Caspofungin: the first in a new class of antifungal agents
Introduction
Fungal disease represents a growing threat, particularly to patients with compromised immune systems. Until recently, the number of available classes of drugs to treat serious fungal infections has been somewhat limited. Prior to the last decade, the antifungal armamentarium had been essentially limited to conventional polyenes (amphotericin B, nystatin) and first-generation triazoles (ketoconazole, itraconazole, and fluconazole). Although effective against a broad spectrum of fungal pathogens, the polyene agents have been significantly limited by well-established toxicities. Conversely, fluconazole has exhibited an excellent safety profile but has been predominantly limited to the treatment of yeast infections. Although itraconazole has offered broader triazole coverage for Aspergillus infections and other dimorphic fungi, significant drug–drug interactions and interpatient pharmacokinetic variability have hampered its use. Inherent and acquired resistance has also negatively impacted on the use of the triazoles and other classes of antifungal agents (i.e. flucytosine) (Patterson, 2000, Walsh et al., 2000, Arikan and Rex, 2000, Chiou et al., 2000).
Fortunately, over the last decade, significant advances in the antifungal arena have been realized. Newer lipid formulations of the polyenes have helped to curb the toxicity noted with conventional amphotericin therapy. The availability of an intravenous itraconazole formulation and the development of second-generation triazoles (i.e. voriconazole) have helped to broaden the use of triazoles to treat serious mold infections. Yet, all these recent advances have continued to focus on agents that ultimately impact the same fungal target, the cell membrane (Patterson, 2000, Walsh et al., 2000, Arikan and Rex, 2000, Chiou et al., 2000).
Caspofungin represents the first approved compound from a new class of antifungal agents, the echinocandins. The echinocandins inhibit the synthesis of β-1,3-d-glucan, an essential component of the cell wall of many pathogenic fungi, including Aspergillus and Candida (Fig. 1). As a result of its novel mechanism, the echinocandins should theoretically lack cross-resistance with approved agents. Additionally, the cell wall is a unique target not encountered in mammalian cells, and, as a result, this is anticipated to confer a generally favorable safety profile upon these agents (Patterson, 2000, Walsh et al., 2000, Arikan and Rex, 2000, Chiou et al., 2000). In addition to caspofungin, other investigational echinocandins, including micafungin and anidulafungin, are currently being evaluated in the clinical arena. The following review will focus on caspofungin, which was first licensed in the Unites States in February 2001 and is marketed as CANCIDAS™.
Section snippets
General considerations for cell wall active agents
Several polysaccharide polymers within the cell wall are critical in the maintenance of fungal cellular integrity. As such polymers are not found in mammalian cells, these compounds represent attractive targets for drug development. Small molecule inhibitors known to target synthesis or assembly of these polymers have been available for some time (Tkacz et al., 1992), but only recently has the promise of an antifungal antibiotic that directly affects cell wall synthesis been realized. The
Compound formulation
Caspofungin acetate, originally developed at Merck Research Laboratories as L-743872 and MK-0991, is a semisynthetic lipopeptide derivative of pneumocandin B0, a fermentation product of the fungus, Glarea lozoyensis (Caspofungin Acetate, 2003). This fungus, a dematiaceous hyphomycete, was isolated from the valley of the Lozoya River in northern Spain. The salt of caspofungin acetate is a water-soluble, white to off-white powder, with a molecular weight of 1213.42 Da (Fig. 2). The formulated
Clinical efficacy
To date, Phase II and III clinical studies evaluating the efficacy and safety of caspofungin monotherapy in documented Candida and Aspergillus infections have been completed (Table 1). The results from these studies are summarized below for each fungal infection.
Clinical safety and tolerability
To date, finalized safety data has been collected from a total of 876 individuals who have received single or multiple doses of caspofungin in Merck-sponsored Phase I through Phase III studies. Of the 482 patients who have received caspofungin for the treatment of documented fungal infections, 412 received at least 50 mg per day for a minimum of 7 days. Therapy durations have ranged between 1 and 162 days (Caspofungin Acetate, 2003). In these studies, caspofungin has demonstrated an excellent
Formulary considerations
Caspofungin acetate is currently approved in the United States as a once-daily, parenteral therapy for the treatment of the following indications (Caspofungin Acetate, 2003):
- 1.
Candidemia and the following Candida infections: peritonitis, intra-abdominal abscesses, and pleural space infections;
- 2.
Esophageal candidiasis;
- 3.
Invasive aspergillosis in patients who are refractory or intolerant of other antifungal agents.
For each indication, the standard daily dose in adult patients is 50 mg per day. However,
Use of echinocandin susceptibility testing in clinical practice
Two specific questions are commonly asked with regards to this new class of antifungal agents:
- (1)
Is there a relationship between in vitro susceptibility to echinocandins and the likelihood of in vivo response to this class of compounds?
- (2)
Should the current in vitro susceptibility testing be implemented in clinical practice?
Evidence from the completed clinical trials tend to suggest that in vitro susceptibility method, as currently implemented, is not a useful tool in clinical practice. In vitro
Conclusions
Caspofungin represents the first of a new class of compounds, the echinocandins, to be added to the current antifungal armamentarium. Caspofungin is active against clinically relevant Candida and Aspergillus species. Preclinical activity against Cryptococcus neoformans is poor, and its activity against non-Aspergillus molds has not been clearly established to date. As a result of its unique mechanism of action, caspofungin is not anticipated to manifest cross resistance with the other approved
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