Antifungals
Antimicrobial agents targeting eukaryotic and heterotrophic microbes. Can be divided by class into:
- Azoles
Inhibit ergosterol synthesis. Subdivided into:- Triazoles
- Fluconazole
- Itraconazole
- Voriconazole
- Posaconazole
- Imidazoles
- Ketoconazole
- Triazoles
- Echinocandins
Inhibit glucan synthesis.- Caspofungin
- Micafungin
- Anidulafungin
- Polyenes
Disrupt cell membrane.- Amphotericin B
- Nystatin
Common Features
Mechanisms of Antifungal Resistance
Three broad mechanisms:
- Increased efflux
Increased expression of transport proteins removing drug from cell. - Alteration of target enzyme
Changes to protein target prevent drug binding or inactivation.- Typically only requires changes in a few amino acids
- Alteration of drug metabolism
Reduced enzyme activity prevents accumulation of toxic product.
Amphotericin resistance is rare in vivo, and is typically via different mechanisms:
- Decreased ergosterol content
- Altered sterol:phospholipid ratio
Comparison of Antifungals
| Drug | Fluconazole | Voriconazole | Caspofungin | Amphotericin B |
|---|---|---|---|---|
| Class | Azole | AzoleEchinocandins | Polyenes | |
| Spectrum of Activity | Candida albicans (most other species, especially C. glabrataand to a lesser extent C. krusei are resistant), as resistance rapidly develops), cryptococcus, coccidioides, histoplasma, blastomyces, and some aspergillus (resistance may also develop rapidly). At least as good as amphotericin in susceptible organisms. | As fluconazole, but broader spectrum of activity | Candida (including azole resistant C. glabrata and C. krusei and Candida biofilms), aspergillus. Notably no activity against cryptococcus, fusarium, and trichosporon. Additionally, echinocandins typically have no cross-resistance with other antifungals |
Effective against many fungi, with notable exceptions being Chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium, and some Fusarium. |
| Pharmaceutics | Poor water solubility | Poor water solubility | Poor water solubility | Four different formulations, most common is amphotericin B colloidal dispersion (ABCD) |
| Dosing | 100-800mg OD, adjust in renal failure | Typically 70mg loading dose, followed by 50mg daily; dose reduced in hepatic impairment | Load with 0.25-0.5kg.kg-1, followed by 0.25-1.5mg.day-1, reduced in severe renal impairment | |
| Route of Administration | IV or PO | IV only (high MW) | IV for systemic indications | |
| Absorption | High PO bioavailability, PO absorption at low pH (interaction with antacids, vitamin supplements) | <5% PO bioavailability | ||
| Distribution | Crosses BBB - good CSF penetration. Very low protein binding (~10%) | Not dialysable due to very high protein binding, VD. Good tissue penetration. | Essentially no CSF penetration, 97% protein bound in serum | Rapid uptake by reticuloendothelial system. Binds to organic anion transporting peptides (important in hepatocyte drug binding), important in key drug interactions (such as tacrolimus) |
| Metabolism | Metabolised by and cause reversible inhibition of multiple hepatic CYP450 enzymes (including 3A4, 2C19, 2C9), leading to increased concentrations of many drugs/metabolites | As fluconazole | Extensive hydrolysis and N-acetylation to inactive metabolites | Minimal metabolism |
| Elimination | 80% of fluconazole renally eliminated unchanged | Mostly cleared via liver. | Renal of metabolites | Renal and faecal elimination of unchanged drug |
| Mechanism of Action | Inhibit ergosterol synthesis by inhibiting CYP450 enzyme | As fluconazole | Prevent cell wall synthesis by blocking production of beta-glucan | Binds sterols, disrupting osmotic integrity of the cell membrane |
| CVS | HTN | Long QT | Histamine release | |
| CNS | Headache, visual disturbances | Hallucinations, psychosis | ||
| Renal | AKI via afferent arteriolar constriction and direct tubular toxicity, hypokalaemia, renal tubular acidosis | |||
| GIT | Hepatotoxicity | Mild hepatotoxicity in up to ~15% | ||
| Haeme | Thrombophlebitis, normocytic anaemia |
References
- Anderson JB. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat Rev Microbiol. 2005 Jul;3(7):547-56.
- Drew RH. Pharmacology of Amphotericin B. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
- Ashley ED, Perfect JR. Pharmacology of azoles. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
- Lewis RE. Pharmacology of echinocandins. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.
- Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2002 Mar;46(3):828-33.