Version May 2024
INTRODUCTION — Treatment of nontuberculous mycobacterial (NTM) infection of the lung is dependent upon a number of factors, including the species of the infecting organism. Members of Mycobacterium avium complex (MAC) are the most common pulmonary NTM pathogens in almost all regions of the world. The three predominant species to cause human disease among the twelve species within the complex are Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera [1,2].
The treatment of MAC pulmonary infections will be reviewed here. The management of pulmonary disease caused by other slow-growing NTM, such as Mycobacterium kansasii, Mycobacterium malmoense, and Mycobacterium xenopi, and by rapidly growing mycobacterium, such as Mycobacterium abscessus, Mycobacterium fortuitum complex, and Mycobacterium chelonae, is discussed separately. (See "Treatment of lung infection with Mycobacterium kansasii and other less common nontuberculous mycobacteria in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
The epidemiology, microbiology, clinical manifestations, and diagnosis of NTM infection are also discussed elsewhere. (See "Overview of nontuberculous mycobacterial infections" and "Epidemiology of nontuberculous mycobacterial infections" and "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
NTM pulmonary infection in patients with cystic fibrosis is also discussed elsewhere. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Nontuberculous mycobacteria'.)
CATEGORIES OF DISEASE — In general, antimycobacterial treatment of MAC should only be considered in patients who meet the clinical, radiographic, and microbiologic criteria for the diagnosis of nontuberculous mycobacterial (NTM) infection (table 1) [3]. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
Pulmonary NTM infection can be further categorized based on radiologic criteria, as follows:
●Noncavitary nodular bronchiectatic disease – This category includes patients who have bronchiectasis, often with clusters of small (<5 mm) nodules.
●Cavitary nodular bronchiectatic disease – This category is similar to the one above, but patients also have lung cavities.
●Fibrocavitary disease – This category includes patients with cavities, nodules, fibrosis, and often pleural involvement over contiguous areas.
Several studies indicate that overlap among the categories is common and some may not fit either category (eg, they may have a solitary pulmonary nodule or other radiographic opacities) [4,5]. Because cavitation has been associated with unfavorable treatment outcomes, treatment decisions are based on the presence of cavitary disease [6] (see 'Deciding to treat' below and 'Regimen selection' below). Expert consultation should be obtained for patients who are difficult to categorize into one of the radiologic groups defined above.
DECIDING TO TREAT
Our approach — Not all patients warrant treatment of MAC pulmonary disease at the time of diagnosis. Antimycobacterial treatment is prolonged, with drugs that can be difficult to tolerate, and the long-term response rates are modest. Frequently, close observation rather than antibiotic treatment is warranted, but most patients progress over time, and many will ultimately merit antibiotic therapy.
For patients who meet the diagnostic criteria of nontuberculous mycobacterial (NTM) pulmonary disease with microbiologically confirmed MAC (table 1), decisions on the timing of treatment depend on the type of disease and the risk of progression:
●For patients with cavitary disease, we suggest proceeding with treatment once the diagnosis is established, because this type of disease may be associated with rapid progression and destructive disease. (See 'Prognosis' below.)
●For patients who have smear-positive sputum, we suggest proceeding with treatment once the diagnosis is established, because smear positivity implies a higher microbiologic burden and is associated with disease progression [7,8].
●For patients with noncavitary nodular bronchiectatic disease with smear-negative sputum, the decision to observe or treat depends on the clinical presentation and the overall clinical status of the patient. Observation, or “watchful waiting,” is reasonable in the setting of minimal symptoms or minimal radiographic findings or in patients with concurrent medical problems that are of greater morbidity than the MAC pulmonary infection. Observation consists of interval clinical evaluation, sputum cultures, and serial imaging with chest radiograph or computed tomography. In one survey, experts in the treatment of MAC pulmonary disease reported that no antimicrobials were used to treat new cases between 10 and 25 percent of the time [9].
Studies have not determined the optimal frequency of monitoring for disease progression among patients who are deferring therapy. In our experience, the appropriate frequency varies depending on the extent of disease. In general, sputum cultures should be obtained every two to three months and repeat imaging after approximately six months. Increasing bacterial load, as evidenced by a change from smear-negative to smear-positive sputum or increasing semi-quantitative culture results (if such cultures are available), suggest progression of disease [10,11]. Development of cavitation or worsening nodularity would also be a sign of progressive disease. These developments typically warrant initiation of therapy. In one study of culture-positive individuals who ultimately received treatment for NTM lung disease, treatment after an initial observation period (median five months) was associated with a similar likelihood of sputum culture conversion as that with immediate treatment [12].
In addition to cavitary disease, low body mass index (BMI) has been consistently identified as a risk factor for progressive disease and/or mortality [4,13-19]. Other described factors include male sex, older age, presence of comorbidities, and the number of lung segments involved. Laboratory parameters associated with disease progression have included elevated estimated sedimentation rate (ESR) or C-reactive protein (CRP) as well as anemia and hypoalbuminemia. These features alone are not necessarily indications to initiate treatment but are considerations when weighing the potential risks of treatment versus the risk of progression.
Objectives of treatment — The main objective of antimicrobial therapy for MAC is to cure the infection and thereby prevent further progression of lung disease. Reducing symptoms and improving quality of life are additional goals. However, data demonstrating improvements in these patient-important outcomes with antimicrobial therapy are limited:
●Symptoms and imaging findings – Some studies have shown that treatment is associated with symptom improvement. In a study of 180 patients with nodular bronchiectatic MAC lung disease, self-reported cough and fatigue, the two most commonly reported symptoms, improved over the course of treatment, particularly among those with eventual culture conversion, as did radiographic findings [11]. Those who with culture conversion within six months were also less likely to have bronchiectatic exacerbations. Similarly, in a retrospective study from Korea that included 217 patients with nodular bronchiectatic MAC lung disease who were treated with daily or intermittent therapy, 75 to 82 percent experienced symptomatic improvement and 68 to 73 percent had radiographic improvement [20].
