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Anidulafungin: a New Addition to the Antifungal Armamentarium

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Anidulafungin: a New Addition to the Antifungal Armamentarium DRUG EVALUATION Anidulafungin: a new addition to the antifungal armamentarium John Mohr1† & Invasive fungal infections continue to be associated with high rates of morbidity and Luis Ostrosky-Zeichner1,2 mortality, primarily in the immunocompromised hosts. Candida and Aspergillus are the †Author for correspondence most common causes of invasive fungal disease; however, other fungi can also cause disease 1University of Texas Health Science Center Houston, in humans. Current therapeutic options for the management of invasive fungal infections Department of Infectious include the polyenes, triazoles and echinocandins. Anidulafungin is a new echinocandin Diseases, 6431 Fannin, antifungal drug with a favorable toxicity profile and minimal drug–drug interactions that MSB 2.112, Houston, TX 77030, USA has activity against Aspergillus and Candida, including azole-resistant strains. Tel.: +1 713 500 6742; Fax: +1 713 500 5495 E-mail: john.mohr@ uth.tmc.edu Despite large advances in the development of bone marrow transplant or in those patients with 2Tel.: +1 713 500 6734; Fax: +1 713 500 5495; antifungal drugs, invasive fungal infections con- cerebral involvement, the case fatality rate E-mail: luis.ostrosky- tinue to contribute greatly to the overall morbid- increases to nearly 90% [6]. [email protected] ity and mortality in immunocompromised With the widespread use of azoles in the man- patients [1]. Candida has been associated with a agement and prevention of fungal infections, there wide spectrum of disease, ranging from catheter- has been a shift towards an increase of non-albi- associated infections to disseminated, deep cans Candida species, primarily Candida glabrata, organ disease [2]. While hematological malignan- which has reduced susceptibility to the azoles [7]. cies and solid organ transplants are well estab- In addition, the use of azoles in prophylaxis of lished risk factors for fungal infections, fungal infections in high-risk patients has shifted prolonged stay in the intensive care unit, the the epidemiology towards invasive molds, such as presence of central venous catheters, prolonged Aspergillus. Newer antifungal agents with activity broad spectrum antibiotics, parenteral nutrition, against a broad spectrum of fungi and favorable recent surgery (particularly intra-abdominal sur- safety profiles are needed. Anidulafungin (Eraxis®, gery), diabetes, hemodialysis and pancreatitis Pfizer Inc., NY, USA) is the newest addition to the have also been identified as risk factors for inva- antifungal armamentarium, which has a broad sive candidiasis [3]. Oropharyngeal/esophageal spectrum of activity to include Aspergillus and candidiasis is the most common opportunistic Candida species (including fluconazole-resistant infection in patients with HIV, occurring in one strains) and a favorable safety and drug–drug in five infected patients. In addition, Candida interaction profile. has become the fourth most common cause of nosocomial-bloodstream infections with an Overview of the antifungal market attributable mortality as high as 40% [1,4]. There have been a large number of new antifun- Aspergillus is ubiquitous mold found in the gal drugs that have emerged since fluconazole environment capable of causing invasive fungal was US FDA approved in 1990. Currently, there infections in nearly every organ in the immuno- are four FDA-approved triazole antifungals avail- compromised host. However, the pulmonary able in the USA: fluconazole (Diflucan®, Pfizer system is most commonly affected [5]. The inci- Inc., NY, USA), itraconazole (Sporonox®, Ortho dence of invasive aspergillosis varies by the Biotech, NJ, USA), voriconazole (Vfend®, underlying host factors; however, it can occur in Pfizer, Inc., NY, USA) and posaconazole (Noxa- as many as 25% of patients with acute leukemia fil®, Schering-Plough, NJ, USA). Generally or undergoing lung transplantation [5]. In speaking, fluconazole has the narrowest spec- patients undergoing hematopoetic stem cell trum of activity, followed by itraconazole and Keywords: anidulafungin, transplantation (HSCT), especially those who voriconazole, which increase in spectrum to Aspergillus, Candida, echinocandins develop Graft-versus-host disease, Aspergillus has include Aspergillus, and finally posaconazole, emerged as a problem pathogen. The overall which has the activity of itraconazole and vorico- part of mortality rate of patients with invasive aspergil- nazole with the additional spectrum to include losis is 60%; however, in patients undergoing the Zygomycetes, such as Rhizopus and Mucor. 