AMERICAN JOURNAL OF

Respiratory andCritical Care Medicine

August 1997 Volume 156, Number 2, Part 2

Supplement:

American Thoracic Society

Diagnosis and Treatment of Disease

Caused by Nontuberculous MycobacteriaScientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections,

American Thoracic Society

CONTENTSAugust 1997 Volume 156 Number 2 Part 2

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

Summaries

Introduction

Epidemiology and Pathogenesis

Clinical Presentation and Diagnostic Criteria

Laboratory Methods

Treatment of Mycohacterium kansasii Disease

Treatment of Pulmonary Mycobacterium avium Complex Disease

Treatment of Localized Extrapulmonary Mycobacterium avium Complex Disease

Treatment of Disseminated Mycobacterium uvium Disease

Prophylaxis of Disseminated Mycobucterium avium Disease in AIDS

Treatment of Rapidly Growing Mycobacterial Disease

Treatment of Mycobucterium murinum Disease

Treatment of Pulmonary Disease due to Other Nontuberculous Mycobacteria

Monitoring for Drug Toxicity

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American Thoracic SocietvMEDICAL SECTION OF THE AMERICAN LUNG ASSOCIATION

Diagnosis and Treatment of Disease Caused byNontuberculous Mycobacteria

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

SUMMARY

Diagnostic Criteria of Nontuberculous Mycobacterial LungDisease in HIV-Seropositive and -Seronegative Hosts

The following criteria apply to symptomatic patients with in-filtrate, nodular or cavitary disease, or a high resolution com-puted tomography scan that shows multifocal bronchiectasisand/or multiple small nodules.

A. If three sputum/bronchial wash results are available fromthe previous 12 mo:1. three positive cultures with negative AFB smear results

or2. two positive cultures and one positive AFB smear

B. If only one bronchial wash is available:1. positive culture with a 2+, 3+, or 4-t AFB smear or 2+,

3+, or 4+ growth on solid media

C. If sputum/bronchial wash evaluations are nondiagnostic oranother disease cannot be excluded:1. transbronchial or lung biopsy yielding a NTM

or2. biopsy showing mycobacterial histopathologic features

(granulomatous inflammation and/or AFB) and one ormore sputums or bronchial washings are positive for anNTM even in low numbers

Comments:

These criteria fit best with M. avium complex, A4. ahscessus,and M. kansasii. Too little is known of other NTM to be cer-tain how applicable these criteria will be.

At least three respiratory samples should be evaluatedfrom each patient. Other reasonable causes for the diseaseshould be excluded. Expert consultation should be soughtwhen diagnostic difficulties are encountered.

KEY LABORATORY FEATURES OF THENONTUBERCULOUS MYCOBACTERIA

1. Staining und culture. Current methods of specimen stainingand culture used for M. tuberculosis are acceptable formost NTM species. The preferred methodology includesfluorochrome staining and culture in a liquid medium aswell as on Middlebrook 7HlO or 7Hll agar. Species forwhich special growth conditions are needed include thoseresponsible for cutaneous disease, which need lower incu-bation temperatures, and the relatively fastidious speciesM. haemophilum, M. genavense, and M. conspicuum.

2. Species identification. Methods of rapid species identifica-

Am ) Respir Crit Care Med Vol. 156. pp. 51-525, 1997

tion including commercial DNA probes (M. oviurn com-plex, M. kansusii, M. gordonae) and high-pressure liquidchromatography are preferred over the slower traditionalbiochemical methods.Susceptibility testing of M. avium complex. Susceptibilitytesting with rifabutin and the antituberculosis drugs is notrecommended. Routine testing against clarithromycin shouldnot be performed, but that test should be performed on iso-lates from patients who have failed prior macrolide therapyor prophylaxis. Minimal inhibitory concentration (MIC) of> 32 pg/ml is the recommended resistance breakpoint.Susceptibility testing of M. kansasii. Routine susceptibilitytesting of M. kansasii should include only rifampin, becausecurrently used resistance breakpoints for isoniazid andstreptomycin often give misleading results and methods forthe other drugs have not been established.Susceptibility testing of the rapid growers. Susceptibility test-ing of clinically significant rapidly growing mycobacteria(M. fortuitum, M. abscessus, M. chelonae) should not beperformed with the antituberculosis agents. They should betested against antibacterial drugs including amikacin, doxy-cycline, imipenem, the fluorinated quinolones, a sulfona-mide, cefoxitin, and clarithromycin.

PROPHYLAXIS AND TREATMENT OFNONTUBERCULOUS MYCOBACTERIA DISEASE

Treatment of M. kansasii pulmonury disease. A regimen ofdaily isoniazid (300 mg), rifampin (600 mg), and ethambu-to1 (25 mg/kg for 2 mo, then 15 mg/kg) for 18 mo with aminimum of 12 mo culture negativity is recommended forpulmonary disease in adults caused by M. kansasii. Clar-ithromycin or rifabutin will need to be substituted forrifampin in HIV-positive patients who take protcase inhib-itors.Treatment of M. avium complex pulmonary diseuse. A regi-men of daily clarithromycin (500 mg twice a day) or azithro-mycin (2.50 mg), rifampin (600 mg) or rifabutin (300 mg),and ethambutol (25 mg/kg for 2 mo, then 15 mg/kg) is rec-ommended for therapy of adults not infected with the HIVvirus. Streptomycin two to three times per week should beconsidered for the first 8 wk as tolerated. Patients shouldbe treated until culture-negative on therapy for 1 yr.Treatment of disseminated M. avium complex disease. Ther-apy in adults should include daily clarithromycin (500 mgtwice a day) or azithromycin (250 to 500 mg), plus ethamb-utol 15 mg/kg per day. Consideration should be given tothe addition of a third drug (preferably rifabutin at a doseof 300 mg/d). Therapy should be continued for life untilmore data becomes available.

3.L AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

4. Prophyluxis of disseminuted M. avium complex diseuse.Prophylaxis should be given to adults with AIDS with CD4counts < SO cells, especially with a history of a prior oppor-tunistic infection. Rifabutin 300 m&d, clarithromycin 500mg twice daily, azithromycin 1,200 mg once weekly, andazithromycin 1,200 mg once weekly plus rifabutin 300 mgdaily arc all proven effective regimens.

5. Treutrnent of nontuherculous mycohacteria cervical lym-phadenitis. Nontuberculous mycobacteria cervical lym-phadenitis is still treated primarily by surgical excisionalone, with a 95% cure rate. A clarithromycin-containingregimen should be considered for patients with extensivedisease or a poor response to surgery.

6. Treatment ofnonpulmonary rupidly growing mycohacteria.Therapy of nonpulmonary disease caused by M. fortuitum,M. uh,scessus, and M. chelonae should include drugs such asamikacin and clarithromycin, based on in vitro susceptibil-ity tests.

INTRODUCTION

The continued growth in the number and prevalence of myco-bacteria species other than the Mycohacterium tuberculosiscomplex, and recent advances in diagnostic methods and drugtherapies for disease caused by these agents, has prompted usto put forth this second, updated diagnostic and therapeuticstandard that deals exclusively with the nontuberculous myco-bacteria. As in the first statement (1) we refer to these myco-bacterial species collectively as the nontuberculous mycobac-teria (NTM). The principles of therapy and diagnosis ofdisease caused by M. tuberculosis have been dealt with sepa-rately and appear in two ATS statements published most re-cently in IYYO and 1994 (2, 3). Like the previous NTM state-ment published in 1990 (l), this statement is designed as abasic guide for professionals involved in the diagnosis andmanagement of disease caused by NTM. Although not all-inclusive, the areas of discussion are referenced in enough de-tail to allow the reader to assess the scientific basis for ideasand recommendations that are put forth. Included within thisstatement are revised recommendations for diagnostic criteriathat apply primarily to the NTM and updated recommenda-tions of specific therapeutic drug regimens for disease causedby M. avium complex and other species of NTM, recognizingthe major impact of the newer macrolides and rifabutin, whichhave become available since 1990. Unless otherwise stated,these drug dosages arc for adults. Pediatric doses are de-scribed where available.

EPIDEMIOLOGY AND PATHOCENESIS

Sources of Infection

Most NTM organisms have been isolated from water and soil(4-6). The best studied of these has been M. avium complex.Extensive environmental studies in the United States haveshown that M. avium complex grows well in natural waters,particularly in the Southeast (7). Mycubacterium &urn com-plex strains with plasmids, possibly associated with virulence,have been shown to be prcfcrentially aerosolized, providing apossible mechanism for airborne acquisition of these organ-isms (8). Although M. avium is an important cause of diseasein poultry and swine, serologic studies have suggested that an-imal-to-human transmission is not important in human infec-tion (Y), and recent molecular studies involving IS9OI-IS902and IS1245 have shown that strains infecting humans and ani-mals (especially swine) are different (10, 11). It is now gener-ally accepted that environmental sources, especially naturalwaters, are the reservoir for most human infections caused by

M. avium complex. The reservoir of M. &urn for most pa-tients with disseminated disease has not been identified, but itis assumed to be the same as or similar to that for patients withnon-HIV-related M. avium complex lung disease. Mycobacte-rium avium complex is present in tap water, and one study ofdisseminated M. avium complex disease in AIDS demon-strated that some cases are likely acquired from hospital tapwater (12). Interestingly, there does not appear to be a geo-graphic predilection with disseminated disease in the UnitedStates, as there is with skin test reactivity and with chroniclung disease.

Water is also the likely source of infection for numerousother NTM species including M. marinum, M. kansasii, noso-comial outbreaks or pseudo-outbreaks due to rapidly growingmycobacteria, M. xenopi, and M. simiae. Mycohucteriutn mari-num has been commonly associated with salt water, fresh wa-ter, fish tanks, and swimming pools (13). Mycohucterium kan-susii has not been recovered from soil or natural water supplies(5). It has been isolated repeatedly, however, from tap water(14, 15) in the same communities where M. kansasii diseaseexists. Interestingly, it has been shown to survive up to 12 moin tap water but not in soil

Rapidly growing mycobacteria such as M. ,fortuitum, M. che-lonae, and M. abscessus can be recovered from soil and natu-ral water supplies, and are the most common NTM associatedwith nosocomial disease (16-24). Investigations of nosocomialoutbreaks or pseudo-outbreaks caused by these species in-cluding the use of DNA fingerprinting with pulsed-field gelelectrophoresis (2.5,26) have demonstrated that tap water (18,19) ice prepared from tap water (20.2 l), processed tap waterused for dialysis (22) and distilled water used for preparingsolutions such as gentian violet (23,24) are the usual nosoco-mial sources of the organisms.

Mycohacterium xenopi is an obligate thermophile that re-quires temperatures of 28” C or above to grow (4). It has beenrecovered almost exclusively from hot water and hot watertaps within hospitals (15,27-29) where it has been associatedwith multiple positive (i.e., probably contaminated) clinicalsamples and a few cases of clinical pulmonary and soft tissuedisease (28-30). These clusters of hospital isolates have beenreported from the United States, the United Kingdom, andother areas in Europe. In two studies, the clinical isolates andhospital water isolates have been shown to be identical byDNA fingerprinting (28, 29). It has been speculated that theorganism enters the hospital from municipal water mains, thenmultiplies in the hospital heating tanks where the temperatureis 43-45” C, the optimal temperature for growth of this organ-ism (30).

Reports of recovery of M. simiae from clinical specimenshave been clustered in three geographic areas: Israel (31).Cuba, and the southwestern United States-Texas. Arizona,and New Mexico (32-34). Most recoveries have been singlepositive specimens that are smear-negative (32,33) and not as-sociated with clinical disease (33) suggesting environmentalcontamination as a likely source. For several clusters of iso-lates, organisms were also recovered from the local tap water(34, M. Yakrus, personal communication, 35) suggesting it asthe likely organism source.

Mycobacterium mulmoense, which has emerged as a majorNTM pathogen in northern Europe. has been recovered fromnatural waters in Finland (36) and soils in Zaire (37) and Ja-pan (38). The recently recognized pathogen M. genuvense hasnot been recovered from soil or water, but it has been recov-ered from a dog and a variety of pet birds including psittacinebirds (39, 40). Mycobucterium ulceruns disease occurs in dis-crete but widely dispersed geographic areas in the watersheds

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of tropical rain forests, primarily in Africa, Southeast Asia,Australia, and South and Central America (35).

Much less is known about the environmental epidemiologyand sources of infection for the other NTM. A number ofNTM species have yet to be recovered from the environment,including M. ulceruns, M. haemophilum, M. szulgai, M. cela-turn, M. genavense, and M. conspicuum. Despite this, environ-mental sources of infection are highly likely. Good reviews ofenvironmental studies have been provided by Wolinsky andRynearson (S), Portaels (35), and Falkinham (41).

Much remains to be understood about the pathogenesis ofNTM infection and disease in humans. Epidemiologic studies,skin test surveys, and more recently DNA fingerprinting stud-ies suggest that person-to-person transmission of infection israre. It is assumed that most persons are infected by environ-mental NTM. Of the likely sources of infection, airborneNTM may play an important role in respiratory disease,whereas ingestion may be the source of infection for childrenwith NTM cervical lymphadenitis and for most patients withAIDS whose disseminated M. avium or M. genavense beginsas gastrointestinal colonization. Bacteremic spread of the or-ganism in patients with AIDS then involves multiple organsystems, including bone marrow, lymph nodes, liver, andspleen. Direct inoculation with NTM organisms from water orother material is likely the source of infection for patients withsoft tissue infections. It is not known whether NTM disease(especially pulmonary disease) develops soon after infectionor, like tuberculosis, develops after a period of latency.

Prevalence in Humans

Although first observed soon after Koch’s discovery of the tu-bercle bacillus, NTM were not widely recognized as humanpathogens until the lYSOs, when several large series of patientswith NTM lung disease were reported (42-44). These patientswere epidemiologically distinct from patients with tuberculo-sis, being older, more commonly white, and quite often havingunderlying chronic lung disease such as bronchiectasis, silico-sis, and healed tuberculosis. Positive reactions of 10 mm ormore to purified protein derivative (PPD) tuberculin were lesscommon than among tuberculous patients, and family con-tacts tended to be tuberculin-negative.

