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

After confirming an NTM lung disease diagnosis:

  • Certain factors like cavitary disease and low BMI have been associated with progressive disease and may necessitate earlier consideration of antibiotic treatment1-6
  • If you decide not to initiate antibiotic treatment, an active monitoring plan is recommended by the 2020 NTM Guidelines1
  • Studies show that a majority of untreated MAC lung disease patients will have progressive disease resulting in the need for antibiotic treatment3,7
    • 62.5% (305/488) of untreated MAC patients experienced progressive disease that required initiation of antibiotic treatment within 3 years of diagnosis3
  • When you decide to initiate antibiotic treatment, the 2020 NTM Guidelines recommend a multidrug regimen1

After initiating antibiotic treatment:

  • 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:

  • Fibrocavitary disease3
  • Extent of disease on CT scan
    • ≥4 lobes involved11
    • Cavities with a maximum inner diameter of ≥10 mm12
    • Presence of consolidation at initial presentation6
  • Low BMI4
  • Low albumin1
  • Elevated inflammatory markers1
  • Immunosuppression1
  • 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
  • ICS use13
  • Male gender4,13
  • 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

Inspired by one patient’s story

UNBREAKABLE

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:

Device independent

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

Read more on how to perform this technique

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

Read more on how to perform this technique

Postural positioning is a drainage technique that uses gravity to promote ventilation to affected areas of the lungs.19,20

Read more on how to perform this technique

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

Read more on how to perform these techniques

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

Device dependent

Mask

This is a flow-regulating technique employing PEPs to maximize collateral ventilation.17,19,20

With oscillation

PEP devices may contain an expiratory oscillatory component to help loosen secretions and reduce mucus viscoelasticity.20

Read more on how to perform these techniques

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

Read more on how to perform this technique

This device enhances mucociliary transport by altering the rheological properties of mucus, creating expiratory flow bias to dislodge mucus, and promoting the movement of mucus.19,20,22

Read more on how to perform this technique

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

  • Patient comorbidities1,2
  • 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

MAC (Mycobacterium avium complex)

MAC treatment varies by presentation1

Scroll to see full chart.

Nodular bronchiectatic disease
(thrice-weekly dosing)
Cavitary or advanced/severe bronchiectatic disease
(daily dosing, or thrice-weekly dosing may be used with aminoglycosides)
Macrolide (Preferred)
(Alternative)
Azithromycin 500 mg per day
or clarithromycin 500 mg twice per day
Azithromycin 250–500 mg per day
or clarithromycin 500 mg twice per day
Rifamycin (Preferred)
(Alternative)
Rifampicin 600 mg per day
or rifabutin 300 mg per day
Rifampicin 10 mg/kg (450 mg or 600 mg) per day
or rifabutin 150–300 mg per day (150 mg per day with clarithromycin)
Ethambutol25 mg/kg per day15 mg/kg per day
Parenteral aminoglycoside (Preferred)
(Alternative)
NoneAmikacin (IV) 10–15 mg/kg per daya-c
Streptomycin (IV or IM) 10–15 mg/kg per daya
aAdjusted according to drug level monitoring.1 bThe 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.1 cDrug 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:
    • Clarithromycin
    • Amikacin
Mycobacterium abscessus
  • There are no drug regimens of proven or predictable efficacy for treatment of the rapidly growing mycobacteria (RGM), M abscessus1
Mycobacterium kansasii
  • 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.

SPECIES
Mycobacterium abscessusMycobacterium kansasiiMycobacterium xenopi
Regimen≥3 (active) drugs:
  • parenteral amikacin
  • imipenem (or cefoxitin)
  • tigecycline
  • macrolide
  • clofazimine
  • linezolid
Rifampicin (rifabutin)
+
ethambutol
+
isoniazid or azithromycin (clarithromycin)
Rifampicin (rifabutin)
+
ethambutol
+
azithromycin (clarithromycin) and/or moxifloxacin
Treatment durationDetermined on a case-by-case basis≥12 months beyond culture conversion≥12 months beyond culture conversion
Drug susceptibilityMacrolides and amikacin should be tested for all M abscessus isolatesRifampicin and macrolide susceptibility should be tested for all M kansasii isolatesInsufficient evidence to recommend susceptibility-based treatment
Additional notes
  • 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
NTM being introduced at 1 week intervals

Subspeciation for M abscessus is important because certain subspecies may have inducible macrolide resistance, which may impact treatment decisions.29,30

SubspeciesInducible erm (41) geneInducible macrolide resistance
M abscessusYesYes
M bolletiiYesYes
M massilienseNoNo

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

Dr Wendi K Drummond on Treatment Monitoring

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


(n=77)

(n=502)
  • 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)
 (n=174/579)
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
Furuuchi 2020

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

Dr Wendi K Drummond on setting treatment expectations

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?
NO
Alternative management approach is recommended
YES
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:

Park 2016

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
Pan 2017

In a study of 126 MAC lung disease patients, patients who remained culture positive were

more likely to experience
 37
  • 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:
      • Visual acuity
      • Color discrimination
      • Liver function
      • Auditory and vestibular function
      • Renal 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

Drug interactions

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:

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

Dr Julie Philley on treatment response

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:

  • Pulmonologists16
  • Infectious disease specialists16
  • Respiratory therapists40
  • Radiologists23
  • Microbiologists23
  • Primary care physicians23,24
  • Nurses40
  • Pharmacists25
  • Ophthalmologists2
  • Audiologists2
  • Surgeons16
  • Dietitians/nutritionists2
  • 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.