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Santiago Grau - One of the best experts on this subject based on the ideXlab platform.
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comparison of the safety and tolerance profile of Micafungin with that of other echinocandins and azoles in patients with pre existing child pugh b or c liver disease a case control retrospective study
Infectious Diseases and Therapy, 2020Co-Authors: Antonio Vena, Santiago Grau, Emilio Bouza, Jesus Fortun, Matteo Bassetti, Francesco Menichetti, Maria Merelli, Maria Isabel Sanchez, Jose Maria AguadoAbstract:To assess the association between exposure to Micafungin, other echinocandins, or azoles and the development of short-term liver injury (STLI) or long-term liver injury (LTLI) in patients with Child–Pugh B or C liver disease. Multicenter case–control study of patients with Child–Pugh B or C liver disease who received antifungals (AF) for ≥ 72 h (May 2009–May 2015) in six Spanish and Italian hospitals. All Micafungin patients were randomly matched with one patient who received another echinocandin and with one patient who received azole treatment. Primary outcome was development of STLI or LTLI (development of any type of liver tumor during the follow-up period). Of 2335 patients with chronic liver disease admitted to the six centers, 20 (0.85%) were found to have Child–Pugh B or C liver disease and received Micafungin for ≥ 72 h. During AF treatment, the frequency of STLI was 10% in each group. Most cases of STLI were asymptomatic, and AFs had to be switched to another class of AF in only two patients (one Micafungin and one azole). No patients developed acute liver insufficiency, were admitted to the ICU, or had to undergo transplantation. Follow-up data (median of 1.3 years) were available for 30 patients. LTLI was observed in only one patient, who had previously received treatment with azoles. Our study suggests that the administration of Micafungin to patients with end-stage liver disease does not imply a higher risk of developing STLI or LTLI.
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pharmacokinetics of Micafungin in critically ill patients receiving continuous venovenous hemodialysis with high cutoff membranes
Therapeutic Drug Monitoring, 2019Co-Authors: Teresa Tenoriocanamas, Sonia Luque, Santiago Grau, Jesus Fortun, Fernando Liano, Jason A RobertsAbstract:BACKGROUND: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on Micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter Micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of Micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). METHODS: Prospective observational study performed in critically ill patients treated with 100 mg/d of Micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and Micafungin concentrations were determined using HPLC-UV. RESULTS: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of Micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. CONCLUSIONS: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of Micafungin, and that standard doses of this antifungal can be used.
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population pharmacokinetics pharmacodynamics of Micafungin against candida species in obese critically ill and morbidly obese critically ill patients
Critical Care, 2018Co-Authors: Sonia Luque, Santiago Grau, Emilio Maseda, Mariapilar Castillomafla, Alejandro Suarezdelarica, Ana Monterofeijoo, Patricia Salgado, Mariajose Gimenez, Carlos A GarciabernedoAbstract:Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the Micafungin probability of reaching adequate 24-h area under the curve (AUC0–24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed Micafungin treatment. Patients received once daily 100–150 mg Micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total Micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0–24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. Overall, 100 mg of Micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of Micafungin dosing for nonalbicans Candida infections.
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comparative population plasma and tissue pharmacokinetics of Micafungin in critically ill patients with severe burn injuries and patients with complicated intra abdominal infection
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Abelardo Garciadelorenzo, A Agrifoglio, Lucia Cachafeiro, Eva Pablos Herrero, M J Asensio, S M Sanchez, Sonia Luque, Santiago Grau, Jason A RobertsAbstract:Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of Micafungin in the plasma and burn eschar of severely burned patients with those of Micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of Micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 +/- 0.47 versus 0.15 +/- 0.06 h(-1), respectively; P< 0.05). Most patients would achieve plasma PK/pharma-codynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of Micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, Micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of < 0.008 mg/liter and < 0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.
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plasma and peritoneal fluid population pharmacokinetics of Micafungin in post surgical patients with severe peritonitis
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Santiago Grau, Sonia Luque, William W Hope, Nuria E Campillo, Enric Samso, U Rodriguez, Carlos A Garciabernedo, E Salas, Raman Sharma, Jason A RobertsAbstract:Objectives: Limited information about the pharmacokinetics of Micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of Micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection.
Donald N Buell - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of Micafungin in neonates and young infants
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: William W Hope, Thomas J. Walsh, Donald N Buell, Antonio Arrieta, Brian P Smith, Atsunori Kaibara, Michael Roy, Michael Cohenwolkowiez, Daniel K BenjaminAbstract:Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that Micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of Micafungin in infants. Here, we describe the population pharmacokinetics of Micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of Micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of Micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).
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pharmacokinetics of an elevated dosage of Micafungin in premature neonates
Pediatric Infectious Disease Journal, 2009Co-Authors: Brian P Smith, Thomas J. Walsh, Antonio Arrieta, William W Hope, Akitsugu Takada, Laura L Kovanda, Gregory L Kearns, David A Kaufman, Taiji Sawamoto, Donald N BuellAbstract:Background Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of Micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma Micafungin concentrations than in older patients because of increased apparent plasma clearance of Micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of Micafungin.
