Reprinted from www.antimicrobe.org

Mycobacterium avium Complex - 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 [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. 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. 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. 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.

               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 [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.

               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. 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. Pill burden, potential drug interactions, and the emergence of macrolide resistant respiratory flora all supported discontinuation if it was found to be safe. 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. 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.

 

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. 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. The antimalarial agent mefloquine also has in vitro activity against clarithromycin resistant MAC strains and a promising activity profile in the mouse model, but there is limited clinical experience. Nannini et al report a case of refractory disseminated cutaneous MAC in a patient with cell mediated immunodeficiency secondary to CLL. 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.

 

TABLE  2

Treatment and Prophylaxis of AIDS associated Mycobacterium avium complex disease

 

  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 

 

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.