Echinocandins in the Management of Invasive Fungal Infections, Part 1

Abstract and Introduction

Abstract

Purpose. The chemistry, pharmacology, spectrum of activity, resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effiects, drug interactions, dosage and administration, cost, and place in therapy of echinocandins are reviewed.

Summary. Three echinocandins are currently available: caspofungin, micafungin, and anidulafungin. The principal mechanism of action of the echinocandins is the noncompetitive inhibition of β-(1,3)-D-glucan synthase, an essential component of the cell wall of many fungi that is not present in mammalian cells. Echinocandins exhibit fungicidal activity against Candida species, including triazole-resistant isolates, and fungistatic activity against Aspergillus species. While fungistatic against mold, echinocandins may hold promise for the treatment of these pathogens when given in combination with amphotericin B or broad-spectrum triazoles, such as voriconazole. To date, resistance to echinocandins has been reported in only two patients. Echinocandins exhibit concentration- dependent activity against Candida species. In clinical trials, caspofungin has demonstrated efficacy in treating candidemia, esophageal candidiasis, and febrile neutropenia. Micafungin has demonstrated efficacy as antifungal prophylaxis in hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis. Anidulafungin received approved labeling from the Food and Drug Administration in February 2006. Clinical efficacy data will be forthcoming.

Conclusion. Echinocandins are fungicidal against yeast and fungistatic against mold. Their limited toxicity profile and minimal drug-drug interactions make them an attractive new option for the treatment of invasive fungal infections. Their cost may limit their use as initial therapy for patients with fungemia in medical centers or intensive care units with a high rate of triazoleresistant Candida infections.

Introduction

Invasive fungal infections caused by yeast and mold are a growing problem in health care. From 1980 through 1997, invasive mycoses increased from the 10th most common cause of death from infectious diseases to the 7th most common.^[1] The major factors responsible for this increase in fungal infections have been advances in medicine, which have enabled or prolonged the survival of susceptible patients, including those undergoing solid organ and bone marrow transplantation, improved therapeutic outcomes for critically ill patients, and the HIV epidemic.

Candida species are the predominant pathogens associated with nosocomial fungal infections, particularly in the intensive care unit (ICU).^[2] This is further complicated by the emergence of non-Candida albicans species, such as Candida glabrata. A recent study describing the annual incidence of primary Candida bloodstream infections among ICU patients noted that there was a significant increase in the rate of bloodstream infections due to C. glabrata and a decrease in C. albicans-related infections.^[3] This trend is alarming, given that C. glabrata has variable susceptibility to the commonly used antifungal agent fluconazole, which has been a drug of choice for the treatment of Candida infections since its introduction in the early 1990s. A recent review of global trends in species distribution and in vitro susceptibility among 6082 bloodstream isolates of Candida species collected from 250 medical centers in 32 nations over a 10-year period (1992-2001) found that fluconazole resistance among C. glabrata isolates was greatest in the United States and varied by U.S. Census region.^[4] The potential for triazole cross-resistance may limit the clinical utility of second-generation triazoles, such as voriconazole, against this pathogen.^[5] Although fungal infections caused by invasive aspergillosis are not as common as those caused by Candida species, their impact on immunosuppressed patients is on the rise. A retrospective cohort study of 5589 patients who underwent hematopoietic stem cell transplantation (HSCT) over a 15-year period at a large cancer center found that the incidence of invasive aspergillosis had at least tripled among both allograft and autograft recipients.^[6] Every antifungal agent used to treat invasive aspergillosis has issues that limit its use. Amphotericin B deoxycholate, the conventional formulation of amphotericin B that has been the mainstay of treatment since the late 1950s, is notorious for infusion-related adverse effects and nephrotoxicity. While lipid-based amphotericin B formulations have helped to reduce these adverse effects, their acquisition cost may present a problem for some institutions. The secondgeneration triazole antifungal, voriconazole, is highly effective against invasive aspergillosis, but the potential for drug-drug interactions is of concern. Therefore, the introduction of a novel antifungal class, the echinocandins, provides clinicians with another treatment option for these pathogens.

Originally the echinocandins were named pneumocandins because of their in vitro activity against Pneumocystis jiroveci (formerly P. carinii) and Candida species.^[7] The first of these compounds to undergo preclinical evaluation was cilofungin; however, further development was not pursued because of toxicity associated with the i.v. polyethylene glycol formulation vehicle. Caspofungin (Cancidas, Merck & Co.), introduced in 2001, was the first echinocandin to receive marketing approval from the Food and Drug Administration (FDA), followed by micafungin (Mycamine, Astellas Pharma) in March 2005. A third echinocandin, anidulafungin (Eraxis, Pfizer), was approved by FDA in February 2006.

This article reviews the chemistry, pharmacology, spectrum of activity, resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and cost of currently available echinocandins. Their place in therapy is also discussed.

Cite this: Echinocandins in the Management of Invasive Fungal Infections, Part 1 - Medscape - Sep 01, 2006.

Table 1. MIC ₉₀ Values for Common *Candida* Species ^4a
Candida Species	MIC₉₀(μg/mL)
Candida Species	Caspofungin	Micafungin	Anidulafungin
Albicans	0.12-1	0.01-0.25	0.01-0.5
Glabrata	0.25-1	0.01-0.5	0.03-8
Parapsilosis	1-4	1.0->8	2.0->8
Tropicalis	0.12-1	0.03-2	0.06-2
Krusei	0.5-2	0.12-0.25	0.03-1
Lusitaniae	0.5-2	2^b	0.12->8
Guilliermondii	1->8	2	1-4^c

^aMIC₉₀ = minimum inhibitory concentration required to inhibit the growth of 90% of organisms; MIC₅₀ = minimum inhibitory concentration required to inhibit the growth of 50% of organisms.
^bData from only one study.
^cMIC₅₀.

Table 2. Echinocandin Pharmacokinetics
Parameter	Anidulafungin^[25,26,a]	Caspofungin^{[25,27,28,29,b]}	Micafungin^[25,30,31,c]
C _max(μg/mL)	3.5	14-15	22
AUC(μg * hr/mL)	51	119	102^d
V _ss (L/kg)	0.6	0.15	0.2
Half-life (hr)	25.6	9-11	15
Protein bound (%)	84	97	>99

^a100 mg on day 1, followed by 50-mg daily dose.
^b70-mg daily dose.
^c100-mg daily dose.
^dValue for patients who underwent bone marrow transplantation.

Table 3. Adverse Effects of Echinocandins ^a
Adverse Effect	No. (%) Patients
Adverse Effect	Anidulafungin⁵⁷(n = 300)	Caspofungin²⁸(n = 163)	Micafungin³⁰ (n = 260)
Leukopenia	2 (0.7)	10 (6.2)	7 (2.7)
Neutropenia	3 (1.0)	3 (1.9)	3 (1.2)
Nausea	3 (1.0)	10 (6.0)	6 (2.3)
Vomiting	2 (0.7)	2 (1.2)	3 (1.2)
Headache	4 (1.3)	10 (6.0)	7 (2.7)
Fever	2 (0.7)	6 (3.6)	5 (1.9)

^aComparison of adverse effects for all three echinocandins from their respective clinical trial for treatment of esophageal candidiasis where fluconazole was the comparator agent.

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Echinocandins in the Management of Invasive Fungal Infections, Part 1

Abstract and Introduction

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Introduction

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