Category Archives: Atypical Mycobacteriosis

Atypical Mycobacteriosis

– Christian Hoffmann –

Atypical mycobacterioses are usually synonymous for infections with Mycobacterium avium complex (MAC). Although MAC is by far the most frequent pathogen, numerous other atypical mycobacterioses exist that cause a similar disease pattern, such as M. celatum, M. kansasii, M. xenopi or M. genavense. MAC bacteria are ubiquitous and can be found in diverse animal species, on land, in water and in food. Exposure prophylaxis is therefore not possible. Consequently, isolation of infected patients is not necessary. While MAC may be detectable in the sputum or stool of asymptomatic patients (colonization), only patients with massive immunodeficiency and less than 50 CD4 T cells/µl develop disease (Horsburgh 1999). This used to include up to 40% of AIDS patients in the pre-HAART era (Nightingale 1992).

The infection has now become very rare in industrialized countries (Karakousis 2004). However, it remains important, as it has developed into a completely new disease in the ART era. It previously occurred mainly with a chronic, disseminated course of disease, often in patients with wasting syndrome. MAC infections under ART are now almost always localized and related to an immune reconstitution inflammatory syndrome. The disease now occurs with manifestations that were previously never seen (see below).

Signs and symptoms

The symptoms of disseminated MAC infection are unspecific. When the CD4 count is less than 100 cells/µl, fever, weight loss and diarrhea should always lead to consideration of atypical mycobacteriosis. Abdominal pain may also occur. As described above, disseminated MAC infection has now become rare.

Localized forms of atypical mycobacterioses are far more frequent. These include, above all, lymph node abscesses, which may occur practically everywhere. We have seen abscesses in cervical, inguinal and also abdominal lymph nodes, some of which developed fistulae and resolved only slowly even after surgical intervention. Any abscess appearing whilst on ART (with severe immunosuppression) is highly suspicious of MAC! In addition to skin lesions, localized forms include osteomyelitis, particularly of the vertebrae, and septic arthritis (observed: knee, hand, fingers).

Diagnosis

Diagnosis of the disseminated form is difficult. Blood cultures (heparinized blood) should always be sent to a reference laboratory. Although atypical mycobacteria usually grow more rapidly than TB bacteria, the culture and differentiation from TB may take weeks. In cases presenting with anemia, bone marrow aspiration is often successful. If atypical mycobacteria are detected in the stool, sputum or even BAL, it is often difficult to distinguish between infection requiring treatment and mere colonization. In such cases, treatment should not be initiated if general symptoms are absent. This is also true for Mycobacterium kansasii (Kerbiriou 2003).

Laboratory evaluations typically show elevated alkaline phosphatase (AP) – a raised AP in severely immunosuppressed patients is always suspicious of MAC. Similarly, MAC infection should be considered in any cases of anemia and constitutional symptoms. Cytopenia, particularly anemia, often indicates bone marrow involvement. Ultrasound reveals enlargement of the liver and spleen. Lymph nodes are often enlarged, but become apparent due to their number rather than their size (Gordin 1997). Here, differential diagnoses should always include TB or malignant lymphoma.

Direct specimens should always be obtained for localized forms, as identification of the organism from material drained from the abscess is usually successful.

Treatment

Treatment of MAC infection detected from culture is complex. Similarly to TB, monotherapy does not suffice. Since 1996, many clinicians prefer the combination of a macrolide (clarithromycin or azithromycin) with ethambutol and rifabutin (Shafran 1996). In the past, this treatment was given lifelong; today it is generally considered sufficient to treat for at least six months and until a ART-induced increase in the CD4 T cell count to above 100 cells/µl has been achieved. After publication of data indicating that rifabutin may be omitted from the regimen (Dunne 2000), the multicenter, randomized ACTG 223 Study demonstrated survival benefit with the triple combination C+R+E compared to C+E and C+R – mortality rates were halved in the triple combination arm (Benson 2003).

Due to the high potential for interactions, however, rifabutin can be discontinued after several weeks when clinical improvement is observed. The clarithromycin dose should not exceed 500 mg bid. In at least two randomized studies, there was a significantly higher number of deaths in treatment arms with a higher clarithromycin dose, for reasons that remain unclear (Chaisson 1994, Cohn 1999). Instead of clarithromycin, azithromycin can also be given, which is cheaper and interacts less with cytochrome P450 enzymes. Azithromycin and clarithromycin have comparable efficacy in combination with ethambutol (Ward 1998).

In disseminated illnesses, treatment should be monitored through regular blood cultures. Cultures must be negative after eight weeks, at the latest. In the localized from, the response can be assessed better clinically. Every MAC therapy has a high potential for side effects and drug interactions. The concomitant medications, including ART, should be carefully examined – dose adjustments are frequently required and there may be contraindications (see Drugs section).

Reserve drugs such as amikacin, quinolones or clofazimine are only required in rare cases today. It is important to perform resistance testing for all atypical mycobacterial infections with species other than M. avium complex.

We have generally stopped treatment of localized MAC infections when the abscess has healed – this usually takes several months. In individual cases, steroids may be helpful temporarily. However, there are no specific guidelines for treatment of local MAC infections.

Prophylaxis

In the US, large placebo-controlled trials have shown that the macrolides, clarithromycin and azithromycin, as well as rifabutin, significantly reduce MAC morbidity and mortality when used for primary prophylaxis in severely immunocompromised patients (Havlir 1996, Nightingale 1992, Pierce 1996, Oldfield 1998). Prophylaxis also saves costs (Sendi 1999). However, MAC infections are more rare in Europe. As a result, and because of concerns over compliance and development of resistance, few patients in Europe receive primary MAC prophylaxis (Lundgren 1997).

For patients failing currently available ART regimens and without new treatment options, prophylaxis with a macrolide should be considered at low CD4 T cell counts (below 50 cells/µl). Weekly dosing with azithromycin is convenient for patients and has comparable efficacy to daily rifabutin (Havlir 1996).

Primary prophylaxis and maintenance therapies can be discontinued quite safely at CD4 T cell counts above 100/µl (Currier 2000, El Sadr 2000, Shafran 2002, Aberg 2003). It is possible that even partial viral suppression suffices for MAC-specific immune reconstitution (Havlir 2000). Complete recovery as a result of immune reconstitution is possible (Aberg 1998).

Treatment/prophylaxis of MAC (daily doses, if not specified otherwise)
Acute therapy    
Treatment of choice Clarithromycin +ethambutol +

possibly rifabutin

Clarithromycin 1 tbl. at 500 mg bid plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Alternative Azithromycin +ethambutol +

possibly rifabutin

Azithromycin 1 tbl. at 600 mg qd plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Maintenance therapy As for acute therapy, but without rifabutinDiscontinue if > 100 CD4 T cells/µl > 6 months
Primary prophylaxis Consider for CD4 cells below 50/µlDiscontinue if > 100 CD4 T cells /µl > 3 months
Treatment of choice Azithromycin Azithromycin 2 tbl. at 600 mg/week
Alternative Clarithromycin Clarithromycin 1 tbl. at 500 mg bid

References

Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in HIV-infected subjects with disseminated Mycobacterium avium complex. J Infect Dis 2003; 187: 1046-52.

Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with HAART. J Infect Dis 1998, 178:1446-9.

Benson CA, Williams PL, Currier JS, et al. 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. Clin Infect Dis 2003; 37:1234-43.

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. Ann Intern Med 1994, 121:905-11.

Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999, 29:125-33.

Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. Ann Intern Med 2000, 133:493-503.

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 HIV. Clin Infect Dis 2000, 31:1245-52.

El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to ART. N Engl J Med 2000, 342:1085-92.

Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997, 176:126-32.

Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996, 335:392-8.

Havlir DV, Schrier RD, Torriani FJ, et al. Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in HIV-infected subjects. J Infect Dis 2000, 182:1658-63.

Horsburgh CR Jr. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS. J Infect Dis 1999, Suppl 3:S461-5.

Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis 2004, 4:557-65.

Kerbiriou L, Ustianowski A, Johnson MA, Gillespie SH, Miller RF, Lipman MC. HIV type 1-related pulmonary Mycobacterium xenopi infection: a need to treat? Clin Infect Dis 2003; 37: 1250-4.

Lundgren JD, Phillips AN, Vella S, et al. Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 16:153-60.

Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in HIV-positive patients. J Infect Dis 1992, 165:1082-5.

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 1998, 26:611-9.

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 AIDS. N Engl J Med 1996, 335:384-91.

Sendi PP, Craig BA, Meier G, et al. Cost-effectiveness of azithromycin for preventing Mycobacterium avium complex infection in HIV-positive patients in the era of HAART. J Antimicrob Chemother 1999, 44:811-7.

Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996, 335:377-83.

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 2002;137:734-7.

Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with HIV infection. Clin Infect Dis 1998, 27:1278-85.

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Filed under 11. Opportunistic Infections, Atypical Mycobacteriosis, Part 3 - AIDS