When and how to treat pulmonary non-tuberculous mycobacterial diseases R

INVITED REVIEW SERIES: INFECTIOUS DISEASES
When and how to treat pulmonary non-tuberculous
mycobacterial diseases
RACHEL M. THOMSON1,2 AND WING-WAI YEW3
1
QLD TB Control Centre, Specialised Health Services, 2Department of Thoracic Medicine, The Prince Charles
Hospital, Brisbane, Queensland, Australia, and 3Tuberculosis and Chest Unit, Grantham Hospital,
Hong Kong, China
ABSTRACT
Non-tuberculous mycobacteria are ubiquitous environmental organisms that have been recognized as a
cause of pulmonary infection for over 50 years. Traditionally patients have had underlying risk factors for
development of disease; however, the proportion of
apparently immunocompetent patients involved
appears to be rising. Not all patients culture-positive
for mycobacteria will have progressive disease, making
the diagnosis difficult, though criteria to aid in this
process are available. The two main forms of disease
are cavitary disease (usually involving the upper lobes)
and fibronodular bronchiectasis (predominantly
middle and lingular lobes). For patients with disease,
combination antibiotic therapy for 12–24 months is
generally required for successful treatment, and this
may be accompanied by drug intolerances and sideeffects. Published success rates range from 30% to 82%.
As the progression of disease is variable, for some
patients, attention to pulmonary hygiene and underlying diseases without immediate antimycobacterial
therapy may be more appropriate. Surgery can be a
useful adjunct, though is associated with risks.
Randomized controlled trials in well-described
patients would provide stronger evidence-based data
to guide therapy of non-tuberculous mycobacteria
lung diseases, and thus are much needed.
losis complex and Mycobacterium leprae. They are
commonly occurring microbes that have differing
geographic distributions worldwide in environmental
reservoirs, particularly the soil and various water
sources.1 The mode of transmission of NTM to
humans has not been fully delineated, although
person-to-person transmission is thought not to
occur, at least in immunocompetent hosts.
EPIDEMIOLOGY OF PULMONARY
NTM INFECTIONS
Correspondence: Rachel M. Thomson, QLD TB Control Centre,
Specialised Health Services, 24-28 Cornwall Street, Annerley, Qld
4103, Australia. Email: [email protected]
Received 30 May 2008; invited to revise 2 July 2008; revised 23
July 2008; accepted 4 August 2008 (Associate Editor: Kenneth
Tsang).
An increase in the prevalence of NTM infection/
disease worldwide has been noted in the past 1–2
decades.2–4 Postulated reasons include (i) a rise
in prevalence of HIV infection and other acquired
immunocompromised states, (ii) an increased understanding of the clinico-pathological relationship
between host and pathogen5 and awareness of these
organisms as potential pathogens, (iii) advances in
methods of detection and recovery of the organisms,
(iv) an aging population (as this is often a disease of
the elderly), (v) increased survival of patients with
conditions that increase susceptibility—such as cystic
fibrosis and COPD, and (vi) increased environmental
exposure. Factors driving this increase in exposure
include (i) disinfection of drinking water with chlorine, selecting mycobacteria by reducing competition
and (ii) disinfection attempts in medical and industrial settings.
In 1999–2000, an estimated 1 in 6 persons in the
USA demonstrated Mycobacterium intracellulare sensitization, up from 1 in 9 persons in 1971–1972. This
observed rising prevalence of sensitization (as a
measure of increased exposure) has paralleled the
increase in rate of pulmonary NTM infections.6 A
similar increase in NTM infections has also occurred
in the Asia-Pacific region.2,7 In Queensland, Australia,
where NTM disease is notifiable and a central laboratory performs all mycobacterial speciation, speciated
pulmonary isolates from patients increased from 5.5
to 10.2 per 100 000 population between 1999 and
2005. M. intracellulare accounted for most of this
increase. Significant pulmonary disease rose from
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Respirology (2009) 14, 12–26
doi: 10.1111/j.1440-1843.2008.01408.x
Key words: anti-mycobacterial therapeutics, bronchiectasis,
lung
diseases,
mycobacteria,
nontuberculous.
INTRODUCTION
Non-tuberculous mycobacteria (NTM) generally refer
to mycobacteria other than Mycobacterium tubercu-
Treatment of pulmonary NTM disease
2.2 to 3.2 per 100 000 (Thomson, unpubl. data, 2007).
Marras et al. reported a similar increase in Ontario,
Canada between 1997 and 2003.4
Mycobacterium avium complex (MAC), Mycobacterium kansasii and rapidly growing mycobacteria
(RGM) such as M. abscessus and M. fortuitum constitute the main species associated with human pulmonary disease.7–9 While the underlying reason has
not been totally unravelled, the higher innate resistance of MAC to chlorine and ozone, in comparison
to other NTM, might help to explain the phenomenon. Other important NTM that can cause pulmonary infections/diseases are Mycobacterium xenopi,
Mycobacterium malmoense and Mycobacterium
szulgai.7–9
DIAGNOSIS OF PULMONARY
NTM DISEASES
Clinical features of NTM lung diseases
Pulmonary diseases due to NTM generally belong to
one of the following four patterns. (i) Fibrocavitary
disease (Fig. 1) classically involves the upper lobes of
middle-aged men with histories of smoking and alcoholism, and often with underlying lung diseases like
COPD, previous tuberculosis and silicosis. This form
of disease is particularly associated with MAC, M.
13
kansasii,10 M. xenopi,11 M. malmoense12 and RGM.13 (ii)
Nodular bronchiectasis (Fig. 2) generally involves
elderly non-smoking women with no underlying lung
disease, but who may have thoracic deformities like
pectus excavatum, kyphosis and scoliosis.14 (iii) Solitary pulmonary nodule15–19 presents very much like a
tuberculoma, and has to be differentiated from a carcinoma.16 (iv) Hypersensitivity pneumonitis occurs in
previously healthy subjects with exposure to contaminated indoor hot tubs19 or contaminated metal
working fluids.20,21
In the interpretation of the literature on NTM
disease, it is important to appreciate the proportion of
patients in each of the above groups. There is a feeling
among clinicians that the cavitary form of disease is
becoming less common, while the nodular bronchiectatic form is more prevalent. This has important
implications for treatment trials and epidemiological
studies.