●Overall quality of life – Although patients with MAC lung disease report low quality of life, it has been difficult to demonstrate a definitive improvement with treatment, in part because there are no validated instruments in this patient population. Nevertheless, several small studies have suggested improved quality of life during and after therapy [21-23]. In one prospective study from South Korea that included 44 patients treated for MAC lung disease, successful treatment was associated with an improvement in the Saint George’s Respiratory Questionnaire score (SGRQ, a 100-point measure of perceived well-being in patients with obstructive airways disease) from 34 to 18 [22]. Other studies have suggested that the SGRQ is a reasonable measure of quality of life in patients with MAC lung disease [24,25].
Another quality-of-life measure, the NTM Module of the Quality of Life Questionnaire-Bronchiectasis (QOL-B), was evaluated in a study of 203 patients with MAC lung disease [23]. The 33 patients starting treatment had improvement in scores for NTM symptoms, digestive symptoms, body image, and quality-of-life-related respiratory symptoms. Several ongoing randomized clinical trials are using this instrument as a study endpoint.
●Mortality – The effect of treatment on mortality has been difficult to assess given the high frequency of underlying lung disease in patients with MAC lung disease. Although several observational studies have not identified an association between treatment initiation and mortality reduction [4,17,26,27], limited data do suggest a potential mortality benefit with treatment, particularly successful treatment [12,28]. In a cohort study of 712 patients who were treated for NTM lung disease in South Korea and followed for a median of 64 months, 67 percent achieved sputum culture conversion, which was associated with a lower risk of death, even after controlling for initial severity of illness (hazard ratio 0.51) [12]. A retrospective study reported that the six-minute walk test and Pulmonary Symptom Severity Score were independent predictors of mortality [29].
ANTIMICROBIAL SUSCEPTIBILITY TESTING — Organisms within MAC are typically susceptible to macrolides, clofazimine, and aminoglycosides, with varying susceptibility to rifampin, rifabutin, ethambutol. They are occasionally susceptible to fluoroquinolone and linezolid.
Antimicrobial susceptibility testing is currently recommended by expert panels on a routine basis for clarithromycin and amikacin [3,30,31]. There is no association between in vitro susceptibility testing and clinical outcomes with MAC other than for the macrolides and amikacin [3,32].
However, testing for additional drugs may provide useful information, since intolerance to the first-line drugs is common and could necessitate the use of alternative agents with in vitro activity. Synergy testing has not been correlated with clinical outcomes [33], but the consistent demonstration of synergy among rifamycins and ethambutol suggest these drugs should be combined when possible.
●Macrolides – Typical minimum inhibitory concentrations (MICs) for clarithromycin are 1 to 4 mcg/mL. With the broth dilution method, MIC cut-offs are ≤8 mcg/mL for clarithromycin-susceptible isolates and 16 mcg/mL for clarithromycin-intermediate isolates [31]. Clarithromycin resistance (and thus macrolide resistance) is defined as an MIC ≥32 mcg/mL with broth microdilution. Under selective pressure of macrolide therapy, mutations in the drug's ribosomal binding site can result in MICs above 64 mcg/mL [34,35].
●Aminoglycosides – Aminoglycosides (amikacin or streptomycin) are important antimicrobial agents for patients with cavitary or macrolide-resistant disease [3,36], and susceptibility testing is recommended prior to use. Clinical Laboratory Standards Institute (CLSI)-recommended MIC cut-offs are slightly different with systemic or inhaled liposomal amikacin:
•Intravenous amikacin – MIC cut-offs are ≤16 mcg/mL for susceptible, 32 mcg/mL for intermediate, and ≥64 mcg/mL for resistant [31]. We do not recommend the use of amikacin as part of an antimycobacterial regimen when MICs are ≥64 mcg/mL or when the A1408G mutation is present.
A study using broth microdilution assays to determine amikacin MICs of 462 clinical MAC isolates suggested that prolonged amikacin exposure can lead to development of amikacin resistance [32]. Of these isolates, seven (1.5 percent) had MICs of >64 mcg/mL and all were noted to have a 16S rRNA gene A1408G mutation, which was not detected in isolates with lower MICs. Clinical data were available for five of those seven isolates and confirmed significant prior amikacin exposure.
•Amikacin liposome inhalation suspension (ALIS) – MIC cut-offs are ≤64 mcg/mL for susceptible and ≥128 mcg/mL for resistant [31]. Thus, with an amikacin MIC of 64, we would use ALIS but not intravenous amikacin.
In a randomized trial evaluating the efficacy of ALIS, microbiologic responses were observed among study participants whose isolates had an MIC to amikacin up to 64, but none of the patients with an isolate with an MIC >64 mcg/mL had a microbiologic response, and all had the same A1408G mutation [37].
INITIAL TREATMENT
Regimen selection — Regimen selection depends on susceptibility to macrolides; most MAC isolates, particularly in patients who have not been treated before, are macrolide susceptible. For initial treatment of patients with MAC pulmonary disease, we administer a three-drug regimen containing a macrolide, a rifamycin, and ethambutol. (See 'Number of drugs' below.)
For patients who have cavitary or severe nodular bronchiectatic disease, a parenteral aminoglycoside is also often used in the initial phase of treatment.
Our preferred macrolide and rifamycin are azithromycin and rifampin, respectively. The dosing depends on the type and severity of disease and patient weight. (See 'Mild to moderate noncavitary nodular bronchiectatic disease' below and 'Cavitary or severe nodular bronchiectatic disease' below.)
The following regimen recommendations are generally consistent with the 2020 American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases/Infectious Diseases Society of America clinical practice guidelines on the treatment of nontuberculous mycobacterial (NTM) pulmonary disease [3] and the 2017 guidelines from the British Thoracic Society [38]. These guidelines apply to patients with cystic fibrosis as well, although there are cystic fibrosis-specific guidelines available [39]. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Nontuberculous mycobacteria'.)
Macrolide-susceptible infection — The vast majority of patients without prior treatment for MAC have macrolide-susceptible infection.
Mild to moderate noncavitary nodular bronchiectatic disease — For most patients with mild to moderate nodular bronchiectatic disease, we suggest a three-times-weekly regimen of:
●Azithromycin (500 mg three times per week) PLUS
●Rifampin (600 mg three times per week) PLUS
●Ethambutol (25 mg/kg three times per week)
Initiating these agents in a staggered manner and at lower initial doses can be helpful for assessing tolerance. Adverse effects are an important consideration when counseling patients on regimens for MAC. These issues are discussed elsewhere. (See 'Initiating therapy' below and 'Monitoring for side effects' below.)
