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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

WHO DAT MOTT

Juzar Ali


Objectives and focus

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

Some basic differences TB /NTM


Who dat mott

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.

***Clinical significance??


Who dat mott

Classification of mycobacterial species commonly causing human disease

The “Staph”

of mycobacteria


Who dat mott

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 aspiration

Contaminant

M Szulgai and M Chelonae and Eye disease


Who dat mott

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


Who dat mott

**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


Who dat mott

CRITERIA FOR DX


Who dat mott

NTM - PD Profile

Patient characteristics

Microbiological

Refractile Gram positive or

Gram neutral rods

AFB stains and growth on solid

and liquid media (BACTEC or MGIT/

Mycobacteria growth indicator tube)

Gene probes

(HPLC) Lipid chromatography on smears

and cultures within hours; some limitations

In identification of MAb & MCh

Imaging

Others


Who dat mott

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


Who dat mott

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).


Who dat mott

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

MAC TB

  • Focus on HIV negative patients

  • MAC – PD

  • Environmental pathogen!!


Who dat mott

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

MAC- PD classifications ?

Radiographic: F/C or F/N bronchiectasis Immunological/structural /clinical:

HIV Non- HIV

** immune , epithelial, mucociliary

impairment

or just an association

  • COPD: structural or airway clearance

  • LW Syndrome /Scoliosis/Pectus**

  • INF –G Il-12 mutation; CTFR


Pathophysiology of bronchiectasis

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


Who dat mott

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.


Who dat mott

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.


Who dat mott

: 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?


Who dat mott

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???


Who dat mott

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 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.


Who dat mott

TB? RIPE

MK

MAC

MAN!! The Mycobacterial Highway/ Route

A


Mott migration dilemma

MOTT “Migration dilemma”

  • Fibrocavitary disease

  • PPD positive

  • MAC by culture

  • Repeat Sputum: M.Chelonei

  • Rx or not?]\

  • What to Rx?

  • Rx LTBI??


Who dat mott

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.


Who dat mott

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.


Who dat mott

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.


Who dat mott

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.


Who dat mott

: Culture positive TB on Rx;

Subsequent 7 sputa all culture negative for TB , positive for MAC

Figure 6


Who dat mott

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.


Who dat mott

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

Suggested algorithm for Culture & Sensitivity

Macrolide/Azalide Sensitive

No

Do Expanded Sensitivity

Consider combination Rx sensitivity

Such as Rif /Rb with Eth

Yes

Rx with macrolide/Azalide

Combination double or triple

Drug Rx


Who dat mott

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


Who dat mott

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


Who dat mott

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

Surveillance Group

Treatment Group

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


Who dat mott

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.


Who dat mott

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,


Who dat mott

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).


Who dat mott

MAC success story

At least one !!!!

At start of Rx


Who dat mott

After 18 months of Rx and culture negativity

Follow up?? Imaging, cultures, Gallium scan, Serology?


M chelonei

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

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

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

A “red herring” / a source search

  • The MOTT/ FAC bugs…………..

  • M. Szulgai ……………….

  • M. Gordonae…………….


Points to remember

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 [


Who dat mott

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


Who dat mott

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

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

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


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