COPD,3 cystic fibrosis,22 gastro-oesophageal reflux
disease and vomiting23 and chest wall disorders14 have
all been associated with NTM lung diseases. One
large, multicentre study reported that NTM were
isolated from the respiratory secretions of 13% of
patients with cystic fibrosis.22 Recently, NTM and
bronchiectasis together have been found to be associated with a higher risk of Aspergillus lung disease.24
The association between NTM colonization/infection
and unselected cases of bronchiectasis still remains
Figure 1 X-ray and CT scan of
a patient with the cavitary form
of pulmonary non-tuberculous
mycobacteria disease, in association with COPD.
Figure 2 Chest X-ray and CT cuts of a patient with the fibro-nodular bronchiectatic form of pulmonary non-tuberculous
mycobacteria disease.
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Respirology (2009) 14, 12–26
14
elusive, though it is likely that bronchiectasis acts as a
predisposing underlying lung disease.
The signs and symptoms of NTM lung diseases are
generally non-specific. Malaise and chronic cough
(with and without sputum production) are very
common. Dyspnoea is more related to underlying
lung disease (except with hypersensitivity pneumonitis). Occasional patients with the nodular bronchiectasis can have bronchiolitis and gas trapping
associated with dyspnoea. Fatigue, weight loss
and sweats also occur particularly as disease
progresses. Haemoptysis occurs in more advanced
lung disease, especially with cavitation and
advanced bronchiectasis.
Radiographic assessment of NTM
lung diseases
Cavitary NTM disease can be readily assessed by plain
chest radiograph. The cavities are said to have thinner
walls, and are associated with less surrounding parenchymal lesions, but more pleural reactions than those
of tuberculosis. Other forms of NTM lung disease are
better assessed by high-resolution CT (HRCT). The
prevalent HRCT findings are bilateral centrilobular
nodules and cylindrical bronchiectasis.25 These
changes correlate with bronchiolar/peribronchiolar
inflammation due to tissue invasion by NTM like
MAC and M. abscessus.5 It has been suggested that
about 30% of patients with changes of bilateral bronchiectasis and bronchiolitis on HRCT had NTM
disease;26 extensive radiographic abnormalities, cavitation or consolidation and female gender provided
additional risks. Classically, multifocal bronchiectasis
and diffuse centrilobular nodules, especially involving the middle and lingular lobes found in elderly
non-smoking women has been referred to as the Lady
Windermere syndrome.27 Serial CT scanning in MAC
lung disease has shown that bronchiectasis tends to
be progressive, alongside spread of nodules. Finally
progression to consolidation can also occur.28,29
In ‘hot tub’ lung due to MAC-associated hypersensitivity pneumonitis, chest CT often demonstrates
diffuse ground-glass infiltrates and centrilobular nodules.30 A similar clinical and radiological syndrome
occurs after exposure to metalworking fluid contaminated with M. immunogenum, a RGM closely related
to M. abscessus.20,21 Solitary pulmonary nodules or
masses have been described in several NTM lung
diseases,15,17 though apparently rare.
Identification of NTM and drug
susceptibility testing
NTM can be divided into slowly growing mycobacteria and RGM (Table 1). The former constitute
members of the Runyon group I to group III, whereas
the latter are equivalent to members of the Runyon
group IV.31 Using modern microbiology laboratory
methods, including liquid culture media, NTM
growth can be detected by culture from patient
specimens 1–3 weeks after incubation.32 Most rapid
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RM Thomson and W-W Yew
Table 1 Classification
of
mycobacterial
commonly causing human disease
species
Mycobacterium tuberculosis complex
M. tuberculosis
M. bovis
M. africanum
M. microti
Slowly growing mycobacteria
Runyon Group I, Photochromogens
M. kansasii
M. marinum
Runyon Group II, Scotochromogens
M. gordonae
M. scrofulaceum
Runyon Group III, Non-chromogens
M. avium complex—M. avium, M. intracellulare
M. terrae complex
M. ulcerans
M. xenopi
M. simiae
M. malmoense
M. szulgai
M. asiaticum
Rapidly growing mycobacteria
Runyon Group IV
M. fortuitum
M. chelonae
M. abscessus
growing NTM will grow in 7–10 days. Slow growers
can grow in 1–3 weeks, but may take much longer.
Cultures are usually kept for 6–8 weeks before being
regarded as negative. In patients with chronic bronchial sepsis, such as cystic fibrosis and bronchiectasis,
where colonization by Pseudomonas aeruginosa and
other bacterial pathogens prevails, sputum specimens can be overgrown before NTM growth appears.
Special decontamination methods are often necessary to reduce this overgrowth. Decontamination
unfortunately reduces the yield of mycobacteria also,
and persistence is needed if there is a clinical suspicion of NTM disease in these patients.
Although semi-quantitative smear and culture
results were used previously as NTM diagnostic criteria,33 the current use of liquid media has put less
emphasis on such an approach. With recovery of the
organism by culture, DNA probes are commercially
available to identify some of the NTM—MAC, M.
kansasii and M. gordonae. Other organisms have
traditionally been identified by a combination of
biochemical testing and HPLC. DNA amplification
with PCR has emerged as a technique to aid the rapid
identification of mycobacterial isolates. One such
approach utilizes a multiplex PCR34 to identify multiple mycobacterial pathogens. Partial sequencing of
a segment of 16S ribosomal RNA, sometimes complemented by sequencing of the 16S–23S internal transcribed spacer, has been used35,36 to identify those
species not identified by other means.
Clinically significant NTM isolates should be identified to the species level, except perhaps for M.
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
15
Treatment of pulmonary NTM disease
avium and M. intracellulare.37 The American Thoracic Society/Infectious Diseases Society of America
(ATS/IDSA) guidelines state that routine testing of
MAC species for antimicrobial susceptibility (other
than clarithromycin) is not generally recommended
because of the paucity of evidence correlating
in vitro results and in vivo (clinical) response.37
However, it has been postulated that drug combinations can produce synergistic activity, in both in vitro
and in vivo settings.38,39 Some authors have shown a
relationship between clinical response to treatment
and administration of drugs to which the strains
had demonstrated susceptibility.40–43 Patients with
nodular bronchiectasis may be infected with multiple strains and even species at different time points
in their disease;44 however, the significance of this
with respect to treatment and antibiotic susceptibility is uncertain.
