micafungin and Hematologic-Neoplasms

Antifungal prophylaxis is the first option to fight against fungal infection in high-risk hematological patients (remission of induction of acute myeloblastic leukemia/myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation). Fluconazole prophylaxis is not effective in preventing infection with moulds, mainly invasive aspergillosis, and consequently the triazole currently recommended in high-risk hematological patients is posaconazole. Nevertheless, given that posaconazole can only be administered orally, alternative prophylaxis may be required. Antifungal prophylaxis with micafungin is an attractive option. At a dose of 50 mg/day (1 mg/kg if weight is ≤ 40 kg) micafungin is approved for the prophylaxis of candidiasis in hematopoietic stem cell transplant recipients. Higher doses have been evaluated in adults (100 mg/day, 150 mg/day) and in children (3 mg/kg/day) with good efficacy and safety. Because of this agent's spectrum of activity, which includes both Candida and Aspergillus, together with its favorable pharmacokinetic profile regarding to the absence of significant drug interactions, this agent is appropriate in hematopoietic stem cell transplant recipients and in hematological patients following therapeutic protocols with vinca alkaloids. The optimal and most cost-effective dose for prophylaxis, as well as alternative regimens to daily intravenous administration, which would allow the use of this drug beyond conventional hospitalization (day care hospital, domiciliary transplantation therapy), remain to be determined.

Topics: Adult; Ambulatory Care; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Kidney Diseases; Lipopeptides; Male; Meta-Analysis as Topic; Micafungin; Mycoses; Postoperative Complications; Practice Guidelines as Topic; Triazoles

Invasive fungal infections are a major cause of morbidity and mortality in children with hematological malignancies and those undergoing allogeneic hematopoietic stem-cell transplantation (HSCT). Although several new antifungal compounds recently became available, some are not yet approved for the use in the pediatric population. Among the new class of echinocandins, micafungin has been licensed in Europe and Japan for children including neonates. Because micafungin is well tolerated and exhibits few clinical relevant drug-drug interactions, the compound is of particular interest for prophylaxis and treatment of invasive mycoses in pediatric patients with cancer or following allogeneic HSCT. This review will focus on the currently available pediatric data of micafungin with emphasis on pharmacokinetics, efficacy, and safety.

Topics: Antifungal Agents; Child; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Hematologic Neoplasms; Humans; Lipopeptides; Micafungin; Mycoses; Treatment Outcome

Invasive candidiasis is a severe infection among onco-hematological patients, with an attributable mortality around 40%. Micafungin has shown efficacy in antifungal prophylaxis among hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis.. To assess the role of micafungin in the treatment of invasive candidiasis among onco-hematological patients.. Literature review.. In a study on 126 patients with candidemia treated with micafungin, an overall response rate of 83% was reported. A double-blind study of 531 patients with invasive candidiasis comparing micafungin (100mg/day) versus liposomal amphotericin B (3mg/kg/day) reported success in 90% of patients in both arms, with a more favorable safety profile with micafungin. Other double blind randomized, phase III study compared two doses of micafungin (100mg/day and 150mg/day) with standard doses of caspofungin (70mg loading dose, then 50mg/day) in adults with invasive candidiasis. Overall success rate was 74% for micafungin 100mg/day, 70% for micafungin 150mg/day, and 71% for caspofungin. A double blind randomized study compared micafungin (2mg/kg/day) to liposomal amphotericin B (3mg/kg/day) in the treatment of invasive candidiasis in children with a predominance of infections with non-albicans Candida spp. Overall success rate was similar (73% for micafungin and 76% for liposomal amphotericin B).. Comparative phase III studies have demonstrated non-inferiority of micafungin compared to standard antifungal agents for invasive candidiasis. Micafungin is safe and effective in the treatment of children and adults with invasive candidiasis. Effectivity in invasive infections caused by non-albicans Candida spp is especially relevant in onco-hematological patients receiving fluconazole prophylaxis.

