Mycobacterium avium Complex (MAC)

Authors: Michelle S. Cespedes, M.D., Judith A. Aberg, M.D.

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History

Mycobacterium avium complex (MAC) includes the organisms Mycobacterium avium and Mycobacterium intracellulare and are ubiquitous in the environment. The spectrum of disease is predominately limited to pulmonary manifestations and lymphadenitis in normal hosts and disseminated disease in severely immunocompromised hosts, namely AIDS patients. Disease due to MAC has increased in incidence since the early 1980’s coinciding with the advent of the AIDS epidemic and improved diagnostic methods. The introduction of newer macrolides has improved treatment outcomes and their prophylactic use for patients with advanced AIDS continues to decrease the incidence of disseminated disease in patients with access to care (33).

MICROBIOLOGY

MAC are facultative intracellular organisms that are aerobic, slow growing (10 – 21 days on solid media) acid fast bacilli. They form translucent or dome-shaped tan to yellow colonies. Colonies can be of the smooth transparent type or domed-opaque type. MAC has a trilaminar cell wall with a lipophilic outer layer and basal peptidoglycan layer. The relative resistance of these organisms to traditional antimycobacterial chemotherapy is attributed to poor penetration of the hydrophilic medications through the lipophilic outer layer.

MAC is divided into 28 serovars via glycopeptide typing, with serovars 1 through 6, 8 through 11, and 21 classified as M. avium, the remainder classified as M. intercellulare. Serovars 1, 4, and 8 are the most commonly isolated strains in AIDS patients with disseminated disease. MAC clinical isolates in disseminated disease are always of the smooth-translucent type.

EPIDEMIOLOGY

Mycobacterium avium complex disease has been increasingly recognized as an important pathogen in both pulmonary disease and as an opportunistic infection in severely immunocompromised AIDS patients.

MAC organisms can be found throughout the environment in soil, water, and animals. In addition to natural water sources, MAC has been cultured from recirculating hot water systems including hospital water systems, hot tubs and swimming pools (67). Investigators have theorized that the increased use of showers which create aerosolized droplets may be a vehicle for respiratory transmission. Humans are thought to acquire the organisms via inhalation or via the gastrointestinal tract through ingestion. Person-to-person transmission has not been documented and not thought to be a route of transmission.

Pulmonary Disease

Pulmonary MAC disease is more common in HIV negative subjects, usually in patients with predisposing pulmonary conditions including COPD, bronchiectasis, or fibrotic lung disease (29). MAC has been recovered from the sputum of patients with cystic fibrosis (68). People with a history of prior pulmonary tuberculosis or heavy smoking may be at increased risk for pulmonary MAC. In developed countries, the average age of a patient presenting with pulmonary MAC is greater than 55 years and there is a predilection for men.

Lymphadenitis

Since the 1980’s MAC has surpassed Mycobacterium scrofulaceum as the etiology for nontuberculous lymphadenitis in the US. MAC cervical lymphadenitis in the US is mostly a disease of children, most cases occurring before the age of three years (43). Infection of the submandibular, submaxillary, cervical, or preauricular lymph nodes in children between 1 and 5 years old is the most common presentation of MAC lymphadenitis. Investigators have speculated that there is a correlation to the ability to culture MAC from pasteurized milk and the cervical adenitis seen in young children (23). It is proposed that ingestion of the organisms via milk leads to dissemination via the lymphatics.

In HIV positive patients, focal lymphadenitis with MAC has also been reported as part of the immune reconstitution syndrome after the initiation of antiretroviral therapy (59).

Disseminated Disease

Prior to the advent of the AIDS epidemic, cases of documented disseminated MAC were extremely rare. MAC is the most common bacterial opportunistic infection in advanced AIDS in the developed world. Disseminated MAC is uncommon in the developing world, possibly due to the high mortality associated with tuberculosis. A retrospective review of PPD positive HIV patients with CD4 less than 200 cells/mm3 suggests that prior infection with tuberculosis may provide protection against MAC infection (35). Prior to the advent of potent antiretroviral therapy, estimates of the prevalence of disseminated MAC in AIDS patients ranged from 20 – 40% (53). Early in the epidemic, more than 50% of patients had evidence of disseminated disease at post-mortem examination (71). The rate of MAC infection in this population has improved substantially. A Johns Hopkins cohort estimated a rate of less than 1% per year in patients with advanced disease (39). Disseminated MAC is rarely seen in patients with CD4 greater than 100 cells/mm3, and is almost exclusively seen in patients with a CD4 of less than 50 cells/mm3. Prior opportunistic infections, particularly PCP or CMV disease, predispose advanced AIDS patients to disseminated MAC. It is thought that the opportunistic infections serve as a marker for the level of immunosuppression rather than any causal relationship (44).

