micafungin and Fever

Non-Candida opportunistic yeasts are emerging causes of bloodstream infection (BSI) in immunocompromised hosts. However, their clinical presentation, management, and outcomes in stem cell transplant (SCT) recipients are not well described. We report the first case to our knowledge of Pseudozyma BSI in a SCT recipient. He had evidence of cutaneous involvement, which has not been previously described in the literature. He became infected while neutropenic and receiving empiric micafungin, which is notable because Pseudozyma is reported to be resistant to echinocandins. He was successfully treated with the sequential use of liposomal amphotericin B and voriconazole. A review of the literature revealed nine reported instances of Pseudozyma fungemia. We performed a retrospective review of 3557 SCT recipients at our institution from January 2000 to June 2015 and identified four additional cases of non-Candida yeast BSIs. These include two with Cryptococcus, one with Trichosporon, and one with Saccharomyces. Pseudozyma and other non-Candida yeasts are emerging pathogens that can cause severe and disseminated infections in SCT recipients and other immunocompromised hosts. Clinicians should have a high degree of suspicion for echinocandin-resistant yeasts, if patients develop breakthrough yeast BSIs while receiving echinocandin therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cryptococcus; Cytarabine; Dermatomycoses; Echinocandins; Exanthema; Fever; Fungemia; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunocompromised Host; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipopeptides; Male; Micafungin; Opportunistic Infections; Retrospective Studies; Saccharomyces; Salvage Therapy; Trichosporon; Ustilaginales; Vidarabine; Voriconazole; Yeasts

The incidence of fungal infections has increased globally, and the introduction of the newer triazoles and echinocandin antifungals is a more-than-welcome and long overdue development. In this report, we review the clinical trials evaluating the therapeutic efficacy of these new antifungal agents and examine possible gaps in coverage. Voriconazole has become the primary treatment for most forms of invasive aspergillosis in a number of centers, posaconazole offers a broad antifungal spectrum, and echinocandins are fungicidal against most Candida species. Moreover, the new agents are active against some fungi that are resistant to amphotericin B, may have a role in the management of fever and neutropenia, and provide exciting options for combination antifungal therapy. However, significant questions remain, including the management of breakthrough infections and treatment failures and the efficacy of the new antifungal agents against less common fungi.

Topics: Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Cryptococcosis; Echinocandins; Fever; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Neutropenia; Peptides, Cyclic; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

The aim of this study was to assess the drug interaction between high doses of micafungin and cyclosporine A (CyA) in allo-HSCT patients.. We assigned 15 patients to Groups 1, 2, or 3. We investigated the serial changes in the blood concentration/dose (C/dose) of intravenous CyA during micafungin coadministration in 5 patients during the switch from the prophylactic dose (150 mg/body) to the therapeutic dose (300 mg/body) of micafungin (Group 1), and compared each of the 5 patients in Group 1 with those who continued to receive the prophylactic doses of 150 mg or 50 mg/body of micafungin (Groups 2 and 3). We collected blood samples from patients in Group 1 receiving CyA at 0 h (C0) and (C3) 3 h on the 7th day after allo-HSCT, and on the 3rd and 10th days after escalation of the dose of micafungin to 300 mg.. In Group 1, no significant difference was observed between C0/dose (2.11 ± 0.14) and C3/dose ratios of CyA (11.1 ± 5.34, p > 0.05) under 150 mg; the C0/dose and C3/dose ratios of CyA were 2.40 ± 0.60 and 10.8 ± 4.72 on the 3rd day and 2.23 ± 0.41 and 11.8 ± 3.06 on the 10th day, respectively, after dose escalation of micafungin to 300 mg. No significant differences were observed in those ratios between Groups 1 and 2 and between Groups 1 and 3.. Thus, high dose of micafungin seems to be safe and does not significantly interact with CyA in allo-HSCT.

Topics: Adult; Aged; Analysis of Variance; Antifungal Agents; Cyclosporine; Drug Interactions; Drug Monitoring; Echinocandins; Female; Fever; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Models, Biological; Neutropenia; Pilot Projects

This observational study was conducted to document the efficacy and safety of the use of micafungin (Mycamine) as an empirical antifungal agent in febrile neutropenic patients.. Micafungin was administered for sustained fever (>38.4°C) on days 3-5 following the initiation of empirical antibiotic therapy. The overall success rate and side effects were evaluated.. A total of 47 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome and lymphoma were enrolled in the study. The overall success rate of micafungin was 61.7% (29/47). A total of 3 patients (6.4%) experienced grade 3/4 elevations in their aspartate aminotransferase levels, and 10 patients (21%) experienced grade 3/4 hyperbilirubinemia, 9 of which resolved. Four patients died of septic shock. Younger patients (<50 years) and patients with acute lymphoblastic leukemia exhibited a better response to micafungin than other patients. Patients that were less profoundly neutropenic (≥0.05 × 10(9)/l) also had a better response to micafungin, as did the patients who recovered from their fever or neutropenia.. Micafungin has an excellent efficacy (61.7%) and safety profile when used as an empirical antifungal agent in febrile neutropenic patients with hematological disorders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antifungal Agents; Echinocandins; Female; Fever; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Micafungin; Middle Aged; Mycoses; Myelodysplastic Syndromes; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; 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

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

Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >/=9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.

