# 70 - 185 Nontuberculous Mycobacterial Infections

### 185 Nontuberculous Mycobacterial Infections

randomized controlled trial has shown that single-dose rifampin, given 
once to household contacts, neighbors, and social contacts, reduces 
the recipients’ risk of leprosy by ~60%. Implementation studies have 
shown that PEP with single-dose rifampin is feasible and well accepted 
by patients, contacts, and health workers in a variety of health care 
settings. Furthermore, modeling studies have indicated the potential 
impact of PEP on transmission of M. leprae in endemic populations. 
This intervention was included in the 2018 WHO Guidelines for the 
Diagnosis, Treatment, and Prevention of Leprosy and is currently being 
introduced in many countries. Research is ongoing into enhanced PEP 
regimens for those close contacts who are at increased risk of leprosy 
(e.g., blood-related household contacts and close contacts of multi­
bacillary leprosy patients).

“Zero Leprosy” 
The WHO has formulated its new Global Lep­
rosy Strategy 2021–2030. As in the organization’s previous strategy, 
a holistic approach to leprosy control is advocated, focusing on zero 
infection and disease, zero disability, and zero stigma and discrimina­
tion. For 2030, the WHO is setting ambitious targets of achieving 120 
countries with zero new autochthonous leprosy cases, reducing the 
annual number of new cases detected by 70%, reducing the rate of new 
cases with grade 2 disability per million population (as a proxy for 
detection delay) by 90%, and reducing the rate of new child cases with 
leprosy per million children (as a proxy for recent transmission) by 
90%. Widespread implementation of PEP with single-dose rifampin is 
one of the key strategies to achieve these goals. The “Triple Zero Strat­
egy” (zeroleprosy.org) has also been embraced by the partners united in 
the Global Partnership for Zero Leprosy, the International Federation 
of Anti-Leprosy Associations, the Novartis Foundation, the Sasakawa 
Health Foundation, and the International Association for Integration, 
Dignity, and Economic Advancement.
PART 5
Infectious Diseases
In July 2023, the WHO launched new “Technical Guidance on 
Interruption of Transmission and Elimination of Leprosy Disease” 
(www.who.int/publications/i/item/9789290210467). This contains clear 
milestones, definitions, and cutoffs for interruption of transmission 
and elimination of leprosy disease. Using the Leprosy Elimination 
Framework and the accompanying tools—the Leprosy Elimination 
Monitoring Tool and Leprosy Programme and Transmission Assessment—
countries can track their progress toward these milestones in detail.
The outlook for achieving “zero leprosy” is better than ever before, 
but this goal is admittedly very ambitious. It can be reached only when 
all leprosy-endemic countries enhance their leprosy control activities 
to include (1) active case-finding strategies, including improved diag­
nosis; (2) contact screening; (3) implementation of PEP; (4) improved 
prevention of disability services; and (5) activities to reduce stigma 
and discrimination and to promote the social inclusion and mental 
well-being of affected patients and their families. Coincident with these 
efforts, an important threat must be confronted. With the waning of 
interest in leprosy and the integration of management of the disease 
into nonspecialized health systems, the number of medical doctors 
and health workers at the primary care level who have experience in 
diagnosing and treating leprosy has decreased substantially all over the 
world. Once lost, expertise is difficult to regain. Therefore, new energy 
and resources need to be invested in bolstering technical capacity for 
all aspects of leprosy services, with a view to strengthening the health 
system in an integrated way and leaving no one behind.
Acknowledgment
We thank Dr. Colette L.M. van Hees, dermatologist at Erasmus MC, 
University Medical Center Rotterdam, for critical review of this chapter.
■
■FURTHER READING
Bratschi MW et al: Current knowledge on Mycobacterium leprae 
transmission: A systematic literature review. Lepr Rev 86:142, 2015.
Collin SM et al: Systematic review of Hansen disease attributed to 
Mycobacterium lepromatosis. Emerg Infect Dis 29:1376, 2023.
Fróes LAR Jr  et al: Bacterial, fungal and parasitic co-infections in 
leprosy: A scoping review. PLoS Negl Trop Dis 17:e0011334, 2023.
Kumar B, Kar HK (eds): IAL Textbook of Leprosy, 2nd ed. New Delhi, 
Jaypee Brothers Medical Publishers (P) Ltd, 2017.

