Treatment of Nontuberculous Mycobacterial Pulmonary Disease
Publication Date: July 6, 2020
Introduction
Introduction
- Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites.
- This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM.
- The Panel recommends that clinical, radiographic, and microbiologic data be collected to monitor response to therapy, expectations be set for the patient's progress and patient cooperation be enlisted in identifying adverse drug reactions. (See full text guideline for further details)
Diagnosis
Diagnosis
Table 1. Clinical, Radiographic and Microbiologic Criteria for Diagnosis NTM Pulmonary Diseasea
| Clinical | Pulmonary or Systemic Symptoms | Both clinical and radiologic criteria required |
| Radiologic | Nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows bronchiectasis with multiple small nodules | |
| and | Appropriate exclusion of other diagnoses | |
| Microbiologicb |
| |
Expert consultation should be obtained when aNTM are recovered that are either infrequently encountered or that usually represent environmental contamination. Patients who are suspected of having NTM pulmonary disease but do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded. Making the diagnosis of NTM pulmonary disease does not per se, necessitate the institution of therapy, which is a decision based on the potential risks and benefits of therapy for individual patients.
When 2 positive cultures are obtained, the isolates should be the same bNTM species (or subspecies in the case of M. abscessus) in order to meet disease criteria.
When 2 positive cultures are obtained, the isolates should be the same bNTM species (or subspecies in the case of M. abscessus) in order to meet disease criteria.
Treatment
Treatment
Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the guidelines provide evidence-based recommendations that have been developed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. GRADE involves structured literature review, systematic reviews and meta-analyses of combined data, and expert discussion to assess the certainty in the evidence and determine the strength of each recommendation. (See Table 5)
Treatment of NTM Pulmonary Disease
In patients who meet the diagnostic criteria for NTM pulmonary disease (Table 1), we suggest initiation of treatment rather than watchful waiting, especially in the context of positive acid-fast bacilli sputum smears and/or cavitary lung disease. (C, VL)
620
In patients with MAC pulmonary disease, we suggest susceptibility-based treatment for macrolides and amikacin over empiric therapy. (C, VL)
620
In patients with M. kansasii pulmonary disease, we suggest susceptibility-based treatment for rifampicin over empiric therapy. (C, VL)
620
In patients with M. xenopi pulmonary disease, the panel members felt there is insufficient evidence to make a recommendation for or against susceptibility-based treatment.
In patients with M. abscessus pulmonary disease we suggest susceptibility-based treatment for macrolides and amikacin over empiric therapy. (C, VL)
For macrolides, a 14-day incubation and/or sequencing of the erm(41) gene is required in order to evaluate for potential inducible macrolide resistance.
620
Mycobacterium avium Complex (MAC) (Table 2)
In patients with macrolide-susceptible MAC pulmonary disease, we recommend a 3-drug regimen that includes a macrolide over a 3-drug regimen without a macrolide. (S, VL)
620
In patients with macrolide-susceptible MAC pulmonary disease we suggest azithromycin-based treatment regimens rather than clarithromycin-based regimens. (C, VL)
620
For patients with cavitary or advanced/severe bronchiectatic or macrolide-resistant MAC pulmonary disease, we suggest that parenteral amikacin or streptomycin be included in the initial treatment regimen. (C, M)
620
In patients with newly diagnosed MAC pulmonary disease, we suggest neither inhaled amikacin (parenteral formulation) nor amikacin liposome inhalation suspension (ALIS) be used as part of the initial treatment regimen (C, VL)
620
In patients with MAC pulmonary disease who have failed therapy after at least 6 months of guideline-based therapy, we recommend addition of ALIS to the treatment regimen rather than a standard oral regimen, only. (S, M)
620
In patients with macrolide-susceptible MAC pulmonary disease, we suggest a treatment regimen with at least 3 drugs (including a macrolide and ethambutol) over a regimen with 2 drugs (a macrolide and ethambutol alone). (C, VL)
620
In patients with noncavitary nodular/bronchiectatic macrolide-susceptible MAC pulmonary disease, we suggest a 3 times per week macrolide-based regimen rather than a daily macrolide-based regimen. (C, VL)
620
