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Antimicrobial Agents and Chemotherapy Mar 2018We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the...
We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the mutation frequency. We studied 20 echinocandin-susceptible, fluconazole-intermediate, and wild-type isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/liter were selected for antifungal susceptibility testing. The genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, MSW, and mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence ( model) of the resulting individual mutant colonies were studied. For micafungin and anidulafungin, we found similar results for the MPC (0.06 to 2 mg/liter and 0.25 to 2 mg/liter, respectively), MSW (0.015 to 2 mg/liter for both echinocandins), and mutation frequency (3.7 × 10 and 2.8 × 10, respectively). A total of 12 isolates were able to grow at 1 mg/liter on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however, mutations (ΔF658, S663P, W715L, and E655A) were observed only in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual mutant colonies. Echinocandin concentrations lower than 2 mg/liter can lead to selection of resistance mutations in isolates .
Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Humans; Micafungin; Mutation
PubMed: 29311063
DOI: 10.1128/AAC.01982-17 -
Population pharmacokinetics of micafungin and its metabolites M1 and M5 in children and adolescents.Antimicrobial Agents and Chemotherapy Feb 2015The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention... (Randomized Controlled Trial)
Randomized Controlled Trial
The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg·h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.
Topics: Adolescent; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Child; Child, Preschool; Echinocandins; Female; Humans; Infant; Lipopeptides; Male; Micafungin
PubMed: 25421470
DOI: 10.1128/AAC.03736-14 -
Pharmaceuticals (Basel, Switzerland) Apr 2021Dengue fever is an arbovirus disease caused by infection with the dengue virus (DENV). Half of the world's population lives under the threat of dengue fever, however,...
Dengue fever is an arbovirus disease caused by infection with the dengue virus (DENV). Half of the world's population lives under the threat of dengue fever, however, researchers have yet to develop any drugs that are clinically applicable to this infection. Micafungin is a member of the echinocandins family of anti-fungal drugs, capable of blocking the synthesis of β-1,3-D-glucan in the walls of fungal cells. Previous studies have demonstrated the effectiveness of Micafungin against infections of enterovirus 71 (EV71) and chikungunya virus (CHIKV). This is the first study demonstrating the effectiveness of micafungin in inhibiting the cytopathic effects of dengue virus serotype 2 (DENV-2) in a dose-dependent manner. Time-of-addition assays verified the inhibitory effects of micafungin in pre-treated, co-treated, and full-treatment groups. Binding and entry assays also demonstrated the effectiveness of micafungin in the early stage of DENV-2 infection. The virucidal efficacy of micafungin appears to lie in its ability to destroy the virion. Molecular docking assays revealed the binding of micafungin to the envelope protein of DENV-2, thereby revealing the mechanism by which micafungin affects the early stage of DENV infection and the stability of DENV. Two other micafungin analogs, caspofungin and anidulafungin, were also shown to have the antiviral effects on DENV-2. Finally, immunofluorescence assay (IFA) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) confirmed the broad anti-DENV ability of micafungin against dengue virus serotypes 1, 3, and 4 (DENV-1, DENV-3, and DENV-4). Taken together, these results demonstrate the potential of micafungin and its analogs as candidates for the development of broad-spectrum treatments for DENV infection.
PubMed: 33917182
DOI: 10.3390/ph14040338 -
European Journal of Medical Research Apr 2011Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity... (Review)
Review
Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity of the fungal cell wall. Currently there are three available agents: caspofungin, micafungin and anidulafungin. While the individual echinocandin antifungals have a different spectrum of licensed indications, basically all of them are available for the treatment of candidemia and invasive candidiasis. Antifungal treatment modalities basically include in therapy for suspected or proven infection and prophylaxis. All three drugs are comparatively expensive. Therefore a systematic review of the literature was performed to investigate the following aspects: * General aspects of cost-effectiveness in the treatment of invasive fungal infections * Cost-effectiveness of the treatment with the above-mentioned antifungals * Cost-effectiveness in two settings: therapy and prophylaxis - Early initiation of antifungal therapy, adjustment after availability of microbiological results, duration of therapy, success and occurrence of severe complications (e.g. renal failure) are the most important cost drivers in antifungal therapy. - Considering the specific antifungals, for caspofungin the best evidence for cost-effectiveness is found in treatment of invasive candidiasis and in empiric therapy of suspected infections. Favourable economic data are available for micafungin as a cost-effective alternative to LAmB for prophylaxis in patients with hematopoietic stem cell transplantation (HSCT). For anidulafungin, cost-effectiveness was demostrated in a pharmacoeconomic model. Net savings - yet not significant - were observed in a retrospective chart review of 234 patients. Generally, however, most analyses are still based on pharmacoeconomic modelling rather than direct analysis of trial data or real-life clinical populations. - As an overall conclusion, using caspofungin, micafungin, or anidulafungin is not more expensive than using other established therapies. Micafungin has proven to be cost-effective in prophylaxis if the local fungal epidemiology indicates a high level of resistance to fluconazole. Switch strategies involving early initiation of broadly active therapy with switch to cheaper alternatives according to microbiology results and clinical status and early initiation of an appropriate therapy have been proven to be cost-efficient independent of the antifungal agent.
