Increasing and More Commonly Refractory Mycobacterium avium Pulmonary Disease, Toronto, Ontario, Canada.

In mid-2014, Public Health Ontario Laboratories identified coincident increasing Mycobacterium avium isolation and falling M. xenopi isolation in the Toronto, Ontario, Canada, area. We performed a retrospective cohort of all patients in a Toronto clinic who began treatment for either M. avium or M. xenopi pulmonary disease during 2009-2012 (early period) or 2015-2018 (late period), studying their relative proportions and sputum culture conversion. We conducted a subgroup analysis among patients who lived in the Toronto-York region. The proportion of patients with M. avium was higher in the late period (138/146 [94.5%] vs. 82/106 [77.4%]; p<0.001). Among M. avium patients, conversion was lower in the late period (26.1% vs. 39.0%; p = 0.05). The increase in the proportion of patients with M. avium pulmonary disease and the reduction in the frequency of sputum culture conversion is unexplained but could suggest an increase in environmental M. avium exposure.

Time to Positive Culture Detection Predicts Mycobacterium avium Pulmonary Disease Severity and Treatment Initiation.

Rationale: Additional biomarkers are needed to guide initiation of treatment for Mycobacterium avium pulmonary disease (Mav-PD). Time to positive sputum culture detection (TTP) may offer potential prognostic and monitoring value. Objectives: To determine whether TTP is associated with infection severity and early treatment response in Mav-PD. Methods: We undertook a retrospective cohort study of patients with two or more sputum cultures positive for M. avium, an "index" sputum M. avium isolate during 2015-2019, a computed tomographic scan within 6 months, and no treatment for at least 6 months before index sputum. TTP was estimated from the date of laboratory receipt of the specimen to the date of culture positivity confirmation. TTP was tested for association with markers of infection severity (Mav-PD, bronchiectasis, cavitary disease, treatment initiation by 3 and 6 months, and acid fast bacilli [AFB] smear) and treatment response using Mann-Whitney U, Spearman's correlation coefficient, and Wilcoxon signed-rank tests. We explored a threshold TTP that could identify significant M. avium disease. Results: We included 125 patients with mean (standard deviation) age 68.5 (12.5) years and 65% fulfilled disease criteria. Median TTP was 12 (interquartile range 10-15; range 6-44) days. TTP and AFB smear grade were negatively correlated (ρ -0.58; P < 0.001). TTP was associated with nontuberculous mycobacteria (NTM) disease (P = 0.03), AFB smear positivity (P < 0.001), and treatment initiation by 3 (P = 0.01) and 6 (P = 0.03) months. A threshold TTP of 10 days or less was associated with Mav-PD (80.6% vs. 58.4%; ð [95% confidence interval (CI)] 22.1% [5.6-38.6%]; P = 0.02), AFB smear positivity (83.3% vs. 20.2%, ð [95% CI] 63.1% [48.3-77.9%]; P < 0.001), treatment by 3 (38.9% vs. 13.5%; ð [95% CI] 25.4% [8.0-42.8%]; P = 0.003) and 6 (47.2% vs. 19.1%; ð [95% CI] 28.1% [9.9-46.4%]; P = 0.003) months. After 3 and 6 months of treatment, the median (interquartile range) change in TTP was 8 (1 undefined; P < 0.001) and 7 (0 undefined; P = 0.001) days, respectively. Conclusions: TTP is associated with bacterial burden and infection severity and increases in response to treatment. A threshold of 10 days or less may be useful in predicting significant Mav-PD. As a readily available biomarker, further exploration of TTP is imperative.

Aspergillus isolation in nontuberculous mycobacterial pulmonary disease: Associated with antimycobacterial treatment initiation but not response.

