Mycobacterium avium complex

Jeffrey J. Post : Senior Specialist, Department of Infectious Diseases and The Albion Centre, Prince of Wales Hospital and Conjoint Associate Professor, Prince of Wales Clinical School, University of New South Wales, Sydney NSW

Mycobacterium avium and Mycobacterium intracellulare are two non-tuberculous mycobacteria that collectively form a group of organisms known as the Mycobacterium avium complex (MAC). MAC is ubiquitous in the environment. Infections with other non-tuberculous mycobacteria are well recognised in HIV infection but occur rarely. There is a strong relationship between the CD4 T-lymphocyte (CD4) cell count and the presence of disseminated MAC infection, with nearly all cases occurring at a CD4 cell count of < 50 cells/μL.1 A MAC-associated immune reconstitution inflammatory syndrome (MAC-IRIS) may occur at higher CD4 cell counts in the setting of combination antiretroviral therapy (cART), with an incidence rate of 3.5% in people commencing cART with a CD4 cell count < 100 cells/μL.2 Disseminated MAC infection has become rare since the introduction of cART.3

Clinical presentation

Immunodeficient people

The most common manifestation of MAC infection in people with HIV infection who are not taking cART is that of disseminated disease. The typical clinical scenario is a markedly immunodeficient person (CD4 cell count < 50 cells/μL) with fevers, drenching night sweats, weight loss, anaemia (or pancytopenia), diarrhoea, lymphadenopathy and hepatosplenomegaly with abnormal liver function tests (particularly an elevation of alkaline phosphatase). Intra-abdominal lymphadenopathy may occur and cause significant abdominal pain. Although uncommon, pulmonary involvement can present with a persistent dry cough, fever and loss of weight.

MAC-associated Immune reconstitution inflammatory syndrome

Restoration of cell-mediated immunity against MAC was recognised after zidovudine monotherapy for HIV,4 although clinical reports of immune reconstitution inflammatory syndromes have been more frequent following the introduction of cART.5-9 There are three main clinical presentations of MAC-IRIS: peripheral lymphadenitis and fever; intra-abdominal disease (abdominal lymphadenopathy, chylous ascites, peritonitis, abscess and lesions or masses in the bowel); and lung disease (mediastinal lymphadenopathy, infiltrates, cavitary lesions and pulmonary nodules).2 The lymphadenopathy may be peripherally located, with sinus formation and chronic percutaneous drainage of purulent material, or intra-abdominal (para-aortic and mesenteric), which is often associated with abdominal pain. A peripheral blood leukocytosis may be present. Biopsy specimens of lymph nodes typically reveal granulomata and acid-fast bacilli may be detected. Osteomyelitis, bursitis, pericarditis, parotitis, cerebral abscess, peritonitis and skin nodules have also been reported. In one study in a resource limited setting, 9 out of 793 (1%) patients developed MAC disease after commencing cART.10

In the event of lymphadenitis caused by MAC-IRIS, treatment should consist of standard therapy for MAC infection. Up to 20% of patients with MAC-IRIS fail to respond to up to 2 years of MAC therapy and experience persistent or relapsing disease. These patients are more likely to have abdominal lymphadenopathy and less likely to have significant rises in CD4 cell counts in response to cART.11 In severe cases, a short course of prednisone may be used,2 but some patients relapse on tapering the dose. In rare cases, surgical drainage, lymphadenectomy or the temporary interruption of cART may be required.12

The presence of MAC infection at the time of cART commencement is associated with a poorer recovery of CD4 cells than matched subjects without MAC infection, possibly reflecting the occurrence of inflammation from a mild form of MAC-IRIS that impairs recovery of CD4 cell counts.13

Diagnosis

The diagnosis of disseminated MAC infection can be made by culture of blood or histological examination and culture of bone marrow, enlarged lymph nodes or liver. Although the presence of MAC in stool culture has a 60% predictive value for the subsequent development of disseminated disease,14 it is not diagnostic of disseminated disease. A presumptive diagnosis, pending the results of appropriate investigations, may be made in the typical clinical context (a person with a CD4 cell count < 50 cells/μL, not taking MAC prophylaxis, with fevers, night sweats, weight loss and anaemia). Such a presumptive diagnosis may only be confirmed by the presence of MAC bacteraemia or bone marrow culture in approximately 20% of cases.15 It is important to consider other causes of the symptom complex as multiple pathological processes can coexist and mimic one another in people with severe immunodeficiency.

Management

The usual regimen for the treatment of MAC infection is clarithromycin 500 mg twice a day and ethambutol 15 mg/kg/day with or without rifabutin 300 mg daily. Treatment with a three drug regimen was associated with reduced mortality compared with two drugs in one study.16,17 If clarithromycin is not tolerated, then azithromycin 500 mg daily may be substituted. If clarithromycin is not used, then the dose of rifabutin should be increased to 450 mg daily. The dose of clarithromycin should not exceed 500 mg twice daily, as excess mortality has been observed at doses of 1000 mg twice daily.18 Alternative agents, including amikacin, ciprofloxacin or clofazimine, should only be used if there is no clinical response to initial therapy after 6 weeks. Antimicrobial-sensitivity testing is not routinely undertaken, but should be performed if a macrolide antibiotic (azithromycin or clarithromycin) has been used for prophylaxis, and breakthrough MAC infection has occurred. Some authors have recommended that macrolide resistance be routinely assessed as two of nine (22%) isolates in one small US study were found to be macrolide resistant despite little or no previous macrolide exposure.19

When cART is used in combination with MAC treatment, consideration of drug interactions between antiretroviral and antimycobacterial agents is required. In all cases where HIV and mycobacterial infections are treated simultaneously, a careful review of potential multi-directional drug interactions should be undertaken, with reference to a pharmacist or reliable drug-interaction website (such as www.hiv-druginteractions.org). The degree of interaction varies, with some combinations being contraindicated and others requiring a dose modification of one or both agents..

In general, cART should be commenced within 2 weeks of commencing MAC therapy.20 This may be associated with an immune reconstitution inflammatory syndrome, but most data suggest a reduced risk of mortality.

MAC therapy needs to be lifelong unless cART-associated immune reconstitution occurs. Maintenance therapy may be ceased when the HIV viral load has been suppressed and the CD4 cell count is > 100 cells/μL after treatment for 12 months.21

If a histological diagnosis of mycobacterial infection is made and the results of cultures are unavailable, empirical therapy should cover both MAC and M. tuberculosis infections. In the circumstance of probable MAC infection, isoniazid 300 mg daily and pyridoxine 50 mg daily (to prevent peripheral neuropathy) should be added to the standard MAC regimen of rifabutin, ethambutol and clarithromycin until the identification of mycobacterial species is available. Isoniazid and pyridoxine should be ceased as soon as MAC has been identified. If M. tuberculosis is the most likely diagnosis then therapy should be targeted at this infection, although clarithromycin should be added to increase the spectrum of activity to include MAC until identification of the organism is available. If M. tuberculosis may be the aetiological agent and samples of sputum are positive on acid-fast bacilli smear22 or there is respiratory involvement, then respiratory isolation of the patient is required until organism identification is complete, or the sputa are negative on the acid-fast bacilli smear, or 2 weeks of effective therapy has been completed.

The side effects of commonly used antimycobacterial agents are listed in Table 1. Regular clinical review should be undertaken while on therapy with at least monthly clinical visits initially. Liver function tests and haematological parameters should be monitored. Ophthalmological complications are extremely rare with a lower dose of ethambutol (15 mg/kg/day) so regular ophthalmological review is not warranted. However, patients should be warned of potential ophthalmological side effects from ethambutol and to report these as soon as they occur.

Prognosis

The prognosis of untreated MAC infection therapy is poor. Combination antimicrobial therapy against MAC improves survival and cART provides an additional survival benefit.23,24

Prophylaxis

Primary prophylaxis

Primary prophylaxis against MAC infection has been shown to reduce the incidence of MAC disease in patients with advanced immunodeficiency (CD4 cell count < 50 cells/μL) and probably improves survival.25-28 Three agents have been studied. Azithromycin (1200 mg orally once weekly) is the best tolerated agent with the fewest drug interactions. Clarithromycin (500 mg orally twice daily) or rifabutin (300 mg orally daily) are alternatives. Both of these medications interact with antiretroviral drugs and other agents and dose adjustment or alteration of the cART regimen may be required. Combination therapy with these agents is more efficacious, but is associated with greater toxicity.26

Before instituting prophylaxis for MAC infection, it is important to exclude active MAC or M. tuberculosis infection. Prophylaxis with a single agent during active MAC or M. tuberculosis infection will lead to antimicrobial resistance.

