1. health and fitness
2. disease

Nontuberculous Mycobacterial
(NTM) Lung Disease
David Griffith, M.D.
Assistant Medical Director,
Heartland National TB Center
Professor of Medicine,
University of Texas Health Center, Tyler
Mycobacteria isolated
Mayo 11/05-03/06
n=1379
• Mycobacterium avium intracellulare
42%
• M. gordonae 19%
• M. chelonae/M. abscessus 12%
• M. tuberculosis 10%
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NTM Incidence and Prevalence
• Why it is difficult to know the exact
incidence and prevalence of NTM disease
– Not all NTM isolates are pathogenic, some
isolates represent specimen contamination
• M. gordonae
• NTM in tap water (MAC, M kansasii, M simiae, M
abscessus)
– Even pathogenic NTM are not always
associated with progressive disease
Epidemiology of Pulmonary
Nontuberculous Mycobacterial Infections
in Ontario 1997-2003 (Marras et al Thorax 2007)
• Prevalence rate for the 4 most common NTM
species (combined) was 9.1/100,000 in 1997 and
14.1/100,000 in 2003 (p < 0.0001)
• An average annual increase in prevalence of 8.4%
• The rates of NTM recovery were greater than TB
throughout the study period and the ratio of NTM/TB
case rates increased during the study period
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Slowly growing mycobacteria associated
with lung disease
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MAC
M. kansasii
M. simiae
M. xenopi
M. malmoense
M. szulgai
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M. triplex
M. scrofulaceum (rarely)
M. intermedium
M. nonchromogenicum (rarely)
M. heidelbergense
M. gordonae (rarely)
M. tusciae (rarely)
M. branderi (rarely)
M. heckseshornesnse
M. interjectum
M. asiaticum (rarely)
M. shimoidei (rarely)
M. lentiflavum
M. genavense
M. cleatum
Rapidly growing mycobacteria
associated with lung disease
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M. abscessus
M. fortuitum
M. chelonae
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M. elephantis
M. goodii
M. wolinskyi
M. smegmatis
M. mageritense
M. immunogenum
M. fortuitum 3rd biovariant group
M. porcinum
M. peregrinum
M. thermoresistible
M. mucogenicum (rarely)
M. alvei (rarely)
M. vaccae (rarely)
M. flavescens (rarely)
M. moriokaense (rarely)
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An Official ATS/IDSA Statement:
Diagnosis, Treatment and
Prevention of Nontuberculous
Mycobacterial Diseases
American Journal of Respiratory
and Critical Care Medicine
2007, 175; 367-416
ATS Diagnostic Guidelines for
NTM Lung Disease
• More than 120 identified species of NTM with a
wide spectrum of virulence
• All NTM lung disease diagnostic criteria
suggested so far are based on experience with
common and well-described respiratory
pathogens including Mycobacterium avium
complex, M. kansasii and M. abscessus
• It is unrealistic (and a leap of faith) to expect that
a single set of diagnositic criteria would apply to
all respiratory NTM pathogens
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ATS Diagnostic Guidelines for
NTM Lung Disease
Under diagnosis
Over diagnosis
Untreated disease
Drug toxicity
Usually enough time for a careful assessment
of patients with bronchiectasis and
possible NTM disease
Diagnosis of NTM Lung Disease
Minimum Evaluation
• Compatible Symptoms
• Radiographic Evaluation
– Chest radiograph (cavitary disease) or,
– HRCT of chest (nodular/bronchiectatic disease)
• Microbiologic Evaluation
– 3 or more sputum for AFB analysis
– Bronchoscopic evaluation
• Exclusion of other diagnoses
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Diagnosis of NTM Lung Disease
• Presumptive diagnosis based on clinical
and radiographic features is inappropriate
for initiation of (empiric) therapy
Diagnosis of NTM Lung Disease:
Microbiologic Criteria
• 1997: 3 sputum or
bronchial wash
samples
• 3 positive cultures
with negative smears
• 2 positive cultures
and one positive
smear
• 2007: 3 sputum
results
• 2 positive cultures
regardless of AFB
smear results
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Diagnosis of NTM Lung Disease:
Microbiologic Criteria
• 1997: Single available
bronchial wash and
inability to obtain
sputum
• Positive culture with
either positive smear
or heavy growth on
culture
• 2007: Single available
bronchial wash or
lavage
• One positive culture
regardless of smear
results
Diagnosis of NTM Lung Disease:
Microbiologic Criteria
• 1997: Tissue biopsy
• Any NTM growth from
biopsy
• Compatible
histopathology with
(+) sputum or
bronchial wash
culture
• Sterile site (+) culture
• 2007: Tissue biopsy
• compatible
histopathology and
(+) culture
• Compatible
histopathology and
(+) sputum or
bronchial wash
culture
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Diagnosis of NTM Lung Disease
• A single positive sputum culture,
especially with small numbers of
organisms (smear negative, liquid media
growth only) is regarded as indeterminate
for diagnosis of NTM lung disease.
Diagnosis of NTM Lung Disease:
Microbiologic Criteria
• A single positive culture from any source
(sputum or bronchoscopy) is suspect if
due to:
– Frequent contaminants, M. gordonae, M.
terrae complex, M. mucogenicum
– NTM species known to be present in tap
water, M. simiae, M. lentiflavum, M.
abscessus, M. kansasii
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Diagnostic Criteria for NTM
Lung Disease
• PATIENTS WHO ARE SUSPECTED OF
HAVING NTM LUNG DISEASE BUT DO
NOT MEET THE DIAGNOSTIC
CRITERIA SHOULD BE FOLLOWED
UNTIL THE DIAGNOSIS IS FIRMLY
ESTABLISHED OR EXCLUDED.
Diagnostic Criteria for NTM
Lung Disease
• MAKING THE DIAGNOSIS OF NTM
LUNG DISEASE DOES NOT, PER SE,
NECESSITATE THE INSTITUTION OF
THERAPY, WHICH IS A DECISION
BASED ON POTENTIAL RISKS AND
BENEFITS OF THERAPY FOR
INDIVIDUAL PATIENTS.
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Factors Influencing the Decision to
Treat NTM Lung Disease
• The decision to initiate treatment for
patients with NTM lung disease is
ultimately a decision based on risk/benefit
analysis taking into account patient
symptoms, radiographic findings
(progression) and microbiologic results vs.
the adverse effects of multiple potentially
toxic and relatively weak drugs.
Factors Influencing the Decision to
Treat NTM Lung Disease
• Diagnostic uncertainty
• Minimal symptoms/minimal radiographic
involvement
• Indolent disease
• Advanced age/severe comorbid medical
conditions/limited life expectancy
• Cost of medications
• Inability to tolerate NTM medications
– The treatment is worse than the disease
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Mycobacterium avium complex
Lung Disease
State of the Art: Nontuberculous
Mycobacteria and Associated Diseases
(Wolinsky, ARRD 1979;119: 107)
• “Chronic pulmonary disease resembling TB
represents the most important clinical problem
associated with NTM…”
• “The average case of M kansasii or MAI disease
would be a 48-year-old man with long-standing
lung disease…with a 3-month history of
increasingly productive cough, night sweats, a
low-grade fever, and moderate weight loss.”
• “The chest roentgenogram shows fibrosis and a
thin-walled cavity in the right upper lobe.”
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M. avium Complex (MAC)
Lung Disease
Clinical presentations:
• Fibronodular cavitary or "tuberculosis" type
– 50% cases
– Heavy smoker, male predominance,
alcoholism, onset <60 years age
– Diagnosed initially as TB suspects
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Nodular Bronchiectasis MAC Lung
Clinical Features
PATIENTS
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50% / cases (?)
80% of patients are women
95% of patients are Caucasian
60% are lifelong non-smokers, no alcohol
mean age is 70 years
most have no serious underlying disease
Nodular Bronchiectasis MAC Lung
Radiographic Features
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Predominantly involve RML and lingula
Cavities are unusual (usually in mid lung)
On CT or HRCT have:
a) Cylindrical bronchiectasis and/or
b) Small nodules <5mm usually in the same
lung segments
c) Rarely neither
• Radiographic progression is usually slow
(years)
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Nontuberculous Mycobacterial
Diseases: Pulmonary Disease
• Usual clinical presentation: chronic cough
(“recurrent pneumonia”), debilitating fatigue,
weight loss, fever, hemoptysis
• Pathogenesis: characteristic morphotype(scoliosis, pectus excavatum, MVP), abnormal
CF genotypes, AAT phenotypes
• Variable disease progression: frequent
bronchiectasis- related symptoms
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Nodular Bronchiectasis MAC Lung
Microbiologic Features
• Predominantly AFB smear negative
• Low colony counts on solid media
• 20% (+) liquid medium BACTEC only
Nodular Bronchiectasis MAC Lung
Microbiologic Features
(continued)
• Frequent presence of other pathogens:
Pseudomonas aeruginosa, Staph aureus
Other NTM (M. abscessus, etc.)
Nocardia, Aspergillus
• Cultures often contaminated with GNR
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Therapy of MAC Lung Disease
New ATS NTM Guidelines
• Cavitary disease:
macrolide/EMB/rifamycin ± injectable:
DAILY
• Nodular/bronchiectatic disease:
macrolide/EMB/rifamycin: INTERMITTENT
• Severe or previously treated disease:
macrolide/EMB/rifamycin/injectable:
DAILY
Strategies for Managing MedicationRelated Obstacles
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Gradual introduction of medication
Splitting medication dosage
Intermittent (TIW) medication dosing
Azithromycin vs clarithromycin
Two drug (macrolide/EMB) DAILY therapy
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Treatment of NTM Lung Disease
• Controversies in the treatment of patients with
NTM lung disease
– Role of in vitro susceptibility testing
– Consequences of ineffective therapy: Diminishing
treatment response with successive treatment efforts
– Disease Relapse vs Re-infection
Increasing numbers of patients receiving
therapy for NTM (MAC) lung disease
magnify these controversies
In Vitro Susceptibility Testing
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M. tuberculosis
The “ideal” for mycobacterial response to therapy
• INH and Rifampin
– Highly active bacteriocidal drugs
– Achievable blood levels 10-100X MIC’s of
susceptible organisms
– Penetrate all tissues
– Clear association between MIC and
resistance
•EMB and PZA: not all drugs are created equal
MAC and In Vitro Susceptibility Testing
(Kobashi et al. J Infect Chemother 2006, 12; 195)
• 52 patients with pulmonary MAC treated with
Rmp, Emb, Clari, and Stm
• No relationship between clinical response and
MICs for Rmp, Emb and Stm (similar findings
BTS study IJTLD 2002, 6; 628)
• Clinical efficacy did correlate with clari MICs
(similar findings AJRCCM 1994; 149:1335, CID
1996; 23:983, Ann Int Med, 1994, 121; 905, CID
1999; 28: 1080)
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Macrolides for MAC Disease
• Effective in pulmonary and disseminated
MAC disease
• Treatment success correlates with in vitro
MIC (susceptible < 8 µg/ml, intermediate
16 µg/ml, resistant > 32 µg/ml
• Disease progression/relapse associated
with MIC > 32 µg/ml
Macrolides for MAC Disease: Summary
• There are no drugs, other than the macrolides
for which there is a correlation between in vitro
susceptibility (MIC) and in vivo response for
disseminated or pulmonary MAC disease.
• The designation of “susceptible” must be used
with caution for all drugs other than macrolides
in MAC disease.
• In vitro susceptibility tests for most drugs do not
predict who will respond and who will fail
therapy.
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MAC In Vitro Susceptibility Testing:
2007 NTM Guidelines
• Clarithromycin susceptibility testing only is
recommended for new MAC isolates
• Clarithromycin is the “class agent” for macrolide
susceptibility testing
• No other drugs are recommended for
susceptibility testing of new MAC isolates
• Clarithromycin susceptibility should be
performed for MAC isolates from patients who
fail macrolide therapy
Nontuberculous mycobacteria for which there
is not an established correlation between
in vitro susceptibility and in vivo response
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M. malmoense
M. scrofulaceum
M. simiae
M. xenopi
M. abscessus
M. immunogenum
Etc.
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Consequences of Macrolide
Resistance
Macrolide Resistant
MAC Lung Disease
(Griffith et al 2006 Am J Resp Crit Care Med)
• 51 patients with macrolide resistant MAC
isolates identified between 1991-2006.
• 27 (53%) Upper lobe Cavitary Disease,
78% male
• 24 (47%) Nodular Bonchiectatic Disease
92% female
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Possible Risk Factors for the
Development of Macrolide Resistance
(Griffith et al 2006 Am J Resp Crit Care Med)
• Macrolide Monotherapy: 28/51 (55%)
• Macrolide plus quinolone: 11/51 (22%)
• Combined, regimens without ethambutol:
39/51 (76%)
• Other risk factors: 12/51 (23%)
• No difference in macrolide resistance based
on macrolide (azi or clari) or dosing interval
(daily or intermittent)
Macrolide Resistant MAC Lung
Disease: Response to Therapy
• Sputum conversion after macrolide
resistance:11/14 (77%) p=0.0001 in patients
who had both injectable therapy and surgery.
• Sputum conversion after macrolide resistance
2/37 (5%) in patients without both injectable
therapy and surgery.
• No difference in response between cavitary and
nodular disease
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Macrolide Resistant MAC Lung
Disease: Response to Therapy
• Of the patients who failed therapy, the one
year mortality was 13/38 (34%), two year
mortality was 17/38 (45%)
• Of the patients whose sputum converted
to negative, the one and two year mortality
was 0/13, (0%)
Macrolide Monotherapy for
Immune Modulation
• Saiman et al. JAMA 2003, 290; 1749:
azithromycin treatment associated with improved
pulmonary function, fewer exacerbations and
weight gain in CF patients infected with
Pseudomonas
• Patients should be screened for NTM disease
prior to initiation of macrolide monotherapy and
periodically during therapy as recommended for
CF patients
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The Effect of Prior Therapy on
MAC Lung Disease Treatment
Response
The Effect of Prior Therapy on MAC
Lung Disease Treatment Response
• Wallace et al: Clarithromycin regimens for pulmonary MAC.
The first 50 patients. AJRCCM 1996, 153; 1766.
• Griffith et al: Azithromycin-containing regimens for treatment
of MAC lung disease. CID 2001, 32; 1547.
• Tanaka et al: Effect of clarithromycin regimen for MAC
pulmonary disease. AJRCCM 1999, 160; 866.
• Kobashi et al: The microbiological and clinical effects of
combined therapy according to guidelines on the treatment
of pulmonary MAC disease in Japan. Respiration 2006
(e-pub)
• Lam et al: Factors related to response to intermittent
treatment of MAC lung disease. AJRCCM 2006, 173; 1283.
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MAC Reinfection
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Significance of Multiple (+) Sputums
Cultures After 10-12 Months (-) Cultures
on Rx: PFGE Study, Summary
1. Occurs in the setting of nodular bronchiectasis
2. May be seen at any time during therapy or
after stopping therapy
3. Approximately 90% will be new infections, and
often involve multiple strains
4. Reinfection isolates usually macrolide
susceptible
5. True clinical/microbiologic relapses are
unusual
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Keys to Successful Therapy of
MAC Lung Disease
• Not a matter of routine in vitro drug
susceptibilities EXCEPT MACROLIDES
• Macrolide (clarithromycin) susceptibility is
paramount and must be protected
– No macrolide monotherapy
– Adequate companion medications
• The first treatment effort is the best
chance for success
State of the Art: Nontuberculous
Mycobacteria and Associated Diseases
(Wolinsky, ARRD 1979;119: 107)
• “Proper management requires
greater expertise than is needed
for treatment of TB, first, to decide
who needs to be treated, and
second, to determine which drug
regimens to use.”
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The Mycobacterial Mystery
N. Schönfield Eur Resp J 2006, 28; 1076
• “Thus, the decision is made by the clinician, who
may, in view of sometimes rather uncomfortable
effects the drugs can have, be wise enough to keep
under observation even some of those patients who
fulfill consensus criteria for mycobacterial disease.
Optimal conservative treatment of underlying
disease should not be underestimated, either in this
or other contexts, despite the fact that drug
treatment has improved over the decades, and
patients with bronchiectasis and chronic
bronchitis…should profit from such an approach.”
The Mycobacterial Mystery
N. Schönfield Eur Resp J 2006, 28; 1076
• “Is this a mere opinion? The ATS
statement is full of opinions, and rightly
so!”
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M. kansasii
• In vitro susceptibilities and response to
medications similar to M. tuberculosis
• Rifampin, INH, Ethambutol effective
• Multiple medications with activity against
M. kansasii: clari, azi, moxi, sulfa, strep,
etc.
• Expect treatment for cure
Mycobacterium abscessus
LUNG DISEASE
1. Female, non-smokers, 60 years or older
2. Mid and lower lung field
nodules/bronchiectasis
3. Lung disease resembles, non-cavitary
Mycobacterium avium complex (MAC)
lung disease
4. No consistently identified immune defect
(unusual pathogen in AIDS)
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Mycobacterium abscessus
IN VITRO SUSCEPTIBILITIES
DRUG
Amikacin
Clarithromycin
Cefoxitin
Flouroquinolones
Imipenem
Linezolid
Tigecycline
% Susceptible Isolates
90
100
70
0
50
50
100
Mycobacterium abscessus
TREATMENT OPTIONS
There is no predictably or reliably effective
medical treatment strategy for M.
abscessus lung disease
• Microbiologic response
• Symptomatic response
• Disease progression
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M. simiae
• In vivo response to therapy may not
correlate with in vitro susceptibility
• Clari, moxi, sulfa, linezolid
• Optimal pharmacologic management for
M. simiae not defined
• surgery
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