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The Use of Combination Antifungal Therapy is Not a Black and White Issue

The use of combination antifungal therapy for invasive mold diseases is a very grey area that remains to be supported by robust data and relies on the clinician’s assessment of the patient. This unclear landscape was exemplified at a Meet-the-Professor session at the annual ID Week meeting held this year in San Diego, California, convened to debate the pros and cons of the issue. The black and white nature of the pro-con format was discarded from the get-go.

In the real-world clinical practice, the tests ordered at the time of the initial consultation can take 1 to several days to process. The patient can’t be in a vacuum during this time; action is necessary. Should mono- or combination therapy be used? If the former, which one and when to evaluate the effects and if necessary switch to another drug? If the latter, which combination and for how long? These are decisions that need to be informed by data.

Herein lies the dilemma, according to Dimitrios P. Kontoyiannis, MD, from the University of Texas MD Anderson Cancer Center, Houston, Texas. “There are no quality data of how to manage breakthrough mold infections in 2017. Most important decisions affecting outcomes are made pre-emptively,” he said.
The data for combination studies involving opportunistic mold infections lags behind other fields, such as cryptococcal meningitis. The first prospective randomized, double-blind, placebo-controlled trial for a combination therapy (voriconazole + anidulafungin) was only published in 2015. While “historic,” the trial was underpowered to reach statistical significance.

Current guidelines recommend primary prophylaxis using monotherapy with a mold-active azole for patients with acute myeloid leukemia and those with infections that occur following allogeneic hematopoietic stem cell transplantation. Reflecting the paucity of trial data, guidelines are appropriately vague when it comes to combination therapy. Getting clinical trial data for patients with breakthrough mold infections is not feasible. Nor do guidelines address this patient population.

Trials and guidelines focus on homogenous, lower-risk populations. The real-life situation is all about diagnostic uncertainty, comorbidities, prior exposure to mold-active agents, co-infections, and advanced stages of underlying diseases.

“We need to think like a microbiologist by considering a spectrum of pre-existing antifungals and biomarker data, like a pharmacologist by considering adequate pharmacokinetics and pharmacodynamics for the offending fungus, like an epidemiologist by considering the most likely pathogen and the potential for resistance, and like an oncologist by staging the disease and gearing treatment to the stage. But above all, think like an infectious disease doctor,” said Dr. Kontoyiannis.

Big advances in treatment can