International guidelines for the treatment of carbapenem-resistant Gram-negative Bacilli infections: A comparison and evaluation.

OBJECTIVES: This study aimed to appraise clinical practice guidelines (CPGs) for the treatment of carbapenem-resistant Gram-negative Bacilli (CRGNB) infections and to summarise the recommendations. METHODS: A systematic search of the literature published from January 2012 to March 2023 was undertaken to identify CPGs related to CRGNB infections treatment. The methodological and reporting quality of eligible CPGs were assessed using six domains of the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and seven domains of the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist. Basic information and recommendations of included CPGs were extracted and compared. RESULTS: A total of 21 CPGs from 7953 relevant articles were included. The mean overall AGREE II score was 62.7%, and was highest for "clarity of presentation" (90.2%) and lowest for "stakeholder involvement" (44.8%). The overall reporting quality of all of the CPGs was suboptimal, with the proportion of eligible items ranging from 45.7 to 85.7%. The treatment of CRGNB infections is related to the type of pathogen, the sensitivity of antimicrobial agents, and the site of infection. In general, the recommended options mainly included novel ß-lactam/ ß-lactamase inhibitors, cefiderocol, ampicillin-sulbactam (mainly for carbapenem-resistant Acinetobacter baumannii [CRAB]), and combination therapy, involving polymyxin B/colistin, tigecycline (except for carbapenem-resistant Pseudomonas aeruginosa), aminoglycosides, carbapenems, fosfomycin, and sulbactam (mainly for CRAB). CONCLUSIONS: The methodological and reporting quality of CPGs for the treatment of CRGNB infections are generally suboptimal and need further improvement. Both monotherapy with novel drugs and combination therapy play important roles in the treatment.

Prompt-enhanced hierarchical transformer elevating cardiopulmonary resuscitation instruction via temporal action segmentation.

The vast majority of people who suffer unexpected cardiac arrest are performed cardiopulmonary resuscitation (CPR) by passersby in a desperate attempt to restore life, but endeavors turn out to be fruitless on account of disqualification. Fortunately, many pieces of research manifest that disciplined training will help to elevate the success rate of resuscitation, which constantly desires a seamless combination of novel techniques to yield further advancement. To this end, we collect a specialized CPR video dataset in which trainees make efforts to behave resuscitation on mannequins independently in adherence to approved guidelines, promoting an auxiliary toolbox to assist supervision and rectification of intermediate potential issues via modern deep learning methodologies. Our research empirically views this problem as a temporal action segmentation (TAS) task in computer vision, which aims to segment an untrimmed video at a frame-wise level. Here, we propose a Prompt-enhanced hierarchical Transformer (PhiTrans) that integrates three indispensable modules, including a textual prompt-based Video Features Extractor (VFE), a transformer-based Action Segmentation Executor (ASE), and a regression-based Prediction Refinement Calibrator (PRC). The backbone preferentially derives from applications in three approved public datasets (GTEA, 50Salads, and Breakfast) collected for TAS tasks, which experimentally facilitates the model excavation on the CPR dataset. In general, we probe into a feasible pipeline that elevates the CPR instruction qualification via action segmentation equipped with novel deep learning techniques. Associated experiments on the CPR dataset advocate our resolution with surpassing 91.0% on Accuracy, Edit score, and F1 score.

The preventive effects of inulin, cellulose, and their mixture on colorectal cancer liver metastasis in mice by regulating gut microbiota.

Many studies have found that dietary fiber can protect against colorectal cancer (CRC). Survival in CRC patients is significantly reduced due to metastasis. However, little is known regarding the impact of dietary fiber on the CRC metastasis. In this study, we analyzed the effects of inulin, cellulose, and their mixture on CRC metastasis in a murine orthotopic transplantation model. BALB/C male mice were divided into the normal control (NC) (AIN-93 M diet), MOD (AIN-93 M diet), INU (10% w/w inulin), CEL (10% w/w cellulose), and MIX (5% w/w inulin + 5% w/w cellulose) groups. Dietary fiber intake inhibited the weights of the orthotopic tumors, liver weights, and liver metastasis area (p < 0.05) and improved the survival rate of tumor-bearing mice. Compared to the NC, the expression of ß-catenin and the epithelial marker E-cadherin were lower, and that of mesenchymal markers, such as N-cadherin, MMP-9, and VEGF, were higher in the MOD group. All inulin, cellulose, and their mixture restored the gut microbiota diversity, and they, respectively, increased the relative abundance of Bifidobacteriales, Lactobacillus, and Lachnospiraceae. Inulin restored the levels of acetic acid, propionic acid, isobutyric acid, and butyric acid. Spearman correlation analysis results showed that there was a positive correlation between five genera and six short-chain fatty acids (SCFAs) (adjusted p < 0.05). In conclusion, all inulin, cellulose, and their mixture have inhibitory effects on CRC metastasis, which may be achieved by the regulation of gut microbiota, the production of SCFAs, and the inhibition of the epithelial-to-mesenchymal transition process. Among the three dietary fiber intervention groups, the inhibitory effect of inulin is more significant.

