Antifungal medicines

Definition and Scope

Antifungal medicines are pharmacological agents used to treat, prevent, or control fungal infections in humans

They act by targeting unique components of fungal cells, disrupting cell membrane integrity, DNA synthesis, or mitotic activity

Fungal infections may be superficial (skin, nails, mucous membranes) or systemic (lungs, bloodstream, CNS), requiring different classes and routes of antifungal drugs

Fungi are eukaryotic organisms, so antifungal therapy must balance efficacy against pathogens with minimal toxicity to human cells

Classification of Antifungal Agents

1. Azoles

Imidazoles: ketoconazole, clotrimazole, miconazole, econazole

Triazoles: fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole

Inhibit fungal cytochrome P450-dependent enzyme lanosterol 14α-demethylase, blocking ergosterol synthesis and compromising cell membrane integrity

2. Polyenes

Amphotericin B, nystatin, natamycin

Bind to ergosterol in fungal cell membranes, creating pores that lead to ion leakage and cell death

3. Echinocandins

Caspofungin, micafungin, anidulafungin

Inhibit β-1,3-D-glucan synthase, blocking fungal cell wall synthesis (not present in human cells)

4. Allylamines

Terbinafine, naftifine, butenafine

Inhibit squalene epoxidase, disrupting ergosterol biosynthesis and leading to accumulation of toxic squalene

5. Antimetabolites

Flucytosine

Converted within fungal cells to 5-fluorouracil, inhibiting RNA and DNA synthesis

6. Other topical agents

Ciclopirox: chelates iron and disrupts enzymatic systems

Tolnaftate: distorts hyphal growth

Undecylenic acid: disrupts fungal cell membranes

7. Newer agents under research

Olorofim, ibrexafungerp, fosmanogepix: target novel fungal pathways

Spectrum of Activity

Superficial mycoses: dermatophytes (Trichophyton, Epidermophyton, Microsporum), Candida spp., Malassezia

Systemic mycoses: Aspergillus, Cryptococcus, Histoplasma, Blastomyces, Coccidioides, Candida (invasive), Mucorales

Fungal nail infections (onychomycosis): Trichophyton rubrum, T. mentagrophytes

Fungal meningitis: Cryptococcus neoformans

Fungal pneumonia: Pneumocystis jirovecii (not responsive to classic antifungals, treated with cotrimoxazole)

Routes of Administration

Topical: creams, gels, lotions, powders, sprays, vaginal pessaries

Oral: tablets, capsules, suspensions

Parenteral: intravenous (used for severe/systemic infections)

Clinical Indications

Topical Use

Tinea corporis, tinea pedis, tinea cruris, candidal intertrigo

Cutaneous candidiasis

Seborrheic dermatitis

Onychomycosis (mild cases)

Oropharyngeal or vulvovaginal candidiasis

Fungal otitis externa

Systemic Use

Invasive candidiasis and candidemia

Aspergillosis

Cryptococcal meningitis

Endemic mycoses (e.g., histoplasmosis)

Tinea unguium (oral terbinafine or itraconazole)

Recurrent vulvovaginal candidiasis

Prophylaxis in immunocompromised patients (e.g., fluconazole or posaconazole in leukemia)

Examples of Common Antifungals by Class

Azoles

Fluconazole: oral, IV; used for Candida, Cryptococcus, Coccidioides

Itraconazole: oral solution preferred; dermatophytes, onychomycosis, histoplasmosis

Voriconazole: first-line for invasive aspergillosis

Posaconazole: prophylaxis in neutropenic patients

Clotrimazole: topical, vaginal

Miconazole: topical, buccal

Ketoconazole: topical only; oral use limited due to hepatotoxicity

Polyenes

Amphotericin B deoxycholate: IV; broad-spectrum for life-threatening infections

Liposomal amphotericin B: reduced nephrotoxicity

Nystatin: oral suspension or topical; used for oral/vaginal candidiasis

Natamycin: ophthalmic antifungal

Echinocandins

Caspofungin, micafungin, anidulafungin: IV only; used for invasive Candida and Aspergillus infections

Well-tolerated with low toxicity profile

No significant activity against Cryptococcus or dimorphic fungi

Allylamines

Terbinafine: oral or topical; highly effective against dermatophytes

Oral form used for nail and scalp fungal infections

Naftifine and butenafine: topical use for tinea infections

Antimetabolites

Flucytosine: oral; used in combination with amphotericin B for cryptococcal meningitis

Monotherapy avoided due to rapid resistance

Topical Agents (Others)

Ciclopirox: used in nail lacquer or cream for dermatophyte infections and seborrheic dermatitis

Tolnaftate: tinea pedis and cruris

Undecylenic acid: mild tinea infections

Pharmacokinetics

Oral azoles: generally well absorbed, especially fluconazole

Itraconazole solution requires acidic pH; tablets require food

Voriconazole has non-linear kinetics and requires monitoring

Fluconazole penetrates CNS; effective for fungal meningitis

Echinocandins exhibit poor CNS penetration but excellent tissue distribution

Terbinafine concentrates in nails and skin, allowing once-daily dosing

Amphotericin B is not absorbed orally; requires IV administration for systemic effect

Adverse Effects

Azoles

Hepatotoxicity (monitor liver enzymes)

QT prolongation (fluconazole, voriconazole)

Visual disturbances (voriconazole)

GI upset: nausea, vomiting, abdominal pain

Endocrine effects (ketoconazole: adrenal suppression, gynecomastia)

Polyenes

Nephrotoxicity (amphotericin B)

Electrolyte disturbances: hypokalemia, hypomagnesemia

Infusion reactions: fever, chills, rigors

Anemia (suppressive effect on erythropoiesis)

Echinocandins

Generally well tolerated

Mild hepatotoxicity

Histamine-mediated infusion reactions

Phlebitis at infusion site

Allylamines

GI upset

Taste disturbances

Rare hepatotoxicity with oral use

Rash, urticaria

Flucytosine

Bone marrow suppression

GI toxicity

Liver enzyme elevation

Rapid resistance when used alone

Topical Agents

Local irritation, burning, itching

Contact dermatitis

Hypersensitivity reactions

Contraindications

Known hypersensitivity to the antifungal agent

Severe hepatic dysfunction (azoles)

Congenital long QT syndrome (certain azoles)

Coadministration with contraindicated interacting drugs (e.g., simvastatin + itraconazole)

Pregnancy: azoles contraindicated in first trimester due to teratogenicity (especially fluconazole at high doses)

Precautions

Monitor liver function tests with systemic azoles and terbinafine

Check drug levels for voriconazole if used long-term

Assess renal function during amphotericin B therapy

Avoid ketoconazole orally unless benefits outweigh risks

Adjust dosage in renal or hepatic impairment when required

Assess cardiac risk if azole-related QT prolongation is a concern

Drug Interactions

Azoles inhibit CYP3A4, leading to interactions with statins, warfarin, immunosuppressants, benzodiazepines, and many others

Rifampin reduces levels of azoles and flucytosine

Amphotericin B may enhance nephrotoxicity when used with aminoglycosides, cyclosporine, or furosemide

Terbinafine is a CYP2D6 inhibitor; interacts with tricyclic antidepressants, SSRIs, beta-blockers

Fluconazole and voriconazole increase serum concentration of sulfonylureas, phenytoin, and cyclosporine

Avoid co-use of drugs that prolong QT interval with azoles unless benefits outweigh risk

Monitoring Parameters

Liver function tests (ALT, AST, bilirubin)

Renal function (urea, creatinine)

Electrolytes (potassium, magnesium) for amphotericin B

Therapeutic drug monitoring for voriconazole or itraconazole

Complete blood count for flucytosine

Assessment of clinical response and resolution of infection

Pregnancy and Lactation

Topical antifungals considered safe during pregnancy

Systemic azoles: generally contraindicated in pregnancy

Amphotericin B: preferred agent for systemic fungal infections during pregnancy

Flucytosine: teratogenic, avoid in pregnancy

Terbinafine: avoid systemic use unless benefit outweighs risk

Limited data on echinocandins in pregnancy; not routinely recommended

For lactation: topical agents generally safe; systemic use requires risk-benefit evaluation

Examples of Antifungal Formulations

Fluconazole tablets, oral suspension, IV vials

Clotrimazole cream, lozenges, vaginal tablets

Terbinafine tablets, topical cream

Nystatin oral suspension, cream, powder

Amphotericin B liposomal injection

Caspofungin IV

Miconazole oral gel, cream, vaginal suppository

Ketoconazole shampoo, cream

Ciclopirox nail lacquer

Emerging Resistance Concerns

Candida auris: multidrug-resistant, nosocomial pathogen

Azole-resistant Aspergillus fumigatus strains

Cross-resistance among azoles in long-term immunocompromised patients

Over-the-counter topical antifungal misuse contributing to resistant dermatophytes

Routine susceptibility testing advised for invasive fungal isolates

Strategic Use and Stewardship

Avoid empirical broad-spectrum antifungal therapy without clear indication

Use topical agents for localized superficial infections

Reserve systemic agents for confirmed or high-risk systemic fungal infections

Promote antifungal stewardship in hospitals to prevent resistance development and preserve efficacy of limited antifungal classes

Implement infection control protocols to prevent spread of resistant fungal pathogens in healthcare settings

Examples of Common Brand Names

Diflucan (fluconazole)

Lamisil (terbinafine)

Nystan (nystatin)

Canesten (clotrimazole)

Daktarin (miconazole)

Sporanox (itraconazole)

VFEND (voriconazole)

Noxafil (posaconazole)

Mycamine (micafungin)

Ambisome (liposomal amphotericin B)

Summary of Clinical Tips

Use topical antifungals first-line for uncomplicated skin infections

Oral terbinafine is most effective for dermatophyte nail infections

Fluconazole is the drug of choice for many Candida infections

Voriconazole is preferred for invasive aspergillosis

Amphotericin B is reserved for severe systemic infections

Echinocandins are ideal for invasive candidiasis, especially in ICU settings

Always assess potential drug interactions and monitor for hepatic toxicity with systemic therapy

Avoid azole use in pregnancy unless life-threatening infection mandates it

Do not use antifungals for non-fungal conditions (e.g., bacterial or inflammatory dermatoses) without confirmed diagnosis