Optimal Use of the Newer Antifungal Agents

The prevention and treatment of invasive fungal infections is being improved by the relatively recent introduction of new antifungal agents. While some of these agents offer better efficacy, others are proving their value more in improved tolerability, said John R. Wingard, md, at a session on Supportive Care for the Immunocompromised Host during the 1999 American Society of Hematology meeting. Dr. Wingard is professor of medicine and director of the bone marrow transplant program at the University of Florida at Gainesville.

One of the most important recent advances is a better formulation of amphotericin, specifically the lipid compounds, he said. These agents were developed to improve upon the narrow therapeutic ratio of amphotericin B, increase efficacy, and reduce toxicity. In the United States, there are three commercial products with different molecular structures: amphotericin B lipid complex (ABLC, Abelcet), amphotericin B cholesteryl (ABCD, Amphotec), and liposomal amphotericin (AmBisome).

 Compared to standard amphotericin B, Dr. Wingard said, these agents achieve lower concentrations in the kidneys, the site of the principal toxicity, and higher concentrations in the liver, lungs, and spleen, where infection frequently occurs.

Four Randomized Trials

Dr. Wingard said that four prospective randomized controlled trials have evaluated the lipid formulations of amphotericin B in treating established invasive fungal infections. Settings have included Candida infection, invasive Aspergillus infection, proven and suspected fungal infections in the neutropenic patient, and cryptococcal meningitis. All three lipid formulations have been much less toxic than amphotericin B, demonstrating substantially lower rates of nephrotoxicity and (with liposomal amphotericin) less infusional toxicity. While these findings are “the good news,” Dr. Wingard said, the disappointing finding has been a lack of superior responses and survival rates vs standard amphotericin B in clinical trials, although there have been trends toward improved responses and the study populations have been limited.

“In the allogeneic transplant patients, who are very susceptible to severe nephrotoxicity to start with, a lipid formulation makes sense,” Dr. Wingard stated. “While they are substantially more expensive, the cost of nephrotoxicity and hemodialysis are higher.”

“I do not use lipid formulations with the idea that I am going to get a better therapeutic advantage except in amphotericin failures, but clearly they are substantially less toxic,” he explained. “ABCD has more cardiorespiratory infusional reactions compared to the other lipid formulations and the parent compound. AmBisome clearly has substantially fewer infusional toxicities but tends to be more expensive, so one has to weigh what one would value in terms of those greater rates of infusional toxicities. Different people are coming down on different sides of that issue,” he commented.

Efforts are underway to find the most effective and least toxic doses of the newer lipid compounds, he said. Most clinical trials have used 4 to 5 mg/kg/d, although several studies have evaluated lower doses. A European Organization for Research and Treatment of Cancer (EORTC) randomized study of liposomal amphotericin B in invasive Aspergillus infections gave ABLC at a dose of either 1 mg/kg/d or 4 mg/kg/d to neutropenic cancer patients and bone marrow recipients with proven or probable infections. The lower dose produced results similar to the higher dose: No statistically significant differences were shown in either response or mortality, although the higher doses tended to be more effective in persons with proven infection. The study lent support to the view that lower and therefore less expensive doses might achieve the same desirable benefits, Dr. Wingard said, but because of its small sample size, more study is needed.

About the Triazoles

Another family of antifungal compounds, the triazoles, are highly efficacious in the treatment of yeast infections, Dr. Wingard said. Studies comparing fluconazole (Diflucan) with amphotericin for the treatment of established systemic Candida infections have found similar efficacy, in the range of 71% to 79%. As with the lipid formulations of amphotericin B, fluconazole has been associated with substantially fewer nephrotoxic events than standard amphotericin. But the majority of study subjects have not been neutropenic; therefore, data remain lacking as to the adequacy of this approach in neutropenic patients. There are also substantial gaps in the antimicrobial coverage provided by fluconazole, especially with several species of Candida and Aspergillus, he noted.

The newest of these agents—itraconazole (Sporanox)—has substantial in vitro activity against Aspergillus. While this antifungal drug might provide an alternative to the polyenes in the management of Aspergillus infections, in the group most susceptible to these infections—leukemic patients and bone marrow recipients—the pharmacokinetic profile of itraconazole is quite variable and may be seriously compromised, according to recent findings.

While a cyclodextran formulation has been developed to improve bioavailability, the taste is unpleasant. Moreover, itraconazole is prone to more drug interactions than fluconazole, particularly in combination with cyclosporin and FK506, Dr. Wingard added.