MAC Immune Reconstitution Inflammatory Syndrome

A more recently recognized phenomenon associated with the initiation of antiretrovirals for HIV positive patients is the immune reconstitution inflammatory syndrome (25, 58, 65). Tending to occur in patients with pretreatment CD4 counts < 100 cells/mm, the syndrome is defined as a recrudescence of previously treated opportunistic infections or a pathological robust immune response to subclinical disease after starting antiretroviral therapy (31). The most common opportunistic infections associated with this paradoxical clinical worsening are ophthalmic cytomegalovirus disease, CNS Cryptococcal disease, tuberculosis, and disseminated MAC.

CLINICAL MANIFESTATIONS

There are three common clinical syndromes due to MAC: (a) Lymphadenitis, (b) disseminated MAC in HIV positive individuals, (c) pulmonary MAC disease. Therapeutics for HIV-positive individuals includes either prophylaxis or treatment depending on the stage of the underlying disease. In general, prophylaxis with monotherapy is the standard, while treatment of infection requires combination therapy including a newer macrolide.

Pulmonary Disease

Pulmonary disease usually presents with chronic productive cough in the absence of hemoptysis. Diagnosis can be delayed due to underlying lung disease. In HIV negative patients, MAC presents as bilateral upper lobe fibrocavitary disease radiographically (15). Pulmonary MAC tends to cavitate more often than pulmonary TB. MAC can also cause hypersensitivity pneumonitis.

Recently pulmonary MAC has been recognized with increasing frequency in elderly women, usually thin, with no history of underlying pulmonary disease. Thoracic lymphadenopathy is uncommon. The syndrome, referred to as Lady Windermere syndrome, is characterized by chronic cough with minimal constitutional symptoms, and atypical chest x-ray findings usually limited to the lingual and right middle lobe. The x-rays tend to demonstrate fibronodular disease with bronchiectasis.

Lymphadenitis

MAC lymphadenitis is generally a disease of young children. It usually manifests as cervical or submandibular involvement identical to that of tuberculosis, except the involvement is usually unilateral. Bilateral disease occurs in fewer than 10% of documented cases. It is rare for more than a single node to be enlarged in MAC lymphadenitis. The presentation is generally painless node enlargement and fever is usually absent.

Disseminated Disease

The presenting signs and symptoms of AIDS related disseminated MAC infection are nonspecific and can mimic other infections. These include tuberculosis, systemic fungal disease, disseminated bartonella, and malignancies such as lymphoma or may be incorrectly attributed to progression of HIV disease itself (38). Patients most commonly report persistent fever, night sweats, fatigue, weight loss, and anorexia. Abdominal pain or chronic diarrhea may result from involvement of retroperitoneal lymph nodes or gut mucosa, respectively. Hepatosplenomegaly, lymphadenopathy, and (rarely) jaundice also may be present. Hematologic dissemination of organisms seed lymph nodes and organs of the reticuloendothelial system, usually the liver, spleen and bone marrow. Anemia, which can be severe, is the most common laboratory abnormality. Leukopenia and elevated alkaline phosphatase levels are common. Rare manifestations of disseminated disease include cutaneous lesions, joint involvement, and osteomyelitis.

MAC Immune Reconstitution Inflammatory Syndrome

MAC immune reconstitution syndrome generally presents as localized peripheral lymphadenitis, but cases of MAC associated intra-abdominal disease, MAC osteomyelitis, joint, and soft tissue disease have been reported (1). The majority of cases are accompanied with fever, but bacteremia is absent.

LABORATORY DIAGNOSIS

MAC can be cultured on solid or liquid media, although liquid media yields results in fewer days (7 – 10 days) and is more sensitive. DNA or RNA hybridization probes can be used to confirm the presence of MAC. Direct detection by PCR is not commercially available outside of specific research laboratories.

