACTERIA

Summaries Sl Introduction s2 Epidemiology and Pathogenesis s2 Clinical Presentation and Diagnostic Criteria s3 Laboratory Methods s7 Treatment of Mycohacterium kansasii Disease s 10 Treatment of Pulmonary Mycobacterium avium Complex Disease Sll Treatment of Localized Extrapulmonary Mycobacterium avium Complex Disease s14 Treatment of Disseminated Mycobacterium uvium Disease s14 Prophylaxis of Disseminated Mycobucterium avium Disease in AIDS s15 Treatment of Rapidly Growing Mycobacterial Disease SlS Treatment of Mycobucterium murinum Disease s17 Treatment of Pulmonary Disease due to Other Nontuberculous Mycobacteria s17 Monitoring for Drug Toxicity s19 American Thoracic Societv MEDICAL SECTION OF THE AMERICAN LUNG ASSOCIATION

Diagnosis and Treatment of Disease Caused by Nontuberculous Mycobacteria

THE OFFIUAI, S,I.AXMEN.I. ~I:.I‘HC AMERKAN THORACIC SOCIETY WAS APPROVED BY THE BOARD OF DIRECTORS. MAR~II 1997

SUMMARY tion including commercial DNA probes (M. oviurn com- plex, M. kansusii, M. gordonae) and high-pressure liquid Diagnostic Criteria of Nontuberculous Mycobacterial Lung chromatography are preferred over the slower traditional Disease in HIV-Seropositive and -Seronegative Hosts biochemical methods. The following criteria apply to symptomatic patients with in- Susceptibility testing of M. avium complex. Susceptibility filtrate, nodular or cavitary disease, or a high resolution com- testing with rifabutin and the antituberculosis drugs is not puted tomography scan that shows multifocal bronchiectasis recommended. Routine testing against clarithromycin should and/or multiple small nodules. not be performed, but that test should be performed on iso- A. If three sputum/bronchial wash results are available from lates from patients who have failed prior macrolide therapy the previous 12 mo: or prophylaxis. Minimal inhibitory concentration (MIC) of 1. three positive cultures with negative AFB smear results > 32 pg/ml is the recommended resistance breakpoint. or Susceptibility testing of M. kansasii. Routine susceptibility 2. two positive cultures and one positive AFB smear testing of M. kansasii should include only rifampin, because currently used resistance breakpoints for isoniazid and B. If only one bronchial wash is available: streptomycin often give misleading results and methods for 1. positive culture with a 2+, 3+, or 4-t AFB smear or 2+, the other drugs have not been established. 3+, or 4+ growth on solid media Susceptibility testing of the rapid growers. Susceptibility test- C. If sputum/bronchial wash evaluations are nondiagnostic or ing of clinically significant rapidly growing mycobacteria another disease cannot be excluded: (M. fortuitum, M. abscessus, M. chelonae) should not be 1. transbronchial or lung biopsy yielding a NTM performed with the antituberculosis agents. They should be or tested against antibacterial drugs including amikacin, doxy- 2. biopsy showing mycobacterial histopathologic features cycline, imipenem, the fluorinated quinolones, a sulfona- (granulomatous inflammation and/or AFB) and one or mide, cefoxitin, and clarithromycin. more sputums or bronchial washings are positive for an NTM even in low numbers PROPHYLAXIS AND TREATMENT OF Comments: NONTUBERCULOUS MYCOBACTERIA DISEASE These criteria fit best with M. avium complex, A4. ahscessus, Treatment of M. kansasii pulmonury disease. A regimen of and M. kansasii. Too little is known of other NTM to be cer- daily isoniazid (300 mg), rifampin (600 mg), and ethambu- tain how applicable these criteria will be. to1 (25 mg/kg for 2 mo, then 15 mg/kg) for 18 mo with a At least three respiratory samples should be evaluated minimum of 12 mo culture negativity is recommended for from each patient. Other reasonable causes for the disease pulmonary disease in adults caused by M. kansasii. Clar- should be excluded. Expert consultation should be sought ithromycin or rifabutin will need to be substituted for when diagnostic difficulties are encountered. rifampin in HIV-positive patients who take protcase inhib- itors. KEY LABORATORY FEATURES OF THE Treatment of M. avium complex pulmonary diseuse. A regi- NONTUBERCULOUS MYCOBACTERIA men of daily clarithromycin (500 mg twice a day) or azithro- mycin (2.50 mg), rifampin (600 mg) or rifabutin (300 mg), 1. Staining und culture. Current methods of specimen staining and ethambutol (25 mg/kg for 2 mo, then 15 mg/kg) is rec- and culture used for M. tuberculosis are acceptable for ommended for therapy of adults not infected with the HIV most NTM species. The preferred methodology includes virus. Streptomycin two to three times per week should be fluorochrome staining and culture in a liquid medium as considered for the first 8 wk as tolerated. Patients should well as on Middlebrook 7HlO or 7Hll agar. Species for be treated until culture-negative on therapy for 1 yr. which special growth conditions are needed include those Treatment of disseminated M. avium complex disease. Ther- responsible for cutaneous disease, which need lower incu- apy in adults should include daily clarithromycin (500 mg bation temperatures, and the relatively fastidious species twice a day) or azithromycin (250 to 500 mg), plus ethamb- M. haemophilum, M. genavense, and M. conspicuum. utol 15 mg/kg per day. Consideration should be given to 2. Species identification. Methods of rapid species identifica- the addition of a third drug (preferably rifabutin at a dose of 300 mg/d). Therapy should be continued for life until Am ) Respir Crit Care Med Vol. 156. pp. 51-525, 1997 more data becomes available. 3.L AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

4. Prophyluxis of disseminuted M. avium complex diseuse. M. avium complex. The reservoir of M. &urn for most pa- Prophylaxis should be given to adults with AIDS with CD4 tients with disseminated disease has not been identified, but it counts < SO cells, especially with a history of a prior oppor- is assumed to be the same as or similar to that for patients with tunistic infection. Rifabutin 300 m&d, clarithromycin 500 non-HIV-related M. avium complex lung disease. Mycobacte- mg twice daily, azithromycin 1,200 mg once weekly, and rium avium complex is present in tap water, and one study of azithromycin 1,200 mg once weekly plus rifabutin 300 mg disseminated M. avium complex disease in AIDS demon- daily arc all proven effective regimens. strated that some cases are likely acquired from hospital tap 5. Treutrnent of nontuherculous mycohacteria cervical lym- water (12). Interestingly, there does not appear to be a geo- phadenitis. Nontuberculous mycobacteria cervical lym- graphic predilection with disseminated disease in the United phadenitis is still treated primarily by surgical excision States, as there is with skin test reactivity and with chronic alone, with a 95% cure rate. A clarithromycin-containing lung disease. regimen should be considered for patients with extensive Water is also the likely source of infection for numerous disease or a poor response to surgery. other NTM species including M. marinum, M. kansasii, noso- 6. Treatment ofnonpulmonary rupidly growing mycohacteria. comial outbreaks or pseudo-outbreaks due to rapidly growing Therapy of nonpulmonary disease caused by M. fortuitum, mycobacteria, M. xenopi, and M. simiae. Mycohucteriutn mari- M. uh,scessus, and M. chelonae should include drugs such as num has been commonly associated with salt water, fresh wa- amikacin and clarithromycin, based on in vitro susceptibil- ter, fish tanks, and swimming pools (13). Mycohucterium kan- ity tests. susii has not been recovered from soil or natural water supplies (5). It has been isolated repeatedly, however, from tap water INTRODUCTION (14, 15) in the same communities where M. kansasii disease The continued growth in the number and prevalence of myco- exists. Interestingly, it has been shown to survive up to 12 mo bacteria species other than the Mycohacterium tuberculosis in tap water but not in soil complex, and recent advances in diagnostic methods and drug Rapidly growing mycobacteria such as M. ,fortuitum, M. che- therapies for disease caused by these agents, has prompted us lonae, and M. abscessus can be recovered from soil and natu- to put forth this second, updated diagnostic and therapeutic ral water supplies, and are the most common NTM associated standard that deals exclusively with the nontuberculous myco- with nosocomial disease (16-24). Investigations of nosocomial bacteria. As in the first statement (1) we refer to these myco- outbreaks or pseudo-outbreaks caused by these species in- bacterial species collectively as the nontuberculous mycobac- cluding the use of DNA fingerprinting with pulsed-field gel teria (NTM). The principles of therapy and diagnosis of electrophoresis (2.5,26) have demonstrated that tap water (18, disease caused by M. tuberculosis have been dealt with sepa- 19) ice prepared from tap water (20.2 l), processed tap water rately and appear in two ATS statements published most re- used for dialysis (22) and distilled water used for preparing cently in IYYO and 1994 (2, 3). Like the previous NTM state- solutions such as gentian violet (23,24) are the usual nosoco- ment published in 1990 (l), this statement is designed as a mial sources of the organisms. basic guide for professionals involved in the diagnosis and Mycohacterium xenopi is an obligate thermophile that re- management of disease caused by NTM. Although not all- quires temperatures of 28” C or above to grow (4). It has been inclusive, the areas of discussion are referenced in enough de- recovered almost exclusively from hot water and hot water tail to allow the reader to assess the scientific basis for ideas taps within hospitals (15,27-29) where it has been associated and recommendations that are put forth. Included within this with multiple positive (i.e., probably contaminated) clinical statement are revised recommendations for diagnostic criteria samples and a few cases of clinical pulmonary and soft tissue that apply primarily to the NTM and updated recommenda- disease (28-30). These clusters of hospital isolates have been tions of specific therapeutic drug regimens for disease caused reported from the United States, the United Kingdom, and by M. avium complex and other species of NTM, recognizing other areas in Europe. In two studies, the clinical isolates and the major impact of the newer macrolides and rifabutin, which hospital water isolates have been shown to be identical by have become available since 1990. Unless otherwise stated, DNA fingerprinting (28, 29). It has been speculated that the these drug dosages arc for adults. Pediatric doses are de- organism enters the hospital from municipal water mains, then scribed where available. multiplies in the hospital heating tanks where the temperature is 43-45” C, the optimal temperature for growth of this organ- EPIDEMIOLOGY AND PATHOCENESIS ism (30). Reports of recovery of M. simiae from clinical specimens Sources of Infection have been clustered in three geographic areas: Israel (31). Most NTM organisms have been isolated from water and soil Cuba, and the southwestern United States-Texas. Arizona, (4-6). The best studied of these has been M. avium complex. and New Mexico (32-34). Most recoveries have been single Extensive environmental studies in the United States have positive specimens that are smear-negative (32,33) and not as- shown that M. avium complex grows well in natural waters, sociated with clinical disease (33) suggesting environmental particularly in the Southeast (7). Mycubacterium &urn com- contamination as a likely source. For several clusters of iso- plex strains with plasmids, possibly associated with virulence, lates, organisms were also recovered from the local tap water have been shown to be prcfcrentially aerosolized, providing a (34, M. Yakrus, personal communication, 35) suggesting it as possible mechanism for airborne acquisition of these organ- the likely organism source. isms (8). Although M. avium is an important cause of disease Mycobacterium mulmoense, which has emerged as a major in poultry and swine, serologic studies have suggested that an- NTM pathogen in northern Europe. has been recovered from imal-to-human transmission is not important in human infec- natural waters in Finland (36) and soils in Zaire (37) and Ja- tion (Y), and recent molecular studies involving IS9OI-IS902 pan (38). The recently recognized pathogen M. genuvense has and IS1245 have shown that strains infecting humans and ani- not been recovered from soil or water, but it has been recov- mals (especially swine) are different (10, 11). It is now gener- ered from a dog and a variety of pet birds including psittacine ally accepted that environmental sources, especially natural birds (39, 40). Mycobucterium ulceruns disease occurs in dis- waters, are the reservoir for most human infections caused by crete but widely dispersed geographic areas in the watersheds American Thoracic Society s3

of tropical rain forests, primarily in Africa, Southeast Asia, 1981 and 1983 showed higher rates of NTM disease among Australia, and South and Central America (35). nonwhites, women, and patients residing in urban areas when Much less is known about the environmental epidemiology compared with the initial study. White males, however, con- and sources of infection for the other NTM. A number of tinued to serve as the major diseased population (49). Using NTM species have yet to be recovered from the environment, combinations of national surveillance data, the prevalence of including M. ulceruns, M. haemophilum, M. szulgai, M. cela- NTM (pulmonary) disease at that time was estimated to be 1.8 turn, M. genavense, and M. conspicuum. Despite this, environ- cases per 100,000 population for the entire United States. Of mental sources of infection are highly likely. Good reviews of this, M. avium complex represented 1. I/l 00,000. environmental studies have been provided by Wolinsky and A more recent Centers for Disease Control (CDC) study Rynearson (S), Portaels (35), and Falkinham (41). from 1991 to 1992 (50) that included results from 33 state lab- Much remains to be understood about the pathogenesis of oratories demonstrated a dramatic change in the prevalence NTM infection and disease in humans. Epidemiologic studies, of NTM. Despite the increases in isolates of M. tuberculosis skin test surveys, and more recently DNA fingerprinting stud- noted in the United States since 1985, there were now more ies suggest that person-to-person transmission of infection is isolates of M. avium complex than M. tuberculosis, with the rare. It is assumed that most persons are infected by environ- latter representing only 26% of the total mycobacterial iso- mental NTM. Of the likely sources of infection, airborne lates. The reasons for this dramatic increase in numbers for NTM may play an important role in respiratory disease, NTM is unknown, but better clinical recognition and more whereas ingestion may be the source of infection for children culturing for both pulmonary and disseminated disease are with NTM cervical lymphadenitis and for most patients with felt to play important roles. AIDS whose disseminated M. avium or M. genavense begins One category of people with NTM disease not represented as gastrointestinal colonization. Bacteremic spread of the or- in the two earliest studies but almost certainly represented in ganism in patients with AIDS then involves multiple organ the 1993 study were patients with AIDS and disseminated systems, including bone marrow, lymph nodes, liver, and NTM disease, HIV-infected patients were at especially high spleen. Direct inoculation with NTM organisms from water or risk of disease due to NTM. The majority of disease in this other material is likely the source of infection for patients with population (> 95%) is due to M. avium (51). Disseminated soft tissue infections. It is not known whether NTM disease M. avium infection is the most common bacterial infection in (especially pulmonary disease) develops soon after infection patients with AIDS, occurring in 20 to 40% of all patients in or, like tuberculosis, develops after a period of latency. several reported series (52-55). Disease in these patients is highly correlated with severe immunosuppression. with the Prevalence in Humans average CD4 cell count at the time of dissemination in the 25 Although first observed soon after Koch’s discovery of the tu- to 30 range (53-55). Patients with < 100 CD4 cells, not receiv- bercle bacillus, NTM were not widely recognized as human ing prophylaxis, develop disseminated M. avium at the rate of pathogens until the lYSOs, when several large series of patients approximately 20% per year (53). The overall incidence of with NTM lung disease were reported (42-44). These patients M. avium as an initial diagnosis has increased among AIDS were epidemiologically distinct from patients with tuberculo- patients while other complications of AIDS, such as Pneumocys- sis, being older, more commonly white, and quite often having tis pneumonia, have decreased (56). Disseminated M. uvium underlying chronic lung disease such as bronchiectasis, silico- occurs in similar rates in all geographic regions and various sis, and healed tuberculosis. Positive reactions of 10 mm or HIV risk groups (57). Localized pulmonary disease in AIDS more to purified protein derivative (PPD) tuberculin were less due to M. avium occurs in less than 5% of patients (58). common than among tuberculous patients, and family con- Other NTM species, including M. kansasii (51, 5Y-61), tacts tended to be tuberculin-negative. M. scrofulaceum (Sl), M. gordonae (51), M. huemophilum (60, As reports of patients with NTM disease increased, it be- 61), M. genavense (39), M. celatum (62), M. conspicuum (63), came apparent there was marked geographic variability both M. xenopi (64), M. fortuitum (51, 65), M. marinum (66), in the prevalence of disease and in the mycobacterial species M. malmoense (67), and M. simiae (68) have also been de- responsible for disease. Most patients in the southeastern scribed as a cause of pulmonary and/or disseminated NTM United States with NTM lung disease were from rural areas disease in AIDS. Some of these, especially M. haemophilum, and had isolates of M. avium complex, whereas those in the M. kansasii, and M. genavense, have occurred in localized geo- central United States more commonly had disease caused by graphic areas. More than 95% of cases of disseminated dis- M. kansusii (45). ease, however, are due to isolates of M. avium (51). In addition, patients with NTM disease tended to react more strongly to skin test antigens prepared from the infecting CLINICAL PRESENTATION AND DIAGNOSTIC CRITERIA mycobacterial species than to standard PPD-S or PPD-T, anti- gens prepared from M. tuberculosis (46). Skin test surveys us- Pulmonary Disease ing NTM antigens suggested that infection by NTM was com- Chronic pulmonary disease is the most common localized clin- mon, especially in rural areas and in the Southeast (47). ical manifestation of NTM (41, 69). Mycohacterium avium NTM disease is not reportable in the United States, and re- complex, followed by M. kansasii, is the most frequent patho- liable estimates of its incidence or prevalence have been lim- gen causing lung disease in the United States. Other pathogens ited. Two national surveys in the early 1980s were the first to occasionally causing pulmonary disease include M. abscessus, try to define the extent of NTM infection in the United States. M. fortuitum, M. szulgai, M. simiae, M xenopi, M. malmoense, The initial study, based on state laboratory reports from 1979- M. celatum, M. asiaticum, and M. shimodii. Mycobacterium 1980, indicated that NTM comprised approximately one-third xenopi is second to M. avium complex as a cause of NTM lung of the 32,000 mycobacterial isolates (48). Of these, 61% were disease in areas of Canada, the United Kingdom, and other ar- M. avium complex, 19% were M. fortuitum complex, and 10% eas of Europe, while M. malmoense is second to M. avium were M. kansasii. complex in Scandinavia and areas of northern Europe (70). A second surveillance study based on reports from tuber- The patients with chronic lung disease due to NTM are gener- culosis control officers on isolates of NTM recovered between ally older adults. Except for patients with cystic fibrosis, chil- 54 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997 dren rarely develop this form of NTM disease (69). Although tion” in the true sense (i.e., no tissue invasion) is probably some NTM patients have a history of underlying chronic lung quite rare. In addition, not all patients with this disease have a disease, not all do. The interpretation of NTM in the sputum benign prognosis, a point first emphasized by Prince and col- of HIV-positive patients presents a particular problem, as leagues in a landmark 1989 paper (76). these patients are frequently infected with NTM without evi- Given these observations, the diagnosis of lung disease dence of pulmonary disease. Such infection may be transient, caused by NTM is usually not difficult if a combination of clin- but it may also reflect disseminated NTM disease or subclini- ical, radiographic, and bacteriologic criteria are used. AFB cal NTM pulmonary disease. In addition, some NTM species smear, culture results, and clinical status suggest a close corre- that are generally considered nonpathogenic have been asso- lation among the three. Minimal evaluation should include ciated with pulmonary disease in the HIV-infected host. three or more sputums for AFB and efforts to exclude other Signs and symptoms of NTM pulmonary disease are vari- confounding disorders such as tuberculosis and lung malig- able and nonspecific. They include chronic cough, sputum nancy. In most patients, a diagnosis can be made without a production, and fatigue. Less commonly, malaise, dyspnea, fe- lung biopsy. Although criteria are based on experience with ver, hemoptysis, and weight loss can also occur, usually with M. avium complex, there is no reason to believe these criteria advanced NTM disease. Evaluation is often complicated by would not be applicable to other species. The diagnostic crite- the symptoms caused by co-existing lung diseases. These con- ria are presented in Table 1. ditions include chronic obstructive airway disease associated Clinical studies have established the validity of bronchial with smoking, bronchiectasis, previous mycobacterial diseases, washings as a culture source for M. tuberculosis. Although cystic fibrosis, and pneumoconiosis. similar studies have not been done for NTM, bronchial wash- There are some differences in the radiographic features of ings are considered to be more sensitive than routine expecto- NTM lung disease compared with those produced by M. tuber- rated sputums; however, their relative specificity for clinical culosis with regard to conventional radiographic studies. Non- disease is unknown. Approximately 90% of patients with dis- tuberculous mycobacteria tend to cause thin-walled cavities ease caused by M. kansusii and most patients with disease with less surrounding parenchymal infiltrate, have less bron- caused by M. avium complex have cavitary infiltrates (77) and chogenic but more contiguous spread of disease, and produce can be readily identified. Among patients without cavities, the more marked involvement of pleura over the involved areas presence of clinical symptoms and HRCT abnormalities are of the lungs. Occasionally, they may produce dense pneu- important adjuncts to defining the presence of NTM disease. monic disease or a solitary pulmonary nodule without cavita- Bacteriologic criteria have been best analyzed with cavitary tion. Basal pleural disease is not often found, and pleura1 effu- disease for M. avium complex and M. kunsusii, and the HRCT sion is rare. Recent studies with high-resolution computed abnormalities, with M. avium complex. Although these are tomography (HRCT) of the chest have shown that up to 90% reasonable criteria for diagnosing other NTM, their use with of patients with mid and lower lung field noncavitary disease other species has not been studied in detail. with M. nvi~n complex have associated multifocal bronchiecta- In the patient with nondiagnostic cultures and radiographic sis, with many patients having clusters of small (< 5 mm) nod- studies, or concern about the presence of another disease pro- ules in associated areas of the lung (71-74). ducing radiographic abnormalities, a lung biopsy is often re- There has been a great deal of interest in the availability of quired for diagnosis. If a tissue sample from a transbronchial, species-specific skin test antigens. Unfortunately, many anti- percutaneous, or open-lung biopsy yields an NTM organism gens are shared by different mycobacterial species for which and shows mycobacterial histopathologic changes (i.e., granu- there are previously tested NTM skin test antigen prepara- lomatous inflammation with or without AFB), this by itself is tions, and extensive cross-reactions were observed with PPDs. sufficient to establish the diagnosis of NTM lung disease. If However, recent studies provide hope for increased specificity the lung biopsy has a negative culture (something that often of a preparation for M. rrviltrrz complex testing, although it is happens when transbronchial biopsies are performed because not yet FDA approved (75). Specific skin test reagents for of the small size of the tissue sample) but demonstrates myco- other NTM infections are not standardized and are neither bacterial histopathology features (without a history of other available nor undergoing clinical trials at this time. granulomatous or mycobacterial disease), NTM lung disease In the absence of specific diagnostic features in the history is considered to be present when one or more sputums or and physical examination, the chest roentgenogram, and dif- bronchial washes are culture-positive for NTM, even if they ferential skin testing, isolation of the NTM in a culture is es- are negative for AFB on smear and result in light growth on sential for diagnosis. However, as these organisms are com- culture. monly found in nature, contamination of culture material or transient infection does occur. Thus, a single positive sputum culture, especially with small numbers of organisms, does not Lymphadenitis always suffice to diagnose NTM disease. Some previous au- Infection of the submandibular, submaxillary, cervical, or pre- thors suggested that the respiratory tract may be infected with auricular lymph nodes in children between 1 and 5 yr old is the the organism without disease, particularly in patients with most common presentation of NTM lymphadenitis (78-81). It chronic respiratory disease (48, 49, 69). This condition was of- is the most common disease manifestation of NTM in children ten referred to as “colonization,” and was described most often and, in the absence of HIV infection, rarely affects adults. The with M. avium complex. It was characterized by the presence disease occurs insidiously, with only rare associated systemic of noncavitary, stable and usually minimal radiographic dis- symptoms. The involved lymph nodes are generally unilateral ease in women, and was associated with sporadic excretion of (95%) and not tender. The nodes may enlarge rapidly, and organisms from the respiratory tract. No pathologic studies even rupture, with formation of sinus tracts that result in pro- were done to demonstrate the absence of tissue invasion, and longed local drainage. Other nodal groups outside of the head more recent studies with HRCT have shown that these pa- and neck may be involved occasionally (80). There is typically tients often have a combination of multifocal bronchiectasis no history of exposure to tuberculosis, screening PPD skin test and nodular parenchymal disease (71-74) with the latter or of family members are usually negative, and the chest radio- both now felt to be due to mycobacterial disease. “Coloniza- graph is normal. American Thoracic Society SS

TABLE 1 CRITERIA FOR DIAGNOSIS OF NONTUBERCULOUS MYCOBACTERIA PULMONARY DISEASE

Presumed or Confirmed HIV Seropositive Potential Presumed or Confirmed HIV Seronegative Potential Risk Factors Risk Factors

I. Local immune suppression II. General severe immune supression Alcoholism (M. ovium complex) Leukemia CD4 count < 200 Bronchiectasis Lymphoma Cyanotic heart disease Organ transplantation Cystic fibrosis Other immunosuppressive therapy Prior mycobacterial disease Pulmonary fibrosis Smoking/chronic obstructive lung disease None 1. Clinical criteria a. Same a. Same a. Compatible signs/symptoms (cough, fatigue most common; fever, weight loss hemoptysis, dyspnea may be present, particularly in advanced disease) with documented deterioration in clinical status if an underlying condition is present and b. Reasonable exclusion of other disease (e.g., tuberculosis, cancer, histoplasmosis) b. Same b. Same to explain condition, or adequate treatment of other condition with increasing signs/symptoms 2. Radiographic criteria a. Same a. Same a. Any of the following chest X-ray abnormalities; if baseline films are more than 1 yr old, should be evidence of progression

l Infiltrates with or without nodules (persistent 3 2 mo or progressive)

l Cavitation

l Nodules alone (multiple) b. Any of these HRCT abnormalities b. Same b. Same

l MultIpIe small nodules

l Multifocal bronchiectasis with or without small lung nodules 3. Bacteriologic criteria a. Same a. Same a. At feast three available sputum/bronchial wash samples within 1 yr

l Three positive cultures with negative AFB smears Or

l Two positive cultures and one positive AFB smear Or b. Single available bronchial wash and inability to obtain sputum samples b. Same except b. Same except

l Positive culture with 2+, 3+, or 4+ growth l Culture positive with 1 + l Culture positive with 1 + Or or greater growth or greater growth

l Positive culture with a 2i-, 3+, or 4+ AFB smear (excludes M. ovium complex) Or c. Tissue biopsy c. Same c. Same

l Any growth bronchopulmonary tissue biopsy

l Granuloma and/or AFB on lung biopsy with one or more positive cultures from sputum/bronchial wash

l Any growth from usually sterile extrapulmonary site

For a diagnosis of pulmonary disease, all three criteria-(7) clinical, (2) radiographic, and (3) bacteriologic- must be satisfied.

