Treatment of Slowly Growing NTM Infections

Treatment of Slowly Growing NTM Infections Charles L. Daley, MD National Jewish Health University of Colorado, Denver

Disclosures Investigator Insmed (inhaled liposomal amikacin) Advisory Committee Insmed (inhaled liposomal amikacin) Johnson and Johnson (bedaquiline) Data Monitoring Committee Novartis (clofazimine)

Objectives After participating in this lecture, you should be able to: Describe an approach to deciding whom to treatment with NTM pulmonary infections Describe how to treat the most common slowly growing mycobacteria

Questions How do you decide whom to treat? How do you treat: Mycobacterium avium complex Mycobacterium kansasii Mycobacterium simiae Mycobacterium xenopi

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 M. boenickei M. mageritense M. branderi M. palustre M. bolletii M. massiliense M. celatum M. saskatchewanse M. brumae M. mucogenicum M. chimaera M. scrofulaceum M. chelonae M. peregrinum M. florentinum M. shimodei M. confluentis M. phocaicum M. heckeshornense M. simiae 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

Percentage of NTM Resistant in vitro to Drugs Species N INH RIF RIB ETH STR AMI CIP CLA CYC CLO PRO M. avium 688 100 99 14 49 100 100 95 20 5 7 4 M. intracellulare 201 99 95 6 86 99 98 99 4 15 2 9 M. kansasii 262 100 2 0 8 15 54 15 1 1 0 0 M. simiae 29 100 97 97 97 100 100 62 75 0 10 34 M. xenopi 50 94 18 0 56 0 6 0 0 2 0 0 Note: bold face indicates that the majority are susceptible DST was performed using the 25-well agar dilution method: dilutions of antimycobacterial drugs were mixed in liquefied 7H10 agar and filled out in 25-well plates. van Ingen J, et al. Intern J Antimicrob Agents 2010;35:169-173

NTM Pulmonary Infections Whom to Treat? Under diagnosis Disease progression Over diagnosis Drug toxicity

ATS Diagnostic Criteria For NTM Lung Disease Clinical Radiographs Bacteriology Cough Fatigue Weight Loss 2 positive sputum cultures ATS/IDSA AJRCCM 2007;175:367

Correlation with Cultures and Progression 14% with 1 positive sputum culture for MAC progressed over median of 16 mos 1 38% with CF/MAC with 1 positive sputum cultures progressed over median of 4.4 yrs 2 98% with 2 positive sputum cultures for MAC progressed over at least 12 mos follow-up 3 1 Koh WJ, et al. Diagn Microbiol Infect Dis 2013 2 Martiniano S, et al. Ann Am Thorac Soc 2016 3 Tsukamura M. Chest 1991;99:667

NTM Pulmonary Infections Whom to Treat? Increased susceptibility? Clinical symptoms and overall condition of patient Extent of radiograph abnormalities and whether there is evidence of progression Species that has been isolated Bacteriologic load (smear + vs. smear -) Cure, bacteriologic conversion, relief of symptoms, prevention of progression

Question #1 Which of the following infections is associated with the lowest culture conversion rate? A. Extensively drug resistant TB (XDR-TB) B. Macrolide resistant Mycobacterium avium complex C. Mycobacterium abscessus subspecies abscessus D. Mycobacterium simiae

NTM Treatment Regimens Goals NTM Drugs Duration Expected Cure M. kansasii Isoniazid (macrolide) >12 mo 95% Ethambutol Rifamycin MAC* Macrolide (azithromycin) >12 mo 56% to 85% Ethambutol Depends on extent of disease Rifamycin M. abscessus Macrolide (azithromycin) >12 mo 25-80% Cefoxitin or imipenem (IV) Depends on subspecies Amikacin (IV or inhaled) Other oral drugs? *Three times weekly for nodular bronchiectatic MAC without cavitation Note: aminoglycoside for cavitary disease ATS/IDSA AJRCCM 2007

Case 1 35 year old healthy Caucasian woman from Florida with cough for several weeks

Mycobacterium avium Complex MAC Tortoli E. Clin Micro Rev 2014;27:727-752

Mycobacterium avium Complex Acquisition Does the species matter? M. avium/m. chimaera are found in water. M. intracellulare? Pathogenicity M. intracellulare M. avium M. chimaera? Clinical Presentation M. intracellulare presents with more advanced disease Treatment outcomes M. chimaera/m. avium have higher rate of clinical recurrence Wallace RJ, et al. J Clin Micro 2013;51:1747-1752 Koh WJ, et al. Chest 2012:142:1482-1488 Boyles DP, et al. AJRRCM 2015:191:1310-1317 Moon SM, et al. Diag Micro Infect Dis 2016;86:382 Kim SY, et al. Diag Micro Infect Dis 2017, in press

Treatment of Pulmonary M. avium complex Yes Cavities Present No 3X/WEEK Azithromycin Rifampin Ethambutol Yes DAILY Azithromycin Rifampin Ethambutol MAC Macrolide sensitive Clofazimine Moxifloxacin Ciprofloxacin Bedaquiline Inh. amikacin Other drugs? Add IV Amikacin No DAILY Rifampin Ethambutol Other drug Duration :12 mos culture negativity

Treatment Outcomes for MAC Macrolide susceptible Non cavitary Cavitary Macrolide resistant No surgery/aminoglycoside Some surgery/aminoglycoside Surgery + prolonged aminoglycoside* * 6 months IV aminoglycoside Culture Conversion 80% <50% 5% 15% 80% 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 Moon SM, et al. Antimicrob Agents Chemother 2016, epub

Three-times Weekly Therapy for Pulmonary MAC Study N Conversion Regimen Modification Daily TIW Daily TIW Wallace 180 7/8 (88%) 147/172 (85%) 24/34 (80%)* 5/180 (3%)* Jeong 217 75/99 (76%) 79/118 (67%) 46/99 (46%)* 25/118 (21%)* *P < 0.001 Lower rate of culture conversion (4 vs 24%), culture improvement (20 vs 71%) and CT improvement (46 vs 77%) with cavitary disease compared with noncavitary disease (Lam) Lower rate of ethambutol toxicity with three times weekly therapy vs. with daily therapy (0 vs 6%) (Griffith) Wallace R, et al. Chest 2014;146:276-282 Jeong BH et al. AJRCCM 2015; 191:96-103 Lam PK, et al. AJRCCM 2006; 173:1283 Griffith DE, et al. AJRCCM 2005;172:250

Treatment of MAC Impact of Aminoglycoside Multicenter randomized placebocontrolled trial in Japan 146 patients with MAC Treatment regimen Rifampin 10 mg/kg Ethambutol 15 mg/kg Clarithromycin 15 mg/kg Strep 15 mg/kg tiw (Group A) or placebo (Group B) Treatment duration - at least 24 mos Sputum conversion: A (71.2%) vs B (50.7%) Sputum Microbiologic Relapse Rates Kobashi Y, et al. Respiratory Medicine 2007;101:130-8

Measure Microbiologic recurrence after sputum conversion New infection* MAC Recurrences Relapse vs reinfection University of Texas, Tyler 1 Northwestern 2 Still on Therapy (n=180) After Completion of Therapy (n=155) After Completion of Therapy (n=190) 14% 48% 25% 48% 75% 46% True Relapse 52% 25% 54% * Determined by pulse field electrophoresis 1. Wallace R, et al. Chest 2014;146:276-282 2. Boyle DP, et al. Ann Am Thorac Soc 2016 (epub)

Question #2 A 75 year old woman is on a three-drug regimen administered three times weekly for non-cavitary pulmonary M. intracellulare infection. Despite 12 months of therapy her sputum cultures remain positive. What would be the most appropriate next step? A. Add once daily intravenous amikacin (15mg/kg) B. Add oral clofazimine (100 mg daily) C. Switch from intermittent to daily therapy D. Add moxifloxacin (400 mg daily)

Strengthen the Treatment Regimen Regimen Intermittent to Daily Dosing 30% culture conversion Repurposed Drugs (moxifloxacin, amikacin, clofazimine) 30% culture conversion New Drugs (bedaquiline, delamanid)

Case 2 45 year old Caucasian woman with chronic cough Chest x-ray - abnormal Three sputum specimens obtained She was started on a 4-drug TB treatment regimen Sputum cultures grew M. kansasii

Mycobacterium kansasii First described by Buhler and Pollack as the yellow bacilli in 1953 and later named in 1955 by Hauduroy. Most cases are associated with progressive disease

Treatment Regimen M. kansasii Yes Cavities Present No 3X/WEEK Isoniazid (or macrolide) Rifampin Ethambutol Yes DAILY Isoniazid (or macrolide) Rifampin Ethambutol MK Rifampin sensitive Azithromycin Clarithromycin Moxifloxacin Clofazimine Add IV Amikacin No DAILY Isoniazid Ethambutol Other drug Duration :12 mos culture negativity

Mycobacterium kansasii Outcomes of Treatment Study N Regimen Duration mos Ahn, 1983 BTS, 1994 Sauret, 1995 Evans, 1996 Santin, 2009 Park, 2010 40 H/R/E SM biw for 3 mo Conversion Cure* Failure Relapse 12 Median 5.5 weeks ND 0 2.5% 173 R/E 9 89% by 3 mo 89% 1 9.7% 14 14 H/R/E H/R/E 12 18 47 H/R/E±Z Mean- 10.3 75 H/R/E SM for 2-3 mo 100%, mean- 4.5±2.0 31 H/R/E Median-16 Median 1 mo 95% by 12 mo 93% 100% 0 3.5% 0 ND 79% ND 0 12 ND 83% 0 6.6% 52% 0 6% *Cure was nearly 100% when non-mycobacterial deaths and lost to follow-up patients are excluded

Outcomes With Clarithromycinbased Regimen Study N Regimen Mean Duration, months* Griffith D, 2003 Shitrit D, 2006 18 Clarithromycin Ethambutol Rifampin, given tiw 56 Clarithromycin Ethambutol Rifampin, given daily *At least 12 months of culture negativity **Among completers, 100% cure rate ***Mean duration of follow-up was 46±8.0 mos Mean Culture Conversion, months Cure n (%) ** 13.3±0.8 1.0 ± 0.9 14** (78) 21.0±7.2 8.9 ± 10.3 56 (100) Failure n (%) Relapse n (%) 0 0*** 0 ND Griffith D, et al. CID 2003;37:1178-82 Shitrit D, et al. Chest 2006;129:771-76

Mycobacterium kansasii Summary M. kansasii pulmonary disease responds well to therapy with INH, rifampin, and ethambutol A macrolide can be substituted for INH and for rifampin when resistance is detected Duration of therapy should follow ATS/IDSA recommendations although shorter durations should be achievable Surgery is seldom necessary

Question #3 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: A. Initiate azithromycin, ethambutol, rifampin B. Initiate moxifloxacin, clofazimine and trimethoprimsulfamethoxazole C. Follow without treatment 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 she was treated with azithromycin, rifampicin, and ethambutol After two months of therapy, all cultures positive for M. simiae Still culture positive after 6 months so 8 weeks of IV amikacin given Despite 18 months of therapy all cultures remained positive for M. simiae!

