Browse the corpus

Nontuberculous mycobacteria (NTM) infections are an underrecognized source of lung disease associated with severe disease manifestations and mortality, particularly in untreated cases. These mycobacteria cause human disease through environmental aerosol exposure, often related to water systems and soil rather than human-to-human transmission. Following infection, an interaction between the human host and the pathogen may lead to pulmonary disease, including bronchiectasis changes, fibrocavitary disease, and extrapulmonary or disseminated disease. Clinical features, radiological opacities, exclusion of differential diagnoses, and positive microbiology from multiple sputum specimens and other respiratory laboratory studies are primarily used to diagnose nontuberculous mycobacterial lung disease. Appropriate management depends on susceptibility testing, knowledge of first-line antimicrobials and their adverse effect profiles, and the crucial role the multidisciplinary team has in achieving treatment success for affected patients. This activity reviews the risk factors, assessment, diagnosis, and treatment of NTM lung infections and highlights the empowering role of the interprofessional, multidisciplinary team in evaluating and treating patients with these infections. Objectives: Identify the risk factors related to nontuberculous mycobacterial lung infections. Identify the typical imaging findings associated with nontuberculous mycobacterial lung infections. Apply knowledge of the pathophysiology of nontuberculous mycobacterial lung infections to tailor treatment strategies. Collaborate with the interprofessional care team to enhance the delivery of patient care. Access free multiple choice questions on this topic.

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and responsible for opportunistic infections affecting both immunocompromised and immunocompetent hosts.[1] The incidence of the disease from NTM has been gradually increasing worldwide, becoming, in recent years, an emerging public health problem.[2][3][4] As a result, various international guidelines, including the American Thoracic Society (ATS) and the British Thoracic Society, have been used to diagnose and manage clinical pulmonary NTM.[5][6] In 2020, a guideline consensus was released as a collaboration between the ATS, the European Respiratory Society (ERS), the Infectious Diseases Society of America (IDSA), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).[7] As new data have led to an increased understanding of pulmonary NTM infections, guidelines continue to be updated to reflect emerging evidence. With new medical advances based on molecular microbiology and the recognition of pulmonary NTM as causing complicated infections, the diagnosis of most NTM is becoming more precise and efficient. This article will summarize and review key features of NTM pulmonary infections, including the epidemiology, clinical features, diagnostic workup, and management of NTM, focusing on the multidisciplinary team approach to improve the clinical care of individuals with NTM pulmonary infections.

Following the discovery of Mycobacterium tuberculosis by Robert Koch in 1882, nontuberculous mycobacteria (NTM) have gradually been identified and categorized.[8][9] The first of these, Mycobacterium avium, was first identified in birds and differentiated from tuberculosis by 1890.[10][11] Further NTM were gradually identified over the years; however, they were not recognized as responsible for human disease until the mid-twentieth century, upon which classifications were developed to categorize these mycobacteria.[12] Today, the number of identified NTM species has reached more than 150.[13] M tuberculosis complex species and NTM are all categorized under the genus Mycobacterium. Mycobacteria are typically weakly gram-positive, acid-fast bacilli characterized by mycolic acid-rich cell walls [14]. They typically are of variable length and measure 0.3 to 0.5 μm. Further identification can be made phenotypically based on pigmentation changes in the presence or absence of light (eg, photochromogens, scotochromogens, or nonchromogenic) and growth characteristics, including the scotochromogenic Mycobacterium szulgai, Mycobacterium xenopi, and Mycobacterium gordonae, which can cause pulmonary disease in humans.[15][16] Other identification methods include growth rates, colony variation, biochemical differences, and chromatography. In particular, NTM species that grow in liquid media within 7 days are classed as rapid growers, and those that take more than 2 weeks to grow are slow growers.[17] However, older phenotypic classifications have been replaced with more advanced molecular and genomic methods for microorganism identification due to more rapid and precise results with these newer modalities.[18] As a result, further species of NTM can be further discovered and differentiated from existing species due to genomic differences. The most commonly identified pulmonary NTM species in countries such as the US, Japan, and French Guiana include Mycobacterium avium complex (MAC), M gordonae, Mycobacterium kansasii, Mycobacterium fortuitum, and Mycobacterium abscessus.[19][20][21] See Image. Mycobacterium Kansasii.

The epidemiology of NTM lung infections has been challenging to determine due to multiple factors, including mandatory reporting to local public health departments not being required in many countries, differentiating between infection and disease often being difficult, unavailable diagnostic testing in all institutions making differentiation between NTM  and tuberculosis infections challenging, and imprecise follow-up due to the burden of treatment and follow-up of sputum cultures to ensure clearance.[22][23][24][2][25][26] There is evidence that individuals of Asian and Pacific Islander background may be at increased risk of NTM pulmonary disease.[27] Part of this may be attributable to a higher incidence of M tuberculosis among these populations, given a history of tuberculosis is associated with pulmonary NTM infections due to structural changes.[28][29] Advanced age, immunosuppression, and the use of corticosteroids are other known risk factors for acquiring these infections.[30] In the 1980s, US laboratories reported an estimated prevalence of NTM infection of 1 to 2 cases per 100,000 individuals.[31] The annual prevalence increased among men and women in Florida by 3.2% and 6.5% per year, respectively; in New York, the prevalence in women increased by 4.6% per year. Conversely, there was no significant increase seen in California. The annual prevalence of NTM pulmonary diseases in US Medicare beneficiaries (ie, all persons aged ≥65) increased from 20 per 100,000 in 1997 to 47 per 100,000 in 2007.[32] Since the initial description of pulmonary NTM in the 1950s, reports of increased incidence and prevalence of pulmonary NTM infections have been documented in Slovakia, the United Kingdom, Ireland, Australia, Japan, South Korea, and the US.[33][34][35][36][37][38] In Queensland, Australia, where NTM is reportable, the incidence of clinically significant pulmonary disease rose from 2.2 per 100,000 in 1999 to 3.2 per 100,000 in 2005.[39]