As reports of patients with NTM disease increased, it be-came apparent there was marked geographic variability bothin the prevalence of disease and in the mycobacterial speciesresponsible for disease. Most patients in the southeasternUnited States with NTM lung disease were from rural areasand had isolates of M. avium complex, whereas those in thecentral United States more commonly had disease caused byM. kansusii (45).

In addition, patients with NTM disease tended to reactmore strongly to skin test antigens prepared from the infectingmycobacterial species than to standard PPD-S or PPD-T, anti-gens prepared from M. tuberculosis (46). Skin test surveys us-ing NTM antigens suggested that infection by NTM was com-mon, especially in rural areas and in the Southeast (47).

NTM disease is not reportable in the United States, and re-liable estimates of its incidence or prevalence have been lim-ited. Two national surveys in the early 1980s were the first totry to define the extent of NTM infection in the United States.The initial study, based on state laboratory reports from 1979-1980, indicated that NTM comprised approximately one-thirdof the 32,000 mycobacterial isolates (48). Of these, 61% wereM. avium complex, 19% were M. fortuitum complex, and 10%were M. kansasii.

A second surveillance study based on reports from tuber-culosis control officers on isolates of NTM recovered between

1981 and 1983 showed higher rates of NTM disease amongnonwhites, women, and patients residing in urban areas whencompared with the initial study. White males, however, con-tinued to serve as the major diseased population (49). Usingcombinations of national surveillance data, the prevalence ofNTM (pulmonary) disease at that time was estimated to be 1.8cases per 100,000 population for the entire United States. Ofthis, M. avium complex represented 1. I/l 00,000.

A more recent Centers for Disease Control (CDC) studyfrom 1991 to 1992 (50) that included results from 33 state lab-oratories demonstrated a dramatic change in the prevalenceof NTM. Despite the increases in isolates of M. tuberculosisnoted in the United States since 1985, there were now moreisolates of M. avium complex than M. tuberculosis, with thelatter representing only 26% of the total mycobacterial iso-lates. The reasons for this dramatic increase in numbers forNTM is unknown, but better clinical recognition and moreculturing for both pulmonary and disseminated disease arefelt to play important roles.

One category of people with NTM disease not representedin the two earliest studies but almost certainly represented inthe 1993 study were patients with AIDS and disseminatedNTM disease, HIV-infected patients were at especially highrisk of disease due to NTM. The majority of disease in thispopulation (> 95%) is due to M. avium (51). DisseminatedM. avium infection is the most common bacterial infection inpatients with AIDS, occurring in 20 to 40% of all patients inseveral reported series (52-55). Disease in these patients ishighly correlated with severe immunosuppression. with theaverage CD4 cell count at the time of dissemination in the 25to 30 range (53-55). Patients with < 100 CD4 cells, not receiv-ing prophylaxis, develop disseminated M. avium at the rate ofapproximately 20% per year (53). The overall incidence ofM. avium as an initial diagnosis has increased among AIDSpatients while other complications of AIDS, such as Pneumocys-tis pneumonia, have decreased (56). Disseminated M. uviumoccurs in similar rates in all geographic regions and variousHIV risk groups (57). Localized pulmonary disease in AIDSdue to M. avium occurs in less than 5% of patients (58).

Other NTM species, including M. kansasii (51, 5Y-61),M. scrofulaceum (Sl), M. gordonae (51), M. huemophilum (60,61), M. genavense (39), M. celatum (62), M. conspicuum (63),M. xenopi (64), M. fortuitum (51, 65), M. marinum (66),M. malmoense (67), and M. simiae (68) have also been de-scribed as a cause of pulmonary and/or disseminated NTMdisease in AIDS. Some of these, especially M. haemophilum,M. kansasii, and M. genavense, have occurred in localized geo-graphic areas. More than 95% of cases of disseminated dis-ease, however, are due to isolates of M. avium (51).

CLINICAL PRESENTATION AND DIAGNOSTIC CRITERIA

Pulmonary Disease

Chronic pulmonary disease is the most common localized clin-ical manifestation of NTM (41, 69). Mycohacterium aviumcomplex, followed by M. kansasii, is the most frequent patho-gen causing lung disease in the United States. Other pathogensoccasionally causing pulmonary disease include M. abscessus,M. fortuitum, M. szulgai, M. simiae, M xenopi, M. malmoense,M. celatum, M. asiaticum, and M. shimodii. Mycobacteriumxenopi is second to M. avium complex as a cause of NTM lungdisease in areas of Canada, the United Kingdom, and other ar-eas of Europe, while M. malmoense is second to M. aviumcomplex in Scandinavia and areas of northern Europe (70).The patients with chronic lung disease due to NTM are gener-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). Althoughsome NTM patients have a history of underlying chronic lungdisease, not all do. The interpretation of NTM in the sputumof HIV-positive patients presents a particular problem, asthese patients are frequently infected with NTM without evi-dence of pulmonary disease. Such infection may be transient,but it may also reflect disseminated NTM disease or subclini-cal NTM pulmonary disease. In addition, some NTM speciesthat are generally considered nonpathogenic have been asso-ciated with pulmonary disease in the HIV-infected host.

Signs and symptoms of NTM pulmonary disease are vari-able and nonspecific. They include chronic cough, sputumproduction, and fatigue. Less commonly, malaise, dyspnea, fe-ver, hemoptysis, and weight loss can also occur, usually withadvanced NTM disease. Evaluation is often complicated bythe symptoms caused by co-existing lung diseases. These con-ditions include chronic obstructive airway disease associatedwith smoking, bronchiectasis, previous mycobacterial diseases,cystic fibrosis, and pneumoconiosis.

There are some differences in the radiographic features ofNTM lung disease compared with those produced by M. tuber-culosis with regard to conventional radiographic studies. Non-tuberculous mycobacteria tend to cause thin-walled cavitieswith less surrounding parenchymal infiltrate, have less bron-chogenic but more contiguous spread of disease, and producemore marked involvement of pleura over the involved areasof the lungs. Occasionally, they may produce dense pneu-monic disease or a solitary pulmonary nodule without cavita-tion. Basal pleural disease is not often found, and pleura1 effu-sion is rare. Recent studies with high-resolution computedtomography (HRCT) of the chest have shown that up to 90%of patients with mid and lower lung field noncavitary diseasewith M. nvi~n complex have associated multifocal bronchiecta-sis, with many patients having clusters of small (< 5 mm) nod-ules in associated areas of the lung (71-74).

There has been a great deal of interest in the availability ofspecies-specific skin test antigens. Unfortunately, many anti-gens are shared by different mycobacterial species for whichthere are previously tested NTM skin test antigen prepara-tions, and extensive cross-reactions were observed with PPDs.However, recent studies provide hope for increased specificityof a preparation for M. rrviltrrz complex testing, although it isnot yet FDA approved (75). Specific skin test reagents forother NTM infections are not standardized and are neitheravailable nor undergoing clinical trials at this time.

In the absence of specific diagnostic features in the historyand physical examination, the chest roentgenogram, and dif-ferential skin testing, isolation of the NTM in a culture is es-sential for diagnosis. However, as these organisms are com-monly found in nature, contamination of culture material ortransient infection does occur. Thus, a single positive sputumculture, especially with small numbers of organisms, does notalways suffice to diagnose NTM disease. Some previous au-thors suggested that the respiratory tract may be infected withthe organism without disease, particularly in patients withchronic respiratory disease (48, 49, 69). This condition was of-ten referred to as “colonization,” and was described most oftenwith M. avium complex. It was characterized by the presenceof noncavitary, stable and usually minimal radiographic dis-ease in women, and was associated with sporadic excretion oforganisms from the respiratory tract. No pathologic studieswere done to demonstrate the absence of tissue invasion, andmore recent studies with HRCT have shown that these pa-tients often have a combination of multifocal bronchiectasisand nodular parenchymal disease (71-74) with the latter orboth now felt to be due to mycobacterial disease. “Coloniza-

tion” in the true sense (i.e., no tissue invasion) is probablyquite rare. In addition, not all patients with this disease have abenign prognosis, a point first emphasized by Prince and col-leagues in a landmark 1989 paper (76).

Given these observations, the diagnosis of lung diseasecaused by NTM is usually not difficult if a combination of clin-ical, radiographic, and bacteriologic criteria are used. AFBsmear, culture results, and clinical status suggest a close corre-lation among the three. Minimal evaluation should includethree or more sputums for AFB and efforts to exclude otherconfounding disorders such as tuberculosis and lung malig-nancy. In most patients, a diagnosis can be made without alung biopsy. Although criteria are based on experience withM. avium complex, there is no reason to believe these criteriawould not be applicable to other species. The diagnostic crite-ria are presented in Table 1.

Clinical studies have established the validity of bronchialwashings as a culture source for M. tuberculosis. Althoughsimilar studies have not been done for NTM, bronchial wash-ings are considered to be more sensitive than routine expecto-rated sputums; however, their relative specificity for clinicaldisease is unknown. Approximately 90% of patients with dis-ease caused by M. kansusii and most patients with diseasecaused by M. avium complex have cavitary infiltrates (77) andcan be readily identified. Among patients without cavities, thepresence of clinical symptoms and HRCT abnormalities areimportant adjuncts to defining the presence of NTM disease.Bacteriologic criteria have been best analyzed with cavitarydisease for M. avium complex and M. kunsusii, and the HRCTabnormalities, with M. avium complex. Although these arereasonable criteria for diagnosing other NTM, their use withother species has not been studied in detail.

In the patient with nondiagnostic cultures and radiographicstudies, or concern about the presence of another disease pro-ducing radiographic abnormalities, a lung biopsy is often re-quired for diagnosis. If a tissue sample from a transbronchial,percutaneous, or open-lung biopsy yields an NTM organismand shows mycobacterial histopathologic changes (i.e., granu-lomatous inflammation with or without AFB), this by itself issufficient to establish the diagnosis of NTM lung disease. Ifthe lung biopsy has a negative culture (something that oftenhappens when transbronchial biopsies are performed becauseof the small size of the tissue sample) but demonstrates myco-bacterial histopathology features (without a history of othergranulomatous or mycobacterial disease), NTM lung diseaseis considered to be present when one or more sputums orbronchial washes are culture-positive for NTM, even if theyare negative for AFB on smear and result in light growth onculture.

Lymphadenitis

Infection of the submandibular, submaxillary, cervical, or pre-auricular lymph nodes in children between 1 and 5 yr old is themost common presentation of NTM lymphadenitis (78-81). Itis the most common disease manifestation of NTM in childrenand, in the absence of HIV infection, rarely affects adults. Thedisease occurs insidiously, with only rare associated systemicsymptoms. The involved lymph nodes are generally unilateral(95%) and not tender. The nodes may enlarge rapidly, andeven rupture, with formation of sinus tracts that result in pro-longed local drainage. Other nodal groups outside of the headand neck may be involved occasionally (80). There is typicallyno history of exposure to tuberculosis, screening PPD skin testof family members are usually negative, and the chest radio-graph is normal.

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TABLE 1

CRITERIA FOR DIAGNOSIS OF NONTUBERCULOUS MYCOBACTERIA PULMONARY DISEASE

Presumed or Confirmed HIVSeropositive Potential

Presumed or Confirmed HIV Seronegative Potential Risk Factors Risk Factors

I. Local immune suppressionAlcoholism (M. ovium complex)BronchiectasisCyanotic heart diseaseCystic fibrosisPrior mycobacterial diseasePulmonary fibrosisSmoking/chronic obstructive lung diseaseNone

II. General severe immune supressionLeukemiaLymphomaOrgan transplantationOther immunosuppressive therapy

CD4 count < 200

1. Clinical criteriaa. Compatible signs/symptoms (cough, fatigue most common; fever, weight loss

hemoptysis, dyspnea may be present, particularly in advanced disease) withdocumented deterioration in clinical status if an underlying condition is presentand

a. Same a. Same

b. Reasonable exclusion of other disease (e.g., tuberculosis, cancer, histoplasmosis)to explain condition, or adequate treatment of other condition with increasingsigns/symptoms

2. Radiographic criteriaa. Any of the following chest X-ray abnormalities; if baseline films are more than

1 yr old, should be evidence of progressionl Infiltrates with or without nodules (persistent 3 2 mo or progressive)l Cavitationl Nodules alone (multiple)

b. Any of these HRCT abnormalitiesl MultIpIe small nodules

b. Same

a. Same

b. Same

b. Same

a. Same

b. Same

l Multifocal bronchiectasis with or without small lung nodules3. Bacteriologic criteria

a. At feast three available sputum/bronchial wash samples within 1 yrl Three positive cultures with negative AFB smears

Or

a. Same a. Same

l Two positive cultures and one positive AFB smearOr

b. Single available bronchial wash and inability to obtain sputum samplesl Positive culture with 2+, 3+, or 4+ growth

Or

l Positive culture with a 2i-, 3+, or 4+ AFB smearOr

c. Tissue biopsyl Any growth bronchopulmonary tissue biopsyl Granuloma and/or AFB on lung biopsy with one or more positive cultures

from sputum/bronchial wash

b. Same exceptl Culture positive with 1 +

or greater growth

c. Same

b. Same exceptl Culture positive with 1 +

or greater growth(excludes M. ovium complex)

c. Same

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 skintest antigens prepared from M. uvium complex, such as PPD-B(79, X2, 8.7). A 1991 multicenter study of NTM antigens fromthe CDC that used PPD-B, however, was terminated early,due to a blistering reaction in several of the children (82). Morerecent studies using a less potent, protein weight-standardizedM. rrviuni skin-test material called “sensitin” and a dual skin-test technique to determine M. uvium-dominant versus PPD-dominant reactions have suggested improved specificity withthis antigen preparation in study populations with known dis-ease (75). Although these antigens may prove beneficial forfuture evaluation of cervical lymphadenitis, no commercialNTM skin-test material is currently available for clinical use inthe United States, and this procedure is not recommended fordiagnosis of NTM. All children in this setting should be testedusing PPD tuberculin. Most children tested with intermediatestrength (5 tuberculin unit [TU]) PPD tuberculin will have aweakly reactive skin test (S-9 mm) due to cross-reactivity withNTM, but some children may be negative, and as many as one-third will have reactions with 10 mm or more induration (SO).

