Chapter 8

NontuberculousmycobacterialinfectionsC.L. Daley

Summary

Nontuberculous mycobacteria (NTM) represent a large groupof bacteria that have been isolated from environmental sources.When NTM are inhaled by a susceptible individual, infectioncan occur and lead to progressive lung disease. Epidemiologicalstudies have described increases in the prevalence of NTMdisease in multiple areas worldwide. Risk factors for diseaseinclude chronic lung diseases, such as bronchiectasis andchronic obstructive pulmonary disease, as well as various formsof immune deficiency. Patients typically present with eitherfibrocavitary or nodular bronchiectatic disease. Isolation ofNTM from respiratory specimens does not always indicatedisease so clinicians must evaluate clinical, radiographic andmicrobiologic information in order to diagnosis NTM-relatedlung disease. The American Thoracic Society has developeddiagnostic criteria that can aid clinicians but the criteria cannotaccount for all clinical scenarios or for all NTM species giventhe large spectrum of pathogenicity encountered. Treatmentusually consists of at least two antibiotics but the exact regimenwill vary depending on the species and there is some variation inrecommendations.

Keywords: Bronchiectasis, mycobacteria, Mycobacteriumavium complex, nontuberculous mycobacterial infections

Correspondence: C.L. Daley, Divisionof Mycobacterial and RespiratoryInfections, National Jewish Health,1400 Jackson Street, Denver, CO80206, USA, Emaildaleyc@njhealth.org

Eur Respir Mon 2011. 52, 115–129.Printed in UK – all rights reserved.Copyright ERS 2011.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.10003810

Nontuberculous mycobacteria (NTM) comprise ,140 species, many of which have beenreported to cause disease in humans. Based on their rate of growth in subculture, NTM have

traditionally been divided into slowly and rapidly growing species (table 1) [1–3]. Also referred toas environmental mycobacteria, NTM have been isolated from natural and drinking watersupplies, as well as soil [4–7]. The presumed source of infection is exposure to these environmentalreservoirs because human-to-human transmission has not been documented. When inhaled bysusceptible individuals, such as those with chronic obstructive lung disease or bronchiectasis,infection with NTM can lead to a chronic, progressive and sometimes fatal lung disease.

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Despite their frequent isolation in the environment and human specimens, NTM were notwidely recognised as a cause of human disease until the late 1950s. Since that time, the numberof new species of NTM has grown dramatically [3] and the rate of disease related to NTM hasalso increased, overtaking the rate of tuberculosis (TB) in some areas [8]. Diagnosis andtreatment of NTM lung disease remains challenging for clinicians and depending on the extentof disease and species involved, a cure may be difficult to achieve. When considering treatment,clinicians must weight the potential benefits of therapy against the cost and potential side-effects of current regimens.

Epidemiology

Incidence and prevalence

The epidemiology of NTM disease has been difficult to determine because reporting is notmandatory in most countries and differentiation between infection and disease is often difficult.Although the incidence and prevalence of NTM infections have varied significantly across studies,recent studies have reported high rates of NTM pulmonary disease, particularly in olderpopulations [9–12]. Among 933 patients with at least 1 NTM isolate in Oregon (USA), 527 (56%)met the American Thoracic Society (ATS) microbiological definition for disease giving anannualised prevalence of 5.6 cases per 100,000 for pulmonary disease [9]. The prevalence wassignificantly higher in females (6.4 cases per 100,000) than males (4.7 cases per 100,000) and washighest in persons aged .50 years (15.5 cases per 100,000). In another report from Oregon, theoverall 2-year prevalence of NTM pulmonary disease was 8.6 cases per 100,000 and increased to20.4 cases per 100,000 in those aged o50 years [10]. The annualised prevalence of NTM lungdisease within four integrated healthcare delivery systems in the USA ranged from 1.4 to 6.6 per100,000 [11]. Among persons aged o60 years, annual prevalence was 26.7 per 100,000.

Studies from Canada [8], Australia [12], Taiwan [13], the Netherlands [14] and the USA [11, 15]have reported increases in the incidence or prevalence of NTM. MARRAS et al. [8] reported anincrease in the number of pulmonary NTM isolates in Ontario (Canada) from 9.1 per 100,000 in1997 to 14.1 per 100,000 in 2003. Difficulty in eradicating NTM infections resulted in a prevalencehigher than that of tuberculosis [16]. More recently, two studies from the USA reported increasesin NTM pulmonary disease [11, 15]. In a study examining the prevalence of NTM lung disease infour integrated healthcare delivery systems, there was a 2.6% and 2.9% increase per year in femalesand males, respectively [11]. Pulmonary NTM hospitalisations increased significantly among bothmales and females between 1998 and 2005 in a study involving 11 states in the USA [15]. Annualprevalence increased among males and females in Florida (3.2% and 6.5%, respectively) andamong females in New York (4.6% per year) with no significant changes in California.

Table 1. Examples of slowly growing and rapidly growing nontuberculous mycobacteria that have beenreported to cause lung disease

Slowly growing mycobacteria Rapidly growing mycobacteria

Mycobacterium arupense Mycobacterium kubicae Mycobacterium abscessus Mycobacterium fortuitumMycobacterium asiaticum Mycobacterium lentiflavum Mycobacterium alvei Mycobacterium mageritenseMycobacterium avium Mycobacterium malmoense Mycobacterium boenickei Mycobacterium massilienseMycobacterium branderi Mycobacterium palustre Mycobacterium bollettii Mycobacterium mucogenicumMycobacterium celatum Mycobacterium saskatchewanse Mycobacterium brumae Mycobacterium peregrinumMycobacterium chimaera Mycobacterium scrofulaceum Mycobacterium chelonae Mycobacterium phocaicumMycobacterium flavescens Mycobacterium shimodei Mycobacterium confluentis Mycobacterium septicumMycobacterium florentinum Mycobacterium simiae Mycobacteium elephantis Mycobacterium smegmatisMycobacterium heckeshornense Mycobacterium szulgai Mycobacterium goodii Mycobaterium thermoresistibleMycobacterium intermedium Mycobacterium triplex Mycobacterium holsaticum

Mycobacterium interjectum Mycobacterium terrae

Mycobacterium intracellulare Mycobacterium xenopi

Mycobacterium kansasii

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Earlier descriptions of pulmonary NTM disease described a male predilection for disease.However, in three recent studies from the USA, a higher proportion of disease was observed infemales than males [9–11]. Over an 8-year period from 1998 to 2005, the overall prevalence rate ofhospitalisations for NTM pulmonary disease in the USA was highest in females aged o70 years(9.4 per 100,000) compared with similarly age matched males (7.6 per 100,000) [11].

The reasons for the increase in incidence and prevalence have not been explained althoughincreased awareness of the disease and improved diagnostic techniques could be factors. A trueincrease in incidence could be related to changes in the host such as an aging population, anincreased prevalence of chronic lung disease or an increase in the number of immunocompro-mised individuals. The observation of a decreased incidence of pulmonary TB and an increasedincidence of pulmonary NTM [8] could be explained by cross-immunity between mycobacterialspecies. Finally, an increase in the prevalence or virulence of organisms in the environment orchanges in human behaviour that would lead to increased exposure to organisms could becontributors. In support of the latter, the frequency of skin reactivity to purified proteinderivative-B, which used antigens from Mycobacterium intracellulare, increased from 11.2% in1971–1972 to 16.6% in 1999–2000 [17].

Risk factors for NTM infection and disease

Studies utilising delayed type hypersensitivity reaction to subcutaneously injected mycobacterialantigens have estimated that 11–33.5% of the population in the USA has been exposed to NTM[18–21]. A prospective study using skin testing data from Palm Beach, Florida reported that 32.9%of 447 participants in a population-based random household survey had a positive reaction toMycobacterium avium sensitin [21]. Predictors of a positive reaction included Black race, birthoutside the USA and .6 years cumulative exposure to soil. Using data from the National Health andNutrition Examination Survey (NHANES), investigators reported similar findings with regards tosensitisation to M. intracellulare [17]. Male sex, non-Hispanic Black race and birth outside the USAwere each independently associated with sensitisation. These two studies are interesting in that skintest reactivity to either M. avium or M. intracellulare antigens was associated with factors probablyassociated with soil exposure. However, at least in the USA, disease seems to be more common inolder Caucasian females. Thus, the risk factors for exposure and infection may be different fromthose associated with disease.

Historically male sex has been considered a risk factor for NTM lung disease and males continueto make up the majority of patients in some areas [14]. However, studies from the USA and SouthKorea have noted a female predominance. In Oregon, as noted previously, the rate of NTMpulmonary diseases was higher in females than males and females made up 60% of cases. Why theshift to a female predominance remains unclear. However, there is likely a genetic link becausemany females who develop bronchiectasis and NTM infection share a similar body typecharacterised by tall slender status with a higher frequency of pectus excavatum, kyphoscoliosisand mitral valve prolapse than females who do not have NTM infection [22–24]. This conditionwas first described by PRINCE et al. [25] in 1989 and later referred to as the ‘‘Lady WindermereSyndrome’’ after the character in Oscar Wilde’s play Lady Windermere’s Fan, the referencereferring to fastidious behaviour in the character [26]. Recently, investigators reported that femalepatients with pulmonary NTM disease were taller, thinner and weighed less than matched controlsubjects [22]. To date, extensive evaluation of the immune system of these patients has beenunrevealing but mutations in the cystic fibrosis transmembrane conductance regulator gene arecommon [22, 27].

Most NTM are significantly less pathogenic than Mycobacterium tuberculosis and probably requiresome degree of host impairment to result in disease. Impairment can be caused by immune defectsor chronic lung disease of which the latter appears to be most common. NTM disease has beendescribed in association with cystic fibrosis (CF), chronic obstructive pulmonary disease in-cluding a1-antitrypsin deficiency, cavitary lung disease, pneumoconiosis, bronchiectasis, prior TB,

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pulmonary alveolar proteinosis and chronic lung injury due to aspiration from gastro-oesophagealdisorders [28–34]. Bronchiectasis is an almost universal finding in females with NTM infectionand it is seen in many males with NTM infection. However, NTM infections have been reported tooccur in only 1–2% of bronchiectasis patients in two small series from the UK [35, 36]. Incontrast, studies have documented a high prevalence of NTM from sputum cultures in patientswith CF, with estimates ranging from 3% to 19.5% [37, 38].

Pulmonary disease due to NTM has been described in several other immunocompromised patientpopulations including transplant recipients [39–42], individuals taking tumour necrosis factor-ainhibitors [43–45], and patients with mutations in interferon (IFN)-c receptor 1, IFN-c receptor2, interleukin (IL)-12 p40 and the IL-12 receptor [46, 47]. Most of these patients present withdisseminated disease. Scientists have hypothesised that in slender, older females, decreased leptin,increased adiponectin and/or decreased oestrogens may account for the increased susceptibility toNTM infections [48]. Additionally, anomalies of fibrillin that lead to the expression of theimmunosuppressive cytokine transforming growth factor-b may further increase susceptibility toNTM lung disease [48].

Diagnosis and management

Chronic pulmonary disease is the most common clinical presentation of NTM disease. In order todiagnose pulmonary NTM infection clinicians must weigh clinical, bacteriologic and radiographicinformation. Diagnostic criteria have been developed to aid the clinician in the diagnosticevaluation of persons suspected of having pulmonary NTM disease (table 2) [3, 49]. Although thediagnostic criteria provide a useful approach for the evaluation of patients with suspected NTMdisease, the approach has yet to be validated and it is impossible for a single set of diagnosticcriteria to be appropriate for all patients and species of NTM.

Unlike with TB, a single positive sputum culture for NTM is not diagnostic of pulmonary disease.However, when two or more sputum cultures are positive the diagnosis of disease is more likely.For example, 98% of patients with two or more positive sputum cultures for M. avium complex(MAC) had evidence of progressive disease in a study from Japan [50]. Whether this microbiologiccriterion holds true for other NTM species is not known but given the wide range of pathogenicityamong the various NTM species it is unlikely. Patients who are suspected of having NTM lungdisease but do not meet the diagnostic criteria should be followed clinically until the diagnosis iseither firmly established or excluded.

Laboratory diagnosis

Ultimately, the diagnosis of NTM disease is based on isolation of these organisms from clinicalspecimens. Both solid and broth media should be used for detection of mycobacteria and a semi-quantitative reporting of colony counts is recommended [3]. Most NTM grow within 2–3 weeks

Table 2. Microbiological criteria for diagnosis of nontuberculous mycobacteria lung disease

Respiratory specimen Culture and histopathological results

ATS recommendations BTS recommendations

Sputum specimen At least two separate positive cultures Positive cultures from specimensobtained at least 7 days apart

Bronchial wash/lavage One positive culture Not describedTissue biopsy Compatible histopathology

(granulomatous inflammation) and apositive biopsy culture and/or a positivesputum or bronchial wash/lavage culture

Not described

ATS: American Thoracic Society; BTS: British Thoracic Society. Data from [3, 49].

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on subculture and rapidly growing mycobacteria usually grow within 7 days of subculture.Identification of specific species can be based on phenotypic, chemotaxonomic and molecularmethods [3]. However, none of these procedures are sufficient to differentiate all NTM.

The clinical usefulness of drug susceptibility testing in the management of patients with NTMdisease remains controversial because in vitro results do not correlate well with clinical outcomesfor some mycobacterial species. Unfortunately, there is no single susceptibility method that isrecommended for all species of slowly growing mycobacteria. For MAC, a broth-based culturemethod with both microdilution and macrodilution methods are considered acceptable [3]. Initialisolates, as well as those from patients who fail or relapse, should be tested to clarithromycin.Isolates of Mycobacterium kansasii should be tested to rifampin as resistance to rifampin isassociated with treatment failure/relapse [3]. Broth microdilution minimum inhibitory con-centration (MIC) determination for susceptibility testing is recommended for rapidly growingmycobacteria.

As noted previously, skin test reactions to mycobacterial antigens are common in people living inendemic areas and, thus, are unable to distinguish NTM infection from disease. Tests that coulddistinguish infection from disease would be very helpful for clinicians. Measurement of anti-A60immunoglobulin (Ig)G was reported to have a sensitivtity of 87% and specificity of 97% fordetection of Mycobacterium abscessus disease in patients with CF [51]. In Japan, KITADA et al. [52]evaluated the performance of an assay that detects serum IgA antibody to glycopeptidolipid coreantigen for the diagnosis of MAC lung disease. The sensitivity and specificity of the assay fordetecting MAC lung disease were 84% and 100%, respectively. Antibody levels were higher inpatients with nodular bronchiectatic disease compared with fibrocavitary disease and levelscorrelated with extent of disease by chest computed tomography (CT) scans. In a follow-up studyof patients who underwent bronchoscopy, the sensitivity, specificity, positive predictive andnegative predictive values were 78.6%, 96.4%, 95.7% and 81.8%, respectively [53]. The sensitivityand specificity of the test for MAC pulmonary disease in patients with rheumatoid arthritis was43% and 100%, respectively [54]. Although these serologic assays are not widely available, theymay eventually find their way into diagnostic algorithms.

Slowly growing mycobacteria

The slowly growing mycobacteria include organisms with wide ranging pathogenicity such asM. kansasii and Mycobacterium szulgai, which are probably second only to M. tuberculosis in termsof disease producing capability and Mycobacterium gordonae and Mycobacterium terrae, whichrarely cause lung disease (table 1). MAC is typically the most common NTM to cause pulmonarydisease but the frequency of M. avium versus M. intracellulare has varied between studies.Recommendations for treatment vary between guidelines as highlighted in table 3 [3, 49, 55].

Mycobacterium avium complex

MAC includes the NTM species M. avium, of which there are several subspecies, M. intracellulare,and some that are as yet poorly described species. The traditionally recognised presentation ofMAC lung disease has been as apical fibrocavitary lung disease similar to TB, usually in older maleswho have a history of cigarette smoking and alcohol abuse (fig. 1). MAC lung disease also presentswith nodular and interstitial nodular infiltrates frequently involving the right middle lobe orlingula, predominantly in post-menopausal, nonsmoking Caucasian females. This form of disease,termed nodular/bronchiectatic disease, tends to have a much slower progression than cavitarydisease. Nodular/bronchiectatic MAC lung disease is radiographically characterised by chest high-resolution CT (HRCT) findings that include multiple small centrilobular pulmonary nodules andbronchiectasis (fig. 2).

Treatment of MAC pulmonary disease involves a two to three drug regimen, which includesethambutol, a rifamycin (rifampicin or rifabutin) and a macrolide (clarithromycin or azithromycin).

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Unfortunately, treatment outcomes havevaried significantly between studies [3, 56].In a randomised controlled clinical trialconducted by the British Thoracic Society(BTS) comparing clarithromcyin versusciprofloxacin in combination with rifam-picin and ethambutol for treatment ofpulmonary MAC, the clarithromycin-con-taining arm was associated with a higherall-cause mortality (48% versus 30%) butlower rates of failure and relapse (13% versus23%) compared with the ciprofloxacin-containing arm [55]. In a previous BTSstudy, rifampicin and ethambutol were asso-ciated with a failure and relapse rate of 41%compared to 16% in the comparator arm,which contained isoniazid. Because themacrolides are the only antimicrobial agentsfor which there is a correlation between invitro susceptibility and clinical response andthe high rate of poor outcomes reportedwith rifampicin and ethambutol, the ATSrecommends inclusion of a macrolide inall patients. [57–62]. Therapy three times aweek is recommended for patients with non-cavitary disease [3]: this recommendation isbased on a study that demonstrated poorbacteriological responses in patients whowere treated three times a week and hadevidence of cavitary disease [63]. Inter-mittent therapy with ethambutol maybe associated with a lower rate of opticneuritis [64].

In patients with extensive radiographicdisease, cavitary disease, marolide resistancedisease or treatment failure, an injectableaminoglycoside (amikacin or streptomycin)should be considered. A randomised trialfrom Japan reported that patients whoreceived streptomycin three times a weekfor the initial 3 months of therapy alongwith three other drugs had a faster sputumconversion rate compared with those thatwere in the placebo arm [65]. However,long-term relapse rates were not differentbetween arms.

Macrolide-resistant MAC lung disease isassociated with a poor prognosis [66]. Thetwo major risk factors for macrolide-resistant MAC disease are macrolide mono-therapy or treatment with macrolide andinadequate companion medications. The

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treatment strategy associated withthe most success for macrolide-resistant MAC lung disease includesthe use of a multidrug regimenincluding a parenteral aminoglyco-side (streptomycin or amikacin) andsurgical resection (debulking) [66].Clofazimine, in combination withethambutol and a macrolide, hasbeen used successfully to treat pul-monary MAC infections and, thus,may be a possible alternative drug formacrolide-resistant disease [67].

Mycobacterium kansasii

M. kansasii is one of the most co-mmon causes of NTM lung diseasein the USA, as well as some parts ofEurope and Asia. While most pa-tients with M. kansasii lung diseasehave upper lobe fibro-cavitary abnor-malities similar to TB (fig. 3), essen-tially any pattern of radiographicabnormality can occur, particularlyin HIV-infected patients [68].

According to the ATS, the re-commended regimen for treatingM. kansasii pulmonary disease in-cludes daily rifampicin (600 mg?

day-1), isoniazid (300 mg?day-1) andethfoambutol (15 mg?kg-1?day-1), alladministered for 12 months beyondthe date of culture conversion [3].However, the BTS recommends ri-fampicin and ethambutol therapy fora total of 9 months [49]. Substitutionof clarithromycin for isoniazid hasbeen associated with good short-termtreatment results with daily [69] andintermittent therapy [70].

Patients whose M. kansasii isolateshave become resistant to rifampi-cin as a result of previous therapyhave been treated successfully witha regimen that consists of high-dose daily isoniazid (900 mg), high-dose ethambutol (25 mg?kg-1?day-1) and sulfamethoxazole (1.0 g three times per day) combinedwith several months of streptomycin or amikacin [71]. The excellent in vitro activity ofclarithromycin and moxifloxacin against M. kansasii suggests that multidrug regimenscontaining these agents are likely to be even more effective for treatment of a patient withrifampicin-resistant M. kansasii disease.

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Figure 1. A 59-year-old male smoker with cavitary Mycobacteriumavium complex lung disease. The patient, who presented withcough, fatigue and weight loss, was found to have acid-fast bacillion smear microscopy. Previous treatment with rifampicin andclarithromcyin resulted in macrolide resistance. a) Chest radiographshowing cavitary consolidation in right upper lobe, volume loss,pleural thickening and scattered nodular opacities. b) Computedtomography slice showing large cavity in right upper lung withadjacent consolidation and bilateral severe emphysema.

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Mycobacterium malmoense

Mycobacterium malmoense is con-sidered the second most seriouspathogen after MAC in northernEurope, although the clinical rele-vance of M. malmoense isolates hasvaried between studies. For exam-ple, in the Netherlands [72, 73],70–80% of isolates are reported tobe clinically relevant whereas inthe USA, M. malmoense is seldomconsidered clinically significant. Pa-tients with M. malmoense lungdisease frequently have pre-existingobstructive lung disease and presentwith radiograph findings similar toother cavitary NTM lung diseasepathogens.

In a recent report, clarithromycin,rifampicin and ethambutol werecompared with a regimen consist-ing of ciprofloxacin, rifampicin andethambutol [55]. Overall, a morefavourable response to therapy wasreported with the macrolide-con-

taining regimen, although overall mortality was not different between the two regimens.Although the optimal management of M. malmoense has yet to be determined [55, 73, 74] a twoto four drug regimen is recommended that would include, at a minimum, ethambutol andrifampicin [73].

Mycobacterium xenopi

Mycobacterium xenopi is a com-mon cause of NTM lung disease inCanada, the UK, and some parts ofEurope [75]. Radiographic find-ings with M. xenopi pulmonarydisease are variable but most ofteninclude upper lobe cavitary changescompatible with TB. M. xenopiisolates were reported to have fa-vourable in vitro MICs to isoniazid,rifampin and ethambutol in a studyfrom the Netherlands [75]; how-ever, studies have failed to find acorrelation between in vitro drugsusceptibility results and treatmentoutcomes [76].

To date, the optimal treatmentregimen has not yet been deter-mined. In a multicentre, rando-mised trial comparing a regimen of

Figure 2. A 65-year-old nonsmoking female with history of cough,fatigue and sinopulmonary infections for several years. Her sputumwas culture positive for Mycobacterium avium complex. Chestcomputed tomography slice showing right middle lobe and lingularbronchiectasis with atelectasis and consolidation. Note the cen-trilobular nodules in the dependent areas of the lower lobesbilaterally.

Figure 3. A 58-year-old female with Mycobacterium kansasii lungdisease. The patient presented with cough, fever and weight loss.She was treated as a tuberculosis suspect initially but her sputumspecimen grew M. kansasii. Chest computed tomography slicedemonstrating a large right upper lobe cavity.

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clarithromycin, rifampin and ethambutol with ciprofloxacin, rifampin and ethambutol [55],there was no difference in the treatment success, failure or relapse rates between groups.All-cause mortality was relatively high and somewhat higher in the ciprofloxacin arm, butdeath directly related to M. xenopi was low. Even with variable treatment regimens,antimicrobial treatment cured 58% of patients who met ATS criteria for M. xenopi lung diseasein a retrospective study from the Netherlands [75]. Currently, the BTS recommendsethambutol and rifampicin for 24 months of therapy whereas the ATS recommends theaddition of a macrolide and isoniazid and possibly an aminoglycoside depending on theseverity of disease.

Rapidly growing mycobacteria

Because many rapidly growing mycobacteria are not pathogenic in humans it is important toidentify organisms within this group to the species level since this could affect both treatment andprognosis (table 1).

Mycobacterium abscessus complex

M. abscessus is one of the most common NTM infections in the USA and accounts for 65–80% oflung infections due to rapidly growing mycobacteria [29, 77]. Recent studies have demonstratedthat M. abscessus consists of three species, M. abscessus (sensu stricto) Mycobacterium massilienseand Mycobacterium bolettii [78, 79]. In the USA, most patients with pulmonary disease due toM. abscessus complex are nonsmoking, Caucasian females with a median age of ,60 years[29, 80]. Similarly, in South Korea the median age of patients with pulmonary disease is 55 yearsand almost all of the patients are nonsmoking females [81]. However, in the Netherlands, over halfof the patients are male many of whom have predisposing lung disease [82].

The chest radiograph usually shows multi-lobar, reticulonodular or mixed reticulonodular-alveolaropacities [29]. HRCT findings include the presence of cylindrical bronchiectasis with multiple smallnodules, similar to MAC lung disease (fig. 4) [29, 83, 84]. Cavitation has been reported in 10–44% ofpatients [29, 80, 81].

Unfortunately, M. abscessus hasdemonstrated in vitro activity toonly a few antimicrobial agents.The ATS recommends therapywith 2–4 months of intravenousantibiotics such as imipenem orcefoxitin plus amikacin given dailyor three times per week [3]. Oralagents that have demonstrated invitro activity should be included inthe treatment regimen. Unfortu-nately, macrolides are the only oralagents typically active in vitroagainst M. abscessus. Studies havedemonstrated the presence of anerythromycin ribosomal methylasegene, erm(41), in M. abscessus,which could result in the develop-ment of macrolide resistance andpossibly affect treatment responses[77, 85]. Other drugs that some-times demonstrate in vitro activity

Figure 4. A 70-year-old nonsmoking female with several year historyof cough, fatigue and weight loss. The patient had a history of severegastro-oesophageal reflux and recurrent pneumonias. Her sputumcultures were consistently positive for Mycobacterium abscessus.Chest computed tomography slice showing diffuse bronchiectasiswith scattered centrilobular and subcentimeter nodules. There is anarea of airspace of opacity in the posterior left lower lobe.

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include linezolid and tigecycline, however, both drugs are associated with frequent adverse effects[86, 87].

Because of the high levels of in vitro resistance, cure is difficult to achieve in patients with lungdisease due to M. abscessus. In South Korea, JEON et al. [81] reported the outcomes of 65 patientswith pulmonary disease who were treated with a standardised regimen. Patients were hospitalisedand treated with intravenous cefoxitin and twice daily amikacin plus oral clarithromycin,ciprofloxacin and doxycycline. After 1 month the intravenous drugs were stopped and the oralmedications continued for a total of 24 months and at least12 months beyond the date of cultureconversion [81]. 83% of the patients reported improvement in symptoms and 74% hadradiographic improvement as documented by HRCT. Sputum conversion and maintenance ofnegative sputum cultures for .12 months was achieved in 38 (53%) patients. However, drug-related adverse events were common. Neutropenia and thrombocytopenia associated withcefoxitin developed in 33 (51%) and four (6%) patients, respectively. Drug-induced hepatoxicityoccurred in 10 (15%) patients. Cefoxitin had to be stopped, and in some cases switched toimipenem, in the majority of patients.

In a recent report from Denver, CO, USA, the outcomes of 107 patients treated for pulmonaryM. abscessus disease were reported [80]. Treatment regimens varied but followed current ATSrecommendations. Cough, sputum production and fatigue remained stable, improved or resolvedin 80%, 69% and 59% of patients, respectively. Treatment outcomes were disappointing: 20 (29%)out of 69 patients remained culture positive, 16 (23%) patients converted but relapsed, 33 (48%)patients converted to negative and did not relapse and 17 patients (16%) died during the studyperiod.

As noted previously, speciation of the rapidly growing mycobacteria may be important becauseoutcomes may vary based on the species of NTM. KOH et al. [77] reported significant differencesin the clinical, radiographic and microbiologic outcomes in patients treated for M. abscessus versusM. massiliense. Sputum conversion and maintenance of negative cultures occurred in 88% ofpatients with M. massiliense compared with 25% of patients with M. abscessus, despite receiving asimilar treatment regimen. When isolates of M. abscessus were incubated with clarithromycin, allbecame resistant within 7 days and the MIC continued to increase at day 14. In contrast, none ofthe M. massiliense isolates acquired resistance upon exposure to clarithromycin. The erm(41) genewas present in all of the M. abscessus isolates but was partially deleted in the M. massiliense isolates.

A combination of surgical resection and chemotherapy may increase the chance of cure in patientswho have focal lung disease and who can tolerate resection. Among 14 (22%) patients withpulmonary M. abscessus infection in South Korea who underwent surgical resection, negativesputum culture conversion was achieved within a median of 1.5 months and was maintained in88% of those with pre-operative culture-positive sputum. Similarly, in a study from the USA,patients who had surgical resection plus medical therapy were more likely to convert their culturesto negative and not relapse compared with medical therapy alone (65% versus 39%; p50.041)[80]. Moreover, significantly more patients who underwent surgery converted sputum cultures tonegative and remained negative for at least 1 year when compared with those who receivedmedical therapy alone (57% versus 28%; p50.022).

Mycobacterium chelonae and Mycobacterium fortuitum

Although Mycobacterium chelonae and Mycobacterium fortuitum are less likely to cause lungdisease than M. abscessus the clinical and radiographic presentations are similar [29, 88]. Of 26patients in South Korea who grew M. fortuitum from two or more sputum specimens, 25 were nottreated and none showed evidence of progressive disease over a median of 12.5 months of follow-up [88].

Isolates of M. chelonae are usually susceptible to the macrolides, linezolid, tobramycin andimipenem and uniformly resistant to cefoxitin [89–91]. Other active drugs may include amikacin,

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clofazimine, doxycycline and fluoroquinolones. The ATS recommends that treatment ofM. chelonae infections should consist of at least two drugs to which in vitro drug susceptibilityhas been demonstrated. Unlike M. abscessus and M. fortuitum, M. chelonae does not appear topossess a copy of erm(41) [85].

In contrast to M. abscessus and M. chelonae, M. fortuitum demonstrates broader in vitro su-sceptibility to both oral and intravenous antimicrobial drugs including the newer macrolides,fluoroquinolones, tetracycline derivatives, sulfonamides and intravenous drugs imipenem andcefoxitin [3]. Although most isolates of M. fortuitum are susceptible in vitro to the macrolides, theyshould be used with caution because of the presence of erm(41) [92]. As with M. chelonae,M. fortuitum lung disease should be treated with at least two drugs to which in vitro susceptibilityhas been demonstrated [3].

Surgical therapy for NTM lung disease

Patients who have failed a standard therapeutic regimen, particularly those who harbour resistantorganisms, may benefit from surgical resection of the most affected areas. In 12 published seriesinvolving a total of 602 patients (range 8–236), the post-operative sputum culture conversion rateranged from 82% to 100% with a mean conversion rate of 94% [93]. Long-term relapse was notreported in all studies but ranged from 0% to 13%.

The benefits must be weighed against the possible complications of surgery. In seven surgicalseries reported during the macrolide era, the rate of complications varied from 0% to 44%averaging approximately 25% [94–100]. In the largest study to date in Colorado (USA),MITCHELL et al. [99] reported the outcomes of 236 patients who underwent lung resection forNTM pulmonary disease over a 23-year period. Minor complications were reported in 18.5% ofthe patients with 31 (11.7%) suffering from serious complications. Bronchopleural fistulaoccurred in 11 (4.2%) cases. No operative mortality was reported in six case series and post-operative mortality ranged from 0% to 11%. In the study from Colorado, seven (2.6%) patientsdied as a result of the procedure; however, the mortality rate was only 0.6% for the last 162patients that were operated on from 2001 to 2006. Many of these latter patients underwentvideo-assisted thoracoscopic surgery. Because case volume may be associated with outcomes,surgery should be performed by thoracic surgeons with extensive experience in performing thistype of surgery [99].

Conclusion

NTM represent a broad array of organisms with varying prevalence and pathogenicity. Pulmonaryinfections due to NTM appear to be increasing and the epidemiology is shifting toward a femalepredominance in some areas. Clinicians must consider clinical, radiographic and bacteriologicinformation when diagnosing NTM pulmonary infection. Although diagnostic criteria exist, thesehave yet to be prospectively validated. Consideration of the species of NTM is an increasinglyimportant element of diagnosis and may impact the outcomes of therapy. Treatment regimensvary by NTM species as do treatment outcomes. Future areas of research should focus on theepidemiology of NTM infections, transmission of infection, risks for disease progression,development of new diagnostics and ultimately development of new drugs and treatmentregimens. Until we have a better understanding of the transmission and pathogenesis of thesedifficult to treat infections, it will be difficult to formulate a rationale plan for prevention ofinfection.

Statement of interest

None declared.

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