Fellow's pre-read · Infectious Diseases
Antifungals
IDSA / ISHAM guidelines + antifungal pharmacology · pre-read 2026-07-07
Pre-read for tomorrow's antifungal didactic. First-line disease therapies are drawn from the IDSA candidiasis (2016) and aspergillosis guidelines and the ISHAM cryptococcosis guideline (2024); class spectra and toxicities are standard antifungal pharmacology. Not a substitute for the full guidelines.
In one line
Four classes do the work: polyenes (broadest, most toxic), azoles (oral, CYP-interacting workhorses), echinocandins (safe; Candida/Aspergillus but NOT Cryptococcus or Mucorales), and flucytosine (a partner drug). Match the bug: echinocandin for candidemia, voriconazole/isavuconazole for Aspergillus, liposomal ampho B + flucytosine for Cryptococcus, ampho B + surgery for Mucorales.◆The four classes
| Class | Agents | Spectrum | Signature toxicity / issue |
|---|---|---|---|
| Polyenes | Amphotericin B (deoxycholate; liposomal) | Broadest: Candida, Cryptococcus, molds incl. Mucorales, endemic dimorphics | Nephrotoxicity, K⁺/Mg²⁺ wasting, infusion reactions (liposomal = less nephrotox) |
| Azoles | Fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole | Agent-dependent (see gaps below) | CYP drug interactions, hepatotoxicity, QT prolongation (isavuconazole shortens QT) |
| Echinocandins | Caspofungin, micafungin, anidulafungin, rezafungin | Candida (cidal), Aspergillus (static) — NOT Cryptococcus, Mucorales, or endemic | Very well tolerated; no CYP interactions; IV only |
| Flucytosine (5-FC) | — | Candida, Cryptococcus (synergy with ampho B) | Myelosuppression, hepatotoxicity; never monotherapy (resistance); follow levels |
◆Spectrum gaps to memorize (the pimp gold)
- Mucorales (mucormycosis): only amphotericin B, isavuconazole, or posaconazole work — voriconazole and fluconazole do NOT.
- Echinocandins miss Cryptococcus, Mucorales, and the endemic dimorphics — so they're wrong for meningitis and mold-in-the-sinus.
- Fluconazole has no mold activity (no Aspergillus, no Mucorales); good for most Candida (weak vs glabrata, none vs krusei) and Cryptococcus.
- Voriconazole covers Aspergillus, Scedosporium, Fusarium — but not Mucorales (the classic trap: starting voriconazole for a "mold" that's actually Mucor).
◆First-line therapy by disease
| Disease | First-line | Note |
|---|---|---|
| Candidemia / invasive candidiasis | An echinocandin (caspofungin 70→50 mg; micafungin 100 mg; anidulafungin 200→100 mg) | De-escalate to fluconazole in 5–7 d if stable + susceptible; remove lines; ophtho exam |
| Invasive aspergillosis | Voriconazole (or isavuconazole) | Echinocandin not recommended as primary; liposomal ampho B = alternative |
| Cryptococcal meningitis | Liposomal ampho B + flucytosine (induction) → fluconazole (consolidation/maintenance) | HIV: single-dose liposomal ampho B 10 mg/kg + 14 d flucytosine + fluconazole 1200 mg (AMBITION) |
| Mucormycosis | Liposomal ampho B + urgent surgical debridement | Step-down to isavuconazole or posaconazole; reverse immunosuppression / control diabetes-DKA |
| Histoplasmosis / blastomycosis | Itraconazole (mild–moderate); liposomal ampho B (severe / CNS) | Same pattern for most endemic mycoses |
| Coccidioidomycosis | Fluconazole (or itraconazole) | Ampho B for severe/disseminated |
◆Toxicity, interactions & monitoring
- Amphotericin B: pre-hydrate, watch creatinine and replace K⁺/Mg²⁺; liposomal formulation for less nephrotoxicity.
- Azoles = CYP3A4 inhibitors → major interactions (e.g., ↑ tacrolimus, statins, warfarin). Voriconazole: visual disturbances, photosensitivity → skin cancer, periostitis (fluoride), hallucinations. Itraconazole: negative inotrope — avoid in heart failure. All (except isavuconazole) can prolong QT.
- Therapeutic drug monitoring: voriconazole, posaconazole, itraconazole (absorption is erratic), and flucytosine (marrow toxicity).
- Echinocandins: the "clean" option — few interactions, but no CNS/urine penetration and no Cryptococcus/Mucorales coverage.
What's changed / worth knowing
Reviewer synthesis — not the guideline text.
- Single-dose liposomal ampho B (AMBITION): a single 10 mg/kg dose + 14 d flucytosine + fluconazole 1200 mg is now standard induction for HIV-associated cryptococcal meningitis. ISHAM 2024; WHO
- Isavuconazole covers Aspergillus and Mucorales, is better tolerated than voriconazole, and shortens (not prolongs) the QT. IDSA aspergillosis
- Rezafungin — a once-weekly echinocandin — is now available for candidemia/invasive candidiasis.
◆Likely pimp questions
- First-line for candidemia? An echinocandin — de-escalate to fluconazole if stable and susceptible.
- First-line for invasive aspergillosis? Voriconazole (or isavuconazole).
- Why are echinocandins wrong for cryptococcal meningitis? No Cryptococcus activity (and no CNS penetration).
- Induction for cryptococcal meningitis? Liposomal ampho B + flucytosine → then fluconazole.
- Which drugs cover Mucorales? Amphotericin B, isavuconazole, posaconazole — NOT voriconazole or fluconazole.
- Treatment of mucormycosis? Liposomal ampho B + urgent surgical debridement.
- Which azole is contraindicated in heart failure? Itraconazole (negative inotrope).
- Voriconazole long-term skin risk? Phototoxicity → squamous cell carcinoma (also periostitis, visual changes).
- Which antifungal must never be used as monotherapy, and why? Flucytosine — rapid resistance.
- Amphotericin electrolyte effects to watch? Potassium and magnesium wasting (plus nephrotoxicity).
- Which azole shortens the QT interval? Isavuconazole (the others prolong it).
Sources: Pappas PG, et al. Clinical Practice Guideline for the Management of Candidiasis — IDSA, 2016 (echinocandin first-line for candidemia). · Patterson TF, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis — IDSA (voriconazole primary; isavuconazole/liposomal AmB alternatives; echinocandin not primary). · Cryptococcosis — ISHAM/ECMM global guideline, 2024 (liposomal ampho B + flucytosine induction; single-dose AMBITION regimen). · Class spectra/toxicities: standard antifungal pharmacology.