Nevertheless, Dr. Wingard called itraconazole “a potentially exciting approach” because it not only controls yeast infections but potentially also Aspergillus. A randomized double-blind study of 405 patients compared prophylactic itraconazole (2.5 mg/kg twice daily of the cyclodextran solution) vs placebo. Patients were neutropenic for about 2 weeks and were receiving autologous bone marrow transplants or chemotherapy for acute leukemia and other cancers. The itraconazole group had significantly fewer episodes of fungemia (0.5% vs 4%), but there was no reduction in proven Aspergillus infections. Moreover, there was a trend toward fewer suspected infections of all types, but no difference in mortality.

“We need more data to help us understand whether itraconazole is just another way of controlling yeast infections, like fluconazole, or whether it will play a substantial role in preventing Aspergillus,” he told the audience.

Several new triazoles are now in randomized trials. Their potential clinical and pharmacologic advantages include a substantially broader spectrum of antifungal activity, improved bioavailability, and fewer drug interactions.

Other new generations of antifungal compounds look promising in clinical trials, including the echinocandins. They have a broad spectrum of activity, lack cross-resistance with the azoles and may have additive or synergistic effects with other antifungals, thus opening the possibility of more effective combination therapy.

Invasive Infections: Changes in Approach

Invasive fungal infections are hard to diagnose early in their course, when they could be most effectively treated. In the immunocompromised host, signs and symptoms are attenuated and clinical clues may be masked by deficits in host defenses. Empiric or prophylactic approaches, therefore, are often relied upon in these patients, and empiric antifungal therapy has become standard in the setting of neutropenia and persistent fever, based on the findings of the EORTC group and other investigators.

The lipid formulations have been evaluated as an alternative to this approach, with mixed results, Dr. Wingard said. Walsh and colleagues conducted a randomized, double-blind trial in neutropenic patients with persistent fever. Subjects received 4 days of antibiotics, then were randomized to either amphotericin B or liposomal amphotericin given at doses of 0.6 mg/kg/d or 3 mg/kg/d, respectively. Success was defined as survival with defervescence, with no breakthrough infection or withdrawal due to toxicity.

“We were disappointed to see that we did not have greater rates of success, survival, or defervescence with liposomal amphotericin. Also, there were no fewer rates of withdrawal from the study in patients receiving the new agent,” Dr. Wingard reported. “There were, however, fewer proven invasive fungal infections—3% vs 8%—in the AmBisome group. . . So if you analyze only the proven infections, there is a clear-cut advantage. Also, as with lipid formulations, there was a substantial benefit in terms of nephrotoxicity and infusional toxicity,” he said.

Dr. Wingard reiterated that itraconazole clearly has a role in invasive fungal infections, although its specific place is still being defined. The new intravenous formulation of itraconazole with suspension in cyclodextran has been compared to amphotericin B in a prospective, randomized, open-label trial in patients with hematologic malignancies and neutropenia. In nearly 400 patients treated for 7 to 8 days, the investigators found a trend toward a better response rate with itraconazole—48% vs 38% (P = .055). Only five infections developed in each group (Candida and Aspergillus in both).

“Clearly, itraconazole has a role,” Dr. Wingard observed.

Fluconazole also has an established prophylactic role in allogeneic bone marrow transplant, where it achieves not only an antifungal effect but a survival advantage as well. The current question is whether fluconazole has a role in nonallogeneic bone marrow transplant patient groups.

A multicenter, randomized, double-blind study from a Canadian cooperative group used 400 mg/d of fluconazole in patients receiving induction therapy for acute leukemia or undergoing autologous bone marrow transplant. The study found a substantial reduction in invasive infections—3% vs 17%—as well as fewer superficial infections and fewer fungal deaths—0.6% vs 4%—with fluconazole. Unfortunately, substantial numbers of patients still had persistent unexplained fever. A meta-analysis of all the fluconazole prophylaxis studies has shown a reduced need for empiric amphotericin B when fluconazole is used prophylactically, he added.

Need for Quicker Diagnosis

“If we could diagnose these infections much earlier, we would be less reliant on empiric and prophylactic approaches,” Dr. Wingard observed. “That would have important advantages in terms of reducing patients’ exposure to these drugs, cost of drugs, antifungal resistance, and toxicity, as well as in improving survival rates. To accomplish this, we need improved diagnostic techniques.”

A number of tests have been under evaluation, including antigenic panels, immunodiagnostic panels, DNA and RNA probes, and polymerase chain reaction (PCR) assays. While all appear promising, these tests are not yet commercially available in the United States. (In Europe, there is an antigen assay for Aspergillus.)

It is also important to enhance host resistance by reducing the exposure of patients to these organisms, he said. “We need to be mindful of infection-control measures in place in our hospitals to prevent breakthrough infections and to reduce nosocomial transmission. And we need to be vigilant with regard to the managed care environment, where more and more patients are seen as out-patients and in home-care settings.”