Topics: Adolescent; Antifungal Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Female; Fever; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Mycoses; Neutropenia; Peptides, Cyclic; Treatment Outcome

We previously reported that Candida albicans responded to mild heat stress in a range of temperature elevations simulating fever, and concluded that mild heat stress increases susceptibility to antifungal drugs. In this study, we show that mild heat stress causes a morphological change in hyphae during the process of biofilm formation. We found that mild heat stress extended the period of hyphal stage maintenance in C. albicans biofilm. Although the rate of hyphal change from yeast form to hyphal form reached the maximum within 3 hr, later, almost every cell quickly reverted to the yeast growth phase within 6 hr at 37°C but not at 39°C, or under mild heat stress. Electron microscopy using a smart specimen preparation technique revealed that mild heat stress significantly increased the thickness of the inner cell wall accompanied by a decrease in density of the outer cell wall in the hyphae of C. albicans biofilm. To identify the gene responsible for the morphological changes associated with mild heat stress, we performed microarray gene expression analysis. Eleven genes were upregulated and 17 genes were downregulated under mild heat stress in biofilm cells. The increased PHR1 gene expression in response to mild heat stress was confirmed in quantitative RT-PCR analysis. The mutant upregulated PHR1 expression showed the same sensitivity against antifungal drug micafungin as dependent on mild heat stress. Our findings point to possible therapeutic effects of hyperthermia as well as to the effect of fever during infections.

Topics: Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Cell Wall; Down-Regulation; Drug Resistance, Fungal; Fever; Fungal Proteins; Gene Expression; Gene Expression Regulation, Fungal; Hot Temperature; Hyphae; Membrane Glycoproteins; Micafungin; Microscopy, Electron; Stress, Physiological; Time Factors

Rhodotorula species are environmental basidiomycete yeasts that have emerged as a cause of fungemia in immunocompromised hosts. The insertion of a central venous catheter was identified as a major risk factor for Rhodotorula fungemia. Few cases reports have reported (1→3)-β-D-glucan testing at the onset of Rhodotorula mucilaginosa fungemia. We report a case of catheter-related bloodstream infection due to R. mucilaginosa. Serum β-D-glucan level was normal at the onset of the bloodstream infection. It took 5 days to culture the isolate. The patient's fever persisted after empiric treatment with micafungin, and a switch to oral voriconazole immediately resolved the fungemia.

Topics: Aged; Antifungal Agents; Catheter-Related Infections; Female; Fever; Fungemia; Glucans; Humans; Immunocompromised Host; Micafungin; Rhodotorula; Risk Factors; Voriconazole

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

Micafungin and caspofungin, which are both echinocandins, elicit their antifungal effects by suppressing the synthesis of β-D-glucan, an essential component of fungal cell walls. If micafungin is not effective against a fungal infection, is it unreasonable to switch to caspofungin?. An 80-year-old Asian man presented to our hospital with brain and lung abscesses. Klebsiella pneumonia and Escherichia coli were identified by sputa culture and Streptococcus mitis was identified in the brain abscess culture obtained by drainage surgery. He was treated with antibiotics and both abscesses shrank after the treatment. But he continued to have a high fever and Candida glabrata was identified by blood culture. The origin of the infection was not clarified and micafungin was administered intravenously. The fungus showed poor susceptibility to micafungin; we then switched the antifungal from micafungin to caspofungin. After caspofungin treatment, his body temperature remained below 37 °C and his β-D-glucan levels decreased remarkably.. In vitro, micafungin is considered more effective against C. glabrata because its minimum inhibitory concentration against C. glabrata is lower than that of caspofungin. However, in vivo, there is no significantly different effect between the two drugs. When micafungin is not effective against candidiasis, a switch to caspofungin might be applicable because the pharmacokinetics in each echinocandin is slightly different.