A novel strategy for therapeutic drug monitoring: application of biosensors to quantify antimicrobials in biological matrices.

Over the past few years, therapeutic drug monitoring (TDM) has gained practical significance in antimicrobial precision therapy. Yet two categories of mainstream TDM techniques (chromatographic analysis and immunoassays) that are widely adopted nowadays retain certain inherent limitations. The use of biosensors, an innovative strategy for rapid evaluation of antimicrobial concentrations in biological samples, enables the implementation of point-of-care testing (POCT) and continuous monitoring, which may circumvent the constraints of conventional TDM and provide strong technological support for individualized antimicrobial treatment. This comprehensive review summarizes the investigations that have harnessed biosensors to detect antimicrobial drugs in biological matrices, provides insights into the performance and characteristics of each sensing form, and explores the feasibility of translating them into clinical practice. Furthermore, the future trends and obstacles to achieving POCT and continuous monitoring are discussed. More efforts are necessary to address the four key 'appropriateness' challenges to deploy biosensors in clinical practice, paving the way for personalized antimicrobial stewardship.

Metabolic characteristics of voriconazole - Induced liver injury in rats.

Voriconazole (VOR) - induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR - induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR - induced liver injury by non - targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR - induced liver injury we proposed. VOR - induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR - induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR - induced liver injury. This study provided new insights into the molecular characterization of VOR - induced liver injury.

Tributyrin alleviates gut microbiota dysbiosis to repair intestinal damage in antibiotic-treated mice.

Tributyrin (TB) is a butyric acid precursor and has a key role in anti-inflammatory and intestinal barrier repair effects by slowly releasing butyric acid. However, its roles in gut microbiota disorder caused by antibiotics remain unclear. Herein, we established an intestinal microbiota disorder model using ceftriaxone sodium via gavage to investigate the effects of different TB doses for restoring gut microbiota and intestinal injury. First, we divided C57BL/6 male mice into two groups: control (NC, n = 8) and experimental (ABx, n = 24) groups, receiving gavage with 0.2 mL normal saline and 400 mg/mL ceftriaxone sodium solution for 7 d (twice a day and the intermediate interval was 6 h), respectively. Then, mice in the ABx group were randomly split into three groups: model (M, 0.2 mL normal saline), low TB group (TL, 0.3 g/kg BW), and high TB group (TH, 3 g/kg BW) for 11 d. We found that TB supplementation alleviated antibiotics-induced weight loss, diarrhea, and intestinal tissue damage. The 16S rRNA sequence analysis showed that TB intervention increased the α diversity of intestinal flora, increased potential short-chain fatty acids (SCFAs)-producing bacteria (such as Muribaculaceae and Bifidobacterium), and inhibited the relative abundance of potentially pathogenic bacteria (such as Bacteroidetes and Enterococcus) compared to the M group. TB supplementation reversed the reduction in SCFAs production in antibiotic-treated mice. Additionally, TB downregulated the levels of serum LPS and zonulin, TNF-α, IL-6, IL-1ß and NLRP3 inflammasome-related factors in intestinal tissue and upregulated tight junction proteins (such as ZO-1 and Occludin) and MUC2. Overall, the adjustment ability of low-dose TB to the above indexes was stronger than high-dose TB. In conclusion, TB can restore the dysbiosis of gut microbiota, increase SCFAs, suppress inflammation, and ameliorate antibiotic-induced intestinal damage, indicating that TB might be a potential gut microbiota modulator.