Topics: Adult; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Candidiasis; Caspofungin; Child; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Double-Blind Method; Echinocandins; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Postoperative Complications; Prosthesis-Related Infections; Randomized Controlled Trials as Topic

Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial.. We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET.. In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2%. A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Topics: Adult; Aged; Antifungal Agents; Febrile Neutropenia; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Itraconazole; Leukocyte Count; Male; Micafungin; Middle Aged; Mycoses; Neutrophils; Young Adult

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

Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antifungal Agents; Echinocandins; Empirical Research; Febrile Neutropenia; Female; Hematologic Neoplasms; Humans; Itraconazole; Length of Stay; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Invasive fungal diseases (IFDs) are an important cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (SCT).. To compare the effectiveness of two prophylactic antifungal regimens used as standard of care (SOC) in the setting of SCT during the periods of May 2006 - September 2009 (oral posaconazole, POS) and October 2009 - July 2011 (oral posaconazole with intravenous micafungin bridging, POS-MIC), data from the Cologne Cohort of Neutropenic Patients (CoCoNut) study were analyzed after nearest-neighbor matching. Endpoints were occurrence of breakthrough probable/proven IFD under prophylaxis, incidence and duration of persistent febrile neutropenia, incidence of unspecific pneumonic infiltrates, possible IFD, positive galactomannan tests, as well as fungal-free and overall survival.. Of 291 patients with 307 SCTs observed during the study period, 212 fulfilled the inclusion criteria and were included into the analysis. Patients receiving POS-MIC were less likely to develop a pneumonic infiltrate (RR 0.71, 95% CI 0.51-1.00) or possible IFD (RR 0.36, 95% 0.15-0.87). They also demonstrated improved fungal-free survival at day 100 (P = 0.009). No significant differences were observed for the incidence of probable or proven IFD, positive galactomannan tests, persistent febrile neutropenia, duration of hospitalization and overall mortality. There was no grade III or IV CTCAE (Common Terminology Criteria for Adverse Events) toxicity related to antifungal prophylaxis.. Our results suggest that both prophylactic regimens, POS and POS-MIC are feasible, safe and effective. Our data suggest that bridging with intravenous micafungin could indeed improve exposure to antifungal prophylaxis, which may explain the reduced incidence of pneumonia and IFD in the bridging group.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antifungal Agents; Antineoplastic Agents; Drug Therapy, Combination; Echinocandins; Female; Follow-Up Studies; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Triazoles

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Bacterial; Aspergillosis; beta-Glucans; Candidiasis, Invasive; Chemical and Drug Induced Liver Injury; Early Diagnosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Mannans; Micafungin; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high-performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non-Hodgkin's lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Antineoplastic Agents; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Kidney Diseases; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Echinocandins; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Prospective Studies; Transplantation, Homologous

The purpose of this study was to prospectively evaluate the efficacy and safety of micafungin (MCFG) in empirical therapy for febrile neutropenic patients for whom antibiotic therapy was not effective for hematological malignancies.. Twenty-three hematological patients aged 27-82 years with febrile neutropenia for whom antibiotic therapy was not effective were enrolled in this study and responses to treatment were evaluated.. Treatment success rate was 73.9%. Treatment success rates by primary diagnosis were 77.8% in patients with AML, 50.0% in patients with NHL and 87.5% in patients with other diseases. Moreover, MCFG at a dose of 100 mg or more have a tendency to be effective. One or more adverse events occurred in five (27.7%) of the patients during the study. All of these adverse events were below grade 2 toxicity.. Although the number of patients studied was limited, MCFG as a monotherapy seems to be effective and safe as an empirical therapy in patients with febrile neutropenia. However, further investigation using large-scale studies is needed. This study demonstrated the clinical efficacy and safety of MCFG in patients with febrile neutropenia and with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Lipopeptides; Lipoproteins; Liver; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Peptides, Cyclic; Prospective Studies; Treatment Outcome

In 20 patients with hematologic malignancies, we measured the plasma concentration of micafungin (MCFG) by high-performance liquid chromatography after drip infusion of MCFG, at 150 mg/day over a 1-h period, and we analyzed the results in relation to the patients' laboratory parameters of liver and kidney function. Measurement of the plasma concentration was performed at the end of the initial administration of MCFG, 5 to 6 h after the start of the initial administration, immediately before the second dosing, immediately before the fourth dosing, and at the end of the fourth dosing. The plasma concentration of MCFG was correlated with the doses of MCFG per kilogram body weight (P = 0.0008-0.0036). The peak after the initial administration was 2.6 times higher than the trough value after the initial administration. The steady-state trough value was 1.2 times higher than the trough value after the initial administration. There was no correlation between the liver/kidney function parameters and the plasma concentration of MCFG. These results suggest that there was a good correlation between the plasma concentration of MCFG and the dose of MCFG per kilogram body weight, and that MCFG can be administered safely to patients with liver or kidney dysfunction without adjusting the dose.

Topics: Adult; Aged; Antifungal Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Echinocandins; Female; Hematologic Neoplasms; Humans; Kidney; Lipopeptides; Lipoproteins; Liver; Male; Micafungin; Middle Aged; Peptides, Cyclic

This prospective, observational, multicenter study evaluated the real-world incidence of invasive fungal infection (IFI) during and after micafungin prophylaxis in France. Patients with a hematological malignancy/solid tumor received micafungin prophylaxis according to usual clinical practice and were followed for 3 months. Primary endpoint was breakthrough IFI incidence during prophylaxis. Secondary endpoints included the identification of IFI risk factors, IFI incidence during follow-up, and adverse events (AEs). One hundred and fifty patients (55 children, 95 adults) were enrolled. Micafungin prophylaxis was initiated at 50 mg in adults and at a median 1.01 mg/kg (range: 0.6-2.2) in children. Fifteen patients (10%) experienced an IFI during prophylaxis. IFI breakthrough occurred in 15% children, 7% adults, 3.1% allogeneic transplant patients, 8.7% acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients, 7.0% other patients (never allotransplanted/non-AML/MDS). Nineteen patients (12.7%) experienced an IFI during 3-month follow-up. Micafungin was well tolerated with few treatment-related AEs, supporting its use in this patient population in France.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Chemoprevention; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; France; Hematologic Neoplasms; Humans; Incidence; Infant; Invasive Fungal Infections; Longitudinal Studies; Male; Micafungin; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Delays in diagnosing pulmonary invasive aspergillosis (IA), a significant cause of morbidity and mortality among heart transplant recipients (HTRs), may impact on successful treatment. The appropriate screening strategy for IA in these patients remains undefined, particularly in the setting of nosocomial outbreaks. We describe our experience employing chest computed tomography (CT) scans as a screening method for IA. In addition, we comment on antimicrobial prophylaxis in HTRs in the setting of an outbreak.. Screening CT scans of the chest and serum galactomannan (GM) were performed in HTRs during an outbreak that followed the index case of IA. Abnormal CT findings prompted a diagnostic workup. Antimicrobial prophylaxis for new transplants recipients included intravenous micafungin while hospitalized, followed by outpatient inhaled amphotericin B for up to 3 months.. During a 10-month period, five cases of IA were identified among HTRs. Two additional asymptomatic patients were diagnosed with IA among 15 asymptomatic HTRs who underwent screening chest CT scans. Among the five cases of IA in HTRs, two of five (40%) had a partial response and the other three failed voriconazole therapy. Complete response to voriconazole therapy assessed at 12 weeks was achieved in these two asymptomatic HTRs diagnosed via screening CTs. Serum GM was positive only in one of the symptomatic cases. The negative predictive value of CT scans was 100% (95% confidence interval, 71.5%-100%).. In an outbreak setting, screening CT scans of the chest may aid in early detection of asymptomatic HTRs with IA and improve outcome.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antibiotic Prophylaxis; Antifungal Agents; Asymptomatic Diseases; Cohort Studies; Disease Outbreaks; Echinocandins; Female; Galactose; Heart Transplantation; Hematologic Neoplasms; Humans; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Mass Screening; Micafungin; Middle Aged; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Transplant Recipients; Voriconazole

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for invasive mold infections (IMI). The goal of the study is to describe the incidence and outcome of IMI in patients after allo-HSCT in a large cohort of patients receiving anti-mold prophylaxis. We conducted a retrospective review of 988 consecutive adults who underwent allo-HSCT in our center from 2008 through 2014. Standard prophylaxis consisted of micafungin 150 mg IV daily from admission to day +7 ± 3 followed by voriconazole until day +75 to +100. Cases meeting criteria for proven or probable IMI according to EORTC-MSG criteria were included. Median age at HSCT was 54 years. The most common diagnoses were acute myeloid leukemia (n = 351, 36%) and lymphoid malignancies (n = 248, 25%). Matched related or unrelated donors (URD) were used in 686 (69%) patients, mismatched URD in 142 (14%) and cord blood units in 154 (16%). Twenty-one patients were diagnosed with IMI after allo-HSCT, 19 probable and 2 proven, and one patient was diagnosed postmortem. Microbiological diagnosis was established in 9 cases, 5 of them being Aspergillus. One-year cumulative incidence (CI) of IMI was 1.6% (95% CI 0.9-2.5) while 12-week overall survival after IMI was 39% (95% CI 24-65) Analyzed by disease, there was a trend for a higher 1-year CI of IMI in patients with ALL (5% [95% CI 1.6-11.4]) when compared with AML (1.4%), MDS (1.5%) and lymphoma (1.2%), P = .06. The 1-year CI of IMI after transplantation is low in patients receiving anti-mold prophylaxis with micafungin bridged to voriconazole, although these infections are associated with a higher risk of mortality.

Topics: Adult; Aged; Antibiotic Prophylaxis; Antifungal Agents; Echinocandins; Female; Fungi; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Invasive Fungal Infections; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies; Transplantation, Homologous; Treatment Outcome; Voriconazole; Young Adult

To investigate the performance of the routine serum galactomannan (sGM) assay in the diagnosis of invasive aspergillosis (IA) in high-risk haematology patients receiving prophylaxis with micafungin.. Retrospective study including all haematological patients who received prophylaxis with micafungin during high-risk IA episodes (neutropenic patients after chemotherapy for acute myeloid leukaemia/myelodysplastic syndrome; allogeneic haematopoietic stem-cell transplantation during early neutropenic phase or graft-versus-host disease requiring high prednisone doses) and for whom at least one sGM result was available. Episodes were classified as follows: true-positive (positive GM in the context of IA), false-positive (positive GM result in patients who had no evidence of IA), true-negative (negative GM test results and no IA), or false-negative (negative GM test in the context of IA). Non-evaluable patients were excluded.. Among 146 evaluable episodes, four were true-positive in the context of probable breakthrough IA (incidence of breakthrough IA, 2.7%); 111/146 high-risk episodes (76%) were considered true-negative and 31/146 (21.2%) were considered false-positive. No false-negative episodes were detected. All but one of the false-positive episodes were detected in surveillance GM tests, leading to high-resolution CT scans in eight cases (8/31; 25.8%), all of which were negative. The positive predictive and negative predictive values of sGM for surveillance and diagnostic approaches were 3.2% (1/31) and 100% (110/110) and 75% (3/4) and 100% (1/1), respectively.. Surveillance of asymptomatic patients receiving prophylaxis with micafungin using sGM is unnecessary, because the results are either negative or false-positive. However, sGM remains useful in the diagnosis of breakthrough IA in symptomatic patients during prophylaxis.

Topics: Adult; Antibiotic Prophylaxis; Aspergillosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Lipopeptides; Male; Mannans; Micafungin; Retrospective Studies

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

This study was retrospectively carried out to compare the efficacy of echinocandins such as micafungin (MCFG) and caspofungin (CPFG) in the treatment of antibiotic-unresponsive febrile patients with hematologic malignancies. A total of 163 patients received either MCFG or CPFG. We evaluated the efficacy of echinocandin against fever decline in all patients. Fever decline, defined as a body temperature of less than 37.5 °C sustained for more than 48 h without scheduled antipyretic medication. Efficacy assessments showed that the incidence of fever decline was not significantly different between the MCFG and CPFG groups (P=0.599). The median number of days from the start of echinocandin administration to fever decline was 5 in both the MCFG and CPFG groups. Multivariate analysis showed that the use of anti-MRSA drugs (HR, 0.64; 95%CI, 0.45-0.90; P=0.011) and a change from echinocandins to voriconazole or liposomal-amphotericin B (HR, 0.50; 95%CI, 0.30-0.74; P<0.001) are significant risk factors for sustained fever. A significant difference (P=0.002) in incidence of fever decline was however associated with differences in the timing of anti-MRSA drug administration. The median number of days from the start of echinocandin administration to fever decline was 5 when administration of the anti-MRSA drug occurred "simultaneously or prior to echinocandin start" and 11 in the "next day or later of echinocandin start" group. In other words, starting anti-MRSA drug treatment after echinocandin treatment is a risk factor. In conclusion, MCFG and CPFG have similar efficacy as empirical antifungal agents in the treatment of antibioticunresponsive febrile patients with hematopoietic malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Lipopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Micafungin; Middle Aged; Mycoses; Retrospective Studies; Risk Factors; Staphylococcal Infections; Young Adult

Mould-active antifungal prophylaxis is increasingly used in patients at risk for invasive fungal disease. Between June 2011 and June 2012, one hundred patients with various haematological malignancies at risk for invasive fungal disease received primary antifungal prophylaxis with intravenous micafungin at a daily dosage of 50 mg during neutropenia. The median number of days on micafungin prophylaxis was 14 (range, 6-48 d). The incidence of proven and probable breakthrough invasive fungal diseases (bIFDs) was 6% and 3%, respectively. There were two bloodstream infections caused by yeasts or yeast-like fungi (Candida krusei, Trichosporon asahii) in two patients during the neutropenic phase after allogeneic haematopoietic stem cell transplantation. Four proven bIFDs caused by non-Aspergillus moulds and three cases of probable pulmonary bIFDs were documented during the neutropenic phase after induction/consolidation chemotherapy for acute leukaemia. Colonisation with Candida spp. was documented in 51% of the patients with none of the isolates being in vitro micafungin resistant. Compared to a historical control, receiving primary prophylaxis with posaconazole micafungin is at least as effective in preventing IFD. In both cohorts, bIFDs were exclusively caused by emerging pathogens with a highly preserved in vitro sensitivity to amphotericin B.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Administration Schedule; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies; Transplantation, Homologous; Triazoles; Trichosporon; Trichosporonosis

Intravenous bridging strategies increase exposure of antifungal prophylaxis in high-risk hematological patients. The cost-effectiveness of such strategies has not been analyzed.. A recent study compared the impact of oral posaconazole (POS) and oral posaconazole with intravenous micafungin bridging (POS-MIC) as prophylactic antifungal regimens in patients undergoing allogeneic stem cell transplantation (aSCT). Based on data from the Cologne Cohort of Neutropenic Patients (CoCoNut), a health economic evaluation of direct treatment costs was performed to analyze the economic impact of micafungin bridging. Analysis was undertaken based on current guidelines for the German societal perspective with an annual discount rate of 5%, whereby indirect costs were disregarded due to the severity of the underlying disease. Sensitivity analysis of cost calculation with different discount rates was performed to improve robustness of our health economic evaluation.. A retrospective case-control analysis of patients undergoing aSCT between 05/2006 and 07/2011 was performed; 106 patients each in the POS and POS-MIC group were included. In the POS and POS-MIC group, mean costs per patient for the treatment on bone marrow transplant ward were €27,228 (95% CI: €24,932-€29,525) vs. €27,894 (95% CI: €26,414-€29,375; P = 0.629), for diagnostic measures €2124 (95% CI: €1823-€2425) vs. €1269 (95% CI: €1168-€1370; P ≤ 0.001), for laboratory findings €10,612 (95% CI: €9681-€11,544) vs. €8836 (95% CI: €8198-€9475; P = 0.002), and for overall antifungal treatment €6105 (95% CI: €4703-€7508) vs. €6943 (95% CI: €5393-€8493; P = 0.428), resulting in mean overall costs per patient of €60,304 (95% CI: €53,969-€66,639) vs. €58,089 (95% CI: €51,736-64,442; P = 0.625).. Our health economic evaluation shows micafungin bridging in aSCT patients did not result in excess cost. Higher acquisition costs of antifungal prophylaxis were balanced by a reduced incidence of possible IFD and lower costs for empirical, preemptive, and targeted antifungal therapy as well as lower costs for diagnostic measures and laboratory tests in the micafungin bridging group.