Diagnosis of MAC lymphadenitis is made by culture of the organism from the node. Excision of the entire node is recommended for diagnosis since biopsy or aspiration of a suspected node frequently results in fistula formation.

Sputum isolation of MAC can be misleading since patients can be asymptomatically colonized. The American Thoracic Society has formal guidelines for the diagnosis of active MAC pulmonary disease that include multiple positive cultures with smear evidence in the presence of symptoms and radiological evidence of disease (4). [Table 1]

Confirmation of disseminated MAC is achieved by isolation of the organism from an otherwise sterile site. These include culture from blood, bone marrow aspirate, liver, or spleen. The vast majority of cases can be confirmed with isolation in a single blood culture, with recovery form two blood cultures increasing the yield to greater than 99%. The number of MAC organisms obtained in quantitative bone marrow cultures can be more than thirty times higher than those obtained in blood cultures (32). Low colony counts seen early in disseminated disease can promote false negative blood culture results, therefore repeat cultures are recommended if there is a high clinical suspicion of MAC. Growth in liquid media will usually become positive in 14 days, but must be held for at least six weeks before they can be called negative. Isolation of MAC from non sterile sites including bronchial washings, gastrointestinal biopsy specimens, or stool may represent only colonization and a full treatment course should not be initiated on recovery of organisms from these sites alone.

PATHOGENESIS

The serovars that infect AIDS patients with disseminated disease have shown to be more aggressive in animal models suggesting associated virulence factors. Investigated virulence factors include enhanced adhesion to gastrointestinal epithelium, interference of lysosomal acidification promoting intracellular persistence, and catalase production (16). Increased pathogenicity has been associated with antibiotic susceptibility, the presence of plasmid, and certain RFLP patterns. Smooth-translucent isolates have decreased antimicrobial susceptibility in vitro and more likely to induce TNF-α and interlukin-1 production.

MAC organisms are phagocytosed by local macrophages where they persist intracellularly. In pulmonary disease after inhalation of the organisms, macrophages organize into granulomas and form nodules which can be visualized on gross pathology.

Disseminated disease can occur after ingestion or inhalation. When acquired through the gastrointestinal tract, phagocytosed organisms that have penetrated the gut wall appear as foamy macrophages in the intestinal lamina propria resulting in gut wall thickening (34, 45). This thickened bowel wall can lead to the rare complications of gastrointestinal hemorrhage, intussusception, or obstruction. Hematologic dissemination occurs after macrophages are transported to abdominal nodes via lymphatic drainage. The spleen, liver, and bone marrow are the organs most commonly seeded after hematologic dissemination.

The predominate symptoms of disseminated MAC disease are fever, night sweats, and cachexia, similar to the presenting signs of tuberculosis. The symptoms are attributed to elevated levels of TNF-α and other cytokines, namely interlukin-6, induced by the presence of MAC in the host’s blood stream. A marked elevation of serum alkaline phosphatase in the absence of other abnormal markers of hepatic function is seen in approximately 5% of patients with disseminated disease.

SUSCEPTIBILITY IN VITRO AND IN VIVO

MAC is resistant to most of the standard agents used for the treatment of tuberculosis. Susceptibility testing for MAC is not standardized to date and is only available in research institutions. The precise MIC (Minimum Inhibitory Concentration) breakpoint for resistance has not been standardized and is being evaluated by the National Committee for Clinical Laboratory Standards (NCCLS). In addition, clinical correlation with in vitro sensitivity testing has not been established. Susceptibility testing is not recommended for initial selection of therapeutic agents.

In vitro testing is dramatically influenced by the pH at which the test is performed and the medium used (30a). Tween-containing broth enhances antimicrobial activity. While in vitro testing has not been standardized, there is consensus among researchers regarding certain features. A broth medium may be more reliable than agar. When using radiometric broth dilution methods, inoculum preparation is critical. An inoculum size of 104 and 105 colony-forming units (CFU)/mL has been recommended. In the absence of well-established correlations with clinical efficacy and outcome, especially in infections in AIDS patients, use of the MIC to determine resistance or susceptibility is problematic (36).

