AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Mycobacterium avium complex (MAC) consists of two species—M avium and M intracellulare. Because these species are difficult to differentiate, they are also collectively referred to as Mycobacterium avium-intracellulare (MAI).

MAC causes disseminated infection in immunocompromised hosts, but only a minority of immunocompetent hosts with MAC infection develop MAC lung disease. Patients with underlying lung disease or immunosuppression may develop progressive MAC lung disease. M avium is the isolate in more than 95% of patients with AIDS who develop MAC infections, M intracellulare is responsible for 40% of such infections in immunocompetent patients. MAC is the most common cause of infection by nontuberculous mycobacteria (NTM) in patients with AIDS.

MAC is ubiquitous in distribution. It has been isolated from freshwater and saltwater worldwide. The common environmental sources of MAC include aerosolized water, piped hot water systems (including household and hospital water supplies), bathrooms,¹ house dust, soil, birds, farm animals, and cigarette components such as tobacco, filters, and paper.

Pathophysiology

MAC is transmitted via inhalation through the respiratory tract and ingestion via the GI tract.

MAC can invade and translocate across the mucosal epithelium. The bacteria subsequently infect the resting macrophages in the lamina propria and spread in the submucosal tissue; they are then carried to the local lymph nodes by lymphatics. In immunocompromised hosts, such as patients with AIDS, they are subsequently spread hematogenously to the liver, spleen, bone marrow, and other sites.

Patients with MAC infection who have AIDS and/or lymphomas usually develop disseminated MAC (DMAC) infection when their CD4 count falls below 50 cells/µL. In patients with AIDS, colonization of the GI or respiratory tract has been associated with an increased risk of developing MAC bacteremia. Approximately 60% of patients with MAC colonization in one series developed bacteremia; however, screening cultures from the respiratory or GI tract is not useful because most patients who develop bacteremia are not colonized prior to developing disseminated disease.

The most important risk factor for MAC infection in patients without HIV infection is underlying lung disease. Pulmonary disease is the most common manifestation MAC infection in these patients. It can also cause lymphadenitis in children. MAC has surpassed Mycobacterium scrofulaceum as the most common cause of cervical adenitis in developed countries.

Both tumor necrosis factor (TNF)–alpha and interferon (IFN)–gamma play important roles in defending against mycobacterial infections. Like other mycobacteria, MAC can cause disseminated infection in multiple family members who have a deficiency of IFN-gamma receptor expression or IFN-gamma production due to genetic defects.

MAC has also been associated with the pulmonary infection and bronchiectasis in elderly women without a pre-existing lung disease. Pulmonary MAC infection in this population is believed to be due to voluntary cough suppression that results in stagnation of secretions, which is suitable for growth of the organisms.² This particular type of infection is also referred to as Lady Windermere syndrome.

MAC has been also associated with a hypersensitivity pneumonitislike reaction (known as hot-tub lung) in patients exposed to aerosolized MAC.³ Hot-tub lung is thought to be caused by a pulmonary response to infectious aerosols of MAC found in water. However, the roles of other organic and inorganic cofactors present in the aerosols and host predispositions have not been established.

Although some studies have reported an association between Mycobacterium avium paratuberculosis and Crohn disease, a clear causation has not been established, and the pathophysiology remains largely unexplored.⁴

Frequency

United States

NTM infections began to be reported more frequently after the incidence of tuberculosis declined in the 1950s. During 1979-80, NTM represented one third of mycobacterial isolates reported to the Centers for Disease Control and Prevention (CDC), and 61% of these were MAC. MAC and Mycobacterium kansasii are two of the most predominant NTM infections in the United States.

In France from 2001-2003, a surveillance estimated that the incidence of NTM pulmonary infections in patients without HIV infection was 0.72-0.74 per 100,000 inhabitants.⁵ In 2004, a similar study in New Zealand showed an incidence of NTM disease estimated at 1.92 per 100,000 population.⁶ Most of these infections were caused by MAC in both countries.

DMAC is the most common mycobacterial infection in patients with advanced AIDS. The overall prevalence of DMAC infection increased in the 1980s and early 1990s in the United States following the advent of HIV and AIDS but has since declined because of the subsequent use of highly active antiretroviral therapy (HAART). Prior to the widespread use of combination antiretroviral therapy, 30% of patients infected with HIV developed DMAC infection. In a 1996 study, only 2% of patients receiving HAART, including a protease inhibitor, developed DMAC infection.

