The nontuberculous mycobacteria
(NTM) have been collectively identified by a variety of terms, including
mycobacteria other than tuberculosis, atypical, nonpathogenic, unclassified,
and environmental or opportunistic mycobacteria. Although grouping
these organisms can be helpful, classification based on specific
etiologic agent is preferable because this has implications for
the predisposing factors, usual clinical course, diagnosis, and
appropriate medical and surgical management of the infection.
Mycobacteria are true bacteria. They are nonmotile, nonspore-forming,
slender pleomorphic rods. Their cell walls have a complex structure
that includes a variety of proteins, carbohydrates, and lipids.
Studies using high-pressure liquid chromatography (HPLC) reveal
a variable species-related distribution of mycolic acids, each species
having a distinct mycolic acid fingerprint that can be used for identification.
More than 60 species of Mycobacterium have been
described, of which about half are pathogenic in humans. The most
commonly encountered are Mycobacterium avium, Mycobacterium
intracellulare, and Mycobacterium scrofulaceum, which
are classified together as the M avium complex
The direct detection of nontuberculous mycobacteria (NTM) is
similar to that for Mycobacterium tuberculosis. All
NTM are acid fast but these are visualized in fluid and tissue samples
less than 50% of the time. Although even a single organism
visualized on an entire slide is suspicious, false-positive results
can be caused by contamination of stain solutions, tap water, distilled
water, delivery tubes, or immersion oil. Direct detection of the
various NTM by nucleic acid amplification is advancing, but appropriate
primers and reagents are not yet commercially available for many
Methods used for the isolation of M tuberculosis from
clinical samples are also useful for the isolation of NTM. All mycobacteria
are obligate aerobes that grow best in the presence of 5% to
10% CO2. Isolation on solid media of slow-growing
NTM takes 2 to 6 weeks. Only the rapid growers (Mycobacterium
fortuitum, Mycobacterium chelonei, and Mycobacterium abscessus)
form visible colonies in less than 10 days. Use of liquid media
systems usually leads to isolation of any species of NTM within
14 days. Some newly recognized species of mycobacteria cannot be
cultivated but can be detected by nucleic acid amplification. Many clinical
laboratories now use high-pressure liquid chromatography (HPLC)
analysis to speciate these organisms.
Determining the species of NTM causing infection is crucial to
directing chemotherapy. Although drug susceptibility testing of
MAC isolates is not predictive of clinical response and does not
contribute significantly to care of the patient, susceptibility
testing for the rapid-growing mycobacteria can be informative. For
these mycobacteria, susceptibility testing to antibiotics such as
amikacin, cefoxitin, doxycycline, sulfonamides, linezolid, and the
macrolides may be particularly helpful.
Transmission of NTM to humans occurs from environmental sources,
including soil, water, dust, and aerosols. NTM have been isolated
from as many as 80% of soil samples, and certain strains
of MAC are found in fresh and brackish waters in warmer climates.
Other mycobacteria have been isolated from natural water supplies and
tap water.1 Although mycobacteria are frequently
found in animals, particularly swine and poultry, there is little
evidence to suggest animal-to-human transmission. There is no evidence that
person-to-person transmission occurs. Clusters and isolated cases
of health care–associated disease due to NTM are being
reported with increasing frequency. Most common are outbreaks caused
by the rapid growers, which are associated with injectors, continuous
ambulatory peritoneal dialysis, contaminated skin marking, and injection
solutions and hemodialysis.
The true incidence and prevalence of NTM infections are difficult
to determine because there is no mandatory reporting. Isolation
of the organism does not prove infection, and distinguishing among
saprophytes, colonizers, and pathogenic organisms can be difficult.2 A
survey in the 1980s estimated the prevalence of NTM disease in the
United States as 1.8 cases per 100,000 population, approximately
20% of the prevalence of tuberculosis. Rates were highest for
disease due to MAC, Mycobacterium kansasii, and M
fortuitum. The age distribution of NTM disease varies by
mycobacterial species and site of disease. Pulmonary disease is
rare in children, but occurs more often in older adults. The majority
of cases of NTM lymph node infection occur in children younger than
Clinical disease caused by NTM is common among both adults and
children with untreated AIDS and other immunosuppressing conditions.
Prior to the advent of antiretroviral therapy, almost 25% of
deceased patients with AIDS in the United States had autopsy evidence
of widespread disease caused by MAC.3 In one epidemiologic
survey, 7.8% of children 0 to 9 years of age with AIDS
had disseminated NTM infection; MAC caused more than 90% of
cases. Patients with malignancies, especially leukemia and lymphoma,
appear to have a higher incidence of NTM infections than the general population
in the same geographic area. NTM infections are being diagnosed
more often in transplant patients, including children.
The majority of NTM that cause human disease are of low virulence.
Infections in immunocompetent hosts require an unusual exposure
or direct route of inoculation such as trauma. These infections
are generally characterized by findings limited to the inoculation
site. NTM infections do not exhibit lymphohematogenous dissemination
in normal hosts. Immunocompromised hosts are at increased risk for
systemic and disseminated NTM infection, but these typically occur
in the setting of extreme and prolonged immunocompromise, such as
in individuals with advanced AIDS. Although the portal of entry for
the MAC is usually the oropharynx or respiratory tract, the pattern
of disseminated disease in patients with AIDS is most consistent
with an intestinal portal.
The most common site of clinically significant nontuberculous
mycobacteria (NTM) infection in children is the superficial lymph
nodes of the head and neck.4 The vast majority
of cases are caused by M avium complex (MAC). Lymph node
infection as a result of NTM is most common in young children because
of their tendency to put objects contaminated with soil, dust, or standing
water into their mouths. Although NTM adenitis is more common in
North America than is tuberculous adenitis, clinicians should never
presume NTM to be the cause of apparent mycobacterial cervical adenitis
until tuberculosis has been ruled out by a thorough epidemiologic
history, evaluation of the family for tuberculosis, skin testing,
and culture. The vast majority of children who develop NTM adenitis are
Lymphadenitis caused by NTM usually involves a group of lymph
nodes, most often located unilaterally, in the anterior cervical
chain or submandibular region. Involvement of the supraclavicular
lymph nodes is unusual and suggests infection with M tuberculosis or
Lymph node enlargement usually occurs over weeks to months.5 Systemic
signs or symptoms are rare in immunocompetent children. The involved
lymph nodes are usually painless, firm, but not hard, and usually
seem fixed to the underlying or overlying tissues. With further
progression, the lymph nodes soften, become fluctuant, and may rupture
through the skin, causing drainage and formation of a sinus tract that
can persist for months or years. Healing is characterized by fibrosis
and scarring of the skin, which can be extensive and disfiguring.
The standard tuberculin skin test may show a reaction with any
NTM lymph node infection, but is more likely to cause a reaction
with disease caused by M fortuitum or the MAC.
The greatest difficulty in differential diagnosis is usually distinguishing
between adenitis caused by NTM and M tuberculosis. The
most important distinguishing feature is the epidemiologic setting, which
determines whether children may have been exposed to M tuberculosis. Lack
of contact with an adult with tuberculosis, a skin test reaction
of less than 10 mm, and a poor response to standard antituberculosis
chemotherapy suggest the diagnosis of NTM cervical adenitis.
In immunocompetent hosts, the most common form of cutaneous nontuberculous
mycobacteria infection is the skin granuloma, frequently called swimmer’s
granuloma, caused by Mycobacterium marinum. These
infections are associated with aquatic activities such as swimming,
boating, fishing, or even care of tropical fish (Fig. 270-1).
Direct trauma from contact with shrimp, barnacles, coral, or fish
hooks may lead to infection. This mycobacterium can be isolated
from swimming pools and natural sources of freshwater and saltwater.
Cases of M marinum infection usually are sporadic,
although outbreaks of swimming pool granuloma involving hundreds of
people have been reported. Typical skin lesions are nontender inflammatory
nodules that progress to ulcerated granuloma or to chronic warty
lesions over several weeks to months. The most commonly affected
sites are areas where trauma is frequent such as the elbows, knees, feet,
and hands (Fig. 270-2).
The typical lesion is 1 to 2 cm in diameter and is not accompanied
by regional adenopathy. Most lesions heal spontaneously within a
few months, but occasionally a nodular, sporotrichoidlike area spreads
up an extremity. The clinical diagnosis is confirmed by culture
of the discharge from the lesions or by biopsy. Many of these children
have a highly reactive Mantoux tuberculin skin test.
Mycobacterium marinum infection of the
hand. Granulomatous nodular lesion with central ulceration at the
site of inoculation.
(Source: Used with permission from A Kuhlwein,
Mycobacterium marinum lesion showing
a verrucous violaceous plaque with central spontaneous clearing
at the the site of an abrasion on the hand sustained in a fish tank.
(Source: Used with permission from Wolff K, Goldsmith
LA, Katz SI, et al (eds). Fitzpatrick’s Dermatology in
General Medicine. 7th ed. New York: McGraw-Hill; 2008.)
In many tropical areas throughout the world, Mycobacterium
ulcerans causes an itching nodule on the arms or legs,
which then breaks down to form a shallow ulcer. This lesion is referred
to as a Buruli ulcer. Isolation of M ulcerans is
extremely difficult, and the diagnosis is usually made on clinical
grounds. Excision of the lesion usually constitutes therapy, and
treatment with several different antibiotics has led to variable
success. (Additional information is provided in Chapter 272.)
An increasing number of mycobacterial cutaneous infections are
caused by the rapidly growing mycobacteria, particularly M
fortuitum, M abscessus, and M chelonei. These
localized skin or subcutaneous lesions are associated with accidental
or iatrogenic trauma. Manifestations usually include cellulitis,
a draining abscess that may be single or multiple, or tender nodules. Seropurulent
drainage, poor wound healing, and development of sinus tracts after
an operative procedure should suggest this diagnosis.
The most common nontuberculous mycobacteria (NTM) infection in
adults is pulmonary disease with M avium complex
(MAC), with or without some form of underlying chronic lung disease.
The clinical presentation includes cough, production of sputum,
low-grade fever, and weight loss. In addition, hemoptysis, pleuritic
and night sweats may occur. Pleural effusions caused by NTM are
rare. Mycobacterium kansasii is the most frequent
cause of mycobacterial lung disease in the midwestern and southwestern
United States. Some patients have underlying chronic lung disease,
and the infection may resemble pulmonary tuberculosis. Dissemination
beyond the lung is rare in immunocompetent patients, but is common
in immunosuppressed hosts.
Pulmonary infection by NTM in children is rare. Strains of the
MAC are the most frequent cause of pediatric NTM pulmonary infection. The
majority of infected children are immunocompetent with no underlying
pulmonary disease. The most common presentation is similar to the
primary tuberculosis complex. Patients have mild cough and low-grade
fever with few systemic signs or symptoms. Occasionally, localized
wheezing is noted and the diagnosis of an aspirated foreign body
should be considered. Enlargement of hilar or mediastinal lymph
nodes is common. These species can be isolated from the gastric
secretions of healthy children, so diagnosis requires repeated isolation
of the same mycobacterium in association with pulmonary deterioration.
Special mention should be made of the association between NTM
colonization and infection and cystic fibrosis (CF).6 Unfortunately,
a standard definition of NTM disease in CF patients, using clinical,
radiographic, and pulmonary function testing results, is not possible.
A single isolation of an NTM in the sputum of a CF patient who is
not experiencing a decline in pulmonary function probably represents
colonization, and treatment is not necessary. However, repeated
isolation of the same species of NTM in association with declining
pulmonary function is more suggestive, but not diagnostic, of invasive NTM
disease in the lung.
Several cases of osteomyelitis caused by the MAC have been described
in children. In these cases, the bony lesions are usually the only
sites of infection. The most frequent findings are lytic lesions
of the long bones or lesions of the small bones of the hands, feet,
skull, ribs, and sternum. In most patients, the lesions persist
for several years, and then become inactive or resolve spontaneously.
Very few cases of NTM meningitis have been reported in children.7 The
clinical presentation and laboratory values are generally similar
to those commonly seen in patients with tuberculous meningitis.
Before the AIDS epidemic, disseminated NTM infection had been reported
in less than 20 children.8 Most of these children
died. Lesions of the lungs, long bones, liver, gastrointestinal
tract, and bone marrow were common.
The major risk factor for nontuberculous mycobacteria (NTM) infection
in patients with AIDS is the level of immune dysfunction, reflected
by the concentration of CD4+ cells in
the blood. The mean concentration of CD4+ cells
in patients with disseminated NTM infection is less than 60/mm3.
The most frequent causative agent of disseminated NTM infection
is the M avium complex (MAC), but disease also
results from infection with M kansasii, M fortuitum, M chelonei,
Mycobacterium xenopi, Mycobacterium haemophilum, and other
novel, unidentified mycobacteria. The incidence of NTM infection in
persons with AIDS is reduced dramatically by highly active antiretroviral
Disseminated NTM infection most commonly affects the blood, bone
marrow, liver, spleen, and lymph nodes, but organisms have been
recovered from virtually every organ of the body. Patients have
a variety of signs and symptoms. The most common presentation is
persistent fever with weight loss or failure to thrive. Gastrointestinal
symptoms are common, especially chronic diarrhea, abdominal pain,
and extrahepatic biliary obstruction. Radiographic imaging of the
abdomen and physical examination often reveal marked hepatosplenomegaly,
focal lesions in the liver or spleen, diffuse thickening of bowel
walls, and enlarged mesenteric lymph nodes. Severe anemia requiring
transfusion is frequent. Less commonly, cutaneous lesions, superficial
lymph node enlargement, or endobronchial disease without pneumonia
may occur. Many of the signs and symptoms described previously are
common in patients with AIDS and other conditions or infections;
however, fever, abdominal pain, diarrhea, anemia, and weight loss
are significantly associated with disseminated NTM infection. Diagnosis
of disseminated NTM infection is easily established by culture of
a normally sterile site. Only one or two mycobacterial blood cultures
are necessary to confirm the diagnosis in most cases.
The key to diagnosis of nontuberculous mycobacteria (NTM) infection
is a high level of suspicion based on epidemiologic factors and clinical
presentation.9 This etiology should be especially
considered in patients with chronic cervical lymphadenitis, in cases
of chronic cutaneous ulcers or other skin lesions with poor wound
healing, and in immunosuppressed hosts.
Nonspecific laboratory tests such as blood counts, ESR, urinalysis,
and serum chemistry tests are usually normal in children with NTM
infections. Skin testing with purified protein derivative from M
tuberculosis may be helpful in the detection of infections caused
by NTM. These infections are usually associated with skin test reactions
less than 10 mm in diameter, but larger areas of induration may
be seen. A negative tuberculin skin test never eliminates consideration
of NTM infection. Of course, similar reactions may be caused by M
tuberculosis infection. NTM antigens for skin testing are
no longer available commercially because of poor sensitivity and
specificity, as well as a lack of quality control during production.
Acid-fast stains of appropriate patient samples may give an early
clue to the presence of NTM infection but are frequently negative because
the number of organisms is small. Histologic studies of affected
tissues may be helpful if classic granulomatous changes are evident.
The most direct method for diagnosing NTM disease is culture
of involved fluid or tissue specimens. Because of their ubiquity in
the environment, isolation of NTM may represent colonization or
infection without recognizable disease. Most experts suggest considering
five clinical observations when determining whether an isolated
NTM is the cause of disease9:
1. Quantity of growth is usually moderate to heavy,
especially in respiratory tract specimens, when disease occurs.
2. Repeated isolation of the same mycobacterium from the same
site is likely to indicate true infection.
3. The site of origin of a positive specimen is important. The
majority of NTM isolated from urine, gastric aspirates, and oropharyngeal
secretions are contaminants, whereas NTM isolation from closed aspiration
of lymph nodes or abscesses, as well as from deep tissue fluids,
biopsy specimens, or resected tissues, usually indicates disease.
4. The species of mycobacteria is important. Isolates of NTM
that rarely cause human disease should be viewed with caution.
5. Host risk factors should be considered. In the presence of
predisposing conditions, the index of suspicion should be raised
so that less stringent criteria are applied to the evaluation of
specimens that are culture positive for NTM.
Specific treatment of NTM disease depends on the location and
extent of the infected tissue, the host immune system, and the mycobacteria
species involved. In general, surgery plays a more important role
in the management of NTM disease than in tuberculosis because chemotherapy
is often ineffective for NTM, and most NTM infections are localized and
therefore amenable to surgical excision.9 An important
initial consideration is determination that M tuberculosis is
not the causative pathogen. Until NTM are identified by culture,
treatment is usually directed at M tuberculosis,
both for therapeutic reasons and for infection control.
To properly direct chemotherapy, it is important to determine
the infecting species of NTM. In general, M kansasii, M
marinum, M xenopi, Mycobacterium gordonae, Mycobacterium malmoense,
Mycobacterium szulgai, and M haemophilum are
susceptible to some or all standard antituberculosis drugs. Treatment
of the rapidly growing mycobacteria and most strains of the MAC
require other antibiotics.
In general, excisional biopsy remains the treatment of choice
for cervical lymphadenitis caused by NTM. Incisional biopsy should
not be performed because it frequently leads to development of a
draining sinus tract or recurrent disease. Total excision of the
inflammatory mass usually precludes persistence or recurrence. However,
removal of all involved lymph nodes may be impossible due to the close
proximity of vital structures. Excision is best performed early,
in order to improve the cosmetic outcome before extension of disease into
the subcutaneous structures occurs. Chemotherapy is not generally
necessary for children with NTM lymphadenitis. If tuberculosis cannot
be reasonably excluded, an initial course of antituberculosis therapy
should be considered. Many cases of cervical adenitis caused by
the M avium complex resolve during treatment with
standard antituberculosis medications, although no controlled trials
have been reported. In these cases, the causative organisms are
usually not susceptible to the chemotherapeutic agents used, and
spontaneous resolution may have occurred. In a small percentage
of cases in which complete surgical excision is not possible, recurrence
of adenitis is a problem. Chemotherapy may be helpful; the purpose
is to prevent extension of recurrence so that a second surgical
procedure is not necessary. The most commonly used regimen is a
combination of at least two drugs, including clarithromycin, rifampin
or rifabutin, and ethambutol.
Many cases of cutaneous disease caused by M marinum resolve
spontaneously. Acceptable chemotherapy regimens for more extensive
lesions include doxycycline, or rifampin plus ethambutol, administered
for a minimum of 3 months. The rate of resolution is variable, but
therapy must be given for at least 3 to 4 weeks before the clinical response
can be evaluated. No controlled clinical trials for treatment of
cutaneous or soft tissue disease caused by rapid-growing mycobacteria
have been reported. Most isolates of M fortuitum are
susceptible to amikacin, cefoxitin, ciprofloxacin, clarithromycin, and
imipenem. Drug susceptibility for M chelonei and M
abscessus is more variable. For serious disease, intravenous
therapy with amikacin and cefoxitin is recommended until clinical
improvement is evident. Removal of foreign bodies is essential for
resolution of infection at these sites. In cases of extensive disease,
surgical excision of affected tissue may shorten the duration and
morbidity of the infection.
Pulmonary infections with NTM in children are rare, and no controlled
therapy trials have been reported.9 Most isolates
of MAC are resistant to antituberculosis drugs used singly. However,
combination therapy with standard antituberculosis drugs generally
has been successful in the treatment of adults with pulmonary MAC
infection. If standard therapy is not effective, second-line drugs
with significantly more side effects and greater toxicity must be
used. Resectional surgery may be necessary for localized disease.
Treatment of disease caused by M kansasii is usually
successful because it is susceptible to rifampin, ethambutol, often
isoniazid, and streptomycin. The usual length of recommended combination
therapy is 12 to 18 months.
More recent studies show that certain multiple-drug regimens
can provide symptomatic relief, prolong life, and lead to partial
clearing or reduction in the level of NTM bacteremia in patients
with AIDS.9 However, treatment with various antimycobacterial
agents may be associated with considerable toxicity. Patients with
HIV infection usually have significantly higher rates of adverse
reactions to most antimycobacterial drugs, just as they do to many
other classes of drugs. The most commonly used drugs for patients
with AIDS and disseminated MAC infection are clarithromycin, azithromycin,
amikacin, ciprofloxacin, ethambutol, and rifampin or rifabutin.
Although many different therapeutic regiments have been studied,
recommendation of any specific drug regimen or duration of therapy
for disseminated MAC disease in patients with AIDS is difficult.
Most experts use the combination of clarithromycin, rifamycin, and
ethambutol as initial therapy. Most experts recommend placing immunocompromised
patients with AIDS who are at high risk for disseminated MAC infection
with CD4+ counts of less than 100 cells/mm3 on
a preventive medication such as clarithromycin or rifabutin (see Chapter 315 for details regarding children
of specific ages).