Non-tuberculous mycobacteria: Difference between revisions

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* Mycobacteria that excludes tuberculosis and leprosy
*Mycobacteria that excludes tuberculosis and leprosy


== Background ==
==Background==
=== Microbiology ===
===Microbiology===
* Acid-fast bacilli, free-living in the environment
** Direct microscopy with auremine rodhamine fluorochrome stain (better than Ziehl-Neelsen)
* Broadly divided into slow-growers and fast-growers
** Fast-growers produce colonies within 7 days on solid media
*** Grows optimally at 28-30º C, with some preferring 35º C
*** May grow in blood culture if mycobacteremic
** Slow-growers produce colonies after more than 7 days on solid media
*** MAC, ''M. xenopi'', and ''M. kansasii'' are the three most important
*** Grows optimally at 35-37º C except ''M. haemophilum'' (28-30º C) and ''M. xenopi'' (42-45º C)
* Media includes blood or chocolate agar, MTBC media, etc
* Species-level identifiation requires molecular tests


*Acid-fast bacilli, free-living in the environment
=== Species ===
**Direct microscopy with auremine rodhamine fluorochrome stain (better than Ziehl-Neelsen)
* More than 200 species of ''Mycobacterium'' spp. that are not in ''M. tuberculosis'' complex or ''M. leprae''
*Broadly divided into slow-growers and fast-growers
**Fast-growers produce colonies within 7 days on solid media
***Grows optimally at 28-30º C, with some preferring 35º C
***May grow in blood culture if mycobacteremic
**Slow-growers produce colonies after more than 7 days on solid media
***MAC, ''M. xenopi'', and ''M. kansasii'' are the three most important
***Grows optimally at 35-37º C except ''M. haemophilum'' (28-30º C) and ''M. xenopi'' (42-45º C)
*Media includes blood or chocolate agar, MTBC media, etc
*Species-level identifiation requires molecular tests

===Species===

*More than 200 species of ''Mycobacterium'' spp. that are not in ''M. tuberculosis'' complex or ''M. leprae''


{| class="wikitable"
{| class="wikitable"
! Species
!Species
! Notes
!Notes
|-
|-
! colspan=2 | Rapid-growers (visible in culture in <7 days)
! colspan="2" |Rapid-growers (visible in culture in <7 days)
|-
|-
| ''M. fortuitum'' complex
|''M. fortuitum'' complex
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. fortuitum''
| style="padding-left:1.5em;" |''M. fortuitum''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. peregrinum''
| style="padding-left:1.5em;" |''M. peregrinum''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. porcinum''
| style="padding-left:1.5em;" |''M. porcinum''
|
|
|-
|-
| ''M. chelonae''
|''M. chelonae''
|
|
|-
|-
| ''[[M. abscessus]]''
|''[[M. abscessus]]''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. abscessus'' subsp. ''abscessus''
| style="padding-left:1.5em;" |''M. abscessus'' subsp. ''abscessus''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. abscessus'' subsp. ''bolletii''
| style="padding-left:1.5em;" |''M. abscessus'' subsp. ''bolletii''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. abscessus'' subsp. ''massiliense''
| style="padding-left:1.5em;" |''M. abscessus'' subsp. ''massiliense''
|
|
|-
|-
| ''M. smegmatis''
|''M. smegmatis''
|
|
|-
|-
| ''M. mucogenicum''
|''M. mucogenicum''
|
|
|-
|-
! colspan=2 | Slow-growers (visible in culture in >7 days)
! colspan="2" |Slow-growers (visible in culture in >7 days)
|-
|-
| colspan=2 | Photochromogens (develop pigments in light)
| colspan="2" |Photochromogens (develop pigments in light)
|-
|-
| style="padding-left:1.5em;" | ''M. kansasii''
| style="padding-left:1.5em;" |''M. kansasii''
| Always assumed to be pathogenic, never colonizer.
|Always assumed to be pathogenic, never colonizer.
|-
|-
| style="padding-left:1.5em;" | ''M. marinum''
| style="padding-left:1.5em;" |''M. marinum''
| Intermediate-grower (7-10 days).
|Intermediate-grower (7-10 days).
|-
|-
|  Scotochromogens
| Scotochromogens
| Develop pigments in darkness.
|Develop pigments in darkness.
|-
|-
| style="padding-left:1.5em;" | ''M. gordonae''
| style="padding-left:1.5em;" |''M. gordonae''
| Intermediate-grower (7-10 days). Common tap-water contaminant.
|Intermediate-grower (7-10 days). Common tap-water contaminant.
|-
|-
| style="padding-left:1.5em;" | ''M. scrofulaceum''
| style="padding-left:1.5em;" |''M. scrofulaceum''
|
|
|-
|-
| colspan=2 | Nonchromogens (do not develop pigments in light)
| colspan="2" |Nonchromogens (do not develop pigments in light)
|-
|-
| style="padding-left:1.5em;" | [[M. avium complex]]
| style="padding-left:1.5em;" |[[M. avium complex]]
| In HIV, rarely pulmonary and almost always disseminated.
|In HIV, rarely pulmonary and almost always disseminated.
|-
|-
| style="padding-left:2.5em;" | ''M. avium''
| style="padding-left:2.5em;" |''M. avium''
| Most common subspecies.
|Most common subspecies.
|-
|-
| style="padding-left:2.5em;" | ''M. intracellulare''
| style="padding-left:2.5em;" |''M. intracellulare''
|
|
|-
|-
| style="padding-left:2.5em;" | ''M. chimaera''
| style="padding-left:2.5em;" |''M. chimaera''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. terrae'' complex
| style="padding-left:1.5em;" |''M. terrae'' complex
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. ulcerans''
| style="padding-left:1.5em;" |''M. ulcerans''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. xenopi''
| style="padding-left:1.5em;" |''M. xenopi''
| Grows optimally at 42-45º C.
|Grows optimally at 42-45º C.
|-
|-
| style="padding-left:1.5em;" | ''M. simiae''
| style="padding-left:1.5em;" |''M. simiae''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. malmoense''
| style="padding-left:1.5em;" |''M. malmoense''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. szulgai''
| style="padding-left:1.5em;" |''M. szulgai''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. asiaticum''
| style="padding-left:1.5em;" |''M. asiaticum''
|
|
|-
|-
| style="padding-left:1.5em;" | ''M. haemophilum''
| style="padding-left:1.5em;" |''M. haemophilum''
| Grows optimally at 28-30º C.
|Grows optimally at 28-30º C.
|}
|}


=== Pathophysiology ===
===Pathophysiology===
* Inhalation ± microaspiration, likely from water source
** Environmental organisms that are essentially unavoidable
* Response is cell-mediated with pulmonary macrophages, with assistance from CD4, IL-2, and IFN-γ


*Inhalation ± microaspiration, likely from water source
=== Epidemiology ===
**Environmental organisms that are essentially unavoidable
* NTMs are distributed worldwide, present in soil, household water, vegetable matter, animals, and birds
*Response is cell-mediated with pulmonary macrophages, with assistance from CD4, IL-2, and IFN-γ
** Also tap water (especially ''M. gordonae'', ''M. kansasii'', ''M. xenopi'', ''M. simiae'', MAC, and ''M. mucogenicum'')

* 90% of patients with NTM infections have underlying pulmonary disease
===Epidemiology===
* In Ontario: ''M. avium'' complex (25%), ''M. xenopi'' (10%), ''M. abscessus''/''M. chelonae'', ''M. fortuitum''

*NTMs are distributed worldwide, present in soil, household water, vegetable matter, animals, and birds
**Also tap water (especially ''M. gordonae'', ''M. kansasii'', ''M. xenopi'', ''M. simiae'', MAC, and ''M. mucogenicum'')
*90% of patients with NTM infections have underlying pulmonary disease
*In Ontario: ''M. avium'' complex (25%), ''M. xenopi'' (10%), ''M. abscessus''/''M. chelonae'', ''M. fortuitum''


{| class="wikitable"
{| class="wikitable"
! Presentation and Species
!Presentation and Species
! Distribution
!Distribution
|-
|-
! colspan=2 | Pulmonary disease
! colspan="2" |Pulmonary disease
|-
|-
| ''M. abscessus''
|''M. abscessus''
| Worldwide; may be found concomitant with MAC
|Worldwide; may be found concomitant with MAC
|-
|-
| ''M. avium'' complex
|''M. avium'' complex
| Worldwide; most common NTM pathogen in US
|Worldwide; most common NTM pathogen in US
|-
|-
| ''M. kansasii''
|''M. kansasii''
| US, Europe, South Africa, and coal-mining regions
|US, Europe, South Africa, and coal-mining regions
|-
|-
| ''M. malmoense''
|''M. malmoense''
| UK, northern Europe; uncommon in US
|UK, northern Europe; uncommon in US
|-
|-
| ''M. xenopi''
|''M. xenopi''
| Europe, Canada; uncommon in US; associated with pseudoinfection
|Europe, Canada; uncommon in US; associated with pseudoinfection
|-
|-
! colspan=2 | Lymphadenitis
! colspan="2" |Lymphadenitis
|-
|-
| ''M. avium'' complex
|''M. avium'' complex
| Worldwide; most common NTM pathogen in US
|Worldwide; most common NTM pathogen in US
|-
|-
| ''M. malmoense''
|''M. malmoense''
| UK, northern Europe (especially Scandinavia)
|UK, northern Europe (especially Scandinavia)
|-
|-
| ''M. scrofulaceum''
|''M. scrofulaceum''
| Worldwide; previously common, now rarely isolated in US
|Worldwide; previously common, now rarely isolated in US
|-
|-
! colspan=2 | Disseminated disease
! colspan="2" |Disseminated disease
|-
|-
| ''M. avium'' complex
|''M. avium'' complex
| Worldwide; AIDS; most common NTM pathogen in US
|Worldwide; AIDS; most common NTM pathogen in US
|-
|-
| ''M. chelonae''
|''M. chelonae''
| US; non-AIDS immunosuppressed skin lesions
|US; non-AIDS immunosuppressed skin lesions
|-
|-
| ''M. haemophilum''
|''M. haemophilum''
| AIDS; US, Australia; non-AIDS immunosuppressed
|AIDS; US, Australia; non-AIDS immunosuppressed
|-
|-
| ''M. kansasii''
|''M. kansasii''
| AIDS; US, South Africa
|AIDS; US, South Africa
|-
|-
! colspan=2 | SSTI and MSK
! colspan="2" |SSTI and MSK
|-
|-
| ''M. abscessus''
|''M. abscessus''
| Penetrating injury
|Penetrating injury
|-
|-
| ''M. chelonae''
|''M. chelonae''
| US, associated with keratitis and disseminated disease
|US, associated with keratitis and disseminated disease
|-
|-
| ''M. fortuitum''
|''M. fortuitum''
| Penetrating injury, footbaths
|Penetrating injury, footbaths
|-
|-
| ''M. marinum''
|''M. marinum''
| Worldwide, fresh- and saltwater
|Worldwide, fresh- and saltwater
|-
|-
| ''M. ulcerans''
|''M. ulcerans''
| Australia, tropics, Africa, Southeast Asia, not US
|Australia, tropics, Africa, Southeast Asia, not US
|-
|-
! colspan=2 | Contaminant
! colspan="2" |Contaminant
|-
|-
| ''M. gordonae''
|''M. gordonae''
| Most common NTM contaminant
|Most common NTM contaminant
|-
|-
| ''M. haemophilum''
|''M. haemophilum''
|
|
|-
|-
| ''M. mucogenicum''
|''M. mucogenicum''
|
|
|-
|-
| ''M. nonchromogenicum''
|''M. nonchromogenicum''
|
|
|-
|-
| ''M. terrae'' complex
|''M. terrae'' complex
|
|
|}
|}


== Clinical Manifestations ==
==Clinical Manifestations==
{| class="wikitable"
{| class="wikitable"
! Syndrome
!Syndrome
! Species
!Species
! Description
!Description
|-
|-
| Pulmonary disease
|Pulmonary disease
| MAC, ''M. kansasii'', ''M. xenopi'', ''M. abscessus''
|MAC, ''M. kansasii'', ''M. xenopi'', ''M. abscessus''
|
|
|-
|-
| style="padding-left:2em;" | Upper lobe cavitary
| style="padding-left:2em;" |Upper lobe cavitary
| MAC, ''M. kansasii''
|MAC, ''M. kansasii''
| Male smokers, often alcohol use, usually early 50s
|Male smokers, often alcohol use, usually early 50s
|-
|-
| style="padding-left:2em;" | RML/lingular nodular bronchiectasis
| style="padding-left:2em;" |RML/lingular nodular bronchiectasis
| MAC, ''M. abscessus'', ''M. absessus'' subsp. ''massiliense''
|MAC, ''M. abscessus'', ''M. absessus'' subsp. ''massiliense''
| Female nonsmokers, usually older than 60
|Female nonsmokers, usually older than 60
|-
|-
| style="padding-left:2em;" | Localized alveolar/cavitary
| style="padding-left:2em;" |Localized alveolar/cavitary
| ''M. abscessus'', MAC
|''M. abscessus'', MAC
| Prior granulomatous dz (usually TB) with bronchiectasis
|Prior granulomatous dz (usually TB) with bronchiectasis
|-
|-
| style="padding-left:2em;" | Reticulonodular or alveolar bilateral lower lobe
| style="padding-left:2em;" |Reticulonodular or alveolar bilateral lower lobe
| ''M. fortuitum''
|''M. fortuitum''
| Achalasia, chronic vomiting, exogenous lipoid pneumonia
|Achalasia, chronic vomiting, exogenous lipoid pneumonia
|-
|-
| style="padding-left:2em;" | Reticulonodular
| style="padding-left:2em;" |Reticulonodular
| MAC, ''M. abscessus'' subsp. ''abscessus'', ''M. abscessus'' subsp. ''massiliense''
|MAC, ''M. abscessus'' subsp. ''abscessus'', ''M. abscessus'' subsp. ''massiliense''
| Adolescents with CF, HIV-positive patients, prior bronchiectasis
|Adolescents with CF, HIV-positive patients, prior bronchiectasis
|-
|-
| style="padding-left:2em;" | Hypersensitivity pneumonitis
| style="padding-left:2em;" |Hypersensitivity pneumonitis
| ''M. immunogenum'', ''M. avium''
|''M. immunogenum'', ''M. avium''
| Metal workers, indoor hot tubs
|Metal workers, indoor hot tubs
|-
|-
| Cervical lymphadenitis
|Cervical lymphadenitis
| MAC
|MAC
|
|
|-
|-
| SSTI
|SSTI
| ''M. fortuitum'', ''M. marinum'', ''M. chelonae'', ''M. ulcerans''
|''M. fortuitum'', ''M. marinum'', ''M. chelonae'', ''M. ulcerans''
|
|
|-
|-
| MSK
|MSK
| ''M. marinum'', MAC, ''M. kansasii'', ''M. fortuitum'', ''M. abscessus'', ''M. chelonae''
|''M. marinum'', MAC, ''M. kansasii'', ''M. fortuitum'', ''M. abscessus'', ''M. chelonae''
|
|
|-
|-
| Disseminated
|Disseminated
| HIV-positive: ''M. avium'' and ''M. kansasii'', HIV-negative: ''M. abscessus'' and ''M. chelonae''
|HIV-positive: ''M. avium'' and ''M. kansasii'', HIV-negative: ''M. abscessus'' and ''M. chelonae''
|
|
|-
|-
| Catheter-related
|Catheter-related
| ''M. fortuitum'', ''M. abscessus'', ''M. chelonae''
|''M. fortuitum'', ''M. abscessus'', ''M. chelonae''
|
|
|}
|}


=== Pulmonary disease ===
===Pulmonary Disease===
* Risk factors include COPD and CF [[CiteRef::honda2015pa]]
* Most common clinical manifestation of NTM
* Most commonly caused by MAC, ''M. kansasii'', ''M. xenopi'', and ''M. abscessus''
* Nonspecific chronic or subacute respiratory syndrome with prominent cough


*Risk factors include COPD and CF [[CiteRef::honda2015pa]]
==== Fibrocavitary disease ====
*Most common clinical manifestation of NTM
* Usually preexisting lung disease (COPD etc), men
*Most commonly caused by MAC, ''M. kansasii'', ''M. xenopi'', and ''M. abscessus''
* Upper-lobe predominant, focal, cavitary
*Nonspecific chronic or subacute respiratory syndrome with prominent cough
* DDx includes TB and lung cancer


====Fibrocavitary Disease====
==== Nodular bronchiectatic disease ====
* Lady Windermere syndrome
* RML/lingula with discrete nodules and bronchiectasis
* Usually no preexisting lung disease, non-smoker, women


*Usually preexisting lung disease (COPD etc), men
==== Investigations ====
*Upper-lobe predominant, focal, cavitary
* Almost always needs CT; may repeat to monitor for progression
*DDx includes TB and lung cancer
* 3 sputums for AFB; may treat ''M. kansasii'' based on only a single colony but everything else needs 2-3 positives
** Rule out TB


==== Diagnosis ====
====Nodular Bronchiectatic Disease====
* Requires both clinical and microbiological evidence of disease
* Clinical diagnosis
** Pulmonary symptoms, or
** Presence of nodules or cavities as seen on chest radiograph, or
** HRCT scan with multifocal bronchiectasis with multiple small nodules, and
** Exclusion of other diagnoses
* Microbiologic diagnosis
** At least 2 (of 3) expectorated sputa (or at least 1 bronchial wash or lavage) with positive cultures for NTM
** Transbronchial or other lung biopsy showing the presence of granulomatous inflammation or AFB with 1 or more sputum or bronchial washings that are culture positive for NTM.


*Lady Windermere syndrome
=== Skin and soft tissue infections (SSTI) ===
*RML/lingula with discrete nodules and bronchiectasis
* From direct inoculation
*Usually no preexisting lung disease, non-smoker, women
* ''M. abscessus'', ''M. fortuitum'', ''M. chelonae'', ''M. marinum'', ''M. ulcerans''
* Dx: tissue biopsy culture (best) or culture of discharge


==== ''M. marinum'' ====
====Investigations====
* "Fish tank granuloma"
* Incubation 2 to 3 weeks
* Small violet papular lesions on hands, which can ulcerate
* Can also cause sporotrichoid disease


*Almost always needs CT; may repeat to monitor for progression
=== Other Infections ===
*3 sputums for AFB; may treat ''M. kansasii'' based on only a single colony but everything else needs 2-3 positives
==== Superficial lymphadenitis ====
**Rule out TB
* Children, usually submandibular
* May be from eating dirt


==== Disseminated disease ====
====Diagnosis====
* Usually in AIDS or other significant cell-mediated immunosuppression


*Requires both clinical and microbiological evidence of disease
==== ''M. chimaera'' infection ====
*Clinical diagnosis
* Outbreaks associated with heater units used in cardiac surgery
**Pulmonary symptoms, or
* Present with IE, sternal wound infections, mediastinitis, etc.
**Presence of nodules or cavities as seen on chest radiograph, or
**HRCT scan with multifocal bronchiectasis with multiple small nodules, and
**Exclusion of other diagnoses
*Microbiologic diagnosis
**At least 2 (of 3) expectorated sputa (or at least 1 bronchial wash or lavage) with positive cultures for NTM
**Transbronchial or other lung biopsy showing the presence of granulomatous inflammation or AFB with 1 or more sputum or bronchial washings that are culture positive for NTM.


===Skin and Soft Tissue Infection===
== Diagnosis ==
* Sputum smear and culture for AFB
** Spontaneous, induced, or BAL
** PCR/NAAT can be done for TB and MAC, but only done on smear positive samples unless specifically requested


*From direct inoculation
== Management ==
*''M. abscessus'', ''M. fortuitum'', ''M. chelonae'', ''M. marinum'', ''M. ulcerans''
* Treatment decisions
*Dx: tissue biopsy culture (best) or culture of discharge
** First is to decide whether or not to treat; must weigh the risks and benefits
** NTM can represent contamination, colonization, or infection/invasion
** The mycobacteria are inherently resistant to many bacteria, sometimes require IV therapy, multiple agents with toxicity, prolonged treatment
** Treatment often ineffective
** Recurrence is common; 50% of patients need a second course within 5 years of the first one
** Decide to start based on shared decision-making model, reviewing:
*** Meets diagnostic criteria
*** Comorbidities
*** Toxicities
*** Goals of care
* All rapid-growers are resistant to first-line TB treatment (RIPE), and have aspiration as an underlying risk factor
** Need susceptibilities for macrolides in MAC; needs to be specifically requested


====''M. marinum''====
=== MAC pulmonary infection ===

* MAC is the prototype
*"Fish tank granuloma"
* Macrolide (azithro/clarithro) backbone, with 2 to 3 other agents depending on the disease type and severity
*Incubation 2 to 3 weeks
* Rifampin and clarithromycin interact, so prefer rifamycin
*Small violet papular lesions on hands, which can ulcerate
* Treat until 12 months after negative cultures
*Can also cause sporotrichoid disease

===Other Infections===
====Superficial Lymphadenitis====

*Children, usually submandibular
*May be from eating dirt

====Disseminated Disease====

*Usually in AIDS or other significant cell-mediated immunosuppression

====''M. chimaera'' Infection====

*Outbreaks associated with heater units used in cardiac surgery
*Present with IE, sternal wound infections, mediastinitis, etc.

==Diagnosis==

*Sputum smear and culture for AFB
**Spontaneous, induced, or BAL
**PCR/NAAT can be done for TB and MAC, but only done on smear positive samples unless specifically requested

==Management==

*Treatment decisions
**First is to decide whether or not to treat; must weigh the risks and benefits
**NTM can represent contamination, colonization, or infection/invasion
**The mycobacteria are inherently resistant to many bacteria, sometimes require IV therapy, multiple agents with toxicity, prolonged treatment
**Treatment often ineffective
**Recurrence is common; 50% of patients need a second course within 5 years of the first one
**Decide to start based on shared decision-making model, reviewing:
***Meets diagnostic criteria
***Comorbidities
***Toxicities
***Goals of care
*All rapid-growers are resistant to first-line TB treatment (RIPE), and have aspiration as an underlying risk factor
**Need susceptibilities for macrolides in MAC; needs to be specifically requested

=== Pulmonary Disease ===

====''Mycobacterium avium'' Complex====

*MAC is the prototype
*Macrolide (azithro/clarithro) backbone, with 2 to 3 other agents depending on the disease type and severity
*Rifampin and clarithromycin interact, so prefer rifamycin
*Treat until 12 months after negative cultures


{| class="wikitable"
{| class="wikitable"
! Class
!Class
! Nodular
!Nodular
! Cavitary or Advanced
!Cavitary or Advanced
|-
|-
| [[Macrolide]]
|[[Macrolide]]
| [[Clarithromycin]] 1000 tiw or [[azithromycin]] 500 tiw
|[[Clarithromycin]] 1000 tiw or [[azithromycin]] 500 tiw
| [[Clarithromycin]] 500 bid or [[azithromycin]] 250 daily
|[[Clarithromycin]] 500 bid or [[azithromycin]] 250 daily
|-
|-
| [[Ethambutol]]
|[[Ethambutol]]
| 25 mg/kg tiw
|25 mg/kg tiw
| 15 mg/kg/day
|15 mg/kg/day
|-
|-
| [[Rifamycin]]
|[[Rifamycin]]
| TMP 600 tiw
|TMP 600 tiw
| RMP 450-600 mg OD, or RFB 150-300 mg daily
|RMP 450-600 mg OD, or RFB 150-300 mg daily
|-
|-
| [[Amikacin]]
|[[Amikacin]]
|
|—
| Consider 10-15 mg/kg/day IV
|Consider 10-15 mg/kg/day IV
|}
|}


=== ''M. kansasii'' pulmonary disease ===
====''M. kansasii''====

* ''M. kansasii'' pulmonary disease: daily isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg/d)
*''M. kansasii'' pulmonary disease: daily isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg/d)
* Patients should be treated until culture negative on therapy for 1 year
*Patients should be treated until culture negative on therapy for 1 year
* Could consider treating based on a single positive colony, as it is rarely a colonizer
*Could consider treating based on a single positive colony, as it is rarely a colonizer

====''M. abscessus''====

*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

=== Non-Pulmonary Disease ===

==== Rapid Growers (''M. abscessus'', ''M. chelonae'', ''M. fortuitum'') ====

*Based on in vitro susceptibilities
*For ''M. abscessus'', a macrolide-based regimen is frequently used
*Surgical debridement may be necessary

====Skin and Soft Tissue Infection====

*3 to 6 months for ''M. marinum'', 6 to 12 months for MAC


====Cervical Lymphadenitis====
=== ''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
* Nonpulmonary disease caused by RGM (''M. abscessus'', ''M. chelonae'', ''M. fortuitum''):
* Based on in vitro susceptibilities
* For ''M. abscessus'', a macrolide-based regimen is frequently used
* Surgical debridement may be necessary


*Mostly due to MAC
=== ''M. marinum'' SSTI ===
*Treated primarily by surgical excision, with a greater than 90% cure rate
* 3 to 6 months for ''M. marinum'', 6 to 12 months for MAC
*A macrolide-based regimen should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy


===Monitoring===
=== NTM cervical lymphadenitis ===
* Mostly due to MAC
* Treated primarily by surgical excision, with a greater than 90% cure rate
* A macrolide-based regimen should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy


*Depends on the antibiotics used
=== Monitoring ===
*Audiology for aminoglycosides
* Depends on the antibiotics used
*Liver enzymes monthly for many others
* Audiology for aminoglycosides
* Liver enzymes monthly for many others


[[Category:Mycobacteria]]
[[Category:Mycobacteria]]

Revision as of 15:31, 18 August 2020

  • Mycobacteria that excludes tuberculosis and leprosy

Background

Microbiology

  • Acid-fast bacilli, free-living in the environment
    • Direct microscopy with auremine rodhamine fluorochrome stain (better than Ziehl-Neelsen)
  • Broadly divided into slow-growers and fast-growers
    • Fast-growers produce colonies within 7 days on solid media
      • Grows optimally at 28-30º C, with some preferring 35º C
      • May grow in blood culture if mycobacteremic
    • Slow-growers produce colonies after more than 7 days on solid media
      • MAC, M. xenopi, and M. kansasii are the three most important
      • Grows optimally at 35-37º C except M. haemophilum (28-30º C) and M. xenopi (42-45º C)
  • Media includes blood or chocolate agar, MTBC media, etc
  • Species-level identifiation requires molecular tests

Species

  • More than 200 species of Mycobacterium spp. that are not in M. tuberculosis complex or M. leprae
Species Notes
Rapid-growers (visible in culture in <7 days)
M. fortuitum complex
M. fortuitum
M. peregrinum
M. porcinum
M. chelonae
M. abscessus
M. abscessus subsp. abscessus
M. abscessus subsp. bolletii
M. abscessus subsp. massiliense
M. smegmatis
M. mucogenicum
Slow-growers (visible in culture in >7 days)
Photochromogens (develop pigments in light)
M. kansasii Always assumed to be pathogenic, never colonizer.
M. marinum Intermediate-grower (7-10 days).
 Scotochromogens Develop pigments in darkness.
M. gordonae Intermediate-grower (7-10 days). Common tap-water contaminant.
M. scrofulaceum
Nonchromogens (do not develop pigments in light)
M. avium complex In HIV, rarely pulmonary and almost always disseminated.
M. avium Most common subspecies.
M. intracellulare
M. chimaera
M. terrae complex
M. ulcerans
M. xenopi Grows optimally at 42-45º C.
M. simiae
M. malmoense
M. szulgai
M. asiaticum
M. haemophilum Grows optimally at 28-30º C.

Pathophysiology

  • Inhalation ± microaspiration, likely from water source
    • Environmental organisms that are essentially unavoidable
  • Response is cell-mediated with pulmonary macrophages, with assistance from CD4, IL-2, and IFN-γ

Epidemiology

  • NTMs are distributed worldwide, present in soil, household water, vegetable matter, animals, and birds
    • Also tap water (especially M. gordonae, M. kansasii, M. xenopi, M. simiae, MAC, and M. mucogenicum)
  • 90% of patients with NTM infections have underlying pulmonary disease
  • In Ontario: M. avium complex (25%), M. xenopi (10%), M. abscessus/M. chelonae, M. fortuitum
Presentation and Species Distribution
Pulmonary disease
M. abscessus Worldwide; may be found concomitant with MAC
M. avium complex Worldwide; most common NTM pathogen in US
M. kansasii US, Europe, South Africa, and coal-mining regions
M. malmoense UK, northern Europe; uncommon in US
M. xenopi Europe, Canada; uncommon in US; associated with pseudoinfection
Lymphadenitis
M. avium complex Worldwide; most common NTM pathogen in US
M. malmoense UK, northern Europe (especially Scandinavia)
M. scrofulaceum Worldwide; previously common, now rarely isolated in US
Disseminated disease
M. avium complex Worldwide; AIDS; most common NTM pathogen in US
M. chelonae US; non-AIDS immunosuppressed skin lesions
M. haemophilum AIDS; US, Australia; non-AIDS immunosuppressed
M. kansasii AIDS; US, South Africa
SSTI and MSK
M. abscessus Penetrating injury
M. chelonae US, associated with keratitis and disseminated disease
M. fortuitum Penetrating injury, footbaths
M. marinum Worldwide, fresh- and saltwater
M. ulcerans Australia, tropics, Africa, Southeast Asia, not US
Contaminant
M. gordonae Most common NTM contaminant
M. haemophilum
M. mucogenicum
M. nonchromogenicum
M. terrae complex

Clinical Manifestations

Syndrome Species Description
Pulmonary disease MAC, M. kansasii, M. xenopi, M. abscessus
Upper lobe cavitary MAC, M. kansasii Male smokers, often alcohol use, usually early 50s
RML/lingular nodular bronchiectasis MAC, M. abscessus, M. absessus subsp. massiliense Female nonsmokers, usually older than 60
Localized alveolar/cavitary M. abscessus, MAC Prior granulomatous dz (usually TB) with bronchiectasis
Reticulonodular or alveolar bilateral lower lobe M. fortuitum Achalasia, chronic vomiting, exogenous lipoid pneumonia
Reticulonodular MAC, M. abscessus subsp. abscessus, M. abscessus subsp. massiliense Adolescents with CF, HIV-positive patients, prior bronchiectasis
Hypersensitivity pneumonitis M. immunogenum, M. avium Metal workers, indoor hot tubs
Cervical lymphadenitis MAC
SSTI M. fortuitum, M. marinum, M. chelonae, M. ulcerans
MSK M. marinum, MAC, M. kansasii, M. fortuitum, M. abscessus, M. chelonae
Disseminated HIV-positive: M. avium and M. kansasii, HIV-negative: M. abscessus and M. chelonae
Catheter-related M. fortuitum, M. abscessus, M. chelonae

Pulmonary Disease

  • Risk factors include COPD and CF 1
  • Most common clinical manifestation of NTM
  • Most commonly caused by MAC, M. kansasii, M. xenopi, and M. abscessus
  • Nonspecific chronic or subacute respiratory syndrome with prominent cough

Fibrocavitary Disease

  • Usually preexisting lung disease (COPD etc), men
  • Upper-lobe predominant, focal, cavitary
  • DDx includes TB and lung cancer

Nodular Bronchiectatic Disease

  • Lady Windermere syndrome
  • RML/lingula with discrete nodules and bronchiectasis
  • Usually no preexisting lung disease, non-smoker, women

Investigations

  • Almost always needs CT; may repeat to monitor for progression
  • 3 sputums for AFB; may treat M. kansasii based on only a single colony but everything else needs 2-3 positives
    • Rule out TB

Diagnosis

  • Requires both clinical and microbiological evidence of disease
  • Clinical diagnosis
    • Pulmonary symptoms, or
    • Presence of nodules or cavities as seen on chest radiograph, or
    • HRCT scan with multifocal bronchiectasis with multiple small nodules, and
    • Exclusion of other diagnoses
  • Microbiologic diagnosis
    • At least 2 (of 3) expectorated sputa (or at least 1 bronchial wash or lavage) with positive cultures for NTM
    • Transbronchial or other lung biopsy showing the presence of granulomatous inflammation or AFB with 1 or more sputum or bronchial washings that are culture positive for NTM.

Skin and Soft Tissue Infection

  • From direct inoculation
  • M. abscessus, M. fortuitum, M. chelonae, M. marinum, M. ulcerans
  • Dx: tissue biopsy culture (best) or culture of discharge

M. marinum

  • "Fish tank granuloma"
  • Incubation 2 to 3 weeks
  • Small violet papular lesions on hands, which can ulcerate
  • Can also cause sporotrichoid disease

Other Infections

Superficial Lymphadenitis

  • Children, usually submandibular
  • May be from eating dirt

Disseminated Disease

  • Usually in AIDS or other significant cell-mediated immunosuppression

M. chimaera Infection

  • Outbreaks associated with heater units used in cardiac surgery
  • Present with IE, sternal wound infections, mediastinitis, etc.

Diagnosis

  • Sputum smear and culture for AFB
    • Spontaneous, induced, or BAL
    • PCR/NAAT can be done for TB and MAC, but only done on smear positive samples unless specifically requested

Management

  • Treatment decisions
    • First is to decide whether or not to treat; must weigh the risks and benefits
    • NTM can represent contamination, colonization, or infection/invasion
    • The mycobacteria are inherently resistant to many bacteria, sometimes require IV therapy, multiple agents with toxicity, prolonged treatment
    • Treatment often ineffective
    • Recurrence is common; 50% of patients need a second course within 5 years of the first one
    • Decide to start based on shared decision-making model, reviewing:
      • Meets diagnostic criteria
      • Comorbidities
      • Toxicities
      • Goals of care
  • All rapid-growers are resistant to first-line TB treatment (RIPE), and have aspiration as an underlying risk factor
    • Need susceptibilities for macrolides in MAC; needs to be specifically requested

Pulmonary Disease

Mycobacterium avium Complex

  • MAC is the prototype
  • Macrolide (azithro/clarithro) backbone, with 2 to 3 other agents depending on the disease type and severity
  • Rifampin and clarithromycin interact, so prefer rifamycin
  • Treat until 12 months after negative cultures
Class Nodular Cavitary or Advanced
Macrolide Clarithromycin 1000 tiw or azithromycin 500 tiw Clarithromycin 500 bid or azithromycin 250 daily
Ethambutol 25 mg/kg tiw 15 mg/kg/day
Rifamycin TMP 600 tiw RMP 450-600 mg OD, or RFB 150-300 mg daily
Amikacin Consider 10-15 mg/kg/day IV

M. kansasii

  • M. kansasii pulmonary disease: daily isoniazid (300 mg/d), rifampin (600 mg/d), and ethambutol (15 mg/kg/d)
  • Patients should be treated until culture negative on therapy for 1 year
  • Could consider treating based on a single positive colony, as it is rarely a colonizer

M. abscessus

  • 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

Non-Pulmonary Disease

Rapid Growers (M. abscessus, M. chelonae, M. fortuitum)

  • Based on in vitro susceptibilities
  • For M. abscessus, a macrolide-based regimen is frequently used
  • Surgical debridement may be necessary

Skin and Soft Tissue Infection

  • 3 to 6 months for M. marinum, 6 to 12 months for MAC

Cervical Lymphadenitis

  • Mostly due to MAC
  • Treated primarily by surgical excision, with a greater than 90% cure rate
  • A macrolide-based regimen should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy

Monitoring

  • Depends on the antibiotics used
  • Audiology for aminoglycosides
  • Liver enzymes monthly for many others

References

  1. ^  Jennifer R. Honda, Vijaya Knight, Edward D. Chan. Pathogenesis and Risk Factors for Nontuberculous Mycobacterial Lung Disease. Clinics in Chest Medicine. 2015;36(1):1-11. doi:10.1016/j.ccm.2014.10.001.