Echinocandins: Clinicians’ Guide

Atul K Patel, MD, FIDSA

Echinocandins are some of the most well tolerated and safest antifungal drugs. All three echinocandins are structurally similar with limited oral bioavailability. They irreversibly inhibit β-1,3-D-glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall so disrupting β-1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture and cell death.^1,2 Echinocandins have fungicidal activity against Candida species and are fungistatic for Aspergillus species. These drugs cause damage to the hyphal tips and branch points of growing Aspergillus cells and decrease invasion potential.^1,2

Spectrum of activity and pharmacology^2-4

Activity against all Candida species (with higher minimum inhibitory concentrations [MICs] for C. parapsilosis and C. guilliermondii) and Aspergillus species
No activity against Cryptococcus, Histoplasma, Fusarium, Scedosporium and Mucorales except Rhizopus oryzae

A comparative pharmacology of all three echinocandins is described in the Table.

Table. Pharmacology of echinocandins⁴

	Caspofungin	Micafungin	Anidulafungin
Absorption/PK	Not orally absorbed/linear PK	Not orally absorbed/linear PK	Not orally absorbed/linear PK
Distribution	Extensive into the tissues, liver, lungs, kidney and heart Minimal CNS penetration	Extensive into the tissues, liver, lungs, kidney and heart Minimal CNS penetration	Extensive into the tissues, liver, lungs, kidney and heart Minimal CNS penetration
Metabolism	Hepatic Spontaneous degradation, hydrolysis and N-acetylation	Hepatic Spontaneous degradation, hydrolysis and N-acetylation	Chemical degradation Not hepatically metabolized
Urine concentrations	Limited urinary excretion Not dialyzable	Limited urinary excretion Not dialyzable	Limited urinary excretion Not dialyzable
CSF penetration	Brain, not CSF	Brain, not CSF	Brain, not CSF
Half-life	9-23 hours	11-21 hours	26.5 hours
Dose	70 mg IV on day 1, 50 mg	100 mg IV	200 mg IV on day 1, 100 mg
Dose adjustment Liver disease CYP inducers	70 mg day 1 then 35 mg 70 mg daily	None	None
CYP 3A4 inhibition	No	Yes, weak	No
Drug interactions	Rifampin, efavirenz, nevirapine, tacrolimus, cyclosporine, phenytoin, dexamethasone, carbamazepine	Sirolimus, nifedipine	Some with cyclosporine

CNS, central nervous system; CSF, cerebrospinal fluid; PK, pharmacokinetics

Adverse drug reactions

Adverse drug reactions (ADRs) are uncommon with echinocandin use.² ADRs include phlebitis, gastrointestinal side effects, hypokalemia and abnormal liver function tests. Caspofungin tends to have a higher frequency of liver-related laboratory abnormalities and a higher frequency of infusion-related pain and phlebitis. Histaminic reactions (rash, pruritus, flushing, hypotension, bronchospasm and angioedema) due to histamine release is reported with rapid infusion of anidulafungin, but these effects are transient and are easily managed by slowing the infusion rate with supportive care. Mitochondrial-damage–related cardiac myosite injury has been reported.

Echinocandin use

Echinocandins are used for the prevention, empiric treatment and treatment of Candida infections.

Candida infections: All major guidelines recommend echinocandins as the preferred agent for treatment of candidemia/invasive candidiasis

Aspergillus infections: In patients who are intolerant or refractory to voriconazole treatment

Who should not receive echinocandins?

Because of less-than-optimal pharmacokinetics in the central nervous system (CNS)/eyes/urine, echinocandins are not recommended for targeted therapy of fungal infections involving the CNS, eyes or the lower urinary tract

Advantages

No breakthrough ophthalmic infections on echinocandin therapy for candidemia
No negative outcomes in C. parapsilosis bloodstream infections treated with echinocandins (central venous catheter management is important)
Echinocandins and liposomal amphotericin B have good activity in Candida biofilms⁵

Which echinocandins should I select in my practice?

All three are equal in efficacy so it would depend on host & cost

In HIV patients on efavirenz-based antiretroviral therapy; patients with tuberculosis (TB) taking rifampin-based anti-TB therapy; post-transplantation patients on triple immunosuppression; and patients with advanced liver disease – avoid caspofungin mainly because of drug-drug interactions and because it requires dosage adjustment (ie, when therapeutic drug monitoring is not done for echinocandins and drug levels are uncertain)

Summary

Echinocandins are an important class of antifungal agent with cidal activity against Candida species
Safe and drug of choice for candidemia
Has fewest drug-drug interactions
Active in biofilms but not in CNS/eye infections

References:

Aguilar-Zapata D, Petraitiene R, Petraitis V. Echinocandins: the expanding antifungal armamentarium. Clin Infect Dis 2015;61 Suppl 6:S604-S611.
Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 2011;71:11-41. Erratum in: Drugs 2011;71:253.
Gallagher JC, MacDougall C, Ashley ES, Perfect JR. Recent advances in antifungal pharmacotherapy for invasive fungal infections. Expert Rev Anti Infect Ther 2004;2:253-268.
Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007;27:369-388.
Ghannoum M, Roilides E, Katragkou A, Petraitis V, Walsh TJ. The role of echinocandins in Candida biofilm-related vascular catheter infections: in vitro and in vivo model systems. Clin Infect Dis 2015;61 Suppl 6:S618-S621.