Topics: Aged, 80 and over; Antifungal Agents; Brain Abscess; Candida glabrata; Candidiasis; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Lung Abscess; Male; Micafungin; Treatment Outcome

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

Caspofungin is approved in the United States for empiric antifungal therapy for persistent febrile neutropenia (FN). There are limited data about the use of other echinocandins in this setting.. After a formulary change, we retrospectively evaluated the safety and effectiveness of caspofungin and micafungin as empiric antifungal therapy for FN at Brigham and Women's Hospital (Boston, Massachusetts).. This was a retrospective, observational, sequential cohort study. We identified patients who had received >or=2 doses on concurrent days of either caspofungin (between November 2005 and October 2006) or micafungin (between November 2006 and October 2007) for empiric FN therapy. Patients were included for analysis if they were neutropenic (absolute neutrophil count <500 cells/microL) and febrile (temperature >or=100.5 degrees F [>or=38 degrees C]). Patients without previous exposure to an echinocandin were included; those included in the caspofungin cohort were excluded from the micafungin cohort. Those who had previously received another systemic antifungal agent for FN therapy (except fluconazole for mucosal candidiasis) were excluded. Patients were followed through hospital discharge. Outcomes analyzed were successful treatment of baseline invasive fungal disease (IFD), incidence of breakthrough IFD, overall mortality, and discontinuation because of adverse events (AEs). IFD was diagnosed and classified according to current European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group criteria.. Three hundred twenty-three patients met inclusion criteria (caspofungin, n = 149; micafungin, n = 174). Median age was 49 years in both the caspofungin and micafungin groups; 80 (53.7%) and 99 (56.9%) patients in each group, respectively, were men. Fluconazole prophylaxis had been administered to 30 patients (20.1%) treated with caspofungin and 21 patients (12.1%) treated with micafungin. Caspofungin was administered at 70 mg for one dose, followed by 50 mg daily; micafungin was administered at 100 mg daily. The median duration of therapy and of hospitalization were 10 days and 29 days, respectively, with caspofungin, and 9 days and 28 days with micafungin (both, P = NS between groups). Twelve patients (8.1%) in the caspofungin cohort and 13 (7.5%) in the micafungin cohort died during the study period (P = NS). There were 3 cases (2.0%) of baseline IFD in the caspofungin cohort and 6 (3.4%) in the micafungin cohort (P = NS); 6 were successfully treated (caspofungin, 2 [1.3% of entire group]; micafungin, 4 [2.37% of entire group]; P = NS). Breakthrough IFD was diagnosed in 16 patients (10.7%) receiving caspofungin and 21 (12.1%) receiving micafungin (P = NS). AEs requiring echinocandin discontinuation were uncommon (caspofungin, 2 cases of rash and 1 anaphylactoid infusion reaction [2.0%]; mica-fungin, 1 liver function test elevation >or=5 times the upper limit of normal and 1 maculopapular rash [1.1%]; P = NS).. Micafungin, as empiric antifungal therapy for persistent FN, did not appear to differ significantly from caspofungin in terms of safety profile or efficacy in the adult patients included in this sequential cohort analysis at one institution. ClinicalTrials.gov identifier: NCT00723073.

Topics: Adult; Aged; Antifungal Agents; Caspofungin; Cohort Studies; Drug Administration Schedule; Echinocandins; Female; Fever; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Retrospective Studies; Young Adult

Invasive fungal infection is a major cause of morbidity and mortality in patients with febrile neutropenia unresponsive to antibacterial treatment. Empirical antifungal therapy with amphotericin B has been the standard of care for these patients; however, there remains a need for less toxic alternative drugs.. We conducted a prospective study to evaluate the efficacy and safety of micafungin (MCFG), a novel antifungal agent of the echinocandin class, in an empirical therapy setting for patients with febrile neutropenia.. A total of 31 patients with acute leukemia who developed febrile neutropenia were enrolled in the study. Among them, 18 patients fulfilling the protocol-defined criteria, including 10 with persistent fever and 8 with recurrent fever, received MCFG empirically. Underlying diseases consisted of acute myeloid leukemia (n=15) and acute lymphoblastic leukemia (n=3). The median duration of neutropenia and drug administration was 22 and 9.5 days, respectively. Treatment success, defined as defervescence during the neutropenic period, absence of breakthrough fungal infections, and requiring no replacement of antifungal drugs, was achieved in 14 patients (78%). None of the patients required discontinuation or dose reduction due to adverse events except for one patient with severe hypokalemia.. Although the studied patients were limited in number, our results indicate that MCFG is an encouraging agent for empirical antifungal therapy in patients with febrile neutropenia, and deserves further investigation in large-scale studies.

Topics: Adolescent; Adult; Algorithms; Antifungal Agents; Echinocandins; Female; Fever; Humans; Leukemia, Myeloid; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Neutropenia; Peptides, Cyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies