Treatment of Nontuberculous Mycobacterial Infections (NTM)

Treatment of Nontuberculous Mycobacterial Infections (NTM) 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)

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

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

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 of 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

Treatment of NTM Background No treatments are approved for treatment of NTM lung infections. Treatment requires multidrug regimens given for long treatment durations (>12 mos). Treatment vary by species, is of long duration, and often associated with drug-related toxicity. Treatment outcomes vary by species and are associated with high rates of recurrence and reinfection. Griffith DE, et al. Curr Opin Infect Dis. 2012;25(2):218-227.

Drugs Used for the Treatment of NTM Oral Parenteral Inhaled Macrolides (azithromycin, clarithromycin) Rifamycins (rifampin, rifabutin) Ethambutol Isoniazid Fluoroquinolones (moxifloxacin, ciprofloxacin) Cyclines (doxycycline, minocycline) Sulfonamides Oxazolidinones (linezolid, tedizolid) Clofazimine Aminoglycosides (streptomycin, amikacin) Carbapenems (imipenem, meropenem) Cefoxitin Tigecycline Aminoglycosides (amikacin)

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

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

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

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

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% <80% 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

Measure Microbiologic recurrence after sputum conversion MAC Recurrences Relapse vs reinfection University of Texas, Tyler 1 After Completion of Therapy (n=155) Northwestern 2 After Completion of Therapy (n=190) 48% 25% New infection* 75% 46% True Relapse 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)

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

M. avium complex Summary MAC pulmonary disease should be treated with a macrolide-based regimen An aminoglycoside should be considered in cavitary disease and when macrolide resistance is present The optimal duration of therapy is not know but should be at least 12 months beyond the point of culture conversion Surgery may increase bacteriologic conversion, particularly in presence of macrolide resistant

Case 68 year old woman with chronic cough and fatigue

Mycobacterium abscessus Mycobacterium abscessus was first identified in a patient with a knee infection and SQ abscesses M. abscessus is the second or third most common cause of lung disease due to NTM and the most common cause of lung disease due to a rapid grower The organism is highly resistant to antibiotics with current in vitro methods Isolated in 1950 from synovial fluid and buttock lesions in a 63 year old woman Moore M et al. J Invest Derm. 1953;20:133

Evolving Taxonomy Functional erm(41) gene 80% 0% 100%? Griffith D, et al. Ann Am Thorac Soc 2015;12:436 Cho YJ, et al. PLoS ONE 2013 8(11):e81560 Tortoli E, et al. Int J Syst Evol Microbiol 2016;epub

Yes Macrolide? 2 other drugs Amikacin M. abscessus Functional erm41 gene No Macrolide 1 other drug Amikacin 2+ mos Imipenem (IV) Cefoxitin (IV) Tigecycline (IV) Linezolid Clofazimine Moxifloxacin Bedaquiline New drug? 2+ mos Macrolide? 2 other drugs Inhaled Amikacin Treatment of M. abscessus complex M. abscessus M. bolletii Duration 12 mos culture negativity M. massiliense Macrolide 1 other drug Inhaled Amikacin

Treatment Outcomes for Pulmonary M. abscessus vs. M. massiliense Study Population Subspecies N Sputum conversion Koh, 2011 Lyu, 2014 Roux, 2015 Non Cystic Fibrosis Non Cystic Fibrosis Cystic Fibrosis M. abscessus M. massiliense M. abscessus M. massiliense M. abscessus M. massiliense 24 33 26 22 12 7 25% 88% 42% 96% 25% 86% Failure to convert 58% 3% 27% 0% - - Relapse 17% 9% 31% 5% - - Koh WJ, et al. Am J Respir Crit Care Med 2011;183:405-10

M. abscessus Summary M. abscessus has high levels of in vitro resistance to many antibiotics Treatment requires a combination of intravenous, oral, and inhaled antibiotics Presence of an erm (41) gene appears to impact treatment outcomes which are usually poor when a functional erm gene is present. Surgical resection may increase bacteriologic conversion

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