Clarithromycin (1000 mg three times per week) can be substituted for azithromycin, although tolerance is likely worse and drug interactions are more common compared with azithromycin. If the patient is taking drugs that interact with rifampin or the patient has had hepatotoxicity to rifampin, rifabutin (300 mg three times per week) can be substituted.
Cavitary or severe nodular bronchiectatic disease — For most patients with cavitary MAC pulmonary disease or severe nodular bronchiectatic disease, we suggest a daily regimen of:
●Azithromycin (250 to 500 mg daily) PLUS
●Rifampin (600 mg daily) PLUS
●Ethambutol (15 mg/kg daily)
In addition, we suggest using parenteral amikacin or streptomycin (both 10 to 15 mg/kg three times per week) as a fourth agent for the first 8 to 12 weeks of therapy (as long as the amikacin minimum inhibitory concentration [MIC] <64 mcg/mL), since treatment outcomes are worse in patients with cavitary disease [4,14-17]. Longer durations of an aminoglycoside course may be warranted in certain cases, including patients who are undergoing surgery for MAC pulmonary disease, for whom both pre- and postoperative treatment is desired. The aminoglycoside dose needs to be adjusted for age, weight, and renal function [3] (see "Dosing and administration of parenteral aminoglycosides", section on 'General principles'). In patients with underlying renal insufficiency (estimated glomerular filtration rate <60 mL/min), aminoglycosides should be used with caution. For patients who cannot use intravenous amikacin, we use amikacin liposome inhalation suspension (ALIS) 590 mg administered once daily; inhaled parenteral amikacin is an alternative for those who cannot access or tolerate ALIS. Inhaled parenteral amikacin is typically dosed at 250 to 500 mg per day and administered three to seven days per week, depending on tolerance, overall strength of the regimen, and extent of disease. Both forms of inhaled amikacin are given for the duration of treatment. (See 'Efficacy of alternative agents' below.)
Initiating these agents in a staggered manner and at lower initial doses can be helpful for assessing tolerance. Adverse effects are an important consideration when counseling patients on regimens for MAC. These issues are discussed elsewhere. (See 'Initiating therapy' below and 'Monitoring for side effects' below.)
Clarithromycin (500 to 1000 mg daily) can be substituted for azithromycin, although tolerance is likely worse and drug interactions more common compared with azithromycin. If the patient is taking drugs that interact with rifampin or has had hepatotoxicity from rifampin, rifabutin (150 to 300 mg daily) can be substituted.
We also refer patients with localized cavitary disease for consideration of surgical resection. If surgical resection is performed, it ideally should be done once negative sputum cultures have been achieved, if possible, and by a team with extensive experience in surgical treatment of NTM pulmonary disease. (See 'Surgical management' below.)
Drug-intolerant patients — Alternative agents, such as clofazimine (100 mg once daily) or moxifloxacin (400 mg once daily), may be reasonable substitutes for certain recommended agents in the setting of drug intolerance. There is some evidence to support substituting clofazimine for a rifamycin [40]; in the United States, clofazimine is not commercially available but can be obtained through an expanded-access program or single-patient investigational new drug application. Although there is also evidence to support using moxifloxacin in treatment-refractory patients [41], our experience has not found moxifloxacin to be a particularly effective or well-tolerated option.
In select patients with mild infection and drug intolerance, a two-drug regimen is another option (see 'Number of drugs' below). However, we advise caution in the selection of a two-drug regimen, because some combinations may promote the development of macrolide resistance. The preferred two-drug regimen is azithromycin and ethambutol. We recommend against the use of a fluoroquinolone or rifamycin combined with a macrolide because these combinations have been associated with an increased risk of macrolide resistance. The selection of alternative drugs should be based on whether drugs have some activity in vitro as determined by antimicrobial susceptibility testing. (See 'Antimicrobial susceptibility testing' above and 'Efficacy of alternative agents' below and 'Number of drugs' below.)
Macrolide-resistant infection — When macrolide resistance is identified, a macrolide should not be used for treatment of MAC, and additional drugs must be substituted in the antimycobacterial regimen. Macrolides may still be used for immunomodulatory purposes. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Macrolides'.)
Data informing the optimal treatment of patients with macrolide-resistant infection are limited, and consultation with an expert in treating MAC infections is recommended. We typically treat macrolide-resistant MAC infections with daily ethambutol 15 mg/kg daily, rifampin 600 mg daily (or rifabutin 150 to 300 mg daily), and clofazimine 100 mg once daily, augmented by two to six months of intravenous amikacin (as long as the amikacin MIC is <64 mcg/mL) 10 to 15 mg/kg per day administered three times a week. Clofazimine is our preferred third agent because of the excellent in vitro activity and synergy with amikacin [42]; in the United States, clofazimine is not commercially available but can be obtained through an expanded-access program or single-patient investigational new drug application. Ciprofloxacin (500 to 750 mg twice daily) or moxifloxacin (400 mg daily) can be used as an alternative if there appears to be in vitro susceptibility, which is relatively unusual. Furthermore, because of the difficulty in medical treatment of macrolide-resistant disease, individuals should be assessed for the feasibility of surgical resection. (See 'Surgical management' below.)
Use of parenteral aminoglycosides has been associated with improved treatment outcomes in patients with macrolide-resistant disease [36,43]. There is minimal clinical evidence to inform the use of other agents such as isoniazid, fluoroquinolones, or clofazimine. Newer drugs such as bedaquiline may have a role in the future [44]. (See 'Efficacy of alternative agents' below.)
Our practice differs somewhat from the British Thoracic Society guidelines, which suggest ethambutol, rifampin, and either a fluoroquinolone or isoniazid, in addition to an aminoglycoside [38].
Initiating therapy — At initiation of therapy, the following baseline laboratory evaluations should be performed:
●Complete blood count (all patients)
●Comprehensive metabolic panel (all patients)
●Electrocardiogram to assess QT interval (patients receiving a macrolide, fluoroquinolone, or clofazimine)
●Audiogram (patients receiving a macrolide or aminoglycoside)
●Visual acuity and color discrimination (patients receiving ethambutol)
We also ensure baseline chest imaging (optimally with computed tomography [CT]); patients should have already had this as part of the diagnostic evaluation. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
Initiating one drug at a time is a useful way to begin therapy, particularly in patients who are older and/or have a history of drug intolerance. We begin with azithromycin followed by ethambutol and then rifampin. In rare cases, each drug can be initiated at a lower dose then increased to the treatment dose over three to five days until the next drug is introduced. In this situation, we begin with half of the planned dose. This approach allows the provider and patient to determine which drug is producing a specific side effect and provides an opportunity to address mild adverse reactions such as nausea before introducing the next drug.