Topics: Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Echinocandins; Humans; Lipopeptides; MEDLINE; Micafungin
PubMed: 21486732
DOI: 10.1186/2047-783x-16-4-180 -
Journal of Fungi (Basel, Switzerland) Jul 2021Micafungin is a recommended echinocandin antifungal agent for candidemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause resistance....
Species Distribution of Candidemia and Their Susceptibility in a Single Japanese University Hospital: Prior Micafungin Use Affects the Appearance of and Elevation of Micafungin MICs in Non- Species.
INTRODUCTION
Micafungin is a recommended echinocandin antifungal agent for candidemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause resistance. There is currently no information available regarding the low susceptibility associated with using micafungin. This study investigated the effect of micafungin use on changes in the detected species and low susceptibility.
METHODS
We conducted a retrospective survey and included records of spp. detected in blood cultures from January 2010 to December 2018 in our hospital. Survey items included clinical outcomes at 30 days after positive cultures, patient characteristics, and drug prescription status. Patient background information included gender, previous hospitalization, stay in the intensive care unit, comorbidities, and history of surgery (within 90 days before candidemia onset) and drug exposure. Species detected and their minimum inhibitory concentrations (MICs) and amount of antifungal prescriptions by department were investigated. Risk factors for detecting and for low susceptibility to micafungin were evaluated using multivariate analysis.
RESULTS
A total of 153 clinical blood isolates were collected and was the most prevalent species, followed by and . In the analysis by department, antifungal use and non- species were most frequently detected in the hematology department. Multivariate analysis showed that prior micafungin use increased the risk of (odds ratio (OR) 4.22; 95% confidence interval (CI) 1.39-12.79; = 0.011). MIC of micafungin on and was 1.0 μg/mL. Prior micafungin use was clarified as a risk factor resulting in MIC > 0.06 μg/mL for micafungin in non- species (OR 13.2; 95% CI 3.23-54.2; < 0.01).
CONCLUSION
Prior micafungin use increased the risk of and the MIC > 0.06 μg/mL of micafungin in non- species. Since there are only a few antifungal options, further antifungal stewardship considering azole antifungal agents use is required.
PubMed: 34436135
DOI: 10.3390/jof7080596 -
International Journal of Infectious... Nov 2020The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings.
METHODS
From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy.
RESULTS
The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups.
CONCLUSIONS
The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.
Topics: Adult; Aged; Antifungal Agents; Febrile Neutropenia; Female; Humans; Male; Micafungin; Middle Aged; Neutrophils; Treatment Outcome; Young Adult
PubMed: 32891738
DOI: 10.1016/j.ijid.2020.08.081 -
Core Evidence 2014Invasive fungal infections have increased throughout the world. Many of these infections occur in patients with multiple comorbidities who are receiving medications with... (Review)
Review
Invasive fungal infections have increased throughout the world. Many of these infections occur in patients with multiple comorbidities who are receiving medications with the potential for interactions with antifungal therapy that could lead to renal and hepatic dysfunction. The second marketed echinocandin, micafungin, was approved in 2005 for the treatment of esophageal candidiasis and prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation. The indication for use was later expanded to include candidemia, acute disseminated candidiasis, Candida abscesses, and peritonitis. Like other echinocandins it is fungicidal against Candida species, including those that are polyene- and azole-resistant and fungistatic against Aspergillus species. Its formulation is by the intravenous route only and it is dosed once daily without a loading dose as 85% of the steady state concentration is achieved after three daily doses. It has a favorable tolerability profile with no significant drug interactions and does not need adjustment for renal or hepatic insufficiency.
PubMed: 24596542
DOI: 10.2147/CE.S36304 -
Mikrobiyoloji Bulteni Jan 2020Micafungin is recommended especially in patients with liver and kidney failure and in the presence of other side effects due to antifungals apart from its known priority...
