Are Echinocandins Superior in Efficacy to Azoles?

To the Editor—Dr. Andes provided a very thoughtful editorial commentary on the latest of 10 published, randomized controlled trials (RCTs) comparing drug regimens for the treatment of disseminated candidiasis [1]. These 10 RCTs, published between 1994 and 2019, have compared polyene, azole, and echinocandin regimens. Nine of the 10 RCTs concluded noninferiority of the regimens; the latest trial is the first to achieve a “superiority” conclusion [2]. Dr. Andes summarized the conclusions of the societal guidelines on this disease, based on meta-analyses of prior RCTs, which is that echinocandins are superior in efficacy to azole-based therapy. Although I understand why this may be believed, I remain confused about 3 related questions on this topic.

First is the importance of the superior rate of clinical cure for echinocandins at the end-of-therapy time point mitigated by the lack of difference 2 weeks later [2]? In an era of crushing healthcare costs, does a difference in “cure” (which is hard to define objectively) at end of therapy but not shortly thereafter justify thousands of dollars of additional healthcare expenditures per patient for an echinocandin versus fluconazole?

Second, is there a mortality difference between echinocandin and azole therapy for disseminated candidiasis? Mortality was not different between the 2 arms in the most recent trial [2]. Dr. Andes indicated a nonsignificant trend to reduced mortality in the echinocandin arms in meta-analysis of the prior RCTs, driven primarily by 1 study comparing anidulafungin to fluconazole, in which there was a clear center effect [3]. Because there was no mortality difference in the new RCT, it would be interesting to know how adding it to the meta-analysis would alter the conclusion. Would it make that trend dissipate, particularly at later time points, or reinforce it?

Third, what is the biological basis of echinocandin superiority? One may be tempted to think it is superior microbiological killing of the cidal echinocandin versus static azoles, despite the recent debunking of the very concept of static versus cidal therapies [4]. Consistent with that debunking, in the current and all prior RCTs, there was no difference in rate of clearance of fungemia between any of the arms, so that cannot be the biological basis of clinical superiority. I worry about biological plausibility of a superiority conclusion given virtually identical rates of microbiological clearance, particularly in light of the fact that all RCTs to date have failed to conclude superiority on the most important objective endpoint, mortality.

Overall, I understand and potentially even agree with the belief that echinocandins may be superior. But I wonder if the fact that clinical cure does not differ at later time points, mortality does not differ, and clearance of fungemia does not differ might give pause to a mandate that echinocandins are superior in efficacy and must be used first-line for all patients. Perhaps a more nuanced approach to the question could be considered in the next iteration of societal guidelines.

Note

Potential conflicts of interest. In the last 12 months, B. S. has received consulting fees from Alexion, Paratek, TheoremDx, Acurx, Shionogi, and Merck, and owned equity in Motif, BioAIM, Mycomed, and ExBaq. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.