Duration of therapy — We agree with recommendations from the international guidelines that treatment be continued until sputum cultures are consecutively negative for at least 12 months [3]. Since sputum conversion usually requires three to six months of treatment, a typical patient will be treated for 15 to 18 months. Although the optimal treatment duration is uncertain, shorter durations are associated with worse outcomes.
Completion of at least 12 months of therapy has been associated with a higher rate of conversion to negative sputum culture compared with shorter duration of therapy. As an example, in a retrospective observational study, receipt of at least 12 months of a three-drug macrolide-based regimen was associated with conversion to negative sputum culture in 86 percent, compared with 22 percent with receipt of less than 12 months [45]. A systematic review also reported that treatment success was higher in persons who received at least 12 months of macrolide-based therapy, although included studies used varying definitions of treatment success [46].
Shorter treatment courses may also be associated with a higher rate of recurrence [47,48]. As an example, in a retrospective study of 154 patients with macrolide-susceptible MAC lung disease (70 percent with noncavitary nodular bronchiectatic disease) who were treated with a standard three-drug regimen (with or without a parenteral aminoglycoside), recurrent disease was independently associated with treatment for <15 months, in addition to post-treatment cavitary disease and higher severity of bronchiectatic disease [47]. Similarly, in a study from Japan, the recurrence rate among 100 patients who had achieved conversion to negative sputum culture after macrolide-based therapy was 5 percent within six to nine months after therapy completion; none of those recurrences occurred in patients who received more than 15 months of therapy [48]. However, these studies were not able to distinguish relapse from reinfection among patients with recurrent disease. (See 'Recurrence' below.)
Rationale for regimen selection — High-quality data evaluating the efficacy of antimycobacterial regimens for MAC are lacking. Most of the evidence supporting treatment regimens is from observational studies among different patient populations and from different clinical settings. Accordingly, most of the recommendations for regimen selection are based on observational data and expert opinion.
Overall efficacy — Macrolides are the cornerstone of antimycobacterial therapy for MAC, based primarily on observational studies. Retrospective studies have reported sputum conversion rates as high as 75 to 86 percent with macrolide-containing regimens [20,45]. In a large nationwide database study from South Korea, use of a macrolide for more than one year was associated with reduced mortality among individuals with a diagnosis of NTM infection [28].
Prior to the use of macrolides, treatment with multidrug regimens, usually including rifampin, ethambutol, and isoniazid, achieved initial sputum conversion rates of only 50 to 70 percent, with 20 to 30 percent recurrence rates [3,49-51]. Nevertheless, even with macrolide-containing regimens, response to MAC therapy is modest, in part because of the difficulty in tolerating the regimen. As an example, in a meta-analysis of 16 studies (mainly observational but also a few trials), the weighted rate of microbiologic treatment success (12 months of negative cultures while on therapy) was 60 percent [52]. Default rates, principally due to drug side effects, were 16 percent overall and 12 percent among subjects given thrice-weekly therapy. When subjects who defaulted within 12 months were excluded, the treatment success rate was 74 percent.
Data from trials are limited [53,54]. One randomized trial conducted by the British Thoracic Society (BTS) included 170 patients with MAC and compared clarithromycin with ciprofloxacin, each used in combination with rifampin and ethambutol [53]. Treatment failure occurred in 13 percent of patients receiving clarithromycin compared with 23 percent in those receiving ciprofloxacin. However, there was no difference in the proportion of patients who completed treatment as allocated and were alive and cured at five years (24 and 23 percent, respectively).
Data on the efficacy of two- versus three-drug regimens are discussed elsewhere. (See 'Number of drugs' below.)
Choice of macrolide — Azithromycin is the preferred macrolide for most patients. It is associated with fewer adverse reactions, fewer drug interactions, improved tolerance, lower pill burden, and more practical dosing (ie, single daily) compared with clarithromycin, and it results in similar treatment outcomes [45,55].
Azithromycin can be given as 250 to 500 mg/day or 500 mg three times per week, depending on the severity or extent of disease and patient tolerability. If lower doses are chosen, we recommend checking drug levels, as there are data to support a correlation between azithromycin drug levels and clinical outcomes [56]. (See 'Therapeutic drug monitoring' below.)
When clarithromycin is used, lower doses (eg, 500 mg once daily) are necessary for patients with renal impairment and may be better tolerated in older patients; however, the impact of dose reduction on treatment outcomes is not known.
Choice of rifamycin — Rifampin is the preferred rifamycin based on its improved tolerance. However, specific drug interactions may make rifabutin a preferable agent for some patients.
The choice of which rifamycin to use should be individualized. Rifampin is often used in place of rifabutin for its more favorable side effect profile. Rifabutin is more active in vitro than rifampin against MAC, but it is not clear that this has any clinical impact. In HIV-infected patients, rifabutin may be preferable in some settings [57]. Either rifamycin will decrease the effective serum concentration of the macrolide, but this is primarily an issue with clarithromycin. Clarithromycin interacts with rifabutin to increase rifabutin levels, while azithromycin does not; we do not typically use this combination. It is important to appreciate these complex interactions as well as interactions with any other drugs the patient is taking that are metabolized through the cytochrome P450 system.
Addition of aminoglycoside — Aminoglycosides such as amikacin and streptomycin are highly active against extracellular organisms and can speed up sputum conversion [37,58]. Thus, addition of an aminoglycoside to the regimen can be especially useful for patients with radiographically extensive or cavitary disease, particularly with positive sputum smears, who have a substantial burden of extracellular organisms. Similarly, adjunctive aminoglycosides may be beneficial for patients preparing for surgical resection, since positive cultures at the time of surgery have been associated with post-surgical complications, such as development of a bronchopleural fistula [59]. For patients with contraindications to parenteral aminoglycosides, inhaled amikacin is an alternative.
