Treatment of Slow Growing NTM

Presenter of Reproduction for Property Not Charles L. Daley, MD National Jewish Health University of Colorado, Denver Disclosures

• Research Grant – Insmed – Spero Presenter • Advisory Board: of – Insmed Reproduction – Johnson and Johnson for – Spero PharmaceuticalsProperty – Horizon PharmaceuticalsNot – Paratek – Meiji Objectives

• After participating in this lecture, you should be able to: – Describe an approach to deciding whom to Presenter treatment with NTM ofpulmonary infections – Describe how to treat Reproductionthe most common slow growing mycobacteriafor Property Not NTM That Have Been Reported to Cause Lung Disease

Slowly Growing Mycobacteria Rapidly Growing Mycobacteria* M. arupense M. kubicae M. abscessus M. holsaticum M asiaticum M. lentiflavum M. alvei M. fortuitum M. avium M. malmoense PresenterM. boenickei M. mageritense M. branderi M. palustre of M. bolletii M. massiliense M. celatum M. saskatchewanse M. brumae M. mucogenicum Reproduction M. chimaera M. scrofulaceum M. chelonae M. peregrinum for M. florentinum M.Property shimodei M. confluentis M. phocaicum M. heckeshornense M. simiaeNot M. elephantis M. septicum M. intermedium M. szulgai M. goodii M. thermoresistible M. interjectum M. terrae M. intracellulare M. triplex M. kansasii M. xenopi * Growth in subculture within 7 days NTM That Have Been Reported to Cause Lung Disease

Clinical Radiographs Bacteriology

Presenter of Reproduction Cough for ≥ 2 positive Property sputum cultures Fatigue Not Weight Loss

ATS/IDSA AJRCCM 2007;175:367 Progression of NTM Pulmonary Disease in Those Who Meet ATS/IDSA Diagnostic Criteria

488 with MAC-PD 551 with MAC-PD 1001 with NTM-PD (per ATS) (per ATS) (per ATS) Presenter 41.4% 45.0% 62.5% 23.6% 58.6% of 55.0% No No Progressed Stable Treated Treated Reproductiontreatment treatment for Spontaneously 51.6% Property 52.2% 35.0% culture converted Not

Hwang JA, et al. Byoung, et al. Moon SM, et al. Eur Respir J 2017;49:1600537 Resp Med 2019;150:45-50 Resp Med 2019;151:1-7. WHO to Treat? Risk Factors Associated with Progression

Host/Demographic Laboratory Radiographic Microbial Factors Factors Factors Factors • Male gender • Elevated Presenter• Fibrocavitary • Bacterial load • Older age inflammatory of • Extent of • Species • Presence of co- indices (ESR, CRP) disease morbidities • Anemia Reproduction • Low body mass • Hypoalbuminemiafor index Property Not

Hwang JA, et al. Eur Respir J 2017;49:1600537 Byoung, et al. Resp Med 2019;150:45-50 Moon SM, et al. Resp Med 2019;151:1-7. Question #1

Which of the following infections is associated with the lowest culture conversion rate?

A. Extensively drug resistantPresenter TB (XDR -TB) B. Macrolide resistant Mycobacteriumof avium complex Reproduction for C. MycobacteriumProperty abscessus subspecies abscessus Not D. Mycobacterium simiae Treatment of MAC

• 65 year old Caucasian woman treated for Mycobacterium avium complex on two previous occasions with macrolide, Presenter rifampin, and ethambutol of

• Now with AFB smear Reproduction positive sputum specimen for and culture positive forProperty M. intracellulare Not Mycobacterium avium Complex 12 Species

Presenter MAC of M. paraintracellulare Reproduction M. lepraemurium for Property Not

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 Tortoli E. Clin Micro Rev 2014;27:727-752 Distribution and Clinical Significance of MAC Species, S. Korea

Mycobacterium • Phenotypic intracellulare (n=91) identification

82% M. intracellularePresenter of 9% M. chimaera • Multilocus 4% M. “indicusReproduction pranii” sequencing 4% M. yongonense for Property M. intracellulare 72% Not M. chimaera 38% • Met ATS M. “indicus pranii” 75% criteria M. yongonese 50%

Kim SY et al. Diag Micro Infect Dis 2017;88:125 Treatment of Pulmonary M. avium complex MAC Duration :

Macrolide Yes sensitive No Presenter mos 12 Cavities Present of Clofazimine DAILY culture negativity culture MoxifloxacinReproduction Rifampin No Yes forCiprofloxacin Ethambutol Property Bedaquiline Other drug 3X/WEEK DAILY Not Inh. amikacin Azithromycin Azithromycin Other drugs? Rifampin Rifampin Ethambutol Ethambutol

Add IV Amikacin Treatment Outcomes of M. avium complex Systematic Review and Meta-analysis

• 42 studies (2,748 patients) – 18 retrospective, 18 prospective, 6 randomized

• Treatment success - sputumPresenter culture conversions after subtractingof posttreatment microbiologic recurrenceReproduction for • Treatment successProperty Not – Overall for macrolide containing regimen – 52.8% – 3-drug ATS regimen – 61.4% – Above taken for at least a year – 65.7% Diel R, et al. Chest 2018;153:888-921 Treatment Outcomes for MAC Macrolide Resistant

Culture Conversion Macrolide resistant No surgery/aminoglycoside Presenter 5% Some surgery/aminoglycosideof 15% Surgery + prolonged Reproduction80% aminoglycoside* for * ≥ 6 months IV aminoglycosideProperty Not

Griffith DE, et al. AJRCCM 2006;174:928 Wallace R, et al. Chest 2014;146:276-282 Jeong BH, et al. AJRCCM 2015;191:96-103 Koh WJ, et al. Eur Respir J 2017;50 Moon SM, et al. Antimicrob Agents Chemother; 2016 Morimoto K, et al. Ann ATS 2016;11:1904 MAC Recurrences After Completion of Therapy: Relapse vs reinfection

University of Texas, Northwestern, Samsung, Tyler 1 Chicago, IL 2 Seoul, Korea3 Number of 155 190 402 patients Presenter of Microbiologic 48% 25% 29% recurrence Reproduction New infection 75%* 46%* 74%** for *Determined by pulse field electrophoresisProperty **Determined by rep-PCR Not

1. Wallace R, et al. Chest 2014;146:276-282 2. Boyle DP, et al. Ann Am Thorac Soc 2016 3. Koh WJ, et al. ERJ 2017;50 epub Treatment Failures Strengthen the Treatment Regimen

Intermittent to Daily Dosing ∼ Presenter 30% conversion of Repurposed Drugs (moxifloxacin, Reproductionamikacin, clofazimine)

Regimen for Property Not New Drugs (bedaquiline, delamanid) CONVERT STUDY

Phase 3 Randomized, Controlled Trial of Liposomal Amikacin Inhalation Suspension (ALIS) + GBT vs GBT alone in treatment refractory MAC lung disease

Presenter of Reproduction for Property Not

Griffith D, et al. AJRCCM 2018 epub Phase 3 – Randomized Controlled Trial of ALIS + GBT vs GBT alone in Treatment Refractory MAC

Proportion of Patients With Negative Sputum Cultures for NTM

Presenter of Reproduction for Property Microbiologic response up Not to MIC ≤64

Griffith D, et al. AJRCCM, 2018. CONVERT STUDY Treatment Emergent Adverse Events (TEAE)

Adverse Event GBT + ALIS GBT Respiratory-related AEs Dysphonia 45.7% 0.9% Cough 37.2% 15.2% Dyspnea 21.5%Presenter 8.9%) Hemoptysis of 17.5% 13.4% Oropharyngeal pain Reproduction10.8% 1.8% Audiological AEs for Tinnitus Property 7.6% 0.9% Dizziness Not 6.3% 2.7% Hearing loss 4.5% 6.3% Serious adverse events 20.2% 17.9% Discontinuation of ALIS 17.5% –

