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.

Infectious disease thinking means starting with a treatment having activity to the target fungi with the option of changing the class of drug if necessary, beginning treatment early, and being aware of co-morbidities.

When faced with a breakthrough mold infection, considering combination therapy can be prudent. The odds are that the offending mold is more resistant and/or virulent. Prompt action is needed, as breakthrough does not bode well for the patient’s prognosis. And, combination therapy can be less toxic than higher doses of 1 drug. “In the optimal scenario, a cautious early pre-emptive use of combination therapy with early re-evaluation seems the most logical and theoretically plausible in real-life,” said Dr. Kontoyiannis.

“I’m not really against combination therapy. And I agree that the clinical data does not reflect real-life. I have done thousands of clinical consults and no 2 have ever been the same. Yet, we have created homogenized patient populations, which makes if very challenging to gain insights on therapy in the face of such variability,” said Lindsey Baden, MD; Infectious Disease, Brigham & Women's Hospital, Boston, Massachusetts.

Gleaning insights from the existing data—knowing that it has largely been based on homogeneous patient populations—that can be fruitfully applied to the decidedly non-homogeneous patients who are a fact of everyday life is challenging. Nonetheless, some important information can be gleaned. Acting sooner rather than later is best. Using more drug is not necessarily good, as that can breed toxicity.

Given these considerations, Dr. Baden argued that combination therapy may have a role to play. “It can manage diagnostic uncertainty and lessen the concern for antifungal resistance. The lower dose of agents can minimize toxicity or shorten the antimicrobial course. And synergistic activity can improve clinical outcome, although there is very limited in vivo data,” said Dr. Baden. On the other hand, potential harms of the combination approach include drug antagonism or interaction, and increased treatment cost.

It is worth considering what we are trying to achieve with combination therapy, according to Dr. Baden. A current treatment like azole-based treatment has a success rate of 60%-80%. That may be near the top end, given that there always be some patients for whom treatment fails. “We have about a 10%-20% margin to work with. So, a 30%-50% relative benefit of combination therapy means an approximately 3%-10% absolute benefit in a very noisy model,” he explained.

Dr. Baden also stressed the need to remember that treating a fungal disease means treating the underlying reason for the disease, not just the disease itself. Initiatives directed at aspects including nutrition and other co-morbid conditions can pay off in terms of future infections.

DISCLOSURES

Dimitrios P. Kontoyiannis: Pfizer: Research Contractor, Research support, and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium

Lindsey Baden: none

PRESENTATIONS

MEET-THE-PROFESSOR SESSION Combination Antifungal Treatment for Mold Infections: Pros and Cons

Combination Antifungal Treatment for Mold Infections: Pros

Dimitrios P. Kontoyiannis, MD, ScD, PhD (Hon), FACP, FIDSA, FECMM, FAAM, The University of Texas MD Anderson Cancer Center, Houston, TX

Combination Antifungal Treatment for Mold Infections: Cons

Lindsey Baden, MD, Brigham & Women's Hospital, Boston, MA

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.