Adherence to NTM Treatment Guidelines Remains Poor, Study Finds

Adherence to current guidelines for the treatment of non-tuberculous mycobacteria (NTM) pulmonary infections remains poor in the United States, with patient outcomes also compromised by poor compliance with prescribed drug regimens and therapy interruptions, researchers reported.

Joint treatment guidelines from the American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) and two European pulmonary societies, published in 2020, call for a three-drug combination of a macrolide, ethambutol, and rifamycin for the treatment of pulmonary disease caused by Mycobacterium avium complex (MAC), which is the most common NTM pathogen.

The guidelines also call for a multidrug regimen for the treatment of M. abscessus to include three or more active drugs determined through in vitro susceptibility testing.

In an interview with BreakingMED, pulmonologist David E. Griffith, MD, of National Jewish Health, Denver, said knowledge about treatments and compliance with treatment guidelines has been poor for many years.

"Compliance may have improved somewhat in recent years, but it remains pretty terrible," Griffith said. "There really hasn’t been some watershed of awakening with regard to knowledge about the treatment of NTM disease over the last 30 or 35 years. It has been more of a slog trying to raise awareness."

In an earlier interview, pulmonologist Charles Daley, MD, also of National Jewish Health, told BreakingMED that it is not yet clear to what extent general practice clinicians and pulmonologists have adopted the 2020 guidelines.

Both Daley and Griffith served on the 2020 guideline update writing committee.

"I think both clinicians and patients are more aware of NTM pulmonary disease than they were when the guidelines were last updated in 2007, so I am hopeful that these guidelines will be utilized," Daley said.

He said a key issue addressed for the first time in the updated guidelines is which patients with NTM pulmonary disease should receive treatment and which could benefit from a "watchful waiting" approach.

The guidelines state that treatment "should be initiated rather than waiting for progression in patients who meet the diagnostic criteria for NTM pulmonary disease, especially when acid-fast bacilli sputum smears are positive and/or there is evidence of cavitary lung disease."

While there are around 200 species of NTM, the guidelines focus on the ones that most commonly cause pulmonary disease, specifically the slow-growing NTM’s MAC, M. kansasii, and M. xenopi, and the fast-growing NTM M. abscessus.

Griffith told BreakingMED that one of the most misunderstood aspects of NTM management is the poor correlation between in vitro drug susceptibility testing and treatment response and patient improvement.

"Not everyone can be an (NTM-treatment) expert, and my plea to clinicians is to just start with the guidelines and don’t freelance," he said. "And when you get stuck, ask an expert."

The newly published analysis of NTM patient treatment patterns, reported by researcher Jennifer Ku, PhD, of Kaiser Permanente Southern California, Pasadena, and colleagues, included 1,038 registry participants with MAC- and 120 with M. abscessus-related pulmonary disease enrolled in the U.S. Bronchiectasis and NTM Research Registry (BRR), which includes 13 treatment sites in the United States. Demographic and clinical data on all participants were collected for the 24 months prior to registry enrollment, along with data collection annually following enrollment.

In all, 82% of the MAC patients were female, and their mean age was 67 years. A total of 411 (40%) started or continued antibiotic treatment during the 24-month baseline period, and those who were and were not treated has similar characteristics.

The most commonly used antibiotic drugs in these patients with MAC were macrolides (68%), azithromycin (59%), ethambutol (65%), rifamycin (60%), and rifampin (58%). The most commonly used drug regimen was the guideline-based therapy combination of macrolide, rifamycin, and ethambutol with or without amikacin, which was used in 48% of treated patients. Other reported regimens included the combination of a macrolide and ethambutol (6%), macrolide, rifamycin, ethambutol, and fluoroquinolone (4%), and macrolide and amikacin (3%). Just 2% of treated MAC patients were treated with macrolide plus rifamycin, which has been associated with an increased risk of acquired macrolide resistance.

Roughly 1-in-5 (21%) patients treated for MAC-related pulmonary disease experienced treatment-related adverse events.

Amikacin-related hearing loss occurred in 17% of patients treated with the drug intravenously and in 9% using inhaled amikacin, and ethambutol-related optic neuritis occurred in 2.6% of patients treated with that drug. Gastrointestinal issues were commonly reported in patients treated with azithromycin, clarithromycin, rifabutin, rifampin, levofloxacin, and moxifloxacin.

A total of 33 (28%) of the 120 study participants with M. abscessus infection started or continued antibiotic treatment during the baseline period, and characteristics were similar between those who did and did not receive treatment during the 24-month period. Most patients with M. abscessus pulmonary disease were non-Hispanic White and female, and the average age was 68 years among treated patients and 64 years among untreated patients.

Other findings among the 33 participants with M. abscessus included the following:

• Macrolides were used in the treatment 81% of treated patients, with azithromycin used in 70% and clarithromycin used in 24%.
• Inhaled amikacin was used by 24%, while 15% used rifamycin, rifampin, linezolid, and/or fluoroquinolone, respectively.
• A total of 33% received macrolide monotherapy, and various macrolide-containing regimens were reported, including macrolide+fluoroquinolone (n=4) and macrolide+linezolid with or without amikacin (n=4).

In all, 18% of patients treated for M. abscessus reported adverse effects, with one patient each reporting rifampin-attributed hepatitis, rifampin-attributed transaminitis, and linezolid-attributed peripheral neuropathy.

A study limitation cited by the researchers was the case definition criteria chosen, which included patients with a single positive respiratory culture. This could have led to the inclusion of patients who did not need treatment, which could have contributed to lower treatment rates than have been reported in previous studies, Ku et al noted.

In addition, they wrote that their results may not be generalizable, since BRR sites specialize in bronchiectasis treatment, and clinicians in these sites "may be more aware of the current treatment guidelines than general clinic settings."

Despite these limitations, Ku and colleagues concluded that the findings "highlight poor adherence to ATS/IDSA treatment guidelines and provide important data on the frequency of adverse events determined to be attributed to various antibiotics.

"Factors such as adverse events and tolerability play important roles in the way patients with pulmonary MAC or M. abscessus infection are treated in the United States," they added. "Further research is necessary to evaluate reasons for therapy interruptions and poor adherence to recommended treatment regimens."

This work was supported by the COPD Foundation, a 501(c)(3) nonprofit organization that manages the Bronchiectasis and NTM Research Registry. The registry is funded by the Richard H. Scarborough Bronchiectasis Research Fund, the Anna-Maria and Stephen Kellen Foundation, and the Bronchiectasis and NTM Industry Advisory Committee.

Ku reported no disclosures.

Researcher Emily Henkle reported receiving advisory and consulting fees from MannKind. Timothy Aksamit andAmanda Brunton reported leadership roles in the U.S. Bronchiectasis and NTM Registry and the COPD Foundation. Kevin Winthrop reported receiving grants and contracts from Insmed, Paratek, Red Hill Biopharma, AN2 and Renovion and receiving consulting fees from Insmed, Paratek, RedHill Biopharma, Spero Therapeutics, AN2, Vast, and Renovion.

Ku JH, et al "Treatment of nontuberculous mycobacteria pulmonary infection in the U.S. bronchiectasis and NTM registry: Treatment patterns, adverse events and adherence to American Thoracic Society/Infectious Disease Society of America treatment guidelines" Clin Infect Dis 2023; DOI: 10.1093/cid/ciac788.