In the 1980s, US laboratories reported an estimated prevalence of NTM infection of 1 to 2 cases per 100,000 individuals.[31] The annual prevalence increased among men and women in Florida by 3.2% and 6.5% per year, respectively; in New York, the prevalence in women increased by 4.6% per year. Conversely, there was no significant increase seen in California. The annual prevalence of NTM pulmonary diseases in US Medicare beneficiaries (ie, all persons aged ≥65) increased from 20 per 100,000 in 1997 to 47 per 100,000 in 2007.[32] Since the initial description of pulmonary NTM in the 1950s, reports of increased incidence and prevalence of pulmonary NTM infections have been documented in Slovakia, the United Kingdom, Ireland, Australia, Japan, South Korea, and the US.[33][34][35][36][37][38] In Queensland, Australia, where NTM is reportable, the incidence of clinically significant pulmonary disease rose from 2.2 per 100,000 in 1999 to 3.2 per 100,000 in 2005.[39] While the prevalence and incidence of NTM pulmonary disease have been increasing through the years, not only in the US but also around the world, this epidemiological variation has not been fully explained. Increased awareness among treating clinicians has been proposed as a reason for increased incidence, along with an increasingly aging and comorbid population among high-income countries.[40] Environmental associations have also been postulated, with increased population exposure to plumbing, indoor swimming pools, high rainfall events, and disruption of local soil being linked with a higher risk of NTM infections.[37] [41][42][43][44] Hot tubs themselves have been clinically linked with cases of MAC.[45] New radiological advances, especially resolution chest computed tomography (CT) scanning, improved diagnosis, and increased chest screening may also be important factors responsible for these epidemiological observations.[46][47] See Image. Chest CT of Mycobacterium Abscessus.

Nontuberculous mycobacterium may cause disease de novo in healthy human hosts; however, the pulmonary disease is commonly implicated in individuals with preexisting structural lung diseases (eg, bronchiectasis) or genetic and immune dysfunction disorders (eg, alpha-1-antitrypsin deficiency, primary ciliary dyskinesia, and granulocyte-macrophage colony-stimulating factor.)[48][49][50][51] T-cell depleting therapies have traditionally been implicated in NTM disease, altering T-cell function responses without major lymphopenia.[52] Human-immunodeficiency virus, which causes a decline in CD4+ cells, is associated with a higher incidence of NTM disease, particularly with lower CD4+ cell counts.[53][54] B-cell–depleting therapies (eg, rituximab) may also be associated with reducing the granuloma response, which contains mycobacteria.[55][56] In those without predisposing structural lung disease, low body mass index, scoliosis, and thoracic cage abnormalities have been associated with NTM pulmonary disease.[57][58][59] Gastroesophageal reflux disease has been associated with pulmonary NTM infection, possibly as a result of the survivability of mycobacteria in low-pH environments.[60] Unlike tuberculosis, NTM pulmonary disease is not thought to be transmitted person-to-person or by exposure to droplets from an infected individual.[61] That all pulmonary NTM become acquired via inhalation of infected aerosolized droplets from the environment or water sources has been accepted. Household water and shower aerosols are known to be colonized with various NTM species, with the most frequently cited being M avium, M kansasii, M abscessus, and Mycobacterium lentiflavum.[62] Similarly, NTM has been isolated throughout the year in natural and municipal potable water in major cities globally, with species differing according to season.[63] Once the organisms enter the individual, they usually settle in the lower airways; in some cases, the bacteria incite an inflammatory reaction with an influx of lymphocytes. The resulting release of cytokines and other mediators can lead to an infectious process that presents as pneumonia. With an insufficient immune response to contain these mycobacteria, the pathogen can disseminate throughout the human host and cause extrapulmonary disease.