In a trial designed to assess the impact of parenteral streptomycin added to a standard three-drug regimen (clarithromycin, rifampicin, ethambutol), the 73 patients randomly assigned to receive streptomycin for the initial three months of therapy had better initial microbiologic response compared with the 73 patients who received only three oral drugs (rate of sputum conversion at the end of therapy 71 versus 51 percent) [58]. There were no differences in clinical improvement (including both clinical symptoms and radiographic findings), and the sputum relapse rates were similarly high in both groups (31 and 35 percent, respectively).
Data on inhaled amikacin are discussed elsewhere. (See 'Efficacy of alternative agents' below.)
Number of drugs — A three-drug regimen is recommended for most patients, although a two-drug regimen of a macrolide and ethambutol may be appropriate for some patients with less severe disease, particularly those who do not tolerate three-drug regimens. Three-drug regimens have been preferred because indirect data from treatment of disseminated disease suggest that a third agent protects against emergence of macrolide resistance in patients who have initial response to therapy [60]. If a two-drug regimen is used, we suggest the combination of a macrolide and ethambutol. We do not recommend a combination of a macrolide and fluoroquinolone or a combination of a macrolide and rifamycin, because these have been reported to lead to macrolide resistance [36].
Randomized controlled trials comparing the treatment outcomes of two- versus three-drug regimens have been small and limited. A British Thoracic Society (BTS) trial compared rifampin and ethambutol (two-drug therapy) with rifampin, ethambutol, and isoniazid (three-drug therapy) in 75 patients with MAC pulmonary disease [51]. Treatment failure was higher with two-drug therapy (41 versus 16 percent), but there was no difference in the proportion of patients who completed treatment as allocated and were alive and cured at five years (27 and 34 percent). Of note, macrolides were not used in this trial.
The only randomized trial evaluating two- or three-drug regimens that contained a macrolide compared outcomes with clarithromycin and ethambutol versus clarithromycin, rifampin, and ethambutol among 119 patients, including 57 (48 percent) with cavitation [61]. There was no difference in sputum conversion rate at 12 months between the two groups (41 percent with three-drug therapy versus 55 percent with two-drug therapy), suggesting that the two-drug regimen was not inferior. Imaging findings improved in 85 and 78 percent receiving two and three drugs, respectively, and study drugs were discontinued in fewer patients receiving two drugs. Clarithromycin resistance did not develop by the end of treatment, but the study was underpowered to detect emergence of resistance. Clarithromycin levels were substantially lower in the three-drug group, probably due to concomitant rifampin, and this may have affected outcomes. Though these data are insufficient to change standard treatment recommendations, they suggest that a two-drug regimen may be an effective option in some patients. A large randomized trial evaluating azithromycin and ethambutol with or without rifampin is underway in the United States [62].
Daily versus intermittent therapy — An intermittent regimen (ie, dosing medications three times weekly versus daily) is recommended for initial therapy in patients with non-cavitary bronchiectatic disease. However, intermittent medication dosing is not effective for patients with severe or cavitary disease or patients who have failed previous therapy [63]. If sputum cultures remain positive after six months of intermittent therapy, we recommend switching to daily therapy.
Observational experience is accumulating with intermittent (three times weekly) dosing of the three-drug regimen, and this suggests that intermittent dosing is as effective as daily therapy and better tolerated in most patients [20,45,52,64,65]. As an example, in a retrospective study from Korea [20], there were no differences in rates of symptom improvement, radiographic improvement, or sputum conversion, but less frequent treatment modification among 118 patients who had received intermittent dosing compared with 99 patients who had received daily dosing.
For those who have failed to achieve sputum conversion on intermittent therapy, a switch to daily therapy may be of microbiological benefit for some patients. In a small study of 20 patients who had positive cultures after 12 months of intermittent therapy, 6 (30 percent) were able to convert their sputum cultures after changing to daily therapy [55].
Efficacy of alternative agents — Data on alternative agents for MAC pulmonary disease are limited.
●Clofazimine – Clofazimine has been used with success as an alternative agent for patients intolerant to rifampin [40,66,67]. In a retrospective review, sputum conversion rates were 100 percent among patients with MAC who were treated with clofazimine, ethambutol, and a macrolide [40]. However, about a third of patients had only one negative sputum culture with no further sputum cultures while on treatment. Similar to a standard regimen, the recurrence rate was high. Forty-nine percent of the patients on this regimen experienced microbiologic relapse, with 37 percent requiring retreatment.
●Moxifloxacin – The utility of moxifloxacin in the treatment of MAC is uncertain. Rifampin can reduce the serum concentration of moxifloxacin [68], and the combination of a fluoroquinolone with a macrolide is a risk factor for the acquisition of macrolide resistance [36]. Moxifloxacin has variable in vitro and in vivo activity against MAC [69-71]. In one study of 41 patients with MAC refractory to a macrolide-based three-drug regimen, 29 percent achieved negative sputum cultures after addition of moxifloxacin [41]. Sputum conversion was not achieved in those who had clarithromycin resistance (0 of 7 patients, 0 percent), in contrast to those with clarithromycin susceptible infection (11 of 33 patients, 33 percent), but the difference between the two groups was not statistically significant.
●Inhaled amikacin – Inhaled amikacin has been used for many years in patients intolerant to parenteral aminoglycosides or as an adjuvant to oral therapy [72-74]. In September 2018, the US Food and Drug Administration conditionally approved amikacin liposome inhalation suspension (ALIS) for patients with treatment-refractory MAC pulmonary disease, defined as persistent culture positivity after six months of therapy.
In a phase 3, open-label randomized trial, the addition of ALIS (590 mg once daily) to guideline-based therapy increased sputum culture conversion rates by the sixth month of treatment (29 versus 9 percent with guideline-based treatment alone; odds ratio 4.22, 95% CI 2.08-8.57) [75]. There was a higher rate of respiratory adverse events in the group receiving ALIS. For example, approximately 46 percent of subjects who received ALIS developed dysphonia, 37 percent developed coughing, and 22 percent developed dyspnea. Respiratory adverse events often improved with time or brief interruptions in therapy, and 17.4 percent of patients discontinued therapy overall related to adverse events. Treatment outcomes were similar to those of an earlier phase 2 randomized trial in which the addition of ALIS to a standard multidrug regimen did not result in a greater reduction in mycobacterial growth on semi-quantitative sputum cultures compared with placebo but did result in a higher proportion of at least one negative sputum culture (32 versus 9 percent) [37]. In both studies, 16 to 17 percent of patients receiving ALIS stopped the drug due to side effects. In neither study was there an improvement in symptoms or spirometry. In the phase 2 study [37], there was improved six-minute walk test performance after 84 days of treatment in the ALIS-treated patients, but this was not demonstrated in the phase 3 study [75].