Most children with NTM lymphadenitis will react to skin Distinguishing tuberculous from nontuberculous lymphad- test antigens prepared from M. uvium complex, such as PPD-B enitis is key, because the former requires drug therapy and (79, X2, 8.7). A 1991 multicenter study of NTM antigens from public health tracking, whereas the latter does not. The pre- the CDC that used PPD-B, however, was terminated early, sumptive diagnosis of NTM lymphadenitis is based on the his- due to a blistering reaction in several of the children (82). More topathologic appearance of the lymph node showing caseating recent studies using a less potent, protein weight-standardized granulomata with or without AFB and a negative tuberculin c M. rrviuni skin-test material called “sensitin” and a dual skin- skin test. Failure of the node to yield M. r74he~c~losis provides test technique to determine M. uvium-dominant versus PPD- stronger presumptive evidence for the diagnosis of NTM lym- dominant reactions have suggested improved specificity with phadenitis. this antigen preparation in study populations with known dis- The utility of fine needle aspiration in obtaining diagnostic ease (75). Although these antigens may prove beneficial for material is controversial (X4-86). However, granulomata or future evaluation of cervical lymphadenitis, no commercial other compatible cytopathology such as a mixture of degener- NTM skin-test material is currently available for clinical use in ating granulocytes, lymphocytes, and epithelioid histiocytes are the United States, and this procedure is not recommended for seen in most cases. A positive culture may be obtained in up diagnosis of NTM. All children in this setting should be tested to 50% of HIV-seronegative patients and in even higher pro- using PPD tuberculin. Most children tested with intermediate portions of HIV-positive patients with tuberculous adenitis. strength (5 tuberculin unit [TU]) PPD tuberculin will have a A definite diagnosis of NTM lymphadenitis is made by re- weakly reactive skin test (S-9 mm) due to cross-reactivity with covery of the causative organism from lymph node cultures. A NTM, but some children may be negative, and as many as one- simple diagnostic biopsy or incision and drainage of the in- third will have reactions with 10 mm or more induration (SO). volved lymph nodes should be avoided, since most of these 56 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

procedures will be followed by fistulae formation with chronic murinum (41, 69) and M. uvium complex (96) are particularly drainage (79). However, even with excised nodes with com- prone to causing tenosynovitis of the hand, although M. fortu- patible histopathology, only about 50% will yield positive cul- itum, M. abscessus, M. chelonae, and M. kunsusii have also tures (79), although the recovery rate may be as high as 82% been implicated (41, 69). Mycobacterium terrue complex (es- in some centers (80). Some of these smear-positive, culture- pecially M. nonchromogenicum) has also been isolated from negative cases may be due to fastidious species such as M. hae- synovial tissue of the hand or wrist, and it tends to be associ- mophilum (87) or M. genavense (39). Currently, approximately ated with a very indolent, chronic type of disease. Occasion- 80% of culture-proven cases of NTM lymphadenitis are due to ally, axial bones and extremities have been infected without M. avium complex (88). In the United States and Australia the apparent trauma and are due presumably to hematogenous in- remaining cases are caused by M. scrofulaceum (79, 80, 88) fection. After open-heart surgery, osteomyelitis of the sternum while in Scandinavia, the United Kingdom, and other areas of caused by M. abscessus or M. fortuitum has been described, northern Europe, M. malmoense has recently emerged as the with both epidemic and sporadic disease (16, 17,21, 94). major pathogen after M. avium complex (70, 89, 90). The pre- dominance of M. uvium complex is a change from 20 years Disseminated Disease in Patients without AIDS ago, when most geographic areas reported M. scrofuluceum as Dissemination of NTM in adult patients with immunosuppres- the most common etiologic agent (78, 80). Now in the United sion but without AIDS (e.g., those with renal or cardiac trans- States, only about 10% of the culture-proved mycobacterial plantation, chronic corticosteroid use, leukemia, etc.) has been cervical lymphadenitis in children is due to M. tuberculosis: observed. Mycobucterium uvium complex (69,97), M. kunsusii the remainder is due to M. uvium complex and M. scrufulu- (98), M. chelonue (91,99-101) M. scrofuluceum (69) M. absces- ceum (88). In contrast, in adults more than 90% of the culture- sus (69), and M. huemophilum (60) have all been reported to proven mycobacterial lymphadenitis is due to M. tuberculosis. cause disease in this setting. In general, the disease caused by M. uvium complex presents as a fever of unknown origin (97) Localized Skin, Soft Tissue, and Skeletal Infection whereas disease caused by M. kunsusii, M. chelonue, M. ubsces- The NTM species that most commonly cause localized infections sus, and M. huemophilum generally presents as multiple sub- of the skin and subcutaneous tissue are M. ,fortuitum, M. ubsces- cutaneous nodules or abscesses that drain spontaneously (60, sus, M. murinum, and M. ulceruns (5). However, virtually all spe- 69, 99-101). The mortality relates directly to the type and se- cies of NTM have been described as a cause of cutaneous dis- verity of underlying disease (101). Lincoln and Gilbert (78) re- ease (41,69). Localized drainage or abscess formation at the site viewed 12 cases, all fatal, of disseminated NTM disease in chil- of puncture wounds (such as occurs after stepping on a nail), dren, Most of the children were infected with M. avium complex, or open traumatic injuries or fractures are most often due to the were less than 3 yr old, and had no apparent underlying dis- rapidly growing mycobacterial species M. fortuitum, M. ubsces- ease. A recent review of disseminated M. uvium complex dis- sus, or M. chelonue (91). Nosocomial skin and soft-tissue dis- ease in children noted its occurrence, rarely, in the setting of ease caused by these three species is also seen (16-26). These severe combined immunodeficiency syndrome or chemother- include infections of long-term intravenous or peritoneal cath- apy for malignancy (102). The isolation of organisms from eters (91,92), postinjection abscesses, or surgical wound infec- sterile, closed sites such as bone marrow or blood or from a tions such as those occurring after augmentation mammoplasty skin biopsy (in the setting of multiple lesions) is diagnostic of (23,93) or cardiac-bypass surgery (16,17,21,94). Diagnosis is the disease. made by culture of the specific pathogen from drainage mate- rial or tissue biopsy. Disseminated Disease in Patients with AIDS Mycohucterium murinum is the cause of “swimming pool Disseminated disease due to NTM in patients with HIV infec- granuloma” or “fish tank granuloma” (69). The lesions usually tion usually occurs only in those with very advanced immuno- appear as papules on an extremity, especially on the elbows, suppression (51-57). Because these patients frequently have knees, and dorsum of feet and hands, progressing subse- other complications, the diagnosis of mycobacterial infection quently to shallow ulceration and scar formation. Most lesions may be confused or delayed. The diagnosis is exceedingly rare are solitary, although occasional “ascending” lesions develop in p rson with > 100 CD4 cells, and it should usually be sus- that resemble sporotrichosis. Clinical involvement of regional pectqd‘\ only in persons with < 50 CD4 cells (53-55). Most pa- nodes is uncommon. The organisms may be introduced into tients (> 90%) have prolonged fevers, which may be as high the skin through previous abrasions contaminated while as 103-104” F, frequently accompanied by night sweats. Weight cleaning fresh-water fish tanks (“fish tank granuloma”) or by loss is common, and some patients complain of abdominal pain scratches or puncture wounds from salt water fish, shrimp, and diarrhea. Physical findings may be only those of advanced fins, etc. Diagnosis is made from biopsy material, histologic HIV disease, although abdominal or retroperitoneal adenopa- examination, and culture. thy and hepatosplenomegaly may be present. Anemia is the Mycobucterium ulceruns causes indolent necrotic lesions of most striking laboratory abnormality, with many patients hav- the skm and underlying tissue in Australia and tropical areas ing a hematocrit of < 25%. Alkaline phosphatase is elevated of the world (34,69,95). It is not endemic in the United States. in approximately one-third of patients and may be indicative The lesions occur most commonly in children and young of hepatic disease due to M. uvium. Thus, the diagnosis of dis- adults and often result in severe deformities of the extremities seminated M. uvium should be aggressively pursued in any (95). Drug treatment of the disease has been disappointing; person with < 50 CD4 cells who has a history of fever, weight surgical debridement combined with skin grafting is the usual loss, anemia, diarrhea, or elevated alkaline phosphatase, espe- treatment of choice. cially in one with a history of other opportunistic infections. The diagnosis of disseminated M. avium is most commonly Infection of Bursae, Joints, Tendon Sheaths, and Bones confirmed by isolation of M. uvium in blood, using any of the Chronic granulomatous infection caused by NTM may de- culture techniques described in the laboratory section. The velop in tendon sheaths, bursae, joints, and bones after direct bacteremia in M. avium is ongoing, and a single culture has a inoculation of the organisms through accidental traumas, sur- sensitivity of approximately 90%. It is recommended that a gical incisions, puncture wounds, or injections. Mycobucterium single culture be drawn, with repeat cultures only if the first is American Thoracic Society s7

negative. Routine blood cultures of asymptomatic patients has or 7Hll (Isolator; Wampole Laboratories, Cranbury, New Jer- a very low yield and is not recommended. In a prospective sey) being the recommended methods. Two general types of study of HIV-infected patients with < 50 CD4 cells, approxi- solid media are available: egg-potato-base media (commonly, mately 67% of patients with M. avium in sputum or stool had Lowenstein-Jensen agar) and a clear agar-base media (com- disseminated disease within 1 yr, although most did not de- monly. Middlebrook 7HlO or 7Hll agar). Quantitation of velop pulmonary disease. However, only one-third of all pa- growth on agar plates (generally 0 to 4+) is important to esti- tients with disseminated disease had a prior positive stool or mates of clinical significance and responses to therapy, and it sputum. Therefore, routine screening of stool or sputum is not is recommended for all samples other than blood cultures. indicated, but a positive culture of one of these sites needs to Blood cultures using the Isolator System can also be quanti- raise concern about future dissemination. Sputums that are tated, which may be useful for similar reasons. Because of its smear-positive for AFB in the setting of HIV should always be greater recovery rate for M. uvium complex and ease of quan- regarded as tuberculosis until proven otherwise, since M. tu- titation, Middlebrook 7HlO or 7Hll agars are the preferred berculosis is a common cause of pulmonary disease in HIV- solid media. Lowenstein-Jensen is an excellent medium for re- infected patients and is more likely than M. avium complex to covery of M. tuberculosis, but is generally inferior to Middle- produce positive AFB smears. brook agar as an all-purpose medium for both M. tuberculosis Nontuberculous mycobacteria other than M. avium may and NTM (105,106). present as disseminated disease. Disseminated M. kansasii is The broth medium can involve one of several automated usually associated with pulmonary disease (51, 59). Mycobac- commercial systems. including radiolabeled BACTEC 12B terium genuvense has been isolated from the blood of patients broth used in the BACTEC TB 460 radiometric system (Bec- with AIDS and requires extensive laboratory analyses for iso- ton Dickinson Instruments Systems, Sparks, Maryland), and lation and identification (39). Mycobacterium huemophilum the nonradiolabeled ESP Culture System II (Difco Laborato- has been associated with infections of the skin, soft tissue, ries, Detroit, Michigan) (107). For lower volume laboratories, bones, and ,joints (60, 61). Disseminated disease has rarely the recently introduced mycobacterial growth indicator tubes been reported with other species, including M. fort&urn (51), with a fluorescent detection system (MGIT; Becton Dickinson M. murinum, M. simiae, M. scrofulaceum, M. celatum, and Microbiology Systems. Cockeysville, Maryland) or biphasic agar/ M. mulmoense (41). broth (Septi-Chek AFB System; Becton Dickinson Microbiol- ogy Systems) may prove more practical. Most slowly growing NTM produce detectable growth in 2 LABORATORY METHODS to 4 wk on the solid media and in 1 to 2 wk with the BACTEC Digestion, Decontamination, and Staining Procedures system. Cultures are generally incubated at 35-37” C for 6 wk. Methods used for digestion and decontamination of clinical All of the currently recognized NTM pathogens will grow on samples to recover M. tuberculosis have also proved useful for these media in this time except M. huemophilum, M. genuvense, the NTM. In general, however, NTM are more susceptible to and M. conspicuum. If M. haernophilurn is suspected, a com- killing by NaOH, and for this reason, care must be taken not mercial paper surface containing hemin (X factor) used to to exceed the recommended concentration and time guide- identify Haemophilus inflclenzue should be added to the sur- lines. Because of the frequent presence of bronchiectasis in face of the 7HlO or 7Hll plate (log), or hemin or ferric am- patients with M. uvium complex and M. abscessus lung disease, monium citrate should be incorporated into the medium. My- Pseudomonas ueruginosa overgrowth in specimens from these cobucterium genavense often grows only from the blood in patients is a more frequent problem than with tuberculosis. BACTEC 13A medium or comparable broth media, and re- Growth of f. ueruginosu can be minimized by processing the quires incubation for at least 8 wk (109). Some authors have specimens with the conventional N-acetyl-L-cysteine-sodium identified better growth in the slightly acidic (pH 6) radiomet- hydroxide (NALC-NaOH) solution followed by 5% oxalic ric Middlebrook 7H12 broth (pyrazinamide test medium). acid, a procedure that should be considered when one or more Mycobucterium conspicuum will grow in BACTEC media at specimens are contaminated in this setting (103). 35-37” C but will only grow on solid media at lower lempera- Staining and microscopy of the NTM also follows the guide- tures, 22-31” C (63). The presence of an AFB smear-positive lines used for M. tuberculosis. Both conventional basic fuchsin sample with no growth on solid media should immediately method (Kinyoun stain) and the fluorochrome method (au- bring to mind M. huemophilum, M. conspicuum, or M. gena- ramine stain) are effective in recognizing NTM in clinical ma- vense. Because of the relatively poor growth of M. gennvense terial, with the fluorochrome method being preferred (104). (only approximately 50% of autopsy-proven cases are culture- The appearance of NTM by microscopy is generally indistin- positive [39]), molecular techniques such as polymerase chain guishable from M. tuberculosis. reaction are the optimal method of identification (39). The major modification of culture techniques for recover- ing NTM species is the need to incubate all skin or soft tissue Culture Techniques for Nontuberculous Mycobacteria samples at two temperatures: 35” C and 28-32” C. This is be- The principles and practices of culturing M. tuberculosis were cause a number of the common pathogens of these tissues, in- updated in 1993 by the CDC (104), with these methods having cluding M. huemophilum, M. ulcerans, M. marinum, and M. che- proved very effective for NTM species. At least three respira- lonue, may grow only at the lower temperatures, especially on tory (sputum) cultures should be used for the initial evalua- primary isolation. Five to ten percent COZ enhances the growth tion. Cultures should be inoculated onto one or more solid of some NTM species, such as M. haemophilum, and should be medias and into a liquid medium. Use of solid media as the used for primary isolation because of its definite growth en- primary or sole culture is no longer recommended by us or by hancement for M. tuberculosis. the CDC (104), given the greater recovery rate and more rapid recovery of all mycobacteria, including M. tuberculosis, in rapid broth systems (104-107). Mycobacterial blood cul- Identification of Nontuberculous Mycobacteria tures may use a single medium, with the BACTEC 13A broth Traditional identification of NTM, as well as M. tuberculosis, (105) or the lysis centrifugation method with plating on 7HlO has relied upon statistical probabilities of presenting a charac- S8 AMERICAN IOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997 teristic reaction pattern in a battery of biochemical tests. The rapid identification of NTM are currently in use. These are the niacin test was the most useful for separating NTM and M. tu- species-specific DNA probes and the BACTEC NAP test. berculosis because the former is usually negative, whereas iso- Commercial nonradiolabeled DNA probes complementary to lates of M. tuhercdosis arc positive. Runyon devised the first ribosomal RNA are available for identifying isolates of M. tuher- good scheme for grouping NTM based on growth rates and culosis, M. gordonue, M. kansasii, M. avium, and M. intracellu- colony pigmentation (69). Species identification has become /are. They are highly sensitive and specific, providing species more sophisticated and the number of potential pathogens has identification using a culture directly from BACTEC broth increased since this scheme was introduced. within 2Z4 h. The presence or absence of serpentine cording on A more appropriate grouping currently for these organisms AFB smear of the BACTEC 12B bottle (114) and the time re- is based on the type of clinical disease they produce: lympha- quired for the bottle to turn positive (115) will help the labora- denitis, cutaneous discasc, disseminated disease, and pulmo- tory decide which probe (M. tuberculosis or M. avium com- nary disease. Grouping of the NTM by this scheme is shown in plex) should be used initially. Table 2. The BACTEC TB 460 system can be used to differentiate Because of the extremely slow nature of traditional bio- between M. tuberculosis and the NTM using a selective growth chemical tests, most clinical and public health laboratories inhibitor called NAP @-nitro-c-acetylamino-B-hydroxypropio- now use one or more rapid diagnostic methods for species phenone) (116). This compound, at a concentration of 5 kg/ml, identification (I 10. 111). These rapid methods are recom- inhibits the growth of M. tuberculosis complex but not NTM mended for identification of the NTM when possible; they in- (with the exception of M. genavense). The average time for clude HPLC, the BACTEC NAP test, and commercial DNA the NAP test is 5 d. However, a species identification schema probes. The HPLC examines the mycolic acid fingerprint pat- other than the use of DNA probes for NTM has not been terns that differ among most species or complexes of myco- worked out for use with the BACTEC, and such identification bacteria (112). Recent increased sensitivity of this technique must depend on one of the previously discussed methods. using fluorescence detection has allowed identification di- Because of its generally poor growth, identification of rectly from the sputum sample in approximately SO% of AFB M. genavense can be difficult (43, 109). A presumptive identi- smear-positive samples of M. tuberculosis and 33% of M. avium fication can be made on the basis of organism morphology complex (113). A small number of species (complexes) are not (small, coccobacillary forms on AFB smear), failure to grow separable by HPLC, including most of the pathogenic rapidly on subculture to solid media, a negative nucleic acid probe for growing mycobacterial species. Two additional techniques for M. avium complex, and a positive NAP test (39). Mycohacte-