The diagnosis of pulmonary NTM infection is based on clinical, radiological, and microbiological criteria. The 2020 ATS/ERS/IDSA/ESCMID guidelines recommend clinical features, radiological opacities, exclusion of differential diagnoses, and positive microbiology from multiple sputum specimens and other respiratory laboratory studies to confirm the diagnosis of pulmonary NTM infection.[7] As such, a thorough history and physical examination are essential in detecting possible cases of pulmonary NTM infection. Compared to other bacteria, nontuberculous mycobacterium have a slow growth process, resulting in a considerable time to infect the lungs and cause symptomatic disease.[64] Sometimes, this particular factor and a low clinical suspicion index may result in either misdiagnosis or a delayed diagnosis. Clinical History Clinical manifestations may bear similarities with pulmonary tuberculosis infection, including respiratory symptoms such as cough, dyspnea, and increased sputum production.[65] Patients with pulmonary NTM often have fewer pulmonary cavitations and infiltrates than tuberculosis; however, constitutional symptoms (eg, fevers, night sweats, and weight loss) have been seen to occur more often in pulmonary NTM than in tuberculosis.[66] Pulmonary NTM disease is associated more with bronchiectasis than tuberculosis, and coinfection with human immunodeficiency virus (HIV) often leads to more disseminated extrapulmonary disease than in tuberculosis, which in tuberculosis patients is more associated with a miliary radiographic appearance.[67] This is mainly in the case of MAC, where a CD4 count of <50 cells/µL is at high risk for dissemination in HIV patients.[54] The duration of symptoms in pulmonary NTM disease may vary from a few days to a few weeks. Chronic pulmonary infection may occur, resulting in structural lung changes such as fibrocavitary disease.[68] This may lead to differentials such as malignancy, sarcoidosis, vasculitis, and fungal pulmonary disease being considered.[69] Physical Examination Findings

Clinical manifestations may bear similarities with pulmonary tuberculosis infection, including respiratory symptoms such as cough, dyspnea, and increased sputum production.[65] Patients with pulmonary NTM often have fewer pulmonary cavitations and infiltrates than tuberculosis; however, constitutional symptoms (eg, fevers, night sweats, and weight loss) have been seen to occur more often in pulmonary NTM than in tuberculosis.[66] Pulmonary NTM disease is associated more with bronchiectasis than tuberculosis, and coinfection with human immunodeficiency virus (HIV) often leads to more disseminated extrapulmonary disease than in tuberculosis, which in tuberculosis patients is more associated with a miliary radiographic appearance.[67] This is mainly in the case of MAC, where a CD4 count of <50 cells/µL is at high risk for dissemination in HIV patients.[54] The duration of symptoms in pulmonary NTM disease may vary from a few days to a few weeks. Chronic pulmonary infection may occur, resulting in structural lung changes such as fibrocavitary disease.[68] This may lead to differentials such as malignancy, sarcoidosis, vasculitis, and fungal pulmonary disease being considered.[69] Physical Examination Findings The physical features on examination are often variable, not specific, and can mimic any infectious process of the lungs. Cutaneous lesions may be present in extrapulmonary disease and could represent NTM lymphadenitis. Disseminated MAC may present with hepatosplenomegaly and abdominal pain.[64] Furthermore, patients with NTM pulmonary infection may have preexisting structural lung disease, including findings of coarse inspiratory crackles on auscultation consistent with bronchiectasis or prolonged expiratory time on spirometry associated with chronic obstructive pulmonary disease.

Diagnostic Imaging Studies As with other lung infections, radiological images are crucial for correctly diagnosing the disease. However, unlike other lung diseases, NTM have characteristic lung presentations. The major radiological patterns of NTM lung infection are fibrocavitary and nodular bronchiectatic patterns (see Image. Mycobacterium Avium-Intracellulare Pneumonia).[5] The fibrocavitary radiological pattern resembles tuberculosis lung infection. It presents with cavities with areas of increased opacity, primarily in the upper lung. On the other hand, the nodular bronchiectasis pattern characteristically shows multilobar bronchiectasis, primarily located in the middle and lower lung fields, with small nodules seen in imaging. This pattern predominantly presents in elderly female nonsmokers without previous lung conditions.[70] Finally, bronchiectasis is highly prevalent in patients with NTM lung infection. A meta-analysis demonstrated that the prevalence of NTM infection in patients with bronchiectasis was 9.3%.[71] Clinicians must be aware that NTM lung infection could present with bronchiectasis on radiological images. Disseminated disease manifestations, such as what can occur with MAC infection, can be nonspecific and reveal radiological evidence of hepatosplenomegaly and intestinal and gallbladder wall thickening.[72] Diagnostic Laboratory Studies Sputum staining: The isolation of NTM in human specimens can be challenging. Since NTM are present in the environment, especially in water sources, a positive test in a sputum specimen may be a false-positive due to specimen contamination or represent upper respiratory tract colonization in patients tested for NTM.[73] Therefore, current international guidelines recommend that 3 early morning sputum specimens be collected on 3 different days to diagnose NTM lung infection accurately.[5] The methods used for acid-fast bacilli staining require the carbol fuchsin stain (eg, Ziehl-Neelsen or Kinyoun method) and the fluorochrome procedure using auramine O alone or combined with rhodamine B.[74][75] However, these staining methods cannot differentiate between tuberculosis and NTM alone, and further tests are required to identify the pathogen.

