D22 Mycobacterium avium complex infection
Mycobacterium avium complex (MAC) refers to infections caused by one of the two nontuberculous mycobacterial species, namely Mycobacterium avium and Mycobacterium intracellulare. The clinical spectrum is limited predominantly to pulmonary diseases and lymphadenitis in normal hosts and disseminated disease in HIV-infected patients. Since 1982, the incidence of disease due to MAC has increased, coinciding with the advent of the AIDS epidemic and advance in diagnostic methods. An estimated 7% to 12% of adults have been previously infected with MAC worldwide. Cumulatively, non-tuberculosis mycobacteria infections accounted for 2% of AIDS-defining illnesses in Hong Kong.
Organisms of the MAC are free living and are ubiquitous in the environment. They can be found 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. The mode of transmission can be through inhalation, ingestion or inoculation via the respiratory or gastrointestinal tract. Person-to-person transmission is unlikely.
Clinical manifestations and diagnosis
In the pre-HAART (highly active antiretroviral therapy) era and absence of effective chemoprophylaxis, patients with HIV infection usually suffered from severe AIDS-related immunosuppression. The incidence of disseminated MAC disease in these patients can reach a level of as high as 20-40%. MAC disease typically occurs among patients when CD4 count falls below 50/μL, with the highest risk at less than 10/μL. Disseminated MAC disease is less commonly seen in patients with CD4 counts greater than 100 cells/μL.
Disseminated MAC disease. Disseminated MAC occurs almost exclusively in persons with advanced HIV disease. It is typically a disseminated multi-organ infection. In patients with AIDS, 80% to 90% of MAC infections are acquired by ingestion. The organisms penetrate the gut wall through the Peyer’s patches, and are subsequently phagocytised by macrophages and other reticuloendothelial cells. Early symptoms may include fever, weight loss, malaise, night sweats, abdominal pain and diarrhoea. Bacteraemia is commonly encountered when disease progresses, with high bacterial burden shown in many patients. In one autopsy study of disseminated MAC disease patients, 70% revealed involvement of reticuloendothelial and gastrointestinal systems. Blood tests may show anaemia and rise in alkaline phosphatase levels. Hepatomegaly and/or splenomegaly may be identified in physical examinations.
Localised disease. Localised manifestations of MAC disease occur mostly in patients with improved immunity after receiving HAART. Localised syndromes include skin or soft tissue abscesses, pneumonitis, pericarditis, cervical or mesenteric lymphadenitis, or diseases involving the central nervous system.
Immune reconstitution with MAC. Clinical deterioration of opportunistic infections following commencement of HAART is well described. These presentations are collectively termed as immune reconstitution inflammatory syndrome (IRIS).[Chapter C17] The syndrome has been described in patients with subclinical MAC disease and advanced immunosuppression following initiation of HAART, and accompanied by rapid and profound rise in CD4 cell count (usually ≥100 cells/μL). Most patients with IRIS present with new onset of fever and painful lymphadenopathy (70%), which occurs within 1 to 12 weeks of antiretroviral therapy initiation. Others may exhibit pulmonary diseases, abdominal pain and hepatosplenomegaly. Bacteraemia is usually absent in patients with MAC associated IRIS.
Pulmonary disease with MAC. This most commonly occurs in immunocompetent patients with underlying chronic lung diseases, including bronchiectasis, chronic obstructive lung diseases, prior tuberculosis and silicosis. The classic presentations are subacute to chronic onset of productive cough, weight loss, fever or night sweats. MAC pneumonitis is not commonly seen in HIV infected patients, except in cases of IRIS.
Diagnosis of disseminated MAC disease is based on the recovery of the mycobacteria from blood or other sterile sites, namely bone marrow, spleen, liver, lymph nodes or other normally sterile body sites. Rapid species differentiation can be achieved by using specific DNA probes.
Primary prophylaxis of MAC disease
Primary chemoprophylaxis is effective in the prevention of disseminated MAC diseases. This should be given to HIV-infected patients with a CD4 count less than 50/μL. Rifabutin was first proven to be effective in preventing the disease, at a dosage of 300mg daily. Subsequent studies revealed the effectiveness of azithromycin or clarithromycin with superiority over rifabutin. Current recommendation for the primary prevention of MAC involves the use of azithromycin or clarithromycin.
