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Chapter 8
Nontuberculous
mycobacterial
infections
C.L. Daley
Summary
Keywords: Bronchiectasis, mycobacteria, Mycobacterium
avium complex, nontuberculous mycobacterial infections
Correspondence: C.L. Daley, Division
of Mycobacterial and Respiratory
Infections, National Jewish Health,
1400 Jackson Street, Denver, CO
80206, USA, Email
[email protected]
C.L. DALEY
Nontuberculous mycobacteria (NTM) represent a large group
of bacteria that have been isolated from environmental sources.
When NTM are inhaled by a susceptible individual, infection
can occur and lead to progressive lung disease. Epidemiological
studies have described increases in the prevalence of NTM
disease in multiple areas worldwide. Risk factors for disease
include chronic lung diseases, such as bronchiectasis and
chronic obstructive pulmonary disease, as well as various forms
of immune deficiency. Patients typically present with either
fibrocavitary or nodular bronchiectatic disease. Isolation of
NTM from respiratory specimens does not always indicate
disease so clinicians must evaluate clinical, radiographic and
microbiologic information in order to diagnosis NTM-related
lung disease. The American Thoracic Society has developed
diagnostic criteria that can aid clinicians but the criteria cannot
account for all clinical scenarios or for all NTM species given
the large spectrum of pathogenicity encountered. Treatment
usually consists of at least two antibiotics but the exact regimen
will vary depending on the species and there is some variation in
recommendations.
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
N
115
ontuberculous mycobacteria (NTM) comprise ,140 species, many of which have been
reported 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 to
as environmental mycobacteria, NTM have been isolated from natural and drinking water
supplies, as well as soil [4–7]. The presumed source of infection is exposure to these environmental
reservoirs because human-to-human transmission has not been documented. When inhaled by
susceptible 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.
Table 1. Examples of slowly growing and rapidly growing nontuberculous mycobacteria that have been
reported to cause lung disease
Slowly growing mycobacteria
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
arupense
asiaticum
avium
branderi
celatum
chimaera
flavescens
florentinum
heckeshornense
intermedium
interjectum
intracellulare
kansasii
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
Mycobacterium
kubicae
lentiflavum
malmoense
palustre
saskatchewanse
scrofulaceum
shimodei
simiae
szulgai
triplex
terrae
xenopi
Rapidly growing mycobacteria
Mycobacterium abscessus
Mycobacterium alvei
Mycobacterium boenickei
Mycobacterium bollettii
Mycobacterium brumae
Mycobacterium chelonae
Mycobacterium confluentis
Mycobacteium elephantis
Mycobacterium goodii
Mycobacterium holsaticum
Mycobacterium fortuitum
Mycobacterium mageritense
Mycobacterium massiliense
Mycobacterium mucogenicum
Mycobacterium peregrinum
Mycobacterium phocaicum
Mycobacterium septicum
Mycobacterium smegmatis
Mycobaterium thermoresistible
NTM INFECTIONS
Despite their frequent isolation in the environment and human specimens, NTM were not
widely recognised as a cause of human disease until the late 1950s. Since that time, the number
of new species of NTM has grown dramatically [3] and the rate of disease related to NTM has
also increased, overtaking the rate of tuberculosis (TB) in some areas [8]. Diagnosis and
treatment of NTM lung disease remains challenging for clinicians and depending on the extent
of 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 sideeffects of current regimens.
Epidemiology
Incidence and prevalence
The epidemiology of NTM disease has been difficult to determine because reporting is not
mandatory 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 older
populations [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 an
annualised prevalence of 5.6 cases per 100,000 for pulmonary disease [9]. The prevalence was
significantly higher in females (6.4 cases per 100,000) than males (4.7 cases per 100,000) and was
highest in persons aged .50 years (15.5 cases per 100,000). In another report from Oregon, the
overall 2-year prevalence of NTM pulmonary disease was 8.6 cases per 100,000 and increased to
20.4 cases per 100,000 in those aged o50 years [10]. The annualised prevalence of NTM lung
disease within four integrated healthcare delivery systems in the USA ranged from 1.4 to 6.6 per
100,000 [11]. Among persons aged o60 years, annual prevalence was 26.7 per 100,000.
