micafungin and Critical-Illness

Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is widespread. To evaluate pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients by comparing the differences in pharmacokinetic parameters between critically ill patients and healthy volunteers or general patients.. MEDLINE, EMBASE, The Cochrane Library and Pubmed were searched from inception until 6 September 2018. Studies investigating the pharmacokinetic parameters of echinocandins in critically ill patients, healthy volunteers or general patients were included. Our primary outcomes included AUC. Of 3235 articles screened, 17 studies were included in the data synthesis. Descriptive data from single-arm studies show that critically ill patients who received caspofungin had more stable AUC. This systematic review provides an analysis of the pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients. Based on the limited data available, caspofungin has less pharmacokinetic/pharmacodynamics variability than anidulafungin and micafungin.

Topics: Anidulafungin; Antifungal Agents; Area Under Curve; Caspofungin; Critical Illness; Echinocandins; Humans; Invasive Fungal Infections; Micafungin

Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15-8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40-80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4-10 mg/kg in premature neonates and 2-4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.

Topics: Adult; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Child; Critical Illness; Dose-Response Relationship, Drug; Esophagitis; Humans; Infant; Infant, Newborn; Micafungin

The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed and the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that compared untargeted antifungal treatments applied to nonneutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2,556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease the incidence of all-cause mortality (odds ratio [OR] = 0.89, 95% confidence interval [95%CI] = 0.70 to 1.14), but it did reduce the incidence of proven IFI (OR = 0.45, 95%CI = 0.29 to 0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR = 0.35, 95%CI = 0.19 to 0.65). Based on drug and hospital costs in China, the incremental cost-effectiveness ratios per life-year saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention corresponded to US$889, US$9,994, and US$10,351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in nonneutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Among the well-tolerated antifungals, fluconazole remains the only one that is effective for IFI prevention and significantly cheaper than echinocandins.

Topics: Antifungal Agents; Caspofungin; Cost-Benefit Analysis; Critical Illness; Echinocandins; Economics, Pharmaceutical; Fluconazole; Humans; Invasive Fungal Infections; Lipopeptides; Micafungin; Network Meta-Analysis; Primary Prevention

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

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

The invasive fungal infections (IFIs) have increased in critically ill patients in recent years and are a serious complication that determine the evolution and prognosis of critically ill patients, especially invasive candidiasis (IC)and candidemia. Fortunately, treatment options for these infections have increased and there is a large arsenal of antifungal agents. This review of the literature, using PubMed and Cochrane databases, assesses the situation of the IFIs in critically ill patients and discusses the role of micafungin in this context. The broader spectrum of this candin, which gets the antifungal effect with lower MICs and that translates into greater clinical efficacy with a lower rate of adverse effects and easier to use, with proven cost-effectiveness compared with other antifungal, position micafungin as a useful therapeutic option for the management of invasive candidiasis / candidemia in critically ill patients.

Topics: Antifungal Agents; Candidiasis; Critical Illness; Echinocandins; Fungi; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Prognosis

The echinocandins have a growing role in the treatment of fungal infections because of their novel mechanism of action. This is reflected in recently published management guidelines, but available in vitro data, animal studies, and clinical studies do not clearly differentiate the three agents in class. Comparative clinical efficacy among agents within the class, pharmacokinetic profiles in special populations, pharmacoeconomics justifications, and place in therapy have been largely unanswered. They share many common properties but marketing strategies of drug manufacturers are engaged in product differentiation. Although exist similarities in the pharmacokinetic (PK) profiles of the echinocandins, limited data have been published regarding their pharmacokinetics in continuous renal replacement therapy (CRRT) patients. The pharmacokinetics of drug removal in critically ill patients receiving CRRT is very complex, with multiple variables affecting clearance. This review outlines the basic principles that determine whether a dose adjustment is required. Two studies with data on PK parameters of micafungin and anidulafungin in CRRT patients have been published and are compared following that basic principles in the review.

