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12/10/2001

Study Identifies Amphotericin B Nephrotoxicity Risks

Kate Traynor

A recently published report describes risk factors for amphotericin B deoxycholate-related kidney toxicity that could help clinicians decide which patients should avoid this antifungal drug.

In this retrospective study of 494 hospitalized adults, 29 percent of the 59 patients who had three or more major risk factors—male sex, a mean daily amphotericin B dosage of >35 mg, body weight of >90 kg, chronic kidney disease, or the concomitant use of amikacin or cyclosporine—suffered from moderate-to-severe kidney toxicity. Eighteen percent of the 117 patients who had two of the five risk factors had moderate-to-severe nephrotoxicity during treatment. In all, 28 percent of the patients had some degree of kidney toxicity.

The report, which appeared in the November 2001 American Journal of Medicine, described patients with two or more of the five nephrotoxicity risk factors as "potential candidates for alternative antifungal therapy."

Stanley L. Pestotnik, M.S., a pharmacist and one of the report’s authors, said he believes that clinicians "already had an idea that these were risk factors."

"This study," he said, "was able to quantify [the risk factors] and put them into perspective."

Pestotnik said he hopes the study’s findings will help clinicians determine when to use liposomal amphotericin B or Cancidas, Merck & Co. Inc.’s caspofungin product, in place of standard amphotericin products.

For patients without risk factors for nephrotoxicity, Pestotnik noted, "there’s no reason not to use amphotericin as a first-line agent and preserve these more expensive agents ... the liposomal or the newer Cancidas-type agents."

The study took place from January 1990 through September 1998. All of the patients for whom data was collected had received a conventional amphotericin B formulation rather than the liposomal formulation that the Food and Drug Administration approved in 1997.

Common underlying conditions among the study participants included leukemia, lymphoma, solid-organ cancer, liver disease, and diabetes mellitus. Confirmed fungal infections diagnosed in the patients were caused by Candida, Aspergillus, and Cryptococcus organisms. The patients’ median cumulative amphotericin dosage was 240 mg, and half of the patients received the drug for 10 or more days.

Pestotnik said that the study had excluded patients for whom azole-type antifungals were indicated.

"These were people who had fungal infections that required amphotericin, for the most part," he said. "Certainly," he added, "if you’ve got a fungus that could be treated with one of the azoles, that would be the way to go."

The study recognized three degrees of nephrotoxicity among amphotericin B users. "Any degree" of toxicity was defined as a 50 percent or greater increase in a patient’s serum creatinine concentration, to a value of 1.5 mg/dL or more, after starting amphotericin B therapy. "Moderate-to-severe" toxicity was characterized by a serum creatinine level of at least 2.0 mg/dL, representing at least a doubling over the baseline value. A threefold or greater rise in a patient’s serum creatinine level, to a value of 3 mg/dL or more, was considered "severe" nephrotoxicity.

According to the report, amphotericin B users who also received amikacin had a 4.8-fold increase in their risk for moderate-to-severe kidney toxicity. Patients who received cyclosporine and amphotericin B had a 2.4-fold increase in this risk. Concomitant use of amphotericin B and tacrolimus, furosemide, vancomycin, or imipenem did not seem to increase the patients’ risk for kidney toxicity.

The cumulative dosage of amphotericin B was tied to the risk of kidney toxicity, which increased by 13 percent for each 10-mg rise in the average daily dose of the drug. Male sex was associated with a 90-percent increase in the risk for moderate-to-severe kidney toxicity, and chronic renal disease was linked to a 2.8-fold increase in risk.

The study was funded in part by a grant from caspofungin manufacturer Merck. Pestotnik said the company "had no editorial oversight on the manuscript, nor did they have any influence on the analysis."