Clinical Evidence for Combination Antifungal Therapies for Aspergillosis Remains Scarce

SAN FRANCISCO, CA—Over the past decade, interest in combination therapies for invasive Aspergillus infections has increased; however, clinical evidence supporting these regimens remains insufficient, according to a report at IDWeek 2013.

Along with this interest has come accelerated antifungal drug discoveries, said Dimitrios Kontoyiannis, MD, ScD, Frances King Black Endowed Professor and deputy head of the division of internal medicine at the University of Texas MD Anderson Cancer Center, Houston, TX.

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The use of combination therapy is a common concept for specialists who treat invasive fungal infections in the presence of endocarditis, AIDS, cancer, and transplants. The rationale behind combination therapy is synergy, reduced toxicity, slow emergence of resistance, and improved spectrum of activity and pharmacokinetics.

“Ultimately the goal of combination therapy, as with any therapy, is improved survival,” Dr. Kontoyiannis said.

Currently, the standard of care for Cryptococcus neoformans is amphotericin plus flucytosine (5FC), whereas the evidence for combination vs. monotherapy therapy in Candida species is lacking. There are many in vitro and in vivo studies for Aspergillus species, but sufficiently powered prospective clinical studies are scarce.

Dr. Kontoyiannis presented a clinical overview of studies showcased at a poster session in 2012. These studies looked at the use of combination therapy in invasive fungal infections.

In a study published in the New England Journal of Medicine, Jeremy N. Day, MD, PhD, concluded that combination therapy with amphotericin B plus flucytosine vs. amphotericin B alone (Day 70; HR 0.61 [0.39–0.97]) improved survival among patients with cryptococcal meningitis.

The Combistrat trial was a randomized pilot study of high-dose liposomal amphotericin B vs. low-dose liposomal amphotericin B plus caspofungin for invasive aspergillosis in patients with hematologic malignancies. At the end of treatment, significantly more favorable overall responses were observed in the combination group (67%) compared with the high-dose monotherapy group (27%; P=0.028).

Another trial studied the efficacy of combination voriconazole and caspofungin in patients with invasive aspergillosis in solid organ transplant recipients. In a logistic regression analysis of variables associated with 90-day mortality, when controlled for renal failure and cytomegalovirus infection, patients in the study group were 2.4 times less likely to die within 90 days compared to the control group (OR=0.419; 95% CI, 0.14-1.3). However, the difference was not statistically significant (P=0.12).

The first prospective, randomized 1:1, double-blind, placebo-controlled clinical trial in invasive aspergillosis studied voriconazole plus placebo vs. voriconazole plus anidulafungin in newly diagnosed patients (n=459) with invasive aspergillosis. This study was conducted at 93 sites in 24 countries from July 9, 2008, to May 12, 2011. The primary endpoint was 6-week all-cause mortality.

Results demonstrated that in the modified intent to treat (mITT) population, 19.3% of the patients in voriconazole plus anidulafungin group and 27.5% in voriconazole plus placebo group resulted in death at week 6 (P=0.09). The 8.2% reduction in 6-week mortality was considered clinically meaningful.

Many questions remain to be answered regarding the use of combination antifungal therapies and the clinical evidence to support this decision. In addition, “current clinical trials for invasive aspergillosis may not reflect the patients treated at every institution,” Dr. Kontoyiannis concluded.