Posaconazole: An extended-spectrum triazole antifungal agent

doi:10.1016/j.clinthera.2007.09.015

Clinical Therapeutics

Volume 29, Issue 9, September 2007, Pages 1862-1886

https://doi.org/10.1016/j.clinthera.2007.09.015 Get rights and content

Abstract

Background: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent.

Objective: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections.

Methods: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592. Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site.

Results: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%).

Conclusions: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.

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Posaconazole: An extended-spectrum triazole antifungal agent

Abstract

J Infect

Clin Microbiol Infect

Infect Dis Clin North Am.

Infect Dis Clin North Am.

Bioorg Med Chem Lett

Diagn Microbial Infect Dis

Clin Microbial Infect

Eur J Pharm Biopharm

J Chromatogr A

Eur J Pharm Sci

Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study [published corrections appear in Clin Infect Dis. 2004;39:1093 and Clin Infect Dis. 2005;40:1077]

Clin Infect Dis.

Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990

J Infect Dis

Emerging fungal pathogens

Eur J Clin Microbiol Infect Dis

Developments in the treatment of candidiasis: More choices and new challenges

Expert Opin Investig Drugs

Schering-Plough news release. Schering-Plough announces FDA approval of NOXAFIL ® (posaconazole) for prevention of invasive fungal infections

NoxaFil ® [package insert]

A new, broad-spectrum azole antifungal: Posaconazole-mechanisms of action and resistance, spectrum of activity

Mycoses

Three-dimensional models of wild-type and mutated forms of cytochrome P450 14alpha-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding

Antimicrob Agents Chemother

Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil)

Drug Metab Dispos

Posaconazole is a potent inhibitor of sterol 14alpha-demethylation in yeasts and molds

Antimicrob Agents Chemother

Reference method for broth dilution antifungal susceptibility testing of yeasts

Reference method for broth dilution antifungal susceptibility testing of filamentous fungi

In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts

Antimicrob Agents Chemother

Head-to-head comparison of the activities of currently available antifungal agents against 3378 Spanish clinical isolates of yeasts and filamentous fungi

Antimicrob Agents Chemother

In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole

Antimicrob Agents Chemother

In vitro activities of posaconazole (Sch 56592) compared with those of itraconazole and fluconazole against 3685 clinical isolates of Candida spp. and Cryptococcus neoformans

Antimicrob Agents Chemother

Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000

J Clin Microbial

Antifungal susceptibility survey of 2000 bloodstream Candida isolates in the United States

Antimicrob Agents Chemother

In vitro activities of voriconazole, posaconazole, and four licensed systemic antifungal agents against Candida species infrequently isolated from blood

J Clin Microbial

Genotypic variation and antifungal susceptibilities of Candida pelliculosa clinical isolates

J Med Microbial

In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents

J Clin Microbial

Global trends in the antifungal susceptibility of Cryptococcus neoformans (1990 to 2004)

J Clin Microbial

In vitro susceptibilities of cerebrospinal fluid isolates of Cryptococcus neoformans collected during a ten-year period against fluconazole, voriconazole and posaconazole (SCH56592)

Mycoses

Antifungal susceptibility of 596 Aspergillus fumigatus strains isolated from outdoor air, hospital air, and clinical samples: Analysis by site of isolation

Antimicrob Agents Chemother

A comparative study of the in vitro susceptibilities of clinical and laboratory-selected resistant isolates of Aspergillus spp. to amphotericin B, itraconazole, voriconazole and posaconazole (SCH 56592)

J Antimicrob Chemother

Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphoteritin B against 448 recent clinical isolates of filamentous fungi

J Clin Microbiol

Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergiflus spp. and other filamentous fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000

Antimicrob Agents Chemother

Susceptibility testing of sequential isolates of Aspergillus fumigatus recovered from treated patients

J Med Microbial

In vitro activities of four novel triazoles against Scedosporium spp

Antimicrob Agents Chemother

In vitro activities of new and conventional antifungal agents against clinical Scedosporiurn isolates

Antimicrob Agents Chemother

In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of Zygomycetes

Antimicrob Agents Chemother

Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: Correlation with galactomannan antigenemia

Antirnicrob Agents Chemother

SCH56592 treatment of murine invasive aspergillosis

J Antimicrob Chemother

Experimental pulmonary aspergillosis due to Aspergillus terreus: Pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B

J Infect Dis

Efficacy of SCH56592 in a rabbit model of invasive aspergillosis

Antimicrob Agents Chemotker

Efficacy of posaconazole in a murine model of central nervous system aspergillosis [published correction appears in Antimicrob Agents Chemother. 2004;48:4931]

Antimicrob Agents Chemother