Guideline-based management and treatment of NTM lung disease
The 2020 NTM Guidelines recommend treatment initiation rather than "watchful waiting" in certain diagnosed patients.1
When making treatment decisions for nontuberculous mycobacterial (NTM) lung disease, such as Mycobacterium avium complex (MAC) lung disease, the 2020 NTM Guidelines recommend initiating treatment rather than watchful waiting for certain diagnosed patients and suggest that the decision should be individualized based on a combination of clinical factors.1
The 2020 NTM Guidelines recommend frequent follow-up visits after initiating MAC treatment, including obtaining sputum cultures every 1 to 2 months to assess response1
Retrospective studies have shown that most MAC patients who convert on treatment do so within 6 months after starting treatment8-10
When should I consider treatment immediately?
After confirming an NTM lung disease diagnosis, the 2020 NTM Guidelines recommend treatment initiation rather than “watchful waiting” in certain diagnosed patients, especially in those with positive AFB sputum smears and cavitary disease. The decision to initiate antibiotic treatment should be individualized based on a risk-benefit analysis, taking into account patient symptoms, radiologic findings, and microbiologic results.1
Read more about the factors and circumstances that should get you thinking about treatment:
Factors associated with progressive disease
Several studies identified specific NTM patient factors that were associated with progressive disease and led to more immediate antibiotic treatment initiation. Other studies have identified factors associated with poor prognosis and radiographic progression.1-6
These factors may warrant closer evaluation of antibiotic treatment initiation:
Extent of disease on CT scan
≥4 lobes involved11
Cavities with a maximum inner diameter of ≥10 mm12
Presence of consolidation at initial presentation6
Elevated inflammatory markers1
Major symptoms diminishing QOL1
More virulent organism1
Organism more responsive to treatment1
Respiratory symptoms, such as cough or sputum production5
AFB smear positivity3,13
NTM species and subspecies
Presence of Mycobacterium intracellulare4,11
Presence of Mycobacterium abscessus4
History of TB5
Chronic pulmonary aspergillosis4
Read studies about the contributors to disease progression or disease progression that may prompt treatment initiation:
A retrospective study of the natural course of stable MAC lung disease in 488 MAC patients found that
(305/488) of untreated MAC patients experienced progressive disease3
Factors identified in this study
Progressive disease was defined as clinical deterioration resulting in initiation of antibiotic treatment within 3 years of diagnosis3
Factors associated with clinical deterioration leading to treatment initiation within 3 years of diagnosis included systemic symptoms (eg, fever, fatigue, or weight loss), sputum AFB smear positivity, and fibrocavitary type or more extensive disease3
In a retrospective study of the natural history of MAC lung disease,
(323/551) of patients with noncavitary nodular bronchiectatic MAC lung disease received treatment11
Factors identified in this study
Risk factors related to the initiation of treatment within 3 years of diagnosis were age ≤60 years, an initial sputum smear result positive for AFB, the presence of M intracellulare, the presence of coughing or systemic symptoms, BMI >18.5 kg/m2, and the involvement of ≥4 lobes11
In a retrospective study,
(126/265) of untreated MAC patients experienced progressive disease6
Factors identified in this study
Progressive disease was defined as radiologic deterioration and worsening symptoms resulting in initiation of antibiotic treatment over a mean follow-up period of 2.7 years6
Independent factors associated with disease progression to treatment were the presence of a cavity and consolidation at initial CT6
Read more about disease progression and treatment initiation:
A retrospective study, including 1445 newly diagnosed South Korean patients with NTM lung disease, determined overall 5-, 10-, and 15-year cumulative mortality rates of 12.4%, 24.0%, and 36.4%, respectively4
Some of the mortality prognostic factors included old age, male gender, low BMI, chronic pulmonary aspergillosis, M intracellulare infection, M abscessus infection, and cavitary disease4
In a retrospective study of newly diagnosed patients with nodular bronchiectatic NTM lung disease caused by MAC or M abscessus, 55% (562/1021) of patients initiated antibiotic treatment after a median of 1.1 years5
The initiation of antibiotic treatment was associated with younger age, lower BMI, history of TB, respiratory symptoms such as cough and sputum production, and extensive disease on HRCT scans5