PURPOSE: Chronic pulmonary aspergillosis is a serious complication of nontuberculous mycobacterial pulmonary disease (NTM-PD), and diagnosis remains challenging. The present study examined associations between the respiratory isolation of Aspergillus and the clinical characteristics and treatment outcomes of patients with NTM-PD. METHODS: All patients meeting NTM-PD criteria as defined by the ATS/IDSA statement, with at least one respiratory sample cultured for fungi, were included in this retrospective cohort analysis. Patients with at least one respiratory sample isolating Aspergillus were compared to patients who did not isolate Aspergillus. The primary outcomes were culture conversion and radiologic evolution 12 months after NTM-PD treatment initiation. RESULTS: During a 12 year period, 497 patients meeting the inclusion criteria were seen in our tertiary care center, of whom 130 grew Aspergillus. Median follow up after NTM-PD diagnosis was 46 months. Inhaled corticosteroid use, a nodular-bronchiectatic CT pattern and NTM-PD treatment initiation were more frequent in patients who isolated Aspergillus compared to those who did not (p-value respectively 0.01, 0.03 and < 0.001). Rates of culture conversion (63.0% vs. 62.2%, respectively; p-value 1) and radiologic evolution (improvement or stability in 69.7% vs. 77.2%, respectively; p-value 0.25) were not significantly different between treatment groups. Likewise, culture reversion rate and 5-year mortality were not significantly different. Additionally, A. fumigatus and repeated detection of Aspergillus were not associated with treatment outcomes. CONCLUSION: There was no association between respiratory isolation of Aspergillus and NTM-PD treatment outcomes in this cohort. However, treatment for NTM-PD was initiated more frequently in patients who isolated Aspergillus.

Safety and effectiveness of low-dose amikacin in nontuberculous mycobacterial pulmonary disease treated in Toronto, Canada.

BACKGROUND: Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data supporting the low-dose approach are limited. The purpose of this study was to describe the safety and efficacy of the use of a low-dose of intravenous amikacin in a cohort of patients with NTM PD. METHODS: We retrospectively reviewed all patients with NTM PD who received amikacin at our institution between July 1, 2003 and February 28, 2017. Demographics, clinical, microbiological and radiological data, indication and dose of amikacin, and adverse drug effects were recorded. RESULTS: A total of 107 patients received a regimen containing amikacin for a median (IQR) of 7 (4-11) months. Seventy (65.4%) were female and the mean age (SD) was 58.3 (14.9) years. Amikacin was started at a median dose of 9.9 (2.5) mg/kg/day. Ototoxicity was observed in 30/77 (39%) patients and it was related to female sex (OR 4.96, 95%CI 1.24-19.87), and total dose of amikacin per bodyweight (OR 1.62, 95%CI 1.08-2.43). Patients of East Asian ethnicity were less likely to develop ototoxicity (0.24, 95%CI 0.06-0.95). Out of 96 patients who received amikacin for more than 3 months, 65 (67.7%) experienced symptom improvement and 30/62 (49.2%) converted their sputum to culture negative within a year. CONCLUSIONS: Patients with NTM PD treated with low-dose intravenous amikacin frequently developed ototoxicity, which was associated with female sex, and total dose of amikacin per bodyweight. Physicians should carefully consider dose, treatment duration, and long term prognosis in balancing risks and benefits of intravenous amikacin in NTM PD.

Adjuvant lung resection in the management of nontuberculous mycobacterial lung infection: A retrospective matched cohort study.

BACKGROUND AND OBJECTIVES: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) is considered when medical therapy alone fails to provide long term control. Data regarding comparative and long-term outcomes are limited. We aimed to review indications and outcomes of adjuvant lung resection for NTM-PD compared with controls. METHODS: We retrospectively studied 27 surgically treated patients, matched 1:1 for age, sex, NTM species, and radiologic pattern of disease, with control patients treated exclusively with antibiotics. RESULTS: In the surgical group, the median (IQR) age was 55 (49-61) years and 74.1% were female. Eighteen patients had Mycobacterium avium complex, and 9 had M. xenopi. Operations included 8 pneumonectomies, 20 lobectomies, one segmentectomy and one lobectomy plus segmentectomy. Post-surgical complications occurred in 6 patients (20%), including 2 acute respiratory distress syndrome, 1 bronchopleural fistula, 1 pericardial tamponade, and 2 empyema. Complications were more common among patients operated upon for progressive disease despite medical therapy (OR 10, p = 0.025). Of 24 matched pairs followed for ≥1 year, sustained culture conversion was observed in 21 (87.5%) patients in the surgical group and in 11 (45.8%) patients in the non-surgical group (RR 2.36, 95%CI 1.37-4.03, p = 0.002). Median (IQR) percentage of follow-up time on antibiotics was 14% (0-100%) in the surgical group and 83% (10.8%-100%) in the non-surgical group (p = 0.195) during a median (IQR) follow-up of 16 (2-36) months. CONCLUSIONS: NTM-PD patients who underwent adjuvant lung resection experienced significant morbidity and more frequently achieved sputum culture conversion. Long term antibiotic requirements may have been reduced.