Micafungin is recommended especially in patients with liver and kidney failure and in the presence of other side effects due to antifungals apart from its known priority indications such as invasive candidiasis. The aim of this study was to evaluate the children who have received micafungin treatment. In the study, 125 children who were hospitalized in the pediatric wards and intensive care units of our hospital and had used micafungin between November 2016 and January 2019 were analyzed retrospectively. Clinical data, micafungin indication, blood values on the first and fourth days of the treatment, side effects of the drug and efficacy were evaluated. Sixty percent (75/125) of the patients were male and the mean age of all the patients were 58 ± 67 (0-215, 30) months. Approximately half of the cases (48%) had malignancy and 13% of them were premature. Sixty-two percent (n= 37) of the malignencies were hematological (27 acute lymphocytic leukemia, nine acute myeloid leukemia, one myelodysplastic syndrome) and 38% (n= 23) were oncological (six neuroblastoma, four Hodgkin lymphoma, two Non-Hodgkin's lymphoma, five sarcomas, one hepatoblastoma, five others) malignencies. The major cause of hospitalization was sepsis (53%). The patients had several risk factors like immunosuppressive therapy (n= 68, 54%), neutropenia (n= 61, 49%), central venous catheter (n= 102, 82%), nasogastric tube (n= 63, 50%), endotracheal intubation tube (n= 49, 39%), urinary catheter (n= 14, 11%) and total parenteral nutrition (n= 81, 65%). Thirteen percent (n= 16) of the cases were post-operative patients. Candida species were cultivated in 97 clinical specimens (blood, endotracheal aspirate, sputum, urine, etc.) among 23 (18%) of the patients. Thirteen (10%) of the patients had candidemia and 62% of them were non-albicans strains. In all candidemias, strains were echinocandin susceptible, and blood cultures were negative within four days. When all the patients (n= 125) were evaluated, a significant decrease in C-reactive protein, an increase in sodium, and a decrease in alanine aminotransferase were observed on the fourth day of micafungin treatment (p<0.05). A total of 39 (31%) patients underwent various antifungal treatments for median seven (1-60) days prior to micafungin treatment. Fourteen (36%) of these 39 patients, had elevated liver function tests (LFT), 10 (26%) of them had hypokalemia, and five (13%) of them had elevated renal function tests. Ten (26%) patients had antifungal-induced hypokalemia previously; and potassium levels were normalized after micafungin treatment (p= 0.0001). The patients for which micafungin treatment was chosen due to elevated liver function tests (n= 47, 38%), whether the antifungalinduced or not; alanine aminotransferase and aspartate aminotransferase levels were decreased after micafungin treatment (p= 0.0001 and p= 0.0001, respectively). Nineteen (15%) of the patients have died within the first 30 days of micafungin treatment and one of them had candidemia. No micafungin treatment related significant side effects were observed in any of the patients. Our study showed that micafungin could be a safe and effective option in pediatric cases including newborns with high liver and kidney function tests.
Topics: Antifungal Agents; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Retrospective Studies
PubMed: 32050883
DOI: 10.5578/mb.68832 -
Antimicrobial Agents and Chemotherapy Dec 2016High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use....
High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.
Topics: Antifungal Agents; Candidiasis; Central Nervous System Diseases; Dose-Response Relationship, Drug; Echinocandins; Female; Humans; Infant; Infant, Newborn; Kidney; Lipopeptides; Liver; Male; Meningitis, Fungal; Micafungin; gamma-Glutamyltransferase
PubMed: 27697761
DOI: 10.1128/AAC.01172-16 -
The Pediatric Infectious Disease Journal Nov 2013Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida spp.
BACKGROUND
Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida spp.
OBJECTIVE
To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable or suspected invasive candidiasis.
METHODS
Micafungin safety and pharmacokinetics were assessed in 2 phase I, open-label, repeat-dose trials. In Study 2101, children aged 2-16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10-14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical.
RESULTS
Safety was analyzed in 78 and 9 children in Studies 2101 and 2102, respectively. Although adverse events (AEs) were experienced by most children (2101: n=62; 2102: n=9), micafungin-related AEs were less common (2101: n=28; 2102: n=1), and the number of patients discontinuing due to AEs was low (2101: n=4; 2102: n=1). The most common micafungin-related AEs were infusion-associated symptoms, pyrexia and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults.
CONCLUSIONS
In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support US dosing recommendations in children.
Topics: Adolescent; Antifungal Agents; Body Weight; Candidiasis, Invasive; Child; Child, Preschool; Drug Administration Schedule; Echinocandins; Female; Humans; Infant; Kidney Function Tests; Lipopeptides; Liver Function Tests; Male; Micafungin
PubMed: 23958810
DOI: 10.1097/INF.0b013e31829efd14