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population pharmacokinetics of Micafungin in pediatric patients and implications for antifungal dosing
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: William W Hope, Patricia M. Flynn, Nita L. Seibel, Donald N Buell, James Keirns, Antonio Arrieta, Cindy L Schwartz, Aziza Shad, Edythe A Albano, Tawanda GumboAbstract:The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of Micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of Micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on Micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of Micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of Micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.
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pharmacokinetics of Micafungin in healthy volunteers volunteers with moderate liver disease and volunteers with renal dysfunction
The Journal of Clinical Pharmacology, 2005Co-Authors: Mary F Hebert, Robert Townsend, Donald N Buell, James Keirns, Helen E Smith, T Marbury, Suzanne K Swan, William B Smith, Ihor BekerskyAbstract:Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of Micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose Micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed Micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in Micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter Micafungin pharmacokinetics.
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concomitant tacrolimus and Micafungin pharmacokinetics in healthy volunteers
The Journal of Clinical Pharmacology, 2005Co-Authors: Mary F Hebert, David K Blough, Robert Townsend, Mark Allison, Donald N Buell, James Keirns, Ihor BekerskyAbstract:Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and Micafungin (100 mg intravenous) alone and with concomitant administration (n=26). Tacrolimus area under the concentration-time curve was 298+/-135 microg*h/L when tacrolimus was administered alone, 305+/-129 microg*h/L (P=.8; confidence interval 89%, 118%) when tacrolimus was given with single-dose Micafungin, and 282+/-138 microg*h/L (P=.4; confidence interval 82%, 107%) when tacrolimus was given with steady-state Micafungin. Despite the mild inhibition of CYP3A in vitro by Micafungin, there does not appear to be a drug interaction with tacrolimus and Micafungin either with single-dose or steady-state Micafungin administration.
Jason A Roberts - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Micafungin in critically ill patients receiving continuous venovenous hemodialysis with high cutoff membranes
Therapeutic Drug Monitoring, 2019Co-Authors: Teresa Tenoriocanamas, Sonia Luque, Santiago Grau, Jesus Fortun, Fernando Liano, Jason A RobertsAbstract:BACKGROUND: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on Micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter Micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of Micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). METHODS: Prospective observational study performed in critically ill patients treated with 100 mg/d of Micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and Micafungin concentrations were determined using HPLC-UV. RESULTS: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of Micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. CONCLUSIONS: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of Micafungin, and that standard doses of this antifungal can be used.
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comparative population plasma and tissue pharmacokinetics of Micafungin in critically ill patients with severe burn injuries and patients with complicated intra abdominal infection
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Abelardo Garciadelorenzo, A Agrifoglio, Lucia Cachafeiro, Eva Pablos Herrero, M J Asensio, S M Sanchez, Sonia Luque, Santiago Grau, Jason A RobertsAbstract:Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of Micafungin in the plasma and burn eschar of severely burned patients with those of Micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of Micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 +/- 0.47 versus 0.15 +/- 0.06 h(-1), respectively; P< 0.05). Most patients would achieve plasma PK/pharma-codynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of Micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, Micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of < 0.008 mg/liter and < 0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.
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plasma and peritoneal fluid population pharmacokinetics of Micafungin in post surgical patients with severe peritonitis
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Santiago Grau, Sonia Luque, William W Hope, Nuria E Campillo, Enric Samso, U Rodriguez, Carlos A Garciabernedo, E Salas, Raman Sharma, Jason A RobertsAbstract:Objectives: Limited information about the pharmacokinetics of Micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of Micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection.
Thomas J. Walsh - One of the best experts on this subject based on the ideXlab platform.
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Micafungin alters the amino acid nucleic acid and central carbon metabolism of candida albicans at subinhibitory concentrations novel insights into mechanisms of action
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Aspasia Katragkou, Michael Williams, Sandi Sternberg, Dennis Pantazatos, Emmanuel Roilides, Thomas J. WalshAbstract:Background Echinocandins are an important class of antifungal agents in the treatment of invasive candidiasis. However, little is known about the metabolomic effects of echinocandins on Candida . We therefore performed LC-high-resolution MS (LC-HRMS)-based metabolomics profiling of the response of Candida albicans cells to increasing concentrations of Micafungin to determine the metabolic response of Candida to Micafungin subinhibitory injury. Methods Isolates of C. albicans were cultured on nitrocellulose filters to mid-logarithmic phase of growth and Micafungin (0-0.25 mg/L) was added. At mid-logarithmic phase, replicates were metabolically quenched. Intracellular metabolites were analysed by LC-HRMS. Changes in pool sizes of individual metabolites were analysed by Student's t -test adjusted for multiple hypothesis testing by Benjamini-Hochberg correction. Metabolites were ascribed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database. Results Among 3446 detected metabolites, 204 were identified by comparison against pure standard or comparison against a library of mass-retention-time pairs. Fifty had significantly altered abundances in response to increasing Micafungin concentrations. Pool sizes of amino acids, nucleic acids and polyamine metabolism were significantly increased at subinhibitory concentrations, while exposure to inhibitory concentrations resulted in a precipitous decrease consistent with fungicidal activity. Conclusions Micafungin induces a re-routing of metabolic pathways inhibiting protein synthesis and cell replication. These results shed light on new mechanisms of action of echinocandins.
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population pharmacokinetics of Micafungin in neonates and young infants
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: William W Hope, Thomas J. Walsh, Donald N Buell, Antonio Arrieta, Brian P Smith, Atsunori Kaibara, Michael Roy, Michael Cohenwolkowiez, Daniel K BenjaminAbstract:Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that Micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of Micafungin in infants. Here, we describe the population pharmacokinetics of Micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of Micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of Micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).
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pharmacokinetics of an elevated dosage of Micafungin in premature neonates
Pediatric Infectious Disease Journal, 2009Co-Authors: Brian P Smith, Thomas J. Walsh, Antonio Arrieta, William W Hope, Akitsugu Takada, Laura L Kovanda, Gregory L Kearns, David A Kaufman, Taiji Sawamoto, Donald N BuellAbstract:Background Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of Micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma Micafungin concentrations than in older patients because of increased apparent plasma clearance of Micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of Micafungin.
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successful medical treatment of cutaneous aspergillosis in a premature infant using liposomal amphotericin b voriconazole and Micafungin
Pediatric Infectious Disease Journal, 2007Co-Authors: Roberto P Santos, Thomas J. Walsh, Daniel K Benjamin, Pablo J Sanchez, Asuncion Mejias, Sanjay Patel, Hasan S JafriAbstract:Treatment options for primary cutaneous aspergillosis in neonates are limited by the lack of pharmacokinetic and safety data of newer antifungal agents that are effective against Aspergillus spp. We report the successful treatment of cutaneous aspergillosis in an extremely low-birth-weight preterm infant with liposomal amphotericin B, voriconazole and Micafungin, and provide pharmacokinetic profiles for voriconazole and Micafungin.
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Comparative antifungal activities and plasma pharmacokinetics of Micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Vidmantas Petraitis, Kristin Roussillon, Melissa Hemmings, Ruta Petraitiene, Tin Sein, Caron A. Lyman, John D. Bacher, Ihor Bekersky, Andreas H Groll, Thomas J. WalshAbstract:Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma Micafungin pharmacokinetics and antifungal activities of Micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with Micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with Micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that Micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with Micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant Micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, Micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in Micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in Micafungin-treated rabbits. In summary, Micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.
Sonia Luque - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of Micafungin in critically ill patients receiving continuous venovenous hemodialysis with high cutoff membranes
Therapeutic Drug Monitoring, 2019Co-Authors: Teresa Tenoriocanamas, Sonia Luque, Santiago Grau, Jesus Fortun, Fernando Liano, Jason A RobertsAbstract:BACKGROUND: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on Micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter Micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of Micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). METHODS: Prospective observational study performed in critically ill patients treated with 100 mg/d of Micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and Micafungin concentrations were determined using HPLC-UV. RESULTS: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of Micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. CONCLUSIONS: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of Micafungin, and that standard doses of this antifungal can be used.
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population pharmacokinetics pharmacodynamics of Micafungin against candida species in obese critically ill and morbidly obese critically ill patients
Critical Care, 2018Co-Authors: Sonia Luque, Santiago Grau, Emilio Maseda, Mariapilar Castillomafla, Alejandro Suarezdelarica, Ana Monterofeijoo, Patricia Salgado, Mariajose Gimenez, Carlos A GarciabernedoAbstract:Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the Micafungin probability of reaching adequate 24-h area under the curve (AUC0–24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed Micafungin treatment. Patients received once daily 100–150 mg Micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total Micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0–24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. Overall, 100 mg of Micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of Micafungin dosing for nonalbicans Candida infections.
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comparative population plasma and tissue pharmacokinetics of Micafungin in critically ill patients with severe burn injuries and patients with complicated intra abdominal infection
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Abelardo Garciadelorenzo, A Agrifoglio, Lucia Cachafeiro, Eva Pablos Herrero, M J Asensio, S M Sanchez, Sonia Luque, Santiago Grau, Jason A RobertsAbstract:Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of Micafungin in the plasma and burn eschar of severely burned patients with those of Micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of Micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 +/- 0.47 versus 0.15 +/- 0.06 h(-1), respectively; P< 0.05). Most patients would achieve plasma PK/pharma-codynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of Micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, Micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of < 0.008 mg/liter and < 0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.
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plasma and peritoneal fluid population pharmacokinetics of Micafungin in post surgical patients with severe peritonitis
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Santiago Grau, Sonia Luque, William W Hope, Nuria E Campillo, Enric Samso, U Rodriguez, Carlos A Garciabernedo, E Salas, Raman Sharma, Jason A RobertsAbstract:Objectives: Limited information about the pharmacokinetics of Micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of Micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection.
