micafungin and Hematologic-Diseases

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

Topics: Adolescent; Adult; Anidulafungin; Antifungal Agents; Candida; Caspofungin; Child; Critical Illness; Drug Interactions; Echinocandins; Hematologic Diseases; Humans; Infant, Newborn; Kidney; Lipopeptides; Liver; Micafungin; Microbial Sensitivity Tests; Obesity

Extended dosing intervals for micafungin could overcome the need for hospitalization for antifungal prophylaxis.. This multicentre, open-label, randomized trial compared the pharmacokinetics of 300 mg of micafungin given twice weekly with 100 mg once daily as antifungal prophylaxis in adult haematology patients at risk of developing invasive fungal disease. Secondary objectives were assessment of adequate exposure with an alternative dosing regimen of micafungin (700 mg once weekly) through Monte Carlo simulations and assessment of safety in this patient population.. Twenty adult patients were randomized to receive either 300 mg of micafungin twice weekly or 100 mg once daily for 8 days. Blood samples were drawn daily and pharmacokinetic curves were determined on days 4/5 and 8. Monte Carlo simulations were performed for both investigated regimens as well as a frequently proposed alternative regimen (700 mg once weekly).. The predicted median AUC0-168h (IQR) for a typical patient on the investigated regimens of 100 mg once daily and 300 mg twice weekly and the hypothetical regimen of 700 mg once weekly were 690 (583-829), 596 (485-717) and 704 (585-833) mg·h/L, respectively.. We observed comparable exposure with 300 mg of micafungin twice weekly and 100 mg of micafungin once daily. We provide the pharmacokinetic proof for an extended dosing regimen, which now needs to be tested in a clinical trial with hard endpoints.

Topics: Adult; Aged; Antifungal Agents; Area Under Curve; Drug Administration Schedule; Female; Hematologic Diseases; Hematology; Humans; Invasive Fungal Infections; Male; Micafungin; Middle Aged; Monte Carlo Method; Prospective Studies

In cases of hematological malignancy, patients with persistent fever and neutropenia receive antifungal empirical therapy to prevent and treat invasive fungal infections. The clinical efficacy and safety of micafungin and voriconazole were compared.. In this randomized, cooperative group, open-label trial, we assessed and compared the efficacy and safety of micafungin and voriconazole as an empirical antifungal therapy in febrile neutropenic patients with hematological malignancy. Patients were classified according to invasive fungal infection risk.. There were no significant differences in clinical efficacy between the two treatments, evaluated based on (i) successful treatment of baseline fungal infection (no evaluation), (ii) absence of breakthrough fungal infection (P = 0.106), (iii) survival for ≥7 days after study completion (P = 0.335), (iv) premature study discontinuation due to poor efficacy (P = 0.424), and (v) resolution of fever during neutropenia (P = 0.756). Discontinuation due to drug-related adverse events (grades 3-4) occurred less frequently in the micafungin group (P = 0.005).. The clinical efficacy did not differ between micafungin and voriconazole. Micafungin was generally better tolerated than voriconazole when given as an empirical antifungal therapy in patients with persistent fever and neutropenia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Echinocandins; Febrile Neutropenia; Female; Hematologic Diseases; Hematologic Neoplasms; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Treatment Outcome; Voriconazole; Young Adult

Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96 h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150 mg/day. Of the 78 evaluable patients, 54 (69 %) achieved defervescence by the time of neutrophil recovery, and 56 (72 %) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60 %, with the lower limit of a 90 % confidence interval (50.3 %) exceeding the predefined threshold success rate (50 %). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Echinocandins; Febrile Neutropenia; Female; Hematologic Diseases; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses

This prospective multicenter study was performed to clarify the efficacy and safety of micafungin (MCFG) as an empirical antifungal therapy for suspected fungal infection in patients with hematological disorders and neutropenia. Three hundred and eighty-eight patients were enrolled; 151 patients with possible fungal infection diagnosed by radiological imaging or serological testing and 237 patients with refractory fever were included in this study. The mean dose and duration of treatment with MCFG were 154.6 mg/day and 14.0 days, respectively. The clinical response rate for patients with possible fungal infection and refractory fever was 60.1% and 65.3%, respectively. Even in persistent neutropenic patients with a neutrophil count of <500/μL throughout the MCFG treatment, the clinical response rate was 46.9%. Ninety-one drug-related adverse events (DAEs) were observed in 56 patients (14.4%) and 9 serious DAEs were observed in 6 patients (1.5%). Neither daily dose nor duration of MCFG treatment affected the incidence of DAEs. It was confirmed that MCFG has adequate clinical efficacy and is safe for the treatment of suspected fungal infections in patients with hematological disorders and neutropenia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Echinocandins; Female; Hematologic Diseases; Humans; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Treatment Outcome; Young Adult

