Antifungals in Dermatology: Tinea, Candida and the Nail Problem

Who the culprits are

Three families cause almost every superficial fungal infection you will meet. First, the dermatophytes — moulds that feed on keratin and therefore colonise skin, hair and nails. They produce the classic scaly, itchy, advancing ring of tinea (ringworm): tinea corporis on the trunk, tinea pedis (athlete's foot) between the toes, tinea cruris in the groin, and tinea capitis on the scalp. Second, Candida — a yeast that overgrows in warm, moist, occluded places: the skin folds under a breast or abdomen (intertrigo), the corners of the mouth, the nappy area, and the vaginal or oral mucosa. Third, Malassezia — a yeast that lives in every sebum-rich follicle and, when it overgrows, produces the patchy pigment changes of pityriasis versicolor and drives the greasy scaling of seborrhoeic dermatitis. Different organisms, different clinical pictures — but as we will see, one shared pharmacological weak point.

The one weak point: the ergosterol membrane

Every fungal cell is wrapped in a plasma membrane, and that membrane depends on a sterol called ergosterol — the fungal equivalent of the cholesterol in our own membranes. Ergosterol keeps the membrane fluid, sealed and functional. Because human cells use cholesterol and not ergosterol, the ergosterol pathway is a target that belongs to the fungus alone — the classic principle of selective toxicity. Nearly every antifungal drug in dermatology attacks this one pathway, just at different steps. Picture the assembly line that builds ergosterol: squalene is converted by squalene epoxidase, then several steps later the enzyme 14-α-demethylase (a fungal cytochrome P450) performs a key conversion, and finished ergosterol is finally slotted into the membrane. Each drug class jams a different point on that line — and one class ignores synthesis altogether and attacks the finished product directly.

Azoles: block 14-α-demethylase

The largest and most familiar antifungal class works by inhibiting one fungal P450 enzyme. The azoles inhibit 14-α-demethylase, the cytochrome P450 enzyme partway down the ergosterol assembly line. Block it and two things happen: ergosterol runs out, and toxic sterol precursors pile up behind the blockade — a double hit that leaves the membrane defective. Topically, the azoles are the everyday workhorses of dermatology: clotrimazole, miconazole and ketoconazole clear tinea corporis, cruris and pedis, cutaneous candidiasis and pityriasis versicolor with a cream applied for a couple of weeks. When infection is too deep or too extensive for a cream — widespread tinea, nail or scalp disease, or stubborn Candida — the oral azoles itraconazole and fluconazole take over, carried by the blood into the skin, nail and hair. Their great strength is breadth; their great weakness is that they inhibit human cytochrome P450 enzymes too.

That off-target P450 inhibition is why oral azoles are pharmacologically noisy. Because the same enzyme family metabolises countless other drugs, itraconazole and fluconazole raise the levels of statins, warfarin, some benzodiazepines, certain calcium-channel blockers and many more — a recipe for drug interactions that must be checked before every prescription. The oral azoles also carry a risk of hepatotoxicity, so liver function is monitored on longer courses; itraconazole in particular is avoided in significant heart failure because of a negative inotropic effect. This is the same CYP-interaction and hepatic-safety story told in full in the Antimicrobials chapter, where the systemic antifungals — the azoles, the polyenes and the echinocandins used for invasive disease — are covered as a complete pharmacology. Here in dermatology, the practical lesson is simpler: a topical azole is almost interaction-free, but the moment you reach for an oral azole you inherit its CYP baggage.

Allylamines: block squalene epoxidase

Terbinafine attacks the assembly line one step earlier — and does more than starve the cell. The allylamine terbinafine inhibits squalene epoxidase, the enzyme near the very start of ergosterol synthesis. This blockade does two things at once: ergosterol production stops (so the membrane can't be maintained), and squalene itself accumulates to toxic levels inside the cell. That accumulated squalene is directly poisonous to the fungus — which is why terbinafine is fungicidal (it kills the organism) rather than merely fungistatic (holding it in check), the mode most azoles rely on against dermatophytes. Fungicidal killing plus a special affinity for keratin makes terbinafine the drug of choice for dermatophyte nail infection (onychomycosis) and, orally, a first-line treatment for tinea capitis. Topical terbinafine handles ordinary tinea of the body and feet in a shorter course than the azoles, but the nail and scalp still demand the oral form to reach the fungus buried in keratin.

Oral terbinafine is generally well tolerated but has two signature adverse effects worth committing to memory. The first is hepatotoxicity: as with the oral azoles, liver function should be checked before and during a long course, and the drug stopped if enzymes climb. The second is oddly specific — a disturbance or loss of taste (dysgeusia) that can persist for weeks and, rarely, longer; patients should be warned, because it is alarming if unexpected. Because onychomycosis courses run for many weeks (fingernails clear faster than the slow-growing toenails), these safety points matter far more than they would for a two-week cream.

Griseofulvin, polyenes and the nail lacquer

A few older or niche agents round out the toolkit. Griseofulvin is the classic — it doesn't touch the membrane at all; instead it disrupts the fungal microtubules that pull chromosomes apart during division, and it deposits in newly formed keratin, making the growing skin and hair resistant to invasion. It was for decades the mainstay of tinea capitis and still has a defined role there, particularly in children and against certain organisms, though terbinafine has largely overtaken it. The polyenes take the direct-attack route from the analogy: nystatin binds ergosterol already sitting in the fungal membrane and punches pores through it, so the cell leaks and dies. Nystatin is too toxic to absorb systemically but is superb applied topically or as a mouth/gut preparation for Candida — oral thrush, candidal intertrigo, the nappy area. It has essentially no activity against dermatophytes, so nystatin is a Candida drug, not a ringworm drug — a distinction students routinely blur. Finally, for very mild nail disease or patients who can't take an oral drug, ciclopirox is available as a medicated nail lacquer painted on the plate, though its cure rate is modest precisely because of the keratin barrier.

The nail-and-scalp problem: why keratin forces oral therapy

The single most important decision in dermatological antifungal therapy is topical versus oral — and keratin decides it. Superficial tinea on ordinary skin has only a thin layer of keratin above the living cells, so a cream diffuses down to the fungus easily and clears it in a week or two. The nail plate and the hair shaft are the opposite: dense, thick, dead keratin that a topical drug cannot penetrate to any useful depth. To reach a fungus living inside the nail or the hair, the drug has to arrive from the inside — carried by the bloodstream, delivered into the nail bed and the hair follicle, and then incorporated into the keratin as it grows. That is exactly what oral terbinafine, itraconazole and griseofulvin do. And because the diseased nail or hair must literally grow out and be replaced by healthy keratin, the courses are long — weeks for the scalp, and months for nails, with toenails slowest of all. This is the Foundations principle of skin and appendage structure made pharmacologically concrete: the barrier that protects us also protects the fungus, and the reasoning is developed further in the Hair and Nails chapter, where onychomycosis gets its full work-up. The clinical corollary is discipline: because an oral course is long and carries hepatotoxicity and interaction risk, you confirm the diagnosis first — a nail clipping for microscopy and culture, or scalp samples — before committing a patient to months of a systemic drug for what might not even be a fungus.