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Learning Objectives
• Analyze recent evidence, guidelines, and best practices in the diagnosis, treatment, and management of NTM and adverse events
• Distinguish appropriate personalized NTM treatment approach according to patient’s clinical presentation
• Review strategies for patient adherence and treatment completion to improve patient outcomes
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Overview: Prevalence, Host Susceptibility, Clinical Manifestations & Diagnostic Criteria
Kenneth N Olivier, MD, MPHSenior Clinician and Chief,
Laboratory of Chronic Airway InfectionChief, Pulmonary Branch/DIR
October 20, 2019Propert
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Nontuberculous Mycobacteria
• Ubiquitous environmental organisms• Water including potable, soil
• >190 species (http://www.bacterio.net/mycobacterium.html)
• Slow Growers (>7 days on solid media) • M. avium complex (12 species)
• M. avium• M. intracellulare• M. chimaera
• Most common cause of lung disease
• Rapid Growers (≤7 days) • M. abscessus group
• ss. abscessus• ss. massiliense• ss. bolletii
• Higher virulence, especially in CF
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ATS/IDSA Pulmonary Dx Criteria
• Clinical (all 3)• Symptoms – cough most common
• Radiographic – cavities, bronchiectasis, nodules
• Exclusion of other diagnoses• And…
• Microbiologic (any of these)• 2 positive sputum specimens• 1 bronchial wash/lavage• Appropriate biopsy histopath & (+) resp culture
Griffith. Am J Respir Crit Care Med 2007
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0-39 40-59 60+
Cas
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M TB F TB M NTM F NTM
• Avg age adj period prevalence 2004‐2006: 5.5/100K ~ 16K
• Increasing 3% per year• NTM more prevalent
• NTM >>TB over age 60• Women > Men
Adapted from Prevots DR, Shaw PA, Strickland D, et al. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med. 2010;182(7):970–976. doi:10.1164/rccm.201002‐0310OC
Methods• Electronic record review• Isolate based• Longitudinal• Linked to billing codes,
radiograph reports, pharmacy records
NTM Prevalence: HMO Study
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NTM Prevalence: HMO Study
• Isolate‐based case definition• Possible – single positive culture• Probable ‐ >1 positive culture
• Frequency of related chronic conditions and symptoms similar
• Radiographic findings similar except for cavities
• ICD 9 (031.0) pulmonary NTM• Possible 16%• Probable 27%
Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Prevots DR, Shaw PA, Strickland D, et al. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir CritCare Med. 2010;182(7):970–976. doi:10.1164/rccm.201002‐0310OCThe American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
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Cases p
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US Medicare 2000‐2007: NTM PrevalenceMethods• Review large existing database• Billing code based• Longitudinal
WomenMen
Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med. 2012;185(8):881–886. doi:10.1164/rccm.201111‐2016OCThe American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
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• Participants were asked to identify up to three symptoms that have the most significant impact on daily life:
• Chronic cough or coughing up blood, phlegm, and sputum mentioned by majority as being the most significant symptom
• Fatigue ‐ descriptions ranged from feeling “tired to your core” to “walking through molasses”
• Nearly half identified shortness of breath as one of their most significant symptoms and for most, the severity had a major impact on their daily life and overall health
The Voice of the Patient
FDA Patient Focused Drug Development Initiative Public Meeting October 15, 2015
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Nodular, bronchiectatic, cavitary, fibrocavitary…
• Fibrocavitary (FC)• Cavitary lesions, pleural thickening predominantly in upper lobes
• Predominantly older males• Previous pulmonary tuberculosis• COPD
• Nodular bronchiectatic (NC‐NB)• Bilateral bronchiectasis with multiple nodules (tree‐in‐bud opacities)
• Predominantly postmenopausal, nonsmoking females
• Cavitary nodular bronchiectatic (C‐NB)• Some NB also have small cavities
Koh. Eur Respir J 2017
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Nodular, bronchiectatic, cavitary, fibrocavitary…
• Favorable outcome (culture conversion + ⩾12 mos (‐) cultures) on ATS/IDSA regimen
Favorable Unfavorable Univariate aOR Multivariate aOR
Subjects 402 (84%) 79 (16%)
Male sex 153 (38) 43 (54) 1.94 (1.20, 3.16) 1.80 (1.07, 3.02)
Disease Type
NC‐NB 246 (61) 32 (41) 1.00 Ref. 1.00 Ref.