Similarly, in retrospective studies of patients with refractory pulmonary MAC or M. abscessus infection, 18 to 25 percent achieved sustained negative cultures with the addition of inhaled parenteral amikacin to the antimycobacterial regimen [73,74]. Among 20 patients with refractory NTM pulmonary disease who received inhaled parenteral amikacin, symptom scores improved in 45 percent, were unchanged in 35 percent, and worsened in 20 percent, and CT scans improved in 30 percent, were unchanged in 15 percent, and worsened in 55 percent [73]. However, adverse effects were common, with 35 percent of patients stopping the drug because of side effects. In another study that included 77 patients with refractory NTM pulmonary disease, at 12 months after initiation of inhaled parenteral amikacin, 49 percent reported symptomatic improvement and 42 percent had radiological improvement [74]. Adverse effects were also common in this study, with 38 percent of patients reporting an adverse event [74].
Some drugs used for treatment of multidrug-resistant tuberculosis have in vitro activity against MAC isolates, but there are limited data on clinical outcomes. Bedaquiline, an adenosine triphosphate (ATP) synthase inhibitor, has MIC90 values of <0.016 mcg/mL for MAC [76], but the clinical experience in treatment of MAC has been limited. Among six patients with refractory MAC pulmonary disease who received bedaquiline as part of a multidrug regimen, three had symptomatic improvement by six months and three had some improvement in semiquantitative sputum cultures [44]. Linezolid, an oxazolidinone, has MICs in the susceptible to intermediate range in only 40 percent of MAC isolates [77]. Furthermore, it is associated with significant drug-related toxicity [78]. As an example, in a study among 102 patients with NTM disease, over 40 percent required discontinuation of linezolid [79]. Delamanid, a nitroimidazooxazole, has little activity against MAC [76].
SURGICAL MANAGEMENT — Lung resection is generally effective in controlling infection, and in patients who have failed medical therapy, surgery appears to offer a greater chance of bacteriologic cure. Surgical treatment should only be undertaken by a team with substantial experience in treating nontuberculous mycobacterial (NTM) pulmonary disease.
Surgery may be useful in the following settings:
●Patients with localized disease, especially upper lobe cavitary disease
●Patients in whom drugs fail to convert the sputum cultures to negative after six months of continuous treatment
●Patients who cannot tolerate medical therapy
●Patients with macrolide-resistant MAC pulmonary disease
For patients undergoing surgery for MAC pulmonary disease, the procedure should be performed, if possible, once sputum cultures are negative, because positive cultures at the time of surgery have been associated with postoperative complications [59].
Lobectomy can be considered in patients with anatomically limited disease [80,81], while pneumonectomy may be required for patients with multiple cavitary lesions or a unilateral destroyed lung [81,82]. Bronchopleural fistula formation can complicate pneumonectomy, even with the use of pedicle flap closure, and is more common on the right side [83]. (See "Preoperative physiologic pulmonary evaluation for lung resection".)
There have been several studies reporting outcomes of surgical resection in patients with pulmonary NTM, most of whom had MAC [59,80-82,84-87]. One retrospective study reported a very low rate of surgical morbidity (7 percent) among 134 patients who underwent video-assisted thoracoscopic surgery for localized pulmonary MAC disease following several months of antimycobacterial treatment [84]. Forty-four percent of patients were culture positive at the time of surgery, whereas only 16 percent remained culture positive post-operatively.
ADJUNCTIVE MEASURES — Most patients with MAC pulmonary disease have underlying lung disease such as bronchiectasis or chronic obstructive pulmonary disease (COPD). Therefore, adjunctive therapies are an important component of treatment. For example, improving airway clearance and preventing aspiration can have an immediate impact on cough. Methods used to improve airway clearance include flutter valves, vests, and inhaled hypertonic saline. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)
Patients with a low body mass index (BMI) or hypoalbuminemia are at higher risk of developing progressive disease than others [4,13,14,16,18] and in our experience, less likely to respond to therapy. Consultation with a dietician and nutritional supplementation to increase weight is an important component of the treatment regimen. In severely malnourished patients, temporary enteral feeds may be needed to achieve nutritional goals in a more rapid manner.
MONITORING
Monitoring for side effects — Patients should be evaluated clinically for evidence of drug-related toxicity every one to two months while on therapy. This includes testing of the complete blood count, blood urea nitrogen (BUN) and creatinine, and liver enzymes as well as color discrimination and visual acuity. Specific testing is dependent on the drugs included in the regimen. For patients receiving aminoglycosides, audiograms and vestibular assessment should be performed routinely; the frequency of such testing depends on the dose used and whether the patient already has hearing loss.
Adverse reactions are common, with approximately 20 and 37 percent of patients with pulmonary MAC discontinuing therapy [40,53,61]. These include the following:
●Gastrointestinal intolerance – Clarithromycin, azithromycin, ethambutol, rifabutin, rifampin, fluoroquinolones, or clofazimine
●Abnormal liver function tests – Clarithromycin, azithromycin, rifabutin, rifampin, or moxifloxacin
●Low white blood cell count – Rifabutin, rifampin
●Impaired visual acuity or color vision – Ethambutol
●Decreased auditory function – Aminoglycosides (systemic or inhaled) or azithromycin
●Vestibular toxicity – Aminoglycosides (systemic or inhaled)
●Decreased renal function – Aminoglycosides (systemic or inhaled)
●Peripheral neuropathy – Ethambutol, clofazimine, or aminoglycosides
●Prolonged QTc – Macrolides, fluoroquinolones, or clofazimine
Decisions on dose modifications or drug discontinuations in the setting of toxicity are complex and depend on the type and severity of the toxicity and the importance of the offending drug in the patient’s regimen. The threshold to discontinue a macrolide because of mild or moderate transaminitis is generally higher than that for discontinuation of ethambutol in the setting of objective visual deficits. Similarly, the decision to stop an aminoglycoside must be weighed against the potential benefits to the patient. Consultation with an expert in MAC treatment is advised in such situations.