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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 an
increase in the number of pulmonary NTM isolates in Ontario (Canada) from 9.1 per 100,000 in
1997 to 14.1 per 100,000 in 2003. Difficulty in eradicating NTM infections resulted in a prevalence
higher than that of tuberculosis [16]. More recently, two studies from the USA reported increases
in NTM pulmonary disease [11, 15]. In a study examining the prevalence of NTM lung disease in
four integrated healthcare delivery systems, there was a 2.6% and 2.9% increase per year in females
and males, respectively [11]. Pulmonary NTM hospitalisations increased significantly among both
males and females between 1998 and 2005 in a study involving 11 states in the USA [15]. Annual
prevalence increased among males and females in Florida (3.2% and 6.5%, respectively) and
among females in New York (4.6% per year) with no significant changes in California.
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 in
females than males [9–11]. Over an 8-year period from 1998 to 2005, the overall prevalence rate of
hospitalisations 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 although
increased awareness of the disease and improved diagnostic techniques could be factors. A true
increase in incidence could be related to changes in the host such as an aging population, an
increased prevalence of chronic lung disease or an increase in the number of immunocompromised individuals. The observation of a decreased incidence of pulmonary TB and an increased
incidence of pulmonary NTM [8] could be explained by cross-immunity between mycobacterial
species. Finally, an increase in the prevalence or virulence of organisms in the environment or
changes in human behaviour that would lead to increased exposure to organisms could be
contributors. In support of the latter, the frequency of skin reactivity to purified protein
derivative-B, which used antigens from Mycobacterium intracellulare, increased from 11.2% in
1971–1972 to 16.6% in 1999–2000 [17].
Studies utilising delayed type hypersensitivity reaction to subcutaneously injected mycobacterial
antigens 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 to
Mycobacterium avium sensitin [21]. Predictors of a positive reaction included Black race, birth
outside the USA and .6 years cumulative exposure to soil. Using data from the National Health and
Nutrition Examination Survey (NHANES), investigators reported similar findings with regards to
sensitisation to M. intracellulare [17]. Male sex, non-Hispanic Black race and birth outside the USA
were each independently associated with sensitisation. These two studies are interesting in that skin
test reactivity to either M. avium or M. intracellulare antigens was associated with factors probably
associated with soil exposure. However, at least in the USA, disease seems to be more common in
older Caucasian females. Thus, the risk factors for exposure and infection may be different from
those associated with disease.
C.L. DALEY
Risk factors for NTM infection and disease
Most NTM are significantly less pathogenic than Mycobacterium tuberculosis and probably require
some degree of host impairment to result in disease. Impairment can be caused by immune defects
or chronic lung disease of which the latter appears to be most common. NTM disease has been
described in association with cystic fibrosis (CF), chronic obstructive pulmonary disease including a1-antitrypsin deficiency, cavitary lung disease, pneumoconiosis, bronchiectasis, prior TB,
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Historically male sex has been considered a risk factor for NTM lung disease and males continue
to make up the majority of patients in some areas [14]. However, studies from the USA and South
Korea have noted a female predominance. In Oregon, as noted previously, the rate of NTM
pulmonary diseases was higher in females than males and females made up 60% of cases. Why the
shift to a female predominance remains unclear. However, there is likely a genetic link because
many females who develop bronchiectasis and NTM infection share a similar body type
characterised by tall slender status with a higher frequency of pectus excavatum, kyphoscoliosis
and mitral valve prolapse than females who do not have NTM infection [22–24]. This condition
was first described by PRINCE et al. [25] in 1989 and later referred to as the ‘‘Lady Windermere
Syndrome’’ after the character in Oscar Wilde’s play Lady Windermere’s Fan, the reference
referring to fastidious behaviour in the character [26]. Recently, investigators reported that female
patients with pulmonary NTM disease were taller, thinner and weighed less than matched control
subjects [22]. To date, extensive evaluation of the immune system of these patients has been
unrevealing but mutations in the cystic fibrosis transmembrane conductance regulator gene are
common [22, 27].
pulmonary alveolar proteinosis and chronic lung injury due to aspiration from gastro-oesophageal
disorders [28–34]. Bronchiectasis is an almost universal finding in females with NTM infection
and it is seen in many males with NTM infection. However, NTM infections have been reported to
occur in only 1–2% of bronchiectasis patients in two small series from the UK [35, 36]. In
contrast, studies have documented a high prevalence of NTM from sputum cultures in patients
with CF, with estimates ranging from 3% to 19.5% [37, 38].