In patients with cavitary or severe/advanced nondular bronchiectatic macrolide-susceptible MAC pulmonary disease we suggest a daily macrolide-based regimen rather than 3 times per week macrolide-based regimen. (C, VL)
620
We suggest that patients with macrolide-susceptible MAC pulmonary disease receive treatment for at least 12 months after culture conversion. (C, VL)
620
Mycobacterium kansasii (Table 2)
In patients with rifampicin-susceptible M. kansasii pulmonary disease, we suggest a regimen of rifampicin, ethambutol, and either isoniazid or macrolide. (C, VL)
620
We suggest that neither parenteral amikacin nor streptomycin be used routinely for treating patients with M. kansasii pulmonary disease. (S, VL)
620
In patients with rifampicin-susceptible M. kansasii pulmonary disease, we suggest using a regimen of rifampicin, ethambutol, and either isoniazid or macrolide instead of a fluoroquinolone. (C, VL)
620
In patients with rifampicin-resistant M. kansasii or intolerance to one of the first-line antibiotics we suggest a fluoroquinolone (eg, moxifloxacin) be used as part of a second-line regimen. (C, VL)
620
In patients with noncavitary nodular/bronchiectatic M. kansasii pulmonary disease treated with a rifampicin, ethambutol, and macrolide regimen, we suggest either daily or 3 times weekly treatment. (C, VL)
620
In patients with cavitary M. kansasii pulmonary disease treated with a rifampicin, ethambutol, and macrolide-based regimen, we suggest daily treatment instead of 3 times weekly treatment. (C, VL)
620
In all patients with M. kansasii pulmonary disease treated with an isoniazid, ethambutol, and rifampicin regimen, we suggest treatment be given daily instead of 3 times weekly. (C, VL)
620
We suggest that patients with rifampin susceptible M. kansasii pulmonary disease be treated for at least 12 months. (C, VL)
620
Mycobacterium xenopi (Table 2)
In patients with M. xenopi pulmonary disease, we suggest using a multidrug treatment regimen that includes moxifloxacin or macrolide. (C, VL)
620
In patients with M. xenopi pulmonary disease, we suggest a daily regimen that includes at least 3 drugs: rifampicin, ethambutol, and either a macrolide and/or a fluoroquinolone (eg, moxifloxacin). (C, VL)
620
In patients with cavitary or advanced/severe bronchiectatic M. xenopi pulmonary disease, we suggest adding parenteral amikacin to the treatment regimen and obtaining expert consultation. (C, VL)
620
Mycobacterium abscessus
In patients with M. abscessus pulmonary disease caused by strains without inducible or mutational resistance, we recommend a macrolide-containing multidrug treatment regimen. (S, VL)
620
In patients with M. abscessus pulmonary disease caused by strains with inducible or mutational macrolide resistance, we suggest a macrolide-containing regimen if the drug is being used for its immunomodulatory properties although the macrolide is not counted as an active drug in the multidrug regimen. (C, VL)
620
In patients with M. abscessus pulmonary disease, we suggest a multidrug regimen that includes at least 3 active drugs (guided by in vitro susceptibility) in the initial phase of treatment. (C, VL)
620
In patients with M. abscessus pulmonary disease, we suggest that either a shorter or longer treatment regimen be used and expert consultation obtained. (C, VL)
620
Surgical Resection
In selected patients with NTM pulmonary disease, we suggest surgical resection as an adjuvant to medical therapy after expert consultation. (C, VL)
620
Table 2. Recommended Treatment Regimens for Mycobacterium avium complex, M. kansasii, and M. xenopi Pulmonary Disease
| Organism | No. of Drugs | Preferred Drug Regimena | Dosing Frequency |
|---|---|---|---|
| M. aviums | |||
| Nodular-bronchiectatic | 3 | Azithromycin (clarithromycin) Rifampicin (rifabutin) Ethambutol | 3 times weekly |
| Cavitary | ≥3 | Azithromycin (clarithromycin) Rifampicin (rifabutin) Ethambutol Amikacin IVb (streptomycin) | Daily (3 times weekly may be used with IV aminoglycosides) |
| Refractoryc | ≥4 | Azithromycin (clarithromycin) Rifampicin (rifabutin) Ethambutol Amikacin liposome inhalation suspension or Amikacin IVb (streptomycin) | Daily (3 times weekly may be used with IV aminoglycosides) |
| M. kansasii | |||
| 3 | Azithromycin (clarithromycin) Rifampicin (rifabutin) Ethambutol | Daily | |
| 3 | Azithromycin (clarithromycin) Rifampicin (rifabutin) Ethambutol | 3 times weekly | |
| 3 | Isoniazid Rifampicin (rifabutin) Ethambutol | Daily | |
| M. xenopi | |||
| ≥3 | Azithromycin (clarithromycin) and/or moxifloxacin Rifampicin (rifabutin) Ethambutol Amikacinb | Daily (3 times weekly may be used with IV aminoglycosides) | |
a See Table 2 for recommended dosages. Alternative drugs for patients who are intolerant of or whose isolate is resistant to first-line drugs include clofazimine, moxifloxacin, and linezolid. Some experts would consider bedaquiline or tedizolid.