Topics: Antifungal Agents; Case-Control Studies; Cost-Benefit Analysis; Costs and Cost Analysis; Echinocandins; Germany; Health Care Costs; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Micafungin; Mycoses; Pre-Exposure Prophylaxis; Retrospective Studies

Topics: Adolescent; Adult; Aged; Antifungal Agents; Bone Marrow Transplantation; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Hematologic Neoplasms; Humans; Lipopeptides; Male; Micafungin; Middle Aged

Invasive fungal infections are a major cause of infectious mortality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation. However, little is known about the efficacy and safety of micafungin (MCFG), an echinocandin antifungal agent, in pediatric patients with febrile neutropenia (FN).. This study was conducted as a prospective multicenter trial to evaluate the efficacy and safety of MCFG for FN in pediatric patients with hematological diseases. Efficacy was assessed based on the response to the 5 composite endpoints established by Walsh and colleagues in addition to body temperature and C-reactive protein values.. Thirty episodes of FN were enrolled in the study. The median dose and duration of MCFG treatment were 3.0 mg/kg/d and 13.5 days, respectively. Using the criteria of Walsh and colleagues, MCFG was effective in 56.7% of the patients. No breakthrough invasive fungal infection occurred during MCFG treatment. Body temperatures on the last day of neutropenia during administration of MCFG and on the last day of MCFG therapy and C-reactive protein values after administration of MCFG were significantly lower than on the day MCFG therapy was started. Adverse effects in the form of mild liver dysfunction were seen in only 2 patients.. MCFG is a very effective and safe antifungal drug for FN in children. Physicians should administer MCFG early in febrile episode in patients in whom first-line antibiotics are not effective in treating FN.

Topics: Adolescent; Antifungal Agents; Child; Child, Preschool; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Neutropenia; Prospective Studies; Treatment Outcome

The objective of this retrospective, multicenter study was to evaluate the efficacy and safety of micafungin as empirical antifungal therapy during febrile neutropenia (FN) in 73 hematological patients from six centers in two countries. All patients received 100 mg of micafungin/day. The overall favorable response rate (RR) was 64.8% when the resolution of fever during neutropenia was included in the response criteria and 84.5% when excluded. A significantly lower favorable RR in patients with persistent fever and non-specific pulmonary infiltrates compared to patients with persistent fever only (82.8 vs. 52.4%, respectively; p = 0.011) was not found when resolution of fever was not included in the composite endpoint criteria (93.1 vs. 78.6%, respectively; p = 0.180). Breakthrough fungal disease developed in 2.7% of patients. Treatment was discontinued in 16.4% of cases. Only one patient (1.4%) discontinued therapy due to an adverse event. Posaconazole prophylaxis improved favorable RR when defervescence was included as composite endpoint criterion (p = 0.047), but not when it was excluded (p = 0.485). However, neutrophil recovery did not influence favorable RR (p = 0.803 and p = 0.112, respectively). These data suggest that micafungin is safe and effective as an empirical therapy in patients with FN.

Topics: Adult; Aged; Antifungal Agents; Antineoplastic Agents; Czech Republic; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Neutropenia; Retrospective Studies; Slovakia; Treatment Outcome; Young Adult

Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n=26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P<0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations.

Topics: Adult; Chromatography, Liquid; Echinocandins; Erythrocytes; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukocytes, Mononuclear; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutrophils; Plasma; Tandem Mass Spectrometry

The aim of the study was to assess the antifungal prophylactic efficacy, safety, and tolerability of micafungin, 150 mg daily, and to evaluate the usefulness of monitoring 1,3-beta-d-glucan (BG) in neutropenic patients undergoing chemotherapy for hematological malignancies. This investigation was a retrospective, non-randomized study. A group of patients who did not receive systemic antifungal prophylaxis was compared to another group of patients who received micafungin 150 mg daily. All patients admitted with hematological malignancy and undergoing chemotherapy or stem cell transplant were included. The plasma BG level was measured once weekly. The clinical endpoint was the diagnosis of invasive fungal infection (IFI). Antifungal prophylaxis led to a significant decrease in the occurrence of IFI (from 12.3% to 1.5%, p = 0.001). Few severe adverse effects clearly attributable to micafungin were seen. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of BG values >8.9 pg/mL for diagnosis of IFI were 0.90, 0.99, 0.82, 0.99, and 0.99, respectively. Micafungin, 150 mg daily, is an effective and safe drug for antifungal prophylaxis, and monitoring of BG antigenemia is a useful tool for diagnosis of IFI in neutropenic patients with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Echinocandins; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Lipopeptides; Male; Maximum Tolerated Dose; Micafungin; Middle Aged; Mycoses; Neutropenia; Prognosis; Proteoglycans; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Young Adult

Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs.. To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation.. The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%.. We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.

Topics: Adult; Aged; Antifungal Agents; Area Under Curve; Cord Blood Stem Cell Transplantation; Drug Therapy, Combination; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lipopeptides; Male; Micafungin; Middle Aged; Recurrence; Tacrolimus; Transplantation, Homologous

We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Candida tropicalis; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fungemia; Hematologic Neoplasms; Humans; Lipopeptides; Male; Middle Aged

Micafungin is a newly approved antifungal agent in the echinocandin class that is active against Candida species and Aspergillus species. However, this agent has limited activity against a number of fungi, including Trichosporon species. We describe 4 patients who developed disseminated trichosporonosis during the use of micafungin. No cases of trichosporonosis had been seen in the 2 years prior to January 2003, when micafungin became available in our hospital.. We reviewed microbiological records of patients at Kameda General Hospital (Kamogawa City, Chiba, Japan) from 1 January 2002 to 31 July 2005, and identified 4 patients whose blood culture results were positive for Trichosporon species.. Since January 2003, four patients--3 with acute myelocytic leukemia and 1 with myelodysplastic syndrome--developed disseminated trichosporonosis while receiving treatment with micafungin with or without amphotericin B. The initial 2 isolates were identified as Trichosporon beigelii, and the later 2 isolates were identified as Trichosporon asahii. All 4 patients received micafungin, and 2 also received amphotericin B concomitantly. Minimal inhibitory concentrations of micafungin were >16 microg/mL for the 2 isolates available for susceptibility testing. One patient with hematologic recovery (neutrophils >500 cells/mm3) showed elimination of the fungus after receiving treatment with voriconazole. However, the 3 other patients without hematologic or immunological recovery died of disseminated infection.. The rarity of trichosporonosis in our hospital and its emergence after the introduction of micafungin therapy support the idea that micafungin may exert a significant, selective pressure toward resistant fungi, such as Trichosporon species. Therefore, care should be taken regarding the possibility of trichosporonosis in patients receiving micafungin with or without amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Hematologic Neoplasms; Humans; Japan; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Mycoses; Peptides, Cyclic; Selection, Genetic; Trichosporon