How Do I Manage Nontuberculous Mycobacterial (NTM) Lung Disease Patients?

How Do I Manage Nontuberculous Mycobacterial (NTM) Lung Disease Patients? David E. Griffith, M.D. Professor of Medicine University of Texas Health Science Center, Tyler

Potential COI Statement I was a co investigator on a recent multicenter trial of inhaled liposomal amikacin (Arykace) sponsored by Insmed I am a co investigator on a new multi center trial of inhaled liposomal amikacin (Arykace) sponsored by Insmed

Specific Aims 1: Understand the differences between innate and acquired drug resistance mechanisms for NTM 2: Understand the limitations of in vitro drug susceptibility testing for many NTM 3: Become familiar with and understand the rationale for the drug treatment options for nodular/bronchiectatic and cavitary Mycobacterium avium complex (MAC) lung disease 4: Become familiar with treatment options for other slowly growing mycobacteria including M. kansasii, M. xenopi, M. malmoense and M. simiae 5: Become familiar with the limited treatment options for Mycobacterium abscessus 6: Understand the role of adjunctive measures such as surgery and treatment of bronchiectasis

Spectrum of disease caused by NTM Lung disease Nodules/bronchiectasis Cavities Hypersensitivity pneumonitis Lymphadenitis Post traumatic skin and soft tissue infection Disseminated disease associated with severe cell mediated immune dysfunction Disseminated disease associated with abnormal pathways of cytokine production or function

NTM Drug Resistance Innate or natural drug resistance Not readily or predictably associated with in vitro measures of resistance such as MICs Inducible macrolide resistance (erm) gene Acquired drug resistance Selection of isolates with naturally occuring mutations that confer resistance to specific antibiotics The form of drug resistance most associated with TB therapy

NTM Drug Resistance Mechanisms: Beyond MICs Brown Elliott et al. Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with NTM. Clin Microbiol Rev 2012, 25; 545 van Ingen J et al. Resistance mechanisms and drug susceptibility testing of NTM. Drug Resistance Updates 2012

Treatment of NTM Correlation between treatment response and in vitro susceptibilities M. kansasii (rmp) M. marinum M. szulgai M. fortuitum (erm gene) Limited or no correlation between treatment response and in vitro susceptibility MAC M. xenopi M. malmoense M. simiae M. abscessus M. chelonae

Resistant Nontuberculous Mycobacteria Mutational Resistance M. tuberculosis: multiple gene mutations M. avium complex: a) 23S rrna gene (macrolides); b) 16S rrna gene (amikacin) M. kansasii: rpo β gene (rifamycins) M. abscessus: 23S rrna gene (macrolides)

Macrolides for MAC Disease Treatment success correlates with in vitro MIC (susceptible 8 µg/ml, resistant 32 µg/ml Disease progression/relapse associated with MIC 32 µg/ml Mechanism of macrolide resistance: selection of isolates with mutation inhibiting macrolide ribosomal binding In vitro susceptibility tests for most drugs do not predict who will respond and who will fail therapy.

In vitro Activity of Amikacin Against MAC (Brown Elliott et al, 2013 JCM) Prolonged exposure to amikacin was present in isolates with amikacin MICs > 64 µg/ml which correlated with 16S rrna gene mutation at position 1408 Amikacin is the only drug, other than clari/azi, for which there is a correlation between in vitro MIC for MAC and in vivo response Because this is mutational resistance, adequate companion drugs for amikacin are necessary

Resistant Nontuberculous Mycobacteria Innate Resistance in Inevitable Mutational Resistance is AVOIDABLE

Therapy of MAC Lung Disease 2007 ATS NTM Guidelines Nodular/bronchiectatic disease: macrolide/emb/rifamycin: INTERMITTENT* Cavitary disease: macrolide/emb/rifamycin ± injectable: DAILY Severe or previously treated disease: macrolide/emb/rifamycin/injectable: DAILY Duration: 12 months sputum culture negativity while on therapy Surgery for selected patients *Not indicated for severe and/or cavitary disease

Macrolide/Azalide Therapy for Nodular/Bronchiectatic Mycobacterium avium Complex Lung Disease (Wallace et al Chest 2014) 180 patients with NB MAC lung disease with 12 months macrolide/azalide based therapy 150/180 (86%) sputum conversion No difference between azi and clari Regimen modification common with daily RX Microbiologic recurrence 14% (73% new genotyope) Treatment success 83% Microbiologic recurrence 74/155 (48%) 75% new genotypes Intermittent antibiotic therapy for nodular bronchiectatic MAC lung disease Jeong et al AJRCCM 2014 e pub

Intermittent Antibiotic Therapy for Nodular Bronchiectatic MAC Lung Disease Jeong et al, AJRCCM 2015 217 pats with NB MAC lung disease 99 daily, 118 intermittent macrolide based therapy No significant differences in symptomatic, radiographic and microbiologic conversion (76 vs 67%) Modification of the initial regimen more common with daily therapy (46 vs 21%)

67 yo, sputum 4+ AFB culture pos for MAC, 17 mos TIW clari/emb/rmp, > 12 mos sputum AFB culture neg

78 yo female, sputum AFB cult + for MAC 16 mos TIW azi/emb/rmp > 12 mos sputum AFB neg

Macrolide/Azalide Therapy for Nodular/Bronchiectatic MAC Lung Disease Current guidelines for macrolide/azalide based regimens for NB MAC lung disease result in favorable microbiologic outcomes for most patients These regimens do not promote macrolide resistance Intermittent regimens as effective as daily regimens with fewer side effects, therefore TIW therapy preferred Microbiologic recurrences common, most due to unique MAC genotypes ( reinfection )

Cavitary MAC (NTM) Lung Disease Pathophysiologically a smoking related disease Smoking likely inhibits favorable treatment response Likely associated with long term respiratory impairment Associated with high all cause mortality, greater than NB MAC lung disease Requires aggressive and appropriate therapy Parenteral agents Surgery Smoking cessation Avoidance of macrolide resistance (fatal disease)

56 yo female, sputum 4+ AFB pos for MAC 19 mos daily azi/emb/rmp + 6 mos TIW amk > 12 mos sputum culture negative

30 yo female, sputum 4+ AFB culture pos for MAC 6 mos TIW azi/emb/rmp Sputum AFB culture neg, still on therapy

MAC Lung Disease Therapy: What Could Possibly Go Wrong? Patient adherence with treatment regimen Patient intolerance to treatment regimen Host factors inhibiting treatment response (bronchiectasis) Microbiologic recurrences (relapse vs reinfection) Wimpy anti MAC drugs Patient prescribed suboptimal treatment regimen Macrolide resistance

MAC therapy Pharmacokinetic and pharmacodynamic indicies frequently suboptimal with standard MAC therapy but no correlation with treatment outcome No demonstrated correlation between circulating MAC drug levels and treatment outcome No correlation between MICs for rim/emb/stm and response to medications

Lack of Adherence to Evidence based Treatment Guidelines for NTM Lung Disease (Adjemian et al, Annals ATS 2014) 18% of MAC patients were treated for the greatest duration with a regimen meeting 2007 ATS/IDSA guidelines Only 4% were treated with this regimen for > 22 weeks Majority of MAC patients (58%) were on a regimen without a macrolide 22% of patient received regimens that were potentially harmful Macolide monotherapy 22% Rifampin only 15% Macrolide plus fluoroquinolone 1%

Development of Macrolide Resistant MAC (Griffith et al 2006 Am J Resp Crit Care Med) Risk factors: Macrolide monotherapy, Macrolide plus quinolone Sputum conversion after macrolide resistance: 77% in patients with both injectable Rx and surgery; 5% in patients without both injectable RX and surgery. Patients who failed therapy, 1 year mortality 34%, 2 year mortality was 45%, Patients with sputum conversion to ( ), the 1 and 2 year mortality was 0%

Macrolide Resistant MAC Lung Disease: Response to Therapy Sputum conversion after macrolide resistance:11/14 (77%) p=0.0001 with both injectable and surgery. Sputum conversion after macrolide resistance 2/37 (5%) in patients without both injectable and surgery. Of the patients who failed therapy, the one year mortality was 13/38 (34%), two year mortality was 17/38 (45%) Of the patients whose sputum converted to negative, the one and two year mortality was 0/13, (0%)

64 yo female with macrolide resistant MAC Multiple courses of antibiotics Chronic respiratory failure

58 yo female with macrolide resistant MAC Multiple courses of antibiotics Chronic respiratory failure

Macrolide Monotherapy and Immune Modulation Panbronchiolitis Asthma Bronchiolitis Obliterans CF related bronchiectasis Non CF related bronchiectasis Chronic Obstructive Lung Disease

Therapy of Macrolide Resistant MAC Rifabutin Ethambutol Surgery Parenteral streptomycin or amikacin Inhaled amikacin with caution Clofazimine Moxifloxacin Linezolid Macrolide as immune modulating therapy

Inhaled amikacin for treatment of refractory pulmonary NTM disease Olivier et al, AATS 2014, 11; 30 20 patients: 15 M. abscessus, 5 MAC 80% female Median 60 months antimycobacterial therapy 5 with persistently negative cultures Decrease in culture growth 10/19 (53%) Symptom scores improved in 9/20 (45%) CT scores improved or unchanged 9/20 (45%) 7/20 (35%) stopped amikacin Ototoxicity (2), hemoptysis (2), nephrotoxicity, dysphonia, vertigo

Proportion of Patients With NTM Negative Cultures in the Double blind Phase Inhaled Lipsomal Amikackin vs Placebo P=0.05 P=0.03 P=0.01 LAI, liposomal amikacin for inhalation; mitt, modified intent to treat; NTM, nontuberculous mycobacteria; PBO, placebo; SOC, standard of care.

Why doesn t MAC go away?

62 yo female with macrolide susceptible MAC, one CFTR mutation, persistently + sputum after RML lobectomy and prolonged drug therapy

58 yo female with 4+ AFB pos culture for MAC > 18 mos TIW azi/rmp/emb Symptomatically improved, sputum AFB culture pos for MAC

Treatment of MAC Lung Disease Do s Risk/benefit assessment for N/B MAC patients Treat cavitary MAC patients aggressively (surgery, parenteral medications) Adhere to guidelines as much as possible Frequent clinical and microbiologic assessments Lifetime care for patients Don ts (?Don t s) Tell patients that MAC therapy will kill them Give macrolide or amikacin without adequate companion drugs Idiosyncratic treatment regimens Abandon clinical and microbiologic assessments early in treatment

Treatment of other slowly growing NTM M. kansasii Rmp/emb, + macrolide or FQ M. xenopi Rmp/emb,, macrolide, amikacin M. malmoense INH/rmp,emb, +/ macrolide/fq M. szulgai Rmp/emb, + macrolide or FQ M. simiae Macrolide/Bactrim, moxifloxacin +/ linezolid, amikacin,?

78 year old man with sputum 4+ pos for M. xenopi 19 mos daily azi/emb/rmp > 12 mos sputum AFB culture negative

28 yo female, sputum 4+ AFB culture + for M. kansasii 13 mos TIW azi/rmp/emb >12 mos sputum AFB culture neg

33 yo male sputum 4+ AFB culture pos for M. szulgai 15 mos daily azi/emb/rmp + 6 mos TIW amk > 12 mos sputum culture neg

Taxonomy: M. abscessus, M. massiliense, M. bolettii M. abscessus described > 20 yrs ago M. fortuium/chelonae complex, M. chelonae complex M. bolettii and M. massiliense genetically IDENTICAL with 16S rrna gene sequencing. M. massiliense with inactive erm gene: so NOT genetically identical to M. bolettii! Currently we have: M abscessus ssp abscessus (erm +) M. abscessus ssp bolettii (erm +) M abscessus ssp massiliense (erm )

Taxonomy Bottom Line for M. abscessus You NEED to know if there is an active inducible macrolide resistance (erm) gene to know if a macrolide is indicated for therapy. Must incubate M. abscessus isolates with macrolide for 2 weeks to determine true MIC or do erm gene sequencing Just to be consistent M. abscessus ssp abscessus, erm gene +, macrolide not indicated M. abscessus subsp massiliense, or M. massiliense, erm gene, macrolide indicated

Treatment of M. abscessus Lung Disease Macrolide: value questionable (erm gene), may be of value as immune modulator Amikacin 10 15 mg/kg 3 5X/week Tigecycline 25 50 mg/day Linezolid 300 600 mg/day Alternatives: Imipenem, cefoxitin, clofazimine There is no predictably or reliably effective medical treatment strategy for M. abscessus lung disease

64 yo female Sputum AFB culture pos for M. abscessus 61 yo female diagnosed with M. abscessus lung disease (cough, fatigue, hemoptysis). Treated with Clari/AM then Clari/Linezolid After 12 mos, M. abscessus meds stopped 2 drug toxicity (ototoxicity, neuropathy) Sputum AFB smear and culture + for macrolide susceptible M. abscessus Re started Azi, Tigecycline, Imipenem