In a retrospective study including 66 patients with NTM lung disease, 28% (17/60) of untreated patients experienced radiographic progression13
Independent risk factors for radiographic progression included male gender, BMI <18.5 kg/m2, use of inhaled corticosteroids, and acid-fast smear Grade ≥213
In a retrospective study of 97 MAC patients presenting with cavities, 53% (52/97) of patients experienced cavity progression12
Characteristics of initial presentation associated with progressive cavities included consolidation, atelectasis, and pleural thickening around the initial cavity12
Active monitoring of patients who are not on antibiotic treatment
If deciding not to initiate immediate antibiotic treatment, an active monitoring plan is recommended by guidelines.1
Study data suggest that untreated NTM could progress. Guidelines recommend regular sputum cultures and routine monitoring in order to assess disease progression.1,3
Read more about the outcomes if NTM/MAC is left untreated:
(126/265) of untreated MAC patients experienced progressive disease that required initiation of antibiotic treatment over a mean follow-up period of 2.7 years6
(305/488) of untreated MAC lung disease patients showed progressive MAC lung disease leading to treatment initiation within 3 years of diagnosis3
(562/1021) of newly diagnosed patients with nodular bronchiectatic NTM lung disease initiated antibiotic treatment after a median of 1.1 years5
NTM treatment decisions are often difficult and require experience managing the disease. This can mean that a peer consultation or referral to a pulmonologist or ID specialist with experience in NTM may be necessary.1,14-16
When my cough wouldn't go away, I saw about 20 different doctors before I finally had my answer.
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Barbara’s long and frustrating misdiagnosis took her from doctor to doctor with no one having the right expertise to help. Watch “Unbreakable,” an animation inspired by Barbara’s story.
Airway clearance is a vital part of all stages of NTM management2,17
Airway clearance techniques are an important aspect of treatment for all patients with NTM lung disease, regardless of whether or not patients are on pharmacotherapy. Airway clearance strategies should be considered in patients with NTM lung disease who have significant mucus production and clearance problems.2,17
In patients with bronchiectasis, various airway clearance techniques have been shown to lead to fewer respiratory symptoms, greater sputum expectoration, and improved health-related QOL.18
Airway clearance techniques include:
Forced exhalation (huff) exploits the equal pressure point theory and accelerates the expiratory airflow, resulting in high linear velocities that shear mucus from the airway walls.17,19,20
This technique is characterized by breathing control using expiratory airflow to mobilize secretions from smaller to larger airways. Secretions are cleared independently by adjusting the depth and speed of respiration in a sequence of controlled breathing techniques during exhalation.19,21
Manual techniques loosen mucus by using percussion, chest wall vibrations or shaking, and chest compressions. These techniques are used to loosen secretions and to reduce fatigue or increase effectiveness of other airway clearance methods.20
Increased mobility increases oxygen demand, resulting in an increase in ventilation and lung volume.17,20
Secretion clearance may be enhanced if patients are encouraged to cough and clear their chests during exercise and activity or if regular and timed forced expiration techniques are included throughout exercise.20
Simple measures of systemic and targeted hydration of the airways can optimize airway clearance in patients with CF and non-CF bronchiectasis.20
Optimal conditions for mucosal function require 37°C and 100% relative humidity.20
This is a flow-regulating technique employing PEPs to maximize collateral ventilation.17,19,20
PEP devices may contain an expiratory oscillatory component to help loosen secretions and reduce mucus viscoelasticity.20
Nebulized solutions, including humidification and the use of mucoactive agents such as dornase alfa (DNase) and hypertonic saline, prevent sputum retention and aid in mucociliary clearance. Bronchodilators may also be beneficial if administered prior to airway clearance techniques.17,20
Initiating a multidrug treatment according to the 2020 NTM Guidelines
When you decide to initiate treatment, whether immediately after an NTM diagnosis or in response to disease progression upon active monitoring of a diagnosed NTM patient, the 2020 NTM Guidelines recommend assessing several patient-specific factors to develop a treatment plan.1,14