The ATS does recommend clarithromycin susceptibility testing for new, previously untreated MAC
isolates37 as macrolide resistance has been associated with a poorer outcome. It should also be performed for MAC isolates from patients who have
failed macrolide treatment, or who have relapsed
from apparently successful treatment. Previously
untreated M. kansasii strains should be tested in
vitro to rifampicin only.37 M. kansasii isolates resistant to rifampicin should be tested against a panel of
secondary agents, inclusive of rifabutin, ethambutol,
isoniazid, clarithromycin, fluoroquinolones, amikacin and sulphonamides. RGM should be tested
against a panel of eight antimicrobials for susceptibility.37 This testing helps in identification of M.
abscessus, M. chelonae and M. fortuitum as well as
guidance of antimicrobial therapy. The eight drugs
are amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, linezolid, sulphamethoxazole and
tobramycin.
Other diagnostic tests for NTM lung diseases
Skin test antigens specific for NTM species are no
longer readily available for use. They do exhibit crossreaction with tuberculin and recent sequencing of the
genome of M. avium has demonstrated that the strain
of M. avium used in the avian skin test is not associated with human disease.45 The sensitivity, specificity
and positive predictive value of PPD-B (M. intracellulare) and NTM disease were 70%, 61% and 64%
respectively in one study, and the authors concluded
it was no more useful in distinguishing pulmonary
disease due to NTM than PPD-T alone.46 Thus, skin
testing using these antigens has little role in the
diagnosis of NTM lung disease.
New interferon-g (IFN-g) release assays utilizing
antigens largely specific for M. tuberculosis may help
to differentiate active pulmonary tuberculosis from
NTM lung disease,47,48 but these data are preliminary
at present. It is useful to note that the M. tuberculosisspecific antigen, ESAT-6 is also present in M. kansasii,
M. marinum and M. szulgai, and thus exposure to
these NTM could result in false-positive test results.
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Diagnostic criteria for NTM lung diseases
Not all patients who have mycobacteria cultured from
sputum or bronchial specimens are considered to
have disease. It has been postulated that they are
transiently contaminated or colonized by these
organisms and that ingested water or inhaled aerosols
are the source of the organisms.49,50 Wolinsky51
described three stages of interaction between the
organism and host—colonization, infection and
disease. The progression through these stages is
dependent on the quantity of growth, repetitive isolation, the site of isolation, the species of organism and
underlying host condition. Colonization can be
defined as repeated isolation of an organism without
evidence of a host response. The concept of colonization with NTM in the lung without infection or
invasion is debated.52 The ATS guidelines on the management of non-tuberculous mycobacterial disease33
state that ‘colonisation in the true sense (i.e. no tissue
invasion) is probably quite rare’.
The ATS have proposed criteria to differentiate
between colonization/contamination and disease,
and encompass bacteriological, radiological and
clinical criteria (Table 2).37 The criteria of 2007 have
relaxed the microbiologic criteria, as it is recognized
that patients with nodular bronchiectasis have paucibacillary disease and shed organisms intermittently,
and therefore it can be difficult to document positive
specimens repeatedly. The bacteriological criteria of
199733 may have led to an under-diagnosis of disease,
yet the criteria from 2007 may allow over-diagnosis.
Hence positive cultures need to be interpreted in light
of the findings on CXR/HRCT (as a means of assessing
Table 2 Summary of the ATS/IDSA criteria for diagnosis
of pulmonary NTM diseases
Clinical and radiographic (both required):
Pulmonary symptoms, nodular or cavitary opacities on
chest radiograph, or a HRCT scan that shows multifocal
bronchiectasis, alongside multiple small nodules,
AND
Appropriate exclusion of other diagnoses, especially
tuberculosis and mycosis
Microbiological
Positive culture results from at least two separately
expectorated sputum samples. If results are
non-diagnostic, consider repeat smears and cultures
OR
Positive culture results from at least one bronchial wash
or lavage
OR
Transbronchial or other lung biopsy with mycobacterial
histopathological features (granulomatous inflammation
or stainable acid-fast bacilli), positive culture for NTM or
biopsy showing mycobacterial histological features, and
ⱖ1 sputum or bronchial washings that are culture
positive for NTM.
ATS/IDSA, American Thoracic Society/Infectious Diseases Society of America; HRCT, high-resolution CT;
NTM, non-tuberculous mycobacteria.
Respirology (2009) 14, 12–26
16
tissue invasion/host response) and the symptoms as
well as underlying diseases of the patient.
The significance of an isolate also varies with the
species of mycobacteria. Isolation of mycobacteria
like M. gordonae, M. mucogenicum, M. haemophilum,
M. flavescens, M. gastri, M. terrae complex or M.
triviale usually indicates transient colonization or
contamination though disease has been reported.
Because M. szulgai is rarely isolated from the environment, a single positive culture is usually pathologically significant.37 Similarly, many would like to relax
the bacteriological criteria for diagnosing M. kansaii
lung disease, by allowing diagnosis of disease with a
single positive culture result, provided the clinical and
radiographic grounds are strong.53
In general, expert consultation should be obtained,
when NTM are recovered, that are either infrequently
encountered, or that usually represent environmental
contaminants. Treatment recommendations for these
NTM are usually made on the basis of only a few
reported cases. On the other hand, treatment recommendations for species like MAC and M. kansasii are
generally more evidence based. Empiric therapy for
suspected NTM lung disease is not recommended.
Such cases should be followed up closely, until diagnosis is firmly established or excluded.37
WHEN TO TREAT PULMONARY
NTM DISEASES
Diagnosing pulmonary NTM infection/disease does
not equate to the need for immediate treatment. Treatment constitutes an important undertaking for the
physician and patient as it usually involves combination antibiotic therapy for 12–24 months. In some
cases disease remits spontaneously. Indeed, lung
involvement may range in severity from subclinical/
mild clinical (indolent) infection to disease associated
with extensive invasion/destruction of the lungs. Early
studies of MAC disease demonstrated a variable progression of infection, but the majority of symptomatic
(and some supposedly asymptomatic) patients had
progressive disease, and often died as a result.54,55
However, most of these early studies consisted of
patients with cavitary disease, often associated with
heavy smoking, COPD or other underlying lung
disease, and alcohol excess—factors likely to affect
mortality and response to treatment. There are few
studies documenting the natural history of nodular
bronchiectasis, which often occurs in the absence of
significant co-morbidity; however, it seems to be quite
variable. While the progression of disease is generally
slower than in cavitary disease, it can lead to respiratory failure and death.56 There are also differences in
the natural history of infection with different species
and probably also between different strains within
species.57 M. kansasii tends to be more associated with
a tuberculosis-like illness, and is generally easier to
treat—therefore the threshold for treatment with antimicrobials is somewhat lower, than for example,
with M. abscessus. This latter pathogen is notoriously
difficult to eradicate and requires a combination of
Respirology (2009) 14, 12–26
RM Thomson and W-W Yew
injectable antibiotics. This prospect often raises the
threshold for the institution of therapy.
