Nontuberculous mycobacteria

NTM species	Disease	Treatment	Comment
MAC	Pulmonary ^a	Clarithromycin 500 mg BID or azithromycin 250 mg/d plus ethambutol 15 mg/kg/d plus rifampin 600 mg/d Consider streptomycin or amikacin 10–15 mg/kg IM or IV for severe disease	Treat for 1 year of negative AFB cultures Rifabutin 150–300 mg daily may be substituted for rifampin
MAC	Disseminated	Clarithromycin 500 mg BID or azithromycin 500 mg/d with ethambutol 15 mg/kg/d ± rifabutin 300 mg/d	Treatment lifetime or may be stopped with CD4+ T-cell count over 100 cells/mm³ for 12 months
MAC	Lymph node Involvement	Complete surgical excision of involved nodes usually curative	If adjunctive chemo-therapy necessary, see drugs for pulmonary disease
M. kansasii	Pulmonary	Rifampin 600 mg/d Isoniazid 300 mg/d Ethambutol 15 mg/kg/d	Treat for 1 year of negative AFB cultures Clarithromycin and moxifloxacin also with excellent activity against M. kansasii
M. kansasii	Disseminated	Substitute rifabutin 150–300 mg/d for rifampin in HIV +	Treatment duration as for disseminated MAC
M. abscessus subsp. bolletii	Pulmonary	Clarithromycin 500 mg BID plus amikacin 10–15 mg/kg 3–5 times per week	Consider second parenteral drug such as cefoxitin or imipenem. Activity of linezolid, tigecycline, and clofazimine is variable
M. abscessus subsp. bolletii	Soft tissue	Clarithromycin 500mg BID plus amikacin 10–15 mg/kg 3–5 times per week for a minimum of 2 weeks, 4–6 months for severe infection	Consider second parenteral drug for severe disease. Removal of foreign body and surgical debridement also important. Other agent activity variable including linezolid, tigecycline, or clofazimine
M. abscessus subsp. abscessus	Pulmonary	Amikacin 10–15 mg/kg 3–5 times per week plus second parenteral drug such as cefoxitin or imipenem	Other agents with variable activity: linezolid, tigecycline, and clofazimine Role of azithromycin in presence of active erm gene is uncertain
M. abscessus subsp. abscessus	Soft tissue	Amikacin 10–15 mg/kg 3–5 times per week plus second parenteral drug such as cefoxitin or imipenem for a minimum of 2 weeks, 4–6 months for severe infection	Other agents with variable activity: linezolid, tigecycline, and clofazimine. Role of azithromycin in presence of active erm gene is uncertain. Removal of foreign body and surgical debridement also important
M. chelonae	Pulmonary	Clarithromycin 500 mg BID plus tobramycin 3–5 mg/kg 3–5 times per week	Consider third agent such as imipenem or linezolid. Clofazimine, doxycycline, and quinolone susceptibility varies
M. chelonae	Soft tissue	Clarithromycin 500 mg BID plus tobramycin 3–5 mg/kg 3–5 times per week for a minimum of 2 weeks, 4–6 months for severe infection	Consider third agent for severe disease. Susceptibility to imipenem, linezolid, clofazimine, doxycycline, and quinolone varies. Removal of foreign body and surgical debridement may be important
M. marinum	Soft tissue	Clarithromycin 500 mg BID plus ethambutol 15 mg/kg/d. Treat 1–2 months after resolution of symptoms (usually 3–4 months total)	Susceptible to multiple agents. Surgical debridement may also be important
M. fortuitum	Pulmonary	2 agents to which the organism is susceptible for 6 months. Consider parenteral medication for severe disease	Susceptible to multiple medications including quinolones, doxycycline, trimethoprim/sulfa, macrolides, amikacin
M. fortuitum	Soft tissue	As above. Treatment 3–6 months
M. simiae, M. xenopi M. malmoense M. szulgai		Too little information to make standard or routine recommendation	Usually a macrolide-based regimen

^a Consider three times weekly therapy (TIW) with clarithromycin 1000 mg, ethambutol 25 mg/kg/dose, and rifampin 600 mg for mild nodular/bronchiectatic (noncavitary) disease.

The presence of the erm gene noted above has recently provided a potential explanation for the discordance between in vitro testing and phenotypic response: erythromycin methylase (erm) genes encode a diverse collection of methylases that impair binding of macrolides to ribosomes, reducing the inhibitory activity of these agents. The primary mechanism of acquired clinically significant macrolide resistance for some mycobacteria, especially RGM, is the presence of an inducible erm gene. All isolates of M. abscessus subsp. abscessus, M. fortuitum, and several other RGM, but not M. chelonae, contain an inducible erm gene. The most interesting aspect of this inducible gene is that if an M. fortuitum or M. abscessus subsp. abscessus isolate is exposed to macrolide, the erm gene activity is induced with subsequent in vivo macrolide resistance which may not be reflected by the initial in vitro minimum inhibitory concentration (MIC) of the organism for the macrolide. It is only with incubation of NTM in the presence of a macrolide that the erm gene and the associated macrolide resistance will be identified.