Mortality/Morbidity

MAC may be isolated from the sputum of immunocompetent patients without any evidence of lung disease. Transient MAC colonization was reported in up to 11% of patients with tuberculosis in the 1950s. Repeated isolation of MAC from sputum, even in the absence of obvious lung disease, may signify an underlying slow progression of lung disease.

• Prior to the availability of newer macrolides, the life expectancy of a patient with AIDS and DMAC infection was 4 months. In a 1999 study, the median survival time was 9 months in patients treated with rifabutin, ethambutol, and clarithromycin.⁷ Life expectancy is now longer because of the advent of HAART. The most common complication of DMAC infection is anemia that may require transfusion. Treatment success rate in patients without HIV infection have ranged from 20-90% in various studies, with an average of 50-60% clinical success and 60-75% of sputum conversion rates.
• The clinical course of pulmonary MAC infection in patients without HIV infection is usually indolent. Approximately 50% of patients in one study were alive 5 years after diagnosis. Patients with extensive parenchymal involvement may die of progressive respiratory failure, but the associated mortality rate is low in patients with milder disease.
• In children, MAC lymphadenitis generally has a benign course. It may resolve spontaneously or may rupture and form a sinus tract in untreated cases.

Race

• MAC infection has no racial predilection.

Sex

• Han and Tarrand (2005) found that, regardless of any underlying disease, M intracellulare is more pathogenic and tends to infect women increasingly beyond menopause. The prevalence of MAC infection in postmenopausal women was 1.86% in this study.⁸

Age

• Elderly women may be at an increased risk for pulmonary MAC disease of the middle lobe, lingula, or both (also known as Lady Windermere syndrome).

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

M avium complex (MAC) infection usually presents in 1 of 3 forms: (1) pulmonary MAC infection in immunocompetent hosts, (2) disseminated MAC (DMAC) infection in individuals with advanced AIDS, or (3) MAC lymphadenitis in children.

• Pulmonary MAC infection in immunocompetent hosts generally manifests as cough, sputum production, weight loss, fever, lethargy, and night sweats. The onset of symptoms is insidious. Symptoms may be present for weeks to months. Many patients have only a chronic cough with purulent sputum production. Hemoptysis is rare in MAC infection. Less commonly, MAC has been associated with hot-tub lung, a type of hypersensitivity pneumonitislike lung disease due to exposure to MAC in hot tubs.
• Patients with advanced AIDS (generally with CD4 counts <50 cells/µL) and DMAC infection commonly present with fever of unknown origin (FUO). They usually also have sweating, weight loss, fatigue, diarrhea, shortness of breath, and right upper quadrant abdominal pain. In addition, other reported MAC infection manifestations in patients with AIDS have included mastitis, pyomyositis, cutaneous abscess, brain abscess, and GI mycobacteriosis. Immune reconstitution syndrome associated with MAC has been reported in patients with underlying MAC infection presenting shortly after the introduction of HAART.
• MAC lymphadenitis is predominantly a disease of children aged 1-4 years, primarily involving unilateral cervical lymph nodes. It usually involves submandibular and submaxillary lymph nodes, although preauricular, postauricular, and submental nodes may also be affected. Rarely, infection of the axillary, epitrochlear, or inguinal lymph nodes may develop following direct cutaneous inoculation. The lymph nodes usually enlarge insidiously but may enlarge more rapidly in younger children. Generally, they resolve spontaneously. The lymph nodes may also caseate and rupture through the skin, forming a sinus tract with chronic discharge.
• Less commonly, patients may present with skin and soft-tissue infections, osteomyelitis, peritonitis (in patients with cirrhosis), bursitis, septic arthritis, and tenosynovitis.

Physical

Physical findings in MAC infection depend on the form of infection and the patient.

