Is there a role for dual antibiotic treatment with ethambutol and macrolide only, as opposed to three-drug antibiotic therapy, in the treatment of treatment-naive pulmonary MAC without cavitary disease?

That is a great question, as the role of rifampin (or rifabutin) regarding its relative contribution to the treatment of MAC is not overly clear. Historic data that is a few decades old raised the possibility of better activity when a rifamycin is combined with ethambutol (at least in vitro and further protection from the evolution of drug resistance); however, to my knowledge, this has not really been shown in clinical practice. To address the specific question of 2 versus 3 drugs for the treatment of pulmonary MAC, there is a current, active multi-center clinical trial evaluating 3 drugs (macrolide + rifampin or rifabutin + ethambutol) compared to a 2-drug program of macrolide/ethambutol for drug-susceptible pulmonary MAC disease.

The sus...

At this time, no. The 2020 multi-society guidelines still recommend rifampin or rifabutin. We have completed enrollment for the MAC2v3 trial, which will help us answer this question more reliably than case reports, small series, and expert pontification.

While it is true that rifamycins do not appear to add much to the anti-MAC treatment regimen (aside from AEs), the large MAC2v3 trial will provide more confidence in that assertion.

That is REALLY helpful, Dr. @Dr. First Last!

When I was in training (1994 era), we saw lots of MAI bacteremia in AIDS patients, and the standard approach was to use 2 drugs: macrolide + Ethambutol. To my memory, I believe there was some data showing that the addition of Rifabutin really did not have benefits.

The most recent DHHS guidelines for disseminated MAI (I'm not changing it to MAC) in AIDS still mention Azith/EMB as the preferred Rx, with the addition of a rifamycin suggested by expert opinion in 'more severe disease.'

So I've always wondered why immunologically more fit hosts with lung disease, not "septicemia" would need three drugs when these AIDS patients should be treated with two drugs.

I'd love to hear more opinions. This wo...

It will be interesting to see the results of the MAC2v3 and ENCORE trials (using Arikayce plus azithromycin and ethambutol in naive patients with non-complicated MAC infection). The data from ARISE is looking compelling!