Sputum staining: The isolation of NTM in human specimens can be challenging. Since NTM are present in the environment, especially in water sources, a positive test in a sputum specimen may be a false-positive due to specimen contamination or represent upper respiratory tract colonization in patients tested for NTM.[73] Therefore, current international guidelines recommend that 3 early morning sputum specimens be collected on 3 different days to diagnose NTM lung infection accurately.[5] The methods used for acid-fast bacilli staining require the carbol fuchsin stain (eg, Ziehl-Neelsen or Kinyoun method) and the fluorochrome procedure using auramine O alone or combined with rhodamine B.[74][75] However, these staining methods cannot differentiate between tuberculosis and NTM alone, and further tests are required to identify the pathogen. Nuclei-acid amplification: Nuclei-acid amplification (NAA) is the most accurate test for identifying mycobacterial strains. Commercial polymerase chain reaction assays have shown a sensitivity of up to 97.7% in acid-fast bacilli smear-positive specimens, with a specificity of up to 97.7%, by targeting conserved sequences such as insertion sequence 6110 and the mpb64 gene.[76][77][78] Sputum culture and sensitivity: Culture remains the test of choice for NTM laboratory confirmation. Solid and liquid media are used for the culture. Solid media includes egg-based media, such as the Löwenstein-Jensen medium, or agar-based media (eg, middlebrook 7H10 and 7H11 media).[79] Solid media allows the visualization of morphology, growth rate, and species characterization. The liquid media system is more sensitive but is more prone to contamination by other microorganisms and bacteria overgrowth. Both culture methods are limited by the growth time of the organisms, the risk posed by potential contaminants, and the effect of prior empirical antimicrobials on mycobacterial growth following collection.[80][81] A timely diagnosis is important as delays between recognizing the causative organism of NTM disease, performing susceptibility testing, and initiating treatment can result in delays ranging from 1.3 to 20.8 months.[82] Nontuberculous Mycobacterium Identification

Sputum culture and sensitivity: Culture remains the test of choice for NTM laboratory confirmation. Solid and liquid media are used for the culture. Solid media includes egg-based media, such as the Löwenstein-Jensen medium, or agar-based media (eg, middlebrook 7H10 and 7H11 media).[79] Solid media allows the visualization of morphology, growth rate, and species characterization. The liquid media system is more sensitive but is more prone to contamination by other microorganisms and bacteria overgrowth. Both culture methods are limited by the growth time of the organisms, the risk posed by potential contaminants, and the effect of prior empirical antimicrobials on mycobacterial growth following collection.[80][81] A timely diagnosis is important as delays between recognizing the causative organism of NTM disease, performing susceptibility testing, and initiating treatment can result in delays ranging from 1.3 to 20.8 months.[82] Nontuberculous Mycobacterium Identification The treatment of NTM infection is specific and different for every NTM species. Correctly identifying the species is the main factor of successful treatment. The most accurate NTM identification method is via gene sequence. Sequencing the 16S rRNA gene allows for the correct identification and discrimination between species, and whole genome sequencing has been used in public health investigations of mycobacterium outbreaks.[83][84] However, species-level identification may need several gene sequences and more complex methods. Only specialized laboratories that identify species levels using different gene sequences can perform this test. The matrix-associated laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method has increasingly been employed for identifying NTM and is highly reproducible for this use.[85] This method identifies target bacteria by comparing mass spectral pattern molecules specific to NTM. Drug Susceptibility

The treatment of NTM infection is specific and different for every NTM species. Correctly identifying the species is the main factor of successful treatment. The most accurate NTM identification method is via gene sequence. Sequencing the 16S rRNA gene allows for the correct identification and discrimination between species, and whole genome sequencing has been used in public health investigations of mycobacterium outbreaks.[83][84] However, species-level identification may need several gene sequences and more complex methods. Only specialized laboratories that identify species levels using different gene sequences can perform this test. The matrix-associated laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method has increasingly been employed for identifying NTM and is highly reproducible for this use.[85] This method identifies target bacteria by comparing mass spectral pattern molecules specific to NTM. Drug Susceptibility When NTM are cultured, drug susceptibility tests are always conducted to assist clinicians with choosing drug regimens due to the variable resistance patterns of different NTM organisms. However, there are difficulties with the drug susceptibility test because each species of NTM may behave differently in vitro than in vivo, and there is limited data regarding clinical outcomes based on in vitro susceptibility testing.[5][86] One exception is using macrolides in MAC, where there is a correlation between in vitro susceptibility and in vivo responses. Macrolide testing in vitro for clarithromycin is also often extrapolated to azithromycin usage in clinical practice due to safer differences in drug-drug interactions, improved dosing regimens, and similar clinical outcomes despite similarities in cross-resistance.[87] NTM species may have variable resistance to certain drugs, and thus, antimicrobial susceptibility tests should be adapted to each organism once cultured. For example, M kansasii may show resistance to rifamycins, and alternative agents (eg, tetracyclines, fluoroquinolones, and carbapenems) may need to be tested.[5] M abscessus has been shown to have inducible macrolide resistance, which can often mean prolonged therapy with intravenous amikacin, imipenem, or cefoxitin if these drugs show NTM susceptibility.[88][89]

