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  • 1. Mycobacterium avium-complex (MAC, MAI, non-HIV)Christopher J. Hoffmann, M.D., M.P.H.MICROBIOLOGY• M. avium and M. intracellulare are slow growing mycobacteria (10-21 days on solid media).• M. intracellulare is principally causes pulmonary disease. M. avium principally causes disseminated disease (among immunocompromised people).• Environmental sources, especially water, are the reservoir for most human infections.CLINICAL • M. avium complex (M. avium and M. intracellulare) strains are frequent causes of mycobacterial lung disease in the USA. • No convincing evidence for person-to-person spread of MAI. • ATS criteria (2007): The minimum evaluation of suspected of nontuberculous mycobacterial (NTM) lung disease: (1) chest radiograph or, in the absence of cavitation, chest high-resolution computed tomography (HRCT) scan; (2) three or more sputum specimens for acid-fast bacilli (AFB) analysis; and (3) exclusion of other disorders, such as tuberculosis (TB). Clinical, radiographic, and microbiologic criteria are equally important and all must be met to make a diagnosis of NTM lung disease. ATS states that criteria apply to symptomatic patients with radiographic opacities, nodular or cavitary, or an HRCT scan that shows multifocal bronchiectasis with multiple small nodules. These criteria fit best with Mycobacterium avium complex (MAC), M. kansasii, and M. abscessus. There is not enough known about most other NTM to be certain that these diagnostic criteria are universally applicable for all NTM respiratory pathogens. • Microbiologic criteria: positive culture results from at least two separate expectorated sputum samples or at least one bronchial wash or lavage, or transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM. • Commercially-available nucleic acid probe test can identify cultured mycobacteria as MAI. No PCR or other rapid test is FDA-approved for direct use on sputum or blood. • Antimicrobial susceptibility testing: correlation between in vitro susceptibility testing and clinical response is only clear for macrolides. Macrolide susceptibility should be assessed before initiating therapy and in the setting of treatment failure. There is no clear role for using susceptibility results for other agents as in vitro susceptibility results do not appear to correlate with rifampin, ethambutol, and aminoglycoside clinical response. In vitro susceptibility and clinical response fluoroquinolones is unclear (absence of prospective study). Macrolides should not be
  • 2. used in treating macrolide resistant disease and fluoroquinolones probably provide little benefit in fluoroquinolone-resistant disease.SITES OF INFECTION • Pulmonary - two major manifestations: a) cavitary, b) nodular with bronchiectasis. Cavitary disease can have upper lobe location (like TB). Associated conditions/risk factors: cystic fibrosis, silicosis, tobacco smoking, bronchiectasis, pectus excavatum/thoracic scoliosis. • Pulmonary - "hot tub lung:" acute, diffuse lung disease with cough/fever/hypoxia due to high inhalation inoculum. Non-necrotizing granulomatous inflammation +/- interstitial pneumonia. Pathogenesis unclear-"infection" vs. hypersensitivity. • Extrapulmonary localized (skin, soft tissue, joints, tendons, bones): less common than pulmonary disease, but may occur after trauma or environmental exposure. • Cervical lymphadenitis: typically in children ages 1-5 years. May occur in immunocompetent children. • Disseminated: rare except in AIDS patients. Typically occurs in immunocompromised hosts (exogenous immunosuppression, SCID, IFN gamma or IL-12 pathway disorders).TREATMENTPulmonary MAI Disease• Severe or cavitary disease: macrolide (clarithromycin 500mg PO twice daily or azithromycin 500 mg PO daily) plus ethambutol 15 mg/kg/d PO plus rifampin 600 mg PO daily. Initial two months of higher dose ethambutol 25/mg/d no longer recommended. Note: use of ethambutol and rifampin reduces emergence of macrolide resistance.• Nodular (non-cavitary) disease: macrolide (clarithromycin 1000 mg t.i.w or azithromycin 500 mg PO t.i.w) plus ethambutol 25 mg/kg PO t.i.w plus rifampin 600 mg PO t.i.w. Note: intermittent therapy not recommended for patients with cavitary lung disease. Use of ethambutol and rifampin reduces emergence of macrolide resistance.• Aminoglycoside choice: sometimes used adjunctively in severe disease or treatment refractory infections. Amikacin (15 mg/kg/dose, max 1 gram, 3 times per week IV) most active against MAI, and the traditional choice. Alternative: streptomycin 15 mg/kg/dose (max 1 gram) 3 times per week IM. Severity of MAI disease, immunosuppression, toxicities important in balancing when considering use of aminoglycoside. Macrolide resistant-MAI: aminoglycoside with ethambutol, rifampin and possibly, isoniazid. Moxifloxacin may also have a role. Fluoroquinolones have activity against MAI but prospective studies are lacking to guide optimal use.• Clinical expectations of treatment: symptomatic and radiographic improvement within 2-6 months, and conversion of sputum culture from positive to negative within approximately 6 months. Outcome usually better with noncavitary (compared with cavitary) disease.
  • 3. • Duration: not definitively established. Typical duration is 18-24 months total, including 12 months after sputum culture becomes negative for MAI. Monitor sputum smear and culture monthly.• Rifabutin is alternative to rifampin . No demonstrated superiority of rifabutin vs rifampin (rifampin usually better tolerated). No head to head comparisons of clarithromycin vs azithromycin for pulmonary MAI; though azithromycin has fewer drug-drug interactions, and is often better tolerated, especially if used t.i.w.• Adjunctive treatment: bronchial hygiene (inhaled beta agonists, mucus-clearing devices) and antibiotic treatment as needed for nonmycobacterial pulmonary superinfection.• Role of surgery: no randomized studies, typically reserved for patients with poor response to medical therapy and who are good surgical candidates, generally localized/cavitary disease. Should be performed in centers with extensive experience. Surgical resection of a solitary pulmonary nodule is considered curative.• Monitoring for drug adverse reactions: hepatotoxicity (rifampin, rifabutin), uveitis (rifabutin), ocular toxicity (ethambutol), nephrotoxicity and/or ototoxicity (aminoglycosides).• Withholding treatment is acceptable in patients with close follow-up to determine if disease is significant (e.g., continue to collect sputa for culture) or who have mild disease and poorly tolerate therapy. In both cases close follow-up (including CT imaging) is needed. Of note, patients with upper lobe fibrocavitary disease tend to progress rapidly and withholding therapy is not recommended.Hot Tub Lung• Discontinuation of exposure necessary.• No consensus opinion about role of corticosteroids and/or antibiotics. Anecdotal reports of rapid improvement after stopping exposure (no steroids or antibiotic).Cervical Lymphadenitis in Children• Excisional surgery without chemotherapy (success rate of > 95%).• If surgical risk high (e.g., facial nerve involvement), macrolide-containing multidrug regimen is reasonable, but limited experience, optimal duration unknown.• Incisional biopsy, or use of non-macrolide-containing regimens often associated with persistent clinical disease including sinus tract formation.Extrapulmonary localized disease• Surgery (excisional or debridement) plus macrolide-containing multidrug regimen (same doses as for pulmonary disease).• Optimal duration unknown, but usually follow pulmonary guidelines.Disseminated disease• Macrolide-containing multidrug regimen as for cavitary pulmonary disease.• Optimal duration unknown and dependent on clinical response and predisposing factors.