Pulmonary disease due to NTM has been described in several other immunocompromised patient
populations including transplant recipients [39–42], individuals taking tumour necrosis factor-a
inhibitors [43–45], and patients with mutations in interferon (IFN)-c receptor 1, IFN-c receptor
2, interleukin (IL)-12 p40 and the IL-12 receptor [46, 47]. Most of these patients present with
disseminated disease. Scientists have hypothesised that in slender, older females, decreased leptin,
increased adiponectin and/or decreased oestrogens may account for the increased susceptibility to
NTM infections [48]. Additionally, anomalies of fibrillin that lead to the expression of the
immunosuppressive cytokine transforming growth factor-b may further increase susceptibility to
NTM lung disease [48].
NTM INFECTIONS
Diagnosis and management
Chronic pulmonary disease is the most common clinical presentation of NTM disease. In order to
diagnose pulmonary NTM infection clinicians must weigh clinical, bacteriologic and radiographic
information. Diagnostic criteria have been developed to aid the clinician in the diagnostic
evaluation of persons suspected of having pulmonary NTM disease (table 2) [3, 49]. Although the
diagnostic criteria provide a useful approach for the evaluation of patients with suspected NTM
disease, the approach has yet to be validated and it is impossible for a single set of diagnostic
criteria 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 microbiologic
criterion holds true for other NTM species is not known but given the wide range of pathogenicity
among the various NTM species it is unlikely. Patients who are suspected of having NTM lung
disease but do not meet the diagnostic criteria should be followed clinically until the diagnosis is
either firmly established or excluded.
Laboratory diagnosis
Ultimately, the diagnosis of NTM disease is based on isolation of these organisms from clinical
specimens. Both solid and broth media should be used for detection of mycobacteria and a semiquantitative 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
Sputum specimen
Bronchial wash/lavage
Tissue biopsy
Culture and histopathological results
ATS recommendations
BTS recommendations
At least two separate positive cultures
Positive cultures from specimens
obtained at least 7 days apart
Not described
Not described
One positive culture
Compatible histopathology
(granulomatous inflammation) and a
positive biopsy culture and/or a positive
sputum or bronchial wash/lavage culture
118
ATS: American Thoracic Society; BTS: British Thoracic Society. Data from [3, 49].
on subculture and rapidly growing mycobacteria usually grow within 7 days of subculture.
Identification of specific species can be based on phenotypic, chemotaxonomic and molecular
methods [3]. However, none of these procedures are sufficient to differentiate all NTM.
As noted previously, skin test reactions to mycobacterial antigens are common in people living in
endemic areas and, thus, are unable to distinguish NTM infection from disease. Tests that could
distinguish infection from disease would be very helpful for clinicians. Measurement of anti-A60
immunoglobulin (Ig)G was reported to have a sensitivtity of 87% and specificity of 97% for
detection 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 core
antigen for the diagnosis of MAC lung disease. The sensitivity and specificity of the assay for
detecting MAC lung disease were 84% and 100%, respectively. Antibody levels were higher in
patients with nodular bronchiectatic disease compared with fibrocavitary disease and levels
correlated with extent of disease by chest computed tomography (CT) scans. In a follow-up study
of patients who underwent bronchoscopy, the sensitivity, specificity, positive predictive and
negative predictive values were 78.6%, 96.4%, 95.7% and 81.8%, respectively [53]. The sensitivity
and specificity of the test for MAC pulmonary disease in patients with rheumatoid arthritis was
43% and 100%, respectively [54]. Although these serologic assays are not widely available, they
may eventually find their way into diagnostic algorithms.
C.L. DALEY
The clinical usefulness of drug susceptibility testing in the management of patients with NTM
disease remains controversial because in vitro results do not correlate well with clinical outcomes
for some mycobacterial species. Unfortunately, there is no single susceptibility method that is
recommended for all species of slowly growing mycobacteria. For MAC, a broth-based culture
method with both microdilution and macrodilution methods are considered acceptable [3]. Initial
isolates, 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 is
associated with treatment failure/relapse [3]. Broth microdilution minimum inhibitory concentration (MIC) determination for susceptibility testing is recommended for rapidly growing
mycobacteria.
