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Echinocandins offer antifungal therapy with low toxicity, few drug-drug interactions.

MIAMI -- The echinocandin antifungal agents appear to have little significant toxicity and may prove safer than the azoles or amphotericin B in terms of potential interactions, said Paul O. Gubbins, Pharm.D.

"Echinocandins are an exciting new class. To date, there are few significant drug-drug interactions," he said at a meeting on fungal infections sponsored by Imedex.

The echinocandin caspofungin (Cancidas) has "no significant interaction" with cytochrome P-450 (CYP450) metabolism or P-glycoprotein, according to product labeling. The most abundant enzyme in the CYP450 system, CYP3A4, metabolizes about 50%-60% of all medicines.

The recently approved echinocandin micafungin (Mycamine) is not a substrate or inhibitor for P-glycoprotein, a trans-membrane efflux pump in the liver, intestine, kidneys, and blood-brain barrier.

With a lower potential for interactions, the echinocandins may be ideal for combination therapy, said Dr. Gubbins, chair of the department of pharmacy practice, University of Arkansas, Little Rock.

Traditional formulations of amphotericin B have renal toxicity that can produce additive drug interactions. "We're all familiar with the toxicities of amphotericin B. They are subtle and, in most cases, unavoidable. Consider renal-sparing alternatives" such as lipid amphotericin B or caspofungin, he suggested.

When prescribing traditional amphotericin B, monitor serum levels of drugs that have a narrow therapeutic index and are eliminated by the kidneys. Examples include aminoglycosides and 5-flucytosine.

Some patients, such as organ transplant recipients, require closer monitoring. They often must use drugs--such as immunosuppressants--that increase the risk of fungal infections, he noted.

The azoles can interact through multiple mechanisms, including CYP450 metabolism, gastric pH-dependent effects, and P-glycoprotein activity.

"Interactions can be managed with alternative drugs in the affected class or by switching agents," Dr. Gubbins said.

Itraconazole leads the azole class in terms of potential interactions. The antifungal interacts through the CYP450 system with statins, especially lovastatin, simvastatin, and atorvastatin (Lipitor), and this can lead to skeletal muscle toxicity. Other affected agents include benzodiazepines, anxiolytics, immunosuppressants, and corticosteroids. With corticosteroids, he said, "The key is, it doesn't matter if you give these orally or IV, or if they're inhaled, you can get interactions."

Itraconazole can also have significant pH interactions. Dr. Gubbins suggested that patients take the tablets with a high-fat meal in order to slow gastric emptying or with a meal that contains enough protein to buffer the stomach contents. Other techniques for reducing pH interactions include spacing the administration of tablets, considering itraconazole oral solution, or switching to another agent.

P-glycoprotein interactions are significant only for itraconazole, not for voriconazole (Vfend), or fluconazole, he said.

Several agents lower serum levels of itraconazole, including phenytoin, phenobarbital, rifampin, and rifabutin (Mycobutin), but "remember that itraconazole affects other medications more than other medications affect itraconazole," he said. "The ones we're worried about are the ones with a narrow therapeutic index, such as digoxin."

Fluconazole affects more CYP450 enzymes than does itraconazole. Interactions depend largely on fluconazole concentration and are typically seen with doses above 200 mg. Of particular concern are interactions between fluconazole and phenytoin or warfarin. "With phenytoin, if you do not see a response, it could be that [phenytoin] is inhibiting fluconazole," he said.

"We also worry about the anticoagulant warfarin .... This interaction is almost guaranteed." Decreasing the warfarin dose might help, but "you almost always need to move to another antifungal."

Drugs that affect voriconazole include phenytoin, rifampin, and rifabutin. Other potential interactions include carbamazepine, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, benzodiazepines, and statins.


Miami Bureau
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Title Annotation:Infectious Diseases
Author:McNamara, Damian
Publication:Internal Medicine News
Date:May 15, 2005
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