b Consider for cavitary, extensive nodular/bronchiectatic disease or macrolide-resistant MAC. Amikacin or streptomycin may be given 3 times a week.
c Refractory disease is defined as remaining sputum culture positive after 6 months of guideline-based therapy. Amikacin liposome inhalation suspension (ALIS) has been shown to improve culture conversion when added to guideline-based therapy in treatment refractory patients with MAC pulmonary disease.
b Consider for cavitary, extensive nodular/bronchiectatic disease or macrolide-resistant MAC. Amikacin or streptomycin may be given 3 times a week.
c Refractory disease is defined as remaining sputum culture positive after 6 months of guideline-based therapy. Amikacin liposome inhalation suspension (ALIS) has been shown to improve culture conversion when added to guideline-based therapy in treatment refractory patients with MAC pulmonary disease.
Table 3. Dosing Guidelines for Drugs Used in the Management of NTM Pulmonary Disease
| Drug | Daily Dosing | Thrice Weekly Dosing | Hepatic Impairment | Renal Impairment |
|---|---|---|---|---|
| Oral | ||||
| Azithromycin | 250–500 mg per day | 500 mg per day | N/A | N/A |
| Ciprofloxacin | 500–750 mg twice per day | N/A | N/A | 250–500 mg dosed at intervals according to CrCl |
| Clarithromycin | 500 mg twice per day | 500 mg twice per day | N/A | Reduce dose by 50% if CrCl <30 mL/min |
| Clofaziminea | 100–200 mg per day | N/A | Caution in severe hepatic impairment | N/A |
| Doxycycline | 100 mg once to twice a day | N/A | N/A | N/A |
| Ethambutol | 15 mg/kg per day | 25 mg/kg per day | N/A | Increase dosing interval (eg, 15–25 mg/kg, 3 times per week) |
| Isoniazid | 5 mg/kg up to 300 mg per day | N/A | Caution | N/A |
| Linezolid | 600 mg once or twice per dayb | N/A | N/A | N/A |
| Moxifloxacin | 400 mg per day | N/A | N/A | N/A |
| Rifabutin | 150–300 mg per day (150 mg per day with clarithromycin) | 300 mg per day | Caution | Reduce dose by 50% if CrCl <30 mL/min |
| Rifampicin (rifampin) | 10 mg/kg (450 mg or 600 mg) per day | 600 mg per day | Caution | N/A |
| Trimethoprim/ sulfamethoxazole | 800 mg/160 mg tab twice daily | N/A | Caution | Reduce dose by 50% if CrCl 5–30 mL/min |
| Parenteral | ||||
| Amikacin (IV) | 10–15 mg/kg per dayc, adjusted according to drug level monitoringd | 15–25 mg/kg per dayc, adjusted according to drug level monitoringd | N/A | Reduce dose or increase dosing interval (eg, 15 mg/kg, 2–3 times per week) |
| Cefoxitin (IV) | 2–4 g 2–3 times daily (maximum daily dose is 12 g/day) | N/A | N/A | Reduce dose or increase dosing interval |
| Imipenem (IV) | 500–1000 mg, 2–3 times per day | N/A | N/A | Reduce dose or increase dosing interval |
| Streptomycin (IV or IM) | 10–15 mg/kg per day, adjusted according to drug level monitoring | 15–25 mg/kg per day, adjusted according to drug level monitoring | N/A | Reduce dose or increase dosing interval (eg, 15 mg/kg, 2–3 times per week) |
| Tigecycline (IV) | 25–50 mg once or twice per dayb | N/A | 25 mg once or twice daily per day in severe hepatic impairment | N/A |
| Inhalation | ||||
| Amikacin liposome inhalation suspension | 590 mg per day | N/A | N/A | N/A |
| Amikacin, parenteral formulation | 250–500 mg per day | N/A | N/A | N/A |
a Clofazimine availability varies by country. In the United States, an investigational new drug application is required.
b Most experts recommend once daily dosing of linezolid and tigecycline due to the high rate of drug-related adverse reactions associated with twice daily dosing.
c The 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.
d Drug level monitoring: Trough <5 mg/L; Peak with daily dosing 35–45 μg/mL; Peak with intermittent dosing 65–80 μg/mL.
b Most experts recommend once daily dosing of linezolid and tigecycline due to the high rate of drug-related adverse reactions associated with twice daily dosing.
c The 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.
d Drug level monitoring: Trough <5 mg/L; Peak with daily dosing 35–45 μg/mL; Peak with intermittent dosing 65–80 μg/mL.
Table 4. Common Adverse Drug Reactions and Monitoring Recommendationsa
| Drug | Adverse Reactions | Monitoring |
|---|---|---|
| Azithromycin/ clarithromycin | Gastrointestinal | Clinical monitoring |
| Tinnitus/hearing loss | Audiogram | |
| Hepatotoxicity | Liver function tests | |
| Prolonged QTc | ECG (QTc) | |
| Clofazimine | Tanning of skin and dryness | Clinical monitoring |
| Hepatotoxicity | Liver function tests | |
| Prolonged QTc | ECG (QTc) | |
| Doxycycline | GI upset | Clinical monitoring |
| Photosensitivity | Clinical monitoring | |
| Tinnitus/vertigo | Clinical monitoring | |
| Ethambutol | Ocular toxicity | Visual acuity and color discrimination |
| Neuropathy | Clinical monitoring | |
| Isoniazid | Hepatitis | Liver function tests |
| Peripheral neuropathy | Clinical monitoring | |
| Linezolid | Peripheral neuropathy | Clinical monitoring |
| Optic neuritis | Visual acuity and color discrimination | |
| Cytopenias | Complete blood count | |
| Moxifloxacin | Prolonged QTc | ECG (QTc) |
| Hepatotoxicity | Liver function tests | |
| Tendinopathy | Clinical monitoring | |
| Trimethoprim/ sulfamethoxazole | GI upset | Clinical monitoring |
| Cytopenias | Complete blood count | |
| Hypersensitivity | Clinical monitoring | |
| Photosensitivity | Clinical monitoring | |
| Rifabutin | Uveitis | Visual acuity |
| Rifabutin/ Rifampicin (rifampin) | Hepatotoxicity | Liver function test |
| Cytopenias | Complete blood count | |
| Hypersensitivity | Clinical monitoring | |
| Orange discoloration of secretions | ||
| Amikacin, streptomycin, tobramycin | Vestibular toxicity | Clinical monitoring |
| Ototoxicity | Audiograms | |
| Nephrotoxicity | BUN, creatinine | |
| Electrolyte disturbances | Calcium, magnesium, potassium | |
| Amikacin liposome inhalation suspension | Dysphonia | Clinical monitoring |
| Vestibular toxicity | Clinical monitoring | |
| Ototoxicity | Audiograms | |
| Nephrotoxicity | BUN, creatinine | |
| Cough | Clinical monitoring | |
| Dyspnea | Clinical monitoring | |
| Cefoxitin | Cytopenias | Complete blood count |
| Hypersensitivity | Clinical monitoring | |
| Imipenem | Rashes | Clinical monitoring |
| Cytopenias | Complete blood count | |
| Nephrotoxicity | BUN/Creatinine | |
| Tigecycline | Nausea/vomiting | Clinical monitoring |
| Hepatitis/pancreatitis | Liver function tests, amylase/lipase |
a The expert panel recommends that patients have a complete blood count, liver function tests, and metabolic panel every 1–3 months in patients on oral therapy and weekly when on intravenous therapy.
Monitoring frequency should be individualized based on treatment regimen, age, comorbidities, concurrent drugs, overlapping drug toxicities, and resources.
Monitoring frequency should be individualized based on treatment regimen, age, comorbidities, concurrent drugs, overlapping drug toxicities, and resources.
Recommendation Grading
Abbreviations
- AFB: Acid-fast Bacilli
- BUN: Blood Urea Nitrogen
- CrCl: Creatinine Clearance
- ECG: Electrocardiogram
- GI: Gastrointestinal
- IM: Intramuscular
- IV: Intravenous
- N/A: Not Applicable
- NTM: Nontuberculous Mycobacteria
- QTc: Corrected QT
Source Citation
Charles L Daley, Jonathan M Iaccarino, Jr, Christoph Lange, Emmanuelle Cambau, Richard J Wallace, Claire Andrejak, Erik C Böttger, Jan Brozek, David E Griffith, Lorenzo Guglielmetti, Gwen A Huitt, Shandra L Knight, Philip Leitman, Theodore K Marras, Kenneth N Olivier, Miguel Santin, Jason E Stout, Enrico Tortoli, Jakko van Ingen, Dirk Wagner, Kevin L Winthrop, Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary, Clinical Infectious Diseases, , ciaa241, https://doi.org/10.1093/cid/ciaa241
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