Mycobacterium simiae Macacus rhesus In 1965, Karassova reported the isolation of M. simiae from rhesus monkeys (Karassova v, et al, Acta Microbiol Acad Sci Hung 1965;12:275-282) Common isolate from Cuba, Israel, and Southwestern US Only 6/28 (21%) of patients in the Netherlands met ATS criteria for disease (van 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 van Ingen, et al. Antimicrob Agents Chemo 2012:56:6324-7 Murine model combination of rifampin, clofazimine, and amikacin demonstrated activity against two strains Watson SR, et al. Immunology 1981;43:459-465 Murine model (disseminated) 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, 1998 Van Ingen J, 2008 Qvist T, 2013 Shitrit D, 2008 Baghaei P, 2012 Israel 3 Clarithromycin Ciprofloxacin Ethambutol Netherlands 3 Macrolide Ethambutol Other Denmark 1 Clarithromycin Moxifloxacin Trim-Sulfa Israel 102 Clarithromycin Ethambutol Rifampin Iran 26 Clarithromycin Ofloxacin Trim-Sulfa Successful in AIDS patients with disseminated M. simiae after 24 months f/u. Also started on ART One improved, One relapsed One died Negative cultures at one year in bilateral lung transplant recipient No failures/relapses during median of 24 mos f/u 24 (92%) cured No recurrences over 2 yrs f/u

Treatment of M. simiae A combination of three or four of the drugs below: Azithromycin (or clarithromycin) Moxifloxacin Trimethoprim-sulfamethoxazole Rifampin Ethambutol Clofazimine IV amikacin (? Inhaled)? bedaquiline

Mycobacterium simiae Summary M. simiae has high levels of in vitro drug resistance but synergy between clofazimine and amikacin in vitro In most patients, isolation of M. simiae is not associated with disease it is important to make sure the patient actually has progressive disease Treatment outcomes have varied but are typically poor consider a MAC regimen supplemented with a fluoroquinolone, clofazimine/amikacin, bedaquiline

Case 4 35 year old physician who developed cough, fever and progressive dyspnea Sputum specimens grew M. xenopi and Aspergillus fumigatus She was treated with azithromycin, moxifloxacin, rifampin, and amikacin 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 South African toad, Xenopus laevis M. xenopi grows optimally at 45 C (113 F) 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) 136 patients Cavitary 39 (31%) Solitary nodule 41 (33%) Infiltrative 45 (36%) 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: Overall, 80% treatment success at end of therapy with 15% relapse leaving 65% sustained disease-free outcome INH containing- and aminoglycoside-containing regimens: worse short and long-term success Fluoroquinolone containing regimens: better longterm success Varadi RG, Marras TK. Int J Tuberc Lung Dis 2009;13:1210

Treatment Outcome for M. xenopi Pulmonary Infections 80 (59%) patients were treated Rifamycin, ethambutol, INH, clarithromycin, fluoroquinolones After 36 mos, 69% had died Acute infiltrative form associated with poor prognosis (p=0.001) Rifamycin-containing regimens were associated with better prognosis (p=0.006) Andrejak C, et al. Thorax 2009;64:291-296

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 CLR/EMB/RIF 5.75 6.57 5.68 4.69 CLR/EMB/RIF/AMK 5.86 5.22 4.83 4.58 MXF/EMB/RIF 6.42 6.19 5.97 5.57 MXF/EMB/RIF/AMK 5.67 5.25 4.49 4.23 MXF/CLR 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

Mycobacterium xenopi Summary M. xenopi pulmonary disease usually occurs in patients with underlying pulmonary disease All cause mortality is very high Treatment should include at least a MAC regimen with either addition of or substitution of a fluoroquinolone Amikacin should be considered in cavitary and acute infiltrative forms

Question #4 If you had to have an NTM infection, which of the following would you want? A. M. avium intracellulare B. M. kansasii C. M. simiae D. M. xenopi E. None of the above

What about all the rest 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 M. boenickei M. mageritense M. branderi M. palustre M. bolletii M. massiliense M. celatum M. saskatchewanse M. brumae M. mucogenicum M. chimaera M. scrofulaceum M. chelonae M. peregrinum M. florentinum M. shimodei M. confluentis M. phocaicum M. heckeshornense M. simiae 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