• In immunocompetent patients with pulmonary MAC infection, generally lung crackles, rhonchi, or both can be heard on auscultation. Additionally, depending on the type of lung lesion and severity of infection, patients with pulmonary MAC infection may have tachypnea, dullness on chest percussion, or bronchial breath sounds.
• DMAC infection in patients with AIDS can cause generalized wasting, skin pallor, tender hepatosplenomegaly, and lymphadenopathy.
• Lymphadenitis in children can cause unilateral enlargement of submandibular, preauricular, parotid, and/or postauricular lymph nodes. They are usually multiple and rubbery to firm and may appear to be fixed to the deeper structures. They may become matted together as the disease progresses. The overlying skin may appear shiny, thin, and erythematous or violaceous. Sinus tracts may be present in advanced cases.
• Patients with synovitis may present with pain and swelling of a joint or features of bursitis or tenosynovitis.

Causes

MAC infections are caused by M avium and M intracellulare, which belong to the Runyon group 3 mycobacteria. M avium is further divided into various subspecies based on molecular, biochemical, and growth characteristics. Mycobacterium avium avium is the only important subspecies associated with human infection, whereas M avium paratuberculosis has been associated with Crohn disease. Although M avium paratuberculosis is a well-known cause of paratuberculosis (Johne Disease) in cattle, its role in the etiology of Crohn disease in humans remains to be proven.

Some of the known predisposing factors for MAC infections include the following:

• Pulmonary MAC infection is associated with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, bronchiectasis, cystic fibrosis, mitral valve prolapse, skeletal abnormalities (eg, pectus excavatum, mild scoliosis, straight back), and lung cancer.
• MAC infection in patients with AIDS or lymphoreticular malignancies is associated with a CD4⁺ lymphocyte count of under 50 cells/µL.
• Deficiency of IFN-gamma and TNF-alpha production and absence or defects of IFN-gamma receptors are also associated with infections with MAC and other mycobacteria.
• Other possible risk factors include gastroesophageal reflux disease (GERD), acid suppression, and aspiration or microaspiration.⁹

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Mumps
Parotid tumor
HIV wasting
Mycobacterium scrofulaceum infection

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• At least 3 sputum specimens, preferably early-morning samples taken on different days, should be collected for acid-fast bacillus (AFB) staining and culture. Sputum AFB stains are positive for M avium complex (MAC) in most patients with pulmonary MAC infection. Mycobacterial cultures grow MAC in about 1-2 weeks, depending on the culture technique and bacterial burden. However, interpretation of sputum AFB stain and culture may be difficult, as MAC can colonize the respiratory tract without causing clinical infection.
• The American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) guidelines recommend the following criteria to establish a diagnosis of NTM lung disease:¹⁰
• • Clinical
  • • Pulmonary signs and symptoms such as cough, fatigue, weight loss; less commonly, fever and weight loss; dyspnea
    • Appropriate exclusion of other diseases (eg, carcinoma, tuberculosis)
  • Radiographic
  • • Chest radiograph with nodular or cavitary opacities
    • High-resolution computerized tomography (HRCT) scan showing multifocal bronchiectasis and multiple small nodules
  • Bacteriologic (meeting one of the below criteria within one year)
  • • At least 2 culture-positive sputum samples
    • At least one culture-positive bronchial washing or lavage
    • Biopsy with histopathologic features consistent with mycobacterial infections (eg, granulomatous inflammation or positive AFB stain) and positive culture result (sputum, endobronchial, or biopsy specimen)
• In a study that evaluated the significance of positive sputum culture results using ATS guidelines for the diagnosis of NTM infection, only 7 of 46 (15%) patients infected with HIV and 1 of 34 (3%) patients without HIV infection but with MAC-positive sputum met the clinical, bacteriologic, and radiographic criteria for MAC pulmonary disease.
• Blood cultures in appropriate mycobacterial culture media should be performed for suspected disseminated MAC (DMAC) infection. This should be performed routinely in patients with advanced AIDS and persistent undiagnosed febrile illness. Cultures generally take 1-2 weeks to turn positive. Early in the course of infection, bacteremia may be low-level or intermittent, possibly causing false-negative blood culture results. Later in the course of infection, blood cultures results are invariably positive.
• Diagnosis of MAC lymphadenitis is based on a high level of clinical suspicion and biopsy of the nodes with histological and microbiological confirmation. Fine-needle aspiration of lymph nodes has been used to obtain tissue for diagnosis when complete excision is not feasible. Results of acid-fast staining of tissue or pus are usually negative because of the small number of bacilli present. The culture result may take a few weeks to become positive. Nucleic acid amplification methods can provide a more rapid diagnosis. Skin testing (MAC tuberculin test) contributes very little in establishing diagnosis.
• ATS and IDSA guidelines recommend to base the diagnosis of hot-tub lung (hypersensitivity pneumonitislike lung disease) on a compatible clinical picture, including hot-tub exposure, microbiological data, radiographic findings, and histopathology. In the absence of histopathology, evidence for hot-tub lung needs to include (1) subacute onset of respiratory symptoms, (2) hot-tub exposure, (3) characteristic radiological changes, and (4) isolation of MAC from sputum, bronchoalveolar lavage (BAL), lung tissue, and hot-tub water. The radiographic changes include ground-glass opacities, centrilobular nodules, and air trapping on expiratory CT scan images.
• The species-specific molecular probes are used for rapid identification of mycobacterial species grown in culture (eg, Mycobacterium tuberculosis, M kansasii, MAC). Various nucleic acid amplification techniques (eg, polymerase chain reaction [PCR], ligase chain reaction, transcription-mediated amplification) are also used for this purpose, as well as for direct detection of mycobacteria in the sputum. However, these assays need further refinement to improve their sensitivity to detect mycobacteria directly in patient's specimens.
• Mycobacterial susceptibility testing for various antimycobacterial agents is available in specialized laboratories. Because studies have shown poor correlations between in vitro susceptibility results and clinical outcome, the ATS and IDSA guidelines recommend routine antibiotic susceptibility for clarithromycin only. Based on the experience at the author's institution, susceptibility tests are reliable if performed selectively at highly experienced laboratories specializing in mycobacteriology.