The Combination of Inositol Hexaphosphate and Inositol Inhibits Metastasis of Colorectal Cancer Cells by Upregulating Claudin 7.

Inositol hexaphosphate (IP6), a widely found natural bioactive substance in grains, effectively inhibits the progression of colorectal cancer (CRC) when used in combination with inositol (INS). We previously showed that supplementation of IP6 and INS upregulated the claudin 7 gene in orthotropic CRC xenografts in mice. The aim of this study was to elucidate the role of claudin 7 in the inhibition of CRC metastasis by IP6 and INS, and explore the underlying mechanisms. We found that IP6, INS and their combination inhibited the epithelial-mesenchymal transition (EMT) of colon cancer cell lines (SW480 and SW620), as indicated by upregulation of claudin 7 and E-cadherin, and downregulation of N-cadherin. The effect of IP6 and INS was stronger compared to either agent alone (combination index < 1). Furthermore, the silencing of the claudin 7 gene diminished the anti-metastatic effects of IP6 and INS on SW480 and SW620 cells. Consistent with in vitro findings, the combination of IP6 and INS suppressed CRC xenograft growth in a mouse model, which was neutralized by claudin 7. Taken together, the combination of IP6 and INS can inhibit CRC metastasis by blocking EMT of tumor cells through upregulation of claudin 7.

Sparse deconvolution for background noise suppression with total variation regularization in light field microscopy.

In this Letter, we present a method aiming at background noise removal in the 3D reconstruction of light field microscopy (LFM). Sparsity and Hessian regularization are taken as two prior knowledges to process the original light field image before 3D deconvolution. Due to the noise suppression function of total variation (TV) regularization, we add the TV regularization term to the 3D Richardson-Lucy (RL) deconvolution. By comparing the light field reconstruction results of our method with another state-of-the-art method that is also based on RL deconvolution, the proposed method shows improved performance in terms of removing background noise and detail enhancement. This method will be beneficial to the application of LFM in biological high-quality imaging.

Determination of vancomycin exposure target and individualized dosing recommendations for critically ill patients undergoing continuous renal replacement therapy.

STUDY OBJECTIVE: Few studies have been conducted to quantify the exposure target of vancomycin in intensive care unit (ICU) patients undergoing continuous renal replacement therapy (CRRT) and provide optimized dosage regimens. We aimed to determine vancomycin exposure target and dosing recommendations using data from an open database in critically ill patients undergoing CRRT. DESIGN: A retrospective observational cohort study. DATA SOURCE: A large public database. PATIENTS: The adult patients who received intravenous vancomycin and CRRT treatment in the database between 2017 and 2019 were reviewed to determine eligibility. A total of 180 patients with 1186 observations were included in the population pharmacokinetic (PPK) model development. The clinical efficacy of vancomycin was analyzed in 159 eligible patients. METHODS: A PPK model was developed to estimate individual pharmacokinetic (PK) parameters. The area under the concentration-time curve (AUC) was estimated by a Bayesian approach based on individual vancomycin concentrations. Multivariate logistic regression analyses were performed to identify the factors of clinical outcomes. Threshold of vancomycin exposure in predicting efficacy was identified via receiver operating characteristic (ROC) curve. Dosing recommendations were designed using Monte Carlo Simulations (MCS) based on the optimized exposure target. MEASUREMENTS AND MAIN RESULTS: On covariate analysis, CRRT intensity significantly affected vancomycin PK. The AUC above 427 mg*h/L was the only significant predictor of clinical efficacy (adjusted odds ratio (aOR): 1.008, 95% confidence interval (CI): 1.004-1.011, p = 0.000). MCS indicated that vancomycin dosage regimens of 5 mg/kg q12h or 7.5 mg/kg q12h were recommended for patients with CRRT intensities of 20-25 mL/kg/h or 25.1-45 mL/kg/h, respectively. CONCLUSIONS: An AUC threshold of 427 mg*h/L (assuming the minimal inhibitory concentration (MIC) = 1 mg/L) was a recommended efficacy exposure target of vancomycin for critically ill patients undergoing CRRT. Vancomycin 5-7.5 mg/kg q12h is recommended as the initial dosage regimens for ICU patients undergoing CRRT.

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

DNA- and RNA-Binding Proteins Linked Transcriptional Control and Alternative Splicing Together in a Two-Layer Regulatory Network System of Chronic Myeloid Leukemia.

