COMMENTARY

Using Oral Ketoconazole in Dermatology: Where Are We Now?

F.W. Danby, MD

Disclosures

August 28, 2013

In This Article

The FDA Warning on Ketoconazole

On July 26, 2013, the US Food and Drug Administration (FDA) released a Drug Safety Communication titled "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems."[1] The drug is known to be a very potent inhibitor of hepatic cytochrome P450 3A4 when used at the approved dose; indeed, it is the standard against which other such inhibitors are compared in pharmacodynamic and pharmacokinetic studies.[2] Serious adverse effects that occurred when used in the approved dose led to France's withdrawal of the drug for use in deep fungal infections . That led to a mandatory review by other European Union (EU) and UK regulators and a similar withdrawal; the FDA essentially followed suit.

Ketoconazole Dosage in Malassezia Infection

Dermatologists have been aware of the risks posed by the full approved dosage of ketoconazole for decades and are likewise aware of less toxic options for managing dermatophyte (athlete's foot fungus) and Candida (vulvovaginal yeast) infections of the skin and nails.

Ketoconazole has, however, one exceedingly valuable property: It is exceptionally lipophilic. This means that even when given at a low dose, it concentrates in the sebum, the oil produced in our sebaceous glands. It thus arrives in exactly the location often occupied by a small and very challenging yeast-like fungus called Malassezia. This organism is also lipophilic, basically because it requires a group of long- chain fatty acids in its diet, and these are supplied by sebum. The organism will not grow in normal cultures taken from skin lesions because the yeast will grow only if appropriate fatty acids are added to the culture medium. This highlights a problem: We are all hosts to the organism, so a positive culture means little, because the yeast is on all our skins wherever sebum is available.

Although the yeast's presence normally goes unnoticed, its influence can be compared to the effect of ragweed or other pollen on skin, up noses, or in eyes. For most people, there is no problem -- but for some who become allergic to the little round pollen granules or the similar-sized spherical yeast, an acute allergic reaction results. This reaction varies by degree and location but triggers the friendly fire of the innate and adaptive immune systems. The patient winds up with distressing symptoms. In both cases, itch predominates. Anyone who has suffered a genital "yeast infection" can confirm the intensity of the itch, and a hot athlete's foot is a close second. The best therapy is to remove the antigen.

Eliminating the yeast from the surface of otherwise healthy skin is relatively simple, and many effective topical antiyeast preparations are available in cream, liquid, lotion, and shampoo format. One can also simply wash yeast off the skin, but a problem arises when the organism finds its way down into the follicular portion of the folliculopilosebaceous unit, where it is beyond the reach of topical agents. It is incapable of migrating into the pilar portion and seems never to actually invade the sebaceous gland itself, probably because it cannot penetrate the sebocyte wall. It remains in the duct where liquid sebum is available, holding onto the ductal keratinocytes.

There is no better remedy for a lipophilic organism than a lipophilic antimicrobial, but in this situation we are not looking at a chemical that can kill the yeast. Instead, ketoconazole interferes with Malassezia's ability to adhere to the walls of the follicular duct, allowing sebum to slowly flush the yeast out of the duct. This seems to work faster in teens than in older adults. Ketoconazole also seems to slow the yeast's ability to evade phagocytosis, allowing its clearance.[3]

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