Imaging Studies

• Chest radiography generally reveals MAC pulmonary lesions. However, in cases with limited lung infection, CT scanning of the chest and even HRCT scanning are needed to reveal the lung lesions. HRCT scanning has been shown to be more sensitive than chest radiography for revealing pulmonary abnormalities associated with MAC infection.
• • Patients with pulmonary MAC infection with underlying lung disease often have cavities revealed by imaging studies. Typically, these patients have fibrocavitary changes and nodules that involve the upper lung zones.
  • Elderly women without underlying lung disease but with MAC pulmonary infection develop a fibronodular bronchiectasis that often involves the lingula and right middle lobe. A strong association between MAC infection and bronchiectasis with circumscribed nodules has been shown in these patients. Surveys of patients with fibronodular bronchiectasis have documented MAC infection in 25-50% of patients.
  • Other radiological changes include atelectasis, consolidation, tree-in-bud appearance, and ground-glass opacities.
• In patients with AIDS and DMAC infection, CT scan of the abdomen reveals retroperitoneal or periaortic lymphadenopathy and hepatosplenomegaly.
• Hypersensitivity pneumonitislike changes characterized by ground-glass attenuation, centrilobular nodules, and air trapping on expiratory images are seen on CT scans in patients with hot-tub lung, which is a type of hypersensitivity pneumonitislike syndrome described in patients exposed to aerosolized MAC. 

Other Tests

• Patients with DMAC usually have elevated transaminase and alkaline phosphatase levels.
• They are also usually anemic and occasionally pancytopenic due to bone marrow suppression secondary to the infection.
• An enzyme immunoassay (EIA) kit used in Japan has been used to detect serum IgA antibody to MAC-specific glycopeptidolipid core antigen. This could be useful for serodiagnosis of MAC pulmonary infection. Sensitivity and specificity of this EIA kit were reported as 84% and 100%, respectively.¹¹

Procedures

• Bronchoscopy and transbronchial biopsy may be needed to diagnose pulmonary MAC infection. Alternatively, a CT-guided needle biopsy, video-assisted thoracoscopic (VAT) biopsy, or open lung biopsy may be performed, depending on the size and location of the lesion.
• Procedures that may be helpful to establish diagnosis of DMAC infection in patients with AIDS include lymph node biopsy, bone marrow biopsy, and liver biopsy. These procedures are indicated if the blood cultures fail to grow the mycobacteria. They are also helpful to exclude other causes of lymphadenopathy, anemia, or pancytopenia. Liver biopsy is rarely necessary to establish a diagnosis of MAC infection.
• The procedure for lymphadenitis in children generally involves lymph node biopsy or complete excision of lymph nodes. A needle aspiration is performed for inaccessible nodes, such as those that overlie the facial nerve.