10.2217/14750708.4.2.125 © 2007 Future Medicine Ltd ISSN 1475-0708 Therapy (2007) 4(2), 125–132 125 DRUG EVALUATION – Mohr & Ostrosky-Zeichner In addition to the triazoles, polyenes have also Since eukaryotic cells do not have cell walls, the been used to manage invasive fungal infections. direct cellular toxicity seen with the polyenes is The polyenes include amphotericin B and the absent with the echinocandins. In addition, lipid formulations amphotericin B lipid com- organisms that are resistant to the polyenes and plex (ABLC; Abelcet®, Enzon, NJ, USA), azoles may be susceptible to the echinocandins. amphotericin B colloidal dispersion (ABCD; Amphotec®, Three Rivers Pharmaceuticals, PA, Microbiology USA) and liposomal amphotericin B (LAmB; Interpretive breakpoints for anidulafungin have Ambisome®, Astellas Pharma US, Inc., IL, not been established by the Clinical and Labora- USA). The polyenes are the broadest spectrum tory Standard Institute (CLSI). The in vitro fungicidal compounds available in the antifun- activity of the anidulafungin may be related to gal armamentarium; however, any pharmaco- the β-glucan content of the organism [11]. Anid- logical advantage of amphotericin B is ulafungin has potent in vitro activity against overshadowed by the high rates of nephrotoxic- Candida albicans, C. glabrata, Candida tropicallis ity and infusion-related reactions. Although the and Candida krusei as well as Aspergillus fumiga- lipid formulations have a lower rate of nephro- tus. Although anidulafungin maintains potent toxicity than the deoxycholate formulation, the in vitro activity against strains of C. glabrata that lipid formulations still have higher rates of have elevated minimum inhibitory concentra- nephrotoxicity when compared with the azoles tions (MICs) to caspofungin, the clinical signifi- or the echinocandins [8,9]. cance of this finding is unknown [12]. The The echinocandins are the most recent class MIC50 and MIC90 for Candida parapsilosis is 2 of drugs to be added to the antifungal arma- and 4 µg/ml, respectively [13]. The higher MIC’s mentarium. Caspofungin acetate (MK991, with C. parapsilosis is consistent with what is Cancidas®, Merck & Co., Inc, NJ, USA), observed with caspofungin and micafungin, and micafungin sodium (FK463, Mycamine®, the clinical relevance is not known [14,15]. In Astellas Pharma US, Inc., IL, USA) and anidu- addition, anidulafungin does not demonstrate lafungin (LY303366, VER002, Eraxis®, Pfizer in vitro activity against Cryptococcus neoformans, Inc.) are the three currently FDA-approved Fusarium spp., Rhizopus spp. or Mucor spp. [16]. echinocandins available in the USA. All three Anidulafungin demonstrates variable activity agents have similar spectrums of activity and against Blastomyces dermatitidis and Hispt- toxicity profiles; however, they have slightly ospasma capsulatum with MICs of 2–8 and different pharmacokinetic profiles. Anidu- 2–4 µg/ml, respectively [17]. lafungin received FDA approval on February 21, 2006, for the treatment of Pharmacokinetics esophageal candidiasis and candidemia with A summary of the pharmacokinetic properties other forms of Candida infections, including of anidulafungin is presented in Table 1. Anidu- intra-abdominal abscess and peritonitis. lafungin is only available as a parenteral product. Upon intravenous injection, it is rapidly taken Introduction to anidulafungin up into the tissues after administration and then Chemistry slowly eliminated with a half-life of approxi- Anidulafungin is a semisynthetic lipopeptide mately 24 h [18,19]. The overall volume of distri- synthesized from a fermentation byproduct of bution of anidulafungin is between 30 and 50 l, Aspergillus nidulans (Figure 1). Unlike the pol- which is similar to total body fluid volume. yenes and azoles, which exert their antifungal Unlike micafungin and caspofungin, anidulafun- activity on the fungal cell membrane, anidu- gin is not metabolized by the liver. Instead, anid- lafungin acts by inhibiting the formation of ulafungin undergoes slow chemical degradation (1,3)-β-D-glucan, an integral component of the into a chemically inactive peptide whereby the fungal cell wall. The inability of the fungi to cleaved ring products are further broken down cross link (1,3)-β-D-glucan and (1,6)-β-D-glu- into peptidic degradants and eliminated [18]. The can results in loss of structural integrity of the majority of the excreted anidulafungin is through cell wall, resulting in rapid fungicidal activity the feces, with 10% excreted as intact drug and against Candida and fungistatic activity against less than 1% of the dosage eliminated in the Aspergillus [10]. The selective effects on the cell urine. The average dose for anidulafungin is wall rather than the cell membrane of the fungi 50–100 mg/day after a 100–200 mg loading are advantageous to the echinocandin class. dose, depending on the indication. Dosage 126 Therapy (2007) 4(2) futurefuture sciencescience groupgroup Anidulafungin
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