The Problem of Azole-Resistant Thrush

The encouraging news is that we are making steady progress in treating -- and preventing -- the opportunistic infections that develop in people with advanced HIV disease. The distinctly discouraging news is that we still have real trouble controlling one of the most frequently seen of these infections -- oral candidiasis, commonly known as thrush.

At first, candida infections respond very well to drug therapy, and for a time it is possible to prevent recurrent infections through daily prophylaxis. But as people with HIV live longer, they develop forms of thrush that do not respond to the drugs we use to treat this infection. Reinfection occurs even in patients who remember to take their prophylactic medications every day, and cases of drug-resistant thrush are now a real problem in people who have been living with HIV for many years.

What is thrush?

Thrush, a common early opportunistic infection in people with HIV, is caused when a fungus called candida -- which is ubiquitous in the environment and is found in all human beings -- begins to grow out of control. Infection usually occurs in the mouth, the throat, or the vagina. When it develops in the mouth and throat, thrush appears as white or red patches on the skin. Infection can make it difficult to swallow and can cause nausea, changes in the way food tastes, and a loss of appetite. If the candidiasis goes untreated, these symptoms can lead to weight loss -- and eventually to wasting and even to death. In particularly severe cases, thrush in the mouth and throat can spread to the lungs or down the digestive tract.

When thrush occurs in the vagina it is referred to as a "yeast infection." Its symptoms are itching, burning, and a thick, yellowish discharge. Vaginal thrush can be a sign that a woman is HIV-positive, and in such women yeast infections tend to recur more often and last longer than they do in HIV-negative women.

Fortunately, a doctor can readily diagnose thrush in the mouth, throat, or vagina just by looking at the infected area.

"When fluconazole or one of its sister drugs is used to treat an initial episode of candidiasis, the response to therapy is usually prompt and complete. Subsequent episodes of thrush tend to respond less rapidly and less fully to azole therapy, which is why physicians have tended to put patients on fluconazole prophylaxis after their first or second bout of thrush."

How is it treated?

Minor cases of oral thrush usually respond to any of several simple treatments: the patient can gargle with a medicinal mouthwash, can suck on lozenges that contain an antifungal medication, or can rinse the affected area with hydrogen peroxide and water. More serious cases of candidiasis are usually treated with a class of antifungal drugs called azoles. The most widely prescribed of these drugs is fluconazole (Diflucan®), but this class also includes itraconazole (Sporanox®) and ketoconazole (Nizoral®).

When fluconazole or one of its sister drugs is used to treat an initial episode of candidiasis, the response to therapy is usually prompt and complete. Subsequent episodes of thrush tend to respond less rapidly and less fully to azole therapy, which is why physicians have tended to put patients on fluconazole prophylaxis after their first or second bout of thrush, hoping to prevent recurrent candida infections. When reinfection does occur, azoles are the most frequently used therapy.

Vaginal thrush is often treated with one of several clotrimazole ointments that can be obtained without a prescription (Mycelex®, Lotrimin®, Gyne-Lotrimin®). Nystatin tablets or fluconazole pills are used for more difficult cases, and here too treatment is usually successful.

"Current estimates are that 5% to 7% of people with advanced HIV infection will develop hard-to-treat thrush. In these patients the chief risk factors for the development of azole-resistant thrush are previous bouts of thrush, especially in the esophagus, and other opportunistic infections, especially MAC."

Who is at risk for fluconazole-resistant thrush?

The increased use of fluconazole -- to treat thrush or to prevent recurrent infection -- has been linked with an increased incidence of fluconazole-resistant candidiasis in people with HIV. A recent study from Johns Hopkins indicates that fluconazole resistance is most likely to develop in PWAs with CD4 cell counts below 50 who have already used fluconazole for a considerable time and have had many outbreaks of thrush. This discovery hardly comes as a surprise, but it does give us a better idea of which patients are at high risk of developing resistance to azole therapy.

Current estimates are that 5% to 7% of people with advanced HIV infection will develop hard-to-treat thrush. Preliminary analysis of an ACTG study of AIDS patients suggests that, over the course of a year, azole-resistant thrush will develop in about 4% of people with CD4 counts below 50. In these patients the chief risk factors for the development of azole-resistant thrush are: 1) previous bouts of thrush (especially in the esophagus); and 2) other opportunistic infections (especially MAC).

Most of the initial cases of thrush seen in people with HIV are caused by the fungus Candida albicans, but some of the people who take fluconazole as long-term prophylaxis against recurrent thrush eventually develop other species of candida -- species that flourish when C. albicans is suppressed. These species tend to be less responsive to treatment with fluconazole or with any of the other azole drugs.

"[The] preliminary data suggest that oral-suspension itraconazole is a safe and effective therapy for patients who develop resistance to fluconazole. Some maintenance therapy is necessary, however, because patients who do respond to treatment relapse when therapy is stopped."

Treating fluconazole-resistant thrush

The symptoms of azole-resistant candidiasis do not differ significantly from those of the more treatable forms of thrush, but they do tend to be more severe. Inflammation of the esophagus is much more common in patients with resistant thrush, for instance. Persistent tenderness in the mouth and soreness in the throat make swallowing difficult, and in especially severe cases these symptoms make the swallowing of solid foods virtually impossible. This makes it hard for affected individuals to get the nutrients they need -- which can lead to malnutrition and AIDS-related wasting.

There are a number of treatment options available when thrush stops responding to standard doses of fluconazole. The problem is that we don't yet know which treatments work best.

One option is simply to use higher doses of fluconazole -- up to 800 mg per day. Higher doses can be effective -- if the thrush is being caused by fungi that are less than fully responsive to treatment but are not yet fully resistant to the drug. With truly resistant strains of candida, no dose of fluconazole, no matter how high, is likely to be effective.

Another situation in which higher doses of fluconazole can be effective is when the potency of the drug has been diminished through interactions with other drugs a patient in taking. When certain drugs are taken in combination with fluconazole, the effect is to reduce the amount of fluconazole in the blood to levels that are too low to be effective. These drug-drug interactions occur most commonly with rifampin (which is often used to treat AIDS-related TB) and with rifabutin (used to treat or prevent MAC). In these situations, the dose of fluconazole must be adjusted upward in order to raise the level of drug in the blood to the point where it is capable of killing the candida.

In some instances it is possible to use one of the other azoles to treat fluconazole-resistant thrush -- because some fluconazole-resistant strains of candida are still sensitive to itraconazole and/or to ketoconazole. A new formulation of itraconazole, this one in an oral suspension, has shown particular promise in this regard, and it may become the therapy of choice for patients who fail fluconazole.

In one recently completed study of oral-suspension itraconazole, patients took 100 mg of the solution twice daily for 14 or 28 days, and 60% of the participants responded favorably to therapy -- meaning that all of their lesions cleared up. A Canadian trial, which involved 34 patients who used a regimen of 100 mg of the oral solution twice daily for 14 days, recorded a response rate of 65%. Although a few of these patients reported some gastrointestinal upset, the drug was generally well tolerated.

These preliminary data suggest that oral-suspension itraconazole is a safe and effective therapy for patients who develop resistance to fluconazole. Some maintenance therapy is necessary, however, because patients who do respond to treatment relapse when therapy is stopped. For this reason a maintenance schedule of 100 mg of oral-suspension itraconazole (taken twice daily, three days a week) is now being studied.

Other treatment options

Improved antiretroviral therapy itself has been reported to lead to the clearance of resistant thrush, with the credit in this instance going to the protease inhibitor component of multidrug treatment regimens. Aggressive antiretroviral therapy that includes a protease inhibitor may help PWAs overcome thrush -- even thrush that has developed resistance to fluconazole.

Intravenous amphotericin-B should be used initially in all PWAs with severe thrush, especially those with esophagitis, and it should be used for those who fail azole therapy. A short course of therapy at low doses (0.3 mg/kg for 7 to 14 days) is usually effective, although here again relapses are common in the absence of some form of maintenance therapy. Some cases of amphotericin B-resistant thrush have been reported.

Lozenges containing amphotericin-B, which are available in Europe but not in the United States, may be effective in controlling mild cases of thrush but are unlikely to have much impact on resistant infection. An oral suspension of amphotericin B is currently being evaluated in people with fluconazole-resistant thrush. Early data suggest that high doses (5 mL q.i.d.) will probably be needed.

Another alternative is flucytosine, which is active against Candida albicans but tends to be less effective against other species. C. albicans rarely develops resistance to flucytosine, even with chronic therapy. One possible approach to the management of fluconazole-resistant C. albicans infection is treatment with amphotericin-B followed by maintenance therapy with flucytosine (at a dose of 25 mg/kg q.i.d.). On this therapy one will have to be wary of flucytosine's potential for serious toxicity; this drug can damage the bone marrow and cause gastrointestinal problems such as abdominal pain, nausea, diarrhea, and bleeding.

Preventing fluconazole resistance

One way to reduce the risk that one will develop azole-resistant thrush is to delay the use of azoles, particularly their use as prophylaxis against recurring bouts of thrush. We now have data suggesting that candida infections are more likely to recur in patients who have a history of PCP, and they are less likely to recur in HIV-positive African-Americans. These recent findings, which my colleagues and I reported last January at the 4th Conference on Retroviruses and Opportunistic Infections, will help people and their doctors decide when prophylaxis should be started and when it can safely be withheld.

What Do You Do When the Medicine Stops Working?

Some therapeutic options for people who develop resistance to standard-dose fluconazole.

Higher doses of fluconazole (Diflucan®) -- up to 800 mg per day Comments: Can be effective if thrush is caused by fungi that are not fully resistant to fluconazole. Also effective in cases where the potency of the drug has been diminished by interactions with other drugs (such as rifampin and rifabutin).

Another azole -- itraconazole (Sporanox®) or ketoconazole (Nizoral®) Comments: A new oral suspension of itraconazole shows particular promise, and it may become the treatment of choice against fungi that develop resistance to fluconazole.

IV amphotericin-B (0.3 mg/kg for 7 to 14 days) Comments: Should be used initially in all PWAs with severe thrush, and in all those who fail azole treatment. Some form of maintenance therapy is necessary, because relapses are common.

Flucytosine (25 mg/kg four times a day) Comments: Active against C. albicans but not other strains of candida. Must be used with caution because of its potential for serious toxicities.

William G. Powderly, M.D., is from the Division of Infectious Diseases, AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, MO.