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

Some basic differences TB /NTM

• Exposure• Human to human

transmission• LTBI• Latent disease• Paucibacillary?• Reactivation• Incidence /Prevalence• Relapse

• 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 andacceptance 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

M. tuberculosis

M. bovis

M. africanum

M. microti

M. leprae

Slowly growing mycobacteria

Photochromogens, Runyon* group I

M. kansasii

M. marinum

Scotochromogens, Runyon group II

M. gordonae

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

M. chelonae

M. abscessus

The “Staph”of mycobacteria

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 ??.

M. fortuitum Associated with aspirationContaminant

M Szulgai and M Chelonae and Eye disease

Health Care– and Hygiene-associated Disease PreventionPrevention of health care–related NTM infections requires thatsurgical wounds, injection sites, and intravenous catheters not

be exposed to tap water or tap water–derived fluids. Endoscopescleaned 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 lungdisease, 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) phenotypesmay predispose some patients to NTM infection

**NTM lung disease also occurs in women without clearly recognizedpredisposing 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 overtime, suggesting either polyclonal infection or recurrent infection

with distinct strains). It is unclear whether this problem isdue to local abnormalities (e.g., bronchiectasis) or to immune defects Am J Respir CC M 178; 1066-1074 , 2008 NHLBI

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

CRITERIA FOR DX

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.

Patient characteristics

Imaging

Others

Microbiological

Refractile Gram positive or Gram neutral rods

AFB stains and growth on solidand liquid media (BACTEC or MGIT/Mycobacteria growth indicator tube)

Gene probes

(HPLC) Lipid chromatography on smearsand cultures within hours; some limitationsIn identification of MAb & MCh

NTM - PD Profile

Semi-quantitative analysis of smears can be useful for diagnosticand post Rx follow up purposes.

The burden of organisms in clinicalmaterial is usually reflected by the number of organisms seen

on microscopic examination of stained smears.

Environmentalcontamination, which usually involves small numbers of organisms,

rarely results in a positive smear examination.

Previous studies have indicated that specimens with a high number ofmycobacteria isolated by culture are associated with positive

smears and, conversely, specimens with a low number of mycobacteriaisolated by culture are less likely to have positive smears

Recommendation: ……. But the most important isCommunication between the clinician and laboratories

is essential for determining the importance and extent ofthe identification analysis for a clinical NTM isolate

(C, III).

ATS Recommendations:1. As much material as possible for NTM culture should beprovided 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 culturemedia 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 growthshould 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

1. COPD: structural or airway clearance

2. LW Syndrome /Scoliosis/Pectus**

3. INF –G Il-12 mutation; CTFR

** immune , epithelial, mucociliary impairment or just an association

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 & NTMIFN-_ and IL-12 control mycobacteria in large part through the

up-regulation of tumor necrosis factor (TNF)-_ made predominantlyby monocytes/macrophages.

The risk posed by TNF-_ blocking agents for predisposing to NTMinfections or promoting progression of active NTM infection is

unknown.

Expert opinionis that patients with active NTM disease should receive TNF-_

blocking agents only if they are also receiving adequate therapyfor 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 AsthmaCXR Nodular opacities ? TB Started RIPETr Bx Bx: Granulamatous InflammationBr Wash: MAC

MAC “Hot tub Lung” ; or Sarcoidosis with MAC?

Epidemiology. MAC exposure associated with hot-tub lungrepresents a commonly recognized form of hypersensitivity-likeNTM pulmonary disease. NTM other than MAC also have the

potential to result in hypersensitivity-like lung disease associatedwith hot tubs.

Role of indoor showerheads???

Microbiologic data are critical for the diagnosis of MAChypersensitivity-like lung disease, but not in isolation nor withoutclinical, radiographic, or pathologic findings consistent with MAC

hypersensitivity-like disease.The histopathology is that of non necrotizing granulomas although

necrotizing granulomas, organizing pneumonia, or interstitialpneumonia may also be described in some patients The

distribution of these discrete granulomas is generally centrilobularand bronchiocentric, differentiating MAC hypersensitivity likelung from sarcoidosis or other hypersensitivity pneumonitis.

MAN!! The Mycobacterial Highway/ Route

TB? RIPE

MK

MAC

A

MOTT “Migration dilemma”

• 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 simultaneouslyfrom 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 tooccur 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 resultsfor MAC and clinical response for agents other than macrolides

has been established, the 2003 CLSI document states that clarithromycinis the only drug for which susceptibility testing for

MAC isolates is recommended

Suggested algorithm for Culture & Sensitivity

Macrolide/Azalide Sensitive

Yes

Rx with macrolide/AzalideCombination double or tripleDrug Rx

No

Do Expanded SensitivityConsider combination Rx sensitivitySuch 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 treatmentinevitably 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-levelclarithromycin-resistant isolates have mutations in the adenineat position 2058 or 2059 of the 23S rRNA gene, which is the

presumed macrolide binding site on the ribosomal unit

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

Based on risk-benefit analysis:Suppressive treatment with two drugs: ETHAMBUTOL & MACROLODE

Suppressive treatment Group

Step 2: CATEGORIZE GROUP

Aggressive treatment group

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

FOCAL DISEASE DIFFUSE NODULAR FIBROCAVITARY COMPLEX BRONCHIECTASIS DISEASE MACROLIDE RESISTANT3 drugs +- SURGERY 3 DRUGS THRICE 3 DRUGS DAILY plus IV CUSTOMIZED WEEKLY AMINOGLYCOSIDE PROTOCOL

A potential consequence ofthe broad adoption of the low-dose and long-term azithromycin

therapy in patients with CF is the evolution of macrolide-resistantNTM.

A careful evaluation for possible pulmonary NTM infection,including multiple sputum cultures for NTM, should precede

any initiation of macrolide monotherapy, and cultures forNTM should be obtained periodically thereafter.

Factors contributingto 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 partialor complete lung resection can be successful in combination

with multidrug treatment regimens for treatingMAC lung disease (B, II).

2. Surgical resection of a solitary pulmonary nodule due toMAC is considered curative (C, III).

3. Mycobacterial lung disease surgery should be performedin centers with expertise in both medical and surgical management

of mycobacterial diseases (C, III).

At start of Rx

MAC success storyAt least one !!!!

After 18 months of Rx and culture negativityFollow 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 regimenis 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 fortreatment of M. abscessus lung disease.

Multidrug regimens that include clarithromycin 1,000 mg/day may causesymptomatic improvement and disease regression.

Surgical resection of localized disease combined with multidrugclarithromycin-based therapy offers the best chance forcure 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

• 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