Echinocandins

Echinocandins are fatty acid derivatives of cyclic hexapeptides and consist of a diverse family of lipopeptides including caspofungin, micafungin, and anidulafungin. Echinocandins are noncompetitive inhibitors of the (1,3)-P-d-glucan synthase (Morrison, 2006; Turner et al., 2006; Randhawa & Sharma, 2004). Fungistatic effects result from blockage of cell wall synthesis that reduces cell growth and fungicidal effects result from loss of cell wall integrity, loss of mechanical strength and inability to resist intracellular osmotic pressure. Caspofungin acetate (MK-991, L-743,872) is a semisynthetic water soluble lipopeptide produced from the fermentation products of the fungus Glarea lozoyensis as a derivative of pneumo-candin B0 (Figure 4.2). It has been approved to treat IA patients unresponsive or intolerant to conventional antifungal therapy in the USA (2001) and Europe (2002) (Letscher-Bru & Herbrecht, 2003). The fungicidal and fungistatic activities of caspofungin have been demonstrated in Candida spp. and Aspergillus spp., respectively (Espinel-Ingroff, 2003) (Table 4.1). MIC values range is 0.015-4 mg/L depending on the species (Randhawa & Sharma, 2004; Perea et al., 2002b). The drug selectively acts on the extremities of hyphae, which are the sites of cell wall synthesis essential for fungus apical growth (Kurtz & Douglas, 1997; Hossain et al., 2003).

The drug is active against cystic P. carinii in animals (Morrison, 2006). Caspofungin is active against Paecilomyces variotii (MIC > 0.5 mg/L) and Scedosporium apiospermum but not against Paecilomyces lilacinus (MIC 3100 mg/L) or S. prolificans, (Pfaller et al., 1998b). Furthermore, it is active against rare molds such as Acremonium, Curvularia, Bipolaris, Trichoderma and Alternaria (Kahn et al., 2006). The proposed susceptibility breakpoint for the drug against Candida spp. is at MIC <1 |g/mL. The drug is metabolized by peptide hydrolysis and N-acetylation to inactive metabolites in the liver without the involvement of the

HO

caspofungin

HO pH

HO pH

Figure 4.2 Echinocandins. (A) Caspofungin, (B) Micafungin micafungin

Figure 4.2 Echinocandins. (A) Caspofungin, (B) Micafungin

Table 4.1 Antifungal activity of the echinocandin

Highly active Very active Some activity

Inactive

C. albicans C. parapsilosis Coccidioides immitis

C. glabrata C. gulliermondii Blastomyces dermatididis

C. tropicalis C. lusitaniae Scedosporium spp.w

C. krusei A. fumigatus Paecilomyces variotii

C. kefyr A. flavus Histoplasma capsulatum

Pneumocystis A. terreus

Zygomycetes Cryptococcus neoformans Fusarium spp. Trichosporon spp.

carinii*

* Only active against cyst form, and probably only useful for prophylaxis.

CYP450 system (Sandhu et al., 2004; Keating & Jarvis, 2001). The efficacy of caspofungin is similar to that of AMB with successful outcome in 73.4% of patients treated with caspofungin versus 61.7% in those treated with AMB. Caspofungin was as effective as AMB in patients who had candidemia with favorable responses in 71.7% and 62.8% of patients, respectively (Mora-Duarte et al., 2002). The efficacy and safety of caspofungin (50 mg) versus fluconazole (200 mg IV) as assessed in adults with esophageal (EC) (Villanueva et al., 2001a, b) was 81% favorable response in patients treated with caspofungin versus 85% in patients treated with fluconazole. Combining voriconazole with caspofungin can extend the survival rate in patients with aspergillosis unresponsive to initial AMB therapy by —3 months (Marr et al., 2004).

Micafungin sodium (FK463) C56H70N9NaO23S (Figure 4.2), is isolated from cultured Coleophoma empedri. It is fungicidal against C. albicans, C. glabrata, C. krusei, and C. tropicalis where most isolates exhibit MICs in the range of 0.030.06 |ig/mL (Ostrosky-Zeichner et al., 2003). Higher MIC values have been reported for C. lusitaniae, C. guilliermondii, and C. parapsilosis (Takakura et al., 2004; Espinel-Ingroff, 2003). Micafungin is fungistatic against Aspergillus spp. (Turner et al., 2006; Matsumoto et al., 2000; Mikamo et al., 2000; Uchida et al., 2000). The relationship of AUC to micafungin is linear over a daily dose range of 50-150 mg, 3-8 mg, or 12.5-200 mg/kg body weight (Chandrasekar and Sobel, 2006; Hiemenz et al., 2005; Carver, 2004). Apparent clearance is 0.150.53 mL/min/kg body weight and apparent volume of distribution is 0.33-0.79 L/kg body weight (Hiemenz et al., 2005). It is metabolized to M-1 (catechol) by arylsul-fatase with further metabolism to M-2 (methoxy) by catechol-O-methyltransferase; M-5 that forms by hydroxylation at the side chain ra-1 position is catalyzed by CYPP450 isozymes. Whereas the average ratio of metabolite to parent exposure AUC at a dose of 150 mg/day is 6% M-1, 1% M-2 and 6% M-5, it is 11% M-1, 2% M-2, and 12% M-5 in patients with EC (Chandrasekar and Sobel, 2006).

Micafungin administered once daily in HIV patients with EC has yielded a side effects-free clinical response rate of 33% at 12.5 mg dose, 54% at 25 mg dose, — 85% at 50-75 mg dose and 95% at 100 mg dose (Pettengell et al., 2004). Treatment of HIV patients with EC using micafungin at 50, 100 and 150 mg/day compared to fluconazole at 200 mg/day IV-infused once daily for 14-21 days resulted in a response rate of 68.6% at 50 mg, 77.4% at 100 mg and 89.8% at 150 mg versus 86.7% for fluconazole (De Wet et al., 2004, 2005). The overall success rate in a study which has compared micafungin at 50 mg IV daily dose and fluconazole at 400 mg IV daily dose in SCT patients receiving either syngeneic or allogeneic cells was 80.7% and 73.7%, respectively (Van Burik et al., 2004). Linear pharmacokinetics and increased clearance occurred in neutropenic pediatric patients receiving a dose of 0.5-4.0 mg/kg/day (Seibel et al., 2005). IV infusion of 12.5-150 mg/day micafungin for up to 56 day in patients with Aspergillus- or Candida spp.-induced deep-seated mycosis resulted in clinical response rates of 60% in IPA patients, 67% in patients with chronic necrotizing PA, 55% in those with PA, 100% in candidemics and 71% in those with EC (Kohno et al., 2004).

Anidulafungin (LY303366, V-echiniocandin), approved for clinical use by the FDA in early 2006, consists of the echinocandin nucleus with a terphenyl head and a C5 tail (Figure 4.2). Anidulafungin MIC values for C. parapsilosis, C. famata, and C. guillermondii are relatively higher (<0.03-4 |ig/mL) than those for other Candida spp. (Pfaller et al., 2005; Pfaller, 2004; Uzun et al., 1997; Zhanel et al., 1997; Cuenca-Estrella et al., 2000). Combinations of fluconazole with caspofungin or anidulafungin produced different but not antagonistic effects against isolates of C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. neoformans (Roling et al.,

2002). Anidulafungin has a minimum effective concentration of 0.02 mg/mL for 90% of clinical isolates and an MIC90 of 10.24 mg/mL against Aspergillus spp. (Zhanel et al., 1997). Excellent activity has been observed against Aspergillus spp., Penicillium spp., and Curvularia spp. (Messer et al., 2004; Espinel-Ingroff,

2003). Although, traces of the drug or its degradation products can be detected in human and animal urine; most degradation products pass into feces via bile (Vazquez and Sobel, 2006). In humans, anidulafungin exhibits linear pharmacokinetics after a single oral dose of 100-1,000 mg. The drug is well tolerated at doses of up to 700 mg with adverse gastrointestinal effects defining the maximal tolerated dose (Pfaller, 2004; Chiou et al., 2000; Vazquez & Sobel, 2006; Vazquez, 2005). In a randomized study that compared the efficacy and safety of IV anidulafungin to that of oral fluconazole in AIDS patients with EC, success rate in anidulafungin-treated patients was 97.2% with 9.3% of patients showing side effects (Krause et al., 2004a). Patients with IC or candidemia who received 3 IV regimens of 50, 75, or 100 mg anidulafungin once daily for 2 weeks beyond resolution or signs of improvement, showed EOT success rates of 84%, 90%, and 89%, respectively (Krause et al., 2004b).

Aminocandin (HMR 3270, IP-960) is active against C. albicans, non-albicans Candida spp., and Aspergillus spp. Aminocandin at the dose of >1.0 mg/kg/day is as effective as AMB in improving survival and reducing organ fungal burden in immunocompromised mice with disseminated C. tropicalis (Warn et al., 2005). In mice with Candida spp. infections (C. glabrata, C. guillermondii, or C. tropicalis), it can reduce kidney fungal burden at doses 20-50 mg/kg making it superior to fluconazole (Turner et al., 2006). The degree of protein binding is >99% in both mice and humans (Andes et al., 2003a).

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