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Amphotericin B: Is Slower Better?

Kate Traynor

Researchers in Switzerland reported in the March 10 BMJ (PDF) that patients tolerate amphotericin B deoxycholate better when it is infused over 24 hours instead of four hours. But two U.S. pharmacists say that for now, continuous infusion of amphotericin B is not right for their practice settings.

The BMJ study involved 80 patients, ages 17 to 75, most of whom had been diagnosed with leukemia and had a refractory fever or a suspected fungal infection. Patients in the rapid-infusion group received 0.95 mg/kg of amphotericin B delivered over four hours each day. The continuous-infusion group received the drug at a dosage of 0.97 mg/kg over 24 hours. Dosages were adjusted as needed during the course of the study.

By measuring patients’ serum creatinine concentrations and calculating creatinine clearance rates, the research team determined that amphotericin B was significantly less toxic to patients’ kidneys when infused over 24 hours instead of four hours.

Fever, chills, and vomiting occurred much less often in patients in the continuous-infusion group than in the rapid-infusion group during the first day of treatment. On subsequent days, patients in the continuous-infusion group were less likely than the others to have chills or vomiting.

Seven of the 40 patients in the rapid-infusion group died during treatment, but none in the continuous-infusion group did. Twelve patients in the rapid-infusion group and four in the continuous-infusion group died within three months of completing treatment.

To Ben M. Lomaestro, Pharm.D., an infectious diseases specialist at Albany Medical Center Hospital in New York, the number of deaths in the rapid-infusion group seemed unusually high.

"When all the mortality is in one group and not the other," Lomaestro said, "with such small numbers [of patients], it may…imply that there was a [baseline] difference amongst the groups."

Lomaestro found the study results interesting but not convincing. In particular, he doubted that the study had sufficient power to detect a statistical difference between the efficacy of the two treatments.

James A. Trovato, Pharm.D., BCOP, gave a different reason why he does not plan to switch from four- or six-hour infusions of amphotericin B to continuous infusions: "It’s not practical in our setting."

Trovato, an assistant professor of pharmacy practice and science at the University of Maryland School of Pharmacy, pointed out that patients need a dedicated intravenous (i.v.) line for continuous infusions of amphotericin B.

"With all the medications these patients are on, I think that’s hard to do," said Trovato, who may also need dedicated i.v. lines for administering his cancer patients’ chemotherapy drugs. "How many lines are you going to put in [the] patient?"

Both clinicians mentioned that chemistry comes into play when amphotericin B is infused over 24 hours. The antifungal drug may precipitate when exposed to other drug solutions.

Although the BMJ study found that kidney toxicity was higher in the rapid-infusion group than in the other patients, Lomaestro was unsure how this related to clinical practice.

"We see the sick patients that are high-risk for fungal infections, and we use an appreciable amount of amphotericin," said Lomaestro, who treats cancer patients and bone-marrow and organ transplant recipients. Despite his hospital’s frequent use of amphotericin B, which is normally infused over four hours, "we haven’t had a tremendous nephrotoxicity issue," he said.

An important practice that the BMJ article did not address, Trovato said, is the fact that patients are often pretreated with drugs that prevent fever or chills. In the BMJ study, patients could not use fever reducers until the second day of amphotericin B treatment.

"I’m not surprised that if you give someone a rapid infusion of [amphotericin B] over four hours, of course they’re going to have fever," Trovato said. "That’s why we premedicate," he added.

"In the BMJ paper," Lomaestro said, "the statistical difference [in fever frequency] was only for the first day when they didn’t allow premedication….I’m not sure I would go to continuous infusion for…weeks just based on that one day of statistical significance."