Topics: Adsorption; Antifungal Agents; Caspofungin; Critical Illness; Echinocandins; Hemodiafiltration; Hemofiltration; Humans; Kidney Failure, Chronic; Lipopeptides; Membranes, Artificial; Metabolic Clearance Rate; Micafungin; Mycoses; Renal Replacement Therapy

Currently there are three main drug groups for the prevention and treatment of fungal infections: polyenes (amphotericin B deoxycholate or its lipid formulations), azoles (fluconazole, itraconazole or posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin). However, a major characteristic to be evaluated when choosing an antifungal agent -apart from antifungal spectrum, pharmacokinetics and adverse effects- is the absence of significant drug interactions. Amphotericin B lacks interactions but may cause renal dysfunction, leading to the accumulation of renally metabolized drugs. Nephrotoxicity is significantly lower with lipid formulations, especially with liposomal amphotericin B. Azoles modify the metabolism of a wide range of drugs by inhibiting their biotransformation or altering their distribution and elimination. These drugs are metabolized in the liver through the P450 cytochrome complex, inhibiting several isoenzymes, especially CYP3A4, the main drug-metabolizing enzyme. Moreover, itraconazole and posaconazole are substrates and inhibitors of the transporter protein, P-glycoprotein. Fluconazole is the azole with the fewest drug-drug interactions. The echinocandins have increased the therapeutic arsenal and a particular feature of these drugs is their safety, due to the absence of severe adverse effects and the scarce number of interactions. The echinocandin with the highest number of interactions is caspofungin. Micafungin is an echinocandin lacking in relevant interactions and consequently its dosage requires no adjustment in any of its indications. This drug can be used both in adults and in the pediatric population, including neonates.

Topics: Adult; Amphotericin B; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Critical Illness; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Echinocandins; Humans; Infant, Newborn; Lipopeptides; Micafungin; Microsomes, Liver; Mycoses; Triazoles

The use of extrarenal depuration techniques is increasingly frequent in patients admitted to the ICU. The use of these procedures has been related to a decrease in plasma concentrations of several antimicrobials, among which fluconazole. The activity of antifungal agents depends on achievement on adequate concentrations in plasma and at the site of infection. Micafungin is a new antifungal drug recently introduced in our country.. To review the published experience of pharmacokinetic (PK) parameters of micafungin in patients requiring some type of extrarenal depuration procedures during their stay in the ICU.. Three studies with data on PK parameters of micafungin during the use of this drug in continuous venovenous hemodialysis (2 publications) and continuous hemodiafiltration (1 publication) were retrieved. In all of them, minimal variations in the plasma concentration of micafungin at the entry and exit sites of the hemofilter and a negligible or minimal presence of micafungin in the ultrafiltration fluid were demonstrated.. Adjustment of the doses or the interval between doses of micafungin during the use of extrarenal depuration techniques in critically ill patients admitted to the ICU is not necessary.

Topics: Antifungal Agents; Critical Care; Critical Illness; Echinocandins; Fungi; Hemodiafiltration; Humans; Kidney Failure, Chronic; Lipopeptides; Micafungin; Mycoses; Renal Dialysis; Renal Replacement Therapy

Over the last 30 years a significant increase of Candida spp. invasive disease has been observed in non-neutropenic critical ill patients. Both fluconazole and amphotericin B have been considered first line treatment for invasive (proven and probable) Candida spp. disease, although the mortality rate is still high.. To review the current data on the use of micafungin for the treatment of Candida invasive disease in critical ill patients.. The pharmacologic, mycological and clinical properties of micafungin are reviewed based on current published data. The use and efficacy of micafungin for the treatment of Candida invasive disease in critical ill patients is discussed.. To reduce the rate of mortality more effective antifungals and pre-emptive treatment strategies are currently warranted. Candins achieve better results for the treatment of invasive Candida disease in non-neutropenic critical ill patients. Micafungin has a good safety profile (similar to fluconazole). Micafungin is a first line drug for the treatment of invasive Candida disease and may be used as a pre- emptive approach followed by a de-escalating strategy with azoles.

Topics: Antifungal Agents; Candidiasis; Caspofungin; Clinical Trials as Topic; Critical Care; Critical Illness; Drug Therapy, Combination; Echinocandins; Fungemia; Humans; Incidence; Leukocyte Count; Lipopeptides; Micafungin; Neutrophils; Randomized Controlled Trials as Topic

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/pharmacodynamic (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.

