Posaconazole: Use in the Prophylaxis and Treatment of Fungal Infections

Abstract

Posaconazole, a fluorinated triazole antifungal drug, is approved by the U.S. Food and Drug Administration (FDA) for (1) prophylaxis against Aspergillus and Candida infections in immunocompromised patients at high risk for these infections and (2) oropharyngeal candidiasis (OPC), including cases refractory to fluconazole and/or itraconazole. The European Medicines Agency (EMA) has approved posaconazole for (1) treatment of aspergillosis, fusariosis, chromoblastomycosis, and coccidioidomycosis in patients who are refractory to or intolerant of other azoles or amphotericin B; (2) first-line therapy for OPC for severe disease or in those unlikely to respond to topical therapy; and (3) prophylaxis of invasive fungal infections in high-risk hematologic patients and stem cell transplant recipients. In addition to approved indications, posaconazole has been used with success as salvage therapy for invasive mold infections and endemic mycoses in patients who are refractory to or intolerant of other antifungal agents, and as prophylaxis or salvage therapy in children, for whom indications are more limited owing to a paucity of data. Posaconazole has potent in vitro activity against a broad range of fungi and molds, including Aspergillus, Candida, Cryptococcus, filamentous fungi, and endemic mycoses including coccidioidomycosis, histoplasmosis, and blastomycosis. Importantly, posaconazole is much more active than other azoles against many Mucorales species and the combination of posaconazole with other antifungal agents may be synergistic. Hence, posaconazole is a potential candidate as a single or combination agent for difficult-to-treat fungal infections. Posaconazole has an excellent safety profile; to date, serious side effects are rare, even with prolonged use. However, newer posaconazole formulations achieve higher blood levels and it remains to be seen whether this may lead to an increase in the rate of adverse effects. Currently, posaconazole is used predominantly for prophylaxis and salvage therapy of fungal infections in adults. Indications for use as initial therapy of fungal infections and for broader use in children will depend on the accrual of additional clinical data.

Clinical Appearance of Oral Candida Infection and Therapeutic Strategies

“…The other antifungals, echinocandins, and flucytosine act through inhibition of D -glucan synthase and DNA/protein synthesis, respectively ( Muir et al, 2009 ; Vandeputte et al, 2012 ). Posaconazole, is available only as an oral solution and is used in immunocompromised patients and patients resistant to other drugs ( Clark et al, 2015 ).…”

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

“…Posaconazole was synthesized at Schering–Plough (currently Merck). The daily dosage is 800 to 1200 mg, duration of therapy can be more than 1 year (Clark et al , 2015; Keating, 2005). Posaconazole is the broadest spectrum azole antifungal available, with activity against Aspergillus , Candida , Cryptococcus , zygomycota, endemic mycoses, and some agents of hyalohyphomycosis (Kauffman et al , 2007).…”

“…Posaconazole is the broadest spectrum azole antifungal available, with activity against Aspergillus , Candida , Cryptococcus , zygomycota, endemic mycoses, and some agents of hyalohyphomycosis (Kauffman et al , 2007). Yet it is mostly used for prophylaxis in immunosuppressed patients at high risk for invasive fungal infections and for salvage therapy in cancer patients (Clark et al , 2015). Kreiter et al report that after a single oral dose of 400 mg a median posaconazole peak plasma concentration of 0.9 µM was achieved in 10 hours, and the drug was still detectable within 183 hours (Krieter et al , 2004).…”

“…Li et al found that after a single dose of 800 mg maximal plasma level of posaconazole was reached at 6 hours, varying from 1.8 µM (high-fat meal) to 0.5 µM (fasting) (Li et al , 2010). Because higher posaconazole concentrations are generally associated with improved treatment response [for example, patients with a mean plasma concentration of 1.25 µg/mL had a 75% response rate, whereas patients with mean concentrations of 0.41 to 0.72 µg/mL and 0.13 µg/mL had response rates of 53 and 24%, respectively], a plasma concentration greater than 1.25 µg/ml (1.8 µM) has been suggested as a conservative target (Clark et al , 2015; Walsh et al , 2007). The PK values reported in mice also vary.…”

The Outcome of Antifungal Prophylaxis with Posaconazole in Patients with Acute Myeloid Leukemia: A Single Center Study

“…The use of mold-specific prophylaxis has increased in recent years, particularly in AML patients, because of the high mortality rate of IFIs [ 1 , 2 , 3 ]. Posaconazole has been recommended as the drug of choice for AML patients undergoing induction chemotherapy based on the results of randomized controlled trials [ 4 , 5 , 6 , 7 , 8 ].…”