For primary prophylaxis, clarithromycin should be given at 500mg twice daily. Some patients may experience taste perversion and gastrointestinal symptoms. Azithromycin is a good alternative at the dosage of 1000 mg once per week. The use of azithromycin is often preferred for its convenience and fewer interactions with concomitant antiretroviral therapy.[Box 22.1] Rifabutin is the alternative if patients cannot tolerate macrolide antibiotics. The combined use of azithromycin and rifabutin showed increase in protection, but with additional costs and adverse effects. Currently combination use of macrolide and rifabutin is not recommended for prophylaxis.
Primary MAC prophylaxis should be continued until patients show good response to antiretroviral therapy. Randomised control studies have demonstrated that the risk of acquiring MAC diseases was minimal in this group of patients. Primary prophylaxis should be reintroduced if CD4 count decreases to below 50/μL. Primary MAC prophylaxis could be discontinued in adults who have responded to HAART with immune recovery of CD4 count >100 cells/μL for 3 months or more.
Box 22.1. Recommended chemoprophylaxis for MAC disease in HIV-infected patients
|Azithromycin||1000mg once per week oral|
|Clarithromycin||500mg twice daily oral|
|Rifabutin||300mg daily oral|
Treatment of disseminated MAC
Initial treatment regimen of disseminated MAC diseases should include two or more antimycobacterial drugs to prevent emergence of drug resistance. The drugs of choice are macrolides, rifabutin and ethambutol. Treatment success is measured by symptom relief together with clearance of bacteraemia. Susceptibility testing to macrolide should be performed in all MAC isolates.
Clarithromycin is often the preferred first agent for treatment while awaiting susceptibility results on the mycobacterium isolates. In one study, clarithromycin (500mg twice daily dose) alone was effective in acute decrease of MAC bacteraemia by more than 99%. However, clarithromycin-resistant isolates of MAC developed in 46% of patients after a median interval of 16 weeks. Azithromycin (500mg once daily) is also effective in reducing MAC bacteraemia. Azithromycin can substitute clarithromycin when drug interactions and drug intolerance are of concern.
Ethambutol is the recommended second drug which is associated with a lower rate of relapse. It is bacteriostatic against MAC and the usual dosage is 15mg/kg daily.
Rifabutin (300mg daily) is the third drug for consideration. One clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and ethambutol significantly reduced emergence of drug resistance.
AIDS Clinical Trials Group Study 223 compared three clarithromycin-containing regimens for the treatment of disseminated MAC. Mycobacteraemic patients were randomised to open label therapy with clarithromycin plus ethambutol (15 mg/kg/day), clarithromycin plus rifabutin (450 mg once daily), or the three-drug combination of clarithromycin, ethambutol, and rifabutin. The rate of complete microbiologic response was similar in the 3 treatment groups at 12 weeks. However, patients with three-drug combination regimen were less likely to relapse than those on two-drug combination. They also had increased survival compared to the two-drug therapy groups.
The preferred regimen for patient with advanced immunosuppression (CD4 <50/μL) is the use of a third drug in addition to a macrolide and ethambutol.[Box 22.2] The same recommendation applies to patients with high mycobacterial loads or in the absence of effective antiretroviral therapy. Alternatively, potentially active agents for use in combination may comprise amikacin or streptomycin, or possibly a fluoroquinolone such as levofloxacin or moxifloxacin.
Box 22.2. Preferred therapeutic regimen for disseminated MAC disease in HIV-infected patients with advanced immunosuppression
|CD4 count <50/μL||Clarithromycin 500mg BD / Azithromycin 500mg daily
*Rifabutin 300mg daily
|*Rifabutin at 150mg daily if concomitant use of protease inhibitor (may consider therapeutic drug monitoring)|
Monitoring and maintenance of treatment
Response to treatment
Clinical improvement is anticipated within 4 to 6 weeks, which correlates with a clearance of mycobacteraemia. Repeat blood culture is not necessary if there is clinical improvement. When there are signs of clinical failure, at least two other new drugs should be added or substituted. Amikacin, a quinolone (moxifloxacin, ciprofloxacin, or levofloxacin), or linezolid may be considered for salvage therapy. Clofazimine should not be used because randomised trials have demonstrated a lack of efficacy and an association with increased mortality.