Distinguishing tuberculous from nontuberculous lymphad-enitis is key, because the former requires drug therapy andpublic health tracking, whereas the latter does not. The pre-sumptive diagnosis of NTM lymphadenitis is based on the his-topathologic appearance of the lymph node showing caseatinggranulomata with or without AFB and a negative tuberculinskin test. Failure of the node to yield M. r74he~c~losis providesstronger presumptive evidence for the diagnosis of NTM lym-phadenitis.

The utility of fine needle aspiration in obtaining diagnosticmaterial is controversial (X4-86). However, granulomata orother compatible cytopathology such as a mixture of degener-ating granulocytes, lymphocytes, and epithelioid histiocytes areseen in most cases. A positive culture may be obtained in upto 50% of HIV-seronegative patients and in even higher pro-portions of HIV-positive patients with tuberculous adenitis.

A definite diagnosis of NTM lymphadenitis is made by re-covery of the causative organism from lymph node cultures. Asimple diagnostic biopsy or incision and drainage of the in-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 chronicdrainage (79). However, even with excised nodes with com-patible histopathology, only about 50% will yield positive cul-tures (79), although the recovery rate may be as high as 82%in some centers (80). Some of these smear-positive, culture-negative cases may be due to fastidious species such as M. hae-mophilum (87) or M. genavense (39). Currently, approximately80% of culture-proven cases of NTM lymphadenitis are due toM. avium complex (88). In the United States and Australia theremaining cases are caused by M. scrofulaceum (79, 80, 88)while in Scandinavia, the United Kingdom, and other areas ofnorthern Europe, M. malmoense has recently emerged as themajor pathogen after M. avium complex (70, 89, 90). The pre-dominance of M. uvium complex is a change from 20 yearsago, when most geographic areas reported M. scrofuluceum asthe most common etiologic agent (78, 80). Now in the UnitedStates, only about 10% of the culture-proved mycobacterialcervical lymphadenitis in children is due to M. tuberculosis:the remainder is due to M. uvium complex and M. scrufulu-ceum (88). In contrast, in adults more than 90% of the culture-proven mycobacterial lymphadenitis is due to M. tuberculosis.

Localized Skin, Soft Tissue, and Skeletal Infection

The NTM species that most commonly cause localized infectionsof the skin and subcutaneous tissue are M. ,fortuitum, M. ubsces-sus, M. murinum, and M. ulceruns (5). However, virtually all spe-cies of NTM have been described as a cause of cutaneous dis-ease (41,69). Localized drainage or abscess formation at the siteof puncture wounds (such as occurs after stepping on a nail),or open traumatic injuries or fractures are most often due to therapidly growing mycobacterial species M. fortuitum, M. ubsces-sus, or M. chelonue (91). Nosocomial skin and soft-tissue dis-ease caused by these three species is also seen (16-26). Theseinclude infections of long-term intravenous or peritoneal cath-eters (91,92), postinjection abscesses, or surgical wound infec-tions such as those occurring after augmentation mammoplasty(23,93) or cardiac-bypass surgery (16,17,21,94). Diagnosis ismade by culture of the specific pathogen from drainage mate-rial or tissue biopsy.

Mycohucterium murinum is the cause of “swimming poolgranuloma” or “fish tank granuloma” (69). The lesions usuallyappear as papules on an extremity, especially on the elbows,knees, and dorsum of feet and hands, progressing subse-quently to shallow ulceration and scar formation. Most lesionsare solitary, although occasional “ascending” lesions developthat resemble sporotrichosis. Clinical involvement of regionalnodes is uncommon. The organisms may be introduced intothe skin through previous abrasions contaminated whilecleaning fresh-water fish tanks (“fish tank granuloma”) or byscratches or puncture wounds from salt water fish, shrimp,fins, etc. Diagnosis is made from biopsy material, histologicexamination, and culture.

Mycobucterium ulceruns causes indolent necrotic lesions ofthe skm and underlying tissue in Australia and tropical areasof the world (34,69,95). It is not endemic in the United States.The lesions occur most commonly in children and youngadults and often result in severe deformities of the extremities(95). Drug treatment of the disease has been disappointing;surgical debridement combined with skin grafting is the usualtreatment of choice.

Infection of Bursae, Joints, Tendon Sheaths, and Bones

Chronic granulomatous infection caused by NTM may de-velop in tendon sheaths, bursae, joints, and bones after directinoculation of the organisms through accidental traumas, sur-gical incisions, puncture wounds, or injections. Mycobucterium

murinum (41, 69) and M. uvium complex (96) are particularlyprone to causing tenosynovitis of the hand, although M. fortu-itum, M. abscessus, M. chelonae, and M. kunsusii have alsobeen implicated (41, 69). Mycobacterium terrue complex (es-pecially M. nonchromogenicum) has also been isolated fromsynovial tissue of the hand or wrist, and it tends to be associ-ated with a very indolent, chronic type of disease. Occasion-ally, axial bones and extremities have been infected withoutapparent trauma and are due presumably to hematogenous in-fection. After open-heart surgery, osteomyelitis of the sternumcaused by M. abscessus or M. fortuitum has been described,with both epidemic and sporadic disease (16, 17,21, 94).

Disseminated Disease in Patients without AIDS

Dissemination of NTM in adult patients with immunosuppres-sion but without AIDS (e.g., those with renal or cardiac trans-plantation, chronic corticosteroid use, leukemia, etc.) has beenobserved. Mycobucterium uvium complex (69,97), M. kunsusii(98), M. chelonue (91,99-101) M. scrofuluceum (69) M. absces-sus (69), and M. huemophilum (60) have all been reported tocause disease in this setting. In general, the disease caused byM. uvium complex presents as a fever of unknown origin (97)whereas disease caused by M. kunsusii, M. chelonue, M. ubsces-sus, and M. huemophilum generally presents as multiple sub-cutaneous nodules or abscesses that drain spontaneously (60,69, 99-101). The mortality relates directly to the type and se-verity of underlying disease (101). Lincoln and Gilbert (78) re-viewed 12 cases, all fatal, of disseminated NTM disease in chil-dren, Most of the children were infected with M. avium complex,were less than 3 yr old, and had no apparent underlying dis-ease. A recent review of disseminated M. uvium complex dis-ease in children noted its occurrence, rarely, in the setting ofsevere combined immunodeficiency syndrome or chemother-apy for malignancy (102). The isolation of organisms fromsterile, closed sites such as bone marrow or blood or from askin biopsy (in the setting of multiple lesions) is diagnostic ofthe disease.

Disseminated Disease in Patients with AIDS

Disseminated disease due to NTM in patients with HIV infec-tion usually occurs only in those with very advanced immuno-suppression (51-57). Because these patients frequently haveother complications, the diagnosis of mycobacterial infectionmay be confused or delayed. The diagnosis is exceedingly rarein p

‘\rson with > 100 CD4 cells, and it should usually be sus-

pectqd only in persons with < 50 CD4 cells (53-55). Most pa-tients (> 90%) have prolonged fevers, which may be as highas 103-104” F, frequently accompanied by night sweats. Weightloss is common, and some patients complain of abdominal painand diarrhea. Physical findings may be only those of advancedHIV disease, although abdominal or retroperitoneal adenopa-thy and hepatosplenomegaly may be present. Anemia is themost striking laboratory abnormality, with many patients hav-ing a hematocrit of < 25%. Alkaline phosphatase is elevatedin approximately one-third of patients and may be indicativeof hepatic disease due to M. uvium. Thus, the diagnosis of dis-seminated M. uvium should be aggressively pursued in anyperson with < 50 CD4 cells who has a history of fever, weightloss, anemia, diarrhea, or elevated alkaline phosphatase, espe-cially in one with a history of other opportunistic infections.

The diagnosis of disseminated M. avium is most commonlyconfirmed by isolation of M. uvium in blood, using any of theculture techniques described in the laboratory section. Thebacteremia in M. avium is ongoing, and a single culture has asensitivity of approximately 90%. It is recommended that asingle culture be drawn, with repeat cultures only if the first is

American Thoracic Society s7

negative. Routine blood cultures of asymptomatic patients hasa very low yield and is not recommended. In a prospectivestudy of HIV-infected patients with < 50 CD4 cells, approxi-mately 67% of patients with M. avium in sputum or stool haddisseminated disease within 1 yr, although most did not de-velop pulmonary disease. However, only one-third of all pa-tients with disseminated disease had a prior positive stool orsputum. Therefore, routine screening of stool or sputum is notindicated, but a positive culture of one of these sites needs toraise concern about future dissemination. Sputums that aresmear-positive for AFB in the setting of HIV should always beregarded as tuberculosis until proven otherwise, since M. tu-berculosis is a common cause of pulmonary disease in HIV-infected patients and is more likely than M. avium complex toproduce positive AFB smears.

Nontuberculous mycobacteria other than M. avium maypresent as disseminated disease. Disseminated M. kansasii isusually associated with pulmonary disease (51, 59). Mycobac-terium genuvense has been isolated from the blood of patientswith AIDS and requires extensive laboratory analyses for iso-lation and identification (39). Mycobacterium huemophilumhas been associated with infections of the skin, soft tissue,bones, and ,joints (60, 61). Disseminated disease has rarelybeen reported with other species, including M. fort&urn (51),M. murinum, M. simiae, M. scrofulaceum, M. celatum, andM. mulmoense (41).

LABORATORY METHODS

Digestion, Decontamination, and Staining Procedures

Methods used for digestion and decontamination of clinicalsamples to recover M. tuberculosis have also proved useful forthe NTM. In general, however, NTM are more susceptible tokilling by NaOH, and for this reason, care must be taken notto exceed the recommended concentration and time guide-lines. Because of the frequent presence of bronchiectasis inpatients with M. uvium complex and M. abscessus lung disease,Pseudomonas ueruginosa overgrowth in specimens from thesepatients is a more frequent problem than with tuberculosis.Growth of f. ueruginosu can be minimized by processing thespecimens with the conventional N-acetyl-L-cysteine-sodiumhydroxide (NALC-NaOH) solution followed by 5% oxalicacid, a procedure that should be considered when one or morespecimens are contaminated in this setting (103).

Staining and microscopy of the NTM also follows the guide-lines used for M. tuberculosis. Both conventional basic fuchsinmethod (Kinyoun stain) and the fluorochrome method (au-ramine stain) are effective in recognizing NTM in clinical ma-terial, with the fluorochrome method being preferred (104).The appearance of NTM by microscopy is generally indistin-guishable from M. tuberculosis.

Culture Techniques for Nontuberculous Mycobacteria

The principles and practices of culturing M. tuberculosis wereupdated in 1993 by the CDC (104), with these methods havingproved very effective for NTM species. At least three respira-tory (sputum) cultures should be used for the initial evalua-tion. Cultures should be inoculated onto one or more solidmedias and into a liquid medium. Use of solid media as theprimary or sole culture is no longer recommended by us or bythe CDC (104), given the greater recovery rate and morerapid recovery of all mycobacteria, including M. tuberculosis,in rapid broth systems (104-107). Mycobacterial blood cul-tures may use a single medium, with the BACTEC 13A broth(105) or the lysis centrifugation method with plating on 7HlO

or 7Hll (Isolator; Wampole Laboratories, Cranbury, New Jer-sey) being the recommended methods. Two general types ofsolid media are available: egg-potato-base media (commonly,Lowenstein-Jensen agar) and a clear agar-base media (com-monly. Middlebrook 7HlO or 7Hll agar). Quantitation ofgrowth on agar plates (generally 0 to 4+) is important to esti-mates of clinical significance and responses to therapy, and itis recommended for all samples other than blood cultures.Blood cultures using the Isolator System can also be quanti-tated, which may be useful for similar reasons. Because of itsgreater recovery rate for M. uvium complex and ease of quan-titation, Middlebrook 7HlO or 7Hll agars are the preferredsolid media. Lowenstein-Jensen is an excellent medium for re-covery of M. tuberculosis, but is generally inferior to Middle-brook agar as an all-purpose medium for both M. tuberculosisand NTM (105,106).

The broth medium can involve one of several automatedcommercial systems. including radiolabeled BACTEC 12Bbroth used in the BACTEC TB 460 radiometric system (Bec-ton Dickinson Instruments Systems, Sparks, Maryland), andthe nonradiolabeled ESP Culture System II (Difco Laborato-ries, Detroit, Michigan) (107). For lower volume laboratories,the recently introduced mycobacterial growth indicator tubeswith a fluorescent detection system (MGIT; Becton DickinsonMicrobiology Systems. Cockeysville, Maryland) or biphasic agar/broth (Septi-Chek AFB System; Becton Dickinson Microbiol-ogy Systems) may prove more practical.

Most slowly growing NTM produce detectable growth in 2to 4 wk on the solid media and in 1 to 2 wk with the BACTECsystem. Cultures are generally incubated at 35-37” C for 6 wk.All of the currently recognized NTM pathogens will grow onthese media in this time except M. huemophilum, M. genuvense,and M. conspicuum. If M. haernophilurn is suspected, a com-mercial paper surface containing hemin (X factor) used toidentify Haemophilus inflclenzue should be added to the sur-face of the 7HlO or 7Hll plate (log), or hemin or ferric am-monium citrate should be incorporated into the medium. My-cobucterium genavense often grows only from the blood inBACTEC 13A medium or comparable broth media, and re-quires incubation for at least 8 wk (109). Some authors haveidentified better growth in the slightly acidic (pH 6) radiomet-ric Middlebrook 7H12 broth (pyrazinamide test medium).Mycobucterium conspicuum will grow in BACTEC media at35-37” C but will only grow on solid media at lower lempera-tures, 22-31” C (63). The presence of an AFB smear-positivesample with no growth on solid media should immediatelybring to mind M. huemophilum, M. conspicuum, or M. gena-vense. Because of the relatively poor growth of M. gennvense(only approximately 50% of autopsy-proven cases are culture-positive [39]), molecular techniques such as polymerase chainreaction 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 tissuesamples at two temperatures: 35” C and 28-32” C. This is be-cause a number of the common pathogens of these tissues, in-cluding M. huemophilum, M. ulcerans, M. marinum, and M. che-lonue, may grow only at the lower temperatures, especially onprimary isolation. Five to ten percent COZ enhances the growthof some NTM species, such as M. haemophilum, and should beused for primary isolation because of its definite growth en-hancement for M. tuberculosis.

Identification of Nontuberculous Mycobacteria

Traditional identification of NTM, as well as M. tuberculosis,has relied upon statistical probabilities of presenting a charac-

S8 AMERICAN IOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1 9 9 7

teristic reaction pattern in a battery of biochemical tests. Theniacin test was the most useful for separating NTM and M. tu-berculosis because the former is usually negative, whereas iso-lates of M. tuhercdosis arc positive. Runyon devised the firstgood scheme for grouping NTM based on growth rates andcolony pigmentation (69). Species identification has becomemore sophisticated and the number of potential pathogens hasincreased since this scheme was introduced.

A more appropriate grouping currently for these organismsis based on the type of clinical disease they produce: lympha-denitis, cutaneous discasc, disseminated disease, and pulmo-nary disease. Grouping of the NTM by this scheme is shown inTable 2.

Because of the extremely slow nature of traditional bio-chemical tests, most clinical and public health laboratoriesnow use one or more rapid diagnostic methods for speciesidentification (I 10. 111). These rapid methods are recom-mended for identification of the NTM when possible; they in-clude HPLC, the BACTEC NAP test, and commercial DNAprobes. The HPLC examines the mycolic acid fingerprint pat-terns that differ among most species or complexes of myco-bacteria (112). Recent increased sensitivity of this techniqueusing fluorescence detection has allowed identification di-rectly from the sputum sample in approximately SO% of AFBsmear-positive samples of M. tuberculosis and 33% of M. aviumcomplex (113). A small number of species (complexes) are notseparable by HPLC, including most of the pathogenic rapidlygrowing mycobacterial species. Two additional techniques for

rapid identification of NTM are currently in use. These are thespecies-specific DNA probes and the BACTEC NAP test.Commercial nonradiolabeled DNA probes complementary toribosomal RNA are available for identifying isolates of M. tuher-culosis, M. gordonue, M. kansasii, M. avium, and M. intracellu-/are. They are highly sensitive and specific, providing speciesidentification using a culture directly from BACTEC brothwithin 2Z4 h. The presence or absence of serpentine cording onAFB smear of the BACTEC 12B bottle (114) and the time re-quired for the bottle to turn positive (115) will help the labora-tory decide which probe (M. tuberculosis or M. avium com-plex) should be used initially.

The BACTEC TB 460 system can be used to differentiatebetween M. tuberculosis and the NTM using a selective growthinhibitor called NAP @-nitro-c-acetylamino-B-hydroxypropio-phenone) (116). This compound, at a concentration of 5 kg/ml,inhibits the growth of M. tuberculosis complex but not NTM(with the exception of M. genavense). The average time forthe NAP test is 5 d. However, a species identification schemaother than the use of DNA probes for NTM has not beenworked out for use with the BACTEC, and such identificationmust depend on one of the previously discussed methods.

Because of its generally poor growth, identification ofM. genavense can be difficult (43, 109). A presumptive identi-fication can be made on the basis of organism morphology(small, coccobacillary forms on AFB smear), failure to growon subculture to solid media, a negative nucleic acid probe forM. avium complex, and a positive NAP test (39). Mycohacte-

TABLE 2

CLASSIFICATION OF THE NONTUBERCULOUS MYCOBACTERIA R E C O V E R E D F R O M H U M A N S

ClinIcal Disease

Pulmonary disease

Lymphadenitis

Cutaneous disease

Disseminated disease

Common EtioloqicFeatures of the Common Species

Species _ Geography

1. M. avium complex Worldwide

2. M. kansasii

3. M. abscessus

4. M. xenopi5. M. malmoense

USA, coal mining

regions, Europe

Worldwide but

mostly USA

Europe, Canada

UK, northern Europe

Morphologic Features*

Usually not pigmented;

slow growth (’ 7 d)

Pigmented; often large and

beaded on acid-fast stain

Rapid growth (< 7 d);

not pigmented

Slow growth; pigmented

Slow growth, not

pigmented

1. M. ovium complex Worldwide Usually not pigmented

2. M. scrofulaceum Worldwide Pigmented

3. M. malmoense UK, northern Europe Slow growth

(especially Scandinavia)

1, M. marinum

2. M. fort&urn3. M. chelonae4. M. abscessus5. M. ulcerans

Worldwide

Worldwide, mostly

USA

Australia, tropics,

Africa, SE Asia

Photochromogen; requires

low temperatures (28-

30” C) for isolation

Rapid growth; not

pigmented

Grows slowly, pigmented

1. M. avium complex Worldwide

2. M. kansasii USA

3. M. chelonae USA

4. M. haemophilum USA, Australia

Isolates from patients with

AIDS usually pigmented

(80%)

Photochromogen

Not pigmented

Not pigmented; requires

hemin, often low

temperatures, and CO2

to grow

Unusual Etiologic

Species

1. M. simiae2. M. szulgai3. M. fortuitum4. M. celatum5. M. asiaticurn6. M. shimodii7. M. haemophilum8. M. smegmatis

1. M. fort&urn2. M. chelonae3. M. abscessus4. M. kansasii5. M. haemophilum

1. M. avium complex

2. M. kansasii3. M. nonchromogenicum4. M. smegmatis5. M. haemophilum

1. M. abscessus2. M. xenopi3. M. malmoense4. M. genavense5. M. simiae6. M. conspicuum7. M. marinum8. M. fortuitum

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 theM. tuberculosis complex, which is inhibited by NAP.

Antimicrobial Susceptibility Testing

hibitory concentrations (MICs) than the agar method (118,119). Too little experience is available with the antibiotic gra-dient strip method (E-test; AB Biodisk, Piscataway, NJ) tomake any general recommendations on its use.

Although there are specific recommendations from the CDC,ATS, and the National Committee for Clinical LaboratoryStandards (NCCLS) regarding which isolates of M. tuberculo-sis should have antimicrobial susceptibility tests, which testmethods to use, and which antimicrobial agents to test, thesame is not true for the NTM. There are however, sufficientdata now available to make temporary recommendations re-garding when, how, and to which agents the NTM should betested. Recommendations will differ for different groups orspecies of the NTM (Table 3). Although routhne testing of allNTM is discouraged, there are circumstances where suscepti-bility testing is warranted, including having baseline dataavailable if the patient does not respond to therapy, or whenrelapses occur.

The agar proportion method uses Middlebrook 7HlO or7Hll agar and the modified method of proportions, definingresistance as growth on the drug-containing medium of 1% ormore of the number of colonies that grow on the drug-freecontrol medium. Details of the agar proportion method arc in-cluded in the 1990 ATS statement “Diagnostic Standards andClassification of Tuberculosis” (3), and a more detailed de-scription is now available as a tentative standard (for M. tuber-culosis) by the NCCLS (126).

Slow-growing Mycobacteria

Antimicrobial susceptibility testing of the slow-growing myco-bacteria can be performed using either the agar proportion orthe radiometric (BACTEC) methods used for testing M. tu-bercdosis ( I 17-125). However, the two methods give varyingresults between some NTM and antimicrobial agents, with theradiometric broth method tending to give lower minimal in-

The radiometric BACTEC method is a more rapid methodcombining antimicrobial agents, the mycobacterium, and aCl”-labeled substrate in a broth medium. Resistance is deter-mined by the rate and amount of labeled CO, produced,which is directly proportional to the rate and amount ofgrowth that occurs in the broth medium. The BACTECmethod has been widely used by some laboratories for testingall drugs for the NTM, but at present no universally agreed-upon method has been developed.

Mycobacterium avium complex. When and how isolates ofthe M. avium complex should be tested remains controversial(127). Recent data suggest that the radiometric broth methodis more reliable than the agar method for testing the M. rrvium

TABLE 3

ANTIMYCOBACTERIAL AGENTS TO CONSIDER FOR SUSCEPTIBILITY TESTINGOF NONTUBERCULOUS MYCOBACTERIA

Mycobacterium Species or Group

Proven Utility

Clinically Relevant

Uncertain

Relevance

Susceptibility

Testinq Results

of No Benefit

Slowly growing NTM

M. ovium complex Clarithromycin*

M. konsasii Rifampin

M. marinum Doxycycline or Minocycline

Ethambutol

Rifampin

Sulfonamide

Other slowly growing NTM

M. haemophilum Clarithromycin*t

M. malmoense Ethambutol*

M. simiae Rifampint

M. srulgai

M. xenopi

Rapidly growing NTM

M. abscessus Amikacin

M. chelonae Cefoxitin

M. fort&urn Ciprofloxacin

M. mucogenicum Clarithromycin*

M. smegmatis Doxycycline or Minocycline

Sulfonamides

* Class drug for macrolides (clarithromycin, azithromycin, roxithromycin).+ Ethambutol is clinically useful for M. smegmatis.* Proven utility/clinically relevant for some but not all species.

lsoniazid

Pyrazinamide

Pyrazinamrde

lsoniarid

Pyrazinamide

Pyrarinamide

Clofazimine

Ethambutol+

lsoniarid

Pyrazinamide

Rifampin

Streptomycin

Amikacin

Ciprofloxacin

Ethambutol

Ethionamide

Rifabutin

Rifampin

Streptomycin

Amikacin

Ciprofloxacin

Clarithromycin*

Ethambutol

lsoniazid

Rifabutin

Streptomycin

Sulfonamide

Amikacin

Ciprofloxacin

Clarithromycin’

Rifabutin

Amikacin

Ciprofloxacin

lsoniazid

Rifabutin

Streptomycin

Cefmetazole

lmipenem

Ofloxacin

Tobramycin (M.

chelonae only)

SlO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL. 156 1997

complex. There is, however, considerable controversy regard-ing the size of the inoculum, the drug concentrations to use,and interpretation of the BACTEC results. Strains of the com-plex are almost always resistant to the relatively low drug con-centrations of isoniazid, rifampin, streptomycin, and ethambu-tol used for defining susceptibility of M. tuberculosis. Usinghigher concentrations of the antituberculous agents with spe-cific NTM breakpoints for susceptibility and resistance, deter-mination of MICs, or determination of the activity of combineddrugs arc some of the newer approaches that may be helpfulin predicting clinical response (118, 120,121,128). Such a ben-efit has not yet been shown by clinical trials, so susceptibilitytesting of M. avium complex isolates to the antituberculosisdrugs is not recommended.

Other drugs have also been tested, including amikacin,rifabutin (118. 122, 123) ciprofloxacin (124, 125) clofazimine(129) azithromycin (127), and clarithromycin (127). Changes inMICs of the antituberculosis drugs following unsuccessfultherapy of M. uvium complex disease have been difficult to dem-onstrate. Such changes have been readily demonstrable withmicrobiologic relapses following monotherapy with clarithro-mycin, however (130). Pretreatment isolates with this drughave MICs Q 4.0 kg/ml when done in media with a pH of 7.4.Post-therapy or relapse isolates follotiing macrolide therapyhave MICs to clarithromycin of > 32 ~g/ml(105,130-132) anda point mutation involving one of two base pairs in the 23s ri-bosomal macrolide binding site (I 31, 132).

Susceptibility testing should not be performed on pretreat-ment or initial isolates against clarithromycin, but it should beperformed with clarithromycin for all isolates from patients onprior macrolide therapy, including those on macrolide prophy-laxis for disseminated disease. The recommended clarithro-mycin resistance breakpoint is > 32 pg/ml for broth or agarwith pH corrected to 7.4 (105). Until more data are available,patients on azithromycin should have their isolates character-ized as susceptible or resistant based on clarithromycin sus-ceptibility values.

Alterations or changes in MlCs following treatment or pro-phylaxis failure have also been difficult to demonstrate withrifabutin. For this reason, testing of susceptibility to rifabutineven after therapy is not recommended. Because of lack ofstandardization, results of testing other nontuberculous drugssuch as amikacin, clofazimine, and ciprofloxacin should beused with caution.

Mycobacterium kansasii. Although wild strains of M. kan-sasii are initially susceptible to rifampin, acquired resistancedoes develop during therapy (133, 134). Since the correct his-tory of therapy may not be known, all initial isolates of M. kan-sasii should be tested against rifampin, using the agar propor-tion method and the interpretive criteria for M. tuberculosis(resistance breakpoint of 1 kg/ml) (134). Also, testing shouldbe performed when the patient’s sputum fails to convert fromsmear- and/or culture-positive or when a relapse occurs duringtherapy. Treatment for rifampin-susceptible isolates is empiricand is not influenced by susceptibility to drugs other thanrifampin (i.e., ethambutol and isoniazid); hence their routinetesting is not recommended. A rifampin-resistant isolate couldbe tested against ciprofloxacin or ofloxacin, clarithromycin,ethambutol, streptomycin and a sulfonamide (e.g., sulf-amethoxazole) (133, 134).

Other slow-growing nontuherculous mycobacteria. Suscep-tibility testing of infrequently isolated species of NTM may behelpful, since knowledge of susceptibility patterns is limited.Pulmonary infections caused by M. rnalmoense, M. xenopi,and M. szulgai have been successfully treated with combina-tions of ethambutol, isoniazid, rifampin, and most recently

clarithromycin (70, 135-137) whereas ciprofloxacin, clarith-romycin, and rifampin are suggested for treating M. huemo-philum infection (60, 61). Thus, susceptibility tests for theseslow-growing NTM might include these five drugs. The agarproportion and broth methods have usually been used for test-ing. For M. marinum, several methods have been used (138),with the desired test drugs being rifampin, ethambutol, doxy-cycline or minocycline, clarithromycin, and a sulfonamide.

Rapidly Growing Nontuberculous Mycobacteria

Because of differences in susceptibilities among species ofrapidly growing mycobacteria and even within species, suscep-tibility testing should be performed on all clinically significantisolates as well as isolates that have been recovered aftertreatment failure or relapse. Antimicrobial susceptibility test-ing of the rapidly growing mycobacteria differs from the otherNTM. Most drugs are different, although the methods are sim-ilar to those used to test other bacteria (138-142). Most infec-tions are caused by three species; M. abscessus, M. chelonae,and M. fortuitum (91). A primary panel of drugs for these spe-cies could include amikacin, cefoxitin, ciprofloxacin, clarithro-mycin, doxycycline, imipenem, and a sulfonamide. The mostconvenient method for susceptibility testing is to use microti-ter MIC trays containing cation-supplemented Mueller-Hin-ton broth. Agar dilution, agar disk elution, and disk diffusionmethods have also been used. Details of these methods can befound in several laboratory handbooks, including the Ameri-can Society for Microbiology’s Manual of Clinical Microbiol-ogy (142).

TREATMENT OF Mycobocterium kansasii DISEASE

Disease caused by M. kansasii is the second most commonNTM pulmonary disease in the United States. It occurs in geo-graphic clusters and affects primarily adult white men, but itcan affect patients of any sex, race, or age. Pulmonary diseaseis the most frequent clinical presentation. The organism fre-quently exhibits a beaded or cross-barred appearance on acid-fast stain, and produces rough buff-colored colonies that de-velop a yellowish pigmentation because of the deposition ofbeta-carotene crystals after exposure to light. Disease-produc-ing strains are usually highly catalase-positive. Recent DNA-based studies suggest that up to five taxonomic groups or sub-species are present among both environmental and humanisolates (143).

Untreated strains of M. kansasii are inhibited by rifampin,isoniazid, ethambutol, ethionamide, streptomycin, and clarithro-mycin at concentrations readily achievable in the serum withusual therapeutic doses (134, 144, 145). Because the concen-trations of antituberculous drugs used in susceptibility testingwere chosen for their usefulness with M. tuberculosis, and be-cause M. kansasii is less susceptible to these drugs, some iso-lates of the latter species may be reported resistant to iso-niazid at 0.2 or 1 yg/ml and to streptomycin at 2 pg/ml. Theseisolates are susceptible to slightly higher drug concentrations(134,144) and laboratory reports of resistance to the low con-centrations of these two drugs have no clinical or therapeuticsignificance as long as a rifampin regimen is being used (146).Thus, when clinically indicated, isoniazid and/or streptomycinshould be used against M. kansasii regardless of their in vitrosusceptibility results. Mycobacterium kansasii is also suscepti-ble in vitro to clarithromycin (134) sulfamethoxazole (133) ami-kacin (133) the newer quinolones (125) and rifabutin (134) al-though there is limited information on the clinical usefulnessof these drugs (133,134). Isolates are usually resistant to achiev-

American Thoracic Society Sl 1

able serum levels of p-aminosalicylic acid, capreomycin, andpyrazinamide. Acquired resistance to rifampin, ethambutol,and isoniazid has been demonstrated in isolates from treat-ment failure cases (133, 134, 145), and resistance to the firsttwo agents is reliably demonstrated by current M. tuberculosissusceptibility test methods (134).

Treatment

The natural history of pulmonary disease caused by M. kan-sasii in patients receiving no drug treatment has been assessed(147). In general, the history has shown persistence of sputumpositivity and progression of clinical and radiographic disease.On this basis, patients with pulmonary disease should receivedrug therapy.

There have been no randomized comparative trials oftreatment for disease caused by M. kansasii, comparing onedrug regimen with another or with no drug treatment at all.There have been, however, several retrospective and prospec-tive studies of various treatment regimens (145-151) that havegiven us a good basis for drug therapy recommendations. Ear-lier reports of treatment with antimycobacterial drugs in theprerifampin period were disappointing when compared withthe much higher success rates achieved in treating tuberculosiswith these same drugs. The sputum conversion rates at 6 moranged from 52 to Xl%, and relapse rates of approximately10% were seen in patients achieving an initial response (145,148). Surgical resection was often recommended to achievebetter initial control and prevent relapse. The advantage ofadding surgery was never established, however (148).

With the advent of rifampin, the picture changed consider-ably for the better. Four-month sputum conversion rates withrifampin-containing regimens were 100% in 180 patients fromthree studies (145,146,149). There were two treatment failurecases, however (an incidence of 1.1%). These patients con-verted their sputa but then became culture-positive againwhile still receiving therapy. Both had been treated with iso-niazid, rifampin, and ethambutol, and both failures were asso-ciated with the development of rifampin resistance (145).Long-term relapse rates with rifampin-containing regimensalso appear to be very low, with only one relapse recordedamong 134 patients (0.8%) who received long-term follow-upin three studies (145, 146, 150). Surgery is now considered tohave no role in managing routine cases of pulmonary disease.

The current recommendation for treatment of pulmonarydisease caused by M. kansasii in adults is the regimen of iso-niazid (300 mg), rifampin (600 mg), and ethambutol(25 mg/kgfor the first 2 mo, then 15 mg/kg) given daily for 18 mo with atleast 12 mo of negative sputum cultures. In patients who areunable to tolerate one of these three drugs, clarithromycinwould seem a reasonable alternative, but its effectiveness hasnot been established by clinical trials (see below). Pyrazina-mide is unacceptable as an alternate or third drug for M. kan-sasii because all isolates are resistant.

The use of intermittent drug regimens or short-coursetreatment for M. kansasii has not been studied enough to rec-ommend it. One study of 40 patients did demonstrate thatadding intermittent streptomycin at 1 g twice weekly for thefirst 3 mo to the previously recommended three-drug regimengiven for 12 mo resulted in apparent cure of all but one patient(149). A trial of daily low-dose ethambutol (15 mg/kg) anddaily rifampin given for 9 mo sponsored by the British Medi-cal Research Council was completed in 155 adult patients(151). Sputum conversion was achieved in 99.4% of patients,but with a relapse rate of 10% with a 5 year follow-up. Thissuggests that isoniazid does not contribute greatly to the treat-

ment of M. kansasii; however, 9 mo is not a long enough treat-ment period for the studied two-drug regimen.

In adult patients whose organisms have become resistant torifampin as a result of previous therapy, a regimen consistingof high-dose daily isoniazid (900 mg), pyridoxine (50 mgdaily), high-dose ethambutol (25 mg/kg per day), and sul-famethoxazole (1.0 gm three times per day) until the patient isculture-negative for 12 to 15 mo has been under investigation(133, 134). The oral therapy has been combined with daily orfive times per week streptomycin or amikacin for the initial 2to 3 mo, followed by intermittent streptomycin or amikacinfor a total of 6 mo. Results with this regimen described sputumconversion in 18 of 20 patients (90%) after a mean of 11 wk,with only one relapse (8%) among patients who were culture-negative for at least 12 mo on therapy (134). The excellent invitro activity of clarithromycin against M. kansasii (134) sug-gests this agent will also be highly useful in retreatment regi-mens, perhaps allowing for omission of the aminoglycoside.The newer quinolones may also be potentially useful in thissetting but have not been studied.

For treatment of extrapulmonary disease in adults, the reg-imen of antimycobacterial drugs should be the same as forpulmonary disease. Pulmonary disseminated disease has beendescribed in patients with AIDS (59), and it is the second mostcommon NTM that produces disease in this setting (51). Ofthe cases detailed in the literature, most have been fatal (59).In the treatment of lymph node disease in children, excision ofall accessible nodes at the time of the initial biopsy should bedone, since the etiologic agent is probably an NTM other thanM. kansasii, for which excision is the indicated treatment.

The use of protease inhibitors for the treatment of HIV dis-ease complicates the management of M. kansasii disease be-cause rifampin dramatically enhances the metabolism of thesedrugs and cannot be used with them concurrently. Options fortreating HIV-infected patients who receive a protease inhibi-tor are to substitute clarithromycin for rifampin in the stan-dard regimen, or to substitute rifabutin 150 mg/d for rifampinif the patient is receiving indinavir. None of these regimenshave been studied clinically; however, they appear likely to besuccessful.

TREATMENT OF PULMONARY Mycobacterium aviumCOMPLEX DISEASE (M. ovium, M. introcellulore)Medical treatment of M. avium complex pulmonary disease inHIV-negative patients has historically been frustrating anddisappointing. In the few studies in which initial sputum con-version rates have been high (> SO%), long-term follow-up toestablish continued sputum conversion is rarely documented(152-156). Relapses after medical therapy with premacrolidetreatment regimens are common, and the best outcomes havefrequently been in those patients subjected to resectional sur-gery (157,158). Recent significant advances in the drugs avail-able for treatment of M. avium complex have been made,however, and there is now greater expectation that pulmonaryM. avium complex disease can be effectively treated (definedas high rates of sputum conversion with long-term culture neg-ativity) with medications alone.

The major limitations for effective therapy have been theabsence of antimicrobial agents with low toxicity and good invivo activity against the organism. Most first-line antitubercu-losis drugs have lo-100 times less in vitro activity againstM. avium complex isolates than against M. tuberculosis. Thisdiminished activity may be due to the lipophilic cell wall ofM. avium complex, which prevents drug penetration (159).

The major therapeutic advances in the treatment of pulmo-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 settingof HIV disease. Recent studies have shown excellent in vivaand clinical activity against M. uvium complex by the newermacrolides, clarithromycin and azithromycin. presumably dueto the high phagocyte and tissue levels achieved by these agents.(The structure of azithromycin is technically an azalide; how-ever, because of the close similarity of azalides to macrolides,the term macrolide will be used to refer to both in subse-quent discussion.) Human trials of patients with disseminatedM. avium complex disease and AIDS have shown both newermacrolides to have clinical and microbiologic activity as mono-therapy (160-163) and clarithromycin to have clinical and mi-crobiologic activity in drug combinations (162). Studies havealso demonstrated significant sterilizing activity of both azithro-mycin and clarithromycin with short-term initial treatment assingle agents in pulmonary M. uvium complex disease (164,165). Although it is not appropriate to treat patients with dis-ease (outside of clinical trials) with single agents, these are thefirst studies demonstrating significant in viva activity of anysingle agent for pulmonary M. avium complex disease.

Rifabutin, a derivative of rifamycin S, has been shown to bemore active in vitro than rifampin against isolates of M. aviumcomplex (117). Peak serum rifabutin concentrations are muchlower than those of rifampin and exceed the MICs for only ap-proximately 70% of M. avirrm complex strains (123). The rele-vance of this finding is uncertain, given higher levels of the drugin tissue than in serum. Rifabutin has demonstrated effective-ness as a prophylactic agent against disseminated M. aviumcomplex disease in AIDS (54) and there is some evidence ofimproved clinical response of pulmonary M. avium complexdisease in HIV-negative patients when rifabutin is added tomultidrug regimens (166). The newer macrolides and rifabutinform the basis of improved treatment regimens for pulmonaryM. uvium complex disease.

Clinical Presentations

The natural history of M. ~viun~ complex lung disease is un-predictable in HIV-negative patients. Some patients maintaina stable clinical and radiographic picture for years, whereasothers have a relatively rapid progression of their disease. Thevariability in the natural history of M. aviurrz complex lung dis-ease appears to relate in part to the presence of two types ofclinical disease and presentation. The traditional presentationof M. uvium complex lung disease has been as apical fibrocav-itary lung disease, sometimes with huge cavities, in males intheir late 40s and early SOS who have a history of heavy ciga-rette smoking and, frequently, alcohol abuse. This form of dis-ease is generally progressive within I to 2 yr if left untreated.More recently. it has become apparent that M. uvium complexlung disease also presents as bilateral nodular and interstitial/nodular disease or as isolated right middle lobe or lingular dis-ease, predominantly in elderly nonsmoking females (71-74,167). These syndromes were often referred to as M. aviumcomplex “colonization,” with bronchiectasis considered to bethe only real disease. This form of disease (nodular bron-chiectasis) tended to have a much slower progression, suchthat long term follow-up (S-10 yr) was often needed to showclinical or radiographic changes. For the nodular bronchiec-tatic forms of M. uvium complex lung disease, sputum submis-sion for AFB analysis was often delayed months to years asthe patient had radiographic and symptomatic progression.

In the past, many patients with nodular bronchiectaticM. uvium complex disease received a variety of nonspecificmeasures (“pulmonary tolict”) rather than specific antimyco-bacterial therapy for their pulmonary disease. These nonspe-

cific therapies included bronchodilators, postural drainage,smoking cessation, and broad spectrum antibiotics (77). Clearly,these measures may be appropriate and can be associated withsymptomatic improvement in bronchiectasis unrelated to anyeffect on M. avium complex. Before the development of newer,more active agents against M. avium complex, it had beenproposed that patients in this group with a stable clinical pic-ture (usually over 3-6 mo) and minimal symptoms, and thosewhose sputum “cleared” with nonspecific therapy, should notbe treated. However, based on recent studies using chestHRCT scans, these patients have specific radiographic fea-tures of parenchymal disease in addition to their multifocalbronchiectasis (71-74). The term “colonization” is, therefore,incorrect. The appropriate distinction is not between coloniza-tion and invasive disease but between those patients with thedisease of nodular bronchiectasis who require immediate ther-apy directed at M. uvium complex and those in whom such adecision can be delayed. If a decision is made to observe sucha patient (e.g., one with minimal symptoms and radiographicfindings such that the treatment seems worse than the disease,or one with other major medial problems), it is incumbentupon the treating physician to continue collecting respiratoryspecimens for AFB analysis as well as follow-up chest radio-graphs and/or CTs over a relatively long period of time (per-haps the patient’s entire lifetime), as the M. uvium complexdisease will likely progress at some time and the patient’ssymptoms and chest radiographs will likely worsen. We rec-ommend careful evaluation of each respiratory M. avium com-plex isolate in the context of the patient’s overall status. Ingeneral, almost any patient with two or three positive respira-tory cultures for M. avium complex has M. uvium complexlung disease. Although not all patients with an M. uvium com-plex respiratory isolate will require immediate therapy, the cli-nician must resist the temptation to make facile clinical deci-sions, particularly if that decision is to not treat a patient witha M. uvium complex respiratory isolate. As treatment regi-mens improve both in effectiveness and the ability of the pa-tient to tolerate the medications, there should be less reluc-tance to treat M. uviunt complex lung disease at an earlier stage.For patients with substantial symptoms and/or advanced orprogressive radiographic abnormalities, an observation periodis not needed to establish the need for therapy.

Drug Treatment

Drug therapy for M. uvium complex disease involves multipledrugs: therefore, the risk of drug toxicities is relatively high.Additionally, the optimal therapeutic regimen has yet to be es-tablished. For these reasons, the treatment of M. uvium com-plex disease may best be served by physicians experienced inpulmonary or mycobacterial diseases.

With empiric combination regimens that include clarithro-mycin and usually ethambutol and a rifamycin (rifampin orrifabutin), sputum conversion rates for pulmonary M. aviumcomplex disease in adult patients able to tolerate the medica-tions are about 90% (164,168,169). Rifabutin is the preferredrifamycin because it is more active in vivo than rifampin againstM. uvium complex, but it may also produce more problematicadverse events (uveitis, leukopenia). All untreated strains ofM. uvium complex are macrolide susceptible (clarithromycinMICs of 0.25 of 4.0 pg/ml), while microbiologic relapses asso-ciated with symptom recurrence reveal isolates with MlCs of> 32 p.g/ml (170). Patients with either pulmonary or dissemi-nated M. uvium complex do not respond to macrolidc-con-taining regimens in which the macrolide is the sole or principleagent if the patient’s isolate is macrolide resistant in vitro (161,

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164. 168. 160). Isolates of M. avium complex resistant to clari-thromycin are cross-resistant to azithromycin (170).

The newer macrolides are the cornerstone of contempo-rary therapy for pulmonary M. avium complex disease, as theyare for disseminated M. avium complex disease. Initial ther-apy for adult HIV-negative patients with M. avium complexdisease needing treatment should consist of a minimum three-drug regimen of clarithromycin (500 mg twice a day) or azithro-mycin (250 mg/d or 500 mg three times a week), rifabutin (300mg/d) or rifampin (600 mg/d), and ethambutol (25 mg/kg perday for 2 mo followed by 1.5 mg/kg per day). For patients ofsmall body mass and/or an age over 70, clarithromycin at 250mg twice a day or azithromycin 250 mg three times a weekmay be better tolerated. Studies are currently ongoing to de-termine the feasibility and efficacy of both azithromycin- andclarithromycin-containing regimens with all drugs given inter-mittently (three times weekly) for pulmonary M. avium com-plex disease.

The potential and method for treating pediatric patients(e.g.. those with underlying cystic fibrosis) with the above reg-imen has not been studied, nor have drug doses for the neweragents such as clarithromycin and rifabutin.

Intermittent streptomycin for the first 2 to 3 mo of therapymay be considered, in addition to the above regimen, for ex-tensive disease. The exact dose of streptomycin in this multi-drug regimen will depend on the patient’s age and weight. Forextensive disease, we recommend at least 2 mo of intermittent(twice or three times weekly) streptomycin, although longertherapy with streptomycin may be desirable in patients withvery extensive disease or for those who do not tolerate otheragents. There are no data, however, comparing clarithromy-tin-containing regimens with and without an aminoglycoside.The patient and physician should be alert to signs and symp-toms of streptomycin toxicity, and these may prevent comple-tion of the full course of therapy. Because ototoxicity due tostreptomycin is often irreversible, patients receiving strepto-mycin should be instructed in the signs and symptoms of toxic-ity (unsteady gait, tinnitus, diminished hearing) at the start oftherapy and again on subsequent visits, with discontinuationor decrease in dosage or frequency if suggestive signs of toxic-ity occur. Suggested doses of streptomycin based on patientage and weight are shown in Table 4.

The optimal length of drug therapy for M. avium complexlung disease has not been established. Recommendations inthe premacrolide era were that patients be treated for 18 to 24mo without considering how long the sputum culture resultswere negative. This recommendation was based on empiricdata, in part, drawing from the early experience in treating tu-berculosis. With macrolides, a shorter length of therapy seemsacceptable. Only two long-term studies of M. uvium complex

TABLE 4

SUGGESTED DOSES OF STREPTOMYCIN RELATIVETO AGE AND WEIGHT IN PATIENTS WITH

NORMAL SERUM CREATININE*

Weight and Age Initial Therapy’ Maintenance Therapy*

z5Okgands5Oyr 1 g 5xlwk 1 g 3x/wki 50 kg and s 50 yr 500 mg sxlwk 750 mg Zx/wk> 50 kg and SO-70 yr 500 mg 5x/wk 750 mg Zx/wk> 7 0 y r 750 mg 2x/wk 750 mg 2x/v/k

l These doses have not been established as optlmal by clinical trials. The reduceddoses with age reflect the reduced renal funtion and increased risk of toxicity withstreptomycin seen in patients older than 50 yr.

’ For the first 6 to 12 wk of therapy as tolerated.r For subsequent therapy as tolerated.

lung disease have been reported to date, both investigatingclarithromycin (168, 169). One study using 12 mo of culturenegativity as the treatment endpoint observed no pulmonarydisease relapses with a mean follow-up of 18 mo (I 68), whilethe second study, which used 7 to 9 mo of culture negativity,resulted in no early pulmonary disease relapses with a meanfollow-up of 7 mo (169). Early relapses with less than IO mo ofculture negativity were seen in the first study. These initialstudies suggest that culture negativity of 10 to 12 mo while ona clarithromycin-containing regimen is adequate for most pa-tients.

Acid-fast bacilli smears and cultures of sputum should beobtained monthly during therapy for pulmonary M. aviumcomplex disease to assess response, then periodically aftercompletion of therapy to evaluate possible relapse. The de-sired endpoint is negative sputum cultures; patients who re-spond to therapy should develop negative AFB smears andcultures. One or more cultures containing small numbers ofM. avium complex organisms (single colonies on solid mediaor positive liquid media cultures only) may occur after sputumconversion and should not necessarily be interpreted as indic-ative of treatment failure or relapse. Rather, these culture re-sults should be interpreted in light of the patient’s overall clin-ical status.

All patients should show clinical improvement within 3 to 6mo and should convert their sputum to negative within 12 moon macrolide-containing regimens (168). Thus, patience is re-quired in evaluating response to therapy. However, failure torespond in these time periods should prompt investigation forpossible noncompliance or macrolide resistance.

For patients whose disease has failed to respond to a mac-rolide-containing regimen (usually as a consequence of in vitromacrolide resistance, noncompliance, or drug intolerance) andhave progressive, symptomatic disease, an alternative drug regi-men will be necessary. The treatment for pulmonary M. uviumcomplex disease in HIV-negative adult patients as recommendedin the first ATS NTM statement published in 1990, consistedof the four-drug regimen of isoniazid (300 mg/d). rifampin(600 mgld), ethambutol (25 mg/kg per day for the first 2 mo,then 1.5 mg/kg per day) with streptomycin for the initial 3 to 6mo of therapy (1). With the use of rifabutin instead of rifampin,this may be a reasonable regimen for patients who are mac-rolide resistant or intolerant. Which drugs are most useful intreating macrolide-resistant strains is a major issue to be ad-dressed in future studies as resistant strains become more prev-alent. Although there are no trials comparing regimens withand without a macrolide for treating pulmonary M. uviumcomplex, most experts consider the regimen without a mac-rolide to be inferior, and one such regimen (rifampin, etham-butol, ciprofloxacin, and clofazimine) has been shown to beinferior to a clarithromycin-containing regimen for dissemi-nated M. uvium (171).

A number of other drugs have been used in multidrug regi-mens in the past, but they are limited by toxicity (e.g., cyclo-serine and ethionamide) or little or no evidence of clinical effi-cacy (e.g., clofazamine, newer quinolones, capreomycin). Someexperts feel that clofazimine 100 mg/d and ciprofloxacin 750mg twice daily or ofloxacin 400 mg twice daily are useful in thesetting of M. avium complex lung diseases, although there areno data corroborating their efficacy. Therapy with only twodrugs, especially isoniazid and rifampin only, is strongly dis-couraged and not likely to be effective. Antituberculosis drugsare generally well tolerated, even by the elderly populationwith M. avium complex lung disease.

If patients are unable to tolerate or fail first-line antituber-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 ciprofloxacin750 mg twice daily or ofloxacin 400 mg twice daily, clofazimine100 mg daily, ethionamide (2.50 mg twice a day, then increasedto three times a day as tolerated), and prolonged use of strep-tomycin or amikacin (three to five times per week). A multi-ple drug regimen including these potentially toxic drugs canalso be associated with at least short-term conversion of thesputum to AFB-negative. The long-term success rate for sal-vage regimens is unknown but is likely very low.

The role of immune therapy in patients who fail drug ther-apy has not been established. Interleukin and gamma inter-feron have been used in selected patients, and some investiga-tion in this area continues.

Surgical Treatment

Patients whose disease is localized to one lung and who cantolerate resectional surgery might also be considered for sur-gery, if there has been poor response to drug therapy or if thepatient’s isolate has become macrolide resistant. For some pa-tients successfully treated by surgical resection, the prognosishas been better than for patients treated medically, althoughthese results predated the use of macrolide-containing regi-mens (157, 158). Lung resectional surgery for mycobacterialdisease is associated with significant morbidity and mortality(172, 173). In one recent series from a thoracic surgeon expe-rienced in mycobacterial surgery, 8 of 38 (21%) of patientsundergoing surgery and 8 of 17 (47%) of patients under-going pneumonectomy developed postoperative bronchopleuralfistulae, especially following a right pneumonectomy (172).Whenever possible, this surgery should be performed at cen-ters with thoracic surgeons who have considerable experiencewith this type of surgery. Overall, the bilateral nature ofM. avium complex lung disease, the advanced age of the pa-tients, and the frequency of underlying chronic lung diseasehave limited the number of patients who are good candidatesfor surgery.

Toxicity Monitoring

Monitoring of patients for toxicity, given the number of drugsand the older age of these patients, is essential. Monitoringshould include visual acuity (ethambutol and rifabutin), red-green color discrimination (ethambutol), liver enzymes (clari-thromycin, azithromycin, rifabutin, rifampin, isoniazid, ethiona-mide) (174) auditory and vestibular function (streptomycin,amikacin, clarithromycin, azithromycin), renal function (strep-tomycin and amikacin), leukocyte and platelet counts (rifabu-tin) (175, 176) and the central nervous system (cycloserine).Patients who receive both a macrolide and rifabutin must bemonitored for the development of toxicity related to the inter-action of these drugs (175,176). Clarithromycin enhances rifabu-tin toxicity (especially uveitis) while the rifamycins, rifampinmore than rifabutin, lower clarithromycin serum drug levels.Details are provided in the section on monitoring for drug tox-icity.

TREATMENT OF LOCALIZED EXTRAPULMONARYMycobacterium avium COMPLEX DISEASE

Lymphadenitis

Excisional surgery without chemotherapy is the recommendedtreatment for children with NTM cervical lymphadenitis, in-cluding those with disease caused by M. avium complex andM. scrofulaceum (79, 80, 177, 178). The success rate with thisprocedure is about 95% (79). Incisional biopsy or the use ofantituberculosis drugs alone (without a macrolide) has fre-quently been followed by persistent clinical disease, including

sinus tract formation and chronic drainage, and should beavoided (79,80, 177,178). For children with recurrent disease,a second surgical procedure is usually performed. An alterna-tive for recurrent disease or for children in whom surgical riskis high (e.g., risk of facial nerve involvement) may be the useof a clarithromycin multidrug regimen such as that used forpulmonary disease (80, 179, 180). Experience with such an ap-proach is limited (179-182) but the proven activity of clarithro-mycin against M. &urn complex in other clinical settings andpreliminary reports makes this approach appear promising.

A special problem is created by the child who has granulo-matous disease with or without AFB on examination of theexcised lymph nodes, and whose PPD tuberculin skin test isstrongly positive (e.g., more than 15 mm). A course of antitu-berculosis therapy while awaiting the results of the lymphnode culture is reasonable, especially when there are any riskfactors for tuberculosis (positive family history, foreign-bornchild, etc.). If the cultures fail to yield any mycobacteria, anti-tuberculosis therapy should be discontinued unless there aresignificant risk factors for tuberculosis.

Skin, Tissue, and Skeletal Disease

For adult patients with extrapulmonary, localized M. aviumcomplex disease involving skin, soft tissue, tendons and joints,and occasionally bone, a combination of excisional surgery (orsurgical debridement) and chemotherapy is usually performed.Whether a three-drug regimen alone in this setting would beadequate is not known. The optimal duration of treatment isalso unknown, but drug treatment usually lasts 6 to 12 mo.

TREATMENT OF DISSEMINATED Mycobacterium&urn DISEASE

Disseminated M. avium is associated with an increased mor-tality in patients with AIDS. In one natural history study, themedian survival was 134 d after the first positive blood culture,and only 13% of patients were alive at 1 yr (53). Initially, someclinicians questioned whether M. avium was a direct cause ofdeath or only present in persons who were dying of other rea-sons. Several controlled studies have shown shortened sur-vival in patients with disseminated M. avium when comparedto cohorts of patients without M. avium (183). Based on theincreased morbidity and mortality associated with dissemi-nated M. hum, prophylaxis should be strongly considered inhigh-risk patients and therapy should be offered to all patientswith established disease.

Early (premacrolide) studies of the treatment of M. aviumin patients with AIDS demonstrated the ability of multidrugregimens to lower the burden of mycobacteria in the bloodand improve symptoms (184, 185). The drugs used in thesestudies such as ethambutol, clofazamine, rifampin, and cipro-floxacin have been shown to have modest activity in vitro, andtwo of the agents (ethambutol and rifabutin) to have modestactivity in single-drug therapy studies of patients with AIDSand M. avium (186, 187). A major advance in therapy camewith the recognition that clarithromycin and azithromycinwere potent agents against M. avium complex. Both clarithro-mycin and azithromycin were shown to markedly reduce thenumber of bacteria in the blood of patients in small pilot stud-ies (160, 163). In a larger study of 1.54 adult patients withAIDS and M. avium bacteremia, clarithromycin was given assingle-drug therapy in doses of 500, 1,000 or 2,000 mg twicedaily. All three groups had clearance of bacteremia and reduc-tion in symptoms, although the groups receiving the higherdoses had greater toxicity and a higher mortality (161). It wasalso noted, however, that resistance was a problem, as clinical

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relapse and in vitro resistance developed in approximately20% of individuals by 12 wk.

Rifabutin has also been demonstrated to be effective inseveral small studies of patients with AIDS who had dissemi-nated M. avium (184, 188). As monotherapy, it was shown toreduce colony counts in the blood (I 87). Clearance of bactere-mia occurred in 7 of 11 patients receiving rifabutin, clofaza-mine, and ethambutol, compared to 0 of 13 patients with clo-fazimine alone in another study (188).

Due to problems with drug resistance, as well as the needto eradicate large numbers of organisms, multidrug therapy isconsidered essential in the treatment of patients with dissemi-nated M. hum. There are currently few well done compara-tive trials of the many possible multidrug regimens. A Cana-dian HIV Trials Network study (171) involving 229 patientsdid demonstrate the combination of clarithromycin, rifabutin,and ethambutol to be superior to rifampin, ethambutol, clofa-zimine, and ciprofloxacin at both reducing bacteremia (69%versus 29%, p < 0.001) and prolonging median survival (8.6mo versus 5.2 mo, p = 0.001).

Based on currently available data, it would be advisable toalways use a minimum of three drugs-one of which should beclarithromycin (500 mg twice daily) or azithromycin (250 mgor 500 mg daily). Most investigators would use ethambutol asthe second agent at a dose of 15 mg/kg per day, although con-sideration should be given to an initial course of 25 mglkg forthe first 2 mo. Rifabutin has the best potential as the thirdagent. Use of rifabutin will be problematic, however, in pa-tients also on protease inhibitors, given its induction of thecytochrome P-450 system that metabolizes all currently ap-proved members of this drug class. Clofazimine has also beenused, as has a quinolone, but neither seems to contributemuch to the regimen, and clofazimine has been associatedwith a higher mortality in two comparative treatment trials(189). Amikacin (191) and streptomycin are both active, andone or the other should be considered for use in patients withsevere symptoms due to M. uvium complex, especially as partof initial therapy.

It should be noted that drugs used to treat mycobacterialdiseases in patients with AIDS are associated with frequentadverse effects, and changes to therapeutic regimens may of-ten be required. Of particular note has been the frequent oc-currence of uveitis when doses of clarithromycin higher than500 mg twice daily have been used in combination with rifabu-tin doses of 600 mg daily (175). This incidence fell to only 6%(3 of 53 patients) in the Canadian HIV trial when the rifabutindose was reduced to 300 mg daily, the currently recommendeddose (171).

Another problem is the interaction of rifamycins with therecently introduced protease inhibitors (saquinavir, ritonavir,and indinavir) for treatment of AIDS. Rifampin, and to alesser degree rifabutin, enhances hepatic metabolism of theprotease inhibitors, which may result in subtherapeutic levelsof these agents and promote the emergence of resistant HIVstrains. The protease inhibitors inhibit metabolism, and there-fore promote dose-related adverse effects, of the rifamycins(especially rifabutin). Recent recommendations, made in thecontext of tuberculosis therapy, suggest that rifampin shouldnot be used with the protease inhibitors, but that rifabutin canbe used at modified doses with at least one of these agents, in-dinavir (190). This recommendation would have little impacton the treatment or prophylaxis of disseminated M. avium dis-ease since rifabutin is the preferred rifamycin. The impact onthe treatment of other NTM such as M. kansasii, whererifampin has traditionally been used, is less clear. Alternativestrategies include treatment of NTM infections without a rifa-

mycin or withholding the protease inhibitor until the myco-bacterial infection has been treated. The improved immunefunction resulting from aggressive antiretroviral therapy, in-cluding a protease inhibitor, might ultimately be the most im-portant factor for clearance of disseminated NTM infection inAIDS patients; therefore, continuing a protease inhibitor is ahigh priority. Optima1 therapy for disseminated NTM disease,especially M. uvium, requires a multidrug treatment regimenincluding a rifamycin. Overall, in a patient on protease inhibi-tors with proven disseminated M. avium, it still seems prudentto include rifabutin in the treatment regimen, even if the doseis attenuated. For other NTM, the importance of the rifamycinshould be evaluated based on the specific organism beingtreated.

PROPHYLAXIS OF DISSEMINATED DISEASE IN AIDS

The incidence of disseminated M. avium can be reduced byprophylactic antimicrobials. Rifabutin was demonstrated to beeffective in two placebo-controlled, double-blind studies. My-cobucterium uvium bacteremia developed in 8% of adult pa-tients receiving 300 mg of rifabutin daily and in 17% of pa-tients on placebo (54). Because rifabutin is highly activeagainst M. tuberculosis, it is probable that daily use of rifabu-tin would also provide prophylaxis against tuberculosis. Ac-tive tuberculosis must be ruled out before initiating rifabutinprophylaxis in order to prevent the development of drug-resis-tant tuberculosis. Clarithromycin in a dose of 500 mg twicedaily was effective in a controlled trial of 667 adult patients inreducing the incidence of M. avium complex bacteremia from16% in the placebo group to 6% in the treatment group (192,193) while in a related trial it was shown to be more effectivethan rifabutin (193). Azithromycin at a dose of 1,200 mg onceweekly, either alone or in combination with rifabutin, has alsobeen shown to be effective in a published clinical trial involv-ing 693 adult patients (194). The final selection of agents maydepend on cost, tolerability, and potential drug interactions ofthe agents. Rifabutin should generally be avoided in patientson protease inhibitors because it markedly enhances their me-tabolism and reduces serum levels of the protease inhibitors.Some clinicians and the United States Public Health Servicehave advocated use of indinavir but not other currently avail-able protease inhibitors (retonavir, saquinquir) with reduced-dose rifabutin if both drugs are deemed essential.

The development of drug resistance during prophylaxis is aconcern, and it has already been noted to occur with the use ofclarithromycin (192, 193) or azithromycin (194) as monother-apy, but not the rifabutin monotherapy (54) or azithromycinwhen combined with rifabutin (194). Because of the very highrisk of disseminated M. uvium in persons with advanced HIVinfection, prophylaxis should be offered to all patients withCC 50 CD4 cells, especially in patients with a history of oppor-tunistic infection (195,196).

TREATMENT OF RAPIDLY CROWINGMYCOBACTERIAL DISEASE

Disease caused by the rapidly growing mycobacteria, espe-cially cutaneous disease, has come to be recognized as rela-tively common in selected areas of the United States. Thesoutheastern United States from Georgia to Texas appears tobe the major endemic area, although disease has been re-ported from all over the United States. Most clinical disease issporadic and community acquired, although nosocomial out-breaks or clustered cases have been reported (16-26) and theassociation 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(16, 17,21, 94) is well recognized.

Most clinical disease (more than 90%) is due to three spe-cies of rapidly growing mycobacteria: M. fortuitum, M. absces-sus, and M. chelonae (91). Two taxa originally identified asbiovariants within M. fortuitum (M. fortuitum third biovariantcomplex, sorbitol-positive and sorb&-negative) are still un-dergoing taxonomic evaluation. Both groups may eventuallyattain species status. Mycohacterium smegmatis (197), M. per-egrinum (91), M. mucogenicum (formerly known as the “M. che-loncre-like organisms” or MCLO) (198), and rarely, chromogenicrapidly growing mycobacteria (199-201) may also occasionallybe responsible for human disease.

Mycohucterium fortuitum, M. ahscessus, and M. chelonaeare resistant to the antituberculous agents, but they are sus-ceptible (especially M. ,fiwtuitum) to a number of traditionalantibacterial agents (100, 138-141). Isolates of M. fortuitumtreatment are susceptible to amikacin (lOO%), ciprofloxacinand ofloxacin (lOO%), sulfonamides (100%) cefoxitin (SO%),imipcncm (lOO%), clarithromycin (80%), and doxycycline(50%). Isolates of M. abscessus arc susceptible to clarithromy-tin (loo%), clofazimine, amikacin (90%), and cefoxitin (70%)and imipenem (SO%). Isolates of M. chelonae are susceptibleto amikacin (SO%), tobramycin (loo%), clarithromycin (loo%),imipenem (600/o), clofazimine, doxycycline (25%), and cipro-floxacin (20%).

Cutaneous Diseases

Clinical disease caused by the rapidly growing mycobacteriausually follows accidental trauma or surgery in a variety ofclinical settings (91). Some minor infections will resolve spon-taneously or after surgical debridement. However, severalstudies of postinjection abscesses in which no therapy wasgiven revealed disease that persisted in most patients for 8 to12 mo before spontaneously resolving. In two outbreaks of

M. abscessus in the era

M. fortuitum, M. ubscessus, or M. chelonae, comparing oneform of treatment with another or with no drug treatment atall, have been performed. However, susceptibility studies(139-141) have demonstrated excellent in vitro activity ofdrugs such as clarithromycin, imipenem, cefoxitin, cefmeta-zole, and amikacin. Several case studies (197, 202, 203) andone clinical trial (204) of patients with cutaneous diseasetreated on the basis of in vitro susceptibilities have showngood results.

On the basis of these studies, guidelines have been sug-gested for drug therapy of nonpulmonary disease caused byrapidly growing mycobacteria (205). Because of variable drugsusceptibility among species and even within species and sub-groups, susceptibility testing of all clinically significant isolatesis essential for good patient management. The first-line antitu-berculosis drugs (isoniazid, rifampin, pyrazinamide, etc.) haveno role in the therapy of rapidly growing mycobacterial dis-ease, with the exception of ethambutol, to which M. smegmatisis susceptible (197).

For serious disease caused by M. fortuitum and M. absces-sus, intravenous amikacin is given at a dose of 10 to 15 mg/kgin two divided doses to adult patients with normal renal func-tion (average 400 mg twice a day) to provide peak serum lev-els in the low 20 kg/ml range. The lower dose (10 mg/kg)

should be used in patients over the age of SO; once-daily dos-ing is unproven clinically but appears reasonable. The amika-tin combined with high-dose cefoxitin (I 2 g/d given intrave-nously) is recommended for initial therapy (minimum 2 wk)until clinical improvement is evident. For M. chelonue, tobra-mycin is more active in vitro than amikacin. Imipenem ap-pears to be a reasonable alternative to cefoxitin for these twospecies, and it should be used with isolates of M. smegndsand M. chelonae that are resistant to cefoxitin (100, 139, 197).Monitoring of renal function, eighth nerve function, and whiteblood cell counts (for the beta lactams) should be done on pa-tients receiving this regimen. If organisms are susceptible tooral agents, therapy can be switched to one or more of theseagents. For M. abscessus, the only oral agents available fortherapy are clofazimine and clarithromycin (140). For M. che-lonae, clarithromycin, clofazimine, and (for approximately20% of strains) ciprofloxacin and doxycycline are the onlyoral drugs susceptible in vitro (100, 140). The only clinical trialfor M. chelonae skin disease was ddne with clarithromycin. Ofpatients (all adults) treated with monotherapy at 500 mg twicea day for 6 mo, all were cured except one patient (8%) who re-lapsed with an isolate that developed resistance to clarithro-mycin (204). For serious disease, a minimum of 4 mo of ther-apy is necessary to provide a high likelihood of cure. For boneinfections, 6 mo of therapy is recommended (202).

Surgery is generally indicated with extensive disease, ab-scess formation, or where drug therapy is difficult. Removal offoreign bodies such as breast implants, percutaneous cathe-ters, etc., is important, or even essential, to recovery.

Pulmonary Disease

The prevalence of lung disease caused by rapidly growing my-cobacteria is unknown; however, it is likely more commonthan early estimates as these organisms have gained increasingrecognition as pathogens. The largest group of patients withthis lung disease are elderly (older than 60), Caucasian, femalenonsmokers with no predisposing conditions or known lungdisease. 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-fection (206). The distinguishing feature of patients with a rec-ognized underlying disease is that their rapidly growing myco-bacteria lung disease occurs at a younger age, usually less than50, and almost all patients under 40 have one of these disor-ders (206).

Although early studies identified most respiratory isolatesof rapidly growing mycobacteria as M. fortuitum, use of mod-ern identification schemes have shown that M. abscessus (for-merly M. chelonae subspecies abscessus) accounts for approxi-mately 80% of rapidly growing mycobacterial respiratory diseaseisolates, while M. fortuitum (formerly M. fortuitum biovariantfortuitum) accounts for approximately 15% of these isolates(206). An important exception is the small group of patients whohave gastroesophageal disorders with chronic vomiting and rap-idly growing mycobacterial lung disease, in whom M. abscessusand M. fortuitum occur with equal frequency. Overall, M. absces-sus appears to be a more virulent respiratory pathogen thanM. fortuitum. Obtaining a single respiratory isolate of M. absces-sus is more likely to indicate significant disease than a singleisolate of M. ,fortuitum, although careful clinical evaluation andfollow-up is always necessary to determine the significance ofan NTM respiratory isolate.

In lung disease due to rapidly growing mycobacteria in pa-tients with no apparent risk factors, the chest radiograph usu-

American Thoracic Society s17

ally shows multilobar, patchy, reticulonodular or mixed inter-stitial-alveolar infiltrates with an upper lobe predominance.Cavitation occurs in only approximately 15% of cases (206).The chest radiograph is usually not typical for or suggestive ofreactivation pulmonary tuberculosis, which likely accounts fora delay in ordering sputum for AFB analysis and therefore adelay in diagnosis. High resolution computed tomography ofthe lung frequently shows associated cylindrical bronchiectasisand multiple small (< 5 mm) nodules, a pattern also seen innonsmokers with M. aviunz complex lung disease (65-68). In-terestingly, approximately 15% of patients with M. abscessuswill also have M. avium complex, suggesting the close rela-tionship of the disorders (206). Some patients have positivesputum cultures for P.se~~rlomonas aeruginosa, further evi-dence of bronchiectasis. The radiographic features of this dis-ease in cystic fibrosis are still under investigation.

The usual presenting symptoms are cough and easy fatiga-bility, often attributed for months or years to bronchitis orbronchiectasis. Fever, night sweats, and weight loss occur, butthey are much less common and less severe than with M. tu-bercuhsis. The constellation of typical presenting symptomsin an elderly nonsmoking patient with no underlying lung dis-case, a compatible chest radiograph, and multiple positivesputa is sufficient to make a diagnosis. The presence of otherdiseases or unusual features may necessitate obtaining a lungbiopsy (bronchoscopy with transbronchial biopsy) to be cer-tain of the diagnosis.

The natural history of this disease depends primarily on thepresence or absence of underlying disorders. For most pa-tients with M. ahsce.ssu.s and no underlying disorder, the dis-ease is indolent and slowly progressive. Some patients showlittle radiographic change over years. More fulminant, rapidlyprogressive disease can occur, particularly in association withgastrocsophageal disorders. Death occurs as a consequence ofM. rrhscessu.s in 20% of cases (206).

,Uycohacterium fortuitum isolates, when they do occur, areusually susceptible to multiple oral antimicrobial agents in-cluding the newer macrolides and quinolones, doxycycline andminocycline, and sulfonamides (139-141). Drug susceptibili-ties for this species are essential for effective therapy. Six totwelve months of therapy with two oral agents to which theM. fortuitum isolate is susceptible in vitro usually results inclinical cure. Unfortunately, the M. fortuitum group producesless than 20% of lung disease due to rapidly growing mycobac-teria.

Mycohcterium uh.sce.ssus isolates are usually susceptible invitro only to the parenteral agents amikacin, cefoxitin, and im-ipenem, and to the newer oral macrolides (clarithromycin andazithromycin). Preliminary studies suggest that monotherapywith the newer macrolides is not sufficient to produce micro-biologic cure for M. abscessus. Combination therapy of low-dose amikacin plus high-dose cefoxitin for 2-4 wk almost in-variably produces clinical and microbiologic improvement,but cost and morbidity prohibit potentially curative courses oftreatment (probably 4-6 mo). Surgical resection for limiteddisease related to prior localized lung disease can also be cura-tive (206). Unfortunately, suppressive therapy, including peri-odic parenteral antibiotic or oral macrolide therapy, may beall that can bc realistically administered to control the symp-toms and progression of M. abscessus lung disease.

TREATMENT OF Mycobacterium marinum DISEASE

A number of treatment modalities have been used for cutane-ous disease caused by M. marinum (69, 13). These include sim-ple observation for minor lesions, surgical excision, the use of

antituberculous agents, and the use of single antibiotic agents.By standard susceptibility testing, these isolates are suscepti-ble to rifampin and ethambutol, intermediately susceptible tostreptomycin, and resistant to isoniazid and pyrazinamide.Isolates are also susceptible to clarithromycin, sulfonamides,or trimethoprim-sulfamethoxazole and susceptible or inter-mediately susceptible to doxycycline and minocycline.

Acceptable treatment regimens in adults include clarithro-mycin 500 mg twice a day, minocycline or doxycycline at 100mg twice a day (207-209). trimethoprim-sulfamcthoxazole at160/800 mg twice a day (210) or rifampin (600 mg) plus etham-butol (15 mg/kg) daily (208, 211) with each regimen beinggiven for at least 3 mo. Rifampin alone has also been recom-mended, but little experience with this regimen has been re-ported (212). The rate of clinical response is quite variable,and a minimum of 4 to 6 wk of therapy should be given beforeconsidering that the patient may not be responding. Surgicaldebridement may also be important, especially for disease in-volving the closed spaces of the hand or disease that respondspoorly to drug therapy (13, 211). If a lesion is excised surgi-cally, many clinicians provide drug coverage during the perio-perative period. It is not clear if longer durations of drug treat-ment after surgery offer any additional advantage.

TREATMENT OF PULMONARY DISEASE DUE TO OTHERNONTUBERCULOUS MYCOBACTERIA

Although most species of NTM have been reported to causepulmonary disease, there are only four additional species thatmerit consideration. Because of the small number of reportedcases and the absence of therapeutic trials or treatment of dis-ease caused by these species, only limited recommendationson drug therapy can be made now. In most cases, if there hasbeen satisfactory clinical and bacteriologic response to chemo-therapy, a treatment period of 18 to 24 mo is recommended.

Mycobacterium malmoense is a slowly growing, nonpig-mented NTM species that causes pulmonary disease. Althoughrare in the United States, it has been increasingly recognizedin England, Wales, and northern Europe. Most isolates are sus-ceptible to ethambutol, and many are susceptible to rifampinand streptomycin, The four-drug regimen recommended fortreating M. avium complex (before the availability of mac-rolides and rifabutin) has resulted in clinical and bacteriologicresponses in most cases (70, 213). Potential improvements intherapeutic response with the macrolides and rifabutin has notbeen assessed.

Mycobacterium simiae is a slowly growing, nonpigmentedMycobacterium that may be confused with M. tuberculosis, asit is the only NTM that is niacin-positive. It is an uncommoncause of pulmonary and disseminated infection, and many pa-tients with respiratory isolates of this species do not have dis-ease. Most isolates are resistant to all first-line antimycobacte-rial drugs, and response to chemotherapy has been variable(32, 214). For patients with disseminated or progressive pul-monary disease in need of treatment, initial therapy may bestarted with the four-drug regimen recommended for M. aviumcomplex (clarithromycin, ethambutol, rifabutin, and strepto-mycin), modified as needed using results of susceptibility tests.

Mycobacterium szulgai is a slowly growing Mycobacteriumthat 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, only24 cases of disease had been reported in the English literature.The organism is usually susceptible to rifampin and higherconcentrations of isoniazid, streptomycin, and ethambutol.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 ORPROPHYLAXIS OF NONTUBERCULOUS MYCOBACTERIAL DISEASE

Drug Major Side Effects/Toxicity Monitoring Procedures

lsonrazid Hypersensitivity (fever, rash)

Hepatitis

Ethambutol

Rifampin,rifabutin

Rifabutin only

Streptomycin

amikacin,tobramycin

Ethionamide

Increased serum levels ofphenytoin (DilantinTM)

Peripheral neuropathy relatedto pyridoxine deficiency

Optic neuritis (loss of red/greencolor discrimination, loss of

visual acuity)

Orange discoloration ofsecretions and urine; staining

of soft contact lensesGastrointestinal disturbance

(nausea, vomiting)

Hypersensitivity (fever, rash)

Hepatitis

Increased hepatic metabolismof numerous agents, includingbirth control pills, ketoconarole,

quinidine, prednisone, oralhypoglycemics (sulfonylureas),

digitalis, methadone, warfarin,clarithromycin, and protease inhibitors

“Flu-like” syndrome,thrombocytopenia, renal failure

Polymyalgia, polyarthralgia,leukopenia, granulocytopenia,anterior uveitis (rifabutin with clarithromycin)

Vestibular/auditory toxicity

(dizziness, vertigo, ataxia,tinnitus, hearing loss)

Renal toxicity

Hypersensitivity (fever, rash,eosinophilia) (streptomycin)

Gastrointestinal disturbance

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

Hepatitis

Cycloserine

Azithromycin,clarithromycin

Central nervous system (anxiety,depression, altered behavior)

Peripheral neuropathyCentral nervous system

(depression, altered behavior,

confusion, anxiety, psychosis,

seizures)Gastrointestinal disturbance

(nausea, vomiting, diarrhea)

Decreased hearing

Hepatitis

Clarithromycin only Inhibited hepatic metabolism of

several agents, including

rifabutin, some proteaseinhibitors, SeldaneTM

Clinical symptomsClinical symptoms; periodic alanine

aminotransferase (ALT) or aspartate

aminotransferase (AST) determinations,especially in first 3 mo of therapy

Monitor serum levels

Clinical symptoms

Discontinue drug immediately withsubjective visual loss; periodic and

symptomatic testing for red/greencolor discrimination and visual acuity

(monthly if receiving 25 mg/kg per day);ophthalmology evalution for symptomatic

patients

None

Clinical symptoms

Clinical symptomsClinical symptoms; AST or ALT

determinations based on symptoms

Monitor clinical status and appropriateserum levels when possible

Clinical symptoms; platelet count, serum

creatinine as indicatedClinical symptoms, periodic WBC counts

Clinical symptoms including changes

in hearing, ability to walk, dizziness;periodic hearing tests in high-risk

patients or those with auditory/vestibular symptoms; periodic

amikacin serum levelsPeriodic serum creatinines; periodic

amikacin or tobramycin serum levels

Clinical symptoms

Clinical symptoms

Clinical symptoms; periodic AST or

ALT determinations

Clinical symptoms

Clinical symptomsClinical symptoms, assessment of

mental status; serum levelsweekly for first month if timely

testing available

Clinical symptoms

Clinical symptomsPeriodic alkaline phosphatase, AST and

gamma glutamyl transpeptidase (GCT)

for first 3 moMonitor clinical status and

appropriate serum levels when

possible; avoid use of Seldane

(continued)

American Thoracic Society s19

TABLE 5

CONTINUED

Drug

Ciprofloxacinofloxacin

Cefoxitln

Tetracyclines(doxycycline,minocycline)

Sulfonamides,trimethoprim/sulfamethoxazole

Major Side Effects/Toxicity

Gastrointestinal disturbance(nausea, vomiting, diarrhea)

Central nervous system(headache, insomnia)

Hypersensitivity (fever, rash,eosinophilia)

Hematologic (anemia, leukopenia)Gastrointestinal disturbance

(nausea, vomiting, diarrhea)Cutaneous (photosensitivity, rash,

hyperpigmentation)Central nervous system

(dizziness, vertigo)(minocycline)

Gastrointestinal disturbance(nausea, vomiting, diarrhea)

Hematologic (leukopenia, anemia,thrombocytopenia)

Hypersensitivity (fever, rash,Stevens-Johnson syndrome)

Monitoring Procedures

Clinical symptoms

Clinical symptoms

Clinical symptoms

Periodic blood countsClinical symptoms

Clinical symptoms

Clinical symptoms

Clinical symptoms

Periodic blood counts

Clinical symptoms

when used in combination has been shown in vitro (215). Mostpatients treated with these drugs respond to therapy.

Relatively uncommon in the United States, M. xerzopi hasbeen reported as a common cause of slowly progressive NTMpulmonary disease in western Europe. In southeast England,it is the most common NTM recovered in the laboratory andhas been since 1977 (216). Disseminated disease and joint dis-ease caused by this organism have also been reported. In vitrosusceptibility to antituberculosis agents is variable, althoughenhanced drug activity has been shown with the combinationof rifampin and streptomycin (215). Although some investiga-tors have reported success with surgical therapy similar to thatused for selected patients with M. avium complex disease, oth-ers have had disappointing results (136, 173). Results withdrug therapy alone in the premacrolide era have also shownvariable results. One recent study of clarithromycin-contain-ing regimens (137) demonstrated an excellent sputum conver-sion rate compared to these older studies. For most patients,initial therapy should consist of a macrolide, rifampin or rifab-utin, and ethambutol with or without initial streptomycin. Pa-tients who fail therapy or who relapse after treatment mightbe considered for surgery (30,136,173).

MONITORING FOR DRUG TOXICITY

Monitoring for drug toxicity of patients who are being treatedfor NTM disease is important, given the number and type ofdrugs used and the older age of these patients. It should in-clude monitoring of the visual system including visual acuity(ethambutol), the presence of eye pain and decreased visualacuity or uveitis (rifabutin) (175,176), and red-green color dis-crimination (ethambutol): the central nervous system (cyclo-serine, ciprofloxacin, ofloxacin, ethionamide); the liver (iso-niazid, rifampin, ethionamide, clarithromycin, rifabutin) (174,176); the kidney (streptomycin, amikacin); auditory and vesti-bular function (streptomycin, amikacin, azithromycin); andhematologic indices (sulfonamides, cefoxitin, rifabutin) (176).Major side effects and monitoring procedures are listed inTable 5.

For the aminoglycosides, this monitoring should includeroutine questioning about balance, ability to walk (especiallyin the dark), tinnitus, dizziness, and difficulty hearing. Base-line blood urea nitrogen and creatinine measurements shouldbe obtained, with reduction of the streptomycin dose and/orfrequency of administration if these are abnormal. Periodicmonitoring of renal function is recommended for high-risk pa-tients receiving drugs daily or five times a week, especiallywith patients older than 50 yr or who have impairment of re-nal function. A baseline hearing test should be considered, es-pecially in high-risk patients, and then repeated if signs orsymptoms of seventh nerve toxicity appear.

For cycloserine, careful attention should be given to signsof central nervous system toxicity, which may include seizures,lethargy, depression, alterations in personality, and even sui-cidal ideations. Because toxicity with this drug relates prima-rily to excessive serum levels (> 40 pg/ml), patients with cen-tral nervous system symptoms or abnormal baseline renalfunction should have serum level determinations. Unfortu-nately, such tests are not available in most clinics and arerarely available in a timely fashion to help with decisions ondosing. 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-nal failure. A lower dose (e.g., 250 mg twice a day) is oftengiven in such cases, and discontinuation of the drug may benecessary if central nervous system symptoms occur and onecannot monitor serum levels.

Given that isoniazid hepatotoxicity is higher in the olderpopulation, some physicians obtain a baseline measurement ofaspartate aminotransferase (AST), then repeat this determi-nation at 2,4, and 8 wk and thereafter during therapy as clini-cally indicated. Other monitoring considerations are the sameas those for patients with tuberculosis (see the ATS Statement“Treatment of Tuberculosis and Tuberculosis Infections inChildren and Adults” (2,217).

The incidence of gastrointestinal side effects such as nau-sea, vomiting, abdominal pain, and cramping is almost prohib-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,and administering it with food. In the older patient, limitingthe total dose to 500 mg may help reduce toxicity. A good re-view of side effects and toxicities experienced at the NationalJewish Hospital with ethionamide and cycloserine is providedin a study by Lester (218).

Some advcrsc events with rifabutin are comparable tothose seen with rifampin. These include rash, fever, nausea,vomiting, and hepatitis. Several adverse events are unique torifabutin. including anterior uveitis, skin hyperpigmentationor pseudojaundice, and a polymyalgia/polyarthralgia syndrome(175, 176). The last three adverse events are seen almost ex-clusively in patients concurrently receiving clarithromycin.These effects can be minimized by giving no more than 300mg/d of rifabutin when combined with clarithromycin. Leuko-penia is also seen with rifampin, but it is much more commonwith rifabutin. Periodic white blood cell counts should be per-formed on all patients taking rifabutin, perhaps at monthly in-tervals. Mild Icukopenia is common (8 of 26 or 31% of pa-tients in one series of HIV-negative patients on 600 mg/ddeveloped WBC counts below 4,000 cells/mm”) (176), and thedrug should be discontinued only if cell counts fall below acomfortable range (perhaps 2,500 cells/mm’ or an absolutegranulocyte count of 1,SOO or less in HIV-negative patients).

This statement was prepared by an ad hoc committee of theScientific Assembly on Microbiology, Tuberculosis, and Pul-monary Infections. Members of the committee were:

RICIIARD J. WALLACE , JR., M.D., ChairmanJI:FFREY GI.AssRorH, M.D.DAVID E. GRIPFITH, M.D.KENNUH N. OLIVIER, M.D.JAMES L. C O O K, M.D.FRED GORUIN, M.D.

Outside consultants: Drs. Timothy Kiehn, Laboratory; ClarkInderlicd. Laboratory; Mark Goldberger, HIV Issues; andBarbara A. Brown, Laboratory.

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American Thoracic Society

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