Flucytosine, Allylamines and Other Antifungal Agents

Features

Feature	Details
Mechanism	A fluorinated pyrimidine taken up by cytosine permease (FCY2) and deaminated by cytosine deaminase (FCA1, absent in human cells) to 5 fluorouracil; 5 fluorouracil is converted to 5 fluorouridine triphosphate (incorporated into RNA, disrupting protein synthesis) and to 5 fluorodeoxyuridine monophosphate (inhibits thymidylate synthase and DNA synthesis)
Spectrum	Candida (except Candida krusei with reduced susceptibility), Cryptococcus neoformans and Cryptococcus gattii, and some dematiaceous fungi (Fonsecaea, Cladophialophora) and Aspergillus (weak)
Resistance	Develops rapidly during monotherapy through mutations in FCY2, FCA1, and FUR1 (uracil phosphoribosyltransferase), so it is used with another drug
Pharmacokinetics	Over 90 percent oral bioavailability; widely distributed, including cerebrospinal fluid (75 percent of serum levels); minimal protein binding; excreted unchanged in urine; half life 3 to 6 hours (up to 85 hours in renal failure)

Dosing

Situation	Dose
Normal renal function	100 mg per kg per day orally in 4 divided doses (25 mg per kg every 6 hours); intravenous form 2.5 g every 6 hours where available
Renal impairment	Creatinine clearance 20 to 40 mL per minute: 25 mg per kg every 12 hours; 10 to 20 mL per minute: 25 mg per kg every 24 hours; below 10 mL per minute: 25 mg per kg every 48 hours or by levels; haemodialysis: 25 to 50 mg per kg after each session
Short course in cryptococcal meningitis	100 mg per kg per day for 7 days with single high dose liposomal amphotericin B and fluconazole in some regimens for HIV
Drug monitoring	Peak (2 hours after dose) 30 to 80 micrograms per mL, avoiding peaks above 100 and troughs above 25 to 50
Adverse effects	Bone marrow suppression (leucopenia and thrombocytopenia, dose related; high in renal failure and with levels above 100), hepatotoxicity, nausea, vomiting, diarrhoea and enterocolitis, rash, and confusion; severe toxicity in dihydropyrimidine dehydrogenase (DPYD) deficiency, which can be fatal
Monitoring	Full blood count twice weekly, liver tests and renal function weekly, and levels
Pregnancy	Avoided (teratogenic in animals)

Indications

Indication	Role
Cryptococcal meningitis	With amphotericin B (induction, 2 weeks, or 1 week with high dose liposomal amphotericin B), which shortens time to cerebrospinal fluid sterilisation and lowers mortality; with fluconazole (800 to 1200 mg daily) if amphotericin B cannot be given
Candida endocarditis, meningitis, and endophthalmitis	Added to amphotericin B in some regimens
Candiduria	Alone, in fluconazole resistant organisms (25 mg per kg every 6 hours for 7 to 10 days)
Chromoblastomycosis	With itraconazole (refractory disease)
Aspergillosis and others	Limited evidence

Terbinafine

Feature	Details
Mechanism	Inhibits squalene epoxidase, blocking ergosterol synthesis and causing accumulation of toxic squalene; fungicidal for dermatophytes
Spectrum	Dermatophytes (excellent), Sporothrix, Aspergillus, dematiaceous fungi (in combination), Candida (fungistatic, weak), and Lomentosporium (in combination with voriconazole)
Pharmacokinetics	Oral bioavailability 70 percent (with first pass metabolism); highly lipophilic, accumulating in skin, hair, nails, and sebum; terminal half life 200 to 400 hours; metabolised by multiple cytochromes (2C9, 1A2, 3A4, 2C8, and 2C19); persists in nails 6 to 9 months
Adult doses	250 mg once daily: tinea pedis 2 to 6 weeks, tinea corporis and cruris 2 to 4 weeks, tinea capitis 4 weeks (6 to 8 weeks for Microsporum), fingernail onychomycosis 6 weeks, toenail onychomycosis 12 weeks (pulse 500 mg per day for 1 week per month for 3 to 4 months); sporotrichosis 500 mg daily
Children	Under 20 kg: 62.5 mg daily; 20 to 40 kg: 125 mg daily; over 40 kg: 250 mg daily (tinea capitis 4 weeks)
Topical	1 percent cream or gel or spray once or twice daily for 1 to 2 weeks (tinea pedis, cruris, corporis)
Adverse effects	Gastrointestinal upset, taste disturbance (reversible), headache, rash, hepatotoxicity (rare; hepatitis, liver failure, and cholestasis), neutropenia, severe skin reactions, lupus like syndrome, and depression
Monitoring	Baseline liver tests and in prolonged courses; avoid in active liver disease
Interactions	Inhibits cytochrome 2D6 (tricyclics, selective serotonin reuptake inhibitors, beta blockers, flecainide, and codeine); rifampicin lowers levels, and cimetidine raises them
Resistance	SQLE point mutations (F397L, L393F, and others) in Trichophyton rubrum and Trichophyton indotineae, with treatment failure and a rising incidence in South Asia and elsewhere; itraconazole is used

Naftifine, butenafine, and tolnaftate

Drug	Use
Naftifine	1 to 2 percent cream or gel once or twice daily for 2 to 4 weeks (tinea pedis, cruris, corporis); anti-inflammatory effect
Butenafine	1 percent cream once or twice daily for 1 to 4 weeks (a benzylamine); tinea and cutaneous candidiasis
Tolnaftate	1 percent cream, powder, or spray twice daily (a thiocarbamate, squalene epoxidase inhibitor); tinea pedis, cruris, and corporis (not for nails or scalp)

Agent	Mechanism and use
Griseofulvin	Binds microtubules and inhibits mitosis (fungistatic, dermatophytes only); micronised 500 to 1000 mg daily in adults, 10 to 20 mg per kg daily in children (ultramicrosize 330 to 375 mg daily); tinea capitis 6 to 8 weeks (up to 12 weeks for Microsporum), tinea corporis 2 to 4 weeks, tinea pedis 4 to 8 weeks, and nails 6 to 12 months (poor); take with fatty food; adverse effects are headache, rash, photosensitivity, gastrointestinal upset, hepatotoxicity, and induction of cytochrome enzymes (reduces warfarin and oral contraceptives); contraindicated in pregnancy, porphyria, and lupus; now second line
Amorolfine	A morpholine; 5 percent nail lacquer once or twice weekly for 6 months (fingernails) to 9 to 12 months (toenails) for distal onychomycosis; 0.25 percent cream
Ciclopirox	A hydroxypyridone (iron chelation, inhibits metal dependent enzymes); 8 percent nail lacquer daily for up to 48 weeks; 1 percent cream or shampoo for tinea, candidiasis, and seborrhoeic dermatitis
Tavaborole	Benzoxaborole inhibiting leucyl tRNA synthetase; 5 percent solution once daily to the toenail for 48 weeks
Efinaconazole	Triazole; 10 percent solution once daily for 48 weeks
Selenium sulphide	2.5 percent lotion or shampoo applied for 10 minutes daily for 7 days (pityriasis versicolor)
Zinc pyrithione, undecylenic acid, Whitfield ointment (benzoic acid with salicylic acid), gentian violet	Topical keratolytic and antiseptic agents for tinea and oral candidiasis (gentian violet 0.5 percent twice daily for oral candidiasis, with staining and mucosal irritation)
Potassium iodide	Saturated solution: 1 mL three times daily, increasing to 4 to 6 mL three times daily as tolerated, for 3 to 6 months (lymphocutaneous sporotrichosis in resource limited settings); iodism and thyroid effects
Ibrexafungerp	Oral triterpenoid glucan synthase inhibitor: 300 mg twice daily for 1 day for vulvovaginal candidiasis, with activity against echinocandin and azole resistant Candida; teratogenic (contraindicated in pregnancy); invasive indications under investigation
Rezafungin	Once weekly echinocandin with a long half life, used for candidaemia and invasive candidiasis

Agent	Class and features
Olorofim	Orotomide; inhibits dihydroorotate dehydrogenase; active against Aspergillus (including azole resistant), Scedosporium, Lomentosporium, Fusarium, Coccidioides, and Histoplasma; not active against Mucorales, Candida, or Cryptococcus; oral and intravenous; hepatic and drug level effects; phase 3 testing
Fosmanogepix	Gwt1 inhibitor (prodrug of manogepix); active against Candida (including Candida auris), Aspergillus, Fusarium, Scedosporium, Lomentosporium, and Mucorales; not active against Candida krusei intrinsically; oral and intravenous; phase 3 testing
Opelconazole	Inhaled triazole for pulmonary prophylaxis and treatment
SUBA itraconazole	Improved bioavailability formulation
Encochleated amphotericin B	Oral lipid crystal formulation
Nikkomycin Z	Chitin synthase inhibitor; for coccidioidomycosis, in trials
Others	Ibrexafungerp for invasive candidiasis, VT-1598, and other CYP51 selective agents; antifungal peptides and immunotherapy are experimental

Combination	Evidence
Amphotericin B with flucytosine	Established for cryptococcal meningitis (faster clearance and lower mortality) and used for Candida central nervous system disease
Voriconazole with an echinocandin	Improved survival in a subgroup with invasive aspergillosis (positive galactomannan), and used in salvage
Liposomal amphotericin B with voriconazole	Used in fusariosis (limited evidence)
Voriconazole with terbinafine	Used in Lomentosporium prolificans infection, with limited evidence
Liposomal amphotericin B with an echinocandin or posaconazole	Used in mucormycosis, with limited evidence
Itraconazole with terbinafine	Used in resistant dermatophytosis
Itraconazole with flucytosine	Chromoblastomycosis
Fluconazole with amphotericin B	A trial in candidaemia showed an advantage in microbiological clearance and no difference in mortality

Infection	First line
Candidaemia	Echinocandin; fluconazole for stable patients with susceptible isolates
Cryptococcal meningitis	Liposomal amphotericin B with flucytosine, then fluconazole
Invasive aspergillosis	Voriconazole or isavuconazole (liposomal amphotericin B as an alternative)
Mucormycosis	Liposomal amphotericin B; posaconazole or isavuconazole for step down
Endemic mycoses (mild)	Itraconazole
Endemic mycoses (severe)	Liposomal amphotericin B, then itraconazole
Dermatophytes	Terbinafine (itraconazole or fluconazole as alternatives)
Pneumocystis	Trimethoprim sulfamethoxazole
Mucosal candidiasis	Topical azoles or nystatin, fluconazole for oral and oesophageal disease

Flucytosine, Allylamines and Other Antifungal Agents

Flucytosine

Features

Dosing

Indications

Allylamines And Related Topical Agents

Other Systemic And Topical Agents

Agents In Development

Combination Therapy

Selection At A Glance