Nonpharmacologic techniques remain an important aspect of a holistic treatment approach for all NTM patients, including airway clearance, nutritional counseling, and exercise, among others. Due to the complexities of NTM, management and treatment may require a multidisciplinary approach with communication across a wide range of specialties—from infectious disease specialists to pulmonologists to primary care physicians to dietitians to pharmacists.2,14,16,20,23-25
Patient-specific considerations when initiating treatment
Disease severity and progression1
NTM species and subspecies1
Patient willingness and needs1,2,26
Guideline-recommended multidrug regimen by species
Rapid species and subspecies identification is paramount in order to implement the right treatment regimen.27
Amikacin (IV) 10–15 mg/kg per daya-c Streptomycin (IV or IM) 10–15 mg/kg per daya
aAdjusted according to drug level monitoring.1bThe use of the described regimens for 15 weeks was associated with permanent ototoxicity in approximately one-third of patients, and the risk was associated with age and cumulative dose. Given the high rates of ototoxicity, risks and benefits should be carefully considered in light of the goals of therapy. Clinicians should consider lower dose ranges and probably rely on intermittent dosing when more prolonged therapy is employed.1cDrug level monitoring: trough <5 mg/L; peak with daily dosing 35–45 μg/mL; peak with intermittent dosing 65–80 μg/mL.1
The multidrug regimen is dependent on disease severity and how the disease initially presents1
A macrolide with a single companion drug, ethambutol, is the regimen with the fewest possible drugs for treating MAC because of the risk of macrolide resistance1
Patients respond best to MAC treatment regimens the first time they are administered; therefore, it is very important that patients receive recommended multidrug therapy the first time they are treated for MAC lung disease2
Treatment is recommended for 12 months after culture conversion1
Baseline susceptibility testing to specific drugs for NTM isolates in patients with definite disease is recommended by the guidelines. Correlation between in vitro susceptibility testing for MAC and clinical response has only been established for a limited number of antibiotics, including1,28:
There are no drug regimens of proven or predictable efficacy for treatment of the rapidly growing mycobacteria (RGM), M abscessus1
Multidrug regimen administered, including rifampin 10 mg/kg/day (maximum 600 mg), ethambutol 15 mg/kg/day, and either isoniazid 5 mg/kg/day (maximum 300 mg) or a macrolide (azithromycin 250 mg/day [maximum 500] or clarithromycin 500 mg/twice a day)1
Patients with rifampin-susceptible M kansasii pulmonary disease should be treated for at least 12 months1
MANAGEMENT RECOMMENDATIONS FOR THE MOST COMMON PATHOGENIC SPECIES1
Scroll to see full chart.
≥3 (active) drugs:
imipenem (or cefoxitin)
Rifampicin (rifabutin) + ethambutol + isoniazid or azithromycin (clarithromycin)
Macrolides and amikacin should be tested for all M abscessus isolates
Rifampicin and macrolide susceptibility should be tested for all M kansasii isolates
Insufficient evidence to recommend susceptibility-based treatment
The inclusion of a macrolide in the multidrug regimen depends on the macrolide susceptibility of the isolate
Treatment regimen should be chosen in collaboration with an expert
Routine use of parenteral streptomycin and amikacin is no longer recommended; may be used for severe disease
Fluoroquinolones may be used for rifampicin-resistant isolates or intolerance to a first-line antibiotic
Parenteral amikacin may be added to the regimen for cavitary or severe disease
Some medications may need to be introduced gradually at 1 to 2 week intervals so appropriate evaluations of tolerance can be performed.2
Subspeciation for M abscessus is important because certain subspecies may have inducible macrolide resistance, which may impact treatment decisions.29,30
Inducible erm (41) gene
Inducible macrolide resistance
Given the differing sensitivities of each M abscessus subspecies, it is essential to choose long-duration (14-day) drug susceptibility tests so that you can more accurately identify the resistance patterns in the sample. This close collaboration with your microbiology laboratory can help you select the most appropriate treatment course for each patient.23,29
When we begin treatment, I always take a lot of time to discuss potential side effects with patients because I think education is the number one strategy for mitigating side effects. And what I mean by that is we want to try to prevent them from happening in the first place. So one of the strategies we use is talking about the timing of when a patient will take the medications.