Scollard DM, Gillis TP (eds): International Textbook of Leprosy. 
Available at https://internationaltextbookofleprosy.org. Accessed 
February 17, 2024.
Smith WC et al: The missing millions: A threat to the elimination of 
leprosy. PLoS Negl Trop Dis 9:e0003658, 2015.
World Health Organization: Guidelines for the diagnosis, treat­
ment and prevention of leprosy. New Delhi, WHO Regional Office 
for South-East Asia, 2018. Available at https://apps.who.int/iris/
handle/10665/274127.  Accessed February 17, 2024.
Steven M. Holland

Nontuberculous 

Mycobacterial Infections
Several terms—nontuberculous mycobacteria (NTM), atypical myco­
bacteria, mycobacteria other than tuberculosis, and environmental 
mycobacteria—all refer to mycobacteria other than Mycobacterium 
tuberculosis, its close relatives (M. bovis, M. caprae, M. africanum, 

M. pinnipedii, M. canetti), and M. leprae. The number of identified 
species of NTM is growing and will continue to do so because of the 
use of DNA sequence typing for speciation. The number of known spe­
cies currently exceeds 199. NTM are highly adaptable and can inhabit 
hostile environments, including industrial solvents.
■
■EPIDEMIOLOGY
NTM are ubiquitous in soil and water. Specific organisms have 
recurring niches, such as M. simiae in certain aquifers, M. fortuitum 
in pedicure baths, and M. immunogenum in metalworking fluids. 
Most NTM cause disease in humans only rarely unless some aspect 
of host defense is impaired, as in bronchiectasis, or breached, as by 
inoculation (e.g., liposuction, trauma, cardiac surgery). There are few 
instances of human-to-human transmission of NTM, which occurs 
almost exclusively in cystic fibrosis. Because infections due to NTM 
are rarely reported to health agencies and because their identification is 
sometimes problematic, reliable data on incidence and prevalence are 
lacking. Disseminated disease denotes significant immune dysfunction 
(e.g., advanced HIV infection), whereas pulmonary disease, which is 
much more common, is highly associated with pulmonary epithelial 
defects but not with systemic immunodeficiency.
In the United States, the incidence and prevalence of pulmonary 
infection with NTM, mostly in association with bronchiectasis 
(Chap. 301), have for many years been severalfold higher than the 
corresponding figures for tuberculosis, and rates of the former are 
increasing among the elderly as rates of tuberculosis continue to fall. 
Among patients with cystic fibrosis, who often have bronchiectasis, rates 
of clinical infection with NTM range from 3 to 15%, with even higher 
rates among older patients. Although NTM may be recovered from the 
sputa of many individuals, it is critical to differentiate active disease 
from commensal harboring of the organisms. A scheme to help with 
the proper diagnosis of pulmonary infection caused by NTM has been 
developed by the American Thoracic Society and is widely used (https://
doi.org/10.1093/cid/ciaa241). The bulk of nontuberculous mycobacte­
rial disease in North America is due to M. kansasii, organisms of the 
M. avium complex (MAC), and organisms in the M. abscessus complex.
In Europe, Asia, and Australia, the distribution of NTM in clinical 
specimens is roughly similar to that in North America, with MAC spe­
cies and rapidly growing organisms such as M. abscessus encountered 
frequently. M. xenopi and M. malmoense are especially prominent in 
northern Europe. M. ulcerans causes the distinct clinical entity Buruli ulcer, 
which occurs throughout tropical zones, especially in western Africa.

