Pharmacology Consult

Focus on the echinocandins

The incidence of systemic fungal infections has increased steadily over the past decade and is the seventh leading cause of infectious disease-related deaths in the United States. The development of new antifungal agents has not kept pace with this increase or with the development of other classes of antimicrobial agents. Since 2000 there have been four new antifungal agents approved by the FDA; three of these agents are in the echinocandin class.

Anidulafungin (Eraxis, Pfizer) was recently approved by the FDA and joins caspofungin (Cancidas, Merck) and micafungin (Fujisawa) in this important class of agents. The echinocandins are safe and effective agents for the treatment of Candida, which is the fourth leading cause of bloodstream infections. They exert their antifungal activity by inhibiting 1,3-beta-D-glucan synthase, which is necessary for fungal cell wall production.

The activity of the echinocandins has been extensively studied against Candida and Aspergillus species. The MIC data can be difficult to interpret because there currently are no interpretive breakpoints or standardized in vitro susceptibility testing methods. Despite these shortcomings, the MIC50 for most clinically relevant Candida is less than or equal to 0.5 µg/mL, with the exception of C. parapsilosis which has MIC values ranging from 1-2 µg/mL. The echinocandins are also fungicidal against susceptible yeast. They have also demonstrated concentration-dependent killing and a prolonged post-antifungal effect of approximately 12 hours for most Candida species. The echinocandins have fungistatic activity against the clinically relevant Aspergillus species but are resistant in vitro to Cryptococcus and Zygomycetes.

Echinocandins differences

Marianne Billeter, PharmD [photo]
Marianne Billeter

There are minor differences in the drug properties of the echinocandins in a side-by-side comparison. The primary difference in the agents is their elimination pathways. Anidulafungin avoids the usual metabolic pathways by undergoing chemical degradation and eliminating byproducts through the feces. Anidulafungin’s lack of hepatic metabolism is credited with its lack of clinically significant drug interactions. Additionally, anidulafungin and micafungin do not need to be adjusted for renal or hepatic insufficiency. This is in contrast with caspofungin in which the daily maintenance dose is cut in half with moderate hepatic dysfunction (Child-Pugh score 7-9) and should not be used with severe hepatic disease (Child-Pugh score greater than 9).

Caspofungin has several drug interactions compared with the others. Concurrent use of carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin or rifampin results in lower concentrations of caspofungin and therefore the daily dose should be increased to 70 mg daily. All three agents have been tested in pediatric patients, but only anidulafungin list a pediatric dose in the package insert.

Caspofungin has the most FDA indications. This is not unexpected since caspofungin has been on the market longer than the other echinocandins. All three echinocandins are indicated for the treatment of esophageal candidiasis. Anidulafungin and caspofungin are indicated for the treatment of candidemia. The registration trials for anidulafungin and caspofungin to receive FDA approval for the treatment of candidemia were identical with respect to study design. This allows for an easy comparison of the trial results. The micafungin vs. caspofungin study for the treatment of candidemia has just been completed, and the results are not yet available.

The primary difference in the registration trials was with the antifungal agent use in the comparator arm. The caspofungin trial used amphotericin B deoxycholate as the comparator, which at the time of the study was considered the ‘gold standard’ treatment by the FDA. However, many practitioners felt a lipid amphotericin product or fluconazole would be a better comparator because these agents are frequently used in clinical practice. Additionally, when amphotericin B deoxycholate is used in a clinical trial, the study conclusions often include the comparator agent having less adverse effects than amphotericin B deoxycholate.

The anidulafungin trial used fluconazole (Diflucan, Pfizer) as the comparator to address some of the concerns raised in the caspofungin trials. In addition, there was a national drug shortage of amphotericin B deoxycholate at the initiation of the anidulafungin study so a different comparator needed to be selected. One could argue that the 800 mg dose of fluconazole followed by 400 mg daily that was used in the anidulafungin trial is too low. However, this is the FDA labeled dose of fluconazole for treatment of candidemia.

The study results show that anidulafungin and caspofungin performed similarly in all aspects of treatment success and Candida eradication. The only difference was in mortality. Anidulafungin had a lower mortality (23%) compared with fluconazole (31%), caspofungin (34%) and amphotericin B deoxycholate (30%). The lower mortality seen with anidulafungin is unexpected since the mortality in most candidemia trials typically ranges from 30% to 35%, as was seen in the comparators. The results of these two studies demonstrate that both anidulafungin and caspofungin are both safe and effective in treating candidemia. However, anidulafungin is the first antifungal agent to show an improvement in mortality in candidemia clinical trials.

Fungal infections like candidemia continue to be a significant problem in health care and the echinocandins are a welcome addition to the antifungal armamentarium. However, the three echinocandins on the market have more similarities than differences, making it difficult for health care practitioners to decide which echinocandin is best to use. Price may be the deciding factor in choosing which echinocandin to use.

For more information:
  • Turner MS, Drew RH, Perfect JR. Emerging echinocandins for treatment of invasive fungal infections. Expert Opin Emerging Drugs. 2006;11:231-250.
  • Ostrosky-Zeichner L, Rex JH, Pappas PG, et al. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother. 2003;47:3149-3154.
  • Marianne Billeter, PharmD, BCPS, a clinical pharmacology specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.

The incidence of systemic fungal infections has increased steadily over the past decade and is the seventh leading cause of infectious disease-related deaths in the United States. The development of new antifungal agents has not kept pace with this increase or with the development of other classes of antimicrobial agents. Since 2000 there have been four new antifungal agents approved by the FDA; three of these agents are in the echinocandin class.

Anidulafungin (Eraxis, Pfizer) was recently approved by the FDA and joins caspofungin (Cancidas, Merck) and micafungin (Fujisawa) in this important class of agents. The echinocandins are safe and effective agents for the treatment of Candida, which is the fourth leading cause of bloodstream infections. They exert their antifungal activity by inhibiting 1,3-beta-D-glucan synthase, which is necessary for fungal cell wall production.

The activity of the echinocandins has been extensively studied against Candida and Aspergillus species. The MIC data can be difficult to interpret because there currently are no interpretive breakpoints or standardized in vitro susceptibility testing methods. Despite these shortcomings, the MIC50 for most clinically relevant Candida is less than or equal to 0.5 µg/mL, with the exception of C. parapsilosis which has MIC values ranging from 1-2 µg/mL. The echinocandins are also fungicidal against susceptible yeast. They have also demonstrated concentration-dependent killing and a prolonged post-antifungal effect of approximately 12 hours for most Candida species. The echinocandins have fungistatic activity against the clinically relevant Aspergillus species but are resistant in vitro to Cryptococcus and Zygomycetes.

Echinocandins differences

Marianne Billeter, PharmD [photo]
Marianne Billeter

There are minor differences in the drug properties of the echinocandins in a side-by-side comparison. The primary difference in the agents is their elimination pathways. Anidulafungin avoids the usual metabolic pathways by undergoing chemical degradation and eliminating byproducts through the feces. Anidulafungin’s lack of hepatic metabolism is credited with its lack of clinically significant drug interactions. Additionally, anidulafungin and micafungin do not need to be adjusted for renal or hepatic insufficiency. This is in contrast with caspofungin in which the daily maintenance dose is cut in half with moderate hepatic dysfunction (Child-Pugh score 7-9) and should not be used with severe hepatic disease (Child-Pugh score greater than 9).

Caspofungin has several drug interactions compared with the others. Concurrent use of carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin or rifampin results in lower concentrations of caspofungin and therefore the daily dose should be increased to 70 mg daily. All three agents have been tested in pediatric patients, but only anidulafungin list a pediatric dose in the package insert.

Caspofungin has the most FDA indications. This is not unexpected since caspofungin has been on the market longer than the other echinocandins. All three echinocandins are indicated for the treatment of esophageal candidiasis. Anidulafungin and caspofungin are indicated for the treatment of candidemia. The registration trials for anidulafungin and caspofungin to receive FDA approval for the treatment of candidemia were identical with respect to study design. This allows for an easy comparison of the trial results. The micafungin vs. caspofungin study for the treatment of candidemia has just been completed, and the results are not yet available.

The primary difference in the registration trials was with the antifungal agent use in the comparator arm. The caspofungin trial used amphotericin B deoxycholate as the comparator, which at the time of the study was considered the ‘gold standard’ treatment by the FDA. However, many practitioners felt a lipid amphotericin product or fluconazole would be a better comparator because these agents are frequently used in clinical practice. Additionally, when amphotericin B deoxycholate is used in a clinical trial, the study conclusions often include the comparator agent having less adverse effects than amphotericin B deoxycholate.

The anidulafungin trial used fluconazole (Diflucan, Pfizer) as the comparator to address some of the concerns raised in the caspofungin trials. In addition, there was a national drug shortage of amphotericin B deoxycholate at the initiation of the anidulafungin study so a different comparator needed to be selected. One could argue that the 800 mg dose of fluconazole followed by 400 mg daily that was used in the anidulafungin trial is too low. However, this is the FDA labeled dose of fluconazole for treatment of candidemia.

The study results show that anidulafungin and caspofungin performed similarly in all aspects of treatment success and Candida eradication. The only difference was in mortality. Anidulafungin had a lower mortality (23%) compared with fluconazole (31%), caspofungin (34%) and amphotericin B deoxycholate (30%). The lower mortality seen with anidulafungin is unexpected since the mortality in most candidemia trials typically ranges from 30% to 35%, as was seen in the comparators. The results of these two studies demonstrate that both anidulafungin and caspofungin are both safe and effective in treating candidemia. However, anidulafungin is the first antifungal agent to show an improvement in mortality in candidemia clinical trials.

Fungal infections like candidemia continue to be a significant problem in health care and the echinocandins are a welcome addition to the antifungal armamentarium. However, the three echinocandins on the market have more similarities than differences, making it difficult for health care practitioners to decide which echinocandin is best to use. Price may be the deciding factor in choosing which echinocandin to use.

For more information:
  • Turner MS, Drew RH, Perfect JR. Emerging echinocandins for treatment of invasive fungal infections. Expert Opin Emerging Drugs. 2006;11:231-250.
  • Ostrosky-Zeichner L, Rex JH, Pappas PG, et al. Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother. 2003;47:3149-3154.
  • Marianne Billeter, PharmD, BCPS, a clinical pharmacology specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.