Monitoring for clinical response
●Microbiologic monitoring – The duration of treatment is determined by the microbiologic response to therapy, with the aim of achieving 12 months of negative cultures. Therefore, we typically obtain sputum cultures every one to two months following treatment initiation to monitor treatment efficacy. Once sustained conversion (repeated negative sputum cultures) has been documented, sputum cultures can be obtained less frequently.
If the patient is not producing sputum, we recommend sputum induction with hypertonic saline. (See 'Duration of therapy' above.)
Lack of microbiologic response after six months of therapy or recurrent positive sputum cultures after achieving negative cultures warrant further evaluation. (See 'Treatment failure' below.)
●Radiographic monitoring – We obtain chest computed tomography every six months while patients are receiving therapy using a "low-radiation dose" protocol. However, there is no evidence that this frequency of imaging changes clinical outcomes. At a minimum, we suggest obtaining imaging at the beginning of treatment, once during treatment, and again at the end of treatment. We additionally obtain imaging at any point during therapy if there are concerns for microbiologic failure or clinical worsening.
Therapeutic drug monitoring — Therapeutic drug monitoring (TDM) should be performed in patients receiving parenteral aminoglycosides. For amikacin, a trough level of <5 mg/L is recommended, with peak levels of 35 to 45 mg/L with daily dosing and 65 to 80 mg/L with intermittent dosing.
Otherwise, the role of TDM in the management of patients with MAC pulmonary disease is uncertain. Clear indications for TDM include the presence of multiple drug interactions, suspected or known malabsorption, and treatment failure. It is also reasonable to obtain ethambutol levels in patients with renal dysfunction.
In one study of patients receiving daily versus intermittent azithromycin therapy, lower azithromycin peak levels (Cmax) were observed in those on daily therapy because of the lower daily dose (250 mg) when used with rifampin [56]. Among those on daily therapy, an azithromycin Cmax >0.4 mcg/mL was independently associated with a favorable microbiologic outcome. This suggests that if the microbiologic response is poor, checking the azithromycin Cmax and adjusting the dose may be beneficial.
However, other studies have not demonstrated such an association. In a pharmacokinetic analysis of drug levels among 481 patients undergoing macrolide-based multidrug therapy for MAC pulmonary disease, suboptimal levels of clarithromycin, azithromycin, and ethambutol were common, rifampin coadministration further decreased macrolide levels, and pharmacodynamic indices infrequently predicted bactericidal activity for most agents [88]. However, the clinical meaningfulness of the minimum inhibitory concentration (on which target drug levels are based) of non-macrolide drugs for MAC is uncertain, and this study did not evaluate the correlation between drug levels and clinical response [89]. In a separate study of 101 patients with MAC lung disease treated with a clarithromycin-based multidrug regimen, there was no difference in peak plasma drug levels between those with (n = 75) and without (n = 26) microbiologic response after 12 months, even though almost all the patients had clarithromycin levels below the target range [90].
TREATMENT FAILURE
Definition — We define treatment failure as failure to convert initially positive cultures to negative by six months of therapy. The Nontuberculous Mycobacteria (NTM)-Network European Trials Group has proposed the somewhat different definition of lack of culture conversion after ≥12 months of treatment [91]. We favor the former definition, as studies suggest that most individuals who convert to negative cultures do so within the first six months of therapy and that culture status at six months is predictive of culture status at 12 months [11,92].
As an example, in a study from Korea that included 470 patients with MAC pulmonary disease, 357 (76 percent) achieved culture conversion within 12 months of treatment and 94 percent of those individuals had achieved conversion by six months [92]. Among the 113 patients who were culture positive at 12 months of treatment, 93 percent were also culture positive at 6 months.
Management of treatment failure — Some patients may respond clinically and/or radiographically but remain culture positive beyond six months. In these settings, we recommend the following:
●Continue the macrolide-based regimen if the isolate is still susceptible.
●Add amikacin liposome inhalation suspension (ALIS; 590 mg once daily) to the standard regimen and use it for the duration of the treatment regimen. If ALIS is not available, inhaled parenteral amikacin (250 to 500 mg once daily administered three to seven days a week) is an alternative. (See 'Efficacy of alternative agents' above.)
●If the patient has been on intermittent therapy, switch to daily administration. In a study from Korea, of 20 patients whose sputum remained positive after 12 months of intermittent antibiotic therapy, six (30 percent) achieved a negative culture after a change to daily therapy [55].
●Evaluate the patient for surgical resection with or without parenteral amikacin. Our practice is to add intravenous amikacin three times a week for six to eight weeks preoperatively and another four weeks postoperatively. (See 'Surgical management' above.)
Patients with treatment failure also warrant evaluation for adherence to the drug regimen, assessment of serum drug concentrations, and antimicrobial susceptibility testing to clarithromycin, amikacin, and other drugs that may be needed for treatment. (See 'Antimicrobial susceptibility testing' above.)
RECURRENCE — For patients who have cleared sputum cultures on treatment, we continue to check sputum cultures every six months after treatment. Recurrent MAC growth in the sputum after having achieved sustained sputum conversion (persistently negative cultures) can represent either relapse of the original infection or reinfection with a new strain. Recurrence rates have been noted to be as high as 48 percent, with a majority likely representing reinfection rather than true relapse identified by genotyping the strains [45]. Unfortunately, genotyping is not readily available, and the methods used have not been validated.
Retreatment is the same regardless of whether the patient has suffered a relapse or reinfection, and regimen selection is the same as for initial treatment, depending on whether the isolate is macrolide sensitive. As with initial infection, the decision to retreat should be based on a comprehensive clinical assessment, including imaging and pulmonary function status. (See 'Deciding to treat' above and 'Macrolide-susceptible infection' above and 'Macrolide-resistant infection' above.)
Macrolide resistance is more likely with relapsed disease. Reinfection should prompt a review of possible environmental sources of infection. (See "Epidemiology of nontuberculous mycobacterial infections", section on 'Mycobacterium avium complex'.)
