Mycobacterium Avium Complex (MAC) (Mycobacterium Avium-Intracellulare [MAI]) Treatment & Management

Mycobacterium avium complex (MAC) is intrinsically resistant to many antibiotics and antituberculosis drugs but is fairly susceptible to the following agents:

• Macrolides (eg, clarithromycin, azithromycin)

• Rifamycins (eg, rifampin, rifabutin)

• Ethambutol

• Clofazimine

• Fluoroquinolones (eg, ciprofloxacin, levofloxacin, moxifloxacin)

• Aminoglycosides (eg, amikacin, streptomycin)

• Inhaled amikacin liposome suspension

In general, MAC infection is treated with 2 or 3 antimicrobials for at least 12 months. Commonly used first-line drugs include macrolides (clarithromycin or azithromycin), ethambutol, and rifamycins (rifampin, rifabutin). Aminoglycosides, such as streptomycin and amikacin, are also used as additional agents. ^[26]

In 2007, aerosolized amikacin was found to be an effective adjunctive therapy in a small case series. ^[27] The FDA approved amikacin liposome inhalation suspension in 2018 for MAC infections as part of a combination antibacterial drug regimen in adults who do not achieve negative sputum culture results after a minimum of 6 consecutive months of a multidrug background regimen therapy. The prescribing information for amikacin liposome inhalation cautions that, since only limited clinical safety and effectiveness data are available, it should be reserved for adults who have limited or no alternate treatment options. The drug gained accelerated approval based on the CONVERT clinical trial (n=336). Patients were randomized 2:1 to receive once-daily amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) or GBT alone. Culture conversion was achieved in 29% of the ALIS-GBT group compared with 8.9% of the GBT group (P< 0.001). ^[28]

Fluoroquinolones (levofloxacin, moxifloxacin) and clofazimine should be used as second-line agents against MAC because of the poor outcome associated with them compared with macrolide-containing regimens. Linezolid and ketolides also demonstrate good in vitro activity against MAC and other mycobacteria, although clinical data to support their use are lacking.

MAC lymphadenitis in children is treated with surgical excision of the affected lymph nodes. Antibiotics are generally not required but may be beneficial in patients with extensive lymphadenitis or with a poor response to surgical therapy.

Clinical trials have failed to show any significant clinical benefit for antimycobacterial drugs used to treat Crohn disease secondary to M aviumparatuberculosis. ^[29]

Pulmonary MAC infection in patients with lung disease may require surgical excision of focal pulmonary nodules. Lobectomy has also been recommended for more extensive lung infection in patients who have not responded to antibiotics in the past. This, however, does not occur as often now that more potent antibiotics are available.

The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) have issued guidelines for the diagnosis, treatment, and prevention of nontuberculous mycobacterial pulmonary infection. ^[25] Since these guidelines were published, recent antibiotic advances have been reviewed. ^[30]

In immunocompetent patients with MAC lung disease, treatment decisions should be based on any underlying comorbid conditions, severity of lung disease, risk of progression, and goals of treatment. ^{[31, 10]} Patients should be informed about the need for long-term treatment with a multiple-drug regimen, along with the potential risks and benefits of treatment. If the decision is to withhold treatment, the patients should be monitored long-term for any progression in clinical symptoms, radiographic changes, and microbiological evaluations. A Korean study found radiographic progression of fibronodular lung disease in over 97% of untreated patients observed for at least 4 years. ^[32] A study from Japan found that negative prognostic factors for MAC-specific and all-cause mortality included fibrocavitary with or without nodular/bronchiectatic lung disease, BMI less than 18.5 kg/m², and anemia. ^[33]

Treatment of MAC infection in immunocompetent patients involves the combination of a newer macrolide (azithromycin or clarithromycin), ethambutol, and rifabutin. Treatment should be continued for 12 months after sputum culture results for MAC turn negative.

ATS/IDSA guidelines recommend that most patients with nodular or bronchiectatic disease can be treated with a thrice-weekly regimen of clarithromycin 1000 mg or azithromycin 500 mg, rifampin 600 mg, and ethambutol 25 mg/kg. Therapy should be continued for at least one year after culture results revert to negative. ^[25] Intermittent treatment with three-times-per-week regimens in patients with noncavitary nodular bronchiectatic MAC lung disease has been shown to yield fewer adverse effects and improved compliance. ^[34]

Lam et al verified comparable results between daily and thrice-weekly therapy in patients with noncavitary lung disease, but found that patients with cavitary lung disease had worse outcomes with thrice-weekly therapy. ^[35] Therefore, patients with fibrocavitary lung disease or severe nodular or bronchiectatic disease should receive a daily regimen of clarithromycin (500-1000 mg) or azithromycin (250-500 mg), rifampin (600 mg) or rifabutin (150–300 mg), and ethambutol (15 mg/kg).

