Echinocandins

Echinocandins are lipopeptide antifungals given intravenously (caspofungin, micafungin, anidulafungin) that inhibit beta-1,3-D-glucan synthase, weakening the fungal cell wall. They are fungicidal against Candida and fungistatic against Aspergillus, and are the first-line choice for invasive candidiasis in critically ill patients.

Pharmacokinetics. Poor oral absorption, highly protein bound, minimal CYP involvement, and low penetration into cerebrospinal fluid, urine and the eye. Caspofungin is hepatically metabolised; micafungin partly by the liver; anidulafungin degrades spontaneously in blood and needs no adjustment for liver or kidney disease.

• Caspofungin: 70 mg loading then 50 mg daily (adult); 35 mg daily for moderate liver impairment (Child-Pugh B); 70 mg daily if used with inducers such as rifampicin or phenytoin, or if weight is over 80 kg.
• Micafungin: 100 mg daily for candidaemia; 150 mg daily for oesophageal candidiasis; 50 mg daily for prophylaxis.
• Anidulafungin: 200 mg loading then 100 mg daily; no dose adjustment for liver or kidney disease.
• Children: caspofungin 70 mg/m2 loading then 50 mg/m2 daily; micafungin 2 mg/kg daily (neonates 10 mg/kg).

Gaps. No activity against Cryptococcus, Fusarium, Mucorales or Trichosporon. Candida parapsilosis has higher minimum inhibitory concentrations; Candida auris is usually susceptible but acquired resistance occurs.

Invasive candidiasis. First choice for candidaemia in ICU patients, those with previous azole exposure, and those with C. glabrata or unknown species. Step down to fluconazole when the isolate is susceptible, the patient is stable, and blood cultures are negative. Treat for 14 days after the first negative blood culture.

Aspergillosis. Salvage therapy or in combination with voriconazole; not for first-line monotherapy.

Prophylaxis. Micafungin in selected high-risk patients with haematological malignancy or transplant, when azoles cannot be given.

Limits. Avoid as sole therapy for infection in the central nervous system, urinary tract or eye, and in endocarditis early on; use amphotericin B or fluconazole with surgery where required.

Contraindications. Hypersensitivity to any echinocandin.

Adverse effects. Generally well tolerated: infusion-related histamine reactions (flushing, rash), phlebitis, raised liver enzymes, hypokalaemia, and rarely hepatic injury. Anidulafungin is infused slowly (not faster than 1.1 mg/minute) to avoid infusion reactions.

Interactions. Caspofungin with ciclosporin raises liver enzymes and modestly raises ciclosporin levels; caspofungin with tacrolimus lowers tacrolimus levels. Rifampicin, carbamazepine, dexamethasone and phenytoin lower caspofungin levels.

Monitoring. Liver enzymes at baseline and twice weekly initially, blood cultures every day or two until negative, repeat ophthalmological examination for candidaemia, and electrolytes.

Special groups.

• Pregnancy: avoid unless clearly needed; embryo toxicity in animals. Breastfeeding: poorly absorbed by the infant but data are limited.
• Kidney impairment: no adjustment. Liver impairment: caspofungin 35 mg daily in Child-Pugh B; avoid in severe disease; no adjustment for anidulafungin.
• Children: weight or surface area dosing.

Referral and escalation. Persistent candidaemia beyond 4 days, suspected resistance, or deep-seated infection needs infectious diseases input.