DNA- and RNA-binding proteins (DRBPs) typically possess multiple functions to bind both DNA and RNA and regulate gene expression from more than one level. They are controllers for post-transcriptional processes, such as splicing, polyadenylation, transportation, translation, and degradation of RNA transcripts in eukaryotic organisms, as well as regulators on the transcriptional level. Although DRBPs are reported to play critical roles in various developmental processes and diseases, it is still unclear how they work with DNAs and RNAs simultaneously and regulate genes at the transcriptional and post-transcriptional levels. To investigate the functional mechanism of DRBPs, we collected data from a variety of databases and literature and identified 118 DRBPs, which function as both transcription factors (TFs) and splicing factors (SFs), thus called DRBP-SF. Extensive investigations were conducted on four DRBP-SFs that were highly expressed in chronic myeloid leukemia (CML), heterogeneous nuclear ribonucleoprotein K (HNRNPK), heterogeneous nuclear ribonucleoprotein L (HNRNPL), non-POU domain-containing octamer-binding protein (NONO), and TAR DNA-binding protein 43 (TARDBP). By integrating and analyzing ChIP-seq, CLIP-seq, RNA-seq, and shRNA-seq data in K562 using binding and expression target analysis and Statistical Utility for RBP Functions, we discovered a two-layer regulatory network system centered on these four DRBP-SFs and proposed three possible regulatory models where DRBP-SFs can connect transcriptional and alternative splicing regulatory networks cooperatively in CML. The exploration of the identified DRBP-SFs provides new ideas for studying DRBP and regulatory networks, holding promise for further mechanistic discoveries of the two-layer gene regulatory system that may play critical roles in the occurrence and development of CML.

IP6 reduces colorectal cancer metastasis by mediating the interaction of gut microbiota with host genes.

Inositol hexaphosphate (IP6) is a phytochemical widely found in grains and legumes that plays an anti-cancer role. However, the mechanism underlying the inhibition of colorectal cancer metastasis by IP6 through host genes, gut microbiota, and their interactions remain elusive. In this study, 16S rRNA sequencing was used to study the effect of IP6 on gut microbiota in an orthotopic transplantation model of colorectal cancer mice. The transcriptome was used to study the changes of host genes in metastasis and the relationship with gut microbiota. The results showed that the gut microbiota composition of model mice was significantly different from that of normal mice. The beta diversity partly tended to return to the normal level after IP6 intervention. Especially, Lactobacillus helveticus and Lactococcus lactis were recovered after IP6-treated. Enrichment analysis showed that the enrichment score of the Cytokine-Cytokine receptor interaction signal pathway decreased after IP6 treatment compared to the model group. Further analysis of differentially expressed genes (DEGs) in this pathway showed that IP6 reduced the expression of the Tnfrsf1b gene related to the area of liver metastasis, and the Tnfrsf1b gene was negatively correlated with the relative abundance of Lactobacillus helveticus. Our results presented that host gene, microbiome and their interaction may serve as promising targets for the mechanism of IP6 intervention in colorectal cancer metastasis.

Pharmacokinetics of Dantrolene in the Plasma Exchange Treatment of Malignant Hyperthermia in a 14-Year-Old Chinese Boy: A Case Report and Literature Review.

Malignant hyperthermia (MH) is a rare life-threatening response that is triggered by exposure to specific anesthetics commonly used during surgical interventions. Dantrolene is a well-known drug used as the first-line therapy for MH. A 14-year-old Chinese boy with a mutation in type 1 Ryanodine receptor (RyR1) whose muscle biopsy diagnosis was central core disease (CCD) had an occurrence of MH after a cervical spine surgery, during which he was placed under general anesthesia without volatile anesthetics or succinylcholine. The MH crisis treatment workflow was started and intravenous dantrolene was used, which was soon combined with sequent continuous veno-venous hemofiltration (CVVH) and plasma exchange (PE) therapy. We explored the pharmacokinetic profile of dantrolene during PE treatment. It showed that a one-compartment model with first-order kinetics was sufficient to characterize dantrolene pharmacokinetics (PK). The renal clearance estimate for dantrolene was 0.33 mL/(min*kg) and the volume of distribution was 0.51 L/kg. Though a 4-h PE elevated about 27% off-clearