Treatment of Nontuberculous Mycobacterial Pulmonary Disease

Remarks:

The decision to initiate antimicrobial therapy for NTM pulmonary disease should be individualized based on a combination of clinical factors, the infecting species, and individual patient priorities. Any treatment decision should include a discussion with the patient that outlines the potential side effects of antimicrobial therapy, the uncertainties surrounding the benefits of antimicrobial therapy, and the potential for recurrence including reinfection (particularly in the setting of nodular/bronchiectatic disease)

• For macrolides, a 14-day incubation and/or sequencing of the erm(41) gene is required in order to evaluate for potential inducible macrolide resistance.

Although in vitro-in vivo correlations have not yet been proven for all major antimycobacterial drugs, baseline susceptibility testing to specific drugs is recommended according to the Clinical and Laboratory Standards Institute (CLSI) guidelines for NTM isolates from patients with definite disease. Testing of other drugs may be useful, but there is insufficient data to make specific recommendations.

Remarks:

Although no well-designed randomized trials of macrolide therapy have been performed, macrolide susceptibility has been a consistent predictor of treatment success for pulmonary MAC. Loss of the macrolide from the treatment regimen is associated with a markedly reduced rate of conversion of sputum cultures to negative and higher mortality. Therefore, the panel members felt strongly that a macrolide should be included in the regimen.

Remarks:

The panel felt that azithromycin was preferred over clarithromycin because of better tolerance, less drug-interactions, lower pill burden, single daily dosing, and equal efficacy. However, when azithromycin is not available or not tolerated, clarithromycin is an acceptable alternative.

Remarks:

In the absence of comparably effective oral medications there are few options other than parenteral aminoglycosides for “intensifying” standard oral MAC therapy. The committee thought that the benefits outweighed risks in those patients with cavitary or advanced/severe bronchiectatic or macrolide-resistant MAC pulmonary disease and that administration of at least 2–3 months of an aminoglycoside was the best balance between risks and benefits.

Randomized controlled trials have demonstrated the efficacy and safety of ALIS when added to guideline-based therapy for treatment refractory MAC pulmonary disease. ALIS is currently approved by the United States Federal Drug Administration for treatment of refractory MAC pulmonary disease. As noted in question 5, we suggest that parenteral amikacin or streptomycin be included in the initial treatment regimen in patients with cavitary or advanced/severe bronchiectatic or macrolide-resistant MAC pulmonary disease.

Remarks:

A priority in MAC pulmonary disease therapy is preventing the development of macrolide resistance. The panel members were concerned that the currently available data were insufficient to determine the risk of acquired macrolide resistance with a 2-drug regimen and therefore suggest a 3 drug macrolide-containing regimen.

Intermittent therapy has similar sputum conversion rates as daily therapy for nodular/bronchiectatic MAC pulmonary disease and is also better tolerated than daily therapy. A critically important finding from the available studies is the lack of development of macrolide resistance with intermittent therapy. There is not similar evidence to justify or support intermittent therapy for cavitary MAC pulmonary disease and it is not recommended.

Remarks:

The optimal duration of therapy for pulmonary MAC disease is not currently known. The panel felt that in the absence of evidence identifying an optimal treatment duration that the recommendation from the 2007 Guideline should be followed.

Remarks:

Isoniazid is widely used at present for treatment of M. kansasii pulmonary disease, and in the experience of the panel members, there have been good outcomes when using a regimen consisting of rifampicin, ethambutol, and isoniazid irrespective of the result of minimal inhibitory concentrations (MICs) for isoniazid and ethambutol. Based on the in vitro activity of macrolides against M. kansasii, and 2 studies that demonstrated good treatment outcomes when clarithromycin was substituted for isoniazid, the panel suggests that either isoniazid or a macrolide can be used in combination with rifampicin and ethambutol.

Remarks:

Regimens of 3 oral agents, rifampicin and ethambutol, and either isoniazid or a macrolide, achieve high rates of sustained culture conversion and treatment success in the treatment of M. kansasii pulmonary disease. Therefore, given the good outcomes observed with oral regimens and the high risk of adverse effects associated with parenteral amikacin or streptomycin, the committee felt strongly that the use of these parenteral agents is not warranted, unless it is impossible to use a rifampicin-based regimen or severe disease is present.

