Antifungal Pharmacology
Ergosterol, glucan, and a fungal-only 5-FU: match drug, fungus, and toxicity
Fungal targets
What sets fungi apart. Fungal cell membranes use ergosterol where human membranes use cholesterol, and fungal cell walls are built from β-(1,3)-D-glucan and chitin, which human cells lack. Antifungals exploit these differences: terbinafine and the azoles block successive steps of ergosterol synthesis (squalene epoxidase, then lanosterol 14α-demethylase), polyenes bind finished ergosterol, echinocandins block glucan synthesis, flucytosine is activated only by a fungal enzyme, and griseofulvin disrupts microtubules.
| Class | Target | Key uses | Signature toxicity |
|---|---|---|---|
| Polyenes (amphotericin B, nystatin) | Bind ergosterol → pores | Severe systemic mycoses; nystatin for thrush | Infusion fevers, nephrotoxicity, hypokalemia, hypomagnesemia |
| Flucytosine | Converted to 5-FU → thymidylate synthase | Cryptococcal meningitis, with amphotericin | Marrow suppression |
| Azoles | CYP51 (lanosterol 14α-demethylase) | Candida, endemic fungi, Aspergillus, Mucorales (by agent) | Hepatotoxicity, QT prolongation, CYP inhibition |
| Echinocandins | β-(1,3)-D-glucan synthase | Candidemia, salvage aspergillosis | Histamine-release flushing |
| Terbinafine | Squalene epoxidase | Onychomycosis, dermatophytes | Hepatotoxicity, taste loss |
| Griseofulvin | Microtubules (mitotic spindle) | Tinea capitis | Teratogenic, CYP induction |
Polyenes and flucytosine
Amphotericin B. It binds ergosterol and assembles into pores that leak K+ and Mg2+, killing the fungus. It has the broadest spectrum and is reserved for severe systemic disease: induction therapy for cryptococcal meningitis (with flucytosine), disseminated histoplasmosis, blastomycosis and coccidioidomycosis, and mucormycosis, where liposomal amphotericin plus surgical debridement is first-line. It also treats visceral leishmaniasis. Because IV amphotericin enters the CSF poorly, it is given intrathecally for coccidioidal meningitis that fails azole therapy.
Amphotericin toxicity. Infusion reactions (fever, rigors, hypotension from cytokine release) are reduced by premedication. Nephrotoxicity is dose-dependent: afferent arteriolar constriction lowers GFR, and tubular damage produces a distal (type 1) renal tubular acidosis with potassium and magnesium wasting, so hypokalemia and hypomagnesemia are expected. Reduced erythropoietin causes a normocytic anemia.
Protect the kidneys with IV saline loading and lipid (liposomal) formulations, and replace potassium and magnesium throughout therapy.
Nystatin. Same target, but too toxic for systemic use and not absorbed from the gut. It is used as an oral suspension (swish and swallow) for thrush and as creams for cutaneous and diaper-area candidiasis.
Flucytosine. Fungal cytosine permease takes the drug up and fungal cytosine deaminase, absent in human cells, converts it to 5-fluorouracil. Its metabolite 5-FdUMP inhibits thymidylate synthase, and fluorinated RNA disrupts protein synthesis. Resistance emerges quickly with monotherapy, so it is combined with amphotericin for cryptococcal meningitis. Marrow suppression and hepatotoxicity rise when renal failure, often amphotericin-induced, lets it accumulate, so levels and blood counts are monitored.
- Inductionamphotericin B plus flucytosine for at least 2 weeks
- Consolidationhigh-dose oral fluconazole for about 8 weeks
- Maintenancelower-dose fluconazole for at least a year, until immune recovery
Azoles
Mechanism. Azoles inhibit fungal CYP51 (lanosterol 14α-demethylase), depleting ergosterol and letting toxic methylated sterols build up; the effect is mostly fungistatic. Resistance arises from ERG11 mutation or overexpression and from efflux pumps. Class effects are hepatotoxicity, QT prolongation and inhibition of human CYP enzymes.
| Drug | Main uses | Distinctive features |
|---|---|---|
| Fluconazole | Candida; cryptococcal consolidation and maintenance; single 150 mg dose for vulvovaginal candidiasis | Excellent CSF and urine levels, renally excreted unchanged; no mold activity; C. krusei intrinsically resistant, C. glabrata and C. auris often resistant |
| Itraconazole | Mild to moderate histoplasmosis and blastomycosis, step-down after amphotericin; coccidioidomycosis; sporotrichosis; onychomycosis | Capsules need food and acid; negative inotropy, so avoid in heart failure |
| Voriconazole | First-line for invasive aspergillosis | Visual disturbances, hallucinations, phototoxicity with cutaneous SCC, periostitis from fluoride; CYP2C19 polymorphisms make levels unpredictable |
| Posaconazole, isavuconazole | Mucormycosis (step-down, salvage or alternative therapy); posaconazole prophylaxis in AML/MDS neutropenia or GVHD | Cover Aspergillus and Mucorales; isavuconazole shortens the QT interval |
| Ketoconazole | Topical for seborrheic dermatitis and tinea versicolor; oral mainly for Cushing syndrome | Blocks adrenal and gonadal steroidogenesis (17,20-lyase): gynecomastia, low libido, adrenal insufficiency; severe hepatotoxicity |
Voriconazole toxicity. Transient visual changes (photopsia, altered color vision) and hallucinations are common early. With long-term use, phototoxicity leads to cutaneous squamous cell carcinoma, especially in transplant recipients, and fluoride released from the drug causes periostitis with bone pain and a raised alkaline phosphatase. Voriconazole has no activity against Mucorales.
Ketoconazole, itraconazole, posaconazole and voriconazole strongly inhibit CYP3A4, raising tacrolimus and cyclosporine to nephrotoxic levels, statins to myopathic levels (rhabdomyolysis) and adding to other QT-prolonging drugs. Fluconazole is a moderate CYP3A4 inhibitor but markedly boosts warfarin through CYP2C9. Rifampin, a strong inducer, drives azole levels below the therapeutic range.
Echinocandins
Mechanism and uses. Caspofungin, micafungin and anidulafungin inhibit β-(1,3)-D-glucan synthase, so the cell wall fails; they are fungicidal for Candida and fungistatic for Aspergillus. Given IV only, they are first-line for candidemia and invasive candidiasis, including C. glabrata, C. krusei and C. auris, and serve as salvage or combination therapy for invasive aspergillosis.
Gaps and safety. They have no activity against Cryptococcus and penetrate the CSF, urine and eye poorly, so they are not used for meningitis, Candida UTI or endophthalmitis. They are well tolerated; the main adverse effect is histamine-release flushing during infusion.
Dermatophyte drugs
Terbinafine. It inhibits squalene epoxidase, so squalene accumulates to toxic levels and ergosterol falls; it is fungicidal against dermatophytes. Concentration in keratin makes oral terbinafine first-line for onychomycosis (about 12 weeks for toenails), and topical forms treat tinea pedis and corporis. Adverse effects are hepatotoxicity (check liver enzymes), taste disturbance or loss, and GI upset.
Griseofulvin. It binds tubulin and disrupts the mitotic spindle, and it deposits in newly formed keratin of skin, hair and nails. Taken with fatty food to improve absorption, it treats tinea capitis in children. It is teratogenic, induces CYP450 enzymes (weakening warfarin and oral contraceptives), is photosensitizing and is contraindicated in porphyria, which it can precipitate.