The study was conducted as a prospective multicenter trial to evaluate the efficacy and safety of micafungin in patients with invasive fungal infections (IFIs) in hematological disorders. A total of 277 patients was registered, and 197 were assessed for clinical efficacy. The mean dosage and duration of micafungin were 170.7 mg/day and 22.0 days, respectively. The efficacy rates were 87.5% (7/8) for patients with candidiasis, 44.7% (17/38) for probable IFIs, 61.9% (39/63) for possible IFIs and 80.7% (71/88) for those who failed to respond to antibacterials. In patients with febrile neutropenia (below 500 microL), despite broad-spectrum antibacterial treatment over 2 days, 86.3% (44/51) of patients had a favourable response to micafungin. The incidence of adverse events related to micafungin was 14.1% (39/277), but most of them were mild and reversible. These data indicate the usefulness of micafungin as a novel therapeutic drug for both empirical and targeted therapy for IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Antifungal Agents; Echinocandins; Female; Hematologic Diseases; Humans; Leukocyte Count; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutrophils

Fungal infections are a major cause of morbidity and mortality in the haematological patients. These infections are mainly due to Candida spp. and Aspergillus spp. Mortality by these infections is high, but rates have descended in the latest series due to better antifungal agents. Echinocan-dins are, in vitro, very active against Candida and Aspergillus spp. The objective of the study is to analyse the efficacy and safety of micafungin in the antifungal prophylaxis of haema-tological patients on chemotherapy.. A multicentre, observational retrospective study was performed in 7 Haematology Depart-ments in Spain. Patients admitted to these departments with chemotherapy or immunosuppressive treatment, and who had received antifungal prophylaxis with micafungin between 1 January 2009 and 31 December 2014 were included.. There were 5 cases of probable or proven fun-gal infection (4.8%) according to the 2008 EORTC criteria: 2 proven, 3 probable. The types of fungal infection were 3 as-pergillosis and 2 candidiasis. There were no drop-outs from the prophylaxis with micafungin due to toxicity.. Micafungin is an antifungal agent which, used in prophylaxis, has demonstrated good efficacy and an excellent toxicity profile, making it an apparently interesting option in patients requiring antifungal prophylaxis during their hospitalisation episode.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Candidiasis; Female; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Lymphoma; Male; Micafungin; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Young Adult

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management.. A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology.. Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous.. A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention.

Topics: Antifungal Agents; Consensus; Delphi Technique; Echinocandins; Health Care Surveys; Hematologic Diseases; Hematologic Neoplasms; Humans; Immunocompromised Host; Invasive Fungal Infections; Lipopeptides; Micafungin

Antifungal prophylaxis is recommended for haematological patients at high risk of invasive fungal infections (IFIs). Incidence, optimal therapeutic management and outcome of breakthrough IFIs (bIFIs) are largely unknown.. To assess bIFI incidence, treatment and outcomes, data on patients undergoing AML remission-induction and consolidation chemotherapy and from allogeneic HSCT recipients on antifungal prophylaxis with itraconazole, micafungin or posaconazole were extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut). bIFIs were classified according to revised EORTC/MSG criteria.. From January 2004 to April 2013, 250 AML patients with 329 hospitalizations and 409 HSCT patients with 496 hospitalizations were identified. In AML patients, there were 16 (6.4%) proven or probable bIFIs and 44 (17.6%) possible bIFIs. In HSCT patients, there were 14 (3.4%) proven or probable bIFIs and 37 (9.0%) possible bIFIs. Proven cases included five candidaemias, two mucormycoses, three aspergilloses and one fusariosis. The most frequent choice for bIFI treatment was liposomal amphotericin B in AML patients (21/60; 35.0%) and continuation of posaconazole prophylaxis in HSCT patients (16/51; 31.4%). In HSCT recipients, survival on day 365 was significantly lower in bIFI patients (AML, 63.3% versus 70.0%; P = 0.297; HSCT, 49.0% versus 66.8%; P = 0.012). Comparison of continuation of prophylaxis versus switch of antifungal class as first-line treatment showed no significant difference regarding response to treatment and survival.. Rates of bIFIs observed in our population were comparable to previous data. There was no clear shift towards rare species, as previously reported. A high variety of treatment approaches was observed.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Chemoprevention; Cohort Studies; Echinocandins; Female; Hematologic Diseases; Humans; Incidence; Invasive Fungal Infections; Itraconazole; Lipopeptides; Male; Micafungin; Middle Aged; Triazoles; Young Adult

We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.

Topics: Antifungal Agents; Chemoprevention; Clinical Trials as Topic; Cost-Benefit Analysis; Diagnostic Tests, Routine; Echinocandins; Hematologic Diseases; Humans; Lipopeptides; Micafungin; Mycoses; Neutropenia; Retrospective Studies; Voriconazole

The frequency of breakthrough invasive fungal diseases (IFDs) during echinocandin therapy is unclear. We retrospectively analyzed 534 hematologic patients treated with echinocandin (caspofungin, N = 55; micafungin, N = 306; anidulafungin, N = 173). Four proven IFDs were found, caused by Candida parapsilosis (N = 2), C. parapsilosis and Candida glabrata (N = 1), and Fusarium species (N = 1). Four cases of possible IFDs were observed, all showing pulmonary infection. One case showed features suggestive of hepatosplenic candidiasis. Six of these eight cases had previously received the purine analog clofarabine. Breakthrough IFD during echinocandin treatment occurred infrequently (1.5 %), caused predominantly by Candida species. Clofarabine usage was an important risk factor.