  • 4. Selected Drug CommentsAmikacin Most active aminoglycoside against most MAC strains. Most common use is for macrolide resistant MAI.Azithromycin Clarithromycin may be modestly more active against MAI than azithromycin, but azithromycin has fewer clinically relevant drug-drug interactions. Specifically, azithromycin can be used safely with rifampin and rifabutin.Clarithromycin Clarithromycin may be modestly more effective than azithromycin, but generally less well-tolerated. Clarithromycin extended release (500mg XL tablet) 1000 mg/day is an alternative. Clarithromycin (substrate and inhibitor of CYP3A4) increases rifabutin levels approximately 50%, and clarithromycin levels are decreased approximately 50%. Azithromycin is alternative.Linezolid Drug may have in vitro activity, but clinical experience is limited and side effects such as neuropathy and anemia with long-term treatment is high[Ntziora, 2007]Moxifloxacin No prospective studies. Has good in vitro activity, but as with other agents(ABX) for MAC disease, there may not be clear correlation between in vitro activity and in vivo activity. In mouse studies, appears to have less activity than predicted byin vitro studies. In situations of macrolide resistance, to avoid drug-drug interactions or drug allergy it may be useful.Rifabutin No prospective studies comparing rifampin to rifabutin in macrolide- containing regimens for MAI lung disease in HIV-negative patients. Anecdotal reports suggest no therapeutic advantage to rifabutin. Given frequent adverse events with rifabutin (when combined with macrolide) and high cost of rifabutin, many experts use rifampin in macrolide-containing regimens for pulmonary MAI in HIV-negative persons.Rifampin No prospective studies comparing rifampin to rifabutin in macrolide- containing regimens for MAI lung disease in HIV-negative patients. Anecdotal reports suggest no therapeutic advantage to rifabutin. Given frequent adverse events with rifabutin (when combined with macrolide) and high cost of rifabutin, many experts use rifampin in macrolide-containing regimens for pulmonary MAI in HIV-negative persons.Tigecycline Glycycline drug that has in vitro activity and has been used in the treatment of some NTM infections such as M. abscessus; however, no clinical experience reported in MAI infections.Drug RecommendationFOLLOW UP • For pulmonary disease, monthly sputum for AFB stain and culture recommended monitoring. • Clinical expectations of treatment: symptomatic and radiographic improvement within 2-6 months, and conversion of sputum culture from positive to negative within approximately 6 months. Outcome usually better with noncavitary (compared with cavitary) disease.
  • 5. • Macrolide-resistant infection: aminoglycoside plus high dose ethambutol 25 mg/kg/day PO plus rifabutin 300-600 mg/day PO. Surgery should be considered. Clinical outcome poor; most patients who remain culture positive die of progressive pulmonary disease with respiratory failure[Griffith, 2006].• Patients respond best to therapy the first time it is administered, therefore multidrug therapy (not clarithromycin monotherapy) is important to initiate the first time patients receive therapy for MAC pulmonary disease.OTHER INFORMATION • Interpretation of a single positive respiratory culture for MAI should take into account the possibility of environmental contamination. • MAI lung disease is typically associated with persistently positive respiratory cultures, with heavy MAI growth. Most experts recommend a thoracic CT as part of diagnostic workup for pulmonary MAI. • For pulmonary MAI disease, ATS diagnostic criteria (see "Clinical" information above) are guidelines and applicability in specific patients should be carefully considered by an experienced clinician. • For patients with positive MAI respiratory cultures in whom decision is made not to treat MAI, long-term close followup is essential (symptoms, repeat sputum exams, thoracic CT scans). • Monitoring for drug toxicity is essential given the long duration of therapy and typical older age of affected individuals: rifampin (hepatitis), rifabutin (uveitis especially when used with macrolide, hepatitis, polyarthralgias), ethambutol (retrobulbar neuritis manifest by decreased visual acuity or red-green color discrimination), amikacin (ototoxicity, nephrotoxicity), clarithromycin (GI upset), azithromycin (reversible hearing loss, GI upset).Basis for recommendation • Griffith DE et al: An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 175:367, 2007 Feb. 15 [PMID:17277290] Comment: Comprehensive document that is the basis of recommendations in this module. It is also well worth reading for patients with MAC not responsive to initial therapy for additional detailed information. Rating: Basis for recommendationReferences 1. Milanés-Virelles MT et al: Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: a randomized, double-blind, placebo-controlled study. BMC Infect Dis 8:, 2008 [PMID:18267006] Comment: Small trial (18 in IFN arm, 14 placebo)in patients with treatment- resistant MAC, with the IFN arm judged as 72% complete responders vs. 36% in placebo arm as all received continued drug therapy with azithromycin, ciprofloxacin, ethambutol and rifampin.