Topics: Adult; Aged; Antifungal Agents; Ascitic Fluid; Burns; Critical Illness; Echinocandins; Female; Humans; Intraabdominal Infections; Lipopeptides; Male; Micafungin; Middle Aged; Monte Carlo Method; Prospective Studies; Tissue Distribution

In critically ill patients the incidence of invasive fungal infections caused by Candida spp. has increased remarkably. Echinocandins are recommended as initial treatment for invasive fungal infections. The safety and efficacy of micafungin compared to caspofungin is similar, but no comparison is made between anidulafungin and micafungin concerning safety and efficacy. We therefore performed a retrospective study to assess these aspects in critically ill patients with invasive candidiasis.. All patients in the intensive care unit (ICU) with invasive candidiasis, who were only treated with anidulafungin or micafungin, between January 2012 and December 2014 were retrospectively included. Baseline demographic characteristics, infection characteristics and patient courses were assessed.. A total of 63 patients received either anidulafungin (n = 30) or micafungin (n = 33) at the discretion of the attending intensivist. Baseline characteristics were comparable between the two groups, suggesting similar risk for developing invasive candidiasis. Patients with invasive candidiasis and liver failure were more often treated with anidulafungin than micafungin. Response rates were similar for both groups. No difference was observed in 28-day mortality, but 90-day mortality was higher in patients on anidulafungin. Multivariable cox regression analysis showed that age and serum bilirubin were the best parameters for the prediction of 90-day mortality, whereas APACHE II, Candida score and antifungal therapy did not contribute (P > 0.05). None of the patients developed impaired liver function related to antifungal use and no differences were seen in prothrombin time, serum transaminases and bilirubin levels between the groups, after exclusion of patients with liver injury or failure.. Micafungin can be safely and effectively used in critically ill patients with invasive candidiasis. The observed increased 90-day mortality with anidulafungin can be explained by intensivists unnecessarily avoiding micafungin in patients with liver injury and failure.

Topics: Anidulafungin; Antifungal Agents; APACHE; Candidiasis, Invasive; Critical Illness; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Liver; Liver Function Tests; Male; Micafungin; Middle Aged; Regression Analysis; Retrospective Studies; Treatment Outcome

Although frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome.. To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28.. Multicenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs.. Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129).. The primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-β-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia.. Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-β-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-β-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008).. Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28.. clinicaltrials.gov Idenitfier: NCT01773876.

Topics: Aged; Anti-Bacterial Agents; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Critical Illness; Cross Infection; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Multiple Organ Failure; Time Factors

Linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin are eight special-grade antimicrobials commonly used for patients with severe infections. Changes in the pharmacodynamics and pharmacokinetics of critically ill patients severely affect the efficacy of antimicrobial drugs. Therefore, conventional or standard dosing regimens do not achieve satisfactory anti-infective effects. In the current study a simple and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneously determining the concentrations of the above-mentioned eight antimicrobials in human plasma only 3 min after one-step magnetic solid phase extraction pre-treatment. Multiple-reaction monitoring and positive ion modes were used for detection. The calibration curves were established over a concentration range of 0.1-25.0 μg/mL for teicoplanin, linezolid, micafungin, voriconazole, imipenem, igecyclin, and meropenem, and 0.2-50.0 μg/mL for vancomycin; the coefficient of correlation was > 0.9971 for all the compounds. The inter- and intra-day coefficients of variation were < 6.88% at the lower limit of quantification and quality control (QC) levels (low concentration-QC, medium concentration-QC, and high-concentration QC). The UPLC-MS/MS method was successfully used for clinical therapeutic drug monitoring of linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin for critically ill patients.

Topics: Anti-Infective Agents; Chromatography, High Pressure Liquid; Chromatography, Liquid; Critical Illness; Drug Monitoring; Humans; Imipenem; Linezolid; Meropenem; Micafungin; Reproducibility of Results; Tandem Mass Spectrometry; Teicoplanin; Tigecycline; Vancomycin; Voriconazole

In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model.. Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma.. The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis.. No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.

Topics: Continuous Renal Replacement Therapy; Critical Illness; Hemodiafiltration; Humans; Micafungin; Microbial Sensitivity Tests

To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens.. An HPLC-fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens.. A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains.. A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidiasis; Chromatography, High Pressure Liquid; Computer Simulation; Critical Illness; Drug Dosage Calculations; Drug Monitoring; Female; Fluorometry; Humans; Infusions, Intravenous; Intensive Care Units; Male; Micafungin; Middle Aged; Models, Biological; Predictive Value of Tests; Reproducibility of Results

A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid.. Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay.. The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.