M. marinum is a common cause of cutaneous and tendon infections in 
coastal regions and among individuals exposed to fish tanks or swim­
ming pools.
The true international epidemiology of infections due to NTM is 
hard to determine because the isolation of these organisms often is not 
reported and speciation often is not performed for M. tuberculosis or 
NTM. The latter issue poses an especially important problem during 
therapy for tuberculosis when smears positive for acid-fast bacilli are 
considered evidence of treatment failure. The increasing ease of iden­
tification and speciation of these organisms is already having a major 
impact on the description of the dynamic international epidemiology 
of tuberculosis and NTM infections.
■
■PATHOBIOLOGY
Because exposure to NTM is essentially universal and disease is rare, 
it can be assumed that normal host defenses against these organisms 
must be strong and that otherwise healthy individuals in whom sig­
nificant disease develops are highly likely to have specific susceptibility 
factors that permit NTM to become established, multiply, and cause 
disease. At the advent of HIV infection, CD4+ T lymphocytes were 
recognized as key effector cells against NTM; the development of dis­
seminated MAC disease was highly correlated with a decline in CD4+ 
T lymphocyte numbers. Such a decrease has also been implicated 
in disseminated MAC infection in patients with idiopathic CD4+ T 
lymphocytopenia. Potent inhibitors of tumor necrosis factor α (TNF-α), 
such as infliximab, adalimumab, certolizumab, golimumab, and etan­
ercept, neutralize this critical cytokine, with consequent inhibition of 
granuloma formation. The occasional result is severe mycobacterial 
or fungal infection; these associations indicate that TNF-α is a crucial 
element in mycobacterial control. However, in cases without the above 
risk factors, much of the basis of susceptibility to disseminated infec­
tion with NTM is accounted for by specific mutations in the interferon 
γ (IFN-γ)/interleukin 12 (IL-12) synthesis and response pathways or 
autoantibodies to IFN-γ itself.
Mycobacteria are typically phagocytosed by macrophages, which 
respond with the production of IL-12, a heterodimer composed 
of IL-12p35 and IL-12p40 moieties that together make up IL12p70. IL-12 activates T lymphocytes and natural killer cells through 
binding to its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R), 
with consequent phosphorylation of STAT4. IL-12 stimulation of 
STAT4 leads to secretion of IFN-γ, which activates neutrophils and 
macrophages to produce reactive oxidants, to increase expression of 
the major histocompatibility complex and Fc receptors, and to concen­
trate certain antibiotics intracellularly. Signaling by IFN-γ through its 
receptor (composed of IFN-γR1 and IFN-γR2) leads to phosphoryla­
tion of STAT1, which in turn regulates IFN-γ-responsive genes, such as 
those coding for IL-12 and TNF-α. TNF-α signals through its own 
receptor via a downstream complex containing the nuclear factor-κB 
(NF-κB) essential modulator (NEMO). Therefore, the positive feed­
back loop between IFN-γ and IL-12/IL-23 drives the immune response 
to mycobacteria and other intracellular infections. These genes are 
known to be the critical ones in the pathway of mycobacterial control: 
specific Mendelian mutations have been identified in IFNG, IFNGR1, 
IFNGR2, STAT1, GATA2, ISG15, IRF8, IL-12A, IL-12RB1, IL-12RB2, 
CYBB (which encodes the gp91phox protein of the NADPH oxidase), 
SPP2A, MCTS1, and IKBKG (which encodes NEMO) (Fig. 185-1). 
Despite the identification of genes associated with disseminated dis­
ease, only ~70% of cases of disseminated nontuberculous mycobacte­
rial infections that are not associated with HIV infection have a genetic 
diagnosis; the implication is that more mycobacterial susceptibility 
genes and pathways remain to be identified.
In contrast to the recognized genes and mechanisms associated 
with disseminated nontuberculous mycobacterial infection, the bestrecognized underlying condition for pulmonary infection with NTM 
is bronchiectasis (Chap. 301). Most of the well-characterized forms 
of bronchiectasis, including cystic fibrosis, primary ciliary dyskinesia, 
STAT3-dominant negative hyper-IgE syndrome (Job’s syndrome), and 
idiopathic bronchiectasis, have high rates of association with nontu­
berculous mycobacterial infection. The precise mechanism by which 

IL-2
IL-2R
T/NK
IFNf
a1
IL-12R
a2
IL-18 ?
IL-15
IFNfR
STAT1
GATA2

IRF8
ISG15
IL-12
NEMO
AFB
Salm.
TNF`
NRAMP1
MΦ
TLR
TNF`R
CD14
LPS
FIGURE 185-1  Cytokine interactions of infected macrophages (MΦ) with T and 
natural killer (NK) lymphocytes. Infection of macrophages by mycobacteria 
(AFB) leads to the release of heterodimeric interleukin 12 (IL-12). IL-12 acts on its 
receptor complex (IL-12R), with consequent STAT4 activation and production of 
homodimeric interferon γ (IFNγ). Through its receptor (IFNγR), IFNγ activates STAT1, 
stimulating the production of tumor necrosis factor α (TNFα) and leading to the 
killing of intracellular organisms such as mycobacteria, salmonellae (Salm.), and 
some fungi. Homotrimeric TNFα acts through its receptor (TNFαR) and requires 
nuclear factor-κB essential modulator (NEMO) to activate nuclear factor-κB, which 
also contributes to the killing of intracellular bacteria. Both IFNγ and TNFα lead to 
upregulation of IL-12. TNFα-blocking antibodies work either by blocking the ligand 
(infliximab, adalimumab, certolizumab, golimumab) or by providing soluble receptor 
(etanercept). Mutations in IFNG, IFNGR1, IFNGR2, IL12B, IL12RB1, IL12RB2, STAT1, 
GATA2, ISG15, IRF8, CYBB, MCTS1, and IKBKG (NEMO) have been associated with 
predisposition to mycobacterial infections. Other cytokines, such as IL-15 and IL-18, 
also contribute to IFNγ production. Signaling through the Toll-like receptor (TLR) 
complex and CD14 also upregulates TNFα production. IRF8, interferon regulatory 
factor 8; ISG15, interferon-stimulated gene 15; LPS, lipopolysaccharide; NRAMP1, 
natural resistance-associated macrophage protein 1.
CHAPTER 185
Nontuberculous Mycobacterial Infections 
bronchiectasis predisposes to locally destructive but not systemic 
involvement is unknown.
Unlike disseminated or pulmonary infection, “hot-tub lung” rep­
resents pulmonary hypersensitivity to NTM—most commonly MAC 
organisms—growing in underchlorinated water, often in indoor hot 
tubs.
■
■CLINICAL MANIFESTATIONS
Disseminated Disease 
Disseminated MAC or M. kansasii infec­
tions in people with advanced HIV infection are now uncommon in 
North America because of effective antimycobacterial prophylaxis 
and improved treatment of HIV infection. When such mycobacterial 
disease was common, the portal of entry was the bowel, with spread to 
bone marrow and the bloodstream. Surprisingly, disseminated infec­
tions with rapidly growing NTM (e.g., M. abscessus, M. fortuitum) are 
very rare in people with advanced HIV infection. Because these organ­
isms are of low intrinsic virulence and disseminate only in conjunction 
with impaired immunity, disseminated disease can be indolent and 
progressive over weeks to months. Typical manifestations of malaise, 
fever, and weight loss are often accompanied by organomegaly, lymph­
adenopathy, and anemia. Because special cultures or stains are required 
to identify the organisms, the most critical step in diagnosis is to sus­
pect infection with NTM. Blood cultures may be negative, but involved 
organs typically have significant organism burdens, sometimes with a 
grossly impaired granulomatous response.
Disseminated involvement (i.e., involvement of two or more 
organs) without an underlying iatrogenic cause should prompt a 
genetic investigation of the IFN-γ/IL-12 pathway. Recessive muta­
tions in IFNGR1 and IFNGR2 typically ablate IFN-γ signaling and lead 
to severe infection with NTM. In contrast, dominant negative muta­
tions in IFNGR1, which lead to overaccumulation of a defective inter­
fering mutant receptor on the cell surface, inhibit but do not abolish

normal IFN-γ signaling and cause nontuberculous mycobacterial 
osteomyelitis. Dominant negative mutations in STAT1 and recessive 
mutations in IL-12RB1 can produce variable phenotypes consistent 
with their residual capacities for IFN-γ synthesis and response. Male 
patients who have disseminated nontuberculous mycobacterial infec­
tions along with bacterial or viral infections; conical, peg, or missing 
teeth; or an abnormal hair pattern should be evaluated for defects in 
the pathway that activates NF-κB through NEMO (IKBKG). These 
patients may have associated immune globulin defects as well. Patients 
with myelodysplasia and mycobacterial disease should be investigated 
for GATA2 deficiency. A recently recognized group of patients who 
often develop disseminated infections with both MAC and rapidly 
growing NTM (predominantly M. abscessus) as well as other opportu­
nistic infections such as Talaromyces have high-titer neutralizing auto­
antibodies to IFN-γ. This syndrome has been reported most frequently 
in East Asian female patients.

IV catheters can become infected with NTM, usually as a conse­
quence of contaminated water. M. abscessus and M. fortuitum some­
times infect deep indwelling lines as well as fluids used in eye surgery, 
subcutaneous injections, and local anesthetics. Infected catheters 
should be removed.
Pulmonary Disease 
Lung disease is by far the most common form 
of nontuberculous mycobacterial infection in North America and the 
rest of the industrialized world. In North America, rates of NTM lung 
disease far exceed rates of tuberculosis. The clinical presentation typi­
cally consists of months or years of throat clearing, nagging cough, and 
slowly progressive fatigue. Patients will often have seen physicians mul­
tiple times and received symptom-based or transient therapy before the 
diagnosis is entertained and samples are sent for mycobacterial stains 
and cultures. Because not all patients can produce sputum, bronchos­
copy may be required for diagnosis. The typical lag between onset of 
symptoms and diagnosis is ~5 years in older women. Predisposing fac­
tors include underlying lung diseases such as bronchiectasis (Chap. 301), 
pneumoconiosis (Chap. 300), chronic obstructive pulmonary disease 
(Chap. 303), primary ciliary dyskinesia (Chap. 301), α1 antitrypsin 
deficiency (Chap. 303), and cystic fibrosis (Chap. 302). Bronchiectasis 
and nontuberculous mycobacterial infection often coexist and progress 
in tandem. This situation makes causality difficult to determine in a 
given index case, but bronchiectasis is certainly among the most critical 
predisposing factors that are exacerbated by infection.
PART 5
Infectious Diseases
MAC are the most common cause of pulmonary nontuberculous 
mycobacterial infection in North America, but rates vary somewhat 
by region. MAC infection most commonly develops during the sixth 
or seventh decade of life in women who have had months or years of 
nagging intermittent cough and fatigue, with or without sputum pro­
duction or chest pain. The constellation of pulmonary disease due to 
NTM in a tall and thin woman who may have chest wall abnormalities 
is often referred to as “Lady Windermere syndrome,” after an Oscar 
Wilde character of the same name. In fact, pulmonary MAC infec­
tion does afflict older nonsmoking white women more than men, 
with onset at ~60 years. Patients tend to be taller and thinner than the 
general population, with high rates of scoliosis, mitral valve prolapse, 
and pectus anomalies. Whereas male smokers with upper-lobe cavi­
tary disease tend to carry the same single strain of MAC indefinitely, 
nonsmoking females with nodular bronchiectasis tend to carry several 
strains of MAC simultaneously, with changes over the course of their 
disease.
M. kansasii can cause a clinical syndrome that strongly resembles 
tuberculosis, consisting of hemoptysis, chest pain, and cavitary lung 
disease. The rapidly growing NTM, such as M. abscessus, have 
been associated with esophageal motility disorders such as achalasia. 
Patients with pulmonary alveolar proteinosis are prone to pulmonary 
nontuberculous mycobacterial and Nocardia infections; the underlying 
mechanism may be inhibition of alveolar macrophage function due to 
the autoantibodies to granulocyte-macrophage colony-stimulating fac­
tor found in many of these patients.
Cervical Lymph Nodes 
The most common form of nontubercu­
lous mycobacterial infection among young children in North America 

is isolated cervical lymphadenopathy, caused most frequently by MAC 
organisms but also by other NTM. The cervical swelling is typically 
firm and relatively painless, with a paucity of systemic signs. Because 
the differential diagnosis of painless adenopathy includes malignancy, 
many children have infection with NTM diagnosed inadvertently 
at biopsy; cultures and special stains may not have been requested 
because mycobacterial disease was not ranked high in the differential. 
Local fistulae usually resolve completely with resection and/or anti­
biotic therapy. Likewise, the entity of isolated pediatric intrathoracic 
nontuberculous mycobacterial infection, which is probably related 
to cervical lymph node infection, is usually mistaken for cancer. In 
neither isolated cervical nor isolated intrathoracic infections with 
NTM have children with underlying immune defects been commonly 
identified, nor do the affected children usually go on to develop other 
opportunistic infections.
Skin and Soft Tissue Disease 
Cutaneous involvement with NTM 
usually requires a break in the skin for introduction of the bacteria. 
Pedicure bath–associated infection with M. fortuitum is more likely 
if skin abrasion (e.g., during leg shaving) has occurred just before 
the pedicure. Outbreaks of skin infection are often caused by rapidly 
growing NTM (especially M. abscessus, M. fortuitum, and M. chelonae) 
acquired via skin contamination from surgical instruments (especially 
in cosmetic surgery), injections, and other procedures. These infec­
tions are typically accompanied by painful, erythematous, draining 
subcutaneous nodules, usually without associated fever or systemic 
symptoms.
M. marinum lives in many water sources and can be acquired from 
fish tanks, swimming pools, barnacles, and fish scales. This organ­
ism typically causes papules or ulcers (“fish-tank granuloma”), but 
the infection can progress to tendinitis with significant impairment 
of manual dexterity. Lesions appear days to weeks after inoculation 
of organisms by a typically minor trauma (e.g., incurred during the 
cleaning of boats or the handling of fish). Tender nodules due to 

M. marinum can advance up the arm in a pattern also seen with 
Sporothrix schenckii (sporotricoid spread). The typical carpal tendon 
involvement may be the first presenting manifestation and may lead 
to surgical exploration or steroid injection. The index of suspicion for 
M. marinum infections must be high to ensure that proper specimens 
obtained during procedures are sent for culture.
M. ulcerans, another waterborne skin pathogen, is found mainly in 
the tropics, especially in tropical areas of Africa. Infection follows skin 
trauma or insect bites that allow admission to contaminated water. 
The skin lesions are typically painless, clean ulcers that slough and can 
cause osteomyelitis. The toxin mycolactone accounts for the dimin­
ished host inflammatory response and the painless ulcerations.
■
■DIAGNOSIS
NTM can be detected on acid-fast or fluorochrome smears of sputum 
or other body fluids. When the organism burden is high, the organ­
isms may appear as gram-positive beaded rods, but this finding is 
unreliable. (In contrast, nocardiae may appear as gram-positive and 
beaded but filamentous bacteria.) Again, the requisite and most sensi­
tive step in the diagnosis of any mycobacterial disease is to think of 
including it in the differential. In almost all laboratories, mycobacte­
rial sample processing, staining, and culture are conducted separately 
from routine bacteriologic tests; thus, many infections go undiagnosed 
because of physician failure to request the appropriate test. In addition, 
mycobacteria usually require separate blood culture media. NTM are 
broadly differentiated into rapidly growing (<7 days) and slowly growing 
(≥7 days) forms. Because M. tuberculosis typically takes ≥2 weeks to 
grow, many laboratories refuse to consider culture results final until 
6 weeks have elapsed. Newer techniques using liquid culture media 
permit more rapid isolation of mycobacteria from specimens than 
is possible with traditional media. Species more readily detected 
with incubation at 30°C include M. marinum, M. haemophilum, and 