Therefore, the decision to treat should involve a
period of observation—usually for between 3 and 12
months—both for radiological and symptomatic
progression. Apart from the usual symptoms of
cough ⫾ sputum production, weight loss, fevers and
sweats, the occurrence of frequent intercurrent infections due to other bacteria may be a suggestion of
underlying inflammation caused by the presence of
mycobacterial infection.
Factors to consider in the decision to treat also
include the patient’s age and potential for progressive
parenchymal damage due to NTM, leading to colonization and infection with other pathogens (such as
other species of mycobacteria, Pseudomonas aeruginosa, Sternotrophomonas and Aspergillus). A younger
patient (<75 years) without major comorbidity has
more to lose in terms of quality of life if disease is left
untreated than a patient in his/her eighties with
multiple comorbidities. It has been suggested that
patients with more advanced radiological changes are
less likely to respond to therapy,58,59 which would
favour early treatment, particularly in the younger
patient.
Similarly, the presence of predisposing conditions,
may affect the rate of progression of disease. Patients
on immunosuppressive medication, or with hereditary disorders of immune function, may have more
rapidly progressive disease and warrant earlier and
more aggressive treatment. Patients with very little
pulmonary reserve due to other disease (such as
severe COPD, advanced bronchiectasis) may also
warrant a more aggressive approach, as a delay in
treatment while waiting for evidence of progressive
NTM disease may contribute to significant morbidity.
In instituting therapy, there is a need to establish
realistic expectations regarding outcomes. In many
patients the aim should be cure, and an aggressive
approach warranted. In others it may simply be suppression in order to achieve symptom control. The
cost, drug–drug interactions, side-effects and unclear
impact of treatment on the quality and quantity of life
should be considered. For some patients close observation and use of adjunctive therapies, such as airway
clearance techniques, attention to underlying lung
disease, gastro-oesophageal reflux disease, swallowing disorders and nutrition, may be a reasonable
option. The risks (including potential adverse reactions) and benefits (such as improvement in symptoms, preservation of lung function, reduced risk
of added infections) of antimicrobial therapy should
be extensively discussed with the patient prior to
deciding whether to institute such therapy.
HOW TO TREAT PULMONARY
NTM DISEASES
General principles
Patients respond best to NTM treatment the first
time it is administered; therefore, it is very important
that patients initially receive a recommended
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
17
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Not recommended for severe/advanced/previously treated disease. ‡ Lower dose for body weight <50 kg. § If intolerance to rifampicin or ethambutol, clarithromycin
or ciprofloxacin may be substituted. ¶ Given intermittently for the first 2–3 months. †† Given intermittently for the first 2–6 months. ‡‡ May be added if the patient is
responding poorly at 12 months. ATS, American Thoracic Society; Azi, azithromycin; BD, two-times daily; BTS, British Thoracic Society; Clar, clarithromycin; JST,
Japanese Society for Tuberculosis; MAC, Mycobacterium avium complex; TIW, three-times weekly.
12 months culture negative
Duration
Other drugs
None
Aminoglycoside
†
12 months culture negative
12 months culture negative
Isoniazid 300 mg/day Or
Ciprofloxacin 750 mg bd‡‡
2 years
None or Amikacin or
Streptomycin¶
Rifabutin 250–300 mg/day or
Rifampicin 450‡–600 mg/day
Amikacin or Streptomycin
Rifampicin 450‡–600 mg/day
Rifamycin
2 years
Streptomycin or
kanamycin††
Rifampicin 10 mg/kg/day
Rifampicin 450‡–600 mg/day
15 mg/kg/day
15 mg/kg/day
None§
Clar 500‡–1000 mg/day
Or
Azi 250‡–300 mg/day
15 mg/kg/day
Clar 500‡–1000 mg/day
Or
Azi 250‡–300 mg/day
15 mg/kg/day
Clar 1000 mg TIW
Or
Azi 500–600 mg TIW
25 mg/kg/day
TIW
Rifampicin 600 mg TIW
Macrolide
ATS
Advanced (severe) or
pretreated disease
ATS
Initial treatment of
cavitary disease
The treatment recommendations for MAC lung
disease are summarized in Table 3.
The ATS/IDSA recommended initial regimen for
patients with mild nodular-bronchiectatic MAC lung
disease is a three-times-weekly regimen including
clarithromycin 1000 mg or azithromycin 500 mg,
ethambutol 25 mg/kg and rifampicin 600 mg.37
Intermittent drug therapy is not recommended for
patients with cavitary disease, patients who have
been previously treated or patients who have
moderate to severe disease.37,64
The ATS/IDSA recommended initial regimen for
fibrocavitary or moderate to severe nodularbronchiectatic MAC lung disease includes daily
clarithromycin 500–1000 mg/day or azithromycin
250 mg/day, ethambutol 15 mg/kg/day and rifampicin 10 mg/kg/day (maximum 600 mg), assuming
normal liver and renal status. Lower doses of
clarithromycin may be necessary in patients over 60
years of age who have low body weights. Aminoglycosides should be considered in the initial phase and are
recommended for patients with severe or previously
treated disease.
The ATS guided primary microbiological goal is 12
months of negative sputum cultures prior to stopping
ATS
Initial treatment of
nodular BE†
MAC lung disease
Table 3 Recommended treatment regimens for pulmonary MAC disease
Only the pulmonary diseases due to the commonly
encountered NTM organisms will be discussed below.
