Antifungals

Antifungal drugs occur in three classes:

• Azoles
  All have excellent oral bioavailability.
  • Generally fungicidal by inhibiting ergosterol synthesis in the cell wall
    Fungistatic in some organism-dependent cases, notably aspergillus with voriconazole.
• Echinocandins
  All three agents are similar enough to be clinically interchangeable.
  • Inhibit β-glucan synthesis causing cell wall instability, which is:
    • Fungicidal for yeasts
    • Fungistatic for aspergillus
• Polyenes
  Essentially restricted to Amphotericin.
  • Fungicidal by binding to ergosterol

Drugs

Comparison of Antifungals

Class	Drug	Indications	Pharmacokinetics	Toxicity
Azoles	Fluconazole	Yeasts Covers most Candida species. Excludes C. glabrata and C. Krusei	Renal elimination unchanged Dose ↓ 50% if GFR <50mL/min Dose ↑ in CRRT Usual renal tubular reabsorption does not occur. Extensive CYP interactions e.g. Tacrolimus, warfarin, phenytoin.	↑ QTc Hepatitis
	Voriconazole	Invasive Aspergillosis Fluconazole-resistant Candida Endemic fungi Coccidiomycosis, histoplasmosis, blastomycosis.	IV contraindicated if GFR <50mL/min PO dosing safe and unchanged. Dose ↓ 50% in hepatic dysfunction Extensive CYP interactions	Neurotoxicity Delirium, myoclonus. Nephrotoxicity IV only. ↑ QTc Psychosis
Echinocandins	Caspofungin	Candida Resistance is rare; may occur with: C. parapsilosis C. glabrata C. guilliermondii Aspergillus Not as monotherapy; synergistic with voriconazole.	No renal or hepatic dose reduction required Very highly protein bound	Avoid in acute hepatic failure Results in deranged LFTs, confounding monitoring.
Polyenes	Amphotericin	Cryptococcus Neoformans Dimorphic fungi Change between yeast and mould form. Moulds Otherwise resistant fungi	No hepatic impact Major role in treating fungal infections in hepatic failure. Contraindicated in renal failure	Infusion reactions Atopic/immune symptoms. AKI RTA

Liposomal amphotericin has replaced other more toxic amphotericin preparations.

Drug	Echinocandins	Liposomal Amphotericin
Dosing	Caspofungin 70mg IV load, then 50mg IV daily. ↑ Dose if on strong enzyme inducer, e.g. phenytoin, rifampicin. Anidulafungin 200mg IV load, then 100mg IV daily. Micafungin 100-150mg IV daily.	3-5mg/kg IV Q24H

Dosing

Dosing of Antifungals

Drug	Indication	Dosing
Amphotericin	Aspergillus	3-5mg/kg Q24H IV
Fluconazole	Mucocutaneous candidiasis	CrCl >50: 200-400mg Q24H IV/PO
		CrCl ⩽50: 100-200mg Q24H IV/PO
		IHD: 200-400mg IV/PO post IHD
		CRRT: 800mg load then 400mg IV/PO daily
Fluconazole	Candidaemia CNS infection Endophthalmitis Endocarditis Susceptible dose dependent Candida	CrCl >50: 800mg load then 400-800mg Q24H IV/PO
		CrCl ⩽50: 800mg load then 200-400mg Q24H IV/PO
		IHD: 800mg IV/PO post IHD
		CRRT: 800mg Q24H Q24H
Voriconazole	Aspergillus	CrCl >50: 6mg/kg IV ×2 doses (load), then 4mg/kg IV Q12H
		CrCl <50: Avoid IV due to risk of accumulation of cyclodextin excipient.
Casofungin	General infection	70mg load then 50mg Q24H IV 70mg daily if on CYP inducer (e.g. phenytoin, rifampicin)
Caspofungin	Endocarditis Endovascular infection	150mg Q24H IV

All CrCl values are given in mL/min.

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References

1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.