WHO DAT MOTT
Juzar Ali
Objectives and focus
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NTM / MOTT Highlights
Some clinical examples
MAC in non-HIV population
Contemporary issues in management of
MOTT / MAC -PD
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References and supportive data available
Some basic differences
TB /NTM
• Exposure
• Human to human
transmission
• LTBI
• Latent disease
• Paucibacillary?
• Reactivation
• Incidence /Prevalence
• Relapse
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Environmental
Ingestion
No H-H transmission*
* not even seen in CF *
Paucibacillary
Mixed infection
Indolent
New Infection
When the last ATS statement about NTM was prepared in 1997,
there were approximately 50 NTM species that had been identified.
Currently, more than 125 NTM species have been cataloged***
The increase relates to
**improved microbiologic techniques and identification
New cases of NTM lung disease may significantly exceed case rates for TB
in some communities and regions
,
**advances in molecular techniques with the development and
acceptance of 16S rRNA gene sequencing as a standard for
defining new species.
***Clinical significance??
Classification of mycobacterial species commonly causing human disease
M. tuberculosis
complex
Slowly growing mycobacteria
M. tuberculosis
M. kansasii
M. bovis
M. marinum
M. africanum
Scotochromogens, Runyon group II
M. microti
M. gordonae
M. leprae
Photochromogens, Runyon* group I
M. scrofulaceum
Nonchromogens, Runyon group III
M. avium complex
M. avium
M. intracellulare
M. scrofulaceum
M. terrae complex
M. ulcerans
M. xenopi
M. simiae
M. malmoense
M. szulgai
M. asiaticum
Rapidly growing mycobacteria
Runyon group IV
M. fortuitum
The “Staph”
of mycobacteria
M. chelonae
M. abscessus
Pulmonary Disease
M. abscessus : Worldwide; may be found concomitant with MAC
M. asiaticum* Rarely isolated
M. avium complex Worldwide; most common NTM pathogen in U.S.
M. celatum* Cross-reactivity with TB-DNA probe
M. kansasii : U.S., Europe, South Africa, coal-mining regions
M. chelonae Pulm Disease ??
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M. fortuitum Associated with aspiration
Contaminant
M Szulgai and M Chelonae and Eye disease
Health Care– and Hygiene-associated Disease Prevention
Prevention of health care–related NTM infections requires that
surgical wounds, injection sites, and intravenous catheters not
be exposed to tap water or tap water–derived fluids. Endoscopes
cleaned in tap water and clinical specimens contaminated with
tap water or ice are also not acceptable.
MAC / Natural Water
MK / Tap Water
**Lung disease due to NTM occurs commonly in structural lung
disease, such as chronic obstructive pulmonary disease (COPD),
bronchiectasis, CF, pneumoconiosis, prior TB, pulmonary alveolar
proteinosis, and esophageal motility disorders
**Abnormal CF genotypes, CFTR Gene mutation and _1-antitrypsin (AAT) phenotypes
may predispose some patients to NTM infection
**NTM lung disease also occurs in women without clearly recognized
predisposing factors There is also an association between bronchiectasis, nodular
pulmonary NTM infections and a particular body habitus,
predominantly in postmenopausal women (e.g., pectus
excavatum, scoliosis, mitral valve prolapse)
“A mean MAC machine in the thin and lean”
**Bronchiectasis and NTM infection,
usually MAC, often coexist, making causality difficult to
determine. These patients may carry multiple MAC strains over
time, suggesting either polyclonal infection or recurrent infection
with distinct strains). It is unclear whether this problem is
due to local abnormalities (e.g., bronchiectasis) or to immune defects
Am J Respir CC M 178; 1066-1074 , 2008 NHLBI
CRITERIA FOR DX
Clinical (both required)
1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed
tomography scan that shows multifocal bronchiectasis with multiple small nodules
and
2. Appropriate exclusion of other diagnoses
Microbiologic
1. Positive culture results from at least two separate expectorated sputum samples. If the results from (1) are
nondiagnostic, consider repeat sputum AFB smears and cultures.
or
2. Positive culture result from at least one bronchial wash or lavage
or
3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous
inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features
(granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive
for NTM.
4. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or
that usually represent environmental contamination.
5. 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.
6. 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.
Griffith, DE, Aksamit, T, Brown-Elliott, BA, et al. An Official ATS/IDSA Statement: Diagnosis, treatment and
prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367. Copyright
©2007 American Thoracic Society.
NTM - PD Profile
Patient characteristics
Microbiological
Refractile Gram positive or
Gram neutral rods
Imaging
AFB stains and growth on solid
and liquid media (BACTEC or MGIT/
Mycobacteria growth indicator tube)
Others
Gene probes
(HPLC) Lipid chromatography on smears
and cultures within hours; some limitations
In identification of MAb & MCh
Semi-quantitative analysis of smears can be useful for diagnostic
and post Rx follow up purposes.
The burden of organisms in clinical
material is usually reflected by the number of organisms seen
on microscopic examination of stained smears.
Environmental
contamination, which usually involves small numbers of organisms,
rarely results in a positive smear examination.
Previous studies have indicated that specimens with a high number of
mycobacteria isolated by culture are associated with positive
smears and, conversely, specimens with a low number of mycobacteria
isolated by culture are less likely to have positive smears
Recommendation: ……. But the most important is
Communication between the clinician and laboratories
is essential for determining the importance and extent of
the identification analysis for a clinical NTM isolate
(C, III).
ATS Recommendations:
1. As much material as possible for NTM culture should be
provided with clear instructions to the laboratory to culture
for mycobacteria (C, III).
2. All cultures for NTM should include both a rapid detection
broth (liquid) media technique and solid media cultures
(C, III).
3. Quantification of the number of colonies on plated culture
media should be performed to aid clinical diagnosis (C,III).
4. Supplemented culture media and special culture conditions
(lower incubation temperatures) should be used for
material cultured from skin lesions, joints, and bone (A,II
5. The time (in days) to detection of mycobacterial growth
should be stated on the laboratory report (C, III).
MAC TB
• Focus on HIV negative patients
• MAC – PD
• Environmental pathogen!!
The M. avium complex (MAC) includes M. avium, M. intracellulare, and a group of
organisms referred to as the "X strains" which do not yet have a species
designation.
M. scrofulaceum was once grouped with these organisms as the "MAIS complex"
(M. avium-intracellulare-scrofulaceum)
While M. avium and M. intracellulare are also separate species, their separation
has no clinical value for individual patients and is generally not performed.
MAC typically produces small, flat, translucent, smooth colonies that occasionally
exhibit a pale yellow color. These colony morphologies differ from M. tuberculosis,
which typically shows cording in broth and appears as rough, buff colored colonies
on agar.
MAC- PD classifications ?
Radiographic: F/C or F/N bronchiectasis
Immunological/structural /clinical:
HIV
Non- HIV
** immune , epithelial, mucociliary
impairment
1. COPD: structural or airway
or just an association
clearance
2. LW Syndrome
/Scoliosis/Pectus**
3. INF –G Il-12 mutation; CTFR
Pathophysiology of Bronchiectasis
• The inflammation /infection cascade
• Interleukin,8, neutrophils, unapposed elastase,
and proteases
• The effect of transmural inflammation, edema,
crater formation, ulceration, and
neovacularization leading to permaneent
parenchymal damage
• Different properties of sputum in dilated airways
• Variance in mycobacterial genetic pool
Tumor Necrosis Factor Inhibition & NTM
IFN-_ and IL-12 control mycobacteria in large part through the
up-regulation of tumor necrosis factor (TNF)-_ made predominantly
by monocytes/macrophages.
The risk posed by TNF-_ blocking agents for predisposing to NTM
infections or promoting progression of active NTM infection is
unknown.
Expert opinion
is that patients with active NTM disease should receive TNF-_
blocking agents only if they are also receiving adequate therapy
for the NTM disease.
A 52-year old Caucasian woman sought medical attention due to
chronic cough. Physical exam was unremarkable. Sputum culture
revealed light growth with few colonies of Mycobacterium avium complex
(MAC). Repeat sputum cultures later again revealed a few colonies of
MAC. The patient was treated symptomatically and followed clinically by
serial sputum test (s) and radiographic evaluation. No specific therapy for
MAC was initiated and the patient did well, remaining asymptomatic.
: Wheezing; Dx Asthma
CXR Nodular opacities ? TB Started RIPE
Tr Bx Bx: Granulamatous Inflammation
Br Wash: MAC
MAC “Hot tub Lung” ;
or
Sarcoidosis with MAC?
Epidemiology. MAC exposure associated with hot-tub lung
represents a commonly recognized form of hypersensitivity-like
NTM pulmonary disease. NTM other than MAC also have the
potential to result in hypersensitivity-like lung disease associated
with hot tubs.
Role of indoor showerheads???
Microbiologic data are critical for the diagnosis of MAC
hypersensitivity-like lung disease, but not in isolation nor without
clinical, radiographic, or pathologic findings consistent with MAC
hypersensitivity-like disease.
The histopathology is that of non necrotizing granulomas although
necrotizing granulomas, organizing pneumonia, or interstitial
pneumonia may also be described in some patients The
distribution of these discrete granulomas is generally centrilobular
and bronchiocentric, differentiating MAC hypersensitivity like
lung from sarcoidosis or other hypersensitivity pneumonitis.
TB? RIPE
MK
MAC
MAN!! The Mycobacterial Highway/ Route
A
MOTT “Migration dilemma”
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Fibrocavitary disease
PPD positive
MAC by culture
Repeat Sputum: M.Chelonei
Rx or not?]\
What to Rx?
Rx LTBI??
The significance of two NTM species isolated simultaneously
from a patient is also unknown. The combination of
MAC and M. abscessus is especially well recognized.
on an individual basis.
Both these events are likely to
occur with increased frequency because of improved recovery
of NTM by mycobacteriology laboratories.
A 76- year old Caucasian woman, smoker, with past history of TB, treated
completely in the 1960’s, was seen with cough and minimal shortness of
breath. Pulmonary function tests revealed moderate obstructive airways
dysfunction. Sputum tests revealed moderate growth of Mycobacterium
avium complex on repeated examinations. The patient was placed on daily
treatment with clarithromycin and ethambutol with bronchodilators. She
remained stable on this regimen without any acute exacerbations. Serial
sputum cultures intermittently revealed light growth of Mycobacterium
avium complex.
A 65-year old woman with a history of nonspecific interstitial pneumonitis (NSIP)
and pulmonary fibrosis and with documented Mycobacterium avium complex
(MAC) on repeated sputum cultures since 2003 was admitted in March 2006 with
increasing dyspnea and respiratory failure. Prior to admission she had had
multiple sputum cultures which were positive for MAC and sensitive only to high
dose clarithromycin, ethambutol and rifabutin with which she was treated for 18
months. Due to concomitant and repeated growth of methicillin-resistant
Staphylococcus aureus (MRSA), she was also given linezolid intermittently. She
was admitted to the hospital and treated empirically with broad-spectrum
antibiotics while her MAC treatment was continued due to persistently positive
sputum cultures. She failed to respond to therapy and died after a month of
hospitalization due to progressive respiratory failure.
A 42-year old man with history of treated TB in 1980 developed fibrocavitary
MAC infection in 1993. His treatment with ethambutol, rifabutin and
clarithromycin was erratic due to non-adherence. He was admitted to the hospital
in March 2004 with increasing cough, night sweats and a ten pound weight loss.
No culture and sensitivity data were available. With the history of erratic
treatment, presumed macrolide resistance and unilateral fibrocavitary right sided
disease, he was evaluated for surgical excision and pneumonectomy. His
pulmonary function tests revealed a FEV1 of 1.4 L and a split perfusion
pulmonary scan showed one percent perfusion of the right lung and 99% of
blood flow to the left lung. The patient had a complicated operative and
perioperative course and died of respiratory failure after a month long stay in the
ICU.
: Culture positive TB on Rx;
Subsequent 7 sputa all culture negative for TB , positive for MAC
Figure 6
A 50-year old man with severe COPD and bronchiectasis was on long term
treatment for Mycobacterium avium complex pulmonary disease (MAC-PD)
initially and later for macrolide-resistant MAC (MRMAC). He was admitted in
moderately severe respiratory distress with fever and increasing cough. In
addition to the multiple drugs used for the treatment of this patient though the
course of his illness, therapeutic trials of thalidomide, interferon gamma and
high dose mefloquine were given. Due to progressive bilateral disease and
poor pulmonary function, surgery was not considered. (The patient later died
of respiratory failure and overwhelming infection.
Because no correlation between in vitro susceptibility results
for MAC and clinical response for agents other than macrolides
has been established, the 2003 CLSI document states that clarithromycin
is the only drug for which susceptibility testing for
MAC isolates is recommended
Suggested algorithm for Culture &
Sensitivity
Macrolide/Azalide Sensitive
No
Yes
Rx with macrolide/Azalide
Combination double or triple
Drug Rx
Do Expanded Sensitivity
Consider combination Rx sensitivity
Such as Rif /Rb with Eth
Untreated MAC isolates usually have minimum inhibitory concentrations
(MICs) of 4 _g/ml or less to clarithromycin and are
considered susceptible.
In contrast, relapse strains after treatment
inevitably have a clarithromycin MIC of 32 _g/ml or greater
and no longer respond to treatment with macrolides
Isolates of MAC have only a single copy of the ribosome, and hence,
macrolide monotherapy carries a significant risk of the development
of mutational resistance.
All high-level
clarithromycin-resistant isolates have mutations in the adenine
at position 2058 or 2059 of the 23S rRNA gene, which is the
presumed macrolide binding site on the ribosomal unit
MANAGEMENT OPTIONS
Step 1: Diagnosis & Clinical Classification**
** Ref: 5. American Thoracic Society Documents: Mycobacterial Diseases Subcommittee. The Official Statement of the American Thoracic
Society (ATS) and the Infectious Diseases Society of America (IDSA) Am J Respir Crit Care Med Vol 175. pp 367–416, 2007
** Ref 9 Chitty S, Ali J. Mycobacterium Avium Complex Pulmonary Disease in immune competent patients. Southern Medical Journal June
2005, 98 (6) pp 646-652
Step 2: CATEGORIZE GROUP
Surveillance Group
Clinical and chest-imaging
follow-up with serial sputum
cultures and colony counts;
?also applicable in the “Hot
Tub Lung Group”
Treatment Group
Suppressive treatment Group
Based on risk-benefit analysis:
Suppressive treatment with two
drugs: ETHAMBUTOL & MACROLODE
Aggressive treatment group
FOCAL DISEASE
3 drugs +- SURGERY
DIFFUSE NODULAR
BRONCHIECTASIS
3 DRUGS THRICE
WEEKLY
FIBROCAVITARY
DISEASE
3 DRUGS DAILY plus IV
AMINOGLYCOSIDE
COMPLEX
MACROLIDE RESISTANT
CUSTOMIZED
PROTOCOL
A potential consequence of
the broad adoption of the low-dose and long-term azithromycin
therapy in patients with CF is the evolution of macrolide-resistant
NTM.
A careful evaluation for possible pulmonary NTM infection,
including multiple sputum cultures for NTM, should precede
any initiation of macrolide monotherapy, and cultures for
NTM should be obtained periodically thereafter.
Factors contributing
to the poor response to therapy included cavitary disease,
previous treatment for MAC lung disease, and a history of
chronic obstructive lung disease or bronchiectasis and
macrolide resistance,
Recommendations:
1. Surgical resection of limited (focal) disease in a patient
with adequate cardiopulmonary reserve to withstand partial
or complete lung resection can be successful in combination
with multidrug treatment regimens for treating
MAC lung disease (B, II).
2. Surgical resection of a solitary pulmonary nodule due to
MAC is considered curative (C, III).
3. Mycobacterial lung disease surgery should be performed
in centers with expertise in both medical and surgical management
of mycobacterial diseases (C, III).
MAC success story
At least one !!!!
At start of Rx
After 18 months of Rx and culture negativity
Follow up?? Imaging, cultures, Gallium scan, Serology?
M. Chelonei
• 83 year old man, pre op CXR LUL nodular
and cavitary disease; AFB positive, TBS
test positive , started on RIPE , referred
from our Baptist Campus ; later all
cultures grew M Chelonei
• Issues and options?? Discussion ; do
ATS criteria apply ?? ; special
considerations?..look out for ???
Other MOTT
• 60 year old , PPD 22 mm, TBS borderline
x 3 ; sputum AFB positive
• Cultures MK* and or M szulgai
• CT next
• Rx?
• What and how
• Lab confusion
• * key determinant in Rx plan…
Eye on MOTT continued:
MOTT in EYE
• 27 year old, PPD positive 12 mm ; TB spot
negative , uveitis , granuloma , decreased visual
acuity
• Past history of lasik surgery
• 80 year old , history of cataracts PPD positive ,
TB spot positive , granulomatous iritis and
uveitis
• Culture data usually NA; Stress on PCR
• Consider MOTT as cause
A “red herring” / a source search
• The MOTT/ FAC bugs…………..
• M. Szulgai ……………….
• M. Gordonae…………….
Points to remember
• Pulmonary disease due to RGM is
predominantly due to M. abscessus (80
percent of cases) and M. fortuitum (15
percent of cases)]. Various series have
emphasized associations of RGM
pulmonary infection with esophageal
disease malignancy], underlying lung
disease [], and rheumatologic conditions [
Treatment of non-pulmonary disease caused by RGM
(M. abscessus, M. chelonae, M. fortuitum).
The treatment regimen for these organisms is based on
in vitro susceptibilities.
For M. abscessus disease, a macrolide-based regimen
is frequently used.
Surgical debridement may also be an important element
of successful therapy
Treatment of M. abscessus pulmonary disease.
There are no drug regimens of proven or predictable efficacy for
treatment of M. abscessus lung disease.
Multidrug regimens that include clarithromycin 1,000 mg/day may cause
symptomatic improvement and disease regression.
Surgical resection of localized disease combined with multidrug
clarithromycin-based therapy offers the best chance for
cure of this disease.
Challenges
• Identification characteristics
• Macrophage barrier to Rx
• Hydrophobicity of MOTT with drugs being hydrophilic in
nature; eg: more hydrophobic drugs i.e rifabutin as
opposed to rifampin
• Cell wall associated permeability barrier specially seen in
M. Chelonei ; hence ethambutol specially in combination
a better choice
• Lack of correlation in vitro and therapeutic efficacy
• Multi strain sero variance specially in AIDS and patients
with nodular / bronchiectasis disease pattern**
• Theory of adaptive resistance due to continual exposure
eg: pigmentation /proteins when clofazimine is used
Summary For NTM
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Environmental Surveillance
Underlying immune or structural lung defect
Specific identification of NTM and source search
Consistent quantification smear/colony count
Stratification of risk/benefit of Rx
Goals of Rx and outcomes be established
Customized approach ( “step ladder method” )based
on tolerance and compliance with Rx and
without compromising overall regimen; drug
drug interaction /role of drug levels?
Thank you for your kind attention
JA