Elsevier

Drug Resistance Updates

Volume 6, Issue 4, August 2003, Pages 197-218
Drug Resistance Updates

Caspofungin: the first in a new class of antifungal agents

https://doi.org/10.1016/S1368-7646(03)00064-5Get rights and content

Abstract

Caspofungin is the first approved agent from a new class of antifungals, the echinocandins. By targeting the fungal cell wall (as opposed to the fungal cell membrane), the echinocandins exhibit a unique mechanism of action relative to the other currently approved antifungal agents. Preclinical (in vitro and in vivo) studies have demonstrated activity for caspofungin against the most commonly encountered fungi in the hospital setting, namely Candida and Aspergillus species. Caspofungin is administered as a once-a-day, intravenous formulation. Notably, caspofungin is neither an inhibitor, inducer, nor metabolite of the cytochrome p450 system. To date, few drug–drug interactions have been seen for this echinocandin. A number of Phase II and III clinical studies in documented invasive candidiasis, esophageal candidiasis, and invasive aspergillosis have been completed and have demonstrated efficacy for caspofungin against all three diseases. In all studies, caspofungin manifested an excellent safety profile with few serious, drug-related adverse events or discontinuations due to drug-related adverse events. Isolated symptoms compatible with histamine release have been infrequently reported. In clinical studies, drug-related nephrotoxicity with caspofungin has been rare, and the incidence of liver transaminase elevations has been similar to the incidence seen with comparator agents. Results from a Phase III study as empirical therapy in patients with febrile neutropenia are anticipated in late 2003. Overall, caspofungin represents an important addition to the current antifungal armamentarium.

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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