Histologic Findings

Histologic findings of MAC infection include necrotizing and nonnecrotizing granulomas and positive AFB smear results. Numbers of AFB are usually higher in MAC infection than in M tuberculosis infection. Patients with HIV/AIDS have evidence of DMAC infection in multiple organs, but granuloma formation is less common. DMAC infection in patients with AIDS typically demonstrates the presence of sheets of macrophages laden with AFB.

Histologic findings of lymph node biopsies in children infected with MAC in a reported series generally showed bright eosinophilic serpiginous necrosis with nuclear debris scattered throughout the necrotic foci. Most of these cases also had Langhans-type giant cells, but infiltration by plasma cells and neutrophils was not consistently observed.

Patients with hypersensitivity pneumonitis secondary to MAC infection show multiple well-formed nonnecrotizing granulomas positive for AFB.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

Compared with tuberculosis, M avium complex (MAC) infection is relatively resistant to chemotherapeutic agents. MAC is intrinsically resistant to common antituberculosis drugs but is fairly susceptible to some antimycobacterial drugs, such as macrolides (clarithromycin, azithromycin), ethambutol, clofazimine, and rifamycins (especially rifabutin). In general, MAC infection is treated with 2 or 3 antimicrobials for at least 12 months.

Antimycobacterial agents used to treat MAC infection include clarithromycin, azithromycin, rifabutin, ethambutol, levofloxacin, and amikacin. Second-line antituberculosis drugs are also occasionally used. Newer fluoroquinolones, linezolid, and ketolides also demonstrate good in vitro activity against MAC and other mycobacteria, although adequate clinical data supporting their use against MAC infection are lacking. Aerosolized amikacin has been found to be an effective adjunct therapy in a small case series.¹²

• Treatment of pulmonary MAC infection in immunocompetent patients
• • Treatment of MAC infection in immunocompetent patients involves the combination of a newer macrolide (azithromycin or clarithromycin), ethambutol, and rifabutin.
  • ATS and 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. Patients with fibrocavitary lung disease or severe nodular or bronchiectatic disease should receive a daily regimen of clarithromycin 500–1000 mg or azithromycin 250 mg, rifampin 600 mg or rifabutin 150–300 mg, and ethambutol (15 mg/kg). In addition, these guidelines suggest considering adding amikacin or streptomycin thrice weekly early in the course of treatment. Therapy should be continued for at least one year after culture results revert to negative.
  • Clofazimine has been used in place of rifamycins with good outcome. Streptomycin has also been used successfully in combination with macrolides for the first 6-12 weeks of treatment in patients with cavitary disease. 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.
  • Patients with a defect in the IFN-gamma pathways may show a better response if IFN-gamma is given in addition to the antimicrobials.
• Treatment of disseminated MAC (DMAC) infection in patients with AIDS
• • A combination of a newer macrolide antibiotic (clarithromycin, azithromycin) with ethambutol and rifabutin is probably the most active regimen.
  • ATS and IDSA guidelines recommend a combination of clarithromycin 1000 mg/d or azithromycin 250 mg/d and ethambutol 15 mg/kg/d with or without rifabutin 150–350 mg/d. The guidelines recommend continuing treatment until resolution of symptoms and reconstitution of cellular immunity.
  • Clear evidence demonstrates the efficacy of clarithromycin and azithromycin, but monotherapy can lead to resistance. Published data suggest efficacy of azithromycin for MAC infection (55-60% success). Ethambutol appears to be the best second choice to combine with a macrolide. Rifabutin should be used as a third agent.
  • A study that compared clarithromycin and ethambutol (dual-therapy) with clarithromycin, ethambutol, and rifabutin (triple-therapy) showed improved microbiological clearance and survival in the triple-therapy arm.
  • A major problem with rifabutin is drug interactions. Higher doses of rifabutin (600 mg/d) are associated with higher rates of uveitis. Higher doses of clarithromycin (1000 mg bid) are associated with higher mortality rates.
  • Fever should improve within 2-4 weeks of therapy initiation. If patients remain febrile for a longer duration than expected, repeat blood cultures 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 a fluoroquinolone (eg, levofloxacin) or amikacin.
  • 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.¹³
• Chemoprophylaxis
• • Antimycobacterial prophylaxis is recommended in patients infected with HIV in whom the CD4⁺ lymphocyte count is under 50 cells/µL. The drug of choice is either clarithromycin 1000 mg/d 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.¹⁴
  • 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 patient's CD4 count rises to more than 100 cells/µL for a sustained period after the initiation of antiretroviral therapy and the viral load response is good, prophylaxis can possibly be discontinued.
• MAC lymphadenitis: 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.
• Hot-tub lung: The role of antimycobacterials and corticosteroids in the treatment of hypersensitivity pneumonitislike 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.
• Crohn disease: Clinical trials have failed to show any significant clinical benefit for antimycobacterial drugs used to treat Crohn disease secondary to M avium paratuberculosis.¹⁵

Surgical Care

• 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.
• Surgical excision of the infected nodes is curative in more than 95% of children with lymphadenitis.

Consultations

• Consultants for MAC infections in patients with AIDS include an infectious diseases specialist, a general surgeon for lymph node biopsy, a gastroenterologist for liver biopsy, and a hematologist-oncologist for bone marrow biopsy.
• Consultants for patients with lung disease who develop pulmonary MAC infection include an infectious diseases specialist, a pulmonologist, and a cardiothoracic surgeon.
• Consultants for lymphadenitis in children include an infectious diseases specialist, a general surgeon, and an ear, nose, and throat (ENT) specialist.

Diet

• No special diet restrictions are necessary.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The drugs used most often for treatment of M avium complex (MAC) infection include clarithromycin, azithromycin, ethambutol, and rifabutin. Amikacin is used for refractory cases. Combination therapy is important for enhancing efficacy and preventing resistance. The duration of treatment is not established. In general, patients with MAC pulmonary infection should be treated for a minimum of one year or until 12 months after sputum stains are negative for MAC. The rate of relapse is high, especially if the treatment duration is too short. A long-term treatment, however, is harder to tolerate and increases the likelihood of adverse effects associated with the medications used.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Patients with AIDS who develop FUO are generally admitted for inpatient care. They may also need to be admitted for various other reasons, including inpatient workup of fever and hepatitis, dehydration, wasting and failure to thrive, initiation of intravenous antibiotics, nonadherence, or other concurrent illnesses.
• Patients with pulmonary M avium complex (MAC) infection may need to be admitted for a lung biopsy or surgical resection of infected lung.
• Children with lymphadenitis may need to be admitted for surgical excision of infected lymph nodes.

Further Outpatient Care

• 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. Antiretroviral agents should be started concurrently for a faster and better response. Patients should also be monitored for immune reconstitution syndrome.
• 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 not undergoing treatment in whom MAC infection is suspected based on a single culture result or radiographic findings but do who not meet diagnostic criteria for MAC disease require close follow-up for clinical and radiographic monitoring.

In/Out Patient Meds

• Clarithromycin or azithromycin in combination with ethambutol and rifabutin are the first-choice drugs. Alternatively, clofazimine, streptomycin, amikacin, or levofloxacin may be used to substitute one of the first-line agents.

Transfer

• Patients with AIDS may need to be transferred to a facility with an infectious diseases or HIV specialist for workup and treatment.
• Patients with pulmonary infection may need to be transferred to a facility that offers bronchoscopy. They may also require transfer for surgical resection of infected lung tissue.

Deterrence/Prevention

• The Department of Health and Human Services panel recommends that patients with AIDS and CD4 cell counts under 50 cells/µL should receive a prophylactic antibiotic to prevent MAC infection. The first-line agent for MAC prophylaxis should be a macrolide, either clarithromycin or azithromycin. Alternatively, rifabutin can be used. Patients who have received treatment for MAC should stay on the treatment regimen until their CD4 count improves to more than 100 cells/µL.

Complications

• Patients with AIDS may develop anemia or weight loss, or they may die.
• Patients with lung disease may develop respiratory insufficiency or weight loss, or they may die.

Prognosis

• The life expectancy among patients with AIDS and MAC infection was once 9 months; however, patients receiving HAART probably have a much longer life expectancy.
• Patients with lung disease and pulmonary MAC infections with focal nodules usually have a benign course. Patients with more extensive disease have a 90% chance of recovery and a 20% chance of relapse.

Patient Education

• Instruct patients with AIDS on how to monitor for potential adverse effects of their medications as well as how to recognize signs of anemia that might indicate the need for a transfusion.
• Educate patients with lung disease who develop pulmonary MAC infection about potential adverse effects of their medications.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center and Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Macrolides are likely to interact with drugs metabolized in the liver.
• Ethambutol may cause optic neuritis and blindness, especially in patients with coexisting renal dysfunction.
• Rifampin and rifabutin may decrease the effectiveness of contraceptives. Advise patients of this potential effect. Rifabutin is also known to cause uveitis, for which patients need regular eye examinations.
• Failing to offer prophylaxis to patients with HIV with a CD4⁺ lymphocyte count of below 50 cells/µL may lead to development of disseminated M avium complex (DMAC) infection.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor William B Harley, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  CT thorax of a 77-year-old woman who presented with chronic cough and sputum production, without a history of underlying pre-existing lung disease. Sputum culture grew Mycobacterium avium complex. The diagnosis was Lady Windermere syndrome.
	View Full Size Image
Media type:  CT