Adverse effects with clarithromycin and azithromycin include gastrointestinal upsets, abnormal taste and acute hepatitis. High dose clarithromycin (>1g per day) have been associated with increase mortality and should be avoided. Rifabutin doses of >450mg per day have been associated with higher risk of drug interactions when combined with clarithromycin. Higher risk of uveitis, arthralgia and other adverse drug reactions may be experienced.
Patients may develop moderate to severe symptoms related to IRIS after initiation of antiretroviral therapy. Initial treatment with non-steroidal anti-inflammatory agents could be considered. For persistent symptoms, short term (4-8 weeks) systemic corticosteroid therapy (20-40mg oral prednisolone daily) has been shown to be effective in reducing symptoms and morbidity.
Chronic maintenance therapy
In the absence of antiretroviral therapy, disease recurrences are almost universal without chronic suppression therapy. Therefore, patients with disseminated MAC disease should receive chronic secondary prophylaxis unless there is immune recovery as a result of HAART. Clarithromycin 500mg twice daily or Azithromycin 1000mg once weekly can be used as chronic suppression therapy.
Discontinuation of secondary prophylaxis
Patients are at low risk for recurrence of MAC if they have completed a course of more than 12 months of treatment and following good immune reconstitution with HAART. Secondary prophylaxis can be discontinued if a patient remains asymptomatic, and has a sustained increase in CD4 counts >100/μL for more than 6 months. Secondary prophylaxis should be resumed if the CD4 count falls below 100/μL.
- Nightingale SD, Byrd LT, Southern PM, Jockusch JD, Cal SX, Wynne BA. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J Infect Dis 1992;165(6):1082-1085. link
- Torriani FJ, McCutchan JA, Bozzette SA, Grafe MR, Havlir DV. Autopsy findings in AIDS patients with Mycobacterium avium complex bacteremia. J Infect Dis 1994;170(6):1601-5. link
- Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5(6):361-73. link
- Nightingale SD, Cameron DW, Gordin FM, Sullam PM, Cohn DL, Chaisson RE, Eron LJ, Sparti PD, Bihari B, Kaufman DL, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med 1993;329(12):828-33. link
- Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR Recomm Rep 2009;58(RR04);1-198. link
- Currier JS, Williams PL, Koletar SL, Cohn SE, Murphy RL, Heald AE, Hafner R, Bassily EL, Lederman HM, Knirsch C, Benson CA, Valdez H, Aberg JA, McCutchan JA. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team. Ann Intern Med 2000;133(7):493-503. link
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected Adults and Adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. (updated November 2018). Available from link
- Chaisson RE, Benson CA, Dube MP, Heifets LB, Korvick JA, Elkin S, Smith T, Craft JC, Sattler FR. 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 1994;121(12):905-11. link
- Gordin FM, Sullam PM, Shafran SD, Cohn DL, Wynne B, Paxton L, Perry K, Horsburgh CR Jr. 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 1999;28(5):1080-5. link
- Benson CA, Williams PL, Currier JS, Holland F, Mahon LF, MacGregor RR, Inderlied CB, Flexner C, Neidig J, Chaisson R, Notario GF, Hafner R; AIDS Clinical Trials Group 223 Protocol Team. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis 2003;37(9):1234-43. link
- Daley CL Mycobacterium avium complex disease. Daley CL. Microbiol Spectr 2017;5(2). link
- Chaisson RE, Keiser P, Pierce M, Fessel WJ, Ruskin J, Lahart C, Benson CA, Meek K, Siepman N, Craft JC. Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS 1997;11(3):311-7. link
- Wormser GP, Horowitz H, Dworkin B. Low-dose dexamethasone as adjunctive therapy for disseminated Mycobacterium avium complex infections in AIDS patients. Antimicrob Agents Chemother 1994;38(9):2215-7. link