Pharmacokinetics and Antifungal Activity of Echinocandins in Ascites Fluid of Critically Ill Patients.
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SUBMITTER: Welte R
PROVIDER: S-EPMC8218616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 ?g/ml) and in pleural effusion (0.32 to 2.02 ?g/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 ?g/ml, respectively) and below the MIC values for several pathogenic Candida strains.
| S-EPMC5913985 | biostudies-literature
Project description:PurposeWound infections caused by Candida are life-threatening and difficult to treat. Echinocandins are highly effective against Candida species and recommended for treatment of invasive candidiasis. As penetration of echinocandins into wounds is largely unknown, we measured the concentrations of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) in wound secretion (WS) and in plasma of critically ill patients.MethodsWe included critically ill adults with an indwelling wound drainage or undergoing vacuum-assisted closure therapy, who were treated with an echinocandin for suspected or proven invasive fungal infection. Concentrations were measured by liquid chromatography with UV (AFG and MFG) or tandem mass spectrometry detection (CAS).ResultsTwenty-one patients were enrolled. From eight patients, serial WS samples and simultaneous plasma samples were obtained within a dosage interval. AFG concentrations in WS amounted to < 0.025-2.25 mg/L, MFG concentrations were 0.025-2.53 mg/L, and CAS achieved concentrations of 0.18-4.04 mg/L. Concentrations in WS were significantly lower than the simultaneous plasma concentrations and below the MIC values of some relevant pathogens.ConclusionEchinocandin penetration into WS displays a high inter-individual variability. In WS of some of the patients, concentrations may be sub-therapeutic. However, the relevance of sub-therapeutic concentrations is unknown as no correlation has been established between concentration data and clinical outcome. Nevertheless, in the absence of clinical outcome studies, our data do not support the use of echinocandins at standard doses for the treatment of fungal wound infections, but underline the pivotal role of surgical debridement.
| S-EPMC8316195 | biostudies-literature
Project description:Background and objectivesAlthough the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients.MethodsThis population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates.ResultsThe data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37-41) L/h and volume of distribution 104 (95 % CI 93-115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2-1.4 μg/kg/h.ConclusionsThe pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2-1.4 μg/kg/h, recommended by the Dexdor(®) summary of product characteristics, are used.
| S-EPMC3717151 | biostudies-literature
Project description:What is known and objectiveAnidulafungin, 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.MethodsMEDLINE, 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 AUC0-24 h , Cmax and Cmin (24 hours). Two reviewers independently reviewed all titles, abstracts and text, and extracted data. We applied R software (R 2017) to conduct meta-analysis.Results and discussionOf 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 AUC0-24 h than those who received anidulafungin and micafungin. The Cmax of critically ill patients who received caspofungin and micafungin was similar to healthy volunteers. However, the Cmax in critically ill patients who received anidulafungin was lower than in healthy volunteers. The Cmin and T1/2 of critically ill patients who received caspofungin were larger than in healthy volunteers. The Vd and CL of critically ill patients receiving anidulafungin and micafungin were larger than in healthy volunteers.What is new and conclusionThis 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.
| S-EPMC7689702 | biostudies-literature
Project description:BackgroundIn intensive-care unit (ICU) patients, pathophysiological changes may affect the pharmacokinetics of enoxaparin and result in underdosing.ObjectivesTo develop a pharmacokinetic model of enoxaparin to predict the time-exposure profiles of various thromboprophylactic regimens in COVID-19 ICU-patients.MethodsThis was a retrospective study in ICUs of two French hospitals. Anti-Xa activities from consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated with enoxaparin for the prevention or the treatment of venous thrombosis were used to develop a population pharmacokinetic model using non-linear mixed effects techniques. Monte Carlo simulations were then performed to predict enoxaparin exposure at steady-state after three days of administration.ResultsA total of 391 anti-Xa samples were measured in 95 patients. A one-compartment model with first-order kinetics best fitted the data. The covariate analysis showed that enoxaparin clearance (typical value 1.1 L.h-1) was related to renal function estimated by the CKD-EPI formula and volume of distribution (typical value 17.9 L) to actual body weight. Simulation of anti-Xa activities with enoxaparin 40 mg qd indicated that 64% of the patients had peak levels within the range 0.2 to 0.5 IU.mL-1 and 75% had 12-hour levels above 0.1 IU.mL-1. Administration of a total daily dose of at least 60 mg per day improved the probability of target attainment.ConclusionIn ICU COVID-19 patients, exposure to enoxaparin is reduced due to an increase in the volume of distribution and clearance. Consequently, enoxaparin 40 mg qd is suboptimal to attain thromboprophylactic anti-Xa levels.
| S-EPMC8294601 | biostudies-literature
Project description:BackgroundMeropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy.MethodsTwenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated.ResultsEleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05).ConclusionsThese findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.
| S-EPMC8285835 | biostudies-literature
Project description:BackgroundFluid responsiveness prediction with continuously available monitoring is an unsettled matter for the vast majority of critically ill patients, and development of new and reliable methods is desired. We hypothesized that the post-ectopic beat, which is associated with increased preload, could be analyzed in relation to preceding sinus beats and that the change in cardiac performance (e.g., systolic blood pressure) at the post-ectopic beat could predict fluid responsiveness.MethodsCritically ill patients were observed when scheduled for a 500-ml volume expansion. The 30-min ECG prior to volume expansion was analyzed for the occurrence of extrasystoles. Classification variables were defined as the change in a variable (e.g., systolic blood pressure or pre-ejection period) from the median of ten preceding sinus beats to extrasystolic post-ectopic beat. A stroke volume increase > 10% following volume expansion defined fluid responsiveness.ResultsTwenty-six patients were included. The change in systolic blood pressure predicted fluid responsiveness with receiver operating characteristic (ROC) area 0.79 (CI [0.52:1.00]), specificity 100%, sensitivity 67%, positive predictive value 100%, and negative predictive value 91% (threshold: 5%). The change in pre-ejection period predicted fluid responsiveness with ROC area 0.74 (CI [0.53:0.94]), specificity 78%, sensitivity 67%, positive predictive value 50%, and negative predictive value 88% (threshold 7.5 ms).ConclusionsBased on standard critical care monitoring, analysis of the extrasystolic post-ectopic beat predicts fluid responsiveness in critical care patients with good accuracy. The presented results are considered preliminary proof-of-concept results, and further validation is needed to confirm these preliminary findings.
| S-EPMC6103985 | biostudies-literature
Project description:IntroductionRegional citrate anticoagulation (RCA) is gaining popularity in continous renal replacement therapy (CRRT) for critically ill patients. The risk of citrate toxicity is a primary concern during the prolonged process. The aim of this study was to assess the pharmacokinetics of citrate in critically ill patients with AKI, and used the kinetic parameters to predict the risk of citrate accumulation in this population group undergoing continuous veno-venous hemofiltration (CVVH) with RCA.MethodsCritically ill patients with AKI (n?=?12) and healthy volunteers (n?=?12) were investigated during infusing comparative dosage of citrate. Serial blood samples were taken before, during 120 min and up to 120 min after infusion. Citrate pharmacokinetics were calculated and compared between groups. Then the estimated kinetic parameters were applied to the citrate kinetic equation for validation in other ten patients' CVVH sessions with citrate anticoagulation.ResultsTotal body clearance of citrate was similar in critically ill patients with AKI and healthy volunteers (648.04±347.00 L/min versus 686.64±353.60 L/min; P?=?0.624). Basal and peak citrate concentrations were similar in both groups (p?=?0.423 and 0.247, respectively). The predicted citrate curve showed excellent fit to the measurements.ConclusionsCitrate clearance is not impaired in critically ill patients with AKI in the absence of severe liver dysfunction. Citrate pharmacokinetic data can provide a basis for the clinical use of predicting the risk of citrate accumulation.Trial registrationClinicalTrials.gov Identifier NCT00948558.
| S-EPMC3688847 | biostudies-literature
Project description:Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.
| S-EPMC7698654 | biostudies-literature
Project description:The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h-1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h-1 A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.
| S-EPMC5328553 | biostudies-other