PROGNOSIS
Without treatment — Untreated patients with MAC pulmonary disease have a high rate of progression with approximately 40 to 60 percent of patients showing signs of clinical and/or radiographic progression over the next 2 to 10 years of follow-up [13-16,93]. In one study, 10-year mortality rates from all causes and MAC pulmonary disease were 27.4 and 4.8 percent, respectively [16]. In another study, radiographic progression at 10 years was noted in 53.3 percent of patients with nodular bronchiectatic MAC who were observed off therapy [14].
As noted previously, risk factors for progression include low body mass index (BMI), cavitary disease, the number of lung segments involved, older age, male sex, and the presence of comorbidities, as well as anemia, hypoalbuminemia, and elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) [13-16].
With treatment — Macrolide-containing regimens have been associated with long-term sputum conversion rates as high as 86 percent [6,45]. However, relapse and reinfection rates remain high. In one study of 155 patients with nodular bronchiectatic MAC who had achieved treatment success (negative sputum cultures for at least 12 months while on therapy without isolation of the original infection pathogen), 48 percent had a microbiologic relapse [45]. Pulsed field electrophoresis identified 25 percent of these as true relapse and 75 percent as possible reinfections. Other studies have reported microbiologic relapse or reinfection in 25 to 29 percent [1,6]. (See 'Treatment failure' above.)
One study reported that the change in semi-quantitative agar sputum cultures from baseline to month 3 of treatment was highly predictive of subsequent long-term culture conversion as well as symptomatic and radiographic improvement [11].
Risk factors associated with recurrence include longer interval between initial diagnosis and treatment, higher number of involved lobes, and failure to achieve negative sputum cultures within six months following treatment initiation [94]. In one study, nodular bronchiectatic MAC was associated with a higher rate of recurrence than fibrocavitary disease [6].
Macrolide-resistant MAC lung disease in particular is associated with a poor prognosis [36,95]. In a retrospective review of 51 patients with macrolide resistance, sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79 percent) patients who received more than six months of parenteral aminoglycoside therapy and lung resection, compared with 2 of 37 (5 percent) who did not [36]. The one-year mortality in patients who remained culture positive was 34 percent (13 of 38) compared with 0 percent (0 of 13) of patients who became culture negative. Among 31 patients with macrolide-resistant MAC in Korea, favorable treatment outcomes were achieved in only 5 (15 percent) patients [95].
Although treatment outcomes were traditionally thought to be equivalent across the various species included in MAC [3], more recent studies have challenged this view, but results from these studies have not been consistent for the specific species [1,2,96,97]. In one study from South Korea, M. intracellulare was associated with a worse treatment response than M. avium [2], but in another study, patients with M. intracellulare were less likely to experience clinical relapse/reinfection compared with patients who had M. avium or M. chimaera (9 versus 29 percent) [1].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria".)
SUMMARY AND RECOMMENDATIONS
●Important MAC species – The most common of the 12 species of Mycobacterium avium complex (MAC) to cause lung disease are Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera. (See 'Introduction' above.)
●Deciding to treat – Antimycobacterial treatment is prolonged and potentially difficult to tolerate and should only be considered in patients who meet the clinical, radiographic, and microbiologic criteria for the diagnosis of nontuberculous mycobacterial (NTM) infection (table 1) (see 'Deciding to treat' above):
•Smear-positive or cavitary disease – For patients who meet the diagnostic criteria and have either smear-positive or cavitary disease, we suggest treatment at the time of initial diagnosis (Grade 2C). Cavitary disease is destructive and associated with more rapid progression.
•Smear-negative nodular bronchiectatic disease – For patients who meet the diagnostic criteria and have nodular bronchiectatic, smear-negative disease, the decision to treat or observe depends on the clinical presentation and the overall clinical status of the patient. Observation is reasonable for those with mild disease or other medical problems that outweigh the morbidity of MAC pulmonary disease and consists of interval clinical evaluation, sputum cultures, and chest imaging. Increasing bacterial load (eg, change from smear-negative to positive sputum), development of cavitation, and worsening nodularity are signs of progressive disease that warrant initiation of therapy.
●Regimen selection – For most patients who are being treated for MAC pulmonary disease, we suggest at least a three-drug combination regimen rather than two or fewer drugs (Grade 2C). For those with mild disease who cannot tolerate three drugs, a two-drug regimen (eg, a macrolide and ethambutol) is a reasonable alternative.
Regimen selection depends, in part, on susceptibility to macrolides; most MAC isolates are macrolide susceptible. (See 'Regimen selection' above and 'Rationale for regimen selection' above.)
•Macrolide-susceptible infection – For patients with macrolide-susceptible disease, we suggest a combination of azithromycin, rifampin, and ethambutol (Grade 2C). The precise dosing and administration differs between nodular bronchiectatic and cavitary disease. (See 'Macrolide-susceptible infection' above.)
For patients with cavitary disease, we also suggest a parenteral aminoglycoside as a fourth agent for the first 8 to 12 weeks (Grade 2B).
•Macrolide-resistant infection – Macrolide-resistant disease should be managed in consultation with an expert in MAC infections. Macrolides are not active in macrolide-resistant disease but may be used as immune modulators when appropriate. (See 'Macrolide-resistant infection' above.)
●Monitoring and duration – Antimycobacterial treatment is continued until sputum cultures are consecutively negative for at least 12 months. We typically obtain sputum cultures every one to two months following treatment initiation and radiographic imaging every six months to monitor treatment efficacy. Patients should also be evaluated clinically for evidence of drug-related toxicity every one to two months while on therapy. This generally includes testing of the complete blood count, blood urea nitrogen (BUN) and creatinine, and liver enzymes as well as color discrimination and visual acuity and, for patients receiving parenteral aminoglycosides, audiograms and vestibular assessment. (See 'Duration of therapy' above and 'Monitoring' above.)
●Treatment failure – We consider patients to have treatment failure when they have not converted sputum cultures to negative by six months of therapy. For such patients, we suggest the addition of amikacin liposome inhalation suspension (ALIS) (Grade 2C).
●Adjunctive measures – Important adjunctive therapies include strategies to improve airway clearance, prevent aspiration, and optimize nutrition. (See 'Adjunctive measures' above.)
●Indications for surgical evaluation – Patients with cavitary disease, treatment failure, and macrolide-resistant infection should be evaluated for lung resection. (See 'Surgical management' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David E Griffith, MD, who contributed to an earlier version of this topic review.
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