In addition, the ATS/IDSA guidelines suggest the addition of amikacin or streptomycin thrice-weekly early in the course of treatment (initial 2-3 months) in patients with severe and extensive fibrocavitary lung disease. ^[25] Streptomycin has been used successfully in combination with macrolides for the first 6-12 weeks of treatment in patients with cavitary lung disease. In situations when rifamycins fail or cannot be taken, clofazimine has also been used with good outcome. ^[36]

A randomized controlled study showed comparable efficacy and tolerance when either clarithromycin or ciprofloxacin was given to patients with pulmonary MAC infection as a third drug in regimens containing rifampin and ethambutol. ^[37] Based on these results, it is suggested that fluoroquinolones can be used as a substitute for macrolides.

A macrolide-containing regimen has been shown to carry a cure rate of about 56%, including the dropouts and relapses in the analysis. Macrolides carry high rates of intolerance. Clarithromycin, a cytochrome P-450 inhibitor, interacts with many drugs metabolized in the liver. Similarly, rifamycins are known to induce hepatic enzymes and can alter metabolism of many drugs taken concomitantly.

In 2017, British guidelines suggested nebulized amikacin as an alternative to intravenous amikacin when long-term treatment with an aminoglycoside is required and intravenous or intramuscular injections are impractical or contraindicated. ^[31] An inhalational form of amikacin liposome was approved by the FDA in 2018 for patients with refractory MAC lung disease defined as failure to achieve negative sputum MAC culture results after 6 months of standard anti-MAC therapy.

A clinical study failed to verify the benefit of inhaled interferon (IFN)-gamma in patients with pulmonary MAC infection. ^[35] However, patients with a defect in the IFN-gamma pathways may show a better response if IFN-gamma is given in addition to the antimicrobials.

A combination of a newer macrolide antibiotic (eg, clarithromycin, azithromycin) with ethambutol and rifabutin is probably the most active regimen. Efficacies of clarithromycin and azithromycin in DMAC infection have been demonstrated in clinical studies, but monotherapy should be avoided, as it can lead to resistance. Ethambutol appears to be the best second choice to combine with a macrolide. Rifabutin should be used as a third agent.

A study comparing clarithromycin and ethambutol (dual therapy) with clarithromycin, ethambutol, and rifabutin (triple therapy) showed improved microbiological clearance and survival in the triple-therapy arm. Published data suggest 50%-60% microbiological clearance rates for both macrolides when used in combination with ethambutol and rifabutin.

Current guidelines recommend a combination of clarithromycin (500 mg twice daily) and ethambutol (15 mg/kg daily) with or without rifabutin (300 mg daily). Azithromycin (500-600 mg daily) can be substituted for clarithromycin. The addition of rifabutin has been recommended, especially in patients with advanced immunosuppression (CD4⁺ count < 50 cells/µL), with high mycobacterial loads (>100 colony-forming units/mL of blood), or in the absence of effective antiretroviral therapy.

Based on experience in patients without HIV infection, the guidelines suggest the use of amikacin or streptomycin as third or fourth drugs in these patients. ^[38]

The guidelines recommend continuing treatment for at least 12 months and until symptoms completely resolve and cellular immunity is reconstituted (sustained CD4 counts >100 cells/µL for 6 months). ^[38]

Drug interactions are a major problem with rifabutin and clarithromycin (see Medication). Higher doses of rifabutin (≥450 mg/day) are associated with higher rates of uveitis. The usual dose of rifabutin (300 mg/day) should be reduced by half (150 mg/day) if the patient is also receiving protease inhibitors. Higher doses of clarithromycin (1000 mg bid) are associated with higher mortality rates. ^[38] Clofazimine use in patients with DMAC infection has been associated with a worse outcome. ^[39]

Fever should improve within 2-4 weeks of therapy initiation. If patients remain febrile for a longer duration than expected, repeat blood cultures in 4-8 weeks, and assess susceptibilities to antimicrobial agents. If the isolate is susceptible to a macrolide and the infection is not responding to therapy, consider adding other agents such as streptomycin or amikacin.

