Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis.
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ABSTRACT:
SUBMITTER: Wang C
PROVIDER: S-EPMC8614878 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: The present study aims to establish a population pharmacokinetic model of ganciclovir and optimize the dosing regimen in critically ill children suffering from cytomegalovirus related disease. Methods: A total of 104 children were included in the study. The population pharmacokinetic model was developed using the Phoenix NLME program. The final model was validated by diagnostic plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. To further evaluate and optimize the dosing regimens, Monte Carlo simulations were performed. Moreover, the possible association between systemic exposure and hematological toxicity were also monitored in the assessment of adverse events. Results: The ganciclovir pharmacokinetics could be adequately described by a one-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates. As showed in this study, the typical population parameter estimates of apparent volume of distribution and apparent clearance were 11.35 L and 5.23 L/h, respectively. Simulations indicated that the current regimen at a dosage of 10 mg/kg/d would result in subtherapeutic exposure, and elevated doses might be required to reach the target ganciclovir level. No significant association between neutropenia, the most frequent toxicity reported in our study (19.23%), and ganciclovir exposure was observed. Conclusion: A population pharmacokinetic model of intravenous ganciclovir for critically ill children with cytomegalovirus infection was successfully developed. Results showed that underdosing of ganciclovir was relatively common in critically ill pediatric patients, and model-based approaches should be applied in the optimizing of empiric dosing regimens.
| S-EPMC7847843 | biostudies-literature
Project description:ObjectivesTo develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure.DesignProspective pharmacokinetic-pharmacogenomic observational study.SettingThirteen PICUs across the United States.PatientsPediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.InterventionsSerial blood sampling for drug quantification and a single blood collection for genomic evaluation.Measurements and main resultsConcentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele.ConclusionsThis work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.
| S-EPMC6432942 | biostudies-literature
Project description:AimsTo describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus.MethodsFive samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NONMEM (v7.4.2). The percentage of patients reaching 100% fT>MICECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus.ResultsThis study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h-1 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h-1 for S. aureus resulted in a minimum of 99% PTA.ConclusionCefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h-1 was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h-1 would be preferred if eGFR and albumin concentration exceed 80 mL min-1 and 40 g L-1 respectively.
| S-EPMC10087439 | biostudies-literature
Project description:Salmonid Rickettsial Septicemia (SRS) is the disease of greatest economic importance in the Chilean salmon farming industry, causing high mortality in fish during the final stage of their productive cycle at sea. Since current, commercially available vaccines have not demonstrated the expected efficacy levels, antimicrobials, most commonly florfenicol, are still the main resource for the treatment and control of this pathogen. The aim of this study was to determine the most appropriate single dose of florfenicol, administered through medicated feed, for the treatment of Piscirickettsia salmonis (P. salmonis), using pharmacokinetic/pharmacodynamic (PK/PD) models. Previously, Minimum Inhibitory Concentrations (MICs) of florfenicol were determined for 87 P. salmonis isolates in order to define the epidemiological cut-off point (COWT). The most commonly observed MIC was 0.125 μg mL-1 (83.7%). The COWT value was 0.25 μg mL-1 with a standard deviation of 0.47 log2 μg mL-1 and 0.36 log2 μg mL-1, for Normalized resistance interpretation (NRI) method and ECOFFinder method, respectively. A MIC of 1 μg mL-1 was considered the pharmacodynamic value (PD) to define PK/PD indices. Three doses of florfenicol were evaluated in fish farmed under controlled conditions. For each dose, 150 fish were used and blood plasma samples were collected at different time points (0-48 hours). PK parameters were obtained from curves representing plasma concentrations as a function of time. The results of Monte Carlo simulation indicate that at a dose of 20 mg/Kg l.w. of florfenicol, administered orally as medicated feed, there is 100% probability (PTA) of achieving the desired efficacy (AUC0-24h/MIC>125). According to these results, we suggest that at the indicated dose, the PK/PD cut-off point for florfenicol versus P. salmonis could be 2 μg mL-1 (PTA = 99%). In order to assess the indicated dose in Atlantic salmon, fish were inoculated with P. salmonis LF-89 strain and then treated with the optimized dose of florfenicol, 20 mg/Kg bw for 15 days.
