Open-Label, Randomized Comparison of Itraconazole versus Caspofungin for Prophylaxis in Patients with Hematologic Malignancies

Mattiuzzi, Gloria; Alvarado, Gladys; Giles, Francis J.; Ostrosky-Zeichner, Luis; Cortes, Jorge; O’Brien, Susan; Verstovšek, Srđan; Faderl, Stefan; Zhou, Xian; Raad, Issam; Bekele, B. Nebiyou; Leitz, G; Lopez-Roman, Ivonne; Estey, Elihu H.

doi:10.1128/aac.50.1.143-147.2006

Cited by 154 publications

(102 citation statements)

References 21 publications

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“…Based on clinical trial data, rates of breakthrough IC range from 2.9% in patients receiving echinocandins empirically during febrile neutropenia to 0.2% in patients receiving echinocandin therapy for documented IC (7,16,25,30,32,35,38,44,48,50). In case reports of breakthrough infection in the literature, the vast majority of patients were severely immunocompromised, and the indication for echinocandin therapy included febrile neutropenia (n ϭ 4), hematologic malignancy prophylaxis (n ϭ 5), and primary treatment for IC (n ϭ 3) (6, 13, 21, 24, 39, 49).…”

Section: Discussionmentioning

confidence: 99%

Breakthrough Invasive Candidiasis in Patients on Micafungin

et al. 2010

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For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 g/ml, but all demonstrated caspofungin MICs of >2 g/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 g/ml, but 4/5 had micafungin MICs of >2 g/ml. The remaining isolates retained echinocandin MICs of <2 g/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 g/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.Invasive candidiasis (IC) is an important, life-threatening infection in hospitalized patients. The echinocandins (micafungin, caspofungin, and anidulafungin) are the newest class of medications approved for the prophylaxis and treatment of IC. They act via noncompetitive inhibition of ␤-1,3-glucan synthase, the enzyme responsible for producing ␤-1,3-D-glucan in the fungal cell wall (41). These drugs have low toxicity and few drug-drug interactions and possess a broad spectrum of antifungal activity against Candida species, including those resistant to fluconazole. In clinical trials, the echinocandins have demonstrated noninferiority for the treatment of IC versus amphotericin B deoxycholate, liposomal amphotericin B, and fluconazole (25,32,44). The echinocandins are considered interchangeable for clinical use, and a recent study comparing micafungin to caspofungin for IC supports this notion (38). Based on the accumulated experience, echinocandins are now considered a first-line therapeutic choice for IC (37).The echinocandins exhibit a bimodal MIC distribution among Candida species. MICs of C. parapsilosis, C. guilliermondii, and C. famata MICs (MIC 90 , 0.25 to 2 g/ml) are up to 133 times higher than those of C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr (MIC 90 , 0.015 to 0.25 g/ml) (42). However, this difference has not...

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Section: Discussionmentioning

confidence: 99%

Breakthrough Invasive Candidiasis in Patients on Micafungin

et al. 2010

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“…In 192 patients with acute myelogenous leukemia, similar efficacy and safety was found in both treatments. 87 Table S7) at a dose of 50 mg/d has been compared to fluconazole 400 mg/d in a large double-blind trial on 882 patients undergoing autologous or allogeneic hematopoietic stem cell transplantation. Invasive candidiasis was effectively prevented by both regimens, and the rate of aspergillosis was lower in the micafungin group but did not reach significance in those subgroups despite the fact of successful prophylaxis in the primary composite endpoint.…”

Section: Lipid-based Amphotericin B Formulations (Online Supplementarymentioning

confidence: 99%

Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology

Cornely¹,

Böhme²,

Buchheidt³

et al. 2009

Haematologica

156

102

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© F e r r a t a S t o r t i F o u n d a t i o nO IntroductionThe rising incidence of invasive fungal infections, especially invasive aspergillosis, compromises therapeutic outcomes in hematologic cancer patients and in transplant recipients. [1][2][3][4][5] The utilization of newly introduced antifungal agents clearly improved the tolerability of patients combating severe underlying diseases. 6,7 Despite better outcome in primary treatment of invasive aspergillosis in comparison to conventional amphotericin B, response and survival require further improvement. 8,9 Additionally, early diagnosis of invasive fungal infections is critical.10 But usually diagnosis is delayed and thus hampers further treatment outcome. 11Therefore, the prevention of invasive fungal infections upfront has become the major goal in patient care in high-risk patient populations. Since the first edition of these recommendations regarding antifungal prophylaxis, close to 20 relevant publications have been added to the field, necessitating an updated review of their impact on clinical decision making. 12 On the other hand new meta-analyses on prophylaxis of invasive fungal infections have also been published, but do not differentiate between specific patient populations and risk factors. 13,14 To maintain comparability with the previous recommendation, the EBM criteria proposed by the Infectious Diseases Society of America (IDSA) are again employed throughout this document (Table 1). 15 Several newly introduced antifungal agents have been utilized in prophylaxis for the first time. These and other new studies have been incorporated into this updated guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Oncology. The aim of this review is to provide the treating physician an up-to-date tool for the daily bedside decisions on primary antifungal prophylaxis. Objectives of antifungal prophylaxisIt is evident that the most relevant endpoint of antifungal prophylaxis is the reduction of mortality. However, death attributable to invasive fungal infection is difficult to prove and a reduction in overall mortality as a desirable endpoint of any clinical decision is difficult to achieve in the context of multiple competing illnesses in a severely immunocompromised host. Thus usually the reduction of the incidence rate of breakthrough invasive fungal infection is chosen as the primary endpoint of clinical trials. Improving rates of mucosal or other superficial infection and reducing colonization are no proper endpoints for antifungal prophylaxis with systemically active compounds. Design and MethodsThe guideline was prepared by a group of German clinicians. Systematic literature search comprised Medline, CancerLit, Embase, Cochrane Library and conference proceedings of Advances Against Aspergillosis, ASH, EBMT, ECCMID, ESMO, Focus on Fungal Infections, and ICAAC/IDSA, yielding a total of 86 clinical trials comprising 16,922 patients. Data extracted by OAC and MSi from each clinical study identifie...

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“…Echinocandins have a potential advantage over fluconazole given the broader spectrum of activity, in particular, against fluconazole resistant C. krusei or C. glabrata, and the anti-Aspergillus activity, although the latter has not yet been proved in clinical trials. A prospective comparison of micafungin to fluconazole for antifungal prophylaxis in neutropenic patients undergoing HCT showed compatible efficacy, safety profile, overall survival and reduced the need for empiric antifungal therapy in patients receiving micafungin [101]. The major disadvantage of micafungin use for a fungal prophylaxis is the need for intravenous administration and substantially greater cost; however this agent might be preferred over fluconazole in the centers with high prevalence of infections caused by non-albicans Candida spp.…”

Section: Antifungal Prophylaxismentioning

confidence: 99%