Echinocandins

Echinocandins are a relatively new class of antifungal agents that have revolutionized the treatment of systemic and invasive fungal infections, particularly those caused by Candida and Aspergillus species. These agents are classified as fungal cell wall synthesis inhibitors, specifically targeting β-(1,3)-D-glucan synthesis, a key structural component of the fungal cell wall not present in human cells. This selective mechanism contributes to their favorable safety profile. Echinocandins are administered intravenously and are considered fungicidal against most Candida spp. and fungistatic against Aspergillus spp.

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1. Classification and Available Agents

Echinocandins are cyclic lipopeptides, all derived semisynthetically from natural products. There are currently three echinocandins approved for clinical use:

1. Caspofungin

   • First echinocandin approved (FDA approval: 2001)

   • Brand: Cancidas

2. Micafungin

   • FDA approval: 2005

   • Brand: Mycamine

3. Anidulafungin

   • FDA approval: 2006

   • Brand: Eraxis (also known as Ecalta in Europe)

Each has slightly different pharmacokinetics but shares the same fundamental mechanism and spectrum of activity.

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2. Mechanism of Action

Echinocandins inhibit the enzyme β-(1,3)-D-glucan synthase, which is essential for the formation of β-glucan, a crucial polysaccharide component of the fungal cell wall.

• This inhibition leads to:

  • Disruption of fungal cell wall integrity

  • Osmotic instability

  • Cell lysis and death (fungicidal for Candida)

  • Growth inhibition (fungistatic for Aspergillus)

Because mammalian cells lack β-glucan and its synthase, echinocandins are highly selective and exhibit low toxicity toward human cells.

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3. Spectrum of Activity

A. Candida spp.

• Fungicidal against most Candida species, including:

  • Candida albicans

  • Candida glabrata

  • Candida tropicalis

  • Candida krusei

  • Candida parapsilosis (higher MICs—reduced susceptibility)

B. Aspergillus spp.

• Fungistatic activity against:

  • Aspergillus fumigatus

  • Aspergillus flavus

  • Aspergillus niger

  • Active against both hyphal and germinating forms

C. Other Fungi:

• Not active against Cryptococcus neoformans, Fusarium spp., Zygomycetes (e.g., Rhizopus, Mucor), and dimorphic fungi such as Histoplasma, Blastomyces.

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4. Clinical Indications

Echinocandins are indicated for the treatment of serious fungal infections, especially in immunocompromised patients:

A. Invasive Candidiasis

• First-line therapy for candidemia and other forms of invasive Candida infections

• Effective in neutropenic and non-neutropenic patients

B. Esophageal Candidiasis

• All three echinocandins are approved

C. Empirical Therapy in Febrile Neutropenia

• Caspofungin is FDA-approved for empiric therapy in febrile neutropenic patients with suspected fungal infections

D. Invasive Aspergillosis (Salvage therapy)

• Used when patients are refractory or intolerant to other antifungals like voriconazole or amphotericin B

E. Prophylaxis

• Micafungin is approved for prophylaxis of Candida infections in hematopoietic stem cell transplant (HSCT) recipients

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5. Resistance Mechanisms

Although resistance to echinocandins is relatively uncommon, emerging cases are being reported, particularly among Candida glabrata.

Mechanisms:

• FKS gene mutations encoding the catalytic subunit of β-(1,3)-D-glucan synthase

• Reduced drug binding affinity

• Resistance can be intrinsic (e.g., C. parapsilosis) or acquired during therapy

Cross-resistance among echinocandins may occur if resistance is due to FKS mutations.

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6. Pharmacokinetics

Feature	Caspofungin	Micafungin	Anidulafungin
Administration	IV only	IV only	IV only
Protein Binding	~97%	~99%	~99%
Half-life	~9–11 hours	~14–17 hours	~24–26 hours
Metabolism	Hepatic (non-CYP)	Hepatic (non-CYP)	Slow chemical degradation (non-hepatic)
Elimination	Urine, bile, feces	Bile	Feces
Dose Adjustment	Required in hepatic impairment	Not usually needed	No dose adjustment needed in hepatic/renal disease

Note: All echinocandins require IV infusion and are not absorbed orally.

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7. Dosage Guidelines

• Caspofungin

  • Loading: 70 mg IV on day 1

  • Maintenance: 50 mg IV daily

  • Reduce to 35 mg in moderate hepatic impairment

• Micafungin

  • Invasive candidiasis: 100 mg IV daily

  • Esophageal candidiasis: 150 mg IV daily

  • Prophylaxis (e.g., HSCT): 50 mg IV daily

• Anidulafungin

  • Loading: 200 mg IV on day 1

  • Maintenance: 100 mg IV daily

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8. Adverse Effects

Echinocandins are generally well tolerated, with lower nephrotoxicity and hepatotoxicity compared to older antifungals like amphotericin B.

Common:

• Fever

• Headache

• Gastrointestinal symptoms (nausea, vomiting, diarrhea)

• Elevated liver enzymes (ALT, AST)

Less Common:

• Hypokalemia, hypomagnesemia

• Histamine-mediated infusion-related reactions (rash, flushing, pruritus)

Rare:

• Anaphylaxis

• Hepatotoxicity (monitor LFTs, especially with caspofungin)

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9. Contraindications and Precautions

• Known hypersensitivity to echinocandins or any of their components

• Caspofungin requires dose adjustment in hepatic impairment

• Monitor for hepatic toxicity, especially in patients on concurrent hepatotoxic drugs

• Not recommended in pregnancy unless clearly indicated (Category C)

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10. Drug Interactions

• Minimal CYP450 involvement → fewer drug interactions compared to azoles

• Caspofungin:

  • Interacts with cyclosporine (↑ hepatotoxicity risk), but may still be used with caution

  • Rifampin, dexamethasone, and efavirenz may reduce caspofungin levels

• Micafungin:

  • May increase levels of sirolimus and nifedipine—monitor blood pressure and drug levels

• Anidulafungin:

  • Very low potential for drug interactions

General recommendation: Always review concurrent medications, particularly immunosuppressants and antiretrovirals.

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11. Monitoring Parameters

• Liver function tests (LFTs) during therapy

• Signs of infusion-related reactions

• Serum potassium and magnesium in prolonged therapy

• Clinical and microbiological response in invasive infections

• Monitor for breakthrough fungal infections in prophylactic use

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12. Comparative Summary

Feature	Caspofungin	Micafungin	Anidulafungin
FDA Approved	2001	2005	2006
Fungal Targets	Candida, Aspergillus	Candida, Aspergillus	Candida, Aspergillus
Use in Liver Dysfunction	Requires dose adjustment	Generally safe	Safe
Drug Interactions	Some (cyclosporine)	Minor	Minimal
Prophylaxis Use	Off-label	Approved (HSCT)	Off-label

13. Future Directions and Clinical Research

• Investigational echinocandin-like drugs with improved oral bioavailability are in development (e.g., rezafungin, a long-acting echinocandin)

• Potential expansion of use to outpatient settings and less intensive care units

• Exploring combination therapy with azoles or polyenes for resistant fungal infections

• Molecular testing for FKS mutations is being integrated to guide therapy in echinocandin-resistant Candida strains