Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis

gOnly one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 g/ml. AR-12 is also active against azole-and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole-and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

Section: Discussionmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

“…The manufacturers of voriconazole and posaconazole recommend an empirical reduction of one-third in the daily tacrolimus dose; however, in clinical practice the required reduction is often substantially greater (4,5). Isavuconazole acts as both a substrate and inhibitor of CYP3A4 (6)(7)(8). Currently, there are no definitive dosing recommendations for tacrolimus in patients receiving isavuconazole.…”

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confidence: 99%

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid-Organ Transplant Patients

Rivosecchi

Clancy

Shields

et al. 2017

We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.KEYWORDS isavuconazole, drug interactions, pharmacokinetics, tacrolimus, zygomycetes A ntifungal prophylaxis is commonly administered following solid-organ transplant (SOT) to prevent invasive fungal infections (1). Tacrolimus, a primary immunosuppressive agent in SOT, is a substrate of cytochrome P450 (CYP) 3A4. The triazole antifungals are CYP3A4 inhibitors that have varied effects on tacrolimus metabolism (2, 3). The manufacturers of voriconazole and posaconazole recommend an empirical reduction of one-third in the daily tacrolimus dose; however, in clinical practice the required reduction is often substantially greater (4, 5). Isavuconazole acts as both a substrate and inhibitor of CYP3A4 (6-8). Currently, there are no definitive dosing recommendations for tacrolimus in patients receiving isavuconazole. Following a cluster of mucormycosis cases among SOT recipients at the University of Pittsburgh Medical Center (UPMC), universal isavuconazole prophylaxis was instituted (Table 1). The objective of this study was to evaluate the effects of isavuconazole on whole-blood trough tacrolimus concentrations in various SOT populations.We performed a retrospective study of consecutive patients who underwent SOT at UPMC between 15 September 2015 and 10 February 2016 and who were initiated on isavuconazole prophylaxis for Ն21 days. Patients were required to have received tacrolimus, have had follow-up for Ն40 days after isavuconazole was stopped, and have had whole blood tacrolimus concentrations measured during and following isavuconazole prophylaxis. Patients were excluded if they were on tacrolimus or other azoles at the time of transplantation or if they required renal replacement therapy beyond the first 5 days after transplantation.A total of 55 SOT recipients were included (Table 2). Tacrolimus levels were obtained during (n ϭ 1,098) or following (n ϭ 3,080) isavuconazole prophylaxis. Tacrolimus

“…The efficacious animal data combined with a recently conducted single-arm open-label clinical trial of ISA in the treatment of mucormycosis (25) and case-control analysis resulted in the FDA and European Commission approving ISA for treating invasive mucormycosis. In the present study, we wanted to compare the activity of ISA to currently used azoles with respect to protection against mucormycosis in the prophylaxis setting.…”

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confidence: 99%

Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis

Gebremariam

Alkhazraji

Baldin

et al. 2017

We assessed prophylactic or continuous therapy of isavuconazole, posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus delemar. In the continuous treatment studies, isavuconazole and posaconazole, but not voriconazole, equally prolonged survival time and lowered tissue fungal burden compared to placebo-treated mice. These results support the use of isavuconazole and posaconazole in prophylaxis treatment.