The treatment of NTM requires a holistic and patient-centered approach based on quality-of-life and patient benefits instead of expecting mycobacterial eradication. Pulmonary NTM infection differs from a TB lung infection in that it does not require immediate initiation of treatment upon diagnosis but should be expected within a reasonable timeframe to limit disease progression.[90] The treatment of NTM lung infection includes an interprofessional approach and a discussion of risks and benefits. The therapy should remain in place for a minimum of 12 months from culture conversion.[5][90] Culture conversion is where 3 consecutive monthly sputum cultures are negative for NTM after initial positive smears.[91] Based on data in cystic fibrosis patients, sputum cultures should also be collected every 4 to 8 weeks until 12 months from culture conversion.[92] For patients unable to expectorate, meeting the definition of culture conversion may be difficult and bronchoscopy and imaging may be required to confirm conversion.[6] During the treatment phase, pulmonary NTM patients require close monitoring for drug adverse effects and medication adherence, as most patients will require a median of 5 with a range of 1 to 10 antibiotics to achieve culture conversion.[93] This is important as the cost for treatment over a lifetime for pulmonary NTM can range anywhere from $398 to $70000, based on 2009 data. Mycobacterium avium-intracellular complex Lung Disease Treatment MAC lung disease treatment depends on clinical presentation, including nodular or bronchiectasis disease, cavitary diseases, and advanced (ie, severe) or previously treated disease. Guideline-based treatment recommends a combination of a macrolide, ethambutol, and a rifamycin 3 times weekly for at least 12 months after culture conversion, with an option to include aminoglycosides for severe and refractory cases. Second-line agents may be required for macrolide-resistant strains.[90] Treatment 3 times per week is recommended due to its tolerability compared to daily dosing and reduced pill costs. The following treatment dosing scenarios for MAC lung disease are based on the 2020 ATS/ERS/IDSA/ESCMID guidelines.[5] Bronchiectasis or Cavitary Disease Treatment

MAC lung disease treatment depends on clinical presentation, including nodular or bronchiectasis disease, cavitary diseases, and advanced (ie, severe) or previously treated disease. Guideline-based treatment recommends a combination of a macrolide, ethambutol, and a rifamycin 3 times weekly for at least 12 months after culture conversion, with an option to include aminoglycosides for severe and refractory cases. Second-line agents may be required for macrolide-resistant strains.[90] Treatment 3 times per week is recommended due to its tolerability compared to daily dosing and reduced pill costs. The following treatment dosing scenarios for MAC lung disease are based on the 2020 ATS/ERS/IDSA/ESCMID guidelines.[5] Bronchiectasis or Cavitary Disease Treatment The first regimen for the treatment of bronchiectasis disease includes clarithromycin 1000 mg 3 times per week or azithromycin 500 to 600 mg 3 times per week together with a rifamycin 600 mg 3 times per week and ethambutol 25 mg/kg 3 times per week. The primary treatment regimen for cavitary disease is clarithromycin 500 to 1000 mg daily or azithromycin 250 to 300 mg daily with ethambutol 15 mg/kg daily and rifampin 450 to 600 mg daily. Furthermore, intramuscular streptomycin or intravenous amikacin 10 mg to 15 mg/kg 3 times weekly can be an added therapy.[87] Advanced Disease Treatment The treatment of advanced (severe) or previously treated disease includes clarithromycin 500 to 1000 mg daily or azithromycin 250 to 300 mg daily together with rifabutin 150 to 300 mg or rifampin 450 to 600 mg once daily, ethambutol 15 mg/kg daily, and streptomycin or amikacin 10 to 15 mg/kg intramuscular or intravenous 3 times/week with a maximum dose of 500 mg for patients older than 50 years for the first 2 to 3 months. Adding moxifloxacin 400 mg orally once daily to the previous combination regimen may improve outcomes in refractory diseases or treatment failure. Refractory Disease Treatment

The treatment of advanced (severe) or previously treated disease includes clarithromycin 500 to 1000 mg daily or azithromycin 250 to 300 mg daily together with rifabutin 150 to 300 mg or rifampin 450 to 600 mg once daily, ethambutol 15 mg/kg daily, and streptomycin or amikacin 10 to 15 mg/kg intramuscular or intravenous 3 times/week with a maximum dose of 500 mg for patients older than 50 years for the first 2 to 3 months. Adding moxifloxacin 400 mg orally once daily to the previous combination regimen may improve outcomes in refractory diseases or treatment failure. Refractory Disease Treatment Refractory pulmonary infection is a failure to achieve negative cultures for more than 6 months. The benefit of additional drugs is controversial as there is a lack of large-scale studies to guide evidence in this scenario.[94] The guideline-directed regimen of treatment is the administration of amikacin liposome inhalation suspension once daily at a dose of 590 mg/8.4 milliliters (one vial) with a specialized nebulizer system only, along with an optimized multi-drug background regimen, still typically consisting of a macrolide, rifamycin, and ethambutol.[91][90][95] Duration of Therapy Nontuberculous mycobacterial antimicrobial therapy aims to achieve culture conversion. Those achieving 3 consecutive monthly negative sputum cultures 12 months after the last positive cultures for 6 months should continue for an additional 12 months.[91] The benefit of extended therapy in those not achieving 3 consecutive monthly negative sputum cultures by 6 months is not entirely established. However, it has been observed that patients treated for longer than 12 months achieve culture conversion within a shorter period, <12 months, associated with reduced mortality in pulmonary NTM infection.[82] Mycobacterium Kansasii Lung Disease Treatment