C‐NB 62 (15) 18 (23) 2.23 (1.07–4.65) 2.36 (1.24–4.52)
FC 94 (23) 29 (37) 2.37 (1.26–4.48) 1.99 (1.11–3.54)
Won‐Jung Koh, Seong Mi Moon, Su‐Young Kim, Min‐Ah Woo, Seonwoo Kim, et al. Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype. European Respiratory Journal 2017 50: 1602503; DOI: 10.1183/13993003.02503‐2016
Reproduced with permission of the © ERS 2019. European Respiratory Journal 50 (3) 1602503; DOI: 10.1183/13993003.02503‐2016 Published 27 September 2017
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Nodular, bronchiectatic, cavitary, fibrocavitary…
• Favorable outcome (culture conversion +⩾12 mos (‐) cultures) on ATS/IDSA regimen
Favorable Unfavorable Univariate aOR Multivariate aOR
Subjects 402 (84%) 79 (16%)
Male sex 153 (38) 43 (54) 1.94 (1.20, 3.16) 1.80 (1.07, 3.02)
Disease Type
NC‐NB 246 (61) 32 (41) 1.00 Ref. 1.00 Ref.
C‐NB 62 (15) 18 (23) 2.23 (1.07–4.65) 2.36 (1.24–4.52)
FC 94 (23) 29 (37) 2.37 (1.26–4.48) 1.99 (1.11–3.54)
Reproduced with permission of the © ERS 2019. European Respiratory Journal 50 (3) 1602503; DOI: 10.1183/13993003.02503‐2016 Published 27 September 2017
Won‐Jung Koh, Seong Mi Moon, Su‐Young Kim, Min‐Ah Woo, Seonwoo Kim, et al. Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype. European Respiratory Journal 2017 50: 1602503; DOI: 10.1183/13993003.02503‐2016
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Impaired local defensesBronchiectasis, emphysema, pneumoconiosis,
previous cavitary tuberculosis, silicosis, COPDClinical history, chest imaging, pulmonary function tests
Cystic fibrosis Sweat chloride test, nasal potential difference, CFTR genotyping
Primary ciliary dyskinesia Measurement of nasal nitric oxide, cardinal clinical features, ciliary beat frequency & ultrastructure; cilia structure/function (>40) genotyping
Impaired systemic immunitySTAT3 deficiency Total IgE, cardinal clinical features & family history, STAT3 genotyping
Immunosuppressant useTumor necrosis factor‐α blockers Drug history
Idiopathic bronchiectasis(Lady Windermere syndrome)
Clinical history with exclusion of the above conditions, special body morphotypic features
Susceptibility to Pulmonary NTM
Adapted from Wu. Lancet Infect Dis 2015
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• Pulmonary nontuberculous mycobacteria (PNTM) disease
• “Idiopathic” nodular bronchiectasis
• No obvious predisposition– Postmenopausal women– Nonsmokers– Chronic cough
• Postulated “fastidious” nature led to voluntary cough suppression
Chest 1992
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Ann Am Thorac Soc 2016
Genetic diseases affecting
airway clearance
Genetic connective
tissue diseases
Genetic immunediseases
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• “Unaffected” family memberso 28% bronchiectasiso 61% other CT traits
PNTM = Pulmonary Nontuberculous Mycobacterial Disease
Szymanski EP, Leung JM, Fowler CJ, et al. Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic
Disease. Am J Respir Crit Care Med. 2015;192(5):618–628. doi:10.1164/rccm.201502‐0387OC
Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society.
The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
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Whole Exome Data Analysis PNTM Cohort
• Candidate gene approach• Categories
• Cystic fibrosis• Cilia• Connective tissue• Immune
• Comparison (based on PCA)• 1000G European controls
Candidate variants
Missense, nonsense, or splicing variant
Missense, nonsense, or splicing variant
Population Frequency less than
2%
Population Frequency less than
2%
Candidate genes of interest
Candidate genes of interest
Szymanski EP, et al. Am J Respir Crit Care Med 2015
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Conclusions: Initial WES Analysis
• PNTM patients & “unaffected” family members• More variants in CF, cilia, & connective tissue genes vs. controls• Overlapping bronchiectasis & connective tissue disease features
• More immune variants only seen in PNTM affected • Whole exome data support
• “Susceptible persons” model of PNTM disease• Increased frequency of “mild” mutations from relevant gene categories increases risk of bronchiectasis and NTM infection
Szymanski EP, et al. Am J Respir Crit Care Med 2015
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Cilia variants –Motility enhancer:Sildenafil, iNO
Immunevariants –Immunemodulator:
GM‐CSF
Connective Tissue Variants ‐TGF‐βattenuator: Losartan
Idiopathic BE/PNTM
CF variants –CFTR Modulators
Environment ‐Behavioralmodification
Pathogen ‐Novel anti‐microbials
Disease Pathogenesis – Modifiable Targets
BE = BronchiectasisPNTM = Pulmonary Nontuberculous Mycobacterial Disease
Adapted, Flume PA, et al. Lancet 2018
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Treatment of Mycobacterium aviumcomplex
Charles L. Daley, MDNational Jewish Health
University of Colorado, DenverIcahn School of Medicine, Mt. SinaiProp
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Treatment of M. avium complexClinical Case
• 65 year old Caucasian woman treated for Mycobacterium avium complex on two previous occasions with macrolide, rifampin, and ethambutol
• Now with AFB smear positive sputum specimen and culture positive for M. intracellulare
• Antimicrobial susceptibility test results are pending
• Restarted on azithromycin, rifampin, and ethambutol Prop
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Mycobacterium avium Complex12 Species
Tortoli E, et al. J System Evol Micro 2004;54:1277‐1285. Van Ingen J, et al. Int J Syst Evol Microb 2018;68:36666
MAC
M. paraintracellulareM. lepraemurium
Tortoli E. Microbiological features and clinical relevance of new species of the genus Mycobacterium. Clin Microbiol Rev. 2014;27(4):727–752. doi:10.1128/CMR.00035‐14
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Antimicrobial Susceptibility Testing (AST)for Mycobacterium avium complex
AST should be performed
Antimicrobial AgentMIC, ug/ml
CommentsS I R
First Line
Clarithromycin ≤ 8 16 ≥ 32 Class drug for macrolides
Amikacin (IV) ≤ 16 32 ≥64
Amikacin (liposomal inhaled)
≤ 64 ‐ ≥ 128
Adapted, CLSI. M62 Performance Standards for Susceptibility Testing… 2018
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Antimicrobial Susceptibility Testing (AST)for Mycobacterium avium complex
AST should be performed
Antimicrobial AgentMIC, ug/ml
CommentsS I R
First Line
Clarithromycin ≤ 8 16* ≥ 32 Class drug for macrolides
Amikacin (IV) ≤ 16 32 ≥64
Amikacin (liposomal inhaled)
≤ 64 ‐ ≥ 128
Second‐Line
Moxifloxacin ≤ 1 2 ≥ 4 Clinical effectiveness unprovenLinezolid ≤ 8 16 ≥ 32
Adapted, CLSI. M62 Performance Standards for Susceptibility Testing… 2018
AST may be performed Prop
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Treatment of Pulmonary Mycobacterium avium complex
MAC
Macrolide sensitive NoYes
Duration :12 mosculture negativity
ATS/IDSA AJRCCM 2007;175:367
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MAC
Macrolide sensitive NoYes
Duration :12 mosculture negativity
3X/weekAzithromycin*
RifampinEthambutol
DailyAzithromycin*
RifampinEthambutol
Cavities Present
NoYes
ATS/IDSA AJRCCM 2007;175:367* Clarithromycin is alternative
Treatment of Pulmonary Mycobacterium avium complex
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MAC
Macrolide sensitive NoYes
DAILYRifampin
EthambutolOther drug
ClofazimineMoxifloxacinBedaquilineInh. amikacinOther drugs?
Duration: 12 m
osculture negativity
3X/weekAzithromycin*
RifampinEthambutol
DAILYAzithromycin*
RifampinEthambutol
Cavities Present
NoYes
ATS/IDSA AJRCCM 2007;175:367
Treatment of Pulmonary Mycobacterium avium complex
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MAC
Macrolide sensitive NoYes
DAILYRifampin
EthambutolOther drug
ClofazimineMoxifloxacinBedaquilineInh. amikacinOther drugs?
Add IV Amikacin
Duration: 12 m
osculture negativity
3X/weekAzithromycin*
RifampinEthambutol
DAILYAzithromycin*
RifampinEthambutol
Cavities Present
NoYes
Treatment of Pulmonary Mycobacterium avium complex
*Infographic: Treatment Options (M. avium complex)
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Treatment Outcomes for MAC
Culture ConversionMacrolide susceptibleNon cavitaryCavitary
80%50‐80%
Griffith DE, et al. AJRCCM 2006;174:928 Wallace R, et al. Chest 2014;146:276‐282Jeong BH, et al. AJRCCM 2015;191:96‐103 Koh WJ, et al. Eur Respir J 2017;50Moon SM, et al. ERJ 2016;50:1602503 Morimoto K, et al. Ann ATS 2016;11:1904
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Treatment Outcomes for MAC
Culture ConversionMacrolide susceptibleNon cavitaryCavitary
80%50‐80%
Macrolide resistantNo surgery/aminoglycoside*Some surgery/aminoglycosideSurgery + prolonged aminoglycoside*
5%15%80%
* ≥ 6 months parenteral aminoglycoside
Griffith DE, et al. AJRCCM 2006;174:928 Wallace R, et al. Chest 2014;146:276‐282Jeong BH, et al. AJRCCM 2015;191:96‐103 Koh WJ, et al. Eur Respir J 2017;50Moon SM, et al. ERJ 2016;50:1602503 Morimoto K, et al. Ann ATS 2016;11:1904
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MAC Recurrences After Completion of Therapy: Relapse vs reinfection
University of Texas, Tyler 1
Northwestern, Chicago, IL 2
Samsung, Seoul, Korea3
Number of patients
155 190 402
Microbiologicrecurrence
48% 25% 29%
New infection 75%* 46%* 74%**
1. Wallace R, et al. Chest 2014;146:276‐2822. Boyle DP, et al. Ann Am Thorac Soc 20163. Koh WJ, et al. ERJ 2017;50 epub
*Determined by pulse field electrophoresis**Determined by rep‐PCR
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Treatment of M. avium complexClinical Case
• By six months, she was still culture positive on daily azithromycin, rifampin, ethambutol
• AST results:• clarithromycin MIC > 32• amikacin MIC = 32
• Amikacin (IV) was startedPropert
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Treatment FailuresStrengthen the Treatment Regimen
Regimen
Repurposed Drugs(moxifloxacin, amikacin, clofazimine)
New Drugs(bedaquiline, delamanid)
Intermittent to Daily Dosing ∼30%
conversion
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Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Griffith D, et al. Am J Respir Crit Care Med. 2018 Dec 15;198(12):1559‐1569. doi: 10.1164/rccm.201807‐1318OC.
The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
Phase 3 Randomized, Controlled Trial of Amikacin Liposome Inhalation Suspension (ALIS) + GBT vs GBT alone
CONVERT STUDY
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Proportion of Patients With Negative Sputum Cultures for NTM
Microbiologic response up to MIC ≤64
CONVERT STUDY
Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Griffith D, et al. Am J Respir Crit Care Med. 2018 Dec 15;198(12):1559‐1569. doi: 10.1164/rccm.201807‐1318OC.
The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
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Monitoring and Management Strategy for Respiratory Adverse Reactions
Dysphonia45.7%
Cough37.2%
Dyspnea21.5%
ClinicalSpirometryChest CT
Clinical
ClinicalSpirometry
Pre‐dose with beta‐agonistStop if evidence of HP
Pre‐dose with beta‐agonist
Temporary halt and re‐introduce
SYMPTOM MONITORING MANAGEMENT
Griffith D, et al. AJRCCM, 2018.
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Monitoring and Management Strategy for Auditory Adverse Reactions
Tinnitus7.6%
Dizziness6.3%
Hearing Loss4.5%
ClinicalAudiograms
ClinicalAudiograms
ClinicalAudiograms
Temporary halt and re‐introduce at three times weekly?
Temporary halt and re‐introduce
Temporary halt and re‐introduce
SYMPTOM MONITORING MANAGEMENT
Griffith D, et al. AJRCCM, 2018.
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Promote Adherence and Prevent Adverse Reactions
• Provide patient education first visit
• Detect side effects early through monitoring
• Manage side effects as they occur
• Improve airway clearance, optimize nutrition, physical
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Treatment of M. avium complexClinical Case
• Ethambutol, rifampin, and amikacin were continued
• Azithromycin was stopped
• Clofazimine was added
• She underwent resectionalsurgery and had inhaled amikacin substituted for IV
Cured!
RML, RLL (sup seg), lingular resection
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Summary
• Antimicrobial susceptibility testing is recommended for macrolides (clarithromycin) and amikacin
• A three drug macrolide‐containing regimen is administered for 12 months beyond culture conversion
• Three times weekly therapy for noncavitary disease• Daily therapy for cavitary disease
• Amikacin liposome inhalational suspension (ALIS) is recommended for treatment refractory MAC• Patient education, active monitoring, and management strategies can improve
tolerance and adherence• Treatment outcomes in macrolide resistant MAC remain poor – need
new drugs• Surgery may be helpful in selected cases
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M. abscessus pulmonary disease
Shannon Kasperbauer, M.D.Associate Professor of Medicine
National Jewish HealthUniversity of Colorado Health Sciences Center
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Evolution of taxonomy
1992 2006 2011 2013 2016
M. abscessus
M. abscessus
M. massiliense
M. boletii
M. abscessus,subsp. abscessus
M. abscessus,subsp. bolletii
M. abscessus,subsp. abscessus
M. abscessus,subsp. massiliense
M. abscessus,subsp. bolletii
Emerg Infect Dis 2015;21:1638Int J Syst Evol Microbiol 2016;66:447
M. abscessus,subsp. abscessus
M. abscessus,subsp. massiliensecomb. nov.
M. abscessus,subsp. bolletii
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MAB Characteristics: Macrolide resistance
Adapted from Haworth CS, Banks J, Capstick T, et alBritish Thoracic Society guidelines for the
management of non‐tuberculous mycobacterial pulmonary disease (NTM‐PD)
Thorax 2017;72:ii1‐ii64.
*15‐20% of M.abscessus have a dysfunctional erm 41 (C28) CLR: Clarithromycin
MAB subspecies CLR susceptibility days 3–5
CLR susceptibility day 14
Macrolide susceptibility phenotype
Genetic implication
MacrolideEffect
massiliense(abscessus*)
Susceptible Susceptible Macrolide susceptible
dysfunctional erm(41) gene
Anti‐mycobacterial
abscessusbolletii
Susceptible Resistant Inducible macrolide resistance
functional erm(41) gene
Immuno‐modulatory
Any Resistant Resistant High‐level constitutive macrolideresistance
23S ribosomal RNA point mutation
Immuno‐modulatory
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2003
2013
2017
Chronic Pulmonary Disease
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Clinical manifestations
Antimicrob Agents Chemother. 2018 Apr 26;62(5)
Characteristic Resistant group (69) Sensitive group (31) p valueAge, median (IQR) 58 (44‐66) 56 (32‐64) 0.562
Males, n (%) 26 (37.7) 17(54.8) 0.107
BMI, mean 19.93 19.69 0.729
Bronchiectasis 66 (95.7) 29 (93.4) 0.655
Cavity 50 (72.5) 8 (25.8) <0.001Nodules 38 (55.0) 19 (61.3) 0.648
Tree in bud 16 (23.2) 14 (45.2) 0.027Cough, n (%) 55 (79.7) 25 (80.6) 0.914
Sputum, n (%) 69 (100.0) 31 (100.0) 1
Fever, n (%) 15 (21.7) 4 (12.9) 0.298
Hemoptysis, n (%) 22 (31.9) 4 (12.9) 0.045
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Predictors of progression
OR 4.79 (1.39–16.48)p .013 OR 3.83 (1.06–13.82)
p .040OR 3.62 (1.02–12.82)
p .046
Bilateral disease Cavitary disease
N=113 median follow up 3.4 years, Seoul National University~40% progress requiring therapy
CID 2017;64(3);301‐8
Cavitary disease
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Association of individual drugs with treatment success in M. abscessus
TotalN=303
M. abscessus subsp. abscessus n=126
M. abscessus subsp. massiliense n=95
Adjusted OR* p‐value Adjusted OR* P‐value Adjusted OR* p‐value
Azithromycin 1.61 (0.93‐2.78) 0.085 3.29 (1.26‐8.62) 0.016 0.23 (0.02‐2.42) 0.226
Imipenem 2.65 (1.36‐5.10) 0.005 7.96 (1.52‐41.6) 0.018 10.2 (0.08‐1364.6) 0.353
Amikacin 2.03 (0.74‐4.11) 0.181 1.44 (1.05‐1.99) 0.020 0.38 (0.01‐53.1) 0.698
*Adjusted for age, sex, BMI, initial radiographic finding and presence of respiratory comorbidity
Eur Respir J. 2019 Jul 11;54(1)
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M. abscessus
“Functional” erm41 gene NoYes
≥2 other drugsAmikacin IVMacrolide
Macrolide≥1 other drugAmikacin IV
Imipenem (IV)Cefoxitin (IV)Tigecycline (IV)Linezolid/TedizolidClofazimineMoxifloxacinBedaquiline
≥2 other drugsInhaled Amikacin
Macrolide
Macrolide≥1 other drug
Inhaled Amikacin
Treatment of M. abscessus group
2+ months 1‐2+ months
Consider surgery for focal diseaseDuration 12 mos culture negativity
M. abscessusM. bolletii M. massiliense
*inhaled parenteral amikacin
*Infographic: Treatment Options (M. abscessus)
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M. abscessus subspecies abscessusC28 sequevar
10/2017 1/2018
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Post right upper lobectomy
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Shorter course therapy was effective in M. massiliense
Koh, W., Jeong, B. Oral Macrolide Therapy Following Short‐term Combination Antibiotic Treatment of Mycobacterium massiliense Lung Disease. CHEST 2016; 150(6):1211‐1221
Treatment outcome dataAfter 12 months of Rx
4week IV group (28) 2 week IV group (43) P value
Symptomatic improvement 25 (89) 43 (100) .057
HRCT improvement 22 (79) 39 (91) .177
Sputum conversion 28 (100) 39 (98) .148
Conversion at the end of Rx 28 (100) 42 (98) 1.00Follow up after Rx completion, Mo 33.8 (12.3‐50.3) 14.7 (0.5‐29.5) .006
Microbiologic recurrent 2/28 (7) 3/42 (7) 1.00
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Treatment of RGM: systematic review
Antimicrob Agents Chemother 2017; Oct 24;61(11).