We know that with certain medications, they're more prone to cause nausea and vomiting. And so, for example, we may ask the patient to take that medication at night before going to bed. Another strategy that we use to identify specific medications that maybe causing side effects is by having the patient introduce the medications one at a time. I typically have them initiate the antibiotic one at a time in alphabetical order, which makes it easier for the patient, and I usually ask them to take that medication for four to five days on its own before adding the second, and then, subsequently, the third medication because then we're able to easilyidentify the culprit.
Macrolide resistance is associated with poor outcomes1,31
Maintaining a multidrug regimen for NTM can be challenging and prescriber adherence to guidelines is sometimes low.32
Macrolide monotherapy is commonly prescribed in NTM lung disease and can be a key driver in the development of macrolide-resistant strains, leading to poor outcomes for NTM treatment.31,32
A nationally representative sample of physicians, including specialists in pulmonology, infectious diseases, internal medicine, and family/general practice, was used to examine treatment practices for MAC and M abscessus lung disease. 349 of 582 eligible physicians completed questionnaires on 915 patients diagnosed with NTM lung disease, including 744 (81%) with MAC infections.32
Results from questionnaire32
Treatment regimens for MAC lung disease meeting 2007 ATS/IDSA Statement guidelines (N=579)
Treatment regimens for MAC lung disease NOT meeting 2007 ATS/IDSA Statement guidelines (N=579)
of treatment regimens prescribed may increase antibiotic resistance
(39/51) of MAC lung disease patients became resistant after being treated with either macrolide monotherapy or a macrolide plus a quinolone compared with 18% (9/51) of patients started on the 3-drug regimen33
As macrolide monotherapy can be commonly prescribed for bronchiectasis patients, it is important to rule out NTM lung disease before starting macrolide monotherapy to avoid creating macrolide-resistant disease.1,32,34
Read more about the importance of checking for NTM before prescribing macrolide monotherapy:
A retrospective review of MAC lung disease patients showed a
5-year all-cause mortality rate after the development of macrolide resistance31
A retrospective cohort study of 108 patients hospitalized with Mycobacterium abscessus lung disease identified clarithromycin resistance as a predictor of early
(OR=79.5; 95% CI: 6.2-3717.1; P<0.001)35
Setting patient expectations is critical for appropriate treatment1,26
Treatment for NTM can be challenging for both patient and physician, so a working partnership between both parties is important.26,32
When initiating treatment, setting expectations for patients is critical for the appropriate management of NTM lung disease. It’s important to discuss length of therapy, treatment response, follow-up appointments, and potential adverse events with patients.1,26
The 2020 NTM Guidelines recommend continuing MAC* treatment for 12 months after culture conversion. When initiating antibiotic treatment in patients with macrolide-susceptible MAC lung disease, especially in the context of positive AFB sputum smears and/or cavitary lung disease, the multidrug regimen should consist of at least 3 drugs (including a macrolide and ethambutol)1
Maintain treatment for 12 months of negative cultures post conversion2
In a study of 154 MAC lung disease patients, patients who were treated for <15 months after culture conversion were
to experience recurrence
than those treated for ≥15 months post culture conversion8
There may be side effects associated with NTM treatment. Discussing what to expect with patients, along with potential management techniques and lifestyle modifications, may help patients complete treatment2,26
After treatment initiation, it is important to establish and maintain a treatment monitoring plan, inclusive of regular follow-ups and sputum cultures1,2,14
Response to treatment will be assessed early and often throughout the treatment duration so that adjustments to the treatment plan can be made, if needed1,2
When I'm starting a patient on treatment for NTM lung disease, I really take the time to have a long discussion with them to try to review expectations of treatment. And we do take an extensive amount of time reviewing each of the antibiotics individually to review potential side effects, but more importantly, to try to provide strategies to limit the side effects in the first place and try to give them some control over how they're taking the medications.