Molecular mechanisms of antimicrobial resistance are not well described for MAC. (48) There is no evidence that MAC produces aminoglycoside- and peptide-inactivating enzymes; however, there is evidence for low-level, β-lactamase production (49). Macrolide resistance has been linked to base pair substitution within the V domain of the 23S ribosomal RNA (47). This mutation appears to confer cross-resistance among the currently available macrolides.

M. avium is an intracellular pathogen, therefore, the intracellular concentration of a therapeutic agent is an important consideration when evaluating the MIC. For example, azithromycin, which has a lower Cmax in the serum than clarithromycin, has a longer half-life and reaches much higher concentrations in the macrophage than clarithromycin (28,37). Intracellular activity is often studied in the human macrophage model. With the aid of the beige-mouse animal model, agents with in vitro activity are selected for human study.

Susceptibility testing with rifabutin and the antituberculosis drugs is not recommended. Routine testing against clarithromycin should not be performed. Susceptibility testing for clarithromycin should only be performed on isolates from patients who have failed prior macrolide therapy or prophylaxis. Minimal inhibitory concentration (MIC) of > 32 µg/ml is the recommended clarithromycin resistance breakpoint.

Due to increased intrinsic resistance, especially in a population with previous exposure to macrolides, in vitro susceptibility is increasingly useful in treatment failures. Treatment failure is defined as poor clinical response and ability to culture organisms 4 - 6 weeks after initiation of first line combination therapy. Recent data suggests that in the era of potent antiretroviral therapy, there is an increasing incidence of macrolide resistance that may warrant consideration of routine susceptibility testing (26).

The quinolones have known anti-M. tuberculosis activity and there is a growing body of work investigating their use as first line agents against MAC (77). The use of quinolones is an attractive prospect because of their proven efficacy in other mycobacterial species and favorable side effect profile. Investigations of several early quinolones against MAC were disappointing (70). In general, MAC has reduced susceptibility to ciprofloxacin and levofloxacin in vitro, and neither have proven to be of clear clinical benefit in the mouse model (9). Moxifloxacin has significant in vitro activity against MAC (27, 61). Moxifloxacin is bacteriostatic and reaches higher intracellular levels in macrophages than levofloxacin. In vitro testing suggests that the addition of moxifloxacin to an azithromycin based regimen may further prevent resistance (8).

ANTIMICROBIAL THERAPY

Combination therapy for MAC that includes a macrolide and the use of potent antiretroviral therapy in HIV patients promoting immune restoration has dramatically improved morbidity and mortality rates. Eradication of disease requires prolonged therapy and careful monitoring is recommended to prevent drug related toxicities.

Pulmonary Disease

The American Thoracic Society recommends a regimen of daily clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol initially at higher doses (25 mg/kg/d for two months, then 15 mg/kg/d) for adults with isolated pulmonary MAC not infected with HIV (4) [Table 3]. The society recommends that a trial of streptomycin two to three times per week should be considered for the first eight weeks as tolerated. Patients should be treated until culture-negative on therapy for one year. The majority of patients with pulmonary MAC disease receive therapy for about 18 – 24 months on average.

MAC Lymphadenitis

For MAC lymphadenitis in children, excisional surgery without concomitant antibiotics is the mainstay of treatment (62, 75). Incisional biopsy often leads to sinus tract formation and drainage and is therefore not recommended. Recurrence is rare after resection in immunocompetent children, and to date there have been no prospective studies on the use of adjunctive antimycobacterials for treatment of recurrent disease.

Disseminated MAC

Mycobacterial infections are notoriously difficult to treat. MAC is intrinsically resistant to most of the standard antimycobacterial agents used to treat tuberculosis. To prevent the emergence of resistance, the use at least two antimycobacterial agents is recommended for the treatment of MAC (21, 38, 46). Clinical trials conducted prior to the availability of potent antiretroviral therapy concluded that the addition of rifabutin further prevented the emergence of resistance and provided some survival benefit. Initial therapy with three agents is recommended for patients in whom antiretroviral therapy has not been initiated. Multiple studies have shown improved treatment success and survival benefit from macrolide containing regimens in disseminated MAC in AIDS patients (13, 14). Clarithromycin is the preferred first agent in the treatment of disseminated MAC and appears to promote more rapid clearance of MAC from blood cultures as compared to azithromycin (22).