Slowly growing mycobacteria
The slowly growing mycobacteria include organisms with wide ranging pathogenicity such as
M. kansasii and Mycobacterium szulgai, which are probably second only to M. tuberculosis in terms
of disease producing capability and Mycobacterium gordonae and Mycobacterium terrae, which
rarely cause lung disease (table 1). MAC is typically the most common NTM to cause pulmonary
disease 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 of
MAC lung disease has been as apical fibrocavitary lung disease similar to TB, usually in older males
who have a history of cigarette smoking and alcohol abuse (fig. 1). MAC lung disease also presents
with nodular and interstitial nodular infiltrates frequently involving the right middle lobe or
lingula, predominantly in post-menopausal, nonsmoking Caucasian females. This form of disease,
termed nodular/bronchiectatic disease, tends to have a much slower progression than cavitary
disease. Nodular/bronchiectatic MAC lung disease is radiographically characterised by chest highresolution CT (HRCT) findings that include multiple small centrilobular pulmonary nodules and
bronchiectasis (fig. 2).
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Treatment of MAC pulmonary disease involves a two to three drug regimen, which includes
ethambutol, a rifamycin (rifampicin or rifabutin) and a macrolide (clarithromycin or azithromycin).
Mycobacterium
xenopi
Mycobacterium
malmoense
Mycobacterium
kansasii
ATS: American Thoracic Society; BTS: British Thoracic Society; MAC: Mycobacterium avium complex. #: treatment should continue for 12 months beyond the date of culture
conversion. Data from [3, 49, 55].
ATS: a fluoroquinolone could be substituted.
BTS: addition of clarithromycin may be best in terms of
efficacy but would be likely to increase risk of side-effects.
Rifampicin
Ethambutol¡
macrolide
12+
24
Rifampicin
Ethambutol
12+
24
Rifampicin
Ethambutol
12+
9
ATS: three times weekly therapy is recommended for those with
non-cavitary disease. In cavitary disease, an aminoglycoside
is recommended for the first 2 months of therapy.
BTS: in patients with compromised immune defences
continue treatment for 15–24 months or until the sputum
has been negative for 12 months.
ATS: specific combinations of these drugs are not described.
24
Rifampicin
Ethambutol
12+
MAC
Rifampicin
Ethambutol
Macrolide
Rifampicin
Ethambutol
Isoniazid
Rifampicin
Ethambutol Isoniazid¡
fluoroquinolone or macrolide
Rifampicin
Ethambutol
Macrolide Isoniazid¡aminoglycoside
Drugs
Drugs
Duration
months#
Duration
months
Comments
BTS recommendations
ATS recommendations
Organism
Table 3. Recommendations for the treatment of select slowly growing nontuberculous mycobacteria
NTM INFECTIONS
120
Unfortunately, treatment outcomes have
varied significantly between studies [3, 56].
In a randomised controlled clinical trial
conducted by the British Thoracic Society
(BTS) comparing clarithromcyin versus
ciprofloxacin in combination with rifampicin and ethambutol for treatment of
pulmonary MAC, the clarithromycin-containing arm was associated with a higher
all-cause mortality (48% versus 30%) but
lower rates of failure and relapse (13% versus
23%) compared with the ciprofloxacincontaining arm [55]. In a previous BTS
study, rifampicin and ethambutol were associated with a failure and relapse rate of 41%
compared to 16% in the comparator arm,
which contained isoniazid. Because the
macrolides are the only antimicrobial agents
for which there is a correlation between in
vitro susceptibility and clinical response and
the high rate of poor outcomes reported
with rifampicin and ethambutol, the ATS
recommends inclusion of a macrolide in
all patients. [57–62]. Therapy three times a
week is recommended for patients with noncavitary disease [3]: this recommendation is
based on a study that demonstrated poor
bacteriological responses in patients who
were treated three times a week and had
evidence of cavitary disease [63]. Intermittent therapy with ethambutol may
be associated with a lower rate of optic
neuritis [64].
In patients with extensive radiographic
disease, cavitary disease, marolide resistance
disease or treatment failure, an injectable
aminoglycoside (amikacin or streptomycin)
should be considered. A randomised trial
from Japan reported that patients who
received streptomycin three times a week
for the initial 3 months of therapy along
with three other drugs had a faster sputum
conversion rate compared with those that
were in the placebo arm [65]. However,
long-term relapse rates were not different
between arms.
Macrolide-resistant MAC lung disease is
associated with a poor prognosis [66]. The
two major risk factors for macrolideresistant MAC disease are macrolide monotherapy or treatment with macrolide and
inadequate companion medications. The
treatment strategy associated with
the most success for macrolideresistant MAC lung disease includes
the use of a multidrug regimen
including a parenteral aminoglycoside (streptomycin or amikacin) and
surgical resection (debulking) [66].
Clofazimine, in combination with
ethambutol and a macrolide, has
been used successfully to treat pulmonary MAC infections and, thus,
may be a possible alternative drug for
macrolide-resistant disease [67].
a)
Mycobacterium kansasii
According to the ATS, the recommended regimen for treating
M. kansasii pulmonary disease includes daily rifampicin (600 mg?
day-1), isoniazid (300 mg?day-1) and
ethfoambutol (15 mg?kg-1?day-1), all
administered for 12 months beyond
the date of culture conversion [3].
However, the BTS recommends rifampicin and ethambutol therapy for
a total of 9 months [49]. Substitution
of clarithromycin for isoniazid has
been associated with good short-term
treatment results with daily [69] and
intermittent therapy [70].
b)
C.L. DALEY
M. kansasii is one of the most common causes of NTM lung disease
in the USA, as well as some parts of
Europe and Asia. While most patients with M. kansasii lung disease
have upper lobe fibro-cavitary abnormalities similar to TB (fig. 3), essentially any pattern of radiographic
abnormality can occur, particularly
in HIV-infected patients [68].
Figure 1. A 59-year-old male smoker with cavitary Mycobacterium
avium complex lung disease. The patient, who presented with
cough, fatigue and weight loss, was found to have acid-fast bacilli
on smear microscopy. Previous treatment with rifampicin and
clarithromcyin resulted in macrolide resistance. a) Chest radiograph
showing cavitary consolidation in right upper lobe, volume loss,
pleural thickening and scattered nodular opacities. b) Computed
tomography slice showing large cavity in right upper lung with
adjacent consolidation and bilateral severe emphysema.
121
Patients whose M. kansasii isolates
have become resistant to rifampicin as a result of previous therapy
have been treated successfully with
a regimen that consists of highdose daily isoniazid (900 mg), highdose ethambutol (25 mg?kg-1?day-1) and sulfamethoxazole (1.0 g three times per day) combined
with several months of streptomycin or amikacin [71]. The excellent in vitro activity of
clarithromycin and moxifloxacin against M. kansasii suggests that multidrug regimens
containing these agents are likely to be even more effective for treatment of a patient with
rifampicin-resistant M. kansasii disease.
Mycobacterium malmoense
Mycobacterium malmoense is considered the second most serious
pathogen after MAC in northern
Europe, although the clinical relevance of M. malmoense isolates has
varied between studies. For example, in the Netherlands [72, 73],
70–80% of isolates are reported to
be clinically relevant whereas in
the USA, M. malmoense is seldom
considered clinically significant. Patients with M. malmoense lung
disease frequently have pre-existing
obstructive lung disease and present
with radiograph findings similar to
other cavitary NTM lung disease
pathogens.
NTM INFECTIONS
Figure 2. A 65-year-old nonsmoking female with history of cough,
fatigue and sinopulmonary infections for several years. Her sputum
was culture positive for Mycobacterium avium complex. Chest
computed tomography slice showing right middle lobe and lingular
bronchiectasis with atelectasis and consolidation. Note the centrilobular nodules in the dependent areas of the lower lobes
bilaterally.
In a recent report, clarithromycin,
rifampicin and ethambutol were
compared with a regimen consisting of ciprofloxacin, rifampicin and
ethambutol [55]. Overall, a more
favourable response to therapy was
reported with the macrolide-containing 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 two
to four drug regimen is recommended that would include, at a minimum, ethambutol and
rifampicin [73].
Mycobacterium xenopi
Figure 3. A 58-year-old female with Mycobacterium kansasii lung
122
disease. The patient presented with cough, fever and weight loss.
She was treated as a tuberculosis suspect initially but her sputum
specimen grew M. kansasii. Chest computed tomography slice
demonstrating a large right upper lobe cavity.
Mycobacterium xenopi is a common cause of NTM lung disease in
Canada, the UK, and some parts of
Europe [75]. Radiographic findings with M. xenopi pulmonary
disease are variable but most often
include upper lobe cavitary changes
compatible with TB. M. xenopi
isolates were reported to have favourable in vitro MICs to isoniazid,
rifampin and ethambutol in a study
from the Netherlands [75]; however, studies have failed to find a
correlation between in vitro drug
susceptibility results and treatment
outcomes [76].
To date, the optimal treatment
regimen has not yet been determined. In a multicentre, randomised trial comparing a regimen of
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, but
death 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 disease
in a retrospective study from the Netherlands [75]. Currently, the BTS recommends
ethambutol and rifampicin for 24 months of therapy whereas the ATS recommends the
addition of a macrolide and isoniazid and possibly an aminoglycoside depending on the
severity of disease.
Rapidly growing mycobacteria
Because many rapidly growing mycobacteria are not pathogenic in humans it is important to
identify organisms within this group to the species level since this could affect both treatment and
prognosis (table 1).
M. abscessus is one of the most common NTM infections in the USA and accounts for 65–80% of
lung infections due to rapidly growing mycobacteria [29, 77]. Recent studies have demonstrated
that M. abscessus consists of three species, M. abscessus (sensu stricto) Mycobacterium massiliense
and Mycobacterium bolettii [78, 79]. In the USA, most patients with pulmonary disease due to
M. 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 years
and almost all of the patients are nonsmoking females [81]. However, in the Netherlands, over half
of the patients are male many of whom have predisposing lung disease [82].
The chest radiograph usually shows multi-lobar, reticulonodular or mixed reticulonodular-alveolar
opacities [29]. HRCT findings include the presence of cylindrical bronchiectasis with multiple small
nodules, similar to MAC lung disease (fig. 4) [29, 83, 84]. Cavitation has been reported in 10–44% of
patients [29, 80, 81].
Figure 4. A 70-year-old nonsmoking female with several year history
of cough, fatigue and weight loss. The patient had a history of severe
gastro-oesophageal reflux and recurrent pneumonias. Her sputum
cultures were consistently positive for Mycobacterium abscessus.
Chest computed tomography slice showing diffuse bronchiectasis
with scattered centrilobular and subcentimeter nodules. There is an
area of airspace of opacity in the posterior left lower lobe.
123
Unfortunately, M. abscessus has
demonstrated in vitro activity to
only a few antimicrobial agents.
The ATS recommends therapy
with 2–4 months of intravenous
antibiotics such as imipenem or
cefoxitin plus amikacin given daily
or three times per week [3]. Oral
agents that have demonstrated in
vitro activity should be included in
the treatment regimen. Unfortunately, macrolides are the only oral
agents typically active in vitro
against M. abscessus. Studies have
demonstrated the presence of an
erythromycin ribosomal methylase
gene, erm(41), in M. abscessus,
which could result in the development of macrolide resistance and
possibly affect treatment responses
[77, 85]. Other drugs that sometimes demonstrate in vitro activity
C.L. DALEY
Mycobacterium abscessus complex
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 lung
disease due to M. abscessus. In South Korea, JEON et al. [81] reported the outcomes of 65 patients
with pulmonary disease who were treated with a standardised regimen. Patients were hospitalised
and treated with intravenous cefoxitin and twice daily amikacin plus oral clarithromycin,
ciprofloxacin and doxycycline. After 1 month the intravenous drugs were stopped and the oral
medications continued for a total of 24 months and at least12 months beyond the date of culture
conversion [81]. 83% of the patients reported improvement in symptoms and 74% had
radiographic improvement as documented by HRCT. Sputum conversion and maintenance of
negative sputum cultures for .12 months was achieved in 38 (53%) patients. However, drugrelated adverse events were common. Neutropenia and thrombocytopenia associated with
cefoxitin developed in 33 (51%) and four (6%) patients, respectively. Drug-induced hepatoxicity
occurred in 10 (15%) patients. Cefoxitin had to be stopped, and in some cases switched to
imipenem, in the majority of patients.
NTM INFECTIONS
In a recent report from Denver, CO, USA, the outcomes of 107 patients treated for pulmonary
M. abscessus disease were reported [80]. Treatment regimens varied but followed current ATS
recommendations. Cough, sputum production and fatigue remained stable, improved or resolved
in 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 study
period.
As noted previously, speciation of the rapidly growing mycobacteria may be important because
outcomes may vary based on the species of NTM. KOH et al. [77] reported significant differences
in the clinical, radiographic and microbiologic outcomes in patients treated for M. abscessus versus
M. massiliense. Sputum conversion and maintenance of negative cultures occurred in 88% of
patients with M. massiliense compared with 25% of patients with M. abscessus, despite receiving a
similar treatment regimen. When isolates of M. abscessus were incubated with clarithromycin, all
became resistant within 7 days and the MIC continued to increase at day 14. In contrast, none of
the M. massiliense isolates acquired resistance upon exposure to clarithromycin. The erm(41) gene
was 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 patients
who have focal lung disease and who can tolerate resection. Among 14 (22%) patients with
pulmonary M. abscessus infection in South Korea who underwent surgical resection, negative
sputum culture conversion was achieved within a median of 1.5 months and was maintained in
88% 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 cultures
to 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 to
negative and remained negative for at least 1 year when compared with those who received
medical therapy alone (57% versus 28%; p50.022).
Mycobacterium chelonae and Mycobacterium fortuitum
Although Mycobacterium chelonae and Mycobacterium fortuitum are less likely to cause lung
disease than M. abscessus the clinical and radiographic presentations are similar [29, 88]. Of 26
patients in South Korea who grew M. fortuitum from two or more sputum specimens, 25 were not
treated and none showed evidence of progressive disease over a median of 12.5 months of followup [88].
124
Isolates of M. chelonae are usually susceptible to the macrolides, linezolid, tobramycin and
imipenem and uniformly resistant to cefoxitin [89–91]. Other active drugs may include amikacin,
clofazimine, doxycycline and fluoroquinolones. The ATS recommends that treatment of
M. chelonae infections should consist of at least two drugs to which in vitro drug susceptibility
has been demonstrated. Unlike M. abscessus and M. fortuitum, M. chelonae does not appear to
possess a copy of erm(41) [85].
In contrast to M. abscessus and M. chelonae, M. fortuitum demonstrates broader in vitro susceptibility to both oral and intravenous antimicrobial drugs including the newer macrolides,
fluoroquinolones, tetracycline derivatives, sulfonamides and intravenous drugs imipenem and
cefoxitin [3]. Although most isolates of M. fortuitum are susceptible in vitro to the macrolides, they
should 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 susceptibility
has been demonstrated [3].
Surgical therapy for NTM lung disease
The benefits must be weighed against the possible complications of surgery. In seven surgical
series 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 for
NTM pulmonary disease over a 23-year period. Minor complications were reported in 18.5% of
the patients with 31 (11.7%) suffering from serious complications. Bronchopleural fistula
occurred in 11 (4.2%) cases. No operative mortality was reported in six case series and postoperative mortality ranged from 0% to 11%. In the study from Colorado, seven (2.6%) patients
died as a result of the procedure; however, the mortality rate was only 0.6% for the last 162
patients that were operated on from 2001 to 2006. Many of these latter patients underwent
video-assisted thoracoscopic surgery. Because case volume may be associated with outcomes,
surgery should be performed by thoracic surgeons with extensive experience in performing this
type of surgery [99].
C.L. DALEY
Patients who have failed a standard therapeutic regimen, particularly those who harbour resistant
organisms, may benefit from surgical resection of the most affected areas. In 12 published series
involving a total of 602 patients (range 8–236), the post-operative sputum culture conversion rate
ranged from 82% to 100% with a mean conversion rate of 94% [93]. Long-term relapse was not
reported in all studies but ranged from 0% to 13%.
Conclusion
NTM represent a broad array of organisms with varying prevalence and pathogenicity. Pulmonary
infections due to NTM appear to be increasing and the epidemiology is shifting toward a female
predominance in some areas. Clinicians must consider clinical, radiographic and bacteriologic
information when diagnosing NTM pulmonary infection. Although diagnostic criteria exist, these
have yet to be prospectively validated. Consideration of the species of NTM is an increasingly
important element of diagnosis and may impact the outcomes of therapy. Treatment regimens
vary by NTM species as do treatment outcomes. Future areas of research should focus on the
epidemiology of NTM infections, transmission of infection, risks for disease progression,
development of new diagnostics and ultimately development of new drugs and treatment
regimens. Until we have a better understanding of the transmission and pathogenesis of these
difficult to treat infections, it will be difficult to formulate a rationale plan for prevention of
infection.
Statement of interest
125
None declared.
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