TABLE 2

CLASSIFICATION OF THE NONTUBERCULOUS MYCOBACTERIA RECOVERED FROM HUMANS

Features of the Common Species Common Etioloqic Unusual Etiologic ClinIcal Disease Species _ Geography Morphologic Features* Species

Pulmonary disease 1. M. avium complex Worldwide Usually not pigmented; 1. M. simiae slow growth (’ 7 d) 2. M. szulgai 2. M. kansasii USA, coal mining Pigmented; often large and 3. M. fortuitum regions, Europe beaded on acid-fast stain 4. M. celatum 3. M. abscessus Worldwide but Rapid growth (< 7 d); 5. M. asiaticurn mostly USA not pigmented 6. M. shimodii 4. M. xenopi Europe, Canada Slow growth; pigmented 7. M. haemophilum 5. M. malmoense UK, northern Europe Slow growth, not 8. M. smegmatis pigmented

Lymphadenitis 1. M. ovium complex Worldwide Usually not pigmented 1. M. fort&urn 2. M. scrofulaceum Worldwide Pigmented 2. M. chelonae 3. M. malmoense UK, northern Europe Slow growth 3. M. abscessus (especially Scandinavia) 4. M. kansasii 5. M. haemophilum

Cutaneous disease 1, M. marinum Worldwide Photochromogen; requires 1. M. avium complex low temperatures (28- 2. M. kansasii 30” C) for isolation 3. M. nonchromogenicum 2. M. fort&urn Worldwide, mostly Rapid growth; not 4. M. smegmatis 3. M. chelonae USA pigmented 5. M. haemophilum 4. M. abscessus 5. M. ulcerans Australia, tropics, Grows slowly, pigmented Africa, SE Asia

Disseminated disease 1. M. avium complex Worldwide Isolates from patients with 1. M. abscessus AIDS usually pigmented 2. M. xenopi (80%) 3. M. malmoense 2. M. kansasii USA Photochromogen 4. M. genavense 3. M. chelonae USA Not pigmented 5. M. simiae 4. M. haemophilum USA, Australia Not pigmented; requires 6. M. conspicuum hemin, often low 7. M. marinum temperatures, and CO2 8. M. fortuitum to grow

l Photochromogen: isolate is buff-colored in the dark but turns yellow with brief exposure to light. American Thoracic Society 59 rium gerzuvense is one of the few mycobacteria, other than the hibitory concentrations (MICs) than the agar method (118, M. tuberculosis complex, which is inhibited by NAP. 119). Too little experience is available with the antibiotic gra- dient strip method (E-test; AB Biodisk, Piscataway, NJ) to Antimicrobial Susceptibility Testing make any general recommendations on its use. Although there are specific recommendations from the CDC, The agar proportion method uses Middlebrook 7HlO or ATS, and the National Committee for Clinical Laboratory 7Hll agar and the modified method of proportions, defining Standards (NCCLS) regarding which isolates of M. tuberculo- resistance as growth on the drug-containing medium of 1% or sis should have antimicrobial susceptibility tests, which test more of the number of colonies that grow on the drug-free methods to use, and which antimicrobial agents to test, the control medium. Details of the agar proportion method arc in- same is not true for the NTM. There are however, sufficient cluded in the 1990 ATS statement “Diagnostic Standards and data now available to make temporary recommendations re- Classification of Tuberculosis” (3), and a more detailed de- garding when, how, and to which agents the NTM should be scription is now available as a tentative standard (for M. tuber- tested. Recommendations will differ for different groups or culosis) by the NCCLS (126). species of the NTM (Table 3). Although routhne testing of all The radiometric BACTEC method is a more rapid method NTM is discouraged, there are circumstances where suscepti- combining antimicrobial agents, the mycobacterium, and a bility testing is warranted, including having baseline data Cl”-labeled substrate in a broth medium. Resistance is deter- available if the patient does not respond to therapy, or when mined by the rate and amount of labeled CO, produced, relapses occur. which is directly proportional to the rate and amount of growth that occurs in the broth medium. The BACTEC Slow-growing Mycobacteria method has been widely used by some laboratories for testing Antimicrobial susceptibility testing of the slow-growing myco- all drugs for the NTM, but at present no universally agreed- bacteria can be performed using either the agar proportion or upon method has been developed. the radiometric (BACTEC) methods used for testing M. tu- Mycobacterium avium complex. When and how isolates of bercdosis ( I 17-125). However, the two methods give varying the M. avium complex should be tested remains controversial results between some NTM and antimicrobial agents, with the (127). Recent data suggest that the radiometric broth method radiometric broth method tending to give lower minimal in- is more reliable than the agar method for testing the M. rrvium

TABLE 3 ANTIMYCOBACTERIAL AGENTS TO CONSIDER FOR SUSCEPTIBILITY TESTING OF NONTUBERCULOUS MYCOBACTERIA

Susceptibility Proven Utility Uncertain Testinq Results Mycobacterium Species or Group Clinically Relevant Relevance of No Benefit

Slowly growing NTM M. ovium complex Clarithromycin* Amikacin lsoniazid Ciprofloxacin Pyrazinamide Ethambutol Ethionamide Rifabutin Rifampin Streptomycin M. konsasii Rifampin Amikacin Pyrazinamrde Ciprofloxacin Clarithromycin* Ethambutol lsoniazid Rifabutin Streptomycin Sulfonamide M. marinum Doxycycline or Minocycline Amikacin lsoniarid Ethambutol Ciprofloxacin Pyrazinamide Rifampin Clarithromycin’ Sulfonamide Rifabutin Other slowly growing NTM M. haemophilum Clarithromycin*t Amikacin Pyrarinamide M. malmoense Ethambutol* Ciprofloxacin M. simiae Rifampint lsoniazid M. srulgai Rifabutin M. xenopi Streptomycin Rapidly growing NTM M. abscessus Amikacin Cefmetazole Clofazimine M. chelonae Cefoxitin lmipenem Ethambutol+ M. fort&urn Ciprofloxacin Ofloxacin lsoniarid M. mucogenicum Clarithromycin* Tobramycin (M. Pyrazinamide M. smegmatis Doxycycline or Minocycline chelonae only) Rifampin Sulfonamides Streptomycin

* Class drug for macrolides (clarithromycin, azithromycin, roxithromycin). + Ethambutol is clinically useful for M. smegmatis. * Proven utility/clinically relevant for some but not all species. SlO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

complex. There is, however, considerable controversy regard- clarithromycin (70, 135-137) whereas ciprofloxacin, clarith- ing the size of the inoculum, the drug concentrations to use, romycin, and rifampin are suggested for treating M. huemo- and interpretation of the BACTEC results. Strains of the com- philum infection (60, 61). Thus, susceptibility tests for these plex are almost always resistant to the relatively low drug con- slow-growing NTM might include these five drugs. The agar centrations of isoniazid, rifampin, streptomycin, and ethambu- proportion and broth methods have usually been used for test- tol used for defining susceptibility of M. tuberculosis. Using ing. For M. marinum, several methods have been used (138), higher concentrations of the antituberculous agents with spe- with the desired test drugs being rifampin, ethambutol, doxy- cific NTM breakpoints for susceptibility and resistance, deter- cycline or minocycline, clarithromycin, and a sulfonamide. mination of MICs, or determination of the activity of combined drugs arc some of the newer approaches that may be helpful in predicting clinical response (118, 120,121,128). Such a ben- Rapidly Growing Nontuberculous Mycobacteria efit has not yet been shown by clinical trials, so susceptibility Because of differences in susceptibilities among species of testing of M. avium complex isolates to the antituberculosis rapidly growing mycobacteria and even within species, suscep- drugs is not recommended. tibility testing should be performed on all clinically significant Other drugs have also been tested, including amikacin, isolates as well as isolates that have been recovered after rifabutin (118. 122, 123) ciprofloxacin (124, 125) clofazimine treatment failure or relapse. Antimicrobial susceptibility test- (129) azithromycin (127), and clarithromycin (127). Changes in ing of the rapidly growing mycobacteria differs from the other MICs of the antituberculosis drugs following unsuccessful NTM. Most drugs are different, although the methods are sim- therapy of M. uvium complex disease have been difficult to dem- ilar to those used to test other bacteria (138-142). Most infec- onstrate. Such changes have been readily demonstrable with tions are caused by three species; M. abscessus, M. chelonae, microbiologic relapses following monotherapy with clarithro- and M. fortuitum (91). A primary panel of drugs for these spe- mycin, however (130). Pretreatment isolates with this drug cies could include amikacin, cefoxitin, ciprofloxacin, clarithro- have MICs Q 4.0 kg/ml when done in media with a pH of 7.4. mycin, doxycycline, imipenem, and a sulfonamide. The most Post-therapy or relapse isolates follotiing macrolide therapy convenient method for susceptibility testing is to use microti- have MICs to clarithromycin of > 32 ~g/ml(105,130-132) and ter MIC trays containing cation-supplemented Mueller-Hin- a point mutation involving one of two base pairs in the 23s ri- ton broth. Agar dilution, agar disk elution, and disk diffusion bosomal macrolide binding site (I 31, 132). methods have also been used. Details of these methods can be Susceptibility testing should not be performed on pretreat- found in several laboratory handbooks, including the Ameri- ment or initial isolates against clarithromycin, but it should be can Society for Microbiology’s Manual of Clinical Microbiol- performed with clarithromycin for all isolates from patients on ogy (142). prior macrolide therapy, including those on macrolide prophy- laxis for disseminated disease. The recommended clarithro- TREATMENT OF Mycobocterium kansasii DISEASE mycin resistance breakpoint is > 32 pg/ml for broth or agar with pH corrected to 7.4 (105). Until more data are available, Disease caused by M. kansasii is the second most common patients on azithromycin should have their isolates character- NTM pulmonary disease in the United States. It occurs in geo- ized as susceptible or resistant based on clarithromycin sus- graphic clusters and affects primarily adult white men, but it ceptibility values. can affect patients of any sex, race, or age. Pulmonary disease Alterations or changes in MlCs following treatment or pro- is the most frequent clinical presentation. The organism fre- phylaxis failure have also been difficult to demonstrate with quently exhibits a beaded or cross-barred appearance on acid- rifabutin. For this reason, testing of susceptibility to rifabutin fast stain, and produces rough buff-colored colonies that de- even after therapy is not recommended. Because of lack of velop a yellowish pigmentation because of the deposition of standardization, results of testing other nontuberculous drugs beta-carotene crystals after exposure to light. Disease-produc- such as amikacin, clofazimine, and ciprofloxacin should be ing strains are usually highly catalase-positive. Recent DNA- used with caution. based studies suggest that up to five taxonomic groups or sub- Mycobacterium kansasii. Although wild strains of M. kan- species are present among both environmental and human sasii are initially susceptible to rifampin, acquired resistance isolates (143). does develop during therapy (133, 134). Since the correct his- Untreated strains of M. kansasii are inhibited by rifampin, tory of therapy may not be known, all initial isolates of M. kan- isoniazid, ethambutol, ethionamide, streptomycin, and clarithro- sasii should be tested against rifampin, using the agar propor- mycin at concentrations readily achievable in the serum with tion method and the interpretive criteria for M. tuberculosis usual therapeutic doses (134, 144, 145). Because the concen- (resistance breakpoint of 1 kg/ml) (134). Also, testing should trations of antituberculous drugs used in susceptibility testing be performed when the patient’s sputum fails to convert from were chosen for their usefulness with M. tuberculosis, and be- smear- and/or culture-positive or when a relapse occurs during cause M. kansasii is less susceptible to these drugs, some iso- therapy. Treatment for rifampin-susceptible isolates is empiric lates of the latter species may be reported resistant to iso- and is not influenced by susceptibility to drugs other than niazid at 0.2 or 1 yg/ml and to streptomycin at 2 pg/ml. These rifampin (i.e., ethambutol and isoniazid); hence their routine isolates are susceptible to slightly higher drug concentrations testing is not recommended. A rifampin-resistant isolate could (134,144) and laboratory reports of resistance to the low con- be tested against ciprofloxacin or ofloxacin, clarithromycin, centrations of these two drugs have no clinical or therapeutic ethambutol, streptomycin and a sulfonamide (e.g., sulf- significance as long as a rifampin regimen is being used (146). amethoxazole) (133, 134). Thus, when clinically indicated, isoniazid and/or streptomycin Other slow-growing nontuherculous mycobacteria. Suscep- should be used against M. kansasii regardless of their in vitro tibility testing of infrequently isolated species of NTM may be susceptibility results. Mycobacterium kansasii is also suscepti- helpful, since knowledge of susceptibility patterns is limited. ble in vitro to clarithromycin (134) sulfamethoxazole (133) ami- Pulmonary infections caused by M. rnalmoense, M. xenopi, kacin (133) the newer quinolones (125) and rifabutin (134) al- and M. szulgai have been successfully treated with combina- though there is limited information on the clinical usefulness tions of ethambutol, isoniazid, rifampin, and most recently of these drugs (133,134). Isolates are usually resistant to achiev- American Thoracic Society Sl 1