Agents that have activity against MAC include macrolides and azalides, ethambutol, rifampin, ciprofloxacin, levofloxacin, streptomycin and amikacin. Antimicrobials that were previously used but limited by adverse effects and poor response to therapy include clofazimine, cycloserine, and ethionamide. Prior to the introduction of macrolides, treatment for MAC usually required at least 36 months of therapy and there was increased risk of toxicity due to available regimens. Macrolides have decreased the occurrence of treatment failures. First line treatment for disseminated MAC is now clarithromycin in combination with ethambutol plus or minus rifabutin (6, 7) [Table 2]. Clarithromycin has a number of significant drug – drug interactions. Azithromycin, which minimally inhibits the hepatic cytochrome P 450 metabolism system, can be substituted for clarithromycin (74).

The use of rifampin in HIV positive patients is avoided whenever possible due to interference with the hepatic metabolism of protease inhibitors. Use of rifampin with protease inhibitors can promote subtherapeutic protease inhibitor levels (5). Rifabutin is preferred over rifampin because it has more activity against MAC in vivo, but it may also increase the risk of certain adverse events, including leukopenia. Higher doses of rifabutin in combination with clarithromycin have lead to an increase risk of uveitis. In individual cases where rifabutin cannot be tolerated due either to side effects or medication pharmacokinetic interactions, the addition of a third line agent (either a fluoroquinolone or parenteral amikacin) is recommended. While the current treatment guidelines recommend the use of ciprofloxacin or levofloxacin as a fourth agent in disseminated disease, moxifloxacin has more potent activity in vivo.

A multicenter prospective study was conducted to determine whether antimycobacterial therapy for disseminated MAC could be discontinued in HIV positive patients once their immune systems recovered after the addition of antiretroviral therapy (2). Pill burden, potential drug interactions, and the emergence of macrolide resistant respiratory flora all supported discontinuation if it was found to be safe (3). All subjects had completed a least 12 months of macrolide based therapy. After a median duration of follow up of 77 weeks, only one patient had a recurrence of MAC disease (MAC osteomyelitis) giving an estimated recurrence rate of 1.44 / 100 person-years of follow up. A French retrospective study found similar results (78). One subject was extremely immunosuppressed with a CD4 T-cell count of <50 cells/cu mm at the time of relapse highlighting the importance of re-initiating prophylaxis in the presence of immunologic failure. Hence, the joint guidelines of the CDC and the HIV Medicine Association of the Infectious Disease Society of America now recommend that HIV positive patients with disseminated MAC should continue on chronic maintenance therapy until they have completed at least 12 months of therapy, remain asymptomatic, and their CD4 count is consistently greater than 100 cells/mm3 for at least six months after the initiation of antiretroviral therapy (6).

MAC Immune Reconstitution Inflammatory Syndrome

Systemic anti-inflammatory therapy can be added to relieve symptomatic complaints in severe cases. In cases of immune reconstitution inflammatory syndrome with recrudescence of MAC disease, patients should be maintained on chronic maintenance therapy as recommended for HIV treatment guidelines. It is not recommended that the antiretroviral regimen to be discontinued or interrupted.

Novel Agents

Management of treatment failures or cases with documented macrolide resistance is challenging. Novel therapies have been implemented for cases of disseminated MAC unresponsive to standard therapy.

Linezolid, used mainly in clinical practice for the treatment of methicillin resistant Staphylococcus aureus, has in vitro activity against MAC (57, 73). While linezolid has been shown to be bactericidal, to date there have been no animal studies conducted to document its usefulness in the treatment in MAC in vivo (76). The antimalarial agent mefloquine also has in vitro activity againstclarithromycin resistant MAC strains and a promising activity profile in the mouse model, but there is limited clinical experience (10,11). Nannini et al report a case of refractory disseminated cutaneous MAC in a patient with cell-mediated immunodeficiency secondary to CLL (50). In this case, the patient’s disseminated MAC infection responded to the addition of moxifloxacin, mefloquine, and linezolid. Further trials using these agents in clinically refractory disease are warranted.

(Printable Version of Antimicrobial Therapy for Mycobacterium avium Complex)

ADJUNCTIVE THERAPY

Surgical Resection

Adjunctive surgical resection of involved lung tissue was of limited survival benefit prior to the availability of macrolides and is not routinely recommended. Surgical intervention should be limited to areas of severe disease where antibiotic penetration of the tissue is poor.

Corticosteroid Therapy

Persons who have symptoms of moderate-to-severe intensity because of an immune reconstitution inflammatory syndrome (IRIS) in the setting of ART should receive treatment initially with nonsteroidal, anti-inflammatory agents. If symptoms fail to improve, short-term (4–8 weeks) systemic corticosteroid therapy, in doses equivalent to 20–40 mg of oral prednisone QD, has been successful (6). To date, there have been no randomized, control trials designed to investigate the long term safety and efficacy of adjuvant corticosteroid use the treatment of disseminated MAC or its use in IRIS.

Immunomodulatory Therapy

The use of immunomodulatory cytokines and GM-CSF, are currently being investigated as adjunctive therapy for use in refractory cases with extensive disease (69). Immunomodulatory cytokines inhibit the growth of MAC in macrophages (65). Both granulocyte-macrophage colony-stimulating factor (GM-CSF ) and TNF-α significantly reduced numbers of organisms in macrophages. In a small randomized study, AIDS patients with MAC bacteremia who received GM-CSF in combination with azithromycin had evidence of increased monocyte activation and mycobactericidal activity as compared those randomized to receive azithromycin alone (40).

The combination of interferon-γ ( INF-γ ) with IL-2 has been used as adjunctive therapy to routine MAC treatment in a refractory case of disseminated MAC in a pediatric AIDS patient (63). CD4 cells produce interferon-γ in vivo, and patients with mutations in INF-γ receptors are exquisitely susceptible to tuberculosis and mycobacterial infections (20, 51). This suggests that INF-γ is integral to host defense to MAC infections. In the aforementioned case, IL-2 was used to increase the number of circulating CD4 cells, which in turn led to sustained increased INF-γ levels. The use of these cytokines in addition to antimicrobials led to eradication of disseminated MAC.

ENDPOINTS FOR MONITORING THERAPY

Disseminated MAC in HIV-Positive Patients

Response to therapy for disseminated MAC is monitored by clinical symptoms and qualitative blood cultures. Patients should respond with resolution of fevers and chills, decreases in abnormal alkaline phosphatase levels, and a feeling of well being within approximately 4 to 8 weeks (13). Quantitative blood cultures are a research tool used to describe the types of response to certain therapies and are not used in routine clinical practice. Response to therapy should result in a negative blood culture for MAC by 12 to 16 weeks (13). However, while the blood may be free of MAC, tissues (including the bone marrow) may still harbor the infection (18, 41). Failure to clear the blood of MAC should lead the clinician to perform sensitivity testing on the clinical isolate to direct future therapeutic choices.

Pulmonary MAC in HIV-Negative Patients

Responses for pulmonary MAC should be measured by negative sputum cultures. Since this is such a difficult disease to treat, as evidenced by Wallace et al. (51% sputum negative at 4 months), the approach to monitoring is similar to that for pulmonary tuberculosis (72). Symptomatic and radiologic improvement should be seen within 4 months. If it is not, individualized therapy decisions should be made on the basis of results of sputum culture and isolate susceptibility testing.

Given the prolonged duration of therapy for pulmonary and disseminated MAC , serial evaluations for the emergence of complications due to medications should be employed (4) [Table 4]. Monitoring should include visual acuity (ethambutol and rifabutin) (30), red-green color discrimination (ethambutol), liver enzymes (clarithromycin, azithromycin, rifabutin, rifampin, isoniazid, ethionamide) (12), auditory and vestibular function (streptomycin, amikacin, clarithromycin, azithromycin), renal function (streptomycin and amikacin), and leukocyte and platelet counts (rifabutin).

Ototoxicity due to streptomycin is often irreversible. Patients who receive both a macrolide and rifabutin must be monitored for the development of toxicity related to the interaction of these drugs. Clarithromycin enhances rifabutin toxicity (especially uveitis) (64) while the rifamycins, rifampin more than rifabutin, lower clarithromycin serum drug levels.

VACCINES

There are currently no vaccines in use against MAC. However, there is increasing interest to develop a vaccine against tuberculosis, which may provide immunity against MAC (19, 55). Mycobacterium tuberculosis, MAC, and other mycobacteria have homologous PPE and PE genomes that express proteins of unknown function, but believed to be related to virulence of the organism (42). Researchers have determined that a PE protein expressed by MAC is an effective T-cell immunogen in the mouse model (56). While these studies are promising, it has already been established that HIV infected patients have variable response rates to vaccines and loss of immunity as T-cell counts decline. This makes it unclear how effective a vaccine with activity against MAC would be for the severely immunocompromised HIV infected population at greatest risk for developing disseminated MAC.

PREVENTION OR INFECTION CONTROL MEASURES CINES

Primary Antibiotic Prophylaxis

Prior to the introduction of macrolides, nearly 50% of AIDS patients developed disseminated MAC disease within two years of AIDS diagnosis. Primary prophylaxis against MAC disease in severely immunocompromised HIV positive patients is now the standard of care (5, 52). Prophylactic therapy is recommended in an effort to reduce the significant morbidity and mortality associated with disseminated MAC in HIV-positive individuals. Currently, the CD4 cell count is used as an indicator for the initiation of prophylactic therapy. Prophylaxis is indicated for patients with a CD4 count below 50 cells/mm3. Azithromycin 1200 mg once a week is the preferred first line regimen (54). Azithromycin's efficacy, long half life, weekly dosing, and its high concentration within intracellular compartments make it the preferred agent. GI intolerance is the most common adverse effect of the high dose of azithromycin. Alternative regimens include clarithromycin 1 gm daily (in two divided doses or 1000mg extended release formulation) or rifabutin 300 mg daily. Care must be taken to insure dose adjustments are made for any possible medication interactions especially with the use of rifabutin.

Prior to the initiation of MAC prophylaxis, symptomatic patients with unexplained fever, malaise, or cachexia should have blood cultures to rule out disseminated MAC infection. If there is a high clinical suspicion of disseminated MAC, the clinical should consider empiric combination therapy while awaiting final culture results. This strategy would prevent the emergence of resistance as the result of partial treatment with monotherapy.

Several double blind, placebo controlled trials have investigated the optimal parameters for the discontinuation of primary MAC prophylaxis for patients who have increased CD4 cell counts with antiretroviral therapy in the absence of prior documented disease (17, 24). The conclusions in these studies were comparable. The current recommendations are that primary MAC prophylaxis in HIV infected patients whose CD4 cell count has been greater that 100 cells/mm3 for at least 3 months in response to antiretroviral therapy may discontinue the antimycobacterial therapy(ies).

Infection Control

Although MAC is found in environmental samples, there are currently no recommendations regarding avoidance of exposure.

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TABLE 1: **Diagnostic Criteria for Mycobacterium avium complex Pulmonary Disease [Download PDF]**

The following criteria apply to symptomatic patients with infiltrate, nodular or cavitary disease, or a high resolution computed

tomography scan that shows multifocal bronchiectasis and/or multiple small nodules.

A. If three sputum/bronchial wash results are available from the previous 12 mo:

1. three positive cultures for MAC with negative AFB smear results or

2. two positive cultures for MAC and one positive AFB smear

B. If only one bronchial wash is available:

1. positive culture with a 2+, 3+, or 4+AFB smear or 2+,3+, or 4+

growth of MAC on solid media

C. If sputum/bronchial wash evaluations are nondiagnostic or another disease cannot be excluded:

1. transbronchial or lung biopsy yielding MAC or

2. biopsy showing mycobacterial histopathologic features

(granulomatous inflammation and/or AFB) and one or

more sputums or bronchial washings are positive for MAC even in low numbers

At least three respiratory samples should be evaluated from each patient. Other reasonable causes for the disease should be excluded. Expert consultation should be sought when diagnostic difficulties are encountered.

