Non Tuberculous Mycobacteria

NTM
PRESENTED BY
DR.MD.SHARIF AHSAN
MD RESIDENT(PULMONOLOGY) PHASE-B

What are nontuberculous
mycobacteria?
NTM = non MTB complex,
Non M. leprae
≥ 166 species described
Much smaller # cause human
disease

Mycobacteria other than mammalian
tubercle bacilli, which may occasionally cause
human disease are called ‘non-tuberculous
mycobacteria’
Other names include
Atypical mycobacteria, anonymous,
Unclassified Mycobacteria and
Mycobacteria other than M. tuberculosis
(MOTT)
What are nontuberculous
mycobacteria?

NTM MTB
Where they live Environment (water, soil) Infected host
Infection Environmental exposure
/ inoculation
Infective aerosols
Spread person to
person?
No Yes
Pathogenic Weakly Strongly
Diagnosis NTM Micro/Clin/Rad Micro
(sometimes clinical)

NTM
They are not usually transmitted from person to
person
Source of infection is water, soil, food and
animals
Human infection with NTM is common in some
areas, disease is rare
Exhibits dysgonic growth on LJ medium
Niacin and nitrate reduction tests are negative
Not able to cause progressive disease in guniea
pigs

Runyoun classification
NTM have been categorized into four groups by
Runyoun (1959) based on pigment production
and the growth rate
1. Photochromogenes
2. Scotochromogens
3. Non-photochromogens
4. Rapid growers

Lesions produced by NTM
1. Localized lymphadenitis
2. Skin lesions (Postinjection abscesses,
swimming pool granuloma and buruli ulcer)
3. Tuberculosis-like pulmonary lesions
4. Disseminated disease

Photochromogens
The important species in this group are M.kansasii, M.
marinum and M. simiae
 M. kansasii causes chronic pulmonary disease
resembling tuberculosis.
 It may also occasionally cause infections of the cervical
lymphnodes, penetrating wound infections and
granulomatous synovitis.
 It can produce generalized infection in HIV patients.

Mycobacterium marinum
 Causes a warty skin lesion known as
swimming pool or fish tank granuloma.
 Closely resembles M. kansasii but can be
differentiated by its poor growth at 370C,
negative nitratase, and positive pyrazinamide
hydrolase.

Scotochromogens
 These strains form pigmented colonies (yellow-
orange-red) even in the dark.
 They are widely distributed in the environment
and sometimes contaminate cultures of
tubercle bacilli.

Important species in this group
M. scrofulaceum may cause scrofula (cervical
adenitis) in children.
M. gordonae often found in tap water is a
common contaminant in clinical specimens
and a rare cause of pulmonary disease .
M. szulgai, an uncommon cause of
pulmonary disease and bursitis .
It is a scotochromogen when incubated at
370C but a photochromogen at 250C

Non-photochromogens
Medically important species in this group are
M. avium, M. intracellulare, M. xenopi and
M. ulcerans .
M. avium
Which causes natural tuberculosis in birds
and lymphadenopathy in pigs, is one of the
most common opportunistic human
pathogens M. intracellulare
Is commonly known as Battey bacillus

MAC
M. avium and M. intracellulare are so similar
that that they have been considered as one
group, the M. avium complex (MAC).
MAC complex cause lymphadenopathy,
pulmonary lesions or disseminated disease,
particulary in AIDS patients.
M. xenopi, originally isolated from toads, may
occasionally cause chronic lung disease in human
beings.
 M. ulcerans cause buruli ulcer.

Rapid growers
This is a heterogeneous group of mycobacteria
capable of rapid growth, colonies appearing
within 7 days of incubation at 370C or 250C.
Within the group, photochromogenic,
scotochromogenic, and non-chromogenic
species occur.
Most of these are purely are environmental
saprophytes.

Rapid growers
The medically important species are M.
fortuitum and M. Chelonae.
Occasionally cause pulmonary or
disseminated disease but are principally
responsible for postinjection abscesses
and wound infections.
 Outbreaks of abscesses following injections
of vaccines contaminated by these
mycobacteria have been reported.

Swimming pool granuloma
It is caused by M. marinum .
M. marinum occurs as a saprophyte in fresh
or salt water .
 Human infection originates from
contaminated swimming pools or fish tanks.
 The bacilli enter scratches and abrasions
and cause warty lesions similar to those
seen in skin tuberculosis

Swimming pool granuloma
 The lesion, beginning as a papule and break
down to form an indolent ulcer.
 The disease is usually self-limiting although
chemotherapy with minocycline,
cotrimoxazole or rifampicin with ethambutol
hastens its resolution.

Buruli ulcer
 Caused by M. ulcerans
The name is derived from the Buruli district of Uganda
where a large outbreak was extensively investigated .
 Ulcers are usually seen on the legs or arms and
are believed to follow infection through minor
injuries.
 After an incubation period of a few weeks,
indurated nodules appear, which break down
forming indolent ulcers which slowly extend under
the skin.
 When the immunoreactive phase sets in ulcers
heal with disfiguring scars.

NTM Clinical syndromes
NTM Pulmonary disease (NTM-PD): ≈ 90%
Superficial lymphadenitis in children (usually
devical)
Disseminated disease in severely
immunocompromised patients.
Skin and soft tissue infections due to direct
inoculation, often nosocomial

Risk Factors Pulmonary NTM
disease
✓ Destroyed lungs due to TB or other diseases like
pneumoconiosis Trauma (direct infection from
environs)
✓ Bronchiectasis (esp. middle lobe and lingula)
✓ Chronic obstructive pulmonary disease
✓ Cystic fibrosis-CFTR gene polymorphism
✓ Primary ciliary dyskinesia
✓ Alpha 1 antitrypsin deficiency
✓ Lung cancer
✓ Thoracic skeletal abnormalities (kyphoscoliosis)
✓ Gastroesophageal reflux disease
✓ Pulmonary alveolar proteinosis

Clinical Phenotypes: NTM-PD
Fibrocavitary Disease.
Usually upper lobe, focal, cavitary, often emphysema.
Males or females.

Clinical Phenotypes: NTM-PD
Nodular Bronchiectatic Disease
Mid-lung accentuated bronchiectasis, centrilobular nodules
Females >> Males

Pulmonary NTM: Microbiology
Ontario's top isolates
MAC = M. Avium Complex ΜΑΙ
M. avium, M. intracellulare, M. chimaera
M. xenopi
(M. gordonae)
M. fortuitum (RGM)
M. abscessus (RGM)

2020 NTM Guidelines: Diagnosis
Clinical Pulmonary/systemic symptoms
Radiology CXR-nodules, cavities, or
CT-bronchiectasis with multiple small nodules
Micro With 2 sputa → 2 positive cultures, or
With 1 BAL/wash → 1 positive bronchial wash, or
With biopsy → positive biopsy culture, or 1 positive culture and biopsy
evidence of disease
Symptoms + Imaging findings + Microbiology = Disease...
...diagnosis does not necessitate treatment

Starting Treatment:A Difficult Decision
Bugs
• Inherently resistant to
most available
antimicrobials.
• Require multiple agents
for prolonged periods.
Drugs
Multiple drugs, long duration
→
many toxicities.
Short term outcomes
• MAC "success"
60% (Kwak et al, CID 2017)
- 71-86% (Jeong et al, AJRCCM
2015; Wallace,
Chest 2014)
Recurrence
(predisposition +
environmental exposures)
30% - 14 mo (Koh et al, 2017)
50% - 4 years (Wallace et al,
2014)

When to Start Antibiotic Treatment?
Guidelines
Natural history
Unpredictable
Majority progress
Minority spontaneously convert to negative sputum
Question: Should patients with NTM pulmonary disease be treated with
antimicrobial
therapy or followed for evidence of progression ("watchful waiting")?
Recommendation: In patients who meet diagnostic criteria for NTM-
PD, we suggest initiating treatment rather than watchful waiting.
Especially in the context of positive AFB smears and/or cavitation
(conditional recommendation, very low confidence in estimates
of effect).

When to Start?
Guidelines
Decision individualized based on clinical
factors and individual patient priorities, in
discussion with the patient outlining potential
adverse effects of therapy, uncertainties
surrounding its benefits, and potential for
recurrence/reinfection (particularly with
nodular bronchiectasis).

When to Start?
Guidelines
Favors observation:
 Mild signs and symptoms.
 Higher potential for
medication
toxicity/intolerance.
 Organisms less responsive
to treatment (e.g., M.
abscessus).
Favors treatment:
 Poor prognostic markers
(cavitation, low BMI/alb,
and elevated inflammatory
markers)
 More virulent and/or more
treatment responsive
species (M. kansasii)
 Immune suppression
 Major symptoms (severe
fatigue and marked
decrease in quality of life)

Deciding When to Initiate Antimicrobial
Treatment
Disease severity
Radiological
Fibrocavitary disease
Clinical
Weight loss, fever,
haemoptysis, respiratory
Failure
Biochemical markers
Microbiological
Smear positivity
Disease progression
Radiological
Development of cavitation or
fibrosis, increasing nodules
or tree-in-bud changes
Clinical
Worsening symptoms,
development of new
symptoms, weight loss
Microbiological
Development of new or
increasing smear positivity

Deciding When to Initiate Antimicrobial
Treatment
Clinical relevance
NTM species
Some species more
pathogenic than others
Immunosuppression
Primary immunodeficiency
HIV infection
Immunosuppresive therapy
Anti-TNF-a therapy
Corticosteroids
Lung transplantation
Need for M. abscessus
eradication
Host factors
Age
Increasing risk of intolerance
and adverse events
Comorbidities
Drug intolerances
Consider dose reduction or
thrice-weekly regimens
Consider interactions with
other drugs, e.g. azoles
Patient wishes
Aim of treatment
Aiming for cure or disease
control?

If you
do not
treat
Patients with NTM-PD who are not treated
should be followed
Pay attention to comorbid respiratory
conditions, especially bronchiectasis
Follow symptoms, micro, (lung function),
imaging
- Development of cavities a reason to treat
- Progressive bronchiectasis a reason to
treat
Often, when treatment is necessary, the
patient knows it

Referral
:
When,
who
Respirology or Infectious Diseases
Patient is suspected to have NTM pulmonary
disease
Patient meets criteria for NTM pulmonary disease
Not always necessary to refer if patient does not
meet disease criteria (ie normal chest imaging, no
symptoms may be transient colonization or
contamination)

Non-antibiotic Treatments
Physiotherapy / airway clearance
Nutrition
Bronchodilators / Inhaled steroids?
Environmental interventions
Vaccinations
Treating non-NTM exacerbations
Surgery

Physiotherapy
Bronchial hygiene (airway/sputum
clearance)
Recommended for bronchiectasis patients with chronic
productive cough or difficulty to expectorate sputum (weak
recommendation, low quality evidence)
- increase sputum volume and reduce impact of cough on quality
of life
Pulmonary rehabilitation
Recommended for patients with impaired exercise capacity
(strong
recommendation, high quality evidence)
- improves exercise capacity and quality of life

Inhaled therapies
 Inhaled corticosteroids are NOT recommended in
bronchiectasis UNLESS they are indicated for asthma /
COPD (conditional recommendation, low quality
evidence)
 Long acting bronchodilators are not routinely
recommended, but are recommended for patients with
breathlessness on an individual basis (weak
recommendation, very low quality evidence)
 Long term inhaled mucoactive agents (ie hypertonic
saline) is recommended in patients with difficulty
expectorating sputum and poor quality of life, where
standard airway clearance techniques have failed to
control symptoms(weak recommendation, low quality
evidence).

Environmental interventions
Believed that susceptible individuals contract
NTM-PD through environmental exposure to
aerosolized water or soil.
Possible interventions (little evidence)
 Minimizing exposure to hot tubs, humidifiers, indoor
swimming pools.
 Carbon filter water pitchers and ice/water dispensers
working with dry soil.
 Changing/cleaning shower heads at regular intervals.
 Use of in-line antimicrobial filters in showers and water
taps
 Increasing temperature of hot water tank to ≥54.4°C

Treatment options
✓ MAC
Clarithromycin or azithromycin + ethambutol +
Rifampicin
✓ M. xenopi
Rifampicin + Ethambutol +INH
✓ M. kansasii
Rifampicin + Ethambutol
✓ Rapid growers
Doxycycline, amikacin, imipenem, quinolones,
sulphonamides, cefoxitin, clarithromycin

MAC-PD Antimicrobial Treatment

Pulmonary MAC
• Drug susceptibility testing
Interpretation unclear for most drugs, except...
Macrolides:
Resistance (clarithromycin
MICge32~mcg/mL)rightarrow por
response/outcomes

Drug Susceptibility Testing
Guidelines
In patients with MAC pulmonary disease, we
suggest susceptibility-based treatment for
macrolides and amikacin over empiric therapy
(conditional recommendation, very low
certainty in estimates of effect).
Daley CL et al. Clin Infect Dis/Eur Respir J. 2020.

MAC-PD
• Treatment duration
Question
In patients with
macrolide-susceptible
MAC pulmonary
disease, should
patients be treated with
< 12 months of
treatment after culture
negativity or ≥ 12
months of treatment
after culture
negativity?
Recommendation
We suggest that patients with
macrolide
susceptible MAC pulmonary
disease receive
treatment for at least 12 months
after culture
conversion (conditional
recommendation, very
low certainty in estimates of
effect).

Strategies for Managing Side Effects o
Antimycobacterial Treatments
Encourage probiotics
Modify dietary habits
(Most) medications can be taken with food
Rifampin absorption reduced, but tolerability
improved
Different times of day, e.g. bedtime dosing
Antiemetics, antidiarrheals, and prokinetics
Caution with additional QTC prolonging agents
Most patients will be able to tolerate a 3-
drug regimen with adequate strategies to
manage toxicities

Strategies for Managing Severe Drug
Intolerance
Consider second-line agents/regimens
Amikacin - IV or inhaled (most data - additional
agent or refractory)
Clofazimine ~100 mg QD (some data)
Fluoroquinolones
>Moxifloxacin ~400 QD (few data)
>Levofloxacin 500 QD (no data)
>Ciprofloxacin ~500-750 bid (no data)
Linezolid ~600 mg QD (few data)

Strategies for Managing Side Effects o
Antimycobacterial Treatments
Strive for a regimen likely to achieve the goal
Don't suppress the host more than the pathogen
Avoid regimens leading to macrolide resistance
Macrolide + fluoroquinolone
Macrolide monotherapy
Strive to include ethambutol whenever possible
If not possible, consider clofazimine and/or
amikacin to prevent macrolide resistance.

Take home points
NTM-PD diagnosis includes clinical,
radiologic, and microbiologic criteria.
Decision to treat NTM-PD is complex and
involves considering disease severity,
progression, clinical relevance, and host
factors.
MAC-PD is treated with 3 or more
antibiotics for 12 months post sputum
culture conversion; regimen is modified
slightly in presence of cavities or
refractory disease.

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