Griffith D, et al. AJRCCM, 2018. Mixed Infection with Different MAC Species

62 y/o woman with fatigue and chronic cough Presenter of

Treatment: azi/rif/embReproduction Cultures for Property Not Mycobacterium avium complex Summary • MAC pulmonary disease responds well to therapy with azithromycin, rifampin, and ethambutol • Culture conversion as high as 80% in macrolide susceptible disease but as lowPresenter as 5% in macrolide resistant disease of • Amikacin liposome inhaled suspension is indicated for Reproduction treatment refractory disease for • Duration of therapyProperty – treatment should continue for at least 12 months beyondNot culture conversion • Recurrence occurs in 25-50% of patients with reinfection in 50-75% Case 2

 45 year old Caucasian woman with chronic cough  Chest x-ray - abnormal Presenter  Three sputum specimens of obtained Reproduction  She was started on a 4-drug for TB treatment regimenProperty Not  Sputum cultures grew M. kansasii Mycobacterium kansasii

• First described by Buhler and Pollack as the Presenter“yellow bacilli” in 1953 of and later named in 1955 Reproductionby Hauduroy. for Property • Most cases are Not associated with progressive disease Treatment Regimen M. kansasii

M. kansasii Duration : Rifampin Yes sensitive No Presenter 12 mos 12 Cavities Present of Moxifloxacin DAILY

Reproduction Isoniazid negativity culture No Yes Clofazimine for Trim/Sulfa Ethambutol Property Macrolide 3X/WEEK DAILY Not Other drug? Macrolide Isoniazid Rifampin (or macrolide) Ethambutol Rifampin Ethambutol Mycobacterium kansasii Outcomes of Treatment

Study N Regimen Duration Conversion Cure* Failure Relapse mos Ahn, 40 H/R/E 12 Median – 5.5 ND 0 2.5% 1983 SM biw for 3 mo weeks Presenter Santin, 75 H/R/E 12 ND 83% 0 6.6% 2009 SM for 2-3 mo of Sauret, 14 H/R/E 12 100%, mean- 93% 0 3.5% 1995 14 H/R/E 18 Reproduction4.5±2.0 100% 0 Evans, 47 H/R/E±Z Mean-for ND 79% ND 0 1996 Property10.3 BTS, 173 R/E Not9 89% by 3 mo 89% 1 9.7% 1994 *Cure was nearly 100% when non-mycobacterial deaths and lost to follow-up patients are excluded Outcomes With Clarithromycin- based Regimen

Study N Regimen Mean Mean Cure Failure Relapse Duration, Culture n (%) n (%) n (%) months* Conversion, ** months Griffith D, 18 Clarithromycin 13.3±0.8 1.0 ± 0.9 14** 0 0*** 2003 Ethambutol Presenter (78) Rifampin, of given tiw Shitrit D, 56 Clarithromycin 21.0±7.2Reproduction8.9 ± 10.3 56 0 ND 2006 Ethambutol (100) Rifampin, for given daily Property Not *At least 12 months of culture negativity **Among completers, 100% cure rate ***Mean duration of follow-up was 46±8.0 mos

Griffith D, et al. CID 2003;37:1178-82 Shitrit D, et al. Chest 2006;129:771-76 Mycobacterium kansasii Summary • iM. kansasi pulmonary disease responds well to therapy with INH, rifampin, and ethambutol • A macrolide can be substituted for INH Presenter • Duration of therapy – oftreatment should continue for at least 12 months Reproduction • Surgery is seldom necessaryfor Property Not Question #2

A 65 year old woman with chronic cough and nodular bronchiectasis has two sputum specimens which grow Mycobacterium simiae. What would be the most appropriate next step: Presenter A. Initiate azithromycin, ethambutol,of rifampin B. Initiate moxifloxacin, clofazimineReproductionand trimethoprim- sulfamethoxazole for Property C. Follow without treatmentNot for evidence of progressive disease D. Discharge the patient as M. simiae is a water contaminant. Case 3

• 66 year old woman from Alaska • Presented with myalgias, night sweats, fatigue, jaw pain and cough • Sputum cultures grew MAC so shePresenter was treated with azithromycin,of rifampicin, and ethambutol • After two months of therapy, allReproduction cultures positive for M. simiaefor • Still culture positiveProperty after 6 months so 8 weeks of IV amikacinNotgiven • Despite 18 months of therapy all cultures remained positive for M. simiae! Mycobacterium simiae

• In 1965, Karassova reported the isolation of M. simiae Presenterfrom rhesus monkeys1 of• Common isolate from Cuba, ReproductionIsrael, and Southwestern US for• Only 6/28 (21%) of patients in Property the Netherlands met ATS Not criteria for disease2 Macacus rhesus

1Karassova v, et al, Acta Microbiol Acad Sci Hung 1965;12:275-282 2van Ingen J, et al. Eur Respir J, 2008;31:106-109 In vitro and In vivo Drug Activity Against M. simiae

• High levels of in vitro resistance – no synergy between rifampin and ethambutol but synergy between clofazimine and amikacin Presenter van Ingen, et al. Antimicrob Agentsof Chemo 2012:56:6324-7 • Murine model – combination of rifampin, clofazimine, and amikacin demonstratedReproduction activity against two strains Watson SR, et al. Immunologyfor 1981;43:459 -465 Property • Murine model (disseminated)Not – ofloxacin and clarithromycin and ethambutol were more effective than clarithromycin alone Valero G, et al. Antimicrob Agents Chemo 1994:38:2676-2677 Treatment Outcomes for M. simiae

Study N Regimen Outcomes Barzilai A, Israel 3 Clarithromycin Successful in AIDS patients with 1998 Ciprofloxacin disseminated M. simiae after 24 Ethambutol months f/u. Also started on ART Van Ingen J, Netherlands 3 MacrolidePresenterOne improved, One relapsed 2008 Ethambutolof One died Other Qvist T, Denmark 1 ClarithromycinReproductionNegative cultures at one year in 2013 Moxifloxacinfor bilateral lung transplant recipient PropertyTrim- Sulfa Shitrit D, Israel 102NotClarithromycin No failures/relapses during median 2008 Ethambutol of 24 mos f/u Rifampin Baghaei P, Iran 26 Clarithromycin 24 (92%) “cured” 2012 Ofloxacin No recurrences over 2 yrs f/u Trim-Sulfa Treatment of Pulmonary M. simiae Use DST to M. simiae guide therapy Duration :

Cavitation Yes PresentPresenter No 12 mos 12 of DAILY Macrolide* Daily Reproduction negativity culture 3-4 drugs + Clofazimine* for 3-4 drugs Amikacin (IV) PropertyMoxifloxacin* for 2-3 mos NotBedaquiline * Trim/Sulfa Linezolid

* QTc prolongation Mycobacterium simiae Summary

• M. simiae has high levels of in vitro drug resistance but synergy between clofazimine and amikacin • In most patients, isolation ofPresenter M. simiae is not associated with disease – it is importantof to make sure the patient actually has progressive disease Reproduction • Treatment outcomes have varied but are often poor – for consider a 3+ drugProperty regimen (macrolide plus moxifloxacin, clofazimine/amikacin,Not trim/sulfa, bedaquiline, linezolid) • Duration of therapy – treatment should continue for at least 12 months beyond culture conversion Case 4

• 35 year old physician who developed cough, fever and progressive dyspnea • Sputum specimens grew M. Presenter xenopi and Aspergillus of fumigatus • She was treated with Reproduction azithromycin, moxifloxacin, for rifampin, and amikacinProperty Not • Her fungal infection was treated with posaconazole • She eventually underwent left upper lobe resection Mycobacterium xenopi

• Identified in 1959 from lesions on the skin of a PresenterSouth African toad, of Xenopus laevis •ReproductionM. xenopi grows optimally for ° ° Property at 45 C (113 F) Not • 25/40 (51%) of patients met ATS criteria in the Netherlands (van Igen J. Emerg Infect Dis 2008;14:385) M. xenopi Pulmonary Infections in North-East France

• 13 hospitals in NE France (1983-2003) Presenter • 136 patients of – Cavitary – 39 (31%) Reproduction – Solitary nodule – 41 (for33%) Property – Infiltrative – 45 (36%)Not

Andrejak C, et al. Thorax 2009;64:291-296 Treatment Outcome for M. xenopi Pulmonary Infections

• 80 (59%) patients were treated • Rifamycin , ethambutol, INH, clarithromycin, fluoroquinolones Presenter • After 36 mos, 69% had diedof – Acute infiltrative form associated with poor prognosis (p=0.001)Reproduction – Rifamycin-containing regimensfor Property were associated with better prognosis (p=0.006) Not

Andrejak C, et al. Thorax 2009;64:291-296 Pulmonary Mycobacterium xenopi Infection – A systematic review

• 48 studies including 1255 subjects were reviewed • Marked heterogeneity among studies • Findings: Presenter of – Overall, 80% treatment success at end of therapy with 15% relapse leaving 65%Reproduction sustained disease-free for outcome Property – INH containing- andNot aminoglycoside-containing regimens: worse short and long-term success – Fluoroquinolone containing regimens: better long- term success Varadi RG, Marras TK. Int J Tuberc Lung Dis 2009;13:1210 Activity of Different Combinations in Murine Model of M. xenopi

Timepoint Relative to the Start of Treatment Group Week 2 Week 4 Week 8 Week 12 Untreated 6.95 6.93 7.76 7.79 Presenter CLR/EMB/RIF 5.75 of 6.57 5.68 4.69 CLR/EMB/RIF/AMK 5.86 5.22 4.83 4.58 Reproduction MXF/EMB/RIF 6.42 6.19 5.97 5.57 for MXF/EMB/RIF/AMK 5.67Property 5.25 4.49 4.23 MXF/CLR Not 6.07 5.23 CLR-clarithromycin, EMB-ethambutol, RIF-rifampicin, AMK-amikacin, MXF-moxifloxacin

Andrejak C, et al. J Antimicrob Chemother 2013;68:659-665 Randomized, Controlled Trial of Moxi vs Clari in M. xenopi • Randomized, controlled trial in France – Clarithromycin, ethambutol, rifampin vs. – Moxifloxacin, ethambutol, rifampin Presenter • Enrolled 56 patients (2/3of of planned) • Results (24 patients withReproduction 6-month conversion for data available):Property Not – 89% culture conversion at 6 months – No difference between regimens

Andrejak C et al. AJRCCM 2016;193:A3733 Treatment of Pulmonary M. xenopi M. xenopi Duration :

Macrolide Yes sensitive No Presenter mos 12 Cavities Present of Clofazimine DAILY culture negativity culture InhReproduction. amikacin Moxifloxacin No Yes forOther drugs? Rifampin Property Ethambutol Daily DAILY Not Other drug? Azithromycin Azithromycin Rifampin Rifampin Ethambutol Ethambutol Moxifloxacin? Add IV Amikacin Mycobacterium xenopi Summary • M. xenopi usually occurs in patients with underlying pulmonary disease • Treatment should include at least a MAC regimen with addition of moxifloxacin for cavitary/extensivePresenter disease • Amikacin should be consideredof in cavitary and acute infiltrative forms Reproduction • Surgical resection should be considered in focal cavitary for disease Property • Duration of therapy Not– treatment should continue for at least 12 months beyond culture conversion • All cause mortality is very high What about all the rest…

Presenter of Reproduction for Property Not

Tortoli E, et al. Inf Gen Evol 2017;56:19 http://www.bacterio.net/mycobacterium.html