The British Thoracic Society (BTS),61 Japanese Society
for Tuberculosis,62 and ATS/IDSA37 have published
guidelines for the management of disease due to
NTM. While the British guidelines have not been
updated since 1999, a recent randomized controlled
trial performed by the BTS63 gives insight into their
latest recommendations. The BTS guidelines are predominantly based on two large randomized controlled studies42,63 and historical studies performed in
patients of the UK and Europe. The Japanese guidelines are very similar to those of the ATS/IDSA. The
ATS/IDSA document is an extensive review of the
available literature on NTM diseases combined with
expert opinion, and the most recent version was published in 2007. The recommended treatment criteria
are based on several smaller prospective nonrandomized controlled studies (using historical controls), in US patients. It is very difficult to compare the
many different treatment studies done in pulmonary
NTM disease. Geographic differences in patient
populations, mix of disease type (i.e. nodular bronchiectasis vs cavitary disease), severity of disease, differing species of NTM, drugs used and dosages and
study design and analysis are all factors contributing
to the significant heterogeneity of findings and hence
the recommendations made by the Societies.
BTS
Specific antimicrobial treatment guidelines
Ethambutol
JST
multi-drug regimen.37,60 During chemotherapy, longterm management consists of microbiological surveillance, management of drug toxicity, nutrition
and comorbidities.
Clar 10 mg/kg/day
Treatment of pulmonary NTM disease
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RM Thomson and W-W Yew
therapy,37 as counted from the first of at least three
consecutive negative sputum cultures. Macrolides
should not be used as monotherapy for MAC disease
because of the risk for developing macrolide-resistant
MAC isolates.65–67 Macrolide-resistant MAC lung disease67 is difficult to treat and often requires prolonged
parenteral aminoglycoside therapy and surgery.
Similar to the ATS/IDSA, the JST recommends a combination of streptomycin, clarithromycin, E and R for
all patients.
In contrast, the BTS recommends 2 years of rifampicin (R) and ethambutol (E) ⫾ isoniazid (H) for MAC
disease.61 Its recent randomized controlled trial (RCT)
compared the addition of ciprofloxacin or clarithromycin to ER over 2 years.63 There was an additional
option to compare M. vaccae immunotherapy in each
arm. It is important to note that this study included 170
patients with MAC, 67% of whom had cavitary disease,
and 54% had evidence of an underlying respiratory
condition on CXR. The authors concluded there was
no additional benefit in adding either clarithromycin
or ciprofloxacin to ER, as the number of patients alive
and cured at 5 years were similar, both for each arm of
the trial and the results of a previous trial comparing
ER and ERH. ERH had the best success rate, but
highest disease associated mortality. ERclarithromycin was associated with the highest all-cause mortality.
Interestingly, the reported side-effects leading to a
change of treatment in the ERclarithromycin/
ERciprofloxacin trial were twice that of the ER/ERH
trial. As such, their suggested treatment regimen
would be 24 months ER with H or ciprofloxacin added
at 12 months if patients were doing poorly. No analysis
was performed according to radiological presentation
as cavitary disease versus nodular bronchiectasis.
Such data may be useful in assessing the relevance of
the findings to these patient groups, as those with
bronchiectasis may potentially benefit from both the
anti-pseudomonal properties of ciprofloxacin, and
the anti-inflammatory properties of clarithromycin.
Similarly, the BTS makes no distinction in recommended therapy between the two radiological groups.
There are still a number of controversies and unresolved questions in the management of MAC lung
disease. First, there have been no head-to-head
comparative trials between clarithromycin- and
azithromycin-containing regimens for MAC lung
disease. Thus, there is no demonstrated superiority of
one macrolide among the two agents regarding efficacy or risk of resistance. It is felt that macrolides have
helped to improve treatment of MAC lung disease,59
though not all studies have supported this.63 It would
appear that this assumption may be more valid for
patients with nodular bronchiectasis, rather than
cavitary disease with the results of clinical studies at
variance. If patients have not been pre-treated and are
able to tolerate the medications for the required
period of time, sputum conversion may be up to
90%,65,66 though overall success rates (12 months
culture negative) with macrolide containing regimens
range between 55% and 83%.37,65,66,68,69 Perhaps the
immunomodulating effect of macrolides could be
beneficial to some patients with bronchiectasis
associated with NTM lung disease.
When multiple drugs are prescribed at once in a
treatment naive patient, gastrointestinal intolerance
frequently results. Many experts would recommend a
stepwise introduction to therapy. Clarithromycin
seems to be the agent most patients have problems
with, and it may be necessary to start at a dose of
250 mg twice daily, increasing to 500 mg twice daily
after 1–2 weeks, prior to the introduction of companion drugs. While this approach would not be
acceptable for tuberculosis, because of the risk
of development of resistance, macrolide resistance
in MAC develops comparatively slowly.65,66
Second, there has also been no demonstrated superiority of one rifamycin (rifabutin or rifampicin) in the
treatment of MAC lung disease, but because of frequent adverse events (uveitis, leucopenia, etc.), most
experts recommend the use of rifampicin.70,71 The
roles for other medications such as fluoroquinolones
and clofazimine in the treatment of MAC lung disease
have not been fully explored, notwithstanding a
report on the clinical efficacy of clofazimine,69 the
recent BTS study63 which included ciprofloxacin, and
a few reports regarding the in vitro and in vivo efficacy
of moxifloxacin against MAC.72,73
The issue of whether an aminoglycoside should be
used in the initial phase of treatment also needs to be
addressed. The majority of early macrolide studies
performed in the USA, included a 2- to 3-month
period of intermittent injectable aminoglycoside.
The JST guidelines from 1998 recommend initial
streptomycin/kanamycin, with oral ERclarithromycin. Kobashi59 compared outcomes between patients
treated 1993–1998, prior to these guidelines (when
only 2.8% of patients received this combination) to
those treated 1998–2003 (64.5% patients received
combination). Sputum conversion rates, relapse rates
and overall outcomes were better in the cohort
treated with the recommended regimen. A Japanese
RCT74 randomized patients to receive ERclarithromycin with or without intramuscular streptomycin for
the first 3 months. Sputum conversion was significantly higher in those that received aminoglycoside,
however, overall outcomes and relapse/reinfection
rates were similar between the two groups at study
conclusion. None of the BTS studies have used aminoglycosides, and the BTS does not include a role for
these injectables in treatment guidelines.
For hypersensitivity pneumonitis due to MAC, the
treatment strategy appears somewhat different.
Removal of the subject from environmental exposure
to the contaminating source is mandatory. Corticosteroids and/or anti-mycobacterial drugs might be
required to bring about improvement of the disease.37
When the latter are needed, a shorter regimen of 3–6
months may be appropriate.75
Respirology (2009) 14, 12–26
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
M. kansaii lung disease
For patients with lung disease due to rifampicin susceptible M. kansasii, treatment recommendations are
summarized in Table 4. The ATS/IDSA recommend a
daily regimen including rifampicin 10 mg/kg/day
(maximum, 600 mg), ethambutol 15 mg/kg/day,
19
Treatment of pulmonary NTM disease
Table 4 Recommended
treatment
regimens
for
rifampicin-susceptible Mycobacterium kansasii pulmonary disease
Ethambutol
Rifampicin
Isoniazid‡
Duration
ATS
BTS
15 mg/kg/day
10 mg/kg/day (max
600 mg)
5 mg/kg/day (max
300 mg/day)
12 months culture
negative
15 mg/kg/day
450†–600 mg/day
9 months
†
Lower dose for body weight <50 kg. ‡ Plus pyridoxine
50 mg/day. ATS, American Thoracic Society; BTS, British
Thoracic Society.
isoniazid 5 mg/kg/day (maximum, 300 mg), assuming normal underlying liver and renal chemistries.37
The treatment duration for M. kansasii lung disease
should include 12 months of negative sputum cultures. There have been no prospective studies evaluating the efficacy of 18 months of therapy versus
shorter (9 or 12 months) treatment durations. One
small study demonstrated that adding intermittent
streptomycin twice weekly for the first 3 months to
the three-drug regimen given for 12 months resulted
in apparent cure in 98% cases.76
The BTS guidelines recommend a combination of
ethambutol and rifampicin given for 9 months.61 This
is largely based on a prospective study organized by
the British Thoracic Society in which good results
(99% sputum culture conversion) were achieved.77
However, the relapse rate of 10% still appeared high
and for many physicians, unacceptable, compared
with results achieved with longer duration of therapy
with the addition of isoniazid.
For patients with rifampicin-resistant M. kansasii
disease, a three-drug regimen is recommended by
the ATS, based on in vitro susceptibilities including clarithromycin or azithromycin, moxifloxacin,
ethambutol, sulphamethoxazole and streptomycin.37
High-dose isoniazid, high-dose ethambutol and
sulphamethoxazole combined with prolonged
streptomycin/amikacin administration gave good
results in one report.78 M. kansasii generally is quite
susceptible in vitro to clarithromycin. A recent preliminary study on 18 patients receiving three-timesweekly therapy with rifampicin (600 mg), ethambutol
(25 mg/kg) and clarithromycin (500–1000 mg) reported that 12 months of negative sputum cultures
was associated with no disease relapses at 46 ⫾ 8
months of (mean ⫾ SD) follow up.79 Moxifloxacin and
linezolid80 are also promising agents based on in vitro
data, but clinical data are still lacking.
M. malmoense, M. szulgai and
M. xenopi lung diseases
Mycobacterium malmoense strains have variable
susceptibility patterns to antimicrobials. They have
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
shown susceptibility in vitro to ethambutol, ethionamide, kanamycin and cycloserine and resistance to
isoniazid and rifampicin.81 Pulmonary disease due to
M. malmoense can be difficult to treat.37 A combination of rifampicin and ethambutol with or without
isoniazid has shown some effectiveness.12,42,82 There
have been two randomized controlled trials performed by the BTS. The first compared ER with ERH,
and the outcomes were similar between the two
groups, with 42% of patients alive and cured at
5 years.42 This study demonstrated no correlation
between in vitro antibiotic susceptibilities to individual drugs and clinical response. The second, more
recent study, compared the addition of ciprofloxacin
or clarithromycin to ER (again with the option of M.
vaccae in each arm).63 The proportion of people alive
and cured at 5 years was 38.4% in the clarithromycin
arm and 19.8% in the ciprofloxacin arm. The authors
conclude that there is little difference between ER,
ERH and ERclarithromycin in terms of outcome, but
the use of clarithromycin is likely to be associated
with increased side-effects.
Mycobacterium szulgai is susceptible in vitro to
most antituberculosis drugs, as well as to fluoroquinolones and macrolides.83,84 Although the optimal
duration of therapy has not been delineated, a 3- or
4-drug regimen that includes 12 months of negative
sputum cultures while on therapy appears adequate.37
Mycobacterium xenopi has variable drug susceptibility testing results that are hard to interpret, especially regarding the first-line antituberculous agents.37
The clinical response to treatment does not always
correlate well with drug susceptibility testing results.
Patients with disease due to M. xenopi were also
included in the two BTS randomized controlled trials;
however the numbers were small in this group. The
BTS approach to treatment has been to use standard
drugs in combination—ER ⫾ isoniazid;61 however,
the more recent study suggests that clarithromycin
may have a role.63 The ATS proposed regimen is a
combination of ER,isoniazid and clarithromycin ⫾
an initial course of streptomycin.37 Moxifloxacin also
has good in vitro activity against M. xenopi.85 Nevertheless, the mortality of lung disease due to M. xenopi
can be high and the outlook from treatment is poor,
possibly reflecting severe underlying pulmonary
conditions.42,86
Lung diseases due to rapidly
growing mycobacteria
The three main species of RGM causing pulmonary
diseases are M. abscessus, M. chelonae and M. fortuitum. Treatment relies heavily on guidance from antimicrobial susceptibility testing as there are virtually
no large-scale clinical studies. Most data emerge from
case reports87,88 or small series.13 The treatment of M.
abscessus particularly can be quite difficult as it is
highly resistant to antituberculous drugs. Treatment usually involves a combination of amikacin,
cefoxitin/imipenem and clarithromycin. However,
this is difficult to administer or tolerate for long
periods.
Respirology (2009) 14, 12–26
20
RM Thomson and W-W Yew
Table 5
Treatment of diseases due to rapidly growing mycobacteria
Mycobacterium abscessus
Mycobacterium chelonae
Mycobacterium fortuitum
†
Active drugs
Duration
Surgery
Clarithromycin†
Amikacin†
Cefoxitin†
Imipenem
Linezolid‡
Tobramycin†
Clarithromycin†
Linezolid‡
Imipenem
Amikacin
Clofazimine
Doxycycline
Ciprofloxacin
Amikacin†
Ofloxacin†/Ciprofloxacin†
Imipenem†
Sulphonamides
Clarithromycin
Doxycycline
4 months (soft tissue)
6 months (bone)
? 12 months (lung)
++
4 months (soft tissue)
6 months (bone)
? 12 months (lung)
+
4 months (soft tissue)
6 months (bone)
? 12 months (lung)
+
Quite active agents. ‡ Newer active agent.
Mycobacterium fortuitum can be more amenable to
treatment as antimicrobial susceptibility testing often
provides a much wider range of oral agents to choose
from, including the macrolides, newer quinolones,
doxycycline, minocycline and sulphonamides.
Table 5 shows a summary of proposed treatment,
inclusive of choice of drugs with duration and use of
surgery. The goal of 12 months of negative sputum
cultures while on therapy may be reasonable37,89 for
M. fortuitum. However, few medication strategies for
M. abscessus appear to be tolerable to achieve this
goal reliably. Isolated case reports of successful treatment without relapse using shorter duration of
therapy have been noted.87,88 It might be more realistic
to consider intermittent treatment courses during
exacerbations of the disease, especially when
parenteral drugs are involved.37 Expert consultation is
recommended for the management of patients with
this disease.
Side-effects and drug interactions
Table 6 depicts the possible adverse reactions of
drugs commonly used in the treatment of NTM lung
diseases. The BTS recommended combination of
rifampicin, and ethambutol only for treatment of lung
diseases due to MAC, M. xenopi and M. malmoense
has managed to produce cure rates of 30–40%.12,42,90
All-cause mortality has been up to 40% but diseaserelated mortality has stayed low. Nevertheless, drug
tolerance was reasonable, especially when only
rifampicin and ethambutol were used. The addition
of clarithromycin or ciprofloxacin resulted in a doubling of drug side-effects.63 Curiously, the combination of ethambutol with clarithromycin resulted in
Respirology (2009) 14, 12–26
more ocular toxicity than with ciprofloxacin, though
there were some difficulties with documentation of
ethambutol as a direct cause of visual problems. It is
thus uncertain whether the conventional ER regimen
should be completely abandoned. Macrolides can be
quite toxic in elderly subjects, and dosage adjustment
is often required.91,92 Ethambutol is reportedly less
oculotoxic when given on an intermittent basis,93 and
this may be advantageous in older patients.
Rifampicin, while commonly administered with
clarithromycin, has been shown to reduce the serum
levels of the macrolide, through induction of
cytochrome P-450 enzymes.94 However, the clinical
significance of this interaction remains unknown.
Laboratory data also revealed that the interaction of
rifabutin with clarithromycin was less. Other drug–
drug interactions of clinical significance involving
clarithromycin in the treatment of patients with
MAC disease have also been reported (Table 7),
largely in HIV-infected patients.95 Compared with
clarithromycin, azithromycin has fewer pharmacokinetic interactions, does not appear to prolong the
QT interval as much and may be better tolerated
overall.
Adjunctive therapies
A substantial proportion of patients with pulmonary
NTM diseases have significant bronchiectasiscausing morbidity, thus mucus clearance strategies
are likely to be beneficial. These methods include
conventional chest physiotherapy and postural drainage, augmented by autogenic drainage and active
cycle of breathing techniques; mucus clearance
devices;96 and inhaled medications such as mannitol97
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
21
Treatment of pulmonary NTM disease
Table 6 Adverse reactions to drugs used for treatment of NTM diseases
Reactions
Drug
Common
Uncommon
Isoniazid
Hepatitis
Cutaneous hypersensitivity
Peripheral neuropathy
Rifampicin
Hepatitis
Cutaneous hypersensitivity
Gastrointestinal reactions
Thrombocytopenic purpura
Febrile reactions
‘Flu syndrome’
Uveitis
Leucopenia
Thrombocytopenia
‘Flu syndrome’
Hepatitis
Retrobulbar neuritis
Arthralgia
Rifabutin
Abnormal taste
Arthralgia
Ethambutol
Streptomycin
Amikacin
Kanamycin
Capreomycin
Clarithromycin
Azithromycin
Ofloxacin
Ciprofloxacin
Levofloxacin
Moxifloxacin
Clofazimine
Linezolid
†
⎧
⎨
⎩
Cutaneous hypersensitivity
Dizziness
Numbness
Tinnitus
Ototoxicity: hearing loss,
vestibular disturbance
Nephrotoxicity: deranged
renal function
Nausea
Dyspepsia
Nausea
Vertigo
Ataxia
Deafness
Rare
Dizziness
Convulsion
Optic neuritis
Mental symptoms
Haemolytic anaemia
Aplastic anaemia
Lupoid reactions
Arthralgia
Gynaecomastia
Shortness of breath
Shock
Haemolytic anaemia
Acute renal failure
Shock
Haemolytic anaemia
Hepatitis
Cutaneous reaction
Peripheral neuropathy
Renal damage
Aplastic anaemia
Clinical renal failure
Hypokalaemia
Hypocalcaemia
Hypomagnesaemia
Diarrhoea
Abdominal pain
Rash
Hepatic dysfunction
Diarrhoea
Abdominal pain
Rash
Anxiety
Dizziness
Headache
Tremor
Hearing loss
QT prolongation
Gastrointestinal reactions
Retinopathy
Intestinal obstruction
Thrombocytopenia
Aplastic anaemia†
Colitis
Peripheral and optic
neuropathies†
Hepatic dysfunction
Tinnitus
Hearing loss
Gastrointestinal
reactions
Convulsion
⎧
Haemolysis
⎨ Insomnia
⎩ Oral candidiasis
Tendonitis/Tendon rupture
Arthropathy
Colitis
Similar to those of ofloxacin or ciprofloxacin except less central nervous system dysfunction
Photosensitization
Hyperpigmentation
Cutaneous reactions
Diarrhoea
Dyspepsia
Headache
More common with prolonged administration. NTM, non-tuberculous mycobacteria.
or hypertonic (7%) saline.98 Nutritional status should
also be monitored in the management of pulmonary
disease. Attention to conditions that cause aspiration
may also help to minimize pulmonary contamination
or prevent re-infection in treated patients. So far,
none of the adjunctive interventions has been specifically evaluated in patients with pulmonary NTM
diseases, and such studies may be warranted.
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Respirology (2009) 14, 12–26
22
RM Thomson and W-W Yew
Table 7 Examples of drug–drug interactions involving
clarithromycin in treatment of MAC disease
Drug
Rifabutin
Statin lipid-lowering agents
Cyclosporine
Terfenadine
Nevirapine
Efavirenz
Itraconazole
Delavirdine
HIV protease inhibitors
Result
↑ level of rifabutin
↑ level of statins
↑ level of cyclosporine
↑ level of terfenadine
↓ level of clarithromycin
↓ level of clarithromycin
⫾↑ level of clarithromycin
⫾↑ level of clarithromycin
⫾↑ level of clarithromycin
MAC, Mycobacterium avium complex.
Surgical treatment
Surgical resection of limited (focal) pulmonary NTM
disease (especially upper lobe cavitary disease) in a
patient with adequate cardiopulmonary reserve can
be successful in combination with multi-drug treatment regimens for MAC and M. abscessus lung diseases.37,99 Surgical resection of a solitary pulmonary
nodule due to MAC is indeed also considered by
experts to be curative, though the data to support this
assumption are lacking.37 Other indications for surgical resection include failure of medical therapy,99,100
serious intolerance to drugs for treatment100 and
macrolide-resistant MAC lung disease.67 Data have
shown that, in light of good long-term results, surgery
should be recommended before disease becomes
exceedingly advanced and unresectable.101,102 In
addition, in extensive disease, the excision of large
cavitary mycobacterial foci might assist medical management of remaining lesions.102 Despite bronchial
stump protection, pneumonectomy still carries a risk
for bronchopleural fistula. However, pneumonectomy does help to confer high cure rates in patients
with NTM lung diseases.103 Surgery should, therefore,
be performed in centres with considerable medical
and surgical expertise in the management of patients
with NTM disease.37
Issues for future exploration
Currently, the evaluation of a patient with a positive
sputum culture for NTM is costly and timeconsuming. Patients require further sputum specimens and often CXRs and CT scans to fully evaluate
for the presence/absence of disease. When there is
doubt these are often repeated over time. Smearpositive specimens create extra testing (DNA probes
where available) to differentiate the pathology from
tuberculosis, and where these tests are not available,
many patients receive unnecessary treatment and
public health management resources in the assumption they have tuberculosis, until mycobacterial cultures confirm otherwise. Better diagnostic tests that
obviate the need for these costly investigations would
significantly improve health care in this area.
Respirology (2009) 14, 12–26
Serodiagnosis of MAC pulmonary disease using an
enzyme immunoassay to assess antibody response to
glycopeptidolipid has been shown to be promising,
though validation in larger populations still appears
warranted. The most recent of four papers published
from Japan,104 consisted of a multicentre study, which
evaluated this test in 70 patients with MAC pulmonary disease (19 with fibrocavitary disease, 35 with
nodular bronchiectasis, 16 unclassifiable), 18 considered contaminated with MAC, 36 patients with pulmonary tuberculosis, 45 with other lung diseases and
76 healthy controls. In discriminating MAC pulmonary disease from the other patient groups—the test
demonstrated 84.3% sensitivity and 100% specificity
(using a cut-off level of 0.7 U/mL). Significantly
higher levels were found in nodular bronchiectasis
than in cavitary disease, but there was no difference
between M. avium and M. intracellulare. There was a
positive correlation between antibody levels and
radiographic extent of disease in patients who had CT
and serodiagnosis at the same time. Future studies
are needed to verify the chosen cut-off point from this
study, using larger samples of cases and controls that
encompass multiple underlying lung diseases, along
with patients from more diverse ethnic and racial
groups and geographic areas.
As mycobacteria are ubiquitous and of low virulence it is presumed that a host defect of immune
regulation must be present for disease to occur, particularly in patients with the nodular-bronchiectatic
form, who are largely non-smokers, with no predisposing conditions. Defects in the IFN-g and IL-12
receptor pathways have been reported in cases of
disseminated NTM infection in young patients.
Unfortunately, no similar defect has been found
in patients with pulmonary NTM infection. Kwon
et al.105 investigated the ability of peripheral blood
mononuclear cells to produce proinflammatory
cytokines such as IFN-g, tumour necrosis factor-a
(TNF-a) and IL-12, and anti-inflammatory cytokines
such as IL-10 in NTM patients and controls. They confirmed the findings of previous investigators106,107 that
patients with NTM pulmonary diseases (both MAC
and M. abscessus) produce less IFN-g, TNF-a and
IL-12 than healthy controls. This opens up a possible
therapeutic approach, by including exogenous cytokine replacement. Aerosolized IFN-g, as adjunctive
therapy for MAC lung disease, appeared initially
promising,108 but a randomized controlled trial of
aerosolized IFN-g was halted early because of lack of
efficacy.64 The efficacy of systemically administered
cytokines is limited to studies in mice.109,110 However,
further evaluation of immunotherapy of NTM lung
diseases appears warranted.
As NTM lung diseases are generally difficult to treat,
new drugs are needed to advance therapy. Aside from
moxifloxacin as discussed, linezolid, a oxazolidinone,
has been shown to have good activities against many
rapidly111,112 and slowly growing mycobacteria.113
However, there are major problems to consider when
using linezolid in the longer term, such as anaemia
and peripheral neuropathy. Tigecycline, a glycylcycline has been shown to have promising activity
against RGM, especially for M. abscessus and M.
© 2008 The Authors
Journal compilation © 2008 Asian Pacific Society of Respirology
Treatment of pulmonary NTM disease
chelonae.114 TMC207, a diarylquinoline developed for
treatment of tuberculosis, incidentally has been
found to have activity against some NTM,115 and
might have potential in treating diseases caused by
these organisms. Inhaled antimicrobial therapy has
appeared attractive to some investigators.116 A preliminary observational case series regarding the
efficacy of aerosolized amikacin against MAC lung
diseases has been reported.117
Finally, randomized controlled trials in welldescribed patients would provide stronger evidencebased data to guide therapy of NTM lung diseases, and
thus are much needed. Elucidation of the mechanism
behind host susceptibility will also add invaluable
information, so therapy can be directed towards the
underlying cause for establishment of infection. Environmental factors contributing to the increased prevalence of infection should also be explored, so as to
reduce reinfection of susceptible patients who are successfully treated. Newer therapies, optimized management of comorbid conditions and a more holistic
approach should be explored in the hope of improving
treatment outcomes of these NTM lung diseases.
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