If the MAC strain is resistant to macrolides, the macrolide can be replaced with a fluoroquinolone. Although macrolide-fluoroquinolone combinations have been used to treat MAC infections in past, studies have suggested antagonism between the two classes of antibiotics in infections with some strains of MAC and higher rates of macrolide resistance among patients receiving the combination. ^[26]

Although patients with MAC infection who are concomitantly receiving antiretroviral therapy may develop immune reconstitution inflammatory syndrome (IRIS), antiretroviral therapy should be started concomitantly or soon after initiating antimycobacterial treatment. If the patient is already receiving antiretroviral therapy and there is a potential drug interaction, the ART regimen should be modified as needed. ^[38] The ART therapy reduces the risk of other opportunistic infections.

Patients with IRIS are generally treated by infectious disease specialists with nonsteroidal anti-inflammatory drugs (NSAIDS) and, if necessary, with a short course (4-8 weeks) of systemic steroids such as prednisone. ^[38]

Addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to be helpful in the treatment DMAC infection in patients with HIV/AIDS in whom traditional antimycobacterial therapy failed. ^[40]

Chemoprophylaxis

Antimycobacterial prophylaxis is recommended in HIV-infected patients with a CD4⁺ T-lymphocyte count under 50 cells/µL if they are not on ART or remain viremic despite taking ART. However, anti-MAC prophylaxis is not indicated in patients who are initiating ART, and it can be discontinued if the viremia is fully suppressed on ART. ^[38]

The drug of choice is either clarithromycin 500 mg twice daily or azithromycin 1200 mg/wk. In a study that compared clarithromycin prophylaxis with placebo, the incidence of MAC bacteremia was 5.6% in the clarithromycin group and 15.5% in the placebo group. Clarithromycin also conferred an improved survival rate. More than half of the patients in the clarithromycin group who developed bacteremia were infected with clarithromycin-resistant isolates. ^[41]

Rifabutin 300 mg/d is an alternative to macrolides for MAC prophylaxis. However, rifabutin-associated drug interactions and complications (eg, uveitis) complicate the use of this agent. Patients should be monitored closely for side effects.

If the HIV viral load is suppressed on ART or the patient's CD4 count rises to more than 100 cells/µL for a sustained period (>6 months), MAC prophylaxis can be discontinued. ^[38]

MAC lymphadenitis in children is treated with surgical excision of the affected lymph nodes, resulting in a cure rate that exceeds 90%. Antibiotics are generally not required but may be beneficial in patients with extensive lymphadenitis or with a poor response to surgical therapy. However, MAC lymphadenitis in immunocompromised patients, including patients with HIV infection/AIDS, generally responds to 6-12 months of antimycobacterial therapy and does not require surgery. ^[26]

A randomized Dutch study found no significant difference in healing time with antibiotic therapy versus a conservative wait-and-see approach in children with advanced nontuberculous mycobacterial cervicofacial lymphadenitis. The study included 50 children (age range, 14–114 mo) whose lymphadenitis was predominantly due to M avium or M hemophilum. The median time of resolution in the group receiving rifabutin and clarithromycin was 36 weeks, compared with 40 weeks for the wait-and-see group. ^[42]

The role of antimycobacterials and corticosteroids in the treatment of hypersensitivity pneumonitis-like lung disease (hot-tub lung) due to MAC infection remains controversial. Removing environmental sources and avoiding exposure to infected aerosols are the best preventive measures. ^[2] Patients with severe lung disease or respiratory failure should be treated with prednisone tapered over 4-8 weeks. Immunocompromised patients and those with bronchiectasis also benefit from a short course (3-6 months) of anti-MAC treatment. ^[25]

An infectious disease specialist should be consulted for MAC infections in patients with AIDS. In addition, a general surgeon for lymph node biopsy, a gastroenterologist for liver biopsy, and a hematologist-oncologist for bone marrow biopsy may be needed.

Consultants for patients with lung disease who develop pulmonary MAC infection include an infectious diseases specialist and a pulmonologist. Occasionally, if surgical resection or biopsy of lungs is desired, a cardiothoracic surgeon may be needed.

Consultants for lymphadenitis in children include a pediatric infectious diseases specialist. A general surgeon or an ear, nose, and throat (ENT) specialist may be needed for lymph node resection.

Monitoring

Carefully monitor patients with AIDS for adverse effects of medications, especially for hepatotoxicity and uveitis. They may also require blood transfusions if anemia is significant. Patients should also be monitored for immune reconstitution inflammatory syndrome (IRIS). ^[38]

Carefully monitor patients with lung disease who develop pulmonary MAC infection for improvement in symptoms and for adverse effects of medications.

After completion of treatment, patients should be monitored clinically and, if needed, radiologically for relapse of the infection. Patients in whom MAC infection is suspected based on a single culture result or radiographic findings but who do not meet diagnostic criteria for MAC disease, and consequently do not undergo treatment, require close long-term follow-up for clinical and radiographic monitoring.