Presentation is loading. Please wait.

Presentation is loading. Please wait.

Non-Tuberculosis Mycobacterium (NTM) in Cystic Fibrosis

Similar presentations

Presentation on theme: "Non-Tuberculosis Mycobacterium (NTM) in Cystic Fibrosis"— Presentation transcript:

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 complex
TB 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

6 NTM - Microscopic

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

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. Accessed February 24, 2014

Download ppt "Non-Tuberculosis Mycobacterium (NTM) in Cystic Fibrosis"

Similar presentations

Ads by Google