Topics: Adult; Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Critical Illness; Echinocandins; Female; Humans; Male; Micafungin; Microbial Sensitivity Tests; Peritonitis; Prospective Studies

We investigated covariates of pharmacokinetics of micafungin in critically ill patients. After application of micafungin, plasma samples were collected. Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. Using this model, the adequacy of a fixed 100 mg dosing regimen was evaluated in the study cohort. A two-compartment model with linear elimination was found to describe the obtained data. SOFA score was identified as a significant covariate on both clearance and central volume of distribution, respectively. Patients in highly critical condition, represented by a SOFA above 10 showed a 30.8% lower central volume of distribution than the less critically ill patients. For patients with bilirubin levels above 4 mg/dl, clearance was decreased by 21.1%. Renal replacement therapy (RRT) did not influence micafungin clearance or the volumes of distribution. In a posthoc evaluation of the modeled population, 100 mg micafungin was suitable when assessing the PKPD targets (AUC/MIC) for C. albicans and C. glabrata, with insufficient target attainment for C. parapsilosis. Micafungin pharmacokinetics appear not to be influenced by the status of RRT. A dose of 100 mg micafungin is suitable for infections with C. albicans and C. glabrata in critically ill patients.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida albicans; Candida glabrata; Candida parapsilosis; Candidiasis; Critical Illness; Drug Monitoring; Female; Humans; Male; Micafungin; Middle Aged; Young Adult

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).. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Continuous Renal Replacement Therapy; Critical Illness; Female; Hemodiafiltration; Humans; Intensive Care Units; Male; Micafungin; Middle Aged; Prospective Studies

To identify the incidence, risk factors and impact on long-term survival of invasive pulmonary aspergillosis (IPA) and Aspergillus colonisation in patients receiving vv-extracorporeal membrane oxygenation (ECMO). A retrospective evaluation was performed of patients receiving vv-ECMO at a tertiary hospital in Manchester (UK) between January 2012 and December 2016. Data collected included epidemiological data, microbiological cultures, radiographic findings and outcomes. Cases were classified as proven IPA, putative IPA or Aspergillus colonisation according to a validated clinical algorithm. One hundred thirty-four patients were supported with vv-ECMO, median age of 45.5 years (range 16.4-73.4). Ten (7%) patients had putative IPA and nine (7%) had Aspergillus colonisation. Half of the patients with putative IPA lacked classical host risk factors for IPA. The median number of days on ECMO prior to Aspergillus isolation was 5 days. Immunosuppression and influenza A infection were significantly associated with developing IPA in a logistic regression model. Cox regression model demonstrates a three times greater hazard of death associated with IPA. Overall 6-month mortality rate was 38%. Patients with putative IPA and colonised patients had a 6-month mortality rate of 80 and 11%, respectively. Immunosuppression and influenza A infection are independent risk factors for IPA. IPA, but not Aspergillus colonisation, is associated with high long-term mortality in patients supported with vv-ECMO.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillus; Critical Illness; Echinocandins; Extracorporeal Membrane Oxygenation; Female; Galactose; Humans; Immunocompromised Host; Influenza, Human; Invasive Pulmonary Aspergillosis; Lipopeptides; Male; Mannans; Micafungin; Middle Aged; Retrospective Studies; Risk Factors; Treatment Outcome; Voriconazole; Young Adult

Topics: Candida; Critical Illness; Echinocandins; Humans; Lipopeptides; Micafungin; Obesity, Morbid

Topics: Candida; Critical Illness; Echinocandins; Humans; Micafungin; Obesity, Morbid

Invasive Candida spp. infections are increasingly diagnosed in critically ill patients. For initial treatment, an echinocandin is recommended with a possible step-down to fluconazole when the patients' condition is improving and the isolate appears susceptible, but there are no data to support such policy. We studied the safety and efficacy of step-down therapy in critically ill patients with culture proven deep seated or bloodstream infections by C. albicans susceptible to fluconazole. All patients admitted into the intensive care unit from January 2010 to December 2014, who had a culture proven invasive C. albicans infection and received initial treatment with an echinocandin for at least 4 days were included. Data on patient characteristics, treatment and vital outcomes were assessed. Of the 56 patients, 32 received step-down fluconazole therapy, at median day 5, whereas the echinocandin was continued in the other 24. No differences where seen in baseline characteristics or risk factors for invasive C. albicans infection between the two groups. Response rates were similar and no difference where seen in 28-day or 90-day mortality between the groups. Step-down therapy to fluconazole may be safe and effective in critically ill patients with invasive infections by C. albicans, susceptible to fluconazole, who have clinically improved as early as 4 days after start of treatment with an echinocandin.