M. ulcerans. M. haemophilum prefers iron supplementation or blood, 
whereas M. genavense requires supplemented medium with the addi­
tive mycobactin J. Bacterial formation of pigment in light conditions

(photochromogenicity) or dark conditions (scotochromogenicity) or 
a lack of bacterial pigment formation (nonchromogenicity) was his­
torically used to help categorize NTM. In contrast to NTM colonies, 

M. tuberculosis colonies are beige, rough, dry, and flat. Current iden­
tification schemes reliably use biochemical, nucleic acid, or cell wall 
composition, as assessed by high-performance liquid chromatography 
or mass spectrometry, for speciation. With the remarkable decline 
in U.S. cases of tuberculosis over recent decades, NTM have become 
the mycobacteria most commonly isolated from humans in North 
America. However, not all isolations of NTM, especially from the lung, 
reflect pathology and require treatment. Whereas identification of an 
organism in a blood or organ biopsy specimen in a compatible clinical 
setting is considered diagnostic, the American Thoracic Society rec­
ommends that pulmonary infection due to NTM be diagnosed only 
when disease is clearly demonstrable—i.e., in an appropriate clinical 
and radiographic setting (nodules, bronchiectasis, cavities) and with 
repeated isolation of NTM from expectorated sputum or recovery of 
NTM from bronchoscopy or biopsy specimens. Given the large num­
ber of species of NTM and the importance of accurate diagnosis for the 
implementation of proper therapy, identification of these organisms is 
ideally taken to the species level.
The purified protein derivative (PPD) of tuberculin is delivered 
intradermally to evoke a memory T-cell response to mycobacterial 
antigens. This test is variously referred to as the PPD test, the tubercu­
lin skin test, and the Mantoux test, among other designations. Unfor­
tunately, the cutaneous immune response to these tuberculosis-derived 
filtrate proteins does not differentiate well between infection with some 
NTM and that with M. tuberculosis. Because intermediate reactions 
(~10 mm) to PPD in latent tuberculosis and nontuberculous myco­
bacterial infections can overlap significantly, the progressive decline 
in active tuberculosis in the United States means that NTM probably 
account for increasing proportions of PPD reactivity. In addition, bac­
ille Calmette-Guérin (BCG) can cause some degree of cross-reactivity 
in PPD testing, posing problems of interpretation for patients who have 
received BCG vaccine. Assays to measure the elaboration of IFN-γ in 
response to the relatively tuberculosis-specific proteins ESAT6 and 
CFP10 form the basis for IFN-γ-release assays (IGRAs). These assays 
can be performed with whole blood or on membranes. It is important 
to note that M. marinum, M. kansasii, and M. szulgai also have ESAT6 
and CFP10 and may cause false-positive reactions in IGRAs. Despite 
cross-reactivity with NTM, large PPD reactions (>15 mm) most com­
monly signify tuberculosis. Conversely, in the setting of anti-IFNγ 
autoantibodies, the IGRA test is indeterminate (failure of IFNγ detec­
tion in response to specific antigens and mitogens, due to neutralizing 
anti-IFNγ autoantibodies).
Isolation of NTM from blood specimens is clear evidence of disease. 
Whereas rapidly growing mycobacteria may proliferate in routine 
blood culture media, slow-growing NTM typically do not; therefore, 
it is imperative to suspect the diagnosis and to use the correct bottles 
for cultures. Isolation of NTM from a biopsy specimen constitutes 
strong evidence for infection, but cases of laboratory contamination 
do occur. Identification of organisms on stained sections of biopsy 
material confirms the authenticity of the culture. Certain NTM require 
lower incubation temperatures (M. genavense) or special additives 
(M. haemophilum) for growth. Some NTM (e.g., M. tilburgii) remain 
noncultivable but can be identified molecularly in clinical samples.
The radiographic appearance of nontuberculous mycobacterial dis­
ease in the lung depends on the underlying disease, the severity of the 
infection, and the imaging modality used. The advent and increase in 
the use of computed tomography (CT) scanning has allowed the iden­
tification of characteristic changes that are highly consistent with non­
tuberculous mycobacterial infection, such as the “tree-in-bud” pattern 
of bronchiolar inflammation (Fig. 185-2). Involvement of the lingual 
and right-middle lobes is commonly seen on chest CT but is difficult 
to appreciate on plain film. Severe bronchiectasis and cavity formation 
are common in more advanced disease.
Isolation of NTM from respiratory samples can be confusing. 

M. gordonae is often recovered from respiratory samples but is not 
usually seen on smear and is almost never a pathogen. Patients with 

FIGURE 185-2  Chest computed tomography of a patient with pulmonary 
Mycobacterium avium complex infection. Arrows indicate the “tree-in-bud” 
pattern of bronchiolar inflammation (peripheral right lung) and bronchiectasis 
(central right and left lungs).
bronchiectasis occasionally have NTM recovered from sputum culture 
with a negative smear. The American Thoracic Society has developed 
guidelines for the diagnosis of infection with MAC, M. abscessus, and 
M. kansasii. A positive diagnosis requires the growth of NTM from 
two of three sputum samples, regardless of smear findings; a positive 
bronchoscopic alveolar sample, regardless of smear findings; or a pul­
monary parenchyma biopsy sample with granulomatous inflammation 
or mycobacteria found on section and NTM found on culture. These 
guidelines probably apply to other NTM as well.
CHAPTER 185
Although many laboratories use DNA probes to identify M. tuber­
culosis, MAC, M. gordonae, and M. kansasii, speciation of NTM helps 
determine the antimycobacterial therapy to be used. Only testing of 
MAC organisms for susceptibility to clarithromycin and of M. kansasii 
for susceptibility to rifampin is indicated; few data support other in 
vitro susceptibility tests, attractive though they appear. MAC isolates 
that have not been exposed to macrolides are almost always suscepti­
ble. NTM that have persisted beyond a course of antimicrobial therapy 
are often tested for antibiotic susceptibility, but the value and meaning 
of these tests are undetermined.
Nontuberculous Mycobacterial Infections 
■
■PREVENTION
Prophylaxis of MAC disease in patients infected with HIV is started 
when the CD4+ T lymphocyte count falls to <50/μL. Azithromycin 
(1200 mg weekly), clarithromycin (1000 mg daily), and rifabutin 
(300 mg daily) are effective. Macrolide prophylaxis in immunodefi­
cient patients who are susceptible to NTM (e.g., those with defects in 
the IFN-γ/IL-12 axis) has not been prospectively validated but seems 
prudent.
TREATMENT
Nontuberculous Mycobacteria
NTM cause chronic infections that evolve relatively slowly over a 
period of weeks to years. Therefore, it is rarely necessary to initi­
ate treatment on an emergent basis before the diagnosis is clear 
and the infecting species is known. Treatment of NTM is complex, 
often poorly tolerated, and potentially toxic. Just as in tuberculosis, 
inadequate single-drug therapy is almost always associated with the 
emergence of antimicrobial resistance and relapse.
MAC infection often requires multidrug therapy, the founda­
tion of which is a macrolide (clarithromycin or azithromycin), 
ethambutol, and a rifamycin (rifampin or rifabutin). For dis­
seminated nontuberculous mycobacterial disease in HIV-infected 
patients, the use of rifamycins poses special problems—i.e., rifa­
mycin interactions with protease inhibitors. For pulmonary MAC 
disease, thrice-weekly administration of a macrolide, a rifamycin,