By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

Dr. Deresinski reports no financial relationships relevant to this field of study.

SYNOPSIS: Current treatment regimens for pulmonary Mycobacterium avium infection leave a great deal to be desired.

SOURCES: Kwak N, Park J, Kim E, et al. Treatment outcomes of Mycobacterium avium complex lung disease: A systematic review and meta-analysis. Clin Infect Dis 2017 Jun 3. doi: 10.1093/cid/cix517. [Epub ahead of print.]

Pan SW, Shu CC, Feng JY, et al. Microbiological persistence in patients with Mycobacterium avium complex lung disease: The predictors and the impact on radiographic progression. Clin Infect Dis 2017;65:927-934.

The studies reviewed here confirm that currently used regimens for the treatment of patients with pulmonary infection due to organisms of the Mycobacterium avium complex (MAC) are frequently unsuccessful.

Kwak and colleagues at the Seoul National University College of Medicine conducted a meta-analysis of 16 studies, including 1,462 patients. All were observational cohort studies, six of which were prospective, two with randomization (albeit lacking blinding of outcome assessment), and eight were retrospective. The median duration of treatment in the studies ranged from 12.0 to 28.4 months.

Treatment success, defined as sustained sputum culture negativity for 12 months while on treatment, was achieved in 60.0% (95% confidence interval [CI], 55.1-64.8%). Of note is that the success rate of macrolide recipients was significantly lower among patients in the two randomized trials (43.2%; 95% CI, 35.6-50.8%) compared to those in the other observational studies (61.9%; 95% CI, 59.3-73.1%). Seven studies reported results in patients who did not receive a macrolide as part of their therapy, and their treatment success was 53.6% (95% CI, 38.0-69.3%). The most frequently reported adverse event was hearing loss.

Pan et al retrospectively reviewed 126 patients with pulmonary MAC infection, 111 of whom received no chemotherapy for their disease during at least the initial year of their care. Of the 126 patients, 60% failed to convert their sputum at 12 months. Failure of conversion was associated with radiographic progression, which occurred in 54%. Those who did convert had a significantly lower risk of radiographic progression. Both lack of conversion and radiographic progression were worse in the 15 patients who did not receive treatment. Low body mass index (BMI), nodular bronchiectatic radiographic pattern, and markedly positive smears were independent predictors of microbiological persistence.

COMMENTARY

The recommended initial treatment of MAC infection of the lungs consists of a multidrug regimen with clarithromycin or azithromycin (which I prefer because of its tolerability and more limited drug-drug interactions), together with ethambutol and a rifamycin. For mild to moderate bronchiectatic disease, the regimen (with appropriate dosing) can be given thrice weekly, while for fibrocavitary or severe disease, it should be taken daily. Some clinicians recommend that the initial portion of the therapeutic course include streptomycin or amikacin, but this, of course, complicates the regimen because of the need for parenteral administration and risk of toxicity. Furthermore, the benefit of this approach may be questioned. While susceptibility testing is performed routinely, the only one with results that are predictive of therapeutic outcome is clarithromycin (which also predicts azithromycin susceptibility).

Whatever the treatment, the results are frequently less than stellar. In a metanalysis, Pasipanodya et al found that the pooled incidence ratio for sustained sputum conversion for regimens that included a macrolide antibiotic was 0.54 (95% CI, 0.45-0.63), while it was 0.38 (0.25-0.52) for a macrolide-free regimen.1 The mean rate of sputum conversion associated with prolongation of therapy beyond 12 months was only 22% (95% CI, 1-44%).

Among the conclusions that can be reached from the results of these and other studies regarding pulmonary MAC disease is that treatment, especially in the absence of administration of a macrolide, frequently fails to eradicate the organism. Furthermore, persistence of MAC in respiratory secretions, with or without treatment, is associated with radiographic progression.

While one could consider current regimens for the treatment of pulmonary MAC to be frequently, at best, minimally ineffective, lack of treatment appears to be worse. Thus, Park and colleagues examined the radiographic changes by computerized tomography of 40 untreated patients, with the nodular bron-chiectatic form of MAC pulmonary infection over a mean of 6.2 years.2 Most were minimally symptomatic. Significant worsening occurred in 39 (97.5%) of the patients.

REFERENCES

  1. Pasipanodya JG, Ogbonna D, Deshpande D, et al. Meta-analyses and the evidence base for microbial outcomes in the treatment of pulmonary Mycobacterium avium-intracellulare complex disease. J Antimicrob Chemother 2017;72(suppl_2):i3-i19.
  2. Park TY, Chong S, Jung JW, et al. Natural course of the nodular bronchiectatic form of Mycobacterium avium complex lung disease: Long-term radiologic change without treatment. PLoS One 2017;12:e0185774.