Nontuberculous mycobacterial antimicrobial therapy aims to achieve culture conversion. Those achieving 3 consecutive monthly negative sputum cultures 12 months after the last positive cultures for 6 months should continue for an additional 12 months.[91] The benefit of extended therapy in those not achieving 3 consecutive monthly negative sputum cultures by 6 months is not entirely established. However, it has been observed that patients treated for longer than 12 months achieve culture conversion within a shorter period, <12 months, associated with reduced mortality in pulmonary NTM infection.[82] Mycobacterium Kansasii Lung Disease Treatment M kansasii lung disease remains a relatively treatable pathogen among NTM lung diseases despite being the second most common cause of pulmonary NTM in the US.[5] With the advent of rifamycin-based treatment regimens, sputum conversion remains high. Guideline-directed therapy is similar to tuberculosis treatment, with a high curative rate. The recommended primary regimens for adults are isoniazid 300 mg daily, pyridoxine 50 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg per day for 12 months of culture-negative sputum. Disseminated disease is treated in the same manner as pulmonary disease. Susceptibility testing should be used to guide treatment in rifamycin-resistant cases, which may include macrolides, sulfamethoxazole, and streptomycin. It has been demonstrated that adding an aminoglycoside such as streptomycin during the first 2 to 3 months to the 3-drug regimen has a high rate of culture conversion with a low relapse rate.[96] Mycobacterium Abscessus  Complex Lung Disease Treatment

M kansasii lung disease remains a relatively treatable pathogen among NTM lung diseases despite being the second most common cause of pulmonary NTM in the US.[5] With the advent of rifamycin-based treatment regimens, sputum conversion remains high. Guideline-directed therapy is similar to tuberculosis treatment, with a high curative rate. The recommended primary regimens for adults are isoniazid 300 mg daily, pyridoxine 50 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg per day for 12 months of culture-negative sputum. Disseminated disease is treated in the same manner as pulmonary disease. Susceptibility testing should be used to guide treatment in rifamycin-resistant cases, which may include macrolides, sulfamethoxazole, and streptomycin. It has been demonstrated that adding an aminoglycoside such as streptomycin during the first 2 to 3 months to the 3-drug regimen has a high rate of culture conversion with a low relapse rate.[96] Mycobacterium Abscessus  Complex Lung Disease Treatment MAC lung infection treatment remains complicated because of the high treatment failure rate due to resistance against standard treatment for mycobacterial species.[97] Therefore, more clinical trials are needed to establish a successful treatment that eradicates and cures the disease. The primary regimen generally consists of a macrolide with 2 parenteral agents for an extended period in isolates without macrolide resistance. Also, the treatment is divided between the intensive phase, which uses imipenem 1000 mg intravenously (IV) every 12 hrs or cefoxitin IV 8 to 12 g daily, divided into 2 or 3 doses, azithromycin 250 to 500 mg orally once daily along with amikacin IV 15 mg/kg once daily with adjustable doses until obtaining peak serum concentration of 20 to 30 µg/mL. Generally, another oral agent, which includes clofazimine or linezolid, is used. This proposed treatment should last 2 or 3 months, depending on the severity of infection, clinical response, tolerability, and toxicity.

MAC lung infection treatment remains complicated because of the high treatment failure rate due to resistance against standard treatment for mycobacterial species.[97] Therefore, more clinical trials are needed to establish a successful treatment that eradicates and cures the disease. The primary regimen generally consists of a macrolide with 2 parenteral agents for an extended period in isolates without macrolide resistance. Also, the treatment is divided between the intensive phase, which uses imipenem 1000 mg intravenously (IV) every 12 hrs or cefoxitin IV 8 to 12 g daily, divided into 2 or 3 doses, azithromycin 250 to 500 mg orally once daily along with amikacin IV 15 mg/kg once daily with adjustable doses until obtaining peak serum concentration of 20 to 30 µg/mL. Generally, another oral agent, which includes clofazimine or linezolid, is used. This proposed treatment should last 2 or 3 months, depending on the severity of infection, clinical response, tolerability, and toxicity. Finally, the continuation phase uses azithromycin 250 to 500 mg once daily, clofazimine 100 to 200 mg once daily, or linezolid 600 mg to 1200 mg once daily with inhaled liposomal amikacin 590 mg 3 times weekly for a minimum of 12 months from culture conversion.[98][99][100][101] Macrolide-resistant isolates are more difficult to treat and often require 2 to 3 parental antimicrobials in addition to 2 to 3 oral agents daily (eg, clofazimine and linezolid) in the induction phase, followed by 3 oral agents and inhaled liposomal amikacin 3 times weekly for a minimum of 12 months following culture conversion based on susceptibility testing.[90] Pharmacologic Adverse Effects Of great importance to patient care is the pre-treatment counseling of potential medication adverse effects, reactions, and drug interactions. Clinicians and pharmacists must never forget that patients should be educated and counseled as much as possible regarding the risks and benefits of any novel treatment, particularly in pulmonary NTM disease, where antimicrobials are not without adverse effects. In the case of treatment with NTM, the most used medications are macrolides and other anti-tuberculosis medications like rifampin.