I also discuss routine monitoring while they're on therapy. And that includes laboratory monitoring, referral to an ophthalmologist, and also the potential for audiometry. I also provide a lot of reassurance to the patient to let them know that there is a partnership between myself and the patient, but also all of the different caregivers on the team, and that they're not alone in this journey, because it can be very stressful.
I think it can cause a lot of anxiety to be on so many medications, and also the fact that they do have to take it for a long period of time. And we let them know that there's psychosocial supports, nutritional support, and that everyone in their care team is communicating. And I think it's important for them to know that and gives them a sense of confidence about their treatment plan.
MONITORING RESPONSE TO TREATMENT
THE 2020 NTM GUIDELINES RECOMMEND THE FOLLOWING STEPS IN MANAGING MAC TREATMENT1
MAC lung disease diagnosis
Initiate multidrug regimen
The 2020 NTM Guidelines recommend treatment initiation rather than “watchful waiting” for certain diagnosed patients, especially in those with positive AFB sputum smears and cavitary disease. The decision should be individualized based on a combination of clinical factors.
1 to 5 months after treatment initiation
Obtain sputum cultures every 1 to 2 months
Guidelines recommend obtaining sputum cultures every 1 to 2 months to assess response and determine duration of therapy.
6 months after treatment initiation
Responding to treatment at 6 months?
Alternative management approach is recommended
Continue initial therapy
Continue MAC* treatment for 12 months after culture conversion1
It is important to have a plan of action ready for your patients who do not respond to treatment.1
Guidelines recommend monitoring sputum cultures regularly to assess treatment response1
The 2020 NTM Guidelines recommend obtaining sputum cultures every 1 to 2 months to assess response and determine duration of therapy. Not seeing a response may be a sign that treatment has failed to achieve a microbiologic response and another treatment option may be needed.1
Monitoring sputum cultures frequently and early in treatment is important because study data suggest that if patients remain culture positive, it may be an early sign that they will have future radiographic progression and lung function decline.36,37
Read more about the effects of patients remaining culture positive:
In a study of 358 NTM lung disease patients, patients who did not convert within 12 months after starting treatment had
as compared to patients who did convert36
The median time from beginning of study to follow-up spirometry was 5.6 years36
Patients who did not convert had a greater median FEV1 decline (-52.2 mL/y) and median FVC decline (-50.4 mL/y) than patients who did convert (-28.2 mL/y and -26.0 mL/y, respectively)36
In a study of 126 MAC lung disease patients, patients who remained culture positive were
more likely to experience
Radiographic progression was defined as an increased number of involved lung segments or cavitary formation after 1 year37
54% of patients who remained culture positive experienced radiographic progression vs 30% of converted patients37
Other treatment monitoring considerations
Side effect monitoring
Monitor for adverse drug reactions routinely as side effects and intolerance can be common with multidrug NTM lung disease regimens. According to the 2020 NTM Guidelines, it’s important to individualize the frequency of monitoring for adverse reactions based on patient age, comorbidities, concurrent drugs, overlapping drug toxicities, and resources1,2,14
Some medications may need to be introduced gradually at 1- to 2-week intervals so appropriate evaluations of tolerance can be performed2
According to the 2020 NTM Guidelines, monitoring for the development of drug toxicity should include, but is not limited to1:
Auditory and vestibular function
Complete blood count
Depending on the antibiotics selected, there may be a need to refer to other specialists for routine monitoring, including an
Ophthalmologist for vision testing2
Audiologist to take baseline audiograms and hearing tests2