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

1. Nishiuchi Y, Maekura R, Kitada S, et al. The recovery of Mycobacterium avium-intracellulare complex (MAC) from the residential bathrooms of patients with pulmonary MAC. Clin Infect Dis. Aug 1 2007;45(3):347-51. [Medline].
2. Dhillon SS, Watanakunakorn C. Lady Windermere syndrome: middle lobe bronchiectasis and Mycobacterium avium complex infection due to voluntary cough suppression. Clin Infect Dis. Mar 2000;30(3):572-5. [Medline].
3. Hartman TE, Jensen E, Tazelaar HD, et al. CT findings of granulomatous pneumonitis secondary to Mycobacterium avium-intracellulare inhalation: "hot tub lung". AJR Am J Roentgenol. Apr 2007;188(4):1050-3. [Medline].
4. Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect Dis. Sep 2007;7(9):607-13. [Medline].
5. Maugein J, Dailloux M, Carbonnelle B, et al. Sentinel-site surveillance of Mycobacterium avium complex pulmonary disease. Eur Respir J. Dec 2005;26(6):1092-6. [Medline].
6. Freeman J, Morris A, Blackmore T, et al. Incidence of nontuberculous mycobacterial disease in New Zealand, 2004. N Z Med J. Jun 15 2007;120(1256):U2580. [Medline].
7. Gordin FM, Sullam PM, Shafran SD, et al. A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex. Clin Infect Dis. May 1999;28(5):1080-5. [Medline].
8. Han XY, Tarrand JJ, Infante R, et al. Clinical significance and epidemiologic analyses of Mycobacterium avium and Mycobacterium intracellulare among patients without AIDS. J Clin Microbiol. Sep 2005;43(9):4407-12. [Medline].
9. Thomson RM, Armstrong JG, Looke DF. Gastroesophageal reflux disease, acid suppression, and Mycobacterium avium complex pulmonary disease. Chest. Apr 2007;131(4):1166-72. [Medline].
10. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. Feb 15 2007;175(4):367-416. [Medline].
11. Kitada S, Kobayashi K, Ichiyama S, et al. Serodiagnosis of Mycobacterium avium-complex pulmonary disease using an enzyme immunoassay kit. Am J Respir Crit Care Med. Apr 1 2008;177(7):793-7. [Medline].
12. Davis KK, Kao PN, Jacobs SS, et al. Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational case series. BMC Pulm Med. Feb 23 2007;7:2. [Medline].
13. de Silva TI, Cope A, Goepel J, et al. The use of adjuvant granulocyte-macrophage colony-stimulating factor in HIV-related disseminated atypical mycobacterial infection. J Infect. Apr 2007;54(4):e207-10. [Medline].
14. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med. Aug 8 1996;335(6):384-91. [Medline].
15. Selby W, Pavli P, Crotty B, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. Jun 2007;132(7):2313-9. [Medline].
16. Bermudez LE, Wagner D, Sosnowska D. Mechanisms of Mycobacterium avium pathogenesis. Arch Immunol Ther Exp (Warsz). 2000;48(6):521-7. [Medline].
17. Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. AIDS Clinical Trials Group Protocol 157 Study Team. Ann Intern Med. Dec 15 1994;121(12):905-11. [Medline].
18. Dailloux M, Abalain ML, Laurain C, et al. Respiratory infections associated with nontuberculous mycobacteria in non-HIV patients. Eur Respir J. Dec 2006;28(6):1211-5. [Medline].
19. Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis. Nov 2000;31(5):1245-52. [Medline].
20. Evans MJ, Smith NM, Thornton CM, et al. Atypical mycobacterial lymphadenitis in childhood--a clinicopathological study of 17 cases. J Clin Pathol. Dec 1998;51(12):925-7. [Medline].
21. Field SK, Cowie RL. Treatment of Mycobacterium avium-intracellulare complex lung disease with a macrolide, ethambutol, and clofazimine. Chest. Oct 2003;124(4):1482-6. [Medline].
22. Field SK, Fisher D, Cowie RL. Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest. Aug 2004;126(2):566-81. [Medline].
23. Fujita J, Higa F, Tateyama M. Radiological findings of mycobacterial diseases. J Infect Chemother. Feb 2007;13(1):8-17. [Medline].
24. Glassroth J. Pulmonary disease due to nontuberculous mycobacteria. Chest. Jan 2008;133(1):243-51. [Medline].
25. Glosli H, Stray-Pedersen A, Brun AC, et al. Infections due to various atypical mycobacteria in a Norwegian multiplex family with dominant interferon-gamma receptor deficiency. Clin Infect Dis. Feb 1 2008;46(3):e23-7. [Medline].
26. Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis. Jun 1 2001;32(11):1547-53. [Medline].
27. Havlik JA Jr, Metchock B, Thompson SE 3rd, et al. A prospective evaluation of Mycobacterium avium complex colonization of the respiratory and gastrointestinal tracts of persons with human immunodeficiency virus infection. J Infect Dis. Oct 1993;168(4):1045-8. [Medline].
28. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N Engl J Med. Aug 8 1996;335(6):392-8. [Medline].
29. Horsburgh CR Jr, Chin DP, Yajko DM, et al. Environmental risk factors for acquisition of Mycobacterium avium complex in persons with human immunodeficiency virus infection. J Infect Dis. Aug 1994;170(2):362-7. [Medline].
30. Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep. Jun 14 2002;51:1-52. [Medline].
31. Lange CG, Woolley IJ, Brodt RH. Disseminated mycobacterium avium-intracellulare complex (MAC) infection in the era of effective antiretroviral therapy: is prophylaxis still indicated?. Drugs. 2004;64(7):679-92. [Medline].
32. Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med. Sep 16 1993;329(12):828-33. [Medline].
33. Ntziora F, Falagas ME. Linezolid for the treatment of patients with [corrected] mycobacterial infections [corrected] a systematic review. Int J Tuberc Lung Dis. Jun 2007;11(6):606-11. [Medline].
34. Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial. Clin Infect Dis. Mar 1998;26(3):611-9. [Medline].
35. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest. Jun 1992;101(6):1605-9. [Medline].
36. Shafran SD, Mashinter LD, Phillips P, et al. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med. Nov 5 2002;137(9):734-7. [Medline].
37. Sison JP, Yao Y, Kemper CA, et al. Treatment of Mycobacterium avium complex infection: do the results of in vitro susceptibility tests predict therapeutic outcome in humans?. J Infect Dis. Mar 1996;173(3):677-83. [Medline].
38. Turenne CY, Wallace R Jr, Behr MA. Mycobacterium avium in the postgenomic era. Clin Microbiol Rev. Apr 2007;20(2):205-29. [Medline].
39. von Reyn CF, Maslow JN, Barber TW, et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet. May 7 1994;343(8906):1137-41. [Medline].

Article Last Updated: Sep 30, 2008