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PH8.8 | PH8.8 | Antifungal Drugs — SDL Guide — SDL Guide (Part 2)

Polyenes and Azoles: Mechanisms, Spectra, and ADRs

Amphotericin B (conventional IV formulation):
- Mechanism: the large polyene macrolide ring has a hydrophobic face (interacts with ergosterol) and a hydrophilic face (lines the pore interior). AmB inserts into the fungal membrane as ergosterol-AmB complexes → forms transmembrane ion-conducting pores → K⁺ and Mg²⁺ leak out → membrane potential lost → cell death. Fungicidal against most susceptible fungi.
- Spectrum: Candida spp. (most including non-albicans), Aspergillus, Cryptococcus, Mucor/Rhizopus (mucormycosis — AmB is first-line), dimorphic fungi (Histoplasma, Blastomyces, Coccidioides), Leishmania.
- ADRs: (a) Nephrotoxicity — the dose-limiting toxicity; proximal renal tubular damage, distal tubular acidosis, hypomagnesaemia, hypokalaemia; creatinine often doubles. Prevention: adequate IV hydration before and after infusion (500mL normal saline), avoid nephrotoxic co-medications (aminoglycosides, NSAIDs, ciclosporin). Monitor Cr, K, Mg daily during therapy. (b) Infusion reactions — fever, chills, rigors, hypotension during infusion (30–60 minutes into infusion); due to cytokine release (TNF-α, IL-1, PGE2). Premedication: paracetamol 1g + diphenhydramine 25–50mg + hydrocortisone 50mg IV (if severe) before infusion. (c) Anaemia (erythropoietin suppression). Lipid formulations (L-AmB) reduce nephrotoxicity by altering pharmacokinetics (less renal tubular accumulation) — but are significantly more expensive.

Fluconazole (first-generation triazole):
- Mechanism: inhibits CYP51 (14α-demethylase) → blocks lanosterol → ergosterol conversion → ergosterol depletion + accumulation of 14α-methylsterols → membrane dysfunction. Fungistatic (requires intact immune function for fungal killing).
- Unique PK: highly water-soluble; excellent oral bioavailability (>90%); excellent CSF penetration (CSF levels 80% of plasma — why it is used for cryptococcal meningitis consolidation/maintenance).
- Spectrum: Candida albicans (most isolates), Candida tropicalis, Cryptococcus neoformans. NOT Aspergillus (fluconazole does not inhibit Aspergillus CYP51 isoform at achievable plasma concentrations — intrinsic resistance — this is the clinical trap in the hook scenario). NOT Candida krusei (intrinsic resistance) or Candida glabrata (high MIC).
- ADRs: well-tolerated; GI (nausea); hepatotoxicity (elevated LFTs, rare fulminant hepatic failure); QT prolongation (dose-related); CYP3A4 and CYP2C9 inhibitor → elevated warfarin (INR up), ciclosporin, tacrolimus, statins, phenytoin levels.

Voriconazole (extended-spectrum triazole):
- Spectrum: Aspergillus spp. (the first-line treatment for invasive aspergillosis — Walsh NEJM 2002, superior to conventional AmB); Candida spp. (including C. krusei and C. glabrata); Fusarium; Scedosporium.
- Unique ADRs: (a) Visual disturbances (photopsia) — transient, dose-related; patients report bright lights, colour changes, blurring during the first weeks of treatment. Resolves spontaneously. Most common unique ADR of voriconazole. (b) Hepatotoxicity — monitor LFTs. (c) Phototoxicity — prolonged voriconazole → increased skin cancer risk. (d) CYP2C19 polymorphism in metabolism: poor metabolisers (absent CYP2C19 — common in Asians ~15–20%) accumulate 4–10× higher levels → toxicity; ultra-rapid metabolisers have subtherapeutic levels → treatment failure. Therapeutic drug monitoring (TDM) recommended (trough 1–5.5 mcg/mL). (e) Potent CYP3A4 inhibitor — drug interactions.