TABLE 2: **Treatment and Prophylaxis of AIDS associated Mycobacterium avium complex disease [Download PDF]**

	Preferred Therapy	Alternate Therapy	Duration	Special Considerations
Initial therapy (at least two drugs)	Clarithromycin 500 mg PO BID + Ethambutol 15 mg/kg PO QD	Alternative to Clarithromycin Azithromycin 500 - 600 mg PO QD	Chronic Maintenance Therapy should be continued lifelong, unless there is a sustained immune response with ARV	Symptomatic assessment should demonstrate improvement in 4 - 6 weeks. If failure is suspected, repeat blood cultures. Consider evaluating sensitivity to macrolides if cultures are positive.
Third Agent	Rifabutin 300 mg PO QD ( dose adjust based on drug interactions as necessary) Consider adding third agent if ARV is not initiated, or evidence of high mycobacterial loads	Alternative third or fourth agent for patients with severe symptoms or disseminated disease Ciprofloxacin 500-750 mg PO BID; or Levofloxacin 500 mg PO QD; or Amikacin 10 - 15 mg/kg IV QD		NSAIDs may be used for patients who experience moderate to sever symptoms attributed to ARV - associated immune reconstitution syndrome. If symptoms of IRIS persist, a short term ( 4 – 8 week ) course of systemic corticosteroid ( prednisone QD 20 - 40 mg PO QD) can be used.
Chronic Maintenance Therapy (secondary prophylaxis)	Clarithromycin 500 mg PO BID + Ethambutol 15 mg/kg PO QD with or without rifabutin 300 mg PO QD	Azithromycin 500 mg PO BID + Ethambutol 15 mg/kg PO QD with or without rifabutin 300 mg PO QD	Maintenance therapy can be discontinued in patients who complete at least 12 months of therapy, remain asymptomatic and have sustained CD4 count > 100 cells/mm3 for at least 6 months
Primary Prophylaxis	Azithromycin 1200 mg PO q week or Clarithromycin 1000 mg PO QD ( extended release) or 500 mg PO BID	Rifabutin 300 mg PO QD

TABLE 3: **Treatment of Mycobacterium avium complex Pulmonary Disease [Download PDF]**

	Preferred Therapy	Alternate Therapy	Duration	Special Considerations
Initial Therapy	Clarithromycin 500 mg PO BID + Rifabutin 300 mg PO QD + Ethambutol 25 mg/kg QD for the first 2 months followed by 15 mg/kq QD	Alternative to Clarithromycin Azithromycin 250 mg PO QD or 500 mg PO three times a week Alternative to Rifabutin - Rifampin 600 mg PO QD	Treatment should be continued for at least 12 months after last positive sputum culture on a macrolide containing regimen.	Patients with small body mass or age over 70, clarithromycin 250 mg QD or azithromycin 250 mg three times a week may be better tolerated.
Adjunctive Therapy	Streptomycin 1 gm QD five times a week (based on normal creatinine clearance )	Ciprofloxacin 750 mg PO BID or Ofloxacin 400 mg PO BID or Ethionamide 250 mg PO BID	Intermittent Streptomycin is recommended for only the first 2 to 3 months of treatment of extensive disease	Patients receiving streptomycin should be instructed on the signs and symptoms of ototoxicity and vestibular toxicity( tinnitus, decreased hearing, unsteady gait). Ototoxicity due to streptomycin is often irreversible.

TABLE 4: Antimycobacterial Agents Commonly Used in the Treatment of MAC Infections [Download PDF]

Agent	Adult Dose	Adverse Effects
Amikacin	7.5 - 15 mg/kg QD IV	Ototoxicity, nephrotoxicity
Azithromycin	500 mg/day	Nausea, diarrhea, vomiting, abdominal pain, headache, dizziness, elevated hepatic enzymes
Ciprofloxacin	750 mg BID	Anorexia, nausea, vomiting, abdominal pain, diarrhea, rash, mental status changes
Clarithromycin	500 mg BID	Diarrhea, nausea, vomiting, elevated hepatic enzymes, abdominal pain, renal insufficiency
Ethambutol	15 mg/kg/day	Anorexia, nausea, vomiting, diarrhea, rash, elevated hepatic enzymes, ocular changes - retrobulbar neuritis
Rifabutin	300 mg/day	Anorexia, nausea, vomiting, diarrhea, rash, uveitis, myalgias, arthralgias, headache
Rifampin	10 mg /kg/day	Anorexia, nausea, vomiting, diarrhea, rash, elevated hepatic enzymes