WHO DAT MOTT. Juzar Ali. Objectives and focus. NTM / MOTT Highlights Some clinical examples MAC in non-HIV population Contemporary issues in management of MOTT / MAC -PD References and supportive data available. Exposure Human to human transmission LTBI Latent disease Paucibacillary?
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WHO DAT MOTT
Human to human transmission
No H-H transmission*
* not even seen in CF *
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 techniquesand 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.
Classification of mycobacterial species commonly causing human 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 ??
M. fortuitum Associated with aspiration
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.
MK / Tap Water
MAC / Natural 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
NTM - PD Profile
Refractile Gram positive or
Gram neutral rods
AFB stains and growth on solid
and liquid media (BACTEC or MGIT/
Mycobacteria growth indicator tube)
(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.
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
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
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).
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.
Radiographic: F/C or F/N bronchiectasis Immunological/structural /clinical:
HIV Non- HIV
** immune , epithelial, mucociliary
or just an association
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
The risk posed by TNF-_ blocking agents for predisposing to NTM
infections or promoting progression of active NTM infection is
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
The histopathology is that ofnon 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.
MAN!! The Mycobacterial Highway/ Route
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 forMAC 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
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
Do Expanded Sensitivity
Consider combination Rx sensitivity
Such as Rif /Rb with Eth
Rx with macrolide/Azalide
Combination double or triple
Untreated MAC isolates usually have minimum inhibitory concentrations
(MICs) of 4 _g/ml or less to clarithromycin and are
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.
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
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
Suppressive treatment Group
Clinical and chest-imaging follow-up with serial sputum cultures and colony counts; ?also applicable in the “Hot Tub Lung Group”
Based on risk-benefit analysis:
Suppressive treatment with two drugs: ETHAMBUTOL & MACROLODE
Step 2: CATEGORIZE GROUP
Aggressive treatment group
FOCAL DISEASE DIFFUSE NODULAR FIBROCAVITARY COMPLEX
BRONCHIECTASIS DISEASE MACROLIDE RESISTANT
3 drugs +- SURGERY 3 DRUGS THRICE 3 DRUGS DAILY plus IV CUSTOMIZED
WEEKLY AMINOGLYCOSIDE 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
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.
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
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?
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.
Thank you for your kind attention