RML lobectomy 64 yo female Sputum AFB culture pos for M. abscessus After 3 mos Imipenem stopped 2 rash, continued Azi/Tigecycline Converted sputum to AFB culture negative Medications stopped after > 12 mos sputum culture neg

65 year old female sputum culture pos for M. abscessus Daily amk/liniezolid/azi Recurrent aspiration, had esophageal surgery > 12 mos sputum culture neg

Surgery for NTM Lung Disease Indications for surgery: medication unresponsive disease (drug resistance, large cavities), uncontrolled symptoms, hemoptysis, destroyed lung Safety: Mitchell JD Ann Thorac Surg 2008, 85; 1887. Eur J CV Surg 2011; April e pub Microbiologic Efficacy: Griffith ARRD 1993, 147: 1271. Jeon AJRCCM 2008, 180; 896. Jarand CID 2011, 52; 565. Nelson Ann Thoracic Surg 1998, 66; 325. Griffith AJRCCM 2006 Symptom Control (+/ )

44 yo female with 4+ AFB pos sputum 12 mos daily clari/emb/rmp, still cutlure pos RML lobectomy Azi/emb/rbt/amk > 12 mos sputum culture neg

58 year old male, sputum 4+ AFB culture pos for MAC 20 mos daily azi/emb/rmp RUL lobectomy >12 mos sputum culture neg

Diagnosis and Treatment of NTM Superimposed on Chronic Lung Disease Why? Because chronic lung disease is inevitably and unavoidably present in patients with NTM lung disease. Because management of chronic lung disease is an inevitable and unavoidable complicating factor in the management of NTM lung disease and sometimes the most important and effective therapy for the patient.

Trends in bronchiectasis Medicare data base query 5% sample of Medicare outpatient data (2000 to 2007) 1106 cases per 100,000 persons Diagnosis increased by 8.7% per year Asians had higher prevalence Seitz AE, et al. Chest. 2012;142:432-9.

Some Chronic Lung Diseases Associated with NTM lung infection Bronchiectasis ( peas and carrots, F. Gump) Cystic Fibrosis, Atypical cystic fibrosis, Alpha one antitrypsin deficiency, Immunoglobulin deficiency, disorders of ciliary function etc. MAC, M. abscessus, M. simiae, etc. Chronic Obstructive Lung Disease M. kansasii, MAC, M. szulgai, M. xenopi, etc. GERD with chronic aspiration Lung Malignancy Pulmonary Fibrosis

Chronic Lung Diseases Associated with NTM lung infection Major challenges of underlying lung diseases (especially bronchiectasis) Cough, sputum production, fatigue, weight loss Infectious exacerbation of bronchiectasis/copd Pseudomonas, Stenotrophamonas, Achromobacter, etc Pneumonia Hemoptysis (+/ mycetoma) Bronchospasm and/or bronchospastic exacerbation of bronchiectasis/copd

62 year old female with M. abscessus lung disease

70 year old female with M. abscessus lung disease after 2 months nebulized hypertonic saline

BRONCHIECTASIS AJRCCM 188: 647 656, 2013

Pseudo infections and Pseudo outbreaks Increase in frequency of NTM isolates recovered from patients without disease M. xenopi and M. simiae the two species most commonly associated with pseudo outbreaks in the US and Canada Frequently involve equipment such as bronchoscopes The recovered species is subsequently isolated from environmental sources If unrecognized, may precipitate un necessary therapy

M. simiae pseudo outbreak from contaminated bronchoscopes 8 bronchoscopic specimens from 8 separate patients culture positive for M. simiae No clinical evidence of active mycobacterial disease from any of the patients Terminal rinse after cleaning the bronchoscope with tap water M. simiae cultured from, a) hospital water tank, b) municipal water tank, c) Edward s aquifer

NTM Guidelines Last ATS/IDSA NTM guidelines published 2007 NTM guidelines 2014 ATS IDSA ERS ESCMID Non member Japanese observers

State of the Art: Nontuberculous Mycobacteria and Associated Diseases (Wolinsky, ARRD 1979;119: 107) Proper management requires greater expertise than is needed for treatment of TB, first, to decide who needs to be treated, and second, to determine which drug regimens to use.