| S-EPMC6513110 | biostudies-literature
Project description:Background and objectivesInappropriate vancomycin use is common in children's hospitals. We report a quality improvement (QI) intervention to reduce vancomycin use in our tertiary care PICU.MethodsWe retrospectively quantified the prevalence of infections caused by organisms requiring vancomycin therapy, including methicillin-resistant Staphylococcus aureus (MRSA), among patients with suspected bacterial infections. Guided by these data, we performed 3 QI interventions over a 3-year period, including (1) stakeholder education, (2) generation of a consensus-based guideline for empiric vancomycin use, and (3) implementation of this guideline through clinical decision support. Vancomycin use in days of therapy (DOT) per 1000 patient days was measured by using statistical process control charts. Balancing measures included frequency of bacteremia due to an organism requiring vancomycin not covered with empiric therapy, 30-day mortality, and cardiovascular, respiratory, and renal organ dysfunction.ResultsAmong 1276 episodes of suspected bacterial infection, a total of 19 cases of bacteremia (1.5%) due to organisms requiring vancomycin therapy were identified, including 6 MRSA bacteremias (0.5%). During the 3-year QI project, overall vancomycin DOT per 1000 patient days in the PICU decreased from a baseline mean of 182 DOT per 1000 patient days to 109 DOT per 1000 patient days (a 40% reduction). All balancing measures were unchanged, and all cases of MRSA bacteremia were treated empirically with vancomycin.ConclusionOur interventions reduced overall vancomycin use in the PICU without evidence of harm. Provider education and consensus building surrounding indications for empiric vancomycin use were key strategies.
| S-EPMC9647566 | biostudies-literature
Project description:BackgroundThe primary objective of this study was to develop a population pharmacokinetic model of meropenem, based on the population of critically ill adult patients undergoing CRRT. The secondary one was to examine the relationship between patient characteristics (covariates) and individual PK parameters. Finally, we aimed to perform Monte Carlo simulations to assess the probability of target attainment (PTA) of %T?>?MIC considering the uncertainty of PK parameters.Materials and methodsThe study population included 19 adult critically ill patients on CRRT, receiving 1 g of meropenem in 1-h infusions every 8 h. Blood samples were collected prior to (time zero) and 15, 30, 45, 60, 75, 90, 120, 180, 240 and 480 min after the start of meropenem administration. Population nonlinear mixed-effects modeling was conducted using NONMEM software, Fortran, and Wings for NONMEM.ResultsA two-compartment model was used to describe the available data. Typical values of the central and peripheral volume of distribution, and the CRRT and inter-compartmental clearance for a theoretical patient with 24.6 g/l albumin concertation were V1?=?27.9 l, V2?=?33.7 l, ClCRRT?=?15.1 l/h, and Q?=?21.1 l/h. A significant covariate relationship between V1 and albumin concentration was observed in the data that was described by a power relationship with - 2.87 exponent. Subsequently performed Monte Carlo simulations of the model allowed us to assess the impact of albumin concentration on PTA. The 40%T?>?2 mg/l target was reached in more than 90% of subjects after 1-h infusion of 1000 mg q8h and steady-state conditions. The more stringent 100%T?>?2 mg/l target requires higher doses and/or longer infusion durations that depend on the albumin concentration.ConclusionsThe population PK model was successfully developed to describe the time course of meropenem concentrations. The hypoalbuminemia was found to be associated with higher PTA in the CRRT patients after multiple short-term infusions.
| S-EPMC7329797 | biostudies-literature
Project description:Area under the curve (AUC)-directed vancomycin therapy is recommended, but Bayesian AUC estimation in critically ill children is difficult due to inadequate methods for estimating kidney function. We prospectively enrolled 50 critically ill children receiving IV vancomycin for suspected infection and divided them into model training (n = 30) and testing (n = 20) groups. We performed nonparametric population PK modeling in the training group using Pmetrics, evaluating novel urinary and plasma kidney biomarkers as covariates on vancomycin clearance. In this group, a two-compartment model best described the data. During covariate testing, cystatin C-based estimated glomerular filtration rate (eGFR) and urinary neutrophil gelatinase-associated lipocalin (NGAL; full model) improved model likelihood when included as covariates on clearance. We then used multiple-model optimization to define the optimal sampling times to estimate AUC24 for each subject in the model testing group and compared the Bayesian posterior AUC24 to AUC24 calculated using noncompartmental analysis from all measured concentrations for each subject. Our full model provided accurate and precise estimates of vancomycin AUC (bias 2.3%, imprecision 6.2%). However, AUC prediction was similar when using reduced models with only cystatin C-based eGFR (bias 1.8%, imprecision 7.0%) or creatinine-based eGFR (bias -2.4%, imprecision 6.2%) as covariates on clearance. All three model(s) facilitated accurate and precise estimation of vancomycin AUC in critically ill children.