The clinician must use in vitro susceptibility data for many NTM with the awareness that, unlike tuberculosis, NTM disease may not be eradicated in a given patient with therapy based on in vitro susceptibility results.

Lastly, the clinician may not uncommonly encounter different NTM isolates synchronously or metachronously, and should monitor microbiologic response during and microbiologic status after a treatment course.

Recommended drug treatment for MAC lung disease

As discussed in the general principles of NTM therapy, the macrolides (clarithromycin and azithromycin) are the only antimicrobial agents for which there is a demonstrated correlation between in vitro susceptibility and in vivo response for MAC lung disease. The cornerstones of MAC therapy, therefore, are the macrolides, clarithromycin and azithromycin, with the addition of ethambutol. These agents are then combined with companion drugs, usually a rifamycin and, possibly, an injectable aminoglycoside. It is necessary to include companion drugs with the macrolide to prevent the emergence of macrolide-resistant MAC isolates. The macrolides should never be used as monotherapy for treatment of MAC disease (pulmonary or disseminated). Likewise, the use of macrolide and fluoroquinolone may be associated with cardiac toxicity and puts the patient at risk for development of macrolide-resistant MAC disease.

An important illustration of how the dichotomy between in vitro susceptibility results and in vivo response in MAC disease can be detrimental is provided by the example of ethambutol. There has not been a demonstrated correlation between ethambutol in vitro susceptibility and clinical response in any previous study; however, the duration of ethambutol use is associated with improved microbiologic response for patients receiving an intermittent clarithromycin-containing regimen and the exclusion of ethambutol from treatment regimens is a major risk factor for the development of macrolide-resistant MAC. It would be potentially risky to the patient for a physician to exclude ethambutol from a multidrug MAC treatment regimen based on in vitro susceptibility results.

There is another difficult-to-explain phenomenon associated with MAC drug therapy. Patients who have failed prior MAC therapy, with or without a macrolide, have lower sputum conversion rates with macrolide-containing treatment regimens, even with macrolide-susceptible MAC isolates, than do patients with no prior therapy. Although the explanation for this observation is also not clear, it is evident that the best chance for treatment success in MAC lung disease is the first treatment effort.

The recommended treatment length for MAC pulmonary disease is a duration of therapy that includes 12 months of sputum culture negativity. This treatment goal dictates that patients should have sputum collected for AFB analysis on a regular basis throughout the course of treatment.

The intensity of MAC treatment should be proportionate to the disease burden; other considerations should be individualized patient factors including tolerance to medications, medication cost, and acceptance of necessary monitoring and risks for the multidrug regimens.

For most patients with nodular/bronchiectatic disease, or those with fibrocavitary disease who cannot tolerate daily therapy, or those patients for whom disease suppression is an appropriate goal, intermittent, three times weekly, therapy is recommended. Recommended intermittent drug dosages include: (1) clarithromycin, 1000 mg, or azithromycin, 500 to 600 mg, (2) ethambutol, 25 mg/kg, and (3) rifampin, 600 mg, given three times weekly. Intermittent therapy is not recommended for patients with cavitary disease or patients who have received previous therapy for MAC.

The recommended regimen for patients with fibrocavitary disease or severe nodular/bronchiectatic disease, includes (1) clarithromycin, 1000 mg/day (or 500 mg twice daily) or azithromycin, 250 mg/day, (2) ethambutol, 15 mg/kg/day, and (3) rifampin, 10 mg/kg/day (maximum 600 mg/day). For some patients, the doses of clarithromycin may need to be split (e.g., 500 mg twice daily) because of gastrointestinal intolerance and for patients of small body mass (less than 50 kg) or age over 70 years, the clarithromycin dose may need to be reduced to 500 mg/day or 250 mg twice a day because of gastrointestinal intolerance.

A more aggressive and less well-tolerated treatment regimen for patients with severe and extensive (multilobar), especially fibrocavitary, disease consists of clarithromycin, 1000 mg/day (or 500 mg twice a day), or azithromycin, 250 mg/day, rifabutin, 150 to 300 mg/day, or rifampin, 10 mg/kg/day (maximum 600 mg/day), ethambutol (15 mg/kg/day), and consideration of inclusion of a parenteral agent, either amikacin or streptomycin, for the first 2 or 3 months of therapy (see dosage discussion below). Patients receiving clarithromycin and rifabutin should be carefully monitored for rifabutin-related toxicity, especially hematologic (leukopenia) and ocular (uveitis) toxicity. Active investigations are ongoing attempting to define the role of inhaled amikacin in the treatment of NTM lung disease. To date, although inhaled amikacin is often used there is very little published data supporting the indication, dose, and duration of the best use as a companion drug.

Macrolide-resistant

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