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Down the Pipeline: Rezafungin, the Once-per-Week Echinocandin

Echinocandins. This is the drug we use mostly on the inpatient side for invasive candidiasis. The most well known is micafungin, but analdafungin is another option that is also commonly used. Besides resistance, the issue with echinocandins are the fact they are intravenous drugs, which makes administration of it easy on the inpatient side but difficult on the outpatient side without a PICC line and a functional OPAT program. If you strike luck and the organism is susceptible to fluconazole, then you can use that. The utility of other tri-azoles is unknown.

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Articles of Interest

Echinocandins

Echinocandins are a class of antifungal drug that inhibit the synthesis of β-D-glucan in the fungal cell wall via non-competitive inhibition of the enzyme 1,3 β-D-glucan synthase. These treatments are delivered intravenously.

Echinocandins – A New Class of Antifungal Drugs

The newest main class of antifungal drugs are the echinocandins which include caspofungin, micafungin, and anidulafungin. The echinocandins are lipoproteins which inhibit fungal cell wall growth by blocking the enzyme 1,3,β-glucan synthase involved in β-glucan synthesis. Humans and other animals lack cell walls. The echinocandins are relatively non-toxic drugs and have shown a broad range of efficacy against common fungal infections including Candida and Aspergillus. The echinocandins can be used by themselves or in combination with azole drugs.

Echinocandins (micaFUNGIN, caspoFUNGIN, anidulaFUNGIN)

Echinocandins are generally the agent of choice for empiric treatment of candidemia in the ICU. Echinocandins may be uniquely effective against Candida embedded in biofilms (e.g., surrounding prosthetic devices), a context where fluconazole or amphotericin-B may be less effective. Echinocandins are fungicidal against Candida (unlike azoles, which are fungistatic).

Echinocandins Pharmacokinetics: A Comprehensive Review of Micafungin, Caspofungin, Anidulafungin, and Rezafungin...

In recent years, many population pharmacokinetic (popPK) models have been developed for echinocandins to better understand the pharmacokinetics (PK) of these antifungals. This comprehensive review aimed to summarize popPK models of echinocandins (micafungin, caspofungin, anidulafungin, and rezafungin), by focusing on dosage optimization to maximize the probability of attaining the PK/PD target proposed in special populations.

Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia

These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Is Caspofungin Used against Fungal Infection?

Caspofungin is a new type of echinocandin antifungal drug. As a prescription drug, it is mainly used to treat invasive candidiasis, invasive aspergillosis that is ineffective or intolerable to other treatments, and empirical treatment of suspected fungal infections in patients with neutropenia and fever. As a representative of a new class of echinocandins, caspofungin will become a research hotspot of systemic antifungal agents because of its obvious advantages of high selectivity, good antibacterial activity, high safety, less drug resistance and expiration of patent protection.

Micafungin

Intravenous micafungin shows very good activity against clinically relevant isolates of Candida spp. Furthermore, the pharmacokinetic profile of micafungin permits once-daily treatment and means that it is associated with relatively few drug-drug interactions. However, like all of the echinocandins and all formulations of amphotericin B, micafungin must be given intravenously.

Micafungin for invasive candidiasis

In clinical practice guidelines, micafungin is one of the options recommended as first-line therapy for candidiasis in adults. However, in neonates the guidelines recommend its use be limited to incidences of fluconazole resistance or toxicity.

Micafungin in the treatment of invasive candidiasis and invasive aspergillosis

Micafungin is a relatively broad-spectrum antifungal agent with in vitro activity against Candida and Aspergillus species, as well as the mycelial forms of dimorphic fungi. The most potent activity of micafungin is against Candida, including non-Candida albicans species, and is conserved against clinically invasive isolates resistant to fluconazole.

Micafungin: A New Echinocandin

Micafungin, a potent inhibitor of 1,3-β-D-glucan synthase, has become the second available agent in the echinocandins class that is approved for use in clinical practice. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans species of Candida, and Aspergillus species, as well as several but not all pathogenic molds. If anything, its in vitro activity appears to be superior to that of caspofungin, although the clinical relevance of this observation is unclear.

Micafungin: an evidence-based review of its place in therapy

Invasive fungal infections have increased throughout the world. Many of these infections occur in patients with multiple comorbidities who are receiving medications with the potential for interactions with antifungal therapy that could lead to renal and hepatic dysfunction. The second marketed echinocandin, micafungin, was approved in 2005 for the treatment of esophageal candidiasis and prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation.

Resistance: The Emerging Reality of Antifungal Treatment

Echinocandins inhibit synthesis of 1,3-beta-D-glucan, which is an integral part of the fungal cell wall. Despite the need for IV administration, echinocandins have emerged as the preferred agents for invasive candidiasis on the basis of a strong safety profile, early fungicidal activity, limited drug interactions, concerns about fluconazole resistance, and a trend toward better outcome. The MICs are low for most Candida species, including C. glabrata and C. krusei, but recently there has been a rise in resistant strains of C. glabrata.

Review on Current Status of Echinocandins Use

Fungal infections are rising all over the world every year. There are only five medical compound classes for treatment: triazoles, echinocandins, polyenes, flucytosine and allylamine. Currently, echinocandins are the most important compounds, because of their wide activity spectrum and much lower sides effects that may occur during therapy with other drugs. Echinocandins are secondary metabolites of fungi, which can inhibit the biosynthesis of β-(1,3)-D-glucan.

The echinocandin micafungin: a review of the pharmacology, spectrum of activity, clinical efficacy and safety

Micafungin is a relatively broad-spectrum antifungal agent available for clinical use in the US and Japan. By inhibiting the production of beta-1,3-glucan, an essential fungal cell wall component, micafungin has reduced toxicity to mammalian cells while maintaining potent antifungal activity against many pathogenic fungi including polyene- and azole-resistant isolates. Indeed, micafungin has been shown to be efficacious in the treatment of infections caused by Candida and Aspergillus species in clinical trials without the associated toxicities of amphotericin B formulations and drug interactions that occur with the azoles.

Treatment of Candida Glabrata With Micafungin: A Case Report and Brief Review of the Literature

As the use of the echinocandins has increased so has selection pressure, and sporadic reports of echinocandin resistance have begun to appear in the literature.

What are the side effects of Micafungin Sodium?

Liver function abnormalities are another potential side effect of Micafungin Sodium. Elevated levels of liver enzymes, such as alanine transaminase (ALT) and aspartate transaminase (AST), have been observed in some patients. In rare cases, more serious liver problems, including hepatitis and jaundice, can occur. Routine monitoring of liver function tests is recommended during treatment to detect any potential issues early.

Resources

Caspofungin

70mg IV loading dose followed by 50mg IV daily (70mg in adults >80kg). Slow infusion over 1 hour.

Micafungin

Dosage & administration - Candidemia and other Invasive Candida Infections: The recommended dosage of Micafungin sodium for the treatment of candidemia, acute disseminated candidiasis and certain invasive Candida infection (peritonitis, abscesses) in adults is 100 mg once daily given by slow IV infusion. Oropharyngeal Candidiasis: The recommended dosage of Micafungin sodium for the treatment of oropharyngeal candidiasis in adults is 100 or 150 mg once daily given by slow IV infusion.