able serum levels of p-aminosalicylic acid, capreomycin, and ment of M. kansasii; however, 9 mo is not a long enough treat- pyrazinamide. Acquired resistance to rifampin, ethambutol, ment period for the studied two-drug regimen. and isoniazid has been demonstrated in isolates from treat- In adult patients whose organisms have become resistant to ment failure cases (133, 134, 145), and resistance to the first rifampin as a result of previous therapy, a regimen consisting two agents is reliably demonstrated by current M. tuberculosis of high-dose daily isoniazid (900 mg), pyridoxine (50 mg susceptibility test methods (134). daily), high-dose ethambutol (25 mg/kg per day), and sul- famethoxazole (1.0 gm three times per day) until the patient is culture-negative for 12 to 15 mo has been under investigation Treatment (133, 134). The oral therapy has been combined with daily or The natural history of pulmonary disease caused by M. kan- five times per week streptomycin or amikacin for the initial 2 sasii in patients receiving no drug treatment has been assessed to 3 mo, followed by intermittent streptomycin or amikacin (147). In general, the history has shown persistence of sputum for a total of 6 mo. Results with this regimen described sputum positivity and progression of clinical and radiographic disease. conversion in 18 of 20 patients (90%) after a mean of 11 wk, On this basis, patients with pulmonary disease should receive with only one relapse (8%) among patients who were culture- drug therapy. negative for at least 12 mo on therapy (134). The excellent in There have been no randomized comparative trials of vitro activity of clarithromycin against M. kansasii (134) sug- treatment for disease caused by M. kansasii, comparing one gests this agent will also be highly useful in retreatment regi- drug regimen with another or with no drug treatment at all. mens, perhaps allowing for omission of the aminoglycoside. There have been, however, several retrospective and prospec- The newer quinolones may also be potentially useful in this tive studies of various treatment regimens (145-151) that have setting but have not been studied. given us a good basis for drug therapy recommendations. Ear- For treatment of extrapulmonary disease in adults, the reg- lier reports of treatment with antimycobacterial drugs in the imen of antimycobacterial drugs should be the same as for prerifampin period were disappointing when compared with pulmonary disease. Pulmonary disseminated disease has been the much higher success rates achieved in treating tuberculosis described in patients with AIDS (59), and it is the second most with these same drugs. The sputum conversion rates at 6 mo common NTM that produces disease in this setting (51). Of ranged from 52 to Xl%, and relapse rates of approximately the cases detailed in the literature, most have been fatal (59). 10% were seen in patients achieving an initial response (145, In the treatment of lymph node disease in children, excision of 148). Surgical resection was often recommended to achieve all accessible nodes at the time of the initial biopsy should be better initial control and prevent relapse. The advantage of done, since the etiologic agent is probably an NTM other than adding surgery was never established, however (148). M. kansasii, for which excision is the indicated treatment. With the advent of rifampin, the picture changed consider- The use of protease inhibitors for the treatment of HIV dis- ably for the better. Four-month sputum conversion rates with ease complicates the management of M. kansasii disease be- rifampin-containing regimens were 100% in 180 patients from cause rifampin dramatically enhances the metabolism of these three studies (145,146,149). There were two treatment failure drugs and cannot be used with them concurrently. Options for cases, however (an incidence of 1.1%). These patients con- treating HIV-infected patients who receive a protease inhibi- verted their sputa but then became culture-positive again tor are to substitute clarithromycin for rifampin in the stan- while still receiving therapy. Both had been treated with iso- dard regimen, or to substitute rifabutin 150 mg/d for rifampin niazid, rifampin, and ethambutol, and both failures were asso- if the patient is receiving indinavir. None of these regimens ciated with the development of rifampin resistance (145). have been studied clinically; however, they appear likely to be Long-term relapse rates with rifampin-containing regimens successful. also appear to be very low, with only one relapse recorded among 134 patients (0.8%) who received long-term follow-up TREATMENT OF PULMONARY Mycobacterium avium in three studies (145, 146, 150). Surgery is now considered to COMPLEX DISEASE (M. ovium, M. introcellulore) have no role in managing routine cases of pulmonary disease. Medical treatment of M. avium complex pulmonary disease in The current recommendation for treatment of pulmonary HIV-negative patients has historically been frustrating and disease caused by M. kansasii in adults is the regimen of iso- disappointing. In the few studies in which initial sputum con- niazid (300 mg), rifampin (600 mg), and ethambutol(25 mg/kg version rates have been high (> SO%), long-term follow-up to for the first 2 mo, then 15 mg/kg) given daily for 18 mo with at establish continued sputum conversion is rarely documented least 12 mo of negative sputum cultures. In patients who are (152-156). Relapses after medical therapy with premacrolide unable to tolerate one of these three drugs, clarithromycin treatment regimens are common, and the best outcomes have would seem a reasonable alternative, but its effectiveness has frequently been in those patients subjected to resectional sur- not been established by clinical trials (see below). Pyrazina- gery (157,158). Recent significant advances in the drugs avail- mide is unacceptable as an alternate or third drug for M. kan- able for treatment of M. avium complex have been made, sasii because all isolates are resistant. however, and there is now greater expectation that pulmonary The use of intermittent drug regimens or short-course M. avium complex disease can be effectively treated (defined treatment for M. kansasii has not been studied enough to rec- as high rates of sputum conversion with long-term culture neg- ommend it. One study of 40 patients did demonstrate that ativity) with medications alone. adding intermittent streptomycin at 1 g twice weekly for the The major limitations for effective therapy have been the first 3 mo to the previously recommended three-drug regimen absence of antimicrobial agents with low toxicity and good in given for 12 mo resulted in apparent cure of all but one patient vivo activity against the organism. Most first-line antitubercu- (149). A trial of daily low-dose ethambutol (15 mg/kg) and losis drugs have lo-100 times less in vitro activity against daily rifampin given for 9 mo sponsored by the British Medi- M. avium complex isolates than against M. tuberculosis. This cal Research Council was completed in 155 adult patients diminished activity may be due to the lipophilic cell wall of (151). Sputum conversion was achieved in 99.4% of patients, M. avium complex, which prevents drug penetration (159). but with a relapse rate of 10% with a 5 year follow-up. This The major therapeutic advances in the treatment of pulmo- suggests that isoniazid does not contribute greatly to the treat- nary M. avium complex disease have come as a result of prog- 512 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997 ress in treating disseminated M. avium complex in the setting cific therapies included bronchodilators, postural drainage, of HIV disease. Recent studies have shown excellent in viva smoking cessation, and broad spectrum antibiotics (77). Clearly, and clinical activity against M. uvium complex by the newer these measures may be appropriate and can be associated with macrolides, clarithromycin and azithromycin. presumably due symptomatic improvement in bronchiectasis unrelated to any to the high phagocyte and tissue levels achieved by these agents. effect on M. avium complex. Before the development of newer, (The structure of azithromycin is technically an azalide; how- more active agents against M. avium complex, it had been ever, because of the close similarity of azalides to macrolides, proposed that patients in this group with a stable clinical pic- the term macrolide will be used to refer to both in subse- ture (usually over 3-6 mo) and minimal symptoms, and those quent discussion.) Human trials of patients with disseminated whose sputum “cleared” with nonspecific therapy, should not M. avium complex disease and AIDS have shown both newer be treated. However, based on recent studies using chest macrolides to have clinical and microbiologic activity as mono- HRCT scans, these patients have specific radiographic fea- therapy (160-163) and clarithromycin to have clinical and mi- tures of parenchymal disease in addition to their multifocal crobiologic activity in drug combinations (162). Studies have bronchiectasis (71-74). The term “colonization” is, therefore, also demonstrated significant sterilizing activity of both azithro- incorrect. The appropriate distinction is not between coloniza- mycin and clarithromycin with short-term initial treatment as tion and invasive disease but between those patients with the single agents in pulmonary M. uvium complex disease (164, disease of nodular bronchiectasis who require immediate ther- 165). Although it is not appropriate to treat patients with dis- apy directed at M. uvium complex and those in whom such a ease (outside of clinical trials) with single agents, these are the decision can be delayed. If a decision is made to observe such first studies demonstrating significant in viva activity of any a patient (e.g., one with minimal symptoms and radiographic single agent for pulmonary M. avium complex disease. findings such that the treatment seems worse than the disease, Rifabutin, a derivative of rifamycin S, has been shown to be or one with other major medial problems), it is incumbent more active in vitro than rifampin against isolates of M. avium upon the treating physician to continue collecting respiratory complex (117). Peak serum rifabutin concentrations are much specimens for AFB analysis as well as follow-up chest radio- lower than those of rifampin and exceed the MICs for only ap- graphs and/or CTs over a relatively long period of time (per- proximately 70% of M. avirrm complex strains (123). The rele- haps the patient’s entire lifetime), as the M. uvium complex vance of this finding is uncertain, given higher levels of the drug disease will likely progress at some time and the patient’s in tissue than in serum. Rifabutin has demonstrated effective- symptoms and chest radiographs will likely worsen. We rec- ness as a prophylactic agent against disseminated M. avium ommend careful evaluation of each respiratory M. avium com- complex disease in AIDS (54) and there is some evidence of plex isolate in the context of the patient’s overall status. In improved clinical response of pulmonary M. avium complex general, almost any patient with two or three positive respira- disease in HIV-negative patients when rifabutin is added to tory cultures for M. avium complex has M. uvium complex multidrug regimens (166). The newer macrolides and rifabutin lung disease. Although not all patients with an M. uvium com- form the basis of improved treatment regimens for pulmonary plex respiratory isolate will require immediate therapy, the cli- M. uvium complex disease. nician must resist the temptation to make facile clinical deci- sions, particularly if that decision is to not treat a patient with a M. uvium complex respiratory isolate. As treatment regi- Clinical Presentations mens improve both in effectiveness and the ability of the pa- The natural history of M. ~viun~ complex lung disease is un- tient to tolerate the medications, there should be less reluc- predictable in HIV-negative patients. Some patients maintain tance to treat M. uviunt complex lung disease at an earlier stage. a stable clinical and radiographic picture for years, whereas For patients with substantial symptoms and/or advanced or others have a relatively rapid progression of their disease. The progressive radiographic abnormalities, an observation period variability in the natural history of M. aviurrz complex lung dis- is not needed to establish the need for therapy. ease appears to relate in part to the presence of two types of clinical disease and presentation. The traditional presentation of M. uvium complex lung disease has been as apical fibrocav- Drug Treatment itary lung disease, sometimes with huge cavities, in males in Drug therapy for M. uvium complex disease involves multiple their late 40s and early SOS who have a history of heavy ciga- drugs: therefore, the risk of drug toxicities is relatively high. rette smoking and, frequently, alcohol abuse. This form of dis- Additionally, the optimal therapeutic regimen has yet to be es- ease is generally progressive within I to 2 yr if left untreated. tablished. For these reasons, the treatment of M. uvium com- More recently. it has become apparent that M. uvium complex plex disease may best be served by physicians experienced in lung disease also presents as bilateral nodular and interstitial/ pulmonary or mycobacterial diseases. nodular disease or as isolated right middle lobe or lingular dis- With empiric combination regimens that include clarithro- ease, predominantly in elderly nonsmoking females (71-74, mycin and usually ethambutol and a rifamycin (rifampin or 167). These syndromes were often referred to as M. avium rifabutin), sputum conversion rates for pulmonary M. avium complex “colonization,” with bronchiectasis considered to be complex disease in adult patients able to tolerate the medica- the only real disease. This form of disease (nodular bron- tions are about 90% (164,168,169). Rifabutin is the preferred chiectasis) tended to have a much slower progression, such rifamycin because it is more active in vivo than rifampin against that long term follow-up (S-10 yr) was often needed to show M. uvium complex, but it may also produce more problematic clinical or radiographic changes. For the nodular bronchiec- adverse events (uveitis, leukopenia). All untreated strains of tatic forms of M. uvium complex lung disease, sputum submis- M. uvium complex are macrolide susceptible (clarithromycin sion for AFB analysis was often delayed months to years as MICs of 0.25 of 4.0 pg/ml), while microbiologic relapses asso- the patient had radiographic and symptomatic progression. ciated with symptom recurrence reveal isolates with MlCs of In the past, many patients with nodular bronchiectatic > 32 p.g/ml (170). Patients with either pulmonary or dissemi- M. uvium complex disease received a variety of nonspecific nated M. uvium complex do not respond to macrolidc-con- measures (“pulmonary tolict”) rather than specific antimyco- taining regimens in which the macrolide is the sole or principle bacterial therapy for their pulmonary disease. These nonspe- agent if the patient’s isolate is macrolide resistant in vitro (161, American Thoracic Society $13

