STEPTRACKERMICROBIOLOGY + PHARMACOLOGY | ANTIFUNGALS | HIGH-YIELD REVIEW

Antifungal Drugs

Most antifungals hit ergosterol — binding it (polyenes), blocking its synthesis (azoles, terbinafine) — or the β-glucan wall (echinocandins). Flucytosine and griseofulvin target nucleic acids and microtubules.

FOCUS ON
Amphotericin B: binds ergosterol → membrane pores; for serious systemic mycoses, cryptococcal meningitis (+ flucytosine), mucormycosis; toxicity: nephrotoxicity (hydrate; liposomal form), hypokalemia/hypomagnesemia, infusion fevers/rigors, anemia. Nystatin: topical/oral swish for thrush. Azoles: inhibit 14α-demethylase (CYP450-dependent lanosterol → ergosterol) — fluconazole (Candida, Cryptococcus maintenance, Coccidioides; CSF penetration), itraconazole (dimorphic fungi, sporotrichosis), voriconazole (Aspergillus; visual disturbance, photosensitivity), posaconazole/isavuconazole (Mucor); class: CYP3A4 inhibition, hepatotoxicity, QT (not isavuconazole), ketoconazole → gynecomastia. Echinocandins (caspofungin): β-1,3-glucan synthase → Candida fungemia, Aspergillus salvage. Terbinafine: squalene epoxidase → onychomycosis. Griseofulvin: microtubules → tinea capitis. Flucytosine: 5-FU in fungi → marrow suppression.
DRUG
MECHANISM
USES
TOXICITY · NOTES
Amphotericin B
Binds ergosterol → pores → K⁺/Mg²⁺ leak
Severe systemic mycoses, cryptococcal meningitis, mucormycosis, visceral leishmaniasis
Nephrotoxicity, hypokalemia, hypomagnesemia, infusion fever/chills, arrhythmias · saline loading, liposomal formulation
Nystatin
Polyene, too toxic for IV
Oral thrush (swish), cutaneous/vaginal Candida
Not absorbed
Fluconazole
Azole: inhibits 14α-demethylase (lanosterol → ergosterol)
Candida (mucosal, vaginal, many invasive), cryptococcal maintenance, coccidioidomycosis
Good CSF/urine levels · no mold coverage · C krusei resistant
Itraconazole
Azole
Histoplasma, Blastomyces, Sporothrix, Paracoccidioides; ABPA; onychomycosis
Negative inotrope — avoid in heart failure
Voriconazole
Azole, broad
Invasive aspergillosis (drug of choice)
Visual changes, photosensitivity → skin cancer, hallucinations, periostitis (fluoride)
Posaconazole · isavuconazole
Azole, broadest
Mucormycosis (step-down), prophylaxis in leukemia/transplant
Isavuconazole shortens QT
Ketoconazole · clotrimazole · miconazole
Azole, mostly topical
Tinea, seborrheic dermatitis, Candida skin and vaginal infections
Oral ketoconazole blocks steroid synthesis → gynecomastia, ↓ libido; hepatotoxic
Azole class effects
Inhibit human CYP3A4 too
—
↑ levels of tacrolimus, cyclosporine, warfarin, statins · hepatotoxicity, QT
Echinocandins
Inhibit β-1,3-D-glucan synthase → wall
Candidemia (first-line), esophageal candidiasis, refractory aspergillosis
IV only · histamine flushing · no Cryptococcus or Mucor activity
Flucytosine
Converted to 5-FU by fungal cytosine deaminase → blocks DNA/RNA
Cryptococcal meningitis with amphotericin
Bone marrow suppression · never alone (resistance)
Terbinafine
Inhibits squalene epoxidase → squalene accumulates
Onychomycosis, tinea capitis, tinea pedis
Hepatotoxicity, taste disturbance
Griseofulvin
Binds microtubules → blocks mitosis; deposits in keratin
Tinea capitis
CYP450 inducer (↓ warfarin, OCPs), teratogen, disulfiram-like reaction, photosensitivity

Mechanism — the ergosterol pathway

Squalene
→
Squalene epoxidase⊣ terbinafine
→
Lanosterol
→
14α-demethylase⊣ azoles
→
Ergosterol in membrane⊣ amphotericin, nystatin bind it

Echinocandins skip ergosterol and block β-glucan in the cell wall — a structure humans lack.

Fungus → drug

FUNGUS
DRUG OF CHOICE
NOTE
Candida mucosal
Fluconazole
Nystatin for thrush
Candidemia
Echinocandin
Pull line
Cryptococcal meningitis
Amphotericin + flucytosine
Then fluconazole
Aspergillus invasive
Voriconazole
—
Mucor
Amphotericin + surgery
Posaconazole step-down
Dimorphic (mild)
Itraconazole
Fluconazole for Cocci
Dermatophytes
Terbinafine
Griseofulvin for capitis

How it's tested

COMMON CONFUSIONVoriconazole covers Aspergillus but not Mucor; posaconazole/isavuconazole and amphotericin cover Mucor.
THE TRAPAdding fluconazole or voriconazole to a transplant patient's regimen raises tacrolimus/cyclosporine levels — nephrotoxicity follows unless doses are cut.
YOUR APPROACHFungus and site → drug that covers it and reaches that site → class toxicity → CYP interactions.

If you see… think…

Rising creatinine, low K⁺ and Mg²⁺ on antifungal → amphotericin B
Fever and rigors during the infusion → amphotericin B
Azole target → 14α-demethylase (ergosterol synthesis)
Gynecomastia on an oral antifungal → ketoconazole
Visual disturbances on Aspergillus therapy → voriconazole
Drug of choice for candidemia → echinocandin (caspofungin)
Antifungal that becomes 5-FU → flucytosine
Toenail onychomycosis oral drug → terbinafine
Antifungal that induces CYP450 and binds microtubules → griseofulvin
Antifungal to avoid in heart failure → itraconazole