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Predictors of favorable outcome
CID 2017;64(3):301–8.
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Predictors of favorable outcomes:Mycobacterial characteristics
CID 2017;64(3):309–16.
Mycobacterialcharacteristics
Culture conversion (20)
Persistently positive (24)
P value
Smooth morphotype 9 (45) 2 (8) .020
Rough morphotype 7 (35) 14 (58)
CLR Susceptible 7 (35) 1 (4) .015
Inducible resistance 13 (65) 23 (96)
C28 sequevar 6 (30) 1(4) .035
T28 sequevar 14 (70) 23(96)Propert
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Treatment refractory considerations
What do we do if someone is still persistently culture + on therapy?
My patient had hearing loss on
amikacin, a rash on cefoxitin and will
never take tigecycline again,
now what?
I cannot get clofazimine because I don’t have an IRB. Linezolid caused neuropathy and insurance won’t
cover bedaquiline…
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Treatment of M. abscessus: Surgery
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Treatment refractory considerations
•Inhaled amikacin•Ann Am Thorac Soc 2014;11:30•AAC 2018;62: e00011•AJRCCM 2017;195:814•Inahled Imipenem•J. Cyst Fibrosis 2019
•Phage therapy•inhaled NO therapy•Pediatr Infect Dis J 2018;37:336•GM‐CSF•Eur Respir J 2018;51:1702127
•Tigecycline/Omadacyline/Eravacycline•JAC 2019,AAC 2019•Clofazimine•Bedaquiline•Oxazolidinone•Beta‐lactam combinations•Beta‐lactamase inhibitors (BLAMAB)
• Curative for focal disease• 65% conversion • CID 2011 ;52(5):565‐571
Surgery Other drugs
Inhaled antibiotics
Adjunctive therapy
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Dual beta‐lactam synergy
Strain Species CAZ+AVI4 CFT CFT+CAZ10 CFT+CAZ50 CFT+CAZ100 CFT+ CAZ100+AVI4
ATCC 1977 M. abscessus 512 32 0.25 0.125 0.125 <0.25
51412 M. abscessus 356 8 0.5 0.5 0.5 1
51403 M. abscessus 128 8 1 0.25 0.125 0.25
CAZ: ceftazidime CFT: ceftaroline AVI: avibactam
MBio. 2019 Feb 12;10(1)
MIC (ug/ml)
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M. abscessus subsp. abscessusT28 sequevar (Dx 2013)
11/2018 3/2019
IV ceftazidime/avibactam + meropenem + clofaz + linezolid
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Engineered Phage Therapy
• 15 yo female with disseminated M. abscessus post lung transplant
• NTM treatment for 8 years prior to transplant
Dedrick, R. Engineered bacteriophages for treatment of a patient with a disseminated drug‐resistant Mycobacterium abscessus. Nature Medicine. 2019 May;25(5):730‐733
Whole‐body (b) and cross‐section (c) PET‐CT scans 12 weeks before and 6 weeks post phage treatmentPropert
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Relapse vs. Re‐infectionSamsung Medical Center (2002‐2012)
original strain
mixed infection
new strain
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
8%
0
42%
0%
50%
41%
%
CID 2017;64:309‐16.
Persistent culture + (33) Culture conversion (34)
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Summary
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