Of great importance to patient care is the pre-treatment counseling of potential medication adverse effects, reactions, and drug interactions. Clinicians and pharmacists must never forget that patients should be educated and counseled as much as possible regarding the risks and benefits of any novel treatment, particularly in pulmonary NTM disease, where antimicrobials are not without adverse effects. In the case of treatment with NTM, the most used medications are macrolides and other anti-tuberculosis medications like rifampin. In the case of macrolides like azithromycin or erythromycin, the most common adverse effects are gastrointestinal symptoms, including nausea, vomiting, diarrhea, abdominal pain, and cholestatic hepatitis.[102] Macrolides can also be associated with QT prolongation, leading to cardiac arrhythmias.[103] Having a baseline EKG when using this medication is essential. Otoxicity and transient reversible tinnitus or deafness have occurred with over 4 g daily of erythromycin IV in renal allograft patients.[104] This effect is thought to be due to drug accumulation and has been seen with azithromycin and clarithromycin.[105] Rifampin is a potentially hepatotoxic cause of drug-induced liver injury, particularly in those with predisposing genotypes.[106][107] It requires caution in patients with preexisting liver impairment or excessive use of alcohol. If elevated bilirubin or a substantive increase in liver-associated enzymes occurs, discontinue rifampin therapy. A visual adverse effect of rifampin is red-orange discoloration of urine, feces, and saliva.[108] It can stain contact lenses permanently. In instances of rifampin overdosage of >14 grams per day, cardiopulmonary arrest may occur.[109] There are also reports of thrombocytopenia and vasculitis, thought to be secondary to the formation of autoantibodies.[110][111] Rifampin is also a potent inducer of cytochrome p450 liver enzymes and can interact with other NTM drugs, including ethambutol and clofazimine.[112] Surgical Therapy

Rifampin is a potentially hepatotoxic cause of drug-induced liver injury, particularly in those with predisposing genotypes.[106][107] It requires caution in patients with preexisting liver impairment or excessive use of alcohol. If elevated bilirubin or a substantive increase in liver-associated enzymes occurs, discontinue rifampin therapy. A visual adverse effect of rifampin is red-orange discoloration of urine, feces, and saliva.[108] It can stain contact lenses permanently. In instances of rifampin overdosage of >14 grams per day, cardiopulmonary arrest may occur.[109] There are also reports of thrombocytopenia and vasculitis, thought to be secondary to the formation of autoantibodies.[110][111] Rifampin is also a potent inducer of cytochrome p450 liver enzymes and can interact with other NTM drugs, including ethambutol and clofazimine.[112] Surgical Therapy Nontuberculosis and mycobacterial pulmonary infections can be challenging to manage with antibiotic therapy. By targeting areas of the lung where antimicrobials have poor perfusion due to parenchymal injury, adjuvant surgical therapy may remove the most severely destroyed lung and promote treatment success. Surgical therapy is recommended in the settings of treatment-refractory disease and symptom control.[113] Surgery may also be the best choice for disease control in the case of massive hemoptysis. Some case series and reviews have reported successful treatment, with 80% to 100% sputum conversion in patients after adjuvant surgical reception[114][115]. Surgery requires a comprehensive preoperative evaluation since recent research has shown that postoperative complications have a morbidity of 7% to 25% and a mortality rate of 0% to 3%.[113]

The clinical manifestation of NTM could mimic other lung infections, such as M tuberculosis, atypical bacterial infections, and chronic lung diseases.[66] Though NTM, including MAC, M abscessus, and M kansasii, are frequently associated with pulmonary disease, others, such as Mycobacterium ulcerans and Mycobacterium marinum, are less associated.[116] Clinicians should approach the differential diagnosis of pulmonary pathologies based on the patient's background risk factors, the disease's clinical manifestations, and any radiological characteristics. Among the differentials, infections, neoplasias, and connective tissue diseases most commonly share similarities to NTM lung infections. Klebsiella pneumoniae, Staphylococcus aureus, and Burkholderia pseudomallei are relevant entities to include in the differential.[117][118][69] Other pertinent infectious differentials include fungal lung infections such as Aspergillus, Cryptococcus, Mucor, Histoplasma, and Coccidiodes species, particularly if cavitary lung disease is present.[69][119][120][121][122] Given their similar radiological appearances, small-cell and non-small-cell lung cancers are important to consider among neoplasias. Moreover, connective tissue disorders, including rheumatoid arthritis, lung diseases, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis, represent an essential part of the differential.[123] Overall, any entity that presents with respiratory manifestations, and either cavitary or bronchiectasis radiological lung pictures on images, is part of the differential diagnostic, and these conditions need to be ruled out by the treating clinician.

