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Less Toxic Broad-Spectrum Antifungals: Facilitating Infection Control in Hematological Malignancies

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

49th Annual Meeting and Exposition of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2007

In some series, up to 20% of adults with hematological malignancy and neutropenia develop invasive mycoses. While mortality rates due to invasive candidiasis have been falling since the 1990s due in part to more effective treatment strategies, rising rates of Aspergillus have posed a new challenge and can be attributed to a variety of factors. In patients undergoing hematopoietic stem cell transplant, for example, late development of fungal infections and increased use of allogeneic transplants have both been cited. The changing epidemiology requires adjustment of infection control strategies with antifungal agents that cover Aspergillus.

“With progress in diagnostic capabilities and the development of safer treatment options, outcome in invasive aspergillosis has improved. However, the frequency of these infections remains high, and additional progress will depend on earlier treatment,” stated Dr. Pranatharthi H. Chandrasekar, Professor of Medicine, Wayne State University School of Medicine and Director, Infectious Diseases Fellowship Program, Harper University Hospital, Detroit, Michigan.

Controlled trials with voriconazole, which is indicated for invasive aspergillosis, have provided the evidence that newer azoles are at least as effective as amphotericin B but better tolerated for control of Aspergillus. In a summary of results from two comparisons for initial treatment of aspergillosis with a total of 277 patients, it achieved a complete or partial response rate of 52.8% vs. 31.6% for amphotericin B at 12 weeks (Herbrecht et al. N Engl J Med 2002;347:408-15). According to the authors, the higher response rate with voriconazole was independent of infection site, certainty of diagnosis, underlying condition, or neutropenia status. Most importantly, the survival rate at week 12 was 70.8% in patients treated with voriconazole vs. 57.9% in those treated with amphotericin B.

Posaconazole, another newer azole, has not been compared to amphotericin B specifically for treatment of Aspergillus in a multicentre study, but it has been found more effective than fluconazole, an older azole, for prophylaxis of invasive fungal infections (Ullmann et al. N Engl J Med 2007; 356:335-47). In that study, conducted in haematological cancer patients with neutropenia, the rate of proven Aspergillus infections was 1% in the posaconazole group vs. 7% in the fluconazole group. However, there was no difference in the rate of Candida infections, and death due to fungal infections, which was approximately 1% in both groups, did not differ significantly.

Prospective studies of prophylaxis for invasive fungal infections remain limited but a newly completed pilot study with 70 consecutive patients generated promising results. In a study led by Dr. José F. Tomás, Centro Oncológico M.D. Anderson International España, Madrid, Spain, oral voriconazole was administered at a fixed dose of 200 mg every 12 hours after two loading doses of 400 mg. The prophylaxis was started on the first day of chemotherapy and continued until recovery from neutropenia. Intravenous administration of voriconazole was permitted for those unable to take this drug orally. The majority of patients were being treated for acute myeloid leukemia, while the remainder were treated for acute lymphoblastic leukemia. The median age of the participants was 57.

Galactomannan screening for infection was positive in only two cases, while high-resolution computed tomography (CT) identified probable fungal infection in three cases. There were no discontinuations due to adverse events. The results of this prospective study, although limited in size, is consistent with a retrospective analysis published last year (Siwek et al. Diagn Microbial Infect Dis 2006;55:209-12). As cited by Dr. Chandrasekar, the study compared proven or probable Aspergillus infections in the 92 patients who received voriconazole to the 223 who received another antifungal, which was itraconazole in the majority of cases. As compared to a 10% incidence of probable or possible aspergillosis infection in the comparator group, there were no such infections in the voriconazole group (P<0.005). There were two Candida glabrata infections among those receiving voriconazole prophylaxis vs. none in the comparator group, but this difference was not significant.

For prophylaxis, one of the advantages of voriconazole relative to amphotericin B is that it has a high bioavailability in oral form. This permits intravenous therapy to be readily switched to an oral formulation for outpatients, which is a major advantage when extended duration of prophylaxis or treatment is needed. However, the most compelling rationale for use of newer azoles over amphotericin is at least comparable efficacy with greater safety. In a meta-analysis of 26 studies of antifungal agents, most of which compared azoles to amphotericin B, including a study that employed liposomal amphotericin B, there was a 30% relative reduction in probable invasive fungal infections and an 11% reduction in mortality associated with the azoles. Although both advantages fell short of statistical significance, these trends were achieved with less toxicity.

“The use of amphotericin B as empirical antifungal therapy seems unwarranted since it appears to be less effective than azoles with no mortality benefit and an increased rate of side effects,” remarked Dr. Elad Goldberg, Internal Medicine, Rabin Medical Center, Petah-Tikva, Israel. Although he advocated more aggressive use of early diagnostic testing through high resolution CT or galactomannan testing, rather than prophylaxis with any agent, including the newer azoles, he indicated that this approach is made possible by the availability of newer drugs with a broad spectrum of antifungal activity.

The rationale for trying to improve rapid diagnosis is the opportunity to match antifungal therapy to the pathogen. In a study that compared amphotericin B and voriconazole for treatment of candidiasis, both agents achieved treatment success in about 70% of patients at 12 weeks (Kulberg et al. Lancet 2005;366:1435-42), but there are increasing reports of Candida resistance to amphotericin B among some Candida species, particularly C. albicans and C. glabrata. Similarly, voriconazole has not demonstrated good efficacy against Zygomycetes infections. Although still rare, these infections have been increasing in incidence among immunocompromised patients. With at least seven antifungals in three drug classes (polyenes, azoles and echinocandins), tools for rapid testing provide considerable promise for selecting optimal therapy.

“The new guidelines from the IDSA [Infectious Diseases Society of America] now recommend susceptibility testing mainly because of the increasing proportion of invasive fungal infections caused by C. glabrata,” reported Dr. Thomas F. Patterson, Director, San Antonio Center for Medical Mycology, University of Texas Health Science Center at San Antonio. Noting that C. glabrata represented almost 40% of Candida infections in a recently reported 24-centre database, Dr. Patterson cautioned that higher drug levels even with otherwise effective agents are typically required to effectively control this infection. C. glabrata has demonstrated particularly poor susceptibility to older azoles, such as fluconazole, although it was found highly susceptible to the newest echinocandin, anidulafungin, in a recently published comparative trial (Reboli et al. N Engl J Med 2007; 356:2472-82).

Summary

In many centres, Aspergillus is now the most common invasive fungal infection for immunosuppressed patients. This change in epidemiology is affecting management strategies, including greater emphasis on employing empiric therapy that provides Aspergillus coverage or considering prophylaxis with broad-spectrum agents. While amphotericin B was once a favoured broad-spectrum antifungal, newer azoles, such as voriconazole, appear to be as effective and better tolerated, including a substantially reduced risk of nephrotoxicity. The bioavailability of oral voriconazole is an additional advantage for prophylaxis and for switching patients from intravenous therapy for regimens of long duration. However, due to the relative strengths and weaknesses of available antifungal drugs, efforts to improve rapid diagnosis in order to match pathogens with optimal therapy are being watched closely.

Note: At the time of printing, voriconazole is not indicated for prophylactic use in Canada.

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