It’s important to review the medication list of NTM patients before starting treatment, and monitor for potential interactions throughout the treatment period.2,14
Response to treatment should be seen within 6 months1
The 2020 NTM Guidelines recommend frequent follow-up visits after initiating MAC treatment, including obtaining sputum cultures every 1 to 2 months to assess response. An alternate management approach is recommended after 6 months of treatment failure.1
Retrospective studies have shown that among the NTM lung disease patients who will convert on standard first-line multidrug treatment, a majority will likely do so within 6 months of treatment initiation.8-10
Read more about treatment response and culture conversion:
In a post-hoc analysis of newly diagnosed MAC lung disease patients who started standard multidrug treatment, 357 patients achieved culture conversion within 12 months9,10
(336/357) achieved conversion within 6 months of starting treatment9
(21/357) achieved conversion between 6 and 12 months9
In a study of 154 MAC lung disease patients who received standard multidrug treatment and converted,
(121/154) of patients converted within 3 months8
Median time to culture conversion was
In a study of 180 treated MAC lung disease patients, 148 patients achieved culture conversion within 12 months38
(123/148) of those patients converted to negative within 6 months after starting treatment38
Refractory disease requires reevaluating and adjusting the treatment regimen1
The 2020 NTM Guidelines recommend an alternate management approach be initiated once a patient with MAC lung disease has failed to achieve sputum conversion after 6 months of treatment.1
Within 6 months of starting treatment, determine if a patient has responded to therapy. Study data show that ~30% of NTM/MAC patients will fail to respond on standard first-line multidrug treatment.1,9,10,39
In a retrospective study of 217 MAC lung disease patients,
of patients failed to achieve sputum culture conversion within 6 months39
In a post-hoc analysis of newly diagnosed MAC lung disease patients,
(113/470) of patients failed to achieve sputum culture conversion within 12 months9,10
I think about patients not being responsive to treatment when their cultures don't convert over a period of months. Now usually, the majority of my patients I see will convert their sputum or their sputum will become negative within six months or so. So it's around that time frame when their sputums remain positive that I start to ask myself some questions-- are they still drug susceptible? Is the patient taking the medication the right way? Do we have a problem with adherence with the medications or side effects?
And so at that point, I'll start to do a deeper dive and investigate the reasons why they may not be responding to therapy. You cancertainly also look at radiographs. And over time if their radiographs do not improve or certainly if they worsen or if the patient says, I simply feel worse, those are other reasons that warrant a prompt investigation.
Treatment success involves a multidisciplinary approach
Comprehensive care and good communication across a multidisciplinary team of healthcare providers is important in NTM management. Due to the complexities of NTM, management and treatment sometimes require multiple specialists to ensure the best quality care.14,16,23
Multidisciplinary treatment includes:
Infectious disease specialists16
Primary care physicians23,24
Mental health care providers24
*In patient with macrolide-susceptible MAC pulmonary disease.1
AFB=acid-fast bacilli; ATS=American Thoracic Society; BMI=body mass index; CF=cystic fibrosis; CI=confidence interval; CT=computed tomography; DNase=dornase alfa; erm=erythromycin ribosome methylation; FEV1=forced expiratory volume in the first second; FVC=forced vital capacity; HFCWO=high-frequency chest wall oscillation; HRCT=high-resolution computed tomography; ICS=inhaled corticosteroids; ID=infectious disease; IDSA=Infectious Diseases Society of America; IM=intramuscular; IV=intravenous; MAC=Mycobacterium avium complex; NTM=nontuberculous mycobacteria; OR=odds ratio; PEP=positive expiratory pressure; QOL=quality of life; RGM=rapidly growing mycobacteria; TB=tuberculosis.
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