Treatment success of M. kansasii pulmonary disease with a rifamycin-based drug regimen is usually excellent but the optimal choice of companion drugs is not clear. While ethambutol is usually the preferred companion drug, the choice of an additional companion drug may be isoniazid, a macrolide or a fluoroquinolone. As there is more experience and better evidence for treatment regimens that include isoniazid or a macrolide as a companion drug, these drugs are preferred. For rifampicin-resistant disease, a regimen such as ethambutol, azithromycin, and a fluoroquinolone would be likely to lead to successful treatment.

Because there are no randomized trials available and the small size of the single study that evaluated 3 times weekly therapy, the committee did not feel that they could recommend intermittent therapy in the setting of cavitary disease until more evidence was available. Similarly, there are no data to support the use of isoniazid on a 3 times weekly basis in patients with M. kansasii pulmonary disease.

Remarks:

Current rifampicin-based treatment regimens are associated with a high rate of success if used for at least 12 months. Randomized controlled trials comparing shorter treatment regimens are currently lacking. Although some experts would favor 12 months of treatment after culture conversion, there is no evidence that relapses could be prevented with treatment courses longer than 12 months. Therefore, the panel members felt that M. kansasii could be treated for a fixed duration of 12 months instead of 12 months beyond culture conversion. Because sputum conversion at 4 months of rifampicin-based regimens is usually observed, expert consultation should be obtained if cultures fail to convert to negative by that time.

Remarks:

There is in vitro evidence that macrolides and fluoroquinolones are active against M. xenopi, whereas rifampicin and ethambutol are inactive in vitro alone and in combinations. Preliminary data from a study in France that randomized patients to receive either moxifloxacin or clarithromycin plus ethambutol and rifampicin reported no difference in the treatment success between the study arms.

Remarks:

Given the high mortality associated with M. xenopi disease, the panel members felt the large risk of treatment failure with a 2-drug regimen warranted at least a 3-drug treatment regimen. However, the absence of universal access to moxifloxacin and the small amount of data for other fluoroquinolones has to be considered when choosing a regimen.

Remarks:

Barring compelling evidence to the contrary, M. xenopi patients should be treated aggressively given the high mortality of the disease [34–36]. In addition to the high mortality, the committee considered the general acceptability and feasibility of parenteral therapy, and potential costs and toxicities, all based on clinical experience.

Remarks:

Data suggest that treatment outcomes improve if the duration of treatment increases [35, 37]. The panel felt that this outweighs the risk of adverse events associated with longer treatment and agrees with previous recommendations.

M. abscessusinfections can be life-threatening, and the use of macrolides is potentially of great benefit. Macrolides are very active in vitro against M. abscessus strains without a functional erm(41) gene, and evidence supports use of macrolides in patients with disease caused by macrolide-susceptible M. abscessus. It is important to perform in vitro macrolide susceptibility testing including detection of a functional or nonfunctional erm(41) gene.

Remarks:

Given the usual disease severity of M. abscessus pulmonary disease, the variable and limited in vitro drug susceptibility of these organisms, the potential for the emergence of drug resistance, and the potential for more rapid progression of M. abscessus pulmonary disease, the panel members suggest using a regimen consisting of three or more active drugs. The panel members felt strongly that treatment regimens should be designed in collaboration with experts in the management of these complicated infections.

Remarks:

The lack of studies, the variation in drug availability, resources, and practice settings made it difficult to come to a consensus on the optimum duration of therapy. In addition, the panel members felt that some subgroups of patients should be considered separately in determining the length of therapy such as: patients with nodular/bronchiectatic versus cavitary disease, patients affected by lung disease caused by different M. abscessus subspecies and importantly, depending on susceptibility to macrolides and amikacin. The panel members suggest that an expert in the management of patients with M. abscessus pulmonary disease be consulted.

Remarks:

Selected patients with failure of medical management, cavitary disease, drug resistant isolates, or complications such as hemoptysis or severe bronchiectasis may undergo surgical resection of the diseased lung. The decision to proceed with surgical resection must be weighed against the risks and benefits of surgery. The panel suggests that surgery be performed by a surgeon experienced in mycobacterial surgery