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Articles

Echinocandins: Clinicians' Guide

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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 pharmacology2-4

 

  • 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: 

  1. Aguilar-Zapata D, Petraitiene R, Petraitis V. Echinocandins: the expanding antifungal armamentarium. Clin Infect Dis 2015;61 Suppl 6:S604-S611.
  2. 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.
  3. 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.
  4. Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007;27:369-388.
  5. 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.
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