Topics: Administration, Intravenous; Adult; Aged; Anidulafungin; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Critical Illness; Echinocandins; Female; Fluconazole; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Multivariate Analysis; Retrospective Studies

Topics: Adolescent; Adult; Aged; Antifungal Agents; Burns; Candidiasis, Invasive; Critical Care; Critical Illness; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Wound Infection; Young Adult

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.. Patients were administered 100 mg/day micafungin. Serial blood and peritoneal fluid samples were collected on day 1 and day 3 (steady-state) of treatment. Concentrations were determined by validated chromatography and were subject to a population pharmacokinetic analysis with Pmetrics(®). Monte Carlo simulations were performed for AUC0-24/MIC ratios in plasma. The PTA was calculated using AUC0-24/MIC cut-offs: 285 for Candida parapsilosis and 3000 for non-parapsilosis Candida spp.. Ten patients were included; six were male. The median (range) age, APACHE II score and Mannheim peritonitis index were 72 (43-85) years, 15 (11-36) and 26 (8-37), respectively. On day 1, median (SD) penetration of micafungin into the peritoneal cavity was 30% (30%-40%). A three-compartment model adequately described the data. The mean (SD) estimates for clearance and volume of distribution of the central compartment were 1.27 (0.75) L/h and 9.26 (1.11) L, respectively. In most patients, the PTA in plasma was ≥ 90% for MICs of 0.008-0.016 mg/L for Candida spp. and 0.125-0.25 mg/L for C. parapsilosis.. After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Ascitic Fluid; Candidiasis; Critical Illness; Drug Monitoring; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Peritonitis; Plasma; Postoperative Complications; Prospective Studies; Time Factors

To explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH).. Ten patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC0-24/MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC0-24/MIC cut-offs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions.. Mean post-filter AUC0-24 (mg·h/L) values were higher than pre-filter values on Day 1 (83.31 ± 15.87 versus 71.31 ± 14.24; P = 0.008) and Day 2 (119.01 ± 27.20 versus 104.54 ± 21.23; P = 0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-off = 285), 0.016 mg/L (cut-off = 3000) and 0.008 mg/L (cut-off = 5000) on Day 1, and for MICs of 0.25 mg/L (cut-off = 285) and 0.016 mg/L (cut-off = 3000 and 5000) on Day 2, without differences between pre- and post-filter values. On Day 2, CFRs >90% were obtained for C. albicans (cut-off = 3000 and 5000) and C. glabrata (cut-off = 3000), but not for C. parapsilosis.. There was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre- and post-filter PD.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Candida; Candidiasis, Invasive; Critical Illness; Echinocandins; Female; Hemofiltration; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method

So-called lock therapy, consisting of high concentrations of antimicrobials instilled into the lumen of the catheter, has been suggested avoid central venous catheter removal during fungal infection. We report a baby who developed catheter-related candidemia. Systemic antifungal treatment did not resolve the candidemia. Lock therapy with 0.3 mL of ethanol 70% and micafungin sodium 5 mg/L was added to the therapy, and blood cultures became sterile.

Topics: Antifungal Agents; Candida albicans; Candidemia; Catheter-Related Infections; Central Venous Catheters; Critical Illness; Echinocandins; Ethanol; Failure to Thrive; Humans; Infant; Lipopeptides; Male; Micafungin; Parenteral Nutrition

Topics: Adult; Antifungal Agents; Candida glabrata; Candidiasis; Critical Illness; Echinocandins; Female; Humans; Lipopeptides; Micafungin; Obesity, Morbid

Currently in Japan, the preferred method for blood purification in patients with acute renal failure is continuous hemodiafiltration (CHDF). However, CHDF filters out various antifungal drugs such as fluconazole through large pores in the membrane used. Systemic fungal infection is still one of the main causes of death and complications in critically ill patients in intensive care units (ICUs). Therefore it is important to determine the appropriate use of antifungal agents. This study was designed to evaluate the influence of CHDF on the pharmacokinetics of the antifungal agent micafungin in ICU patients. The pharmacokinetics of micafungin were studied in four ICU patients receiving CHDF and in nine ICU patients not receiving CHDF. To evaluate the pharmacokinetics, the ratio of serum micafungin concentration to dose per body weight (C/D) was used in this study. There was no progressive accumulation or exclusion of micafungin in patients receiving CHDF. The mean (+/-S.D.) extraction rate (%) for micafungin during CHDF was 3.6+/-3.9. There was no significant difference in the serum micafungin C/D-time profiles between the patients receiving and not receiving CHDF. These results show that CHDF does not affect the pharmacokinetics of micafungin. Therefore it is not necessary to adjust the micafungin dose in patients receiving CHDF.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Antifungal Agents; Critical Illness; Echinocandins; Hemodiafiltration; Humans; Intensive Care Units; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic