Faculty Bibliography

Background: Aspiration is associated with non-tuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile.Methods: 297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and a nested mycobacteriome sequencing approaches characterised microbiota composition. Inflammatory profiles of lower airway samples were also examined.Results: The prevalence of NTM+ cultures was 58%. Few changes were noted in microbiota characteristic or composition in oral wash and sputum samples among groups. Among NTM+ samples, 27% of the lower airway samples were enriched with Mycobacterium A mycobacteriome approach identified Mycobacterium in a greater percentage of samples, including some non-pathogenic strains. In NTM+ lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers.Conclusions: The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples which are culture positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.

PURPOSE OF REVIEW/OBJECTIVE:To highlight recent original research and specialty society guidelines regarding the diagnosis and treatment of nontuberculous mycobacterial (NTM) pulmonary disease. RECENT FINDINGS/RESULTS:The prevalence of NTM pulmonary disease has risen in recent years. The prevalence of individual NTM species varies geographically, although Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABC) remain among the most commonly encountered in many regions. Diagnosis and treatment of NTM pulmonary disease can be complex but guideline-based recommendations have been published. However, adherence to guideline recommendations is poor. Drug susceptibility testing plays a role with important caveats for treatment. Alternative therapies are being explored with older antimycobacterial drugs like clofazimine, which has demonstrated efficacy and tolerability for treatment-refractory NTM infections, and a novel formulation of amikacin for inhalation which may be better tolerated than parenteral administration. Several studies have shown that patients will have recurrences as high as 48%, and that these are not solely relapses but many cases are reinfections with a new organism. United States and European research registries of patients with non-cystic fibrosis bronchiectasis are expected to provide needed data on clinical characteristics of patients at risk for NTM pulmonary disease. SUMMARY/CONCLUSIONS:The evidence base for optimal management of NTM pulmonary disease is expanding but notable gaps in the literature remain.

Rationale Lengthy multi-drug, toxic, and low efficacy regimens limit management of pulmonary nontuberculous mycobacterial (PNTM) disease. Objective This phase 2 study investigated efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory PNTM (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multi-drug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. Primary endpoint was change from baseline to day 84 on a semi-quantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute walk distance, and adverse events. Measurements and Main Results Modified intent-to-treat population included 89 (LAI=44; placebo=45) patients. Average age was 59 years, 88% were female, 92% were Caucasian; 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. Primary endpoint was not achieved (P=0.072); however, a greater proportion of the LAI group demonstrated >/=1 negative sputum cultures (32% [14/44] vs. 9% [4/45]; P=0.006) and improvement in 6-minute walk test (+20.6 vs. -25.0 meters; P=0.017) at day 84. Treatment effect was predominantly in patients without cystic fibrosis with MAC and was sustained 1 year post-LAI. Most adverse events were respiratory and in some patients led to drug discontinuation. Conclusions Although the primary endpoint was not reached, LAI added to a multi-drug regimen produced improvements in sputum conversion and 6-minute walk distance vs. placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research is needed. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01315236.