The prognosis of NTM lung infection is guarded, particularly if left untreated. A South Korean population study analyzed 183267 NTM infections and found the 6-, 10- and 14-year survival probabilities were 86.3%, 80.8%, and 77.1%, respectively, despite treatment.[124] Similar findings have also been found in Croatia, where a study of 436 pulmonary NTM patients observed a 5-year survival rate of 60% compared to 70% in patients without pulmonary NTM. Patients with a fragile immune system are more prone to worse outcomes when compared with immunocompetent patients. Furthermore, pulmonary NTM patients with comorbidities have been observed to have survival expectancy following diagnosis reduced to as low as 8.6 years compared to those without comorbidities.[125] The method of diagnosis has also been shown to correlate with disease progression, with patients who have NTM pulmonary disease diagnosed through means other than sputum having a lower risk of disease progression over 5 years compared to those diagnosed by sputum culture.[126] The prognosis also depends on the type of NTM lung infection. Studies have shown that patients with MAC lung infections have a better prognosis when compared to patients with other NTM infections.[127] Conversely, the mortality rate of patients with pulmonary infections with M abscessus is greater when compared with patients with other NTM lung infections.[128] Other prognostic risk factors for mortality identified on multivariable analyses from 15-year cohort studies include older age ≥65 years, male sex, a body mass index <18.5 kg per square meter, underlying chronic cardiac and liver diseases, chronic pulmonary aspergillosis and cavitary lung disease at presentation.[129]

Pulmonary NTM infections can affect both immunocompetent and immunocompromised hosts in several ways. Affected patients can be asymptomatic, minimally symptomatic, or have serious complications such as pulmonary cavitations or constitutional disease.[66][130] In a systemic review of 206 pulmonary NTM infections, 29% had pleural disease alone, 43% developed pneumothorax, 16% empyema, and 16.5% broncho-pleural fistulas. From this cohort, 53% required pleural effusion drainage, and 26% required surgical intervention.[131] The cohort experienced a mortality rate of 24%, with 53% requiring pleural effusion drainage and 26% requiring surgical intervention. Necrotizing granulomas and chronic interstitial pneumonia and organization may occur.[132] In patients with NTM and chronic thromboembolic pulmonary disease, those with NTM have been observed to be more thrombus-obstructed than those without NTM.[133] Among lung transplant recipients, survival is similar among NTM-infected and uninfected patients, but there is a trend toward having NTM infection and having bronchiolitis obliterans.[134] Treatment among cystic fibrosis patients may also be challenging as host physiology may mean altered drug absorption and clearance of drugs, resulting in persisting NTM disease if drug monitoring is not available.[135] Extrapulmonary complications may also develop following initial pulmonary NTM infection, particularly in immunocompromised patients. Osteoarticular diseases such as tenosynovitis, arthritis, and vertebral osteomyelitis can occur following initial pleural infection with NTM.[136] The most frequently cited NTM associated with osteoarticular infection includes M kansasii and M marinum, though other NTM species such as MAC, M chelonae, M szulgai, and M abscessus have also been implicated.[137] In severe immunosuppression, disseminated MAC has been associated with impaired erythropoiesis and elevated liver alkaline phosphatase.[138][139] This may be linked to the clinical manifestations in disseminated MAC of hepatosplenomegaly and osteoarticular disease.[136][137]

Prevention of NTM is a rather challenging task due to its ubiquitous presence in the environment, limiting the precautions that can be put in place to limit exposure to susceptible individuals. Compounding this challenge is the difficulty of assessing which patients are susceptible to NTM infection. A notable example is that hot showers, indoor swimming pools, and plumbing may be associated with viable NTM, but not all individuals who take hot showers have NTM infection.[41][42][44] Whether educating the patient on avoiding hot showers will decrease the chances of infection is unclear. There is limited data that supports evidence-based environmental strategies to limit the transmission of NTM. Therefore, discussing general precautions with patients at risk for pulmonary NTM infection may be prudent. Concerning management, the patient should be advised regarding the estimated duration of any proposed treatment, as this could be very lengthy. An organized and structured care plan agreed to by the patient and their family that details dosing regimens, follow-up appointments, and contact details of healthcare clinicians can optimize adherence and patient engagement. The plan may also include adverse effects and a timeframe for treatment completeness. Patients must be aware of potential complications from any disease progression. They also should be counseled on the expected time for sputum culture conversion and the anticipated duration of antimicrobial treatment for more than 12 months following culture conversion to achieve disease-free status. Building patient rapport and healthy relationships with the patient to obtain the best results is essential.

The diagnosis and treatment of NTM are complex and best done with an interprofessional, multidisciplinary team with a holistic approach to management. The pharmacist should educate the patient on the importance of drug adherence and counsel on potential adverse effects while checking the medication record and verifying dosing and drug interactions. An infectious disease pharmacist can also review antibiogram data with the clinician to optimize antimicrobial effectiveness, limit adverse effects, and determine antibiotic resistance. Infectious disease or respiratory nurses are essential for patient care, infection control measures while tuberculosis is being excluded, medication administration, verifying adherence, monitoring for adverse events, offering patients counsel, and reporting any concerns to the treating physicians. Daily observed therapy may sometimes be necessary to maintain medication adherence until treatment completion.[140] The patient should be urged to cease smoking to limit symptom burden and any progression of disease. A holistic approach considers all these factors in partnership with the patient to determine the buy-in and optimal pathway to complete the long-anticipated treatment duration for pulmonary NTM.[141] Therefore, a patient-centered approach can improve clinical outcomes, patient safety, and multidisciplinary team performance.