Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants

Marr, Kieren A.; Crippa, Fulvio; Leisenring, Wendy M.; Hoyle, Maggie; Boeckh, Michael; Balajee, S. Arunmozhi; Nichols, W. Garrett; Musher, Benjamin; Corey, Lawrence

doi:10.1182/blood-2003-08-2644

Cited by 399 publications

(314 citation statements)

References 29 publications

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“…However, its use was costly because most patients suffered from severe stomatitis and required the intravenous administration of FLCZ instead of oral capsules. Moreover, the rates of treatment success of FLCZ in allogeneic SCT settings are 68 to 81% [7,10,11]. One of the major concerns about the use of FLCZ is its lack of activity against Aspergillus species and some non-albicans Candida species.…”

Section: Discussionmentioning

confidence: 99%

Administration of micafungin as prophylactic antifungal therapy in patients undergoing allogeneic stem cell transplantation

et al. 2007

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Objective: Invasive fungal infection is one of the major causes of death in neutropenic patients undergoing allogeneic stem cell transplantation (SCT). Although prophylactic antifungal therapy with fluconazole (FLCZ) has become the standard care for these patients, there remains a need for more effective and cost-beneficial alternative drugs.Patients and Methods: We conducted a prospective study to evaluate the usefulness of the administration of micafungin (MCFG) as a prophylactic antifungal therapy for patients undergoing allogeneic SCT. The results were compared with previous data for patients who had received FLCZ.Results: A total of 44 patients who underwent allogeneic SCT were enrolled in the study.Data from 29 patients who received allogeneic SCT using prophylactic FLCZ before this study were used as historical control data. Underlying diseases included acute leukemia (n=16), non-Hodgkin's lymphoma (n=11), myelodysplastic syndrome (n=6), and others (n=11) in the MCFG group and acute leukemia (n=18), chronic myelogenous leukemia (n=6), and others (n=5) in the FLCZ group. The median durations of administration of MCFG and FLCZ were 36 and 34 days, respectively. Prophylactic success, defined as the absence of proven, probable, and possible invasive fungal infection (IFI) until the end of prophylactic therapy was achieved in 36 (87.8%) of the 41 evaluated patients in the MCFG group and in 65.5% of the patients in the FLCZ group (p=0.038). No patients in the MCFG group showed proven or probable IFI, whereas proven or probable IFI was observed in 3 patients in the FLCZ group. Four patients in the MCFG group required dose escalation due to febrile neutropenia. Although one patient in the MCFG group required the discontinuation of MCFG due to allergic skin eruption (grade 2), none of the other patients in either group required dose reduction due to adverse effects.Conclusions: Although the study design was not a prospective randomized trial, our results indicate that the administration of MCFG at a daily dose of 100 mg is promising for prophylactic antifungal therapy in patients undergoing allogeneic SCT.

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Section: Discussionmentioning

confidence: 99%

Administration of micafungin as prophylactic antifungal therapy in patients undergoing allogeneic stem cell transplantation

et al. 2007

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“…Fluconazole, itraconazole, posaconazole, voriconazole, and micafungin are recommended for prophylactic use in patients with hematologic malignancies (9,10). Although the results of randomized clinical trials support the prophylactic benefits of these agents (7,8,11), each may be limited in their use: fluconazole has no activity against molds (12); posaconazole demonstrates broad-spectrum activity against both yeasts and molds (13), but optimal absorption of the oral suspension of posaconazole is dependent on administration with a high-fat meal (however, the delayed-release tablets have improved bioavailability) (14); voriconazole is as effective as fluconazole in preventing IFIs (15) but has been associated with breakthrough mucormycosis and a high incidence of side effects (16,17); itraconazole tablets have variable bioavailability, and its oral suspension has poor tolerability (18); and micafungin is available only as an intravenous (i.v.) formulation and has no activity against the Mucorales or Fusarium species (19).…”

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confidence: 99%

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Cornely

Böhme²,

Schmitt‐Hoffmann

et al. 2015

Antimicrob Agents Chemother

103

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Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n ‫؍‬ 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n ‫؍‬ 12). The mean ؎ standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ؎ 22.3 g · h/ml and 113.1 ؎ 19.6 g · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n ‫؍‬ 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.) I nvasive fungal infections (IFIs) are associated with significant morbidity, mortality, and health care costs in patients with hematologic malignancies (1, 2). Allogeneic hematopoietic stem cell transplantation and chemotherapy-associated neutropenia place patients with acute myeloid leukemia (AML) at risk of developing an IFI (3). Aspergillus spp. and Candida spp. are the predominant IFI pathogens in patients with acute leukemia (1, 3, 4). However, other molds, such as the Mucorales, Scedosporium spp., and Fusarium spp., are emerging as pathogens in this setting and are associated with high mortality rates (1).Because IFIs are often difficult to diagnose, and delays in treatment can significantly increase the risk of mortality (5, 6), antifungal prophylaxis has become a commonly used strategy in patients at high risk of IFIs (7, 8). Fluconazole, itraconazole, posaconazole, voriconazole, and micafungin are recommended for prophylactic use in patients with hematologic malignancies (9, 10). Although the results of randomized clinical trials support the prophylactic benefits of these agents (7,8,11), each may be limited in their use: fluconazole has no activity against molds (12); posaconazole demonstrates broad-spectrum activity against both yeasts and mo...

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“…Prophylactic micafungin 17 and caspofungin 18 have been studied at daily IV doses of 50 mg. Table 2 shows the distribution of reported start and end dates for antifungal prophylaxis reported in the literature. 13,15,16,[19][20][21][22][23] Prophylaxis should usually be initiated in parallel with the administration of cytotoxic therapy in order to ensure a protective effect at the time of maximal neutropenia and intestinal epithelial damage. Concerns over drug interactions have compelled some investigators to modify the application of triazoles-based prophylaxis until after the administration of cytotoxic therapy.…”

Section: Antifungal Chemoprophylaxismentioning

confidence: 99%

“…Concerns over drug interactions have compelled some investigators to modify the application of triazoles-based prophylaxis until after the administration of cytotoxic therapy. 15,16,21 The end date should be dictated by the termination of the specific risk. Mould-active prophylaxis may require administration into the late post-engraftment period in allogeneic HSCT for those patients with higher risk due to acute or chronic graft-versus-host disease requiring augmented immunosuppressive therapy.…”

Section: Antifungal Chemoprophylaxismentioning

confidence: 99%

“…Mould-active prophylaxis may require administration into the late post-engraftment period in allogeneic HSCT for those patients with higher risk due to acute or chronic graft-versus-host disease requiring augmented immunosuppressive therapy. 16,21 How effective are these strategies? Several systematic reviews evaluating the published clinical trials of antifungal prophylaxis efficacy are available for review.…”

Section: Antifungal Chemoprophylaxismentioning

confidence: 99%

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Of Yeasts and Hyphae: A Hematologist’s Approach to Antifungal Therapy

Bow¹

2006

Hematology

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Improvements in anticancer treatments, the ability to modify myelosuppression profiles, greater duration and intensity of immunosuppression, and the variety of available antimicrobial therapies have influenced the spectrum of pathogens associated with invasive fungal infection complicating treatment of hematological malignancies and hematopoietic stem cell transplantation. The approaches to the management of these infections encompass strategies of prevention for all those at risk, pre-emptive therapy based upon surrogates of infection before the onset of clinical disease, empirical therapy for patients with clinical evidence of early disease, and directed or targeted therapy for infected patients with established disease. Chemoprophylaxis is effective if applied to the highest risk patients over the duration of the risk. Pre-emptive strategies, while promising, have yet to be validated and linked to reliably predictive nonmicrobiological diagnostic techniques. Empirical antifungal therapy, as it is currently applied, now seems questionable. Patients with probable or proven invasive fungal infection still have suboptimal outcomes despite the availability of promising anti-fungal agents. Strategies examining the concept of dose-intensity and combination regimens require careful study and cannot yet be regarded as an acceptable standard of practice. Changing Epidemiology of Invasive Fungal Infection in Hematological Malignancies and Stem Cell TransplantsInterest in the field of medical mycology has expanded considerably as the numbers of immuno-and myelo-suppressed patients susceptible to opportunistic invasive fungal infections (IFI) increase. While the majority (95-97%) of invasive yeast infections are due to five species, predominantly Candida albicans, followed by C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei, emerging importance of infections due to non-albicans Candida spp. including C. glabrata, C. parapsilosis, and C. krusei in high-risk cancer patients is noteworthy. 1 The remaining 3% to 5% of pathogens include other non-albicans Candida spp.. and non-Candida yeasts such as Trichosporon spp., Cryptococcus spp., Blastoschizomyces spp., and Malassezia spp.. 2,3 The risks for IFI among hematopoietic stem cell transplants (HSCT) increases as the disparity of the donor:recipient pair (autologous HSCT, 0.6%; matched related donor HSCT, 3.7%; mismatched related or unrelated donor HSCT, 5.9%, P < 0.0001). 4 The changing character of the HSCT populations together with effective antiCandida agents contribute to a changing spectrum of opportunistic mycoses. In a comparison of transplant patients with IFI to a more general population of patients at risk, the proportion of Candida infections decreased by approximately 45% (77% to 42%); however, that due to Aspergillus spp. has more than doubled (13% to 29%) and that due to other environmental moulds including Fusarium spp., Scedosporium spp., the zygomycetes, and the less com-

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Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants

Cited by 399 publications

References 29 publications

Administration of micafungin as prophylactic antifungal therapy in patients undergoing allogeneic stem cell transplantation

Administration of micafungin as prophylactic antifungal therapy in patients undergoing allogeneic stem cell transplantation

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Of Yeasts and Hyphae: A Hematologist’s Approach to Antifungal Therapy

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