| S-EPMC10220925 | biostudies-literature
Project description:Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.
| S-EPMC4764242 | biostudies-other
Project description:INTRODUCTION:Vancomycin is widely used to treat infections caused by Gram positive bacteria, mostly methicillin-resistant strains. Despite its therapeutic effectiveness, vancomycin is a nephrotoxic drug that has been associated with the occurrence of acute kidney injury (AKI). In this study, we sought to evaluate the variability of serum trough concentrations of vancomycin and to determine the incidence and risk factors of vancomycin-associated nephrotoxicity (VAN) in non-critically ill patients. METHODS:This was a prospective cohort including Brazilian public hospital inpatients from April 2017 to June 2018. The participants received intravenous vancomycin therapy for at least 48 hours for any suspected or confirmed infection by Gram positive bacteria. Demographic, clinical and laboratory data were collected. Information on vancomycin therapy and concomitant use of other nephrotoxic drugs were also recorded. Patients were followed up until discontinuation of vancomycin treatment or death, whatever occurred first. The primary outcome was the occurrence of AKI. We performed a Poisson regression to determine risk factors for AKI. RESULTS:Overall, 98 participants were included in the study. Median age was 55.9 (interquartile range [IQR] 40.6-66.8) years and 58 (59.2%) were men. Most of them showed subtherapeutic (<10mg/L) or supratherapeutic (>20mg/L) trough levels of vancomycin; 42.9% and 15.3%, respectively. A total of 19 (19.4%) patients developed AKI. Poisson regression showed that male sex (odds ratio [OR] 2.90; confidence interval [CI] 95% 1.28-6.53; p = 0.011), concomitant use of piperacillin-tazobactam (OR 4.66; CI 95% 2.26-9.58; p <0.001) and vancomycin trough levels above 20mg/mL (OR 4.21; CI 95% 1.57-11.278; p = 0.004) were independently associated with AKI. CONCLUSIONS:Our study showed that usual doses of vancomycin did not reach recommended therapeutic serum trough levels of vancomycin in non-critically ill patients. Besides that, nephrotoxicity was common in this population, being associated with male sex, concomitant use of piperacillin-tazobactam and supra-therapeutic trough serum levels of vancomycin.
| S-EPMC6728013 | biostudies-literature
Project description:AIMS:Vancomycin is frequently used in critically ill children in whom the drug pharmacokinetics are significantly altered as a result of changes in renal clearance and volume of distribution. Therapeutic drug monitoring (TDM) is recommended to achieve vancomycin trough concentrations between 10 and 20 mg/L. In this study we reviewed vancomycin dosing, TDM and treatment outcomes in paediatric and neonatal intensive care unit patients. METHODS:We reviewed the medical records of all patients receiving intravenous vancomycin in a tertiary paediatric and neonatal intensive care unit over a 10-month period. Demographic, vancomycin dosing, TDM and drug-related adverse effects data were collected. RESULTS:In total, 115 children received 126 courses of vancomycin and had at least 1 TDM blood sample taken at steady state. In only 38/126 (30%) courses was the target concentration (10-20 mg/L) achieved at the initial steady state trough sample. Of the 88 courses that had initial trough concentrations outside the target range, the dose was adjusted in only 49 (56%). Overall, minimum doses of 30 mg/kg/day in neonates with a corrected gestational age of <35 weeks, and 50 mg/kg/day in older children, were required to achieve target vancomycin concentrations. Vancomycin-attributable nephrotoxicity occurred in 10/126 (8%) courses and there were no episodes of red man syndrome. CONCLUSION:In critically ill children, individualised dosing is needed. In the absence of Bayesian model-based dosing, in children with normal renal function, empiric vancomycin doses of at least 30 mg/kg/day in neonates of <35 weeks corrected gestational age, and 50 mg/kg/day in older children, should be considered. Optimisation of TDM practices through the development of protocols, ideally built into electronic medical records, should be considered.
| S-EPMC6848905 | biostudies-literature