  • 6. 2. Kasperbauer SH, Daley CL: Diagnosis and treatment of infections due to Mycobacterium avium complex. Semin Respir Crit Care Med 29:569, 2008 [PMID:18810690] Comment: Good review co-authored by experts in the field from National Jewish Hospital in Denver, Colorado.3. Ntziora F, Falagas ME: Linezolid for the treatment of patients with atypical mycobacterial infection: a systematic review. Int J Tuberc Lung Dis 11:606, 2007 [PMID:17519090]4. Lam PK et al: Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 173:1283, 2006 June 1 [PMID:16514112] Comment: One-year prospective noncomparative trial of thrice weekly treatment of MAI pulmonary disease in 91 HIV-negative adults who originally participated in trial of inhaled IFN-gamma therapy. Patients received thrice weekly treatment with clarithromycin 1000 mg (or 750 mg if wt < 50 kg) or azithromycin 600 mg (or 375 mg if wt < 50 kg), plus ethambutol 25 mg/kg, plus rifampin 600 mg or rifabutin 5-10 mg/kg. Culture and CT response rates were 4 to 5 times higher in patients with noncavitary than cavitary disease. Patients who were AFB smear negative at baseline were twice as likely to have culture response. Rating: Important5. Griffith DE et al: Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 174:928, 2006 Oct. 15 [PMID:16858014] Comment: Retrospective review of 51 patients over 15 yr period with clarithromycin -resistant MAC lung disease at single referral center. Risk factors for resistance were macrolide monotherapy or combination of macrolide plus quinolone (dual therapy). Sputum culture conversion occurred in 11/14 (79%) of patients who received more than 6 months of injectable aminoglycoside therapy and lung resection, c/w 2/37 (5%) who did not. One year mortality in patients with persistently positive cultures was 34% (13/38) c/w 0% (0/13) of patients who became culture negative. Rating: Important6. Iseman MD: Medical management of pulmonary disease caused by Mycobacterium avium complex. Clin Chest Med 23:633, 2002 [PMID:12370999] Comment: Detailed management guidelines by world-recognized expert. Rating: Important7. Griffith DE et al: Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 32:1547, 2001 June 1 [PMID:11340525] Comment: Open, prospective trials of intermittent, azithromycin-containing regimens for MAC pulmonary disease in HIV-negative persons: treatment with azithromycin 600 mg three times weekly (TIW) plus ethambutol 25 mg/kg/dose TIW plus rifabutin 300 or 600 mg/dose TIW plus initial twice-weekly streptomycin resulted in conversion of sputum culture from positive to negative in 65% of enrolled patients. This sputum conversion rate was similar to that reported for patients treated
  • 7. with daily clarithromycin- or azithromycin-containing regimens, but no simultaneous head-to-head comparison done. Rating: Important8. Khoor A et al: Diffuse pulmonary disease caused by nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 115:755, 2001 [PMID:11345841] Comment: Clinical description of hot tub lung. Dyspnea, cough, fever, hypoxia most common symptoms/signs. Histopathologic exam of lung biopsy material showed non-necrotizing granulomatous inflammation in all cases.9. Griffith DE et al: Early results (at 6 months) with intermittent clarithromycin- including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis 30:288, 2000 [PMID:10671330] Comment: Open, noncomparative, prospective trial of treatment for MAC lung disease in HIV-negative patients with a 3-times per week clarithromycin-containing regimen (clarithromycin 1000 mg/dose TIW plus ethambutol 25 mg/kg/dose TIW plus rifabutin 150 or 300 mg/dose TIW). 78% of patients converted sputum cultures from positive to negative within 6 months, which was similar to conversion rates in previous studies using regimens with daily clarithromycin. Rating: Important