The Association of Long-term Macrolide Therapy and Nontuberculous Mycobacterial Culture Positivity in Patients With Bronchiectasis

Abstract

Bronchiectasis guidelines recommend chronic macrolide therapy for patients suffering at least two exacerbations per year.1Polverino E. Goeminne P.C. McDonnell M.J. et al.European Respiratory Society guidelines for the management of adult bronchiectasis.Eur Respir J. 2017; 50: 1700629Crossref PubMed Scopus (433) Google Scholar Patients with bronchiectasis are at increased risk of pulmonary infection with nontuberculous mycobacteria (NTM); approximately 9% of bronchiectasis patients will develop NTM culture positivity.2Chu H. Zhao L. Xiao H. et al.Prevalence of nontuberculous mycobacteria in patients with bronchiectasis: a meta-analysis.Arch Med Sci. 2014; 10: 661-668Crossref PubMed Scopus (53) Google Scholar Long-term macrolide monotherapy increases the risk of macrolide-resistant Mycobacterium avium complex disease (MAC),3Griffith D.E. Brown-Elliott B.A. Langsjoen B. et al.Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease.Am J Respir Crit Care Med. 2006; 174: 928-934Crossref PubMed Scopus (226) Google Scholar leading to concern that bronchiectasis patients started on chronic macrolide therapy who have unrecognized MAC infection or who develop MAC infection while on therapy may develop macrolide-resistant MAC. To study the association between long-term macrolide monotherapy and incident NTM pulmonary infection and macrolide resistance, we analyzed data from the United States Bronchiectasis and NTM Research Registry (BRR). The BRR is a centralized database of patients with bronchiectasis entered at 16 sites throughout the United States sponsored and funded by the COPD Foundation, a 501(c)(3) nonprofit organization. Adult patients with a diagnosis of bronchiectasis confirmed by CT scan are eligible for inclusion. The Institutional Review Board (IRB) of each site approved the study, as did an administrative IRB for the data-collecting center (Western IRB, tracking number 20141341.) BRR methods have been previously reported.4Aksamit T.R. O’Donnell A.E. Barker A. et al.Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry.Chest. 2017; 151: 982-992Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar Subjects included in this study must have had at least one documented negative NTM culture at the time of the baseline study visit (look-back period up to 1 year), no positive NTM cultures documented at the baseline visit, and follow-up at a second study visit, generally approximately 1 year after the baseline visit. Patients were stratified into two groups, those on macrolide therapy at the time of the baseline visit and those not on macrolide therapy. The primary end point was the percentage of patients with at least one positive NTM culture at the 1-year follow-up visit, because exploratory analyses showed low numbers of patients who had all of the relevant data at the second follow up visit. Values between the strata were compared using t tests for continuous variables, and χ2 or Fisher exact tests for categorical variables. Fisher exact test was used to compare the rate of incident NTM culture positivity between the macrolide and nonmacrolide groups. The primary analysis included both of these groups; a secondary analysis excluded patients with no culture results available. SAS 9.4 was used to perform all statistical analyses (SAS Institute). Significance tests were two-sided, with a significance level of .05. At the time of this analysis (April 2020), 3,472 subjects were enrolled in the BRR. We excluded 2,259 subjects with a history of at least one positive NTM culture, documented history of NTM disease, or unknown NTM culture or history. Among the remaining 1,213 subjects, 174 were excluded because of missing data on macrolide treatment at baseline, and 629 were excluded because of lack of availability of 1-year follow-up data. This left 410 included subjects, 91 in the macrolide group and 319 in the non-macrolide group. Patient characteristics were mostly similar between the two groups (Table 1). Table 2 shows the mycobacterial culture results at the follow-up visit. Three of 91 (3.3%) macrolide patients had at least one positive NTM culture, two with MAC and one with Mycobacterium chelonae/abscessus. One MAC patient had two positive cultures, with the isolate being sensitive to macrolides. He had previously been treated for MAC pulmonary disease. The other MAC patient had one positive culture (antimicrobial susceptibility testing not available), and five subsequent negative mycobacterial cultures. Among the non-macrolide patients, 44 of 319 (13.8%) had at least one positive NTM culture. Patients in the macrolide group had significantly lower odds of NTM culture positivity at the first follow-up visit (OR = 0.21; 95% CI, 0.06-0.70; P = .005). When only patients who had a documented negative follow-up NTM culture were included (ie, excluding those with no documented follow-up NTM cultures), the difference remained statistically significant (OR = 0.20; 95% CI, 0.06-0.67; P = .004).Table 1Baseline CharacteristicsDemographicsNo. Available (N = 410)Non-macrolide Group (n = 319)Macrolide Group (n = 91)PSex, No. (%)410Female257 (80.6)73 (80.2).5729Age, y409Mean (SD)61.6 (15.7)60.6 (15.4).6535Age at diagnosis, y319Mean (SD)52.3 (18.7)53.2 (18.1).7037Prior diagnoses/characteristics, No. (%)Ever had a TB diagnosis4088 (2.5)5 (5.6).1472Ever diagnosed with alpha-1 antitrypsin deficiency4035 (3.2)4 (3.3).1172Ever diagnosed with a primary immunodeficiency39317 (5.6)10 (11.2).0641Ever diagnosed with Kartagener’s or primary ciliary dyskinesia40619 (6.0)15 (16.5).0015Ever diagnosed with a rheumatologic disease40220 (6.4)4 (4.4).4880Ever diagnosed with inflammatory bowel disease40612 (3.8)2 (2.2).7439History of gastroesophageal reflux409134 (42.14)47 (51.65).1202Chest wall deformity39710 (3.19)5 (5.95).3286Scoliosis39730 (9.58)14 (16.67).0780Isolated right middle lobe or lingula bronchiectasis on CT scan282160 (75.12)46 (66.67).1691Tobacco use, No. (%)394.9419Past or present110 (35.4)29 (34.9)Never201 (64.6)54 (65.1)Pre-bronchodilator FEV1 (% predicted) at entry354Mean (SD)70.0 (22.6)64.9 (22.4).0829Pulmonary exacerbations in the past two years, No. (%)379238 (79.1)63 (80.8).7408No. of bronchiectasis exacerbations in the past 2 years335Median (IQR)2 (1-3)2 (1-4).2725Treatment, No. (%)Inhaled steroids401128 (40.76)51 (58.62).0034Inhaled antibiotics38360 (20.13)25 (29.41).0694Bacterial culture results (at baseline)Haemophilus influenza33617 (6.7)7 (8.6).5476Pseudomonas aeruginosa339119 (46.1)44 (54.3).1977Staphylococcus aureus33749 (19.1)13 (16.1).5314Aspergillus species11629 (34.5)10 (31.3).7387 Open table in a new tab Table 2Mycobacterial Culture Results at the 1-Year Follow-up VisitMycobacterial Culture ResultsMacrolide GroupNon-Macrolide Group(n = 91)(n = 319)Patients with any positive mycobacterial culture3bP = .005, OR = 0.21 (95% CI, 0.06-0.70) macrolide vs non-macrolide group, including patients with at least one documented negative follow-up culture and those with no follow-up cultures available.,cP = .004, OR = 0.20 (95% CI, 0.06-0.67) macrolide vs non-macrolide group, including only patients with at least one documented negative follow-up culture. (3.3%)44 (13.8%) Organisms culturedaPatients with cultures that grew M gordonae were not considered as having grown an NTM; however, two macrolide and three non-macrolide patients grew M gordonae. Mycobacterium avium complex238 Mycobacterium chelonae/abscessus12 Mycobacterium fortuitum02 Mycobacterium terrae group01 Nonspeciated01Patients with more than one positive culture1 (1.1%)13 (4.1%)dP = .322, OR = 0.2616 (95% CI, 0.03-2.02), macrolide vs non-macrolide group, including patients with documented negative cultures and those with no follow-up cultures. Two1 (M avium complex)11 (M avium complex) Three or more02 (M avium complex)Patients with only negative mycobacterial cultures64 (70.3%)188 (58.9%)Patients with no mycobacterial culture results24 (26.4%)87 (27.3%)a Patients with cultures that grew M gordonae were not considered as having grown an NTM; however, two macrolide and three non-macrolide patients grew M gordonae.b P = .005, OR = 0.21 (95% CI, 0.06-0.70) macrolide vs non-macrolide group, including patients with at least one documented negative follow-up culture and those with no follow-up cultures available.c P = .004, OR = 0.20 (95% CI, 0.06-0.67) macrolide vs non-macrolide group, including only patients with at least one documented negative follow-up culture.d P = .322, OR = 0.2616 (95% CI, 0.03-2.02), macrolide vs non-macrolide group, including patients with documented negative cultures and those with no follow-up cultures. Open table in a new tab The number of patients with 2-year follow-up data was small. After excluding patients with a positive NTM culture at the first follow-up visit, those that changed treatment category (macrolide vs non-macrolide) and those with missing data, 0 of nine macrolide patients had a positive NTM culture and six of 49 (12.2%) non-macrolide patients had at least one positive NTM culture (four MAC, two other mycobacteria) (OR = 0.35; 95% CI, 0.02-6.80; P =.58 ). These results have important implications. Chronic macrolide treatment is the only bronchiectasis therapy supported by multiple randomized controlled studies,1Polverino E. Goeminne P.C. McDonnell M.J. et al.European Respiratory Society guidelines for the management of adult bronchiectasis.Eur Respir J. 2017; 50: 1700629Crossref PubMed Scopus (433) Google Scholar yet most patients do not receive this therapy.4Aksamit T.R. O’Donnell A.E. Barker A. et al.Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry.Chest. 2017; 151: 982-992Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar,5Martinez-Garcia M.A. Villa C. Dobarganes Y. et al.RIBRON: the spanish Online Bronchiectasis Registry: characterization of the first 1912 patients.Arch Bronconeumol. 2020; 57: 28-35Crossref PubMed Google Scholar Concern regarding macrolide-resistant NTM may limit utilization. We found low rates of NTM positivity in patients receiving chronic macrolide therapy. Although our results must be considered as preliminary, they suggest that chronic macrolide therapy is associated with low rates of subsequent NTM positivity and might even be protective against NTM infection. It therefore may be most beneficial in bronchiectasis patients at increased risk for NTM because of patient characteristics6Kim R.D. Greenberg D.E. Ehrmantraut M.E. et al.Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.Am J Respir Crit Care Med. 2008; 178: 1066-1074Crossref PubMed Scopus (276) Google Scholar or receipt of immunosuppressive medications including inhaled corticosteroids.7Dirac M.A. Horan K.L. Doody D.R. et al.Environment or host?: A case-control study of risk factors for Mycobacterium avium complex lung disease.Am J Respir Crit Care Med. 2012; 186: 684-691Crossref PubMed Scopus (84) Google Scholar,8Liu V.X. Winthrop K.L. Lu Y. Sharifi H. Nasiri H.U. Ruoss S.J. Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection.Ann Am Thorac Soc. 2018; 15: 1169-1176Crossref PubMed Scopus (26) Google Scholar If our results are confirmed in larger studies, similar to the use of macrolide therapy for prophylaxis of disseminated MAC in advanced HIV disease,9Uthman M.M. Uthman O.A. Yahaya I. Interventions for the prevention of mycobacterium avium complex in adults and children with HIV.Cochrane Database Syst Rev. 2013; : CD007191PubMed Google Scholar bronchiectasis patients with these risk factors might be considered for chronic macrolide therapy even if they do not meet the current guideline-recommended indication of having frequent exacerbations. We are aware of no similar studies in patients with bronchiectasis. However, supporting the potential relevance of our study, a study of 90% of CF patients in the United States found a lower risk of incident culture positivity for both M abscessus and MAC in patients on chronic macrolide,10Binder A.M. Adjemian J. Olivier K.N. Prevots D.R. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis.Am J Respir Crit Care Med. 2013; 188: 807-812Crossref PubMed Scopus (96) Google Scholar and the longer the patient was on a macrolide, the lower the NTM incidence. A prior report suggesting that macrolide therapy might predispose CF patients to NTM disease by inhibiting autophagy11Renna M. Schaffner C. Brown K. et al.Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.J Clin Invest. 2011; 121: 3554-3563Crossref PubMed Scopus (225) Google Scholar was subsequently refuted by evidence that autophagy is not needed for M abscessus killing.12Pohl K. Grimm X.A. Caceres S.M. et al.Mycobacterium abscessus clearance by neutrophils is independent of autophagy.Infect Immun. 2020; 88: e00024-20Crossref PubMed Scopus (5) Google Scholar Our study has limitations. The number of patients on macrolide therapy was relatively small, and we only had 1 year of follow-up for most patients. Nonetheless, both of these limitations increase the likelihood of a type 2 statistical error, yet we demonstrated a significantly lower risk of NTM culture positivity in patients receiving macrolide therapy. Although some patients did not have documented follow-up mycobacterial cultures, our finding persisted even when we included only patients with documented mycobacterial cultures. Because we do not know how long patients were receiving macrolide therapy before the baseline visit, we could not investigate a macrolide dose-effect. Unmeasured differences between the macrolide and non-macrolide patients may have contributed to the differences in NTM positivity. However, this issue is not relevant to the finding of low NTM positivity in the macrolide group. We did not have enough cases to estimate the risk of macrolide-resistant NTM. In summary, bronchiectasis patients receiving long-term macrolide therapy have a low incidence of NTM culture positivity. These results, although preliminary in nature, suggest that in addition to current indications, there could be a role for prophylactic long-term macrolide therapy in bronchiectasis patients at high risk of NTM pulmonary disease. Further studies demonstrating safety and efficacy would be needed before using macrolide monotherapy for this purpose. Our study was too small to determine whether the rare patient who may develop MAC disease while receiving long-term macrolide therapy would have an increased risk of macrolide-resistant disease. An important caveat is that each macrolide patient had a negative mycobacterial culture at their baseline visit. Our results in no way minimize the importance of ruling out unsuspected NTM infection before beginning chronic macrolide therapy. ∗Bronchiectasis and NTM Research Registry Investigators: Doreen Addrizzo-Harris, MD; Timothy R. Aksamit, MD; Alan Barker, MD; Ashwin Basavaraj, MD; Radmila Choate, PhD, MPH; Charles L. Daley, MD; M. Leigh Anne Daniels, MD, MPH; Edward Eden, MD; Angela DiMango, MD; Kevin Fennelly, MD; Margaret M. Johnson, MD; Michael R. Knowles, MD; Diego Maselli, MD; Pamela J. McShane, MD; Mark L. Metersky, MD; Edward Naureckas, MD; Peadar G. Noone, MD; Anne E. O’Donnell, MD; Kenneth N. Olivier, MD, MPH; Julie Philley, MD; Marcos Restrepo, MD; Matthias A. Salathe, MD; Andreas Schmid, MD; Byron Thomashow, MD; Gregory Tino, MD; Kevin L. Winthrop, MD, MPH. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.