164. 168. 160). Isolates of M. avium complex resistant to clari- lung disease have been reported to date, both investigating thromycin are cross-resistant to azithromycin (170). clarithromycin (168, 169). One study using 12 mo of culture The newer macrolides are the cornerstone of contempo- negativity as the treatment endpoint observed no pulmonary rary therapy for pulmonary M. avium complex disease, as they disease relapses with a mean follow-up of 18 mo (I 68), while are for disseminated M. avium complex disease. Initial ther- the second study, which used 7 to 9 mo of culture negativity, apy for adult HIV-negative patients with M. avium complex resulted in no early pulmonary disease relapses with a mean disease needing treatment should consist of a minimum three- follow-up of 7 mo (169). Early relapses with less than IO mo of drug regimen of clarithromycin (500 mg twice a day) or azithro- culture negativity were seen in the first study. These initial mycin (250 mg/d or 500 mg three times a week), rifabutin (300 studies suggest that culture negativity of 10 to 12 mo while on mg/d) or rifampin (600 mg/d), and ethambutol (25 mg/kg per a clarithromycin-containing regimen is adequate for most pa- day for 2 mo followed by 1.5 mg/kg per day). For patients of tients. small body mass and/or an age over 70, clarithromycin at 250 Acid-fast bacilli smears and cultures of sputum should be mg twice a day or azithromycin 250 mg three times a week obtained monthly during therapy for pulmonary M. avium may be better tolerated. Studies are currently ongoing to de- complex disease to assess response, then periodically after termine the feasibility and efficacy of both azithromycin- and completion of therapy to evaluate possible relapse. The de- clarithromycin-containing regimens with all drugs given inter- sired endpoint is negative sputum cultures; patients who re- mittently (three times weekly) for pulmonary M. avium com- spond to therapy should develop negative AFB smears and plex disease. cultures. One or more cultures containing small numbers of The potential and method for treating pediatric patients M. avium complex organisms (single colonies on solid media (e.g.. those with underlying cystic fibrosis) with the above reg- or positive liquid media cultures only) may occur after sputum imen has not been studied, nor have drug doses for the newer conversion and should not necessarily be interpreted as indic- agents such as clarithromycin and rifabutin. ative of treatment failure or relapse. Rather, these culture re- Intermittent streptomycin for the first 2 to 3 mo of therapy sults should be interpreted in light of the patient’s overall clin- may be considered, in addition to the above regimen, for ex- ical status. tensive disease. The exact dose of streptomycin in this multi- All patients should show clinical improvement within 3 to 6 drug regimen will depend on the patient’s age and weight. For mo and should convert their sputum to negative within 12 mo extensive disease, we recommend at least 2 mo of intermittent on macrolide-containing regimens (168). Thus, patience is re- (twice or three times weekly) streptomycin, although longer quired in evaluating response to therapy. However, failure to therapy with streptomycin may be desirable in patients with respond in these time periods should prompt investigation for very extensive disease or for those who do not tolerate other possible noncompliance or macrolide resistance. agents. There are no data, however, comparing clarithromy- For patients whose disease has failed to respond to a mac- tin-containing regimens with and without an aminoglycoside. rolide-containing regimen (usually as a consequence of in vitro The patient and physician should be alert to signs and symp- macrolide resistance, noncompliance, or drug intolerance) and toms of streptomycin toxicity, and these may prevent comple- have progressive, symptomatic disease, an alternative drug regi- tion of the full course of therapy. Because ototoxicity due to men will be necessary. The treatment for pulmonary M. uvium streptomycin is often irreversible, patients receiving strepto- complex disease in HIV-negative adult patients as recommended mycin should be instructed in the signs and symptoms of toxic- in the first ATS NTM statement published in 1990, consisted ity (unsteady gait, tinnitus, diminished hearing) at the start of of the four-drug regimen of isoniazid (300 mg/d). rifampin therapy and again on subsequent visits, with discontinuation (600 mgld), ethambutol (25 mg/kg per day for the first 2 mo, or decrease in dosage or frequency if suggestive signs of toxic- then 1.5 mg/kg per day) with streptomycin for the initial 3 to 6 ity occur. Suggested doses of streptomycin based on patient mo of therapy (1). With the use of rifabutin instead of rifampin, age and weight are shown in Table 4. this may be a reasonable regimen for patients who are mac- The optimal length of drug therapy for M. avium complex rolide resistant or intolerant. Which drugs are most useful in lung disease has not been established. Recommendations in treating macrolide-resistant strains is a major issue to be ad- the premacrolide era were that patients be treated for 18 to 24 dressed in future studies as resistant strains become more prev- mo without considering how long the sputum culture results alent. Although there are no trials comparing regimens with were negative. This recommendation was based on empiric and without a macrolide for treating pulmonary M. uvium data, in part, drawing from the early experience in treating tu- complex, most experts consider the regimen without a mac- berculosis. With macrolides, a shorter length of therapy seems rolide to be inferior, and one such regimen (rifampin, etham- acceptable. Only two long-term studies of M. uvium complex butol, ciprofloxacin, and clofazimine) has been shown to be inferior to a clarithromycin-containing regimen for dissemi- nated M. uvium (171). TABLE 4 A number of other drugs have been used in multidrug regi- mens in the past, but they are limited by toxicity (e.g., cyclo- SUGGESTED DOSES OF STREPTOMYCIN RELATIVE TO AGE AND WEIGHT IN PATIENTS WITH serine and ethionamide) or little or no evidence of clinical effi- NORMAL SERUM CREATININE* cacy (e.g., clofazamine, newer quinolones, capreomycin). Some experts feel that clofazimine 100 mg/d and ciprofloxacin 750 Weight and Age Initial Therapy’ Maintenance Therapy* mg twice daily or ofloxacin 400 mg twice daily are useful in the z5Okgands5Oyr 1 g 5xlwk 1 g 3x/wk setting of M. avium complex lung diseases, although there are i 50 kg and s 50 yr 500 mg sxlwk 750 mg Zx/wk no data corroborating their efficacy. Therapy with only two > 50 kg and SO-70 yr 500 mg 5x/wk 750 mg Zx/wk drugs, especially isoniazid and rifampin only, is strongly dis- > 70yr 750 mg 2x/wk 750 mg 2x/v/k couraged and not likely to be effective. Antituberculosis drugs

l These doses have not been established as optlmal by clinical trials. The reduced are generally well tolerated, even by the elderly population doses with age reflect the reduced renal funtion and increased risk of toxicity with with M. avium complex lung disease. streptomycin seen in patients older than 50 yr. ’ For the first 6 to 12 wk of therapy as tolerated. If patients are unable to tolerate or fail first-line antituber- r For subsequent therapy as tolerated. culosis medications, an alternative “salvage” regimen should s14 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

be considered with potential agents including ciprofloxacin sinus tract formation and chronic drainage, and should be 750 mg twice daily or ofloxacin 400 mg twice daily, clofazimine avoided (79,80, 177,178). For children with recurrent disease, 100 mg daily, ethionamide (2.50 mg twice a day, then increased a second surgical procedure is usually performed. An alterna- to three times a day as tolerated), and prolonged use of strep- tive for recurrent disease or for children in whom surgical risk tomycin or amikacin (three to five times per week). A multi- is high (e.g., risk of facial nerve involvement) may be the use ple drug regimen including these potentially toxic drugs can of a clarithromycin multidrug regimen such as that used for also be associated with at least short-term conversion of the pulmonary disease (80, 179, 180). Experience with such an ap- sputum to AFB-negative. The long-term success rate for sal- proach is limited (179-182) but the proven activity of clarithro- vage regimens is unknown but is likely very low. mycin against M. &urn complex in other clinical settings and The role of immune therapy in patients who fail drug ther- preliminary reports makes this approach appear promising. apy has not been established. Interleukin and gamma inter- A special problem is created by the child who has granulo- feron have been used in selected patients, and some investiga- matous disease with or without AFB on examination of the tion in this area continues. excised lymph nodes, and whose PPD tuberculin skin test is strongly positive (e.g., more than 15 mm). A course of antitu- Surgical Treatment berculosis therapy while awaiting the results of the lymph Patients whose disease is localized to one lung and who can node culture is reasonable, especially when there are any risk tolerate resectional surgery might also be considered for sur- factors for tuberculosis (positive family history, foreign-born gery, if there has been poor response to drug therapy or if the child, etc.). If the cultures fail to yield any mycobacteria, anti- patient’s isolate has become macrolide resistant. For some pa- tuberculosis therapy should be discontinued unless there are tients successfully treated by surgical resection, the prognosis significant risk factors for tuberculosis. has been better than for patients treated medically, although these results predated the use of macrolide-containing regi- Skin, Tissue, and Skeletal Disease mens (157, 158). Lung resectional surgery for mycobacterial For adult patients with extrapulmonary, localized M. avium disease is associated with significant morbidity and mortality complex disease involving skin, soft tissue, tendons and joints, (172, 173). In one recent series from a thoracic surgeon expe- and occasionally bone, a combination of excisional surgery (or rienced in mycobacterial surgery, 8 of 38 (21%) of patients surgical debridement) and chemotherapy is usually performed. undergoing surgery and 8 of 17 (47%) of patients under- Whether a three-drug regimen alone in this setting would be going pneumonectomy developed postoperative bronchopleural adequate is not known. The optimal duration of treatment is fistulae, especially following a right pneumonectomy (172). also unknown, but drug treatment usually lasts 6 to 12 mo. Whenever possible, this surgery should be performed at cen- ters with thoracic surgeons who have considerable experience TREATMENT OF DISSEMINATED Mycobacterium with this type of surgery. Overall, the bilateral nature of &urn DISEASE M. avium complex lung disease, the advanced age of the pa- tients, and the frequency of underlying chronic lung disease Disseminated M. avium is associated with an increased mor- have limited the number of patients who are good candidates tality in patients with AIDS. In one natural history study, the for surgery. median survival was 134 d after the first positive blood culture, and only 13% of patients were alive at 1 yr (53). Initially, some Toxicity Monitoring clinicians questioned whether M. avium was a direct cause of Monitoring of patients for toxicity, given the number of drugs death or only present in persons who were dying of other rea- and the older age of these patients, is essential. Monitoring sons. Several controlled studies have shown shortened sur- should include visual acuity (ethambutol and rifabutin), red- vival in patients with disseminated M. avium when compared green color discrimination (ethambutol), liver enzymes (clari- to cohorts of patients without M. avium (183). Based on the thromycin, azithromycin, rifabutin, rifampin, isoniazid, ethiona- increased morbidity and mortality associated with dissemi- mide) (174) auditory and vestibular function (streptomycin, nated M. hum, prophylaxis should be strongly considered in amikacin, clarithromycin, azithromycin), renal function (strep- high-risk patients and therapy should be offered to all patients tomycin and amikacin), leukocyte and platelet counts (rifabu- with established disease. tin) (175, 176) and the central nervous system (cycloserine). Early (premacrolide) studies of the treatment of M. avium Patients who receive both a macrolide and rifabutin must be in patients with AIDS demonstrated the ability of multidrug monitored for the development of toxicity related to the inter- regimens to lower the burden of mycobacteria in the blood action of these drugs (175,176). Clarithromycin enhances rifabu- and improve symptoms (184, 185). The drugs used in these tin toxicity (especially uveitis) while the rifamycins, rifampin studies such as ethambutol, clofazamine, rifampin, and cipro- more than rifabutin, lower clarithromycin serum drug levels. floxacin have been shown to have modest activity in vitro, and Details are provided in the section on monitoring for drug tox- two of the agents (ethambutol and rifabutin) to have modest icity. activity in single-drug therapy studies of patients with AIDS and M. avium (186, 187). A major advance in therapy came TREATMENT OF LOCALIZED EXTRAPULMONARY with the recognition that clarithromycin and azithromycin Mycobacterium avium COMPLEX DISEASE were potent agents against M. avium complex. Both clarithro- mycin and azithromycin were shown to markedly reduce the Lymphadenitis number of bacteria in the blood of patients in small pilot stud- Excisional surgery without chemotherapy is the recommended ies (160, 163). In a larger study of 1.54 adult patients with treatment for children with NTM cervical lymphadenitis, in- AIDS and M. avium bacteremia, clarithromycin was given as cluding those with disease caused by M. avium complex and single-drug therapy in doses of 500, 1,000 or 2,000 mg twice M. scrofulaceum (79, 80, 177, 178). The success rate with this daily. All three groups had clearance of bacteremia and reduc- procedure is about 95% (79). Incisional biopsy or the use of tion in symptoms, although the groups receiving the higher antituberculosis drugs alone (without a macrolide) has fre- doses had greater toxicity and a higher mortality (161). It was quently been followed by persistent clinical disease, including also noted, however, that resistance was a problem, as clinical American Thoracic Society S15 relapse and in vitro resistance developed in approximately mycin or withholding the protease inhibitor until the myco- 20% of individuals by 12 wk. bacterial infection has been treated. The improved immune Rifabutin has also been demonstrated to be effective in function resulting from aggressive antiretroviral therapy, in- several small studies of patients with AIDS who had dissemi- cluding a protease inhibitor, might ultimately be the most im- nated M. avium (184, 188). As monotherapy, it was shown to portant factor for clearance of disseminated NTM infection in reduce colony counts in the blood (I 87). Clearance of bactere- AIDS patients; therefore, continuing a protease inhibitor is a mia occurred in 7 of 11 patients receiving rifabutin, clofaza- high priority. Optima1 therapy for disseminated NTM disease, mine, and ethambutol, compared to 0 of 13 patients with clo- especially M. uvium, requires a multidrug treatment regimen fazimine alone in another study (188). including a rifamycin. Overall, in a patient on protease inhibi- Due to problems with drug resistance, as well as the need tors with proven disseminated M. avium, it still seems prudent to eradicate large numbers of organisms, multidrug therapy is to include rifabutin in the treatment regimen, even if the dose considered essential in the treatment of patients with dissemi- is attenuated. For other NTM, the importance of the rifamycin nated M. hum. There are currently few well done compara- should be evaluated based on the specific organism being tive trials of the many possible multidrug regimens. A Cana- treated. dian HIV Trials Network study (171) involving 229 patients did demonstrate the combination of clarithromycin, rifabutin, PROPHYLAXIS OF DISSEMINATED DISEASE IN AIDS and ethambutol to be superior to rifampin, ethambutol, clofa- zimine, and ciprofloxacin at both reducing bacteremia (69% The incidence of disseminated M. avium can be reduced by versus 29%, p < 0.001) and prolonging median survival (8.6 prophylactic antimicrobials. Rifabutin was demonstrated to be mo versus 5.2 mo, p = 0.001). effective in two placebo-controlled, double-blind studies. My- Based on currently available data, it would be advisable to cobucterium uvium bacteremia developed in 8% of adult pa- always use a minimum of three drugs-one of which should be tients receiving 300 mg of rifabutin daily and in 17% of pa- clarithromycin (500 mg twice daily) or azithromycin (250 mg tients on placebo (54). Because rifabutin is highly active or 500 mg daily). Most investigators would use ethambutol as against M. tuberculosis, it is probable that daily use of rifabu- the second agent at a dose of 15 mg/kg per day, although con- tin would also provide prophylaxis against tuberculosis. Ac- sideration should be given to an initial course of 25 mglkg for tive tuberculosis must be ruled out before initiating rifabutin the first 2 mo. Rifabutin has the best potential as the third prophylaxis in order to prevent the development of drug-resis- agent. Use of rifabutin will be problematic, however, in pa- tant tuberculosis. Clarithromycin in a dose of 500 mg twice tients also on protease inhibitors, given its induction of the daily was effective in a controlled trial of 667 adult patients in cytochrome P-450 system that metabolizes all currently ap- reducing the incidence of M. avium complex bacteremia from proved members of this drug class. Clofazimine has also been 16% in the placebo group to 6% in the treatment group (192, used, as has a quinolone, but neither seems to contribute 193) while in a related trial it was shown to be more effective much to the regimen, and clofazimine has been associated than rifabutin (193). Azithromycin at a dose of 1,200 mg once with a higher mortality in two comparative treatment trials weekly, either alone or in combination with rifabutin, has also (189). Amikacin (191) and streptomycin are both active, and been shown to be effective in a published clinical trial involv- one or the other should be considered for use in patients with ing 693 adult patients (194). The final selection of agents may severe symptoms due to M. uvium complex, especially as part depend on cost, tolerability, and potential drug interactions of of initial therapy. the agents. Rifabutin should generally be avoided in patients It should be noted that drugs used to treat mycobacterial on protease inhibitors because it markedly enhances their me- diseases in patients with AIDS are associated with frequent tabolism and reduces serum levels of the protease inhibitors. adverse effects, and changes to therapeutic regimens may of- Some clinicians and the United States Public Health Service ten be required. Of particular note has been the frequent oc- have advocated use of indinavir but not other currently avail- currence of uveitis when doses of clarithromycin higher than able protease inhibitors (retonavir, saquinquir) with reduced- 500 mg twice daily have been used in combination with rifabu- dose rifabutin if both drugs are deemed essential. tin doses of 600 mg daily (175). This incidence fell to only 6% The development of drug resistance during prophylaxis is a (3 of 53 patients) in the Canadian HIV trial when the rifabutin concern, and it has already been noted to occur with the use of dose was reduced to 300 mg daily, the currently recommended clarithromycin (192, 193) or azithromycin (194) as monother- dose (171). apy, but not the rifabutin monotherapy (54) or azithromycin Another problem is the interaction of rifamycins with the when combined with rifabutin (194). Because of the very high recently introduced protease inhibitors (saquinavir, ritonavir, risk of disseminated M. uvium in persons with advanced HIV and indinavir) for treatment of AIDS. Rifampin, and to a infection, prophylaxis should be offered to all patients with lesser degree rifabutin, enhances hepatic metabolism of the CC 50 CD4 cells, especially in patients with a history of oppor- protease inhibitors, which may result in subtherapeutic levels tunistic infection (195,196). of these agents and promote the emergence of resistant HIV strains. The protease inhibitors inhibit metabolism, and there- TREATMENT OF RAPIDLY CROWING fore promote dose-related adverse effects, of the rifamycins MYCOBACTERIAL DISEASE (especially rifabutin). Recent recommendations, made in the context of tuberculosis therapy, suggest that rifampin should Disease caused by the rapidly growing mycobacteria, espe- not be used with the protease inhibitors, but that rifabutin can cially cutaneous disease, has come to be recognized as rela- be used at modified doses with at least one of these agents, in- tively common in selected areas of the United States. The dinavir (190). This recommendation would have little impact southeastern United States from Georgia to Texas appears to on the treatment or prophylaxis of disseminated M. avium dis- be the major endemic area, although disease has been re- ease since rifabutin is the preferred rifamycin. The impact on ported from all over the United States. Most clinical disease is the treatment of other NTM such as M. kansasii, where sporadic and community acquired, although nosocomial out- rifampin has traditionally been used, is less clear. Alternative breaks or clustered cases have been reported (16-26) and the strategies include treatment of NTM infections without a rifa- association of rapidly growing mycobacteria wound infections 516 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

with augmentation mammoplasty (23,93) and cardiac surgery should be used in patients over the age of SO; once-daily dos- (16, 17,21, 94) is well recognized. ing is unproven clinically but appears reasonable. The amika- Most clinical disease (more than 90%) is due to three spe- tin combined with high-dose cefoxitin (I 2 g/d given intrave- cies of rapidly growing mycobacteria: M. fortuitum, M. absces- nously) is recommended for initial therapy (minimum 2 wk) sus, and M. chelonae (91). Two taxa originally identified as until clinical improvement is evident. For M. chelonue, tobra- biovariants within M. fortuitum (M. fortuitum third biovariant mycin is more active in vitro than amikacin. Imipenem ap- complex, sorbitol-positive and sorb&-negative) are still un- pears to be a reasonable alternative to cefoxitin for these two dergoing taxonomic evaluation. Both groups may eventually species, and it should be used with isolates of M. smegnds attain species status. Mycohacterium smegmatis (197), M. per- and M. chelonae that are resistant to cefoxitin (100, 139, 197). egrinum (91), M. mucogenicum (formerly known as the “M. che- Monitoring of renal function, eighth nerve function, and white loncre-like organisms” or MCLO) (198), and rarely, chromogenic blood cell counts (for the beta lactams) should be done on pa- rapidly growing mycobacteria (199-201) may also occasionally tients receiving this regimen. If organisms are susceptible to be responsible for human disease. oral agents, therapy can be switched to one or more of these Mycohucterium fortuitum, M. ahscessus, and M. chelonae agents. For M. abscessus, the only oral agents available for are resistant to the antituberculous agents, but they are sus- therapy are clofazimine and clarithromycin (140). For M. che- ceptible (especially M. ,fiwtuitum) to a number of traditional lonae, clarithromycin, clofazimine, and (for approximately antibacterial agents (100, 138-141). Isolates of M. fortuitum 20% of strains) ciprofloxacin and doxycycline are the only treatment are susceptible to amikacin (lOO%), ciprofloxacin oral drugs susceptible in vitro (100, 140). The only clinical trial and ofloxacin (lOO%), sulfonamides (100%) cefoxitin (SO%), for M. chelonae skin disease was ddne with clarithromycin. Of imipcncm (lOO%), clarithromycin (80%), and doxycycline patients (all adults) treated with monotherapy at 500 mg twice (50%). Isolates of M. abscessus arc susceptible to clarithromy- a day for 6 mo, all were cured except one patient (8%) who re- tin (loo%), clofazimine, amikacin (90%), and cefoxitin (70%) lapsed with an isolate that developed resistance to clarithro- and imipenem (SO%). Isolates of M. chelonae are susceptible mycin (204). For serious disease, a minimum of 4 mo of ther- to amikacin (SO%), tobramycin (loo%), clarithromycin (loo%), apy is necessary to provide a high likelihood of cure. For bone imipenem (600/o), clofazimine, doxycycline (25%), and cipro- infections, 6 mo of therapy is recommended (202). floxacin (20%). Surgery is generally indicated with extensive disease, ab- scess formation, or where drug therapy is difficult. Removal of Cutaneous Diseases foreign bodies such as breast implants, percutaneous cathe- Clinical disease caused by the rapidly growing mycobacteria ters, etc., is important, or even essential, to recovery. usually follows accidental trauma or surgery in a variety of clinical settings (91). Some minor infections will resolve spon- Pulmonary Disease taneously or after surgical debridement. However, several The prevalence of lung disease caused by rapidly growing my- studies of postinjection abscesses in which no therapy was cobacteria is unknown; however, it is likely more common given revealed disease that persisted in most patients for 8 to than early estimates as these organisms have gained increasing 12 mo before spontaneously resolving. In two outbreaks of recognition as pathogens. The largest group of patients with M. abscessus in the era this lung disease are elderly (older than 60), Caucasian, female nonsmokers with no predisposing conditions or known lung disease. Underlying disorders that are associated with the dis- ease include lung damage produced by prior mycobacterial in- fection (usually tuberculosis or M. avium complex), gastroe- sophageal disorders with chronic vomiting, lipoid pneumonia, cystic fibrosis, and bronchiectasis due to a prior respiratory in- M. fortuitum, M. ubscessus, or M. chelonae, comparing one fection (206). The distinguishing feature of patients with a rec- form of treatment with another or with no drug treatment at ognized underlying disease is that their rapidly growing myco- all, have been performed. However, susceptibility studies bacteria lung disease occurs at a younger age, usually less than (139-141) have demonstrated excellent in vitro activity of 50, and almost all patients under 40 have one of these disor- drugs such as clarithromycin, imipenem, cefoxitin, cefmeta- ders (206). zole, and amikacin. Several case studies (197, 202, 203) and Although early studies identified most respiratory isolates one clinical trial (204) of patients with cutaneous disease of rapidly growing mycobacteria as M. fortuitum, use of mod- treated on the basis of in vitro susceptibilities have shown ern identification schemes have shown that M. abscessus (for- good results. merly M. chelonae subspecies abscessus) accounts for approxi- On the basis of these studies, guidelines have been sug- mately 80% of rapidly growing mycobacterial respiratory disease gested for drug therapy of nonpulmonary disease caused by isolates, while M. fortuitum (formerly M. fortuitum biovariant rapidly growing mycobacteria (205). Because of variable drug fortuitum) accounts for approximately 15% of these isolates susceptibility among species and even within species and sub- (206). An important exception is the small group of patients who groups, susceptibility testing of all clinically significant isolates have gastroesophageal disorders with chronic vomiting and rap- is essential for good patient management. The first-line antitu- idly growing mycobacterial lung disease, in whom M. abscessus berculosis drugs (isoniazid, rifampin, pyrazinamide, etc.) have and M. fortuitum occur with equal frequency. Overall, M. absces- no role in the therapy of rapidly growing mycobacterial dis- sus appears to be a more virulent respiratory pathogen than ease, with the exception of ethambutol, to which M. smegmatis M. fortuitum. Obtaining a single respiratory isolate of M. absces- is susceptible (197). sus is more likely to indicate significant disease than a single For serious disease caused by M. fortuitum and M. absces- isolate of M. ,fortuitum, although careful clinical evaluation and sus, intravenous amikacin is given at a dose of 10 to 15 mg/kg follow-up is always necessary to determine the significance of in two divided doses to adult patients with normal renal func- an NTM respiratory isolate. tion (average 400 mg twice a day) to provide peak serum lev- In lung disease due to rapidly growing mycobacteria in pa- els in the low 20 kg/ml range. The lower dose (10 mg/kg) tients with no apparent risk factors, the chest radiograph usu- American Thoracic Society s17

ally shows multilobar, patchy, reticulonodular or mixed inter- antituberculous agents, and the use of single antibiotic agents. stitial-alveolar infiltrates with an upper lobe predominance. By standard susceptibility testing, these isolates are suscepti- Cavitation occurs in only approximately 15% of cases (206). ble to rifampin and ethambutol, intermediately susceptible to The chest radiograph is usually not typical for or suggestive of streptomycin, and resistant to isoniazid and pyrazinamide. reactivation pulmonary tuberculosis, which likely accounts for Isolates are also susceptible to clarithromycin, sulfonamides, a delay in ordering sputum for AFB analysis and therefore a or trimethoprim-sulfamethoxazole and susceptible or inter- delay in diagnosis. High resolution computed tomography of mediately susceptible to doxycycline and minocycline. the lung frequently shows associated cylindrical bronchiectasis Acceptable treatment regimens in adults include clarithro- and multiple small (< 5 mm) nodules, a pattern also seen in mycin 500 mg twice a day, minocycline or doxycycline at 100 nonsmokers with M. aviunz complex lung disease (65-68). In- mg twice a day (207-209). trimethoprim-sulfamcthoxazole at terestingly, approximately 15% of patients with M. abscessus 160/800 mg twice a day (210) or rifampin (600 mg) plus etham- will also have M. avium complex, suggesting the close rela- butol (15 mg/kg) daily (208, 211) with each regimen being tionship of the disorders (206). Some patients have positive given for at least 3 mo. Rifampin alone has also been recom- sputum cultures for P.se~~rlomonas aeruginosa, further evi- mended, but little experience with this regimen has been re- dence of bronchiectasis. The radiographic features of this dis- ported (212). The rate of clinical response is quite variable, ease in cystic fibrosis are still under investigation. and a minimum of 4 to 6 wk of therapy should be given before The usual presenting symptoms are cough and easy fatiga- considering that the patient may not be responding. Surgical bility, often attributed for months or years to bronchitis or debridement may also be important, especially for disease in- bronchiectasis. Fever, night sweats, and weight loss occur, but volving the closed spaces of the hand or disease that responds they are much less common and less severe than with M. tu- poorly to drug therapy (13, 211). If a lesion is excised surgi- bercuhsis. The constellation of typical presenting symptoms cally, many clinicians provide drug coverage during the perio- in an elderly nonsmoking patient with no underlying lung dis- perative period. It is not clear if longer durations of drug treat- case, a compatible chest radiograph, and multiple positive ment after surgery offer any additional advantage. sputa is sufficient to make a diagnosis. The presence of other diseases or unusual features may necessitate obtaining a lung TREATMENT OF PULMONARY DISEASE DUE TO OTHER biopsy (bronchoscopy with transbronchial biopsy) to be cer- NONTUBERCULOUS MYCOBACTERIA tain of the diagnosis. The natural history of this disease depends primarily on the Although most species of NTM have been reported to cause presence or absence of underlying disorders. For most pa- pulmonary disease, there are only four additional species that tients with M. ahsce.ssu.s and no underlying disorder, the dis- merit consideration. Because of the small number of reported ease is indolent and slowly progressive. Some patients show cases and the absence of therapeutic trials or treatment of dis- little radiographic change over years. More fulminant, rapidly ease caused by these species, only limited recommendations progressive disease can occur, particularly in association with on drug therapy can be made now. In most cases, if there has gastrocsophageal disorders. Death occurs as a consequence of been satisfactory clinical and bacteriologic response to chemo- M. rrhscessu.s in 20% of cases (206). therapy, a treatment period of 18 to 24 mo is recommended. ,Uycohacterium fortuitum isolates, when they do occur, are Mycobacterium malmoense is a slowly growing, nonpig- usually susceptible to multiple oral antimicrobial agents in- mented NTM species that causes pulmonary disease. Although cluding the newer macrolides and quinolones, doxycycline and rare in the United States, it has been increasingly recognized minocycline, and sulfonamides (139-141). Drug susceptibili- in England, Wales, and northern Europe. Most isolates are sus- ties for this species are essential for effective therapy. Six to ceptible to ethambutol, and many are susceptible to rifampin twelve months of therapy with two oral agents to which the and streptomycin, The four-drug regimen recommended for M. fortuitum isolate is susceptible in vitro usually results in treating M. avium complex (before the availability of mac- clinical cure. Unfortunately, the M. fortuitum group produces rolides and rifabutin) has resulted in clinical and bacteriologic less than 20% of lung disease due to rapidly growing mycobac- responses in most cases (70, 213). Potential improvements in teria. therapeutic response with the macrolides and rifabutin has not Mycohcterium uh.sce.ssus isolates are usually susceptible in been assessed. vitro only to the parenteral agents amikacin, cefoxitin, and im- Mycobacterium simiae is a slowly growing, nonpigmented ipenem, and to the newer oral macrolides (clarithromycin and Mycobacterium that may be confused with M. tuberculosis, as azithromycin). Preliminary studies suggest that monotherapy it is the only NTM that is niacin-positive. It is an uncommon with the newer macrolides is not sufficient to produce micro- cause of pulmonary and disseminated infection, and many pa- biologic cure for M. abscessus. Combination therapy of low- tients with respiratory isolates of this species do not have dis- dose amikacin plus high-dose cefoxitin for 2-4 wk almost in- ease. Most isolates are resistant to all first-line antimycobacte- variably produces clinical and microbiologic improvement, rial drugs, and response to chemotherapy has been variable but cost and morbidity prohibit potentially curative courses of (32, 214). For patients with disseminated or progressive pul- treatment (probably 4-6 mo). Surgical resection for limited monary disease in need of treatment, initial therapy may be disease related to prior localized lung disease can also be cura- started with the four-drug regimen recommended for M. avium tive (206). Unfortunately, suppressive therapy, including peri- complex (clarithromycin, ethambutol, rifabutin, and strepto- odic parenteral antibiotic or oral macrolide therapy, may be mycin), modified as needed using results of susceptibility tests. all that can bc realistically administered to control the symp- Mycobacterium szulgai is a slowly growing Mycobacterium toms and progression of M. abscessus lung disease. that has been associated with skin, joint, lymphatic, pulmo- nary, and disseminated disease (135). When isolated from hu- mans, it should be considered pathogenic. Through 1986, only TREATMENT OF Mycobacterium marinum DISEASE 24 cases of disease had been reported in the English literature. A number of treatment modalities have been used for cutane- The organism is usually susceptible to rifampin and higher ous disease caused by M. marinum (69, 13). These include sim- concentrations of isoniazid, streptomycin, and ethambutol. ple observation for minor lesions, surgical excision, the use of Enhanced activity of rifampin, ethambutol, and streptomycin 518 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

TABLE 5 COMMON SIDE EFFECTS AND TOXICITIES OF DRUGS USED FOR THERAPY OR PROPHYLAXIS OF NONTUBERCULOUS MYCOBACTERIAL DISEASE

Drug Major Side Effects/Toxicity Monitoring Procedures

lsonrazid Hypersensitivity (fever, rash) Clinical symptoms Hepatitis Clinical symptoms; periodic alanine aminotransferase (ALT) or aspartate aminotransferase (AST) determinations, especially in first 3 mo of therapy Increased serum levels of Monitor serum levels phenytoin (DilantinTM) Peripheral neuropathy related Clinical symptoms to pyridoxine deficiency Ethambutol Optic neuritis (loss of red/green Discontinue drug immediately with color discrimination, loss of subjective visual loss; periodic and visual acuity) symptomatic testing for red/green color discrimination and visual acuity (monthly if receiving 25 mg/kg per day); ophthalmology evalution for symptomatic patients Rifampin, Orange discoloration of None rifabutin secretions and urine; staining of soft contact lenses Gastrointestinal disturbance Clinical symptoms (nausea, vomiting) Hypersensitivity (fever, rash) Clinical symptoms Hepatitis Clinical symptoms; AST or ALT determinations based on symptoms Increased hepatic metabolism Monitor clinical status and appropriate of numerous agents, including serum levels when possible birth control pills, ketoconarole, quinidine, prednisone, oral hypoglycemics (sulfonylureas), digitalis, methadone, warfarin, clarithromycin, and protease inhibitors “Flu-like” syndrome, Clinical symptoms; platelet count, serum thrombocytopenia, renal failure creatinine as indicated Rifabutin only Polymyalgia, polyarthralgia, Clinical symptoms, periodic WBC counts leukopenia, granulocytopenia, anterior uveitis (rifabutin with clarithromycin) Streptomycin Vestibular/auditory toxicity Clinical symptoms including changes amikacin, (dizziness, vertigo, ataxia, in hearing, ability to walk, dizziness; tobramycin tinnitus, hearing loss) periodic hearing tests in high-risk patients or those with auditory/ vestibular symptoms; periodic amikacin serum levels Renal toxicity Periodic serum creatinines; periodic amikacin or tobramycin serum levels Hypersensitivity (fever, rash, Clinical symptoms eosinophilia) (streptomycin) Ethionamide Gastrointestinal disturbance Clinical symptoms (anorexia, nausea, vomiting, abdominal pain, diarrhea) Hepatitis Clinical symptoms; periodic AST or ALT determinations Central nervous system (anxiety, Clinical symptoms depression, altered behavior) Cycloserine Peripheral neuropathy Clinical symptoms Central nervous system Clinical symptoms, assessment of (depression, altered behavior, mental status; serum levels confusion, anxiety, psychosis, weekly for first month if timely seizures) testing available Azithromycin, Gastrointestinal disturbance Clinical symptoms clarithromycin (nausea, vomiting, diarrhea) Decreased hearing Clinical symptoms Hepatitis Periodic alkaline phosphatase, AST and gamma glutamyl transpeptidase (GCT) for first 3 mo Clarithromycin only Inhibited hepatic metabolism of Monitor clinical status and several agents, including appropriate serum levels when rifabutin, some protease possible; avoid use of Seldane inhibitors, SeldaneTM

(continued) American Thoracic Society s19

TABLE 5 CONTINUED

Drug Major Side Effects/Toxicity Monitoring Procedures

Ciprofloxacin Gastrointestinal disturbance Clinical symptoms ofloxacin (nausea, vomiting, diarrhea) Central nervous system Clinical symptoms (headache, insomnia) Cefoxitln Hypersensitivity (fever, rash, Clinical symptoms eosinophilia) Hematologic (anemia, leukopenia) Periodic blood counts Tetracyclines Gastrointestinal disturbance Clinical symptoms (doxycycline, (nausea, vomiting, diarrhea) minocycline) Cutaneous (photosensitivity, rash, Clinical symptoms hyperpigmentation) Central nervous system Clinical symptoms (dizziness, vertigo) (minocycline) Sulfonamides, Gastrointestinal disturbance Clinical symptoms trimethoprim/ (nausea, vomiting, diarrhea) sulfamethoxazole Hematologic (leukopenia, anemia, Periodic blood counts thrombocytopenia) Hypersensitivity (fever, rash, Clinical symptoms Stevens-Johnson syndrome)

when used in combination has been shown in vitro (215). Most For the aminoglycosides, this monitoring should include patients treated with these drugs respond to therapy. routine questioning about balance, ability to walk (especially Relatively uncommon in the United States, M. xerzopi has in the dark), tinnitus, dizziness, and difficulty hearing. Base- been reported as a common cause of slowly progressive NTM line blood urea nitrogen and creatinine measurements should pulmonary disease in western Europe. In southeast England, be obtained, with reduction of the streptomycin dose and/or it is the most common NTM recovered in the laboratory and frequency of administration if these are abnormal. Periodic has been since 1977 (216). Disseminated disease and joint dis- monitoring of renal function is recommended for high-risk pa- ease caused by this organism have also been reported. In vitro tients receiving drugs daily or five times a week, especially susceptibility to antituberculosis agents is variable, although with patients older than 50 yr or who have impairment of re- enhanced drug activity has been shown with the combination nal function. A baseline hearing test should be considered, es- of rifampin and streptomycin (215). Although some investiga- pecially in high-risk patients, and then repeated if signs or tors have reported success with surgical therapy similar to that symptoms of seventh nerve toxicity appear. used for selected patients with M. avium complex disease, oth- For cycloserine, careful attention should be given to signs ers have had disappointing results (136, 173). Results with of central nervous system toxicity, which may include seizures, drug therapy alone in the premacrolide era have also shown lethargy, depression, alterations in personality, and even sui- variable results. One recent study of clarithromycin-contain- cidal ideations. Because toxicity with this drug relates prima- ing regimens (137) demonstrated an excellent sputum conver- rily to excessive serum levels (> 40 pg/ml), patients with cen- sion rate compared to these older studies. For most patients, tral nervous system symptoms or abnormal baseline renal initial therapy should consist of a macrolide, rifampin or rifab- function should have serum level determinations. Unfortu- utin, and ethambutol with or without initial streptomycin. Pa- nately, such tests are not available in most clinics and are tients who fail therapy or who relapse after treatment might rarely available in a timely fashion to help with decisions on be considered for surgery (30,136,173). dosing. If serum levels are not available, physicians should re- member that the drug is excreted by the kidney, and high se- rum levels tend to occur in the elderly or in the presence of re- MONITORING FOR DRUG TOXICITY nal failure. A lower dose (e.g., 250 mg twice a day) is often Monitoring for drug toxicity of patients who are being treated given in such cases, and discontinuation of the drug may be for NTM disease is important, given the number and type of necessary if central nervous system symptoms occur and one drugs used and the older age of these patients. It should in- cannot monitor serum levels. clude monitoring of the visual system including visual acuity Given that isoniazid hepatotoxicity is higher in the older (ethambutol), the presence of eye pain and decreased visual population, some physicians obtain a baseline measurement of acuity or uveitis (rifabutin) (175,176), and red-green color dis- aspartate aminotransferase (AST), then repeat this determi- crimination (ethambutol): the central nervous system (cyclo- nation at 2,4, and 8 wk and thereafter during therapy as clini- serine, ciprofloxacin, ofloxacin, ethionamide); the liver (iso- cally indicated. Other monitoring considerations are the same niazid, rifampin, ethionamide, clarithromycin, rifabutin) (174, as those for patients with tuberculosis (see the ATS Statement 176); the kidney (streptomycin, amikacin); auditory and vesti- “Treatment of Tuberculosis and Tuberculosis Infections in bular function (streptomycin, amikacin, azithromycin); and Children and Adults” (2,217). hematologic indices (sulfonamides, cefoxitin, rifabutin) (176). The incidence of gastrointestinal side effects such as nau- Major side effects and monitoring procedures are listed in sea, vomiting, abdominal pain, and cramping is almost prohib- Table 5. itive with ethionamide. These symptoms can be minimized by 520 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

starting with a 250 mg single dose, slowly increasing the dose, 1053. and administering it with food. In the older patient, limiting Il. Guerrero, C.. C. Bernasconi, D. Burki, T. Bodmer. and A. Telenti. the total dose to 500 mg may help reduce toxicity. A good re- 1995. A novel insertion element from Myc~obacreriwrr wirrm. lS124.5. is a specific target for analysis of strain relatedness. ./. C/in. Muo- view of side effects and toxicities experienced at the National bid. 33:304-307. Jewish Hospital with ethionamide and cycloserine is provided 12. von Reyn. C. F.. J. N. Maslow. T. W. Barber. J. 0. Falkinham. III, and in a study by Lester (218). R. D. Arbeit. 1994. Persistent colonization of potable waler as a Some advcrsc events with rifabutin are comparable to source of Mycobacrrrirrm nvium infection in AIDS. /,crrrcc/ 343: I 137- those seen with rifampin. These include rash, fever, nausea, 1141. vomiting, and hepatitis. Several adverse events are unique to 13. Collins, C. H., J. M. Grange. W. C. Noble, and M. D. Yates. IYXS. My- cohacrerium marinfrm infections in man. ./. //yg. (‘trrrlh. Y4: 135-149. rifabutin. including anterior uveitis, skin hyperpigmentation 14. Steadman, J. E. 1980. High-catalase strains of Mvc.,,boc,/eriltnr krrmusii or pseudojaundice, and a polymyalgia/polyarthralgia syndrome isolated from water in Texas. ./. C/in. Microbid. 1 I :406-W. (175, 176). The last three adverse events are seen almost ex- 15. McSwiggan, D. A., and C. H. Collins. lY74. The isolation of M. krrnsasii clusively in patients concurrently receiving clarithromycin. and M. xenopi from water systems. 7’uhrrck. S5:2Y I-297. These effects can be minimized by giving no more than 300 16. Hoffman, P. C., D. W. Fraser. F. Rohicsek. P. R. O’Bar. and C. U. mg/d of rifabutin when combined with clarithromycin. Leuko- Mauney. 1981. Two outbreaks of sternal wound infeeclions due to or- ganisms of the Mycohucrerium fortrrimm complex. J. Inkcr. Dis. 143: penia is also seen with rifampin, but it is much more common 533-542. with rifabutin. Periodic white blood cell counts should be per- 17. Szabo, I. 1980. Mycobocrerium chrlonei cndemy after heart surgery formed on all patients taking rifabutin, perhaps at monthly in- with fatal consequences. Am. Rev. Respir. Die. 121:607. tervals. Mild Icukopenia is common (8 of 26 or 31% of pa- IX. Lowry, P. W., W. R. Jarvis, A. D. Ohcrle. L. A. Bland. R. Silherman, tients in one series of HIV-negative patients on 600 mg/d J. A. Bocchini. Jr., H. D. Dean, J. M. Swenson. and R. J. Wallace. Jr. developed WBC counts below 4,000 cells/mm”) (176), and the 1988. Mycobacterirtm che/onue causing otiti‘; media in an ear-nosc- and-throat practice. N. Engl. J. Md. 3 I Y:Y7%YX2. drug should be discontinued only if cell counts fall below a 19. Maloney, S., S. Welhel, B. Daves, K. Adams, S. Becker. L. Bland, M. comfortable range (perhaps 2,500 cells/mm’ or an absolute Arduino. R. J. Wallace. Jr., Y. Zhang. G. Buck, P. Risch. and W. granulocyte count of 1,SOO or less in HIV-negative patients). Jarvis. 1994. Mycobucfrrium ubscrsstcs pscudoinfcction traced lo an automated endoscope washer: utility of epidemiologic and labora- This statement was prepared by an ad hoc committee of the tory investigation. J. Infect. /Ii.\. 169:1166-I 160. Scientific Assembly on Microbiology, Tuberculosis, and Pul- 20. Laussucq, S., A. L. Baltch. R. P. Smith. R. W. Smilhwick. B. J. Davis, E. K. Desjardin, V. A. Silcox, A. B. Spellacy, R. 7‘. Zeimis. 11. M. monary Infections. Members of the committee were: Gruft, R. C. Good, and M. L. Cohen. 1YXX. Nosocomial Mvwbnctr- rium fortuirum colonization from a contaminated ice machine. Am. RICIIARD J. WALLACE, JR., M.D., Chairman Rev. Respir. Di.c. 13X:X9 l-X04. JI:FFREY GI.AssRorH, M.D. 21. Kuritsky, J. N.. M. Bullen. C. V. Broome, V. Silcox. R. Good. R. J. Wal- DAVID E. GRIPFITH, M.D. lace, Jr. 1983. 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