Topics: Adenine Nucleotides; Adult; Anidulafungin; Antibiotic Prophylaxis; Antifungal Agents; Antimetabolites, Antineoplastic; Arabinonucleosides; Candida; Candidiasis, Invasive; Caspofungin; China; Clofarabine; Cohort Studies; Cross Infection; Echinocandins; Fusariosis; Fusarium; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lipopeptides; Lung Diseases, Fungal; Micafungin; Retrospective Studies; Risk Factors

This study was conducted as a retrospective, observational, exploratory cohort study with the aim of elucidating the safety profile of micafungin at doses exceeding 150 mg daily. We identified adult patients with hematological diseases who had received micafungin therapy for ≥ 7 consecutive days. Twenty-six patients administered micafungin at 300 mg daily (high-dose group) were compared with 58 patients administered micafungin at 150 mg daily (standard-dose group). The most frequent adverse events (AEs) were hepatotoxicity, hypertension and diarrhea. AEs were recorded in 42 (72%) and 19 (73%) patients in the standard-dose and high-dose groups, respectively (p = 1.00). Hepatobiliary AEs were noted in 28 (48%) and 15 (58%) patients, respectively (p = 0.48). Serious AEs and resultant treatment discontinuation were infrequent. Our results suggest that micafungin was safe and well tolerated at 300 mg daily.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Chemical and Drug Induced Liver Injury; Diarrhea; Dose-Response Relationship, Drug; Echinocandins; Female; Hematologic Diseases; Humans; Hypertension; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Retrospective Studies; Treatment Outcome; Young Adult

The detection of serum 1,3-β-d-glucan (BDG) has been reported to be useful for the diagnosis and therapeutic monitoring of various invasive fungal infections. Although Trichosporon fungemia is increasingly recognized as a fatal mycosis in immunocompromised patients, the utility of this assay for Trichosporon fungemia is still unknown. In our experience (28 cases), the level of BDG rose in about half of the patients with hematologic disorders who developed Trichosporon fungemia. Among them, early death from this infection was more frequently seen in BDG-negative patients than in BDG-positive patients. In addition, overall survival was also significantly worse in BDG-negative patients than in BDG-positive patients. There were no significant differences between these two patient groups in terms of clinical background. Unlike for other invasive fungal infections, elevation of BDG level may indicate a paradoxical sign for Trichosporon fungemia in patients with hematologic disorders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; beta-Glucans; Echinocandins; Female; Fluconazole; Fungemia; Hematologic Diseases; Humans; Immunocompromised Host; Lipopeptides; Male; Micafungin; Miconazole; Middle Aged; Proteoglycans; Retrospective Studies; Treatment Outcome; Trichosporon; Young Adult

We report 2 pediatric cases of cerebral fungal infection. A patient with severe aplastic anemia developed an Aspergillus species brain abscess and pulmonary aspergillosis after peripheral blood stem cell transplantation. Despite administration of micafungin, amphotericin B, and flucytosine, the patient died 2 months after the transplantation because of underlying pulmonary aspergillosis. Another patient with acute myelogenous leukemia developed a huge brain abscess with histopathologic findings suspicious of mucormycosis. This patient was cured with combination therapy of antifungal agents and intensive surgery, without sequelae. It is important to perform aggressive multimodality treatment, when indicated, including surgical intervention, even if in myelosuppression.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Central Nervous System Fungal Infections; Child; Drug Combinations; Echinocandins; Fatal Outcome; Female; Flucytosine; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Magnetic Resonance Imaging; Male; Micafungin; Mucormycosis; Peripheral Blood Stem Cell Transplantation; Remission Induction; Treatment Outcome

In 29 patients (40 samples) with hematological diseases who had been treated with a candin antifungal agent, micafungin (MCFG), we measured the blood level of MCFG by high-performance liquid chromatography (HPLC). There was a correlation between the dose and the blood level of MCFG (r = 0.729, p < 0.001). In addition, there was a correlation between the total bilirubin level and the C/D value (r = 0.458, p < 0.01), which was calculated by dividing the blood level of MCFG by the dose, although there was no correlation between creatinine clearance and the C/D value. These findings suggest that the dose of MCFG must be regulated in patients with biliary stasis-type liver hypofunction. In addition, there was no significant difference in the blood level of MCFG between the group in which tacrolimus (FK506) was combined with MCFG and the group in which MCFG alone was administered. These results suggest that there are no changes in the blood level of MCFG even when MCFG is combined with FK506.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Hematologic Diseases; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic; Tacrolimus