Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) 1 Radbound University Nihmegen Medical Center Milestones in NTM research 1980s: Nodular bronchiectatic lung disease Lady Windermere syndrome 1882-1890 Atypical M. tubeculosis 1882 M. tubeculosis 1900-1950 Sporadic case reports 1953 M. kansasii 1980 s Lady Windermere syndrome M. avium in HIV patients 2 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 4 distinct disease entities Non Tuberculous Mycobacteria (NTM) pulmonary disease (90% of the NTM disease case load) NTM cervicofacial lymphadenitis in immunocompetent children Disseminated NTM disease in the severely immunocompromised Skin/soft tissue infection or osteomyelitis after inoculation 3 1 1
Section 1 Diagnosis of NTM-PD 4 NTM-PD - not a single disease entity 5 Fibro-cavitary NTM-PD Epidemiology Mostly males Middle-aged (50-70 years old) Pre-existing COPD, silicosis, fibrosis Clinical course TB-like, but slower Microbiology Often Ziehl-Neelsen positive sputum High yield of culture Radiology Fibro-cavitary lesions, upper lobes 6 2 2
7 Nodular-bronchiectatic NTM-PD Epidemiology Elderly (>60 yrs old) females Scoliosis, mitral valve prolapse, low BMI No pre-existing lung disease, CFTR mut. Clinical course Prolonged cough, fatigue, weight loss Microbiology Low yield of ZN & culture, repeat or BAL Radiology Bronchiectasis w/ nodules, tree-in-bud Middle lobe and lingula worst affected Lady Windermere Syndrome NTM hypersensitivity pneumonitis Epidemiology Rare / underdiagnosed Relation to aerosol exposure Clinical course Subacute dyspnea, fever Microbiology BAL preferred; high yield of culture Radiology Ground glass opacities on HR-CT Hot Tub Lung Infection or Inflammation? 8 Special case: Cystic fibrosis and NTM Prevalence increases with age Accelerates lung function decline Mycobacterium abscessus Mycobacterium avium complex Nodular-bronchiectatic Later cavitary 9 Risk factors uncertain S. maltophilia co-infections A. fumigatus co-infections Steroid use for ABPA 3 3
Diagnosis of NTM pulmonary disease American Thoracic Society diagnostic criteria* Symptoms compatible with NTM lung disease Radiology compatible with NTM lung disease (cavities / nod.-bronch.) Obtain 3 respiratory samples, over the course of at least a week Disease: at least 2 positive cultures with the same species Lab: Always use solid + liquid media Identify all isolates by molecular methods nomen est omen 10 *Griffith D.E. et al., Am J Respir Crit Care Med 175, 367-416 (2007) Clinical relevance of pulmonary NTM isolates in NL 0% 25% 50% 75% 100% Clinical relevance differs by species! (% of patients who met diagnostic criteria, per species) 11 Van Ingen J. et al., Thorax 64, 502-506 (2009) Van Ingen J. et al., Infect Gen. Evol. 12(4), 832-837 (2011) Section 2 Management of NTM-PD 12 4 4
Management of NTM-PD - first steps Can the pre-existing / predisposing conditions be optimised? Does the burden of treatment outweigh the burden of disease? Is the patient willing and able to be on multi-drug treatment for >1 year? Is there a potential role for surgical resection of the worst affected areas? Do I want to do this myself, or do I refer to a specialist centre? 13 Treatment recommendations American thoracic society M. avium complex RIF-EMB-macrolide (+/- aminoglycoside) >12 mo M. kansasii INH-RIF-EMB 12 mo M. xenopi RIF-EMB-macrolide-moxifloxacin? M. simiae Macrolide-moxifloxacin-cotrimoxazole-? M. abscessus 3-4 of amikacin, cefoxitin/imipenem, macrolide*, linezolid, tigecycline With surgical debulking whenever feasible Treatment duration Pulmonary disease: 12 months after culture conversion 14 Griffith D.E. et al., Am J Respir Crit Care Med 175, 367-416 (2007) Treatment outcomes Prolonged culture conversion in M. avium complex pulmonary disease RIF-EMB-macrolide regime: 332/478 (69%) Cavitary 50-60%, Nodular-Bronchiectatic 70-85% M. abscessus pulmonary disease Macrolide(?), amikacin, cefoxitin / imipenem / tigecycline / linezolid Jarand et al., CID 2011: 69 pt, 48% culture conversion Jeon et al., AJRCCM 2009: 65 pt, 58% culture conversion 4wk cefoxitin-amikacin, followed by cipro-doxy-clarithromycin M. xenopi & M. simiae Extremely poor; less than 30% culture conversion 15 Field S. et al., Chest (2003) 5 5
Focus on M. avium complex M. avium complex: rifamycin + ethambutol + macrolide Duration: 12 months after culture conversion Fibro-cavitary: Daily Tx. consider amikacin during 1st three months Nodular-bronchiectatic: thrice weekly Tx NTM-NET survey: 446 physicians in EU, 5 countries 1012 patients 8% >6 mo recommended Tx UK did best in Europe % receiving >6mo RE-macrolide UK 19 SPAIN 6 ITALY 6 GERMANY 4 FRANCE 6 JAPAN 45 USA 21 0 10 20 30 40 50 16 Griffith D.E. et al., Am J Respir Crit Care Med 175, 367-416 (2007) Van Ingen J. & Wagner D. manuscript in preparation 17 Case series on MAC-PD Prolonged culture conversion: RIF-EMB-macrolide based regimen: 178/298 (60%) Clofazimine based regimen: 34/52 (65%) Macrolide resistance in vitro is a risk factor for treatment failure Fibro-cavitary disease is a risk factor for treatment failure Differences in exact regimens Adjunctive aminoglycosides Adjunctive quinolones % prolonged culture conversion 90 80 70 60 50 40 30 20 10 0 0 20 40 60 80 100 % cavitary disease in cohort 18 Field S. et al., Chest (2003) Lam P.K. et al., Am. J. Respir. Crit. Care Med 173(11), 1283-1289 (2006) % cure Linear (% cure) 6 6
Rationale for regimens - MAC RIF-EMB: a legacy from TB Hardly active Synergystic (relevant?) BTS trial: RE 27% cure rate The macrolides matter most But are weak bacteriostatic drugs Amikacin works in vitro, for a while No influence on outcome in vivo Drug In vitro In vivo Serum [c] PD Rifampicin R R Good Poor Ethambutol R R Good Poor RIF+EMB I/R I Good Poor Macrolide S S/I Low (rif!) Good Amikacin S/I I/R Good Poor 19 Ferro B.E. et al., J Antimicrob. Chemother. 70(3) 811-817 (2014) Ferro BE & van Ingen J. Manuscript in preparation Focus on M. abscessus Utter depression Treatment recommendation: 3 or 4 of cefoxitin/imipenem + amikacin + tigecycline + linezolid + Macrolide if no functional erm gene Or other drugs based on in vitro susceptibility (which there isn t) IV drugs, long-term use difficult Severe toxicity (ototoxicity of amikacin, cytopenia of cefoxitin and linezolid) Practice: 4-8 weeks intensive phase, then long term continuation phase Clarithromycin, ciprofloxacin, doxycycline Inhaled amikacin(?) 20 Jeon K. et al., Am. J. Respir. Crit. Care Med. 180(9) 869-902 (2009) Jarand et al., CID 2011: Focus on M. abscessus In vitro in vivo correlations of drug susceptibility testing? 69 pt, 48% culture conversion Regimens based on susceptibility test results No clear link between MICs and outcomes Similar MICs and regimens as in this patient Jeon et al., AJRCCM 2009: 65pt, 58% culture conversion 4wk cefoxitin-amikacin (cefox often interrupted) cont w/ ciprofloxacin-doxycycline-clarithromycin Regardless of susceptibility test results Ciprofloxacin and doxycycline hardly active, in vitro 21 Mycobacterium abscessus AMIKACIN S CEFOXITIN I IMIPENEM I CLARITROMYCIN S CO-TRIMOXAZOLe R DOXYCYCLINE R CIPROFLOXACIN R MOXIFLOXACIN R LINEZOLID R TIGECYCLINE MIC 0.125 CLOFAZIMINE MIC 0.25 7 7
Rationale for regimens M. abscessus Amikacin Amikacin-cefoxitin effective in SSTI 34/47 (72%) cure rate Time-kill cefoxitin, amikacin, clarithromycin Amikacin strongest among the weak >30x less active than against E. coli Adaptation to amikacin and clarithromycin Regrowth at all concentrations No mutational resistance Detection limit Detection limit Fits with low cure rates of pulmonary disease Cefoxitin Clarithromycin 22 Wallace R.J. et al., J Infect Dis (1986) Detection Koh W.J et al., Am J Respir. Crit. Care Med. 183:405 410 (2011) limit Jeon K. et al., Am J Respir. Crit. Care Med. 180(9) 892-900 (2009) Ferro B.E. et al., J Antimicrob. Chemother. 70(3) 811-817 (2015) The many, many caveats Can the patient be treated with recommended regimens? Drug interactions (Rifamycins! Macrolides!) Rifamycins lower macrolide concentrations Concomitant fungal disease rifampicin azole interaction Toxicity Rifampicin: hepatotoxicity Amikacin: ototoxicity, nefrotoxicity Macrolides, moxifloxacin, linezolid: QTc interval prolongation Cefoxitin, linezolid, rifabutin: bone marrow toxicity Are there alternatives? 23 Van Ingen J. et al., Am. J. Respir. Crit. Care Med. 186(6) 559-565 (2012) The light at the end of the tunnel? Clofazimine prevents emergence of claritromycin and amikacin resistance In vitro manuscript submitted for publication Liposomal amikacin for inhalation is currently in trials for NTM-PD Solithromycin is a new fluoroketolide with likely activity against NTM Teixobactin is a new potent antimycobacterial drug Bedaquiline is active against NTM, but producers refuses use in NTM-PD In vitro evaluations ongoing 24 Van Ingen J. Lancet Respir. Med. (2015); in press 8 8
Conclusions Establish a clear diagnosis use ATS diagnostic criteria Use recommended treatment regimens ATS document Always consider surgical intervention Be aware of potential drug-drug interactions and toxicity but don t use inferior regimens just to prevent all that! Recommended regimens do not guarantee good outcomes Currenty recommended regimens are intrinsically weak Consult an expert 25 Acknowledgements Radboud University Medical Center NTM team Wouter Hoefsloot Martin Boeree Cecile Magis Rob Aarnoutse Melanie Wattenberg Beatriz Ferro 26 27 9 9