Table 1  Side effects of commonly used antimycobacterial agents
Drug  Side effects
Amikacin Nephrotoxicity, ototoxicity, neuromuscular blockade
Azithromycin Diarrhoea, nausea, abdominal pain, vomiting, ototoxicity, abnormal liver function tests, central nervous system toxicity, leukopenia, erythema multiforme
Ciprofloxacin Anorexia, nausea, diarrhoea, vomiting, abdominal pain, headache, restlessness, insomnia, psychosis, seizures, rash, arthralgia, intestinal nephritis, tendon rupture.
Clarithromycin Diarrhoea, nausea, taste change, abdominal pain, headache, taste perversion, abnormal liver function tests, rash
Clofazimine Skin pigmentation, anorexia, nausea, skin dryness, pruritus, abdominal pain, conjunctival irritation, retinal crystal deposition
Ethambutol Optic neuritis (usually at higher dose i.e. 25 mg/kg/day), reduced visual acuity, restricted visual fields, scotomata, loss of colour discrimination, peripheral neuropathy, headache, rash, arthralgia, hyperuricaemia, gastrointestinal side effects
Isoniazid Peripheral neuropathy (prevent with co-administration of pyridoxine), allergy, lymphadenopathy and vasculitis, hepatitis (greater risk with increasing age, alcohol consumption and chronic liver disease), antinuclear antibody, blood dyscrasia, liver failure, other neurological manifestations (optic neuritis, encephalopathy, convulsions, psychosis) fever
Pyrazinamide Arthralgia, hyperuricaemia, hepatitis, gastric irritation, photosensitivity, rash, fever, pruritus, thrombocytopenia, skin discolouration, side roblastic anaemia
Rifabutin Leukopenia, nausea, vomiting, diarrhoea, polyarthralgia, uveitis, rash, discolouration of urine, tears, sweat, saliva, stool and skin, neutropenia, febrile illness, hepatitis, haemolysis, myositis
Rifampicin Anorexia, nausea, vomiting, diarrhoea, rash, febrile reaction, hepatitis, abnormal liver function tests, discolouration of urine, tears, sweat, saliva, stool and skin, haemolysis, febrile illness

Blood specifically cultured for MAC, chest radiograph and full investigation of fevers, weight loss, night sweats, anaemia, abnormal liver function tests, hepatosplenomegaly, respiratory symptoms or unexplained lymphadenopathy are required. A stool culture for MAC should be undertaken in people with diarrhoea to exclude MAC enteritis before commencing prophylaxis.

Some authors have suggested that primary prophylaxis for disseminated MAC is not required for those who commence cART with CD4 cell counts below 50 cells/μL, because the risk of disseminated MAC infection is low, and patients can be followed closely for the signs of disseminated MAC infection29 The strength of the evidence for this recommendation is not strong.30

In the event that MAC infection develops despite macrolide prophylaxis, antimicrobial sensitivity testing of MAC to macrolides is warranted, as macrolide resistance is detected in up to 30% of breakthrough isolates after clarithromycin prophylaxis31 and 11% after azithromycin prophylaxis.26

Secondary prophylaxis

Secondary prophylaxis involves the life-long continuation of therapy for MAC infection unless cART-induced immune reconstitution occurs. As with other mycobacterial infections, a maintenance phase of treatment with two drugs is recommended. Rifabutin is most commonly eliminated, as it is associated with significant drug interactions and uveitis. A strategy of 12 months of MAC treatment followed by cessation of treatment if the CD4 cell count is greater than 100 cells/μL while on fully suppressive cART appears to be safe for people that achieve this degree of immune reconstitution.21

Discontinuing prophylaxis

Primary prophylaxis against MAC infection may be ceased with cART-associated immune reconstitution when the CD4 cell count is > 100 cells/μL for 3 months in the setting of adequate viral suppression32-34 and after 12 months of MAC treatment in those receiving maintenance treatment (secondary prophylaxis).21

References

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