Echinocandins – A New Class of Antifungal Drugs

There are 4 main classes of drugs used to treat human and animal fungal infections including: 1) polyenes including amphotericin B and nystatin, 2) 5- fluorocytosine  3) azole drugs such as fluconazole, itraconazole, voriconazole, posanconazole, and isovucanazole, 4) the newest class the echinocandins which include caspofungin, micafungin, and anidulafungin (1-3).

Many pathogenic fungi such as Candida and Aspergillus are developing resistance to all 4 classes of antifungal drugs (1, 2, 4, 5). Some studies have reported resistance rates of Amphotericin B to Aspergillus as high as 24 to 84% (4). Worldwide, many strains of Candida and Aspergillus are developing resistance to azole drugs with up to 30% of strains showing resistance (2, 4).  Fungal resistance rates are much smaller for the echinocandins, however some studies have reported Echinocandin resistance rates of 1 to 12% of various Candida and Aspergillus species (4). Candida auris is an especially bad pathogen since some strains show resistance to all 4 classes of antifungal drugs and about half the strains show resistance to 2 or more classes of antifungals (2)!

Fungi are able to develop resistance to anti-fungal drugs by many methods including effuxor pumps to reduce cellular drug cell concentrations, changes in target site of the drug, and increased production of the target enzyme (2, 4). There is an urgent need to develop new antifungal drugs and better use the existing anti-fungal drugs.

The newest main class of antifungal drugs are the echinocandins which include caspofungin, micafungin, and anidulafungin (1-3). The echinocandins are lipoproteins which inhibit fungal cell wall growth by blocking the enzyme 1,3,β-glucan synthase involved in β-glucan synthesis (3). 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 (3). The echinocandins can be used by themselves or in combination with azole drugs (3).

Clinical trials suggest that the echinocandin drugs are effective against many invasive fungal infections. A Japanese study of 120 patients reported that caspofungin effectively treated 100%, 100%, and 47% of esophageal candidiasis, invasive candidiasis and chronic pulmonary aspergillus, respectively and micafungin successfully treated 83%, 100%, and 42% of esophageal candidiasis, invasive candidiasis and chronic pulmonary aspergillus, respectively (6). Echinocandin drugs may also give significantly higher treatment rates with significantly lower rates of adverse side effects as compared to azole anti-fungal drugs. A meta-analysis of 9 studies involving 2,008 patients with neutropenia and blood cancers reported that compared to patients treated with azole drugs, use of micafungin was associated with a 25% lower risk of invasive fungal infections (RR 0.75, 95% CI 0.61-0.92, p=0.0056) and a 55% lower risk of severe adverse events (RR=0.45, 95% CI 0.25-0.83, p=0.0105) (7).

A new echinocandin drug called Rezafungin has shown good efficacy in animal studies and is currently undergoing human clinical trials (8). Rezafungin has the advantage of having a very long half life of about 150 hours in humans (8). A new class of antifungal drugs called the orotomides (Olorofim) are being developed (8). The orotomides block fungal growth by inhibiting dihydroorotate dehydrogenase (DHODH) which is involved in RNA, DNA and cell wall synthesis (8). Stay tuned for further developments in the development of antifungal drugs.

References

1. Wiederhold NP. Antifungal resistance: current trends and future strategies to combat. Infection and drug resistance. 2017;10:249-59.
2. Pristov KE, Ghannoum MA. Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect. 2019;25(7):792-8.
3. Patil A, Majumdar S. Echinocandins in antifungal pharmacotherapy. J Pharm Pharmacol. 2017;69(12):1635-60.
4. Goncalves SS, Souza ACR, Chowdhary A, Meis JF, Colombo AL. Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus. Mycoses. 2016;59(4):198-219.
5. Aruanno M, Glampedakis E, Lamoth F. Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside. Antimicrob Agents Chemother. 2019;63(8).
6. Kohno S, Izumikawa K, Yoshida M, Takesue Y, Oka S, Kamei K, et al. A double-blind comparative study of the safety and efficacy of caspofungin versus micafungin in the treatment of candidiasis and aspergillosis. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2013;32(3):387-97.
7. Lee CH, Lin JC, Ho CL, Sun M, Yen WT, Lin C. Efficacy and safety of micafungin versus extensive azoles in the prevention and treatment of invasive fungal infections for neutropenia patients with hematological malignancies: A meta-analysis of randomized controlled trials. PLoS One. 2017;12(7):e0180050.
8. Van Daele R, Spriet I, Wauters J, Maertens J, Mercier T, Van Hecke S, et al. Antifungal drugs: What brings the future? Medical mycology. 2019;57(Supplement_3):S328-s43.