1. Non-Tuberculosis Mycobacterium (NTM) in Cystic Fibrosis
Elika Rad, MS, RN, NP-C
Nurse Practitioner
Adult Cystic Fibrosis Center
Stanford University Medical Center

2. Cystic Fibrosis (CF) Defect in the CFTR gene Sinuses Lungs
Pancreas (Endocrine/Exocrine)
Liver
Absorption/Nutrition
Bowel health/digestive transit
Reproductive System
Bones/Joints

3. CF Epidemiology One of the most common genetic diseases
~30,000 US (~70,000 worldwide)
~1,000 new cases per year
>70% of patients are diagnosed by age two.
>45% of the patient population is >18 years old!
Dramatic improvement in survival over the past 50 years
Predicted median age early 40s.
After sickle cell anemia
5 years ago when I started this was 37 years old!
Cystic Fibrosis Foundation, 2014

4. Other Pathogenic organisms
Burkholderia cepacia
Stenotrophomonas maltophilia
Achromobacter (Alcaligenes xyloxidans)
Nontuberculousis mycobacteria (NTM)

5. What are mycobacteria? M. tuberculosis complexTB
M. leprae and M. lepromatosis
Hansen’s disease or leprosy
NTM – also known as:
Environmental mycobacteria (Water and soil)
Atypical mycobacteria
Mycobacteria other than tuberculosis (MOTT)
Family of small, rod-shaped bacilli
Common species/Broad categories
NTM:
Considered ubiquitous: found everywhere, especially in soil and water > natural and treated water sources (indoor hot tubs).
“Opportunistic” pathogens
High exposure to natural environments
Attraction to structural lung disease/ineffective lung clearance; unclear why > structural or immune/defense issues.
> Specific source of infection usually cannot be identified
en.wikipedia.org/wiki/Nontuberculous_mycobacteria

6. NTM - Microscopic
aapredbook.aappublications.org

7. NTM – Acid Fast Bacilli (AFB)

8. NTM Species M. avium Complex M. fortuitum M. kansasii M. genavense
M. abscesus
M. gordonae
M. haemophilium
M. marinum
M. immunogenum
M. mucogenicum
M. malmoense
M. scrofulaceum
M. smegmatis
M. simiae
M. szulgai
M. ulcerans
M. terrae Complex
M. xenopi
M. chelonae
Other NTM*
* Complete list can be found at

9. Common NTM species Slow growers Rapid growers (RGM)
M. avium complex (MAC)
M. kansasii
Rapid growers (RGM)
M. abscessus complex
M. chelonae
M. fortuitum

10. Common NTM species M. avium complex (MAC) M. abscessus complex
M. intracellulare
M. chimaera
M. abscessus complex
M. abscessus
M. massiliense
M. bolletii
MAC organisms are common in many environmental sites, including water and soil, and in animals.
found to colonize natural water sources, indoor water systems, pools, and hot tubs.
M.abscessus (rapid grower)
The third most frequently recovered NTM respiratory pathogen in the United States and accounts for approximately 80% of RGM respiratory disease isolates(32).

11. Prevalence in Cystic Fibrosis
Before 1990 rarely reported
No routine AFB testing
Poor culture technique
Younger CF population
1990s-2000: 2-28% N. America/Europe
based on single sputum sample
Poor culture techniques
Only screened patients when ill
No adult data
Prevalence = subjects having at least one positive culture divided by all subjects
Olivier, et al. AJRCCM. 2003

12. Prevalence in Cystic Fibrosis
United States overall prevalence ~13%
MAC (75%)
M. abscessus (21%)
Mac and M. abscessus (2%)
Other species (2%)
Olivier et el. (NTM in CF Study Group) 2003: First comprehensive study of NTM in CF patients in US: ~1000 patients, > 10 years old, 21 CF centers
Martiniano et al. The largest CF cohort described to date from the time of subjects’ first positive NTM culture in which NTM culture data
all patients receiving standard care at the CF Center: Colorado CF Center & National Jewish Health
least one positive NTM respiratory culture
Followed January 2000 to December 2010.
Olivier, et al. AJRCCM. 2003
Martiniano et al., AATS. 2014

13. Associated Risk Factors
NTM Associated with
More frequent in adults; lower age (median 32 yrs)
Higher baseline FEV-1
Lower frequency of P. aeruginosa
higher frequency of S. aureus
coinfection with Stenotrophomonas maltophilia and Aspergillus fumigatus
Older age: suggests the high prevalence may be a phenomenon of increased life span in CF
Milder disease:
patients with more severe CF disease die before having enough expire time to acquire and retain NTM OR
some factor associated with the ability to reach older age with relatively mild disease may predispose to the presence of NTM
Olivier, et al. AJRCCM. 2003
Martiniano et al., AATS. 2014

14. NTM Transmission No Person-to-person transmission
No nosocomial acquisition
Most patients had unique bacterial strains
Only cases of same strain laboratory cross- contamination
No correlation between NTM culture status and
Number of hospitalizations
Days in the hospital
Outpatient visits
Olivier, et al. AJRCCM. 2003

15. Relevance of Positive Culture
Single positive culture
Clears spontaneously
Recurrent, no disease
> 2+ cultures
No symptomatic progression
No radiographic progression
NTM disease
> 2+ cultures and
Symptomatic progression and
Radiographic progression
So we have a lot of data about the epidemiology of NTM in CF (its prevalence and potential risk factors), but this is not sufficient to guide clinical decision-making: does one positive culture mean disease? Do we treat? How do we know it causes disease?
It’s essential to distinguish between….
Single +: With NTM widely present in the environment, these organisms are likely transiently present in the CF airway at any point in time, with no clinical significance.
Martiniano et al., AATS. 2014

16. Diagnosing NTM Disease
Symptoms
Radiology
Microbiology
Appropriate exclusion of other diagnoses
Overlapping
Overlapping
Difficult to interpret in CF
Cannot account for all NTM species
Bacterial overgrowth
Distinguishing treatment failure/reinfection
ATS/IDSA look at 4 broad criteria to define NTM disease
> HRCT findings overlap with those commonly in CF (cysts or cavities, segmental consolidation, peripheral nodules, and tree-in-bud type infiltrates)
ATS Statement AJRCCM 2007

17. Diagnosis: Symptoms Single or recurrent infections (61.5%)
no significant difference in decline in FEV1 before or after 1st +NTM culture.
Active NTM disease (38.5%)
lower baseline FEV1 at first positive culture
FEV1 decline in year before 1st +culture
FEV1 decline 3 years after 1st + culture
Not linked to other clinical characteristics
Gender/age
Azithromycin use/resistance
CF genotype
Co-infection with other CF pathogens
-5.8% predicted/yr
-4.1% predicted/yr
61%: Supports the conclusion that the majority of subjects with CF will not progress to require treatment for their NTM after a first positive culture.
A larger sample size may have increased our power to detect a difference between these groups.
Possible that over decades of follow-up, patients with apparently indolent infection will eventually demonstrate accelerated lung decline.
Possible that, over time, the NTM will acquire additional virulence factors, such as a “rough” morphotype (33, 34), which could potentially alter the host response and result in active disease in an individual after years of indolent infection (31, 35).
A long-term prospective trial is needed to conclusively determine if the benefit of not treating patients with apparently indolent infection outweighs the long-term risk of developing NTM disease.
Accelerated decline in lung function in patients with NTM disease before the time of a first positive culture likely reflects the presence of NTM before initial detection.
Authors think that an unexpected decrease in FEV1 in patients receiving standard CF care is a potentially useful indicator of the significance of a first positive NTM culture
Martiniano et al., AATS. 2014

18. Diagnosis: Symptoms
Martiniano et al., AATS. 2014

19. Diagnosis: Radiology Bronchiectasis and M. abscessus disease

20. Diagnosis: Radiology
MAI
radiographics.highwire.org

21. Diagnosis: Radiology MAC recovered from 299 non-CF patients
98% of patient with > 2 isolates showed radiographic progression.
Patients
MAC Isolates
New cavitation or infiltrate
114 1 2% 29 2
90% 40 3
98%
116
> 4
100%
Tsukamura studied the Isolation of MAC from sputum specimen of 299 patients (non-CF) in association with the appearance of a new cavitary (or infiltrative) lesions.
Of 114, only two patients (2 percent) had association with appearance of a cavitary lesion.
Of 29 patients who showed two isolations, 26 (90 percent) had the association.
Of 40 patients who showed three isolations, 39 (98 percent) had the association.
All 116 patients who showed four or more isolations had the association with appearance of a cavitary lesion.
M Tsukamura. Chest. 1991

22. Diagnosis: Radiology NTM in CF patients Entry HRCT:
Progression on exit HRCT:
38% control subjects
22% <2 NTM+ culture
100% >3 NTM+ cultures
Oliver et al. looked at longitudinal effects of NTM on the clinical course of CF lung disease with respect to FEV-1 and CT changes
17 US CF centers
NTM vs control (two-culture neg)
NTM group
NTM-positive (transient)
NTM meeting ATS criteria
Subjects followed for only 15 months
Olivier, et al. AJRCCM. 2003

23. Diagnosis: Microbiology
Initial MAC isolate
24% grew 2nd NTM (primarily M. abscessus)
Initial M. abscessus
34% grew 2nd NTM (primarily MAC)
Overall
5 years: 26% with second NTM species
10 years: 36% with second NTM species
presence of a second species of NTM = more than an occasional occurrence
it is a likely development in patients with CF after an initial positive culture.
Findings support the need for lifelong strategies for NTM surveillance and management in patients with CF who present with a positive NTM culture.
Martiniano et al., AATS. 2014

24. Diagnosis: Other Diseases
In the setting of CF, documented deterioration from baseline and “reasonable exclusion of other disease to explain (the patient’s) condition” is an essential component.
Suboptimal CF care
Pulmonary exacerbation (usual pathogens)
New bacterial infection (B. cepacia, etc)
Poorly controlled sinus disease
ABPA
CFRD
Poorly controlled sinusitis
Chronic aspiration
ATS criteria mentioned excluding other diseases; in CF that is interpreted as other complications/causes of deterioration in CF.
ATS Statement AJRCCM 2007

25. Clinical Criteria for diagnosis
Symptoms - Overlapping
Radiology – non specific
Microbiology - difficult
Appropriate exclusion of other diagnoses
Despite these limitations, and given the most recent data, the ATS definition appears most appropriate for CF

26. ATS/IDSA 2007 Definition of NTM Pulmonary Disease
Pulmonary Symptoms
Increased Cough/SOB
Massive hemoptysis
Radiology
CXR with nodular or cavitary opacities
In absence of cavitation, HRCT with multifocal bronchiectasis*** with multiple small nodules.
Microbiology
+ AFB > 2 separated sputum samples, or
+ AFB from > BAL, or
TBBx with mycobacterial histopathologic feature +
One or more sputum or BAL +ve for NTM
Appropriate exclusion of other diagnoses
Underlying CF lung disease ***
Tuberculosis (TB)
IDSA = Infectious Disease Society of America
Large recommendation in general pulmonary disease
mycobacterial histopathologic feature = granulomatous inflammation or AFB
ATS Statement AJRCCM 2007

27. ATS/IDSA 2007 Definition of NTM Pulmonary Disease
Expert consultation once NTM recovered
Close follow up of patients with suspected NTM lung disease who don’t meet ATS criteria
NTM lung disease ≠ initiation of therapy
Risk vs benefit
ATS Statement AJRCCM 2007

28. Diagnosis of NTM in CF: CFF and ECFS Recommendations
ATS/IDSA criteria should be used in individuals with CF
Rule out other CF pathogens and co-morbidities with decline in symptoms and radiological changes with 1st + NTM cultures.
Discontinue azithromycin treatment while evaluation for NTM disease is underway.
Minimum annual sputum AFB cultures in Non- sputum producers: if no clinical/radiologic features resembling NTM pulmonary disease, do not require screening cultures for NTM.
ECFS = European CF Society?
Induce or expectorated; Recommend against the use of oropharyngeal swabs.
Stanford being progressive
This is the Stanford CF protocol protocol

29. Stanford NTM Surveillance Protocol
Follow CFF guidelines: biannual AFB cultures
If positive, monthly AFB
If 2-3 persistent positive, CT of chest
If FEV-1 stable and no disease on CT
Cont monitoring AFB
Annual chest CT or sooner if increase in symptoms or decline in FEV-1

30. When Should NTM Therapy Start?
Under treat
Over treat
Disease Progression
Drug Toxicity

31. When Should NTM Therapy Start?
The patient
Symptoms, overall condition of patient
Imaging progression
Transplant listed or post transplant
The organism
Species
Bacterial load
Treatment goals?
Eradication
Prevent progression
Symptoms relief

32. Time to Treat
The CFF and the ECFS recommend that NTM treatment should be considered for individuals with CF who have ATS/IDSA defined NTM pulmonary disease.
Treatment Goals:
Symptomatic improvement
Radiographic improvement
Microbiological improvement:
Conversion to negative cultures
12 months negative cultures ON Rx

33. Treatment Success 43% DID NOT clear NTM after 1st +culture
Treatment success of NTM pulmonary disease at Colorado CF center is similar to rates reported in non-CF
37 subjects treated for active NTM disease.
Initiated ~ 18 months after 1st +NTM culture
Variety IH, oral, IV agents (lack of standardized therapy in CF)
Forty percent of subjects with MAC never converted their sputum cultures to negative or achieved temporary clearance with recurrence, and 55% of subjects with M. abscessus never converted their sputum cultures during the observation period.
Martiniano et al., AATS. 2014

34. Common MAC Treatment Azithromycin IV/IH Amikacin Other agents
HIGH DAILY DOSING ONLY.
NEVER USE AS MONOTHERAPY
IV/IH Amikacin
Other agents
in collaboration with experts in CF/NTM
ATS Statement AJRCCM 2007

35. Common M. Abscessus Therapy
Intensive phase:
Daily oral macrolide + IV amikacin
And one or more of:
Tigecycline
Imipenem
Cefoxitin (?)
Continuation phase:
Daily oral macrolide + IH amikacin
And 2-3 of the following:
Moxifloxacin
Linezolid
Minocycline (?)
Clofazimine (?)
Guided but not dictated by susceptibility results
3-12 weeks
Duration of intensive phase determined by
severity of infection
Response to treatment
Tolerability of the regimen
ATS Statement AJRCCM 2007

36. Drug Toxicities Drug Toxicities Clarithromycin
GI (metallic taste, nausea, diarrhea
Rare: REVERSIBLE vestibular and hearing impairment
Azithromycin
GI (diarrhea, nausea)
Rifampin
Orange discoloration of secretions and urine
GI (Nausea, vomiting)
Hypersensitivity reactions (fever/rash)
Rifabutin
Neutropenia
Myalgia and arthralgia
Ethambutol
Ocular toxicity/optic neuritis (loss of acuity, red-green discrimination)
Peripheral neuropathy, headache, disorientation
Amikacin
Hearing impairment
Renal impairment
Vestibular impairment
Tigecycline
GI (nausea, vomiting, diarrhea)
Linezolid
Bone marrow suppression
Peripheral neuropathy
ATS Statement AJRCCM 2007

37. Management of NTM in CF patients is complex/difficult
Validated CF-specific diagnostic criteria
Standardize treatment protocols
Understanding NTM species/behavior
Analysis of standard antimicrobial agents
NTM-specific antibiotics for prolonged treatment
Defined rates of treatment response
Markers of response and treatment endpoints specific to CF
MORE DATA, MORE RESEARCH!!!

38. References
American Thoracic Society. An Official ATS/IDSA Statement: Diagnosis,Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med 2007; 175:
Binder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of Nontuberculous Mycobacterial Infections and Associated Chronic Macrolide Use among Persons with Cystic Fibrosis. Am J Respir Crit Care Med Vol 188, Iss. 7, pp 807–812, Oct 1, 2013
Cystic Fibrosis Foundation. About Cystic Fibrosis: What y ou Need to Know. Available at . cff . org/ AboutCF/. Accessed February 20, 2014
Griffith, et al. An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med Vol 175. pp 367–416, 2007
Olivier KN, Weber DJ, Wallace RJ et al. Nontuberculous Mycobacteria I: Multicenter Prevalence Study in Cystic Fibrosis. Am J Respir Crit Care Med. 2003;167:
Olivier KN, Weber DJ, Wallace RJ et al. Nontuberculous Mycobacteria
II: Nested-Cohort Study of Impact on Cystic Fibrosis Lung Disease. Am J Respir Crit Care Med ;167:
M Tsukamura. Diagnosis of disease caused by Mycobacterium avium complex.Chest ;99(3):
Martiniano SL, Sontag MK, Daley CL, et al. Clinical Significance of a First Positive Nontuberculous Mycobacteria Culture in Cystic Fibrosis. Ann Am Thorac Soc Vol 11, No 1, pp 36–44, Jan 2014
Wikipedia. en.wikipedia.org/wiki/Nontuberculous_mycobacteria/. Accessed February 24, 2014