Itraconazole: Broad spectrum (Candida, Aspergillus, Cryptococcus, dimorphic fungi including Histoplasma, Blastomyces, Sporotrichosis); oral; capsule formulation requires acidic pH for absorption (take with food, not with proton pump inhibitors or antacids); solution (cyclodextrin) has better absorption. ADRs: hepatotoxicity; negative inotrope (avoid in cardiac failure); drug interactions (CYP3A4 inhibitor).

Posaconazole: Broadest-spectrum azole including Mucor/Rhizopus (mucormycosis) and most Candida spp.; oral suspension or tablets; used for prophylaxis in high-risk neutropenic patients and salvage therapy for mucormycosis.

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Echinocandins, Allylamines, and Other Antifungals

Echinocandins (caspofungin, micafungin, anidulafungin):
- Mechanism: cyclic lipopeptides that inhibit β-(1,3)-D-glucan synthase — an enzyme encoded by FKS1/FKS2 genes, responsible for polymerising glucose into β-glucan, a structural polysaccharide in the fungal cell wall. Inhibition reduces β-glucan content → cell wall weakness → osmotic lysis → cell death. This target is absent in mammalian cells — the reason echinocandins have an exceptionally wide safety margin and minimal drug interactions (not metabolised by CYP enzymes).
- Spectrum: Fungicidal vs Candida (including azole-resistant Candida krusei and C. glabrata); Fungistatic vs Aspergillus; No activity vs Cryptococcus (Cryptococcus has minimal β-glucan and a thick polysaccharide capsule that the echinocandin molecule cannot penetrate effectively — intrinsic resistance).
- Clinical use: invasive candidiasis/candidaemia (first-line, especially in azole-resistant or haemodynamically unstable patients); Aspergillus as second-line or salvage; NOT for Cryptococcus.
- IV formulation only (large lipopeptide — poor oral bioavailability); long half-lives allowing once-daily dosing.
- ADRs: Minimal — excellent tolerability profile. Histamine-mediated infusion reactions with rapid caspofungin infusion (administer over ≥1 hour). Transient liver enzyme elevations. No renal toxicity. No significant CYP interactions (a major advantage over azoles).

Terbinafine (allylamine):
- Mechanism: inhibits squalene epoxidase → blocks squalene → squalene oxide conversion → two toxic effects: (1) ergosterol depletion; (2) squalene accumulation (directly toxic to fungal membranes, disrupting their integrity). Fungicidal vs dermatophytes (Trichophyton, Epidermophyton, Microsporum) — particularly effective because the combination of ergosterol depletion + squalene toxicity kills dermatophytes more effectively than azoles.
- Spectrum: Dermatophytes (tinea pedis, tinea corporis, tinea cruris, onychomycosis). NOT Candida (terbinafine has poor activity vs Candida — squalene epoxidase isoform in Candida is less susceptible).
- PK: highly lipophilic; accumulates in skin, hair, nails (long tissue half-life → sustained nail levels during oral therapy for onychomycosis).
- ADRs: Hepatotoxicity (check LFTs at baseline; stop if LFTs >3× ULN — rare, but liver failure reported); GI (nausea, diarrhoea); taste disturbance (ageusia — reversible); headache. Dose: 250mg/day × 12 weeks for toenail onychomycosis (superior to griseofulvin which requires 6–18 months).

Flucytosine (5-FC):
- Mechanism: prodrug; cytosine permease in the fungal membrane transports 5-FC into the cell → fungal cytosine deaminase converts 5-FC to 5-fluorouracil (5-FU) → 5-FU incorporated into RNA (disrupts translation) AND converted to 5-FUMP (inhibits thymidylate synthase → blocks thymidine synthesis → inhibits DNA synthesis). Human cells lack significant cytosine deaminase activity — selective toxicity.
- NEVER use as monotherapy — single-step mutations in cytosine deaminase or permease cause rapid high-level resistance. Combine with amphotericin B (synergistic for cryptococcal meningitis): AmB disrupts the fungal membrane, increasing 5-FC uptake; 5-FC inhibits DNA synthesis — the combination is more rapidly fungicidal than either alone.
- ADRs: Myelosuppression (anaemia, leukopenia, thrombocytopenia) — because some 5-FU does form in the gut (from intestinal bacteria deaminating 5-FC) and is absorbed systemically → bone marrow toxicity. Monitor CBC weekly. Hepatotoxicity (elevated LFTs). Requires renal dose adjustment (renally excreted).

Griseofulvin:
- Mechanism: binds to tubulin, disrupting microtubule assembly → impairs mitotic spindle function → dermatophyte cells cannot complete cell division. Fungistatic. Active ONLY against dermatophytes.
- Uses: tinea capitis (preferred in children — griseofulvin has better paediatric data), tinea corporis (increasingly replaced by terbinafine). Onychomycosis requires 6–18 months; largely superseded by terbinafine.
- ADRs: GI (nausea, diarrhoea — take with fatty food for better absorption), headache, teratogenic in animals (avoid in pregnancy and for 1 month after in men + 6 months in women — may impair fertility), hepatotoxicity (rare), photosensitivity, peripheral neuropathy (prolonged use), drug interaction with warfarin (CYP inducer — reduces warfarin levels, like rifampicin).

Clinical Decision-Making: Matching Antifungal to Clinical Syndrome

The clinical application of antifungal pharmacology follows a syndrome-based algorithm that integrates organism likelihood, site of infection, immune status, drug spectrum, and drug interactions.

Oral candidiasis (thrush): Most often C. albicans in HIV (CD4 <200), denture wearers, patients on inhaled corticosteroids. First-line: nystatin suspension (swish and swallow 4–6 hourly × 7–14 days) for mild disease; fluconazole 150mg single dose or 50–100mg daily × 7–14 days for moderate-severe or recurrent. Oesophageal candidiasis (dysphagia, retrosternal pain) — fluconazole 200–400mg/day × 14–21 days (IV if not tolerating oral).

Vulvovaginal candidiasis: Uncomplicated: topical clotrimazole 1% cream × 7 days OR oral fluconazole 150mg single dose. Complicated/recurrent: fluconazole 150mg every 72 hours × 3 doses, then weekly maintenance × 6 months.

Candidaemia and invasive candidiasis: Echinocandin first-line (caspofungin, micafungin, anidulafungin) — IDSA guidelines; step-down to fluconazole when clinically stable AND the isolate is fluconazole-susceptible AND blood cultures are negative. Remove central venous catheter. Duration: ≥14 days after last positive culture and symptom resolution.

Invasive aspergillosis: Voriconazole — first-line (IDSA 2016); superior to AmB (Walsh NEJM 2002). Primary alternative: isavuconazole or L-AmB. Duration: ≥6–12 weeks, depending on immunosuppression resolution. Galactomannan surveillance and CT halo sign monitoring guide response. Echinocandins (caspofungin) as salvage or combination therapy.

Mucormycosis (Rhizopus, Mucor, Lichtheimia): Liposomal amphotericin B (L-AmB) first-line — amphotericin B is the only established active agent (mucormycetes are intrinsically resistant to most azoles except posaconazole; voriconazole is NOT active vs Mucor — this is clinically important given its role in prophylaxis which may allow Mucor breakthrough). Posaconazole or isavuconazole as step-down or combination. Surgical debridement essential. Correct the underlying predisposing factor (diabetes, corticosteroids).

Cryptococcal meningitis: AmB (conventional or L-AmB) + 5-FC × 2 weeks (induction) → fluconazole 400mg/day × 8 weeks (consolidation) → fluconazole 200mg/day (maintenance until CD4 >200 on ART). Crucial adjunct: therapeutic lumbar puncture (repeated LP) to control raised intracranial pressure — ICP management is as important as antifungal therapy in preventing morbidity.

Dermatophytosis (tinea): Terbinafine topical (cream) × 2–4 weeks for tinea pedis/corporis/cruris. Systemic terbinafine 250mg/day × 4–12 weeks for tinea capitis or extensive disease; × 12 weeks for toenail onychomycosis. Griseofulvin for tinea capitis in children (better paediatric evidence than terbinafine for this indication). Itraconazole as alternative for onychomycosis.

Prophylaxis in immunocompromised: Fluconazole (Candida prophylaxis in solid organ transplant, haematology); posaconazole (Aspergillus prophylaxis in AML/MDS on high-dose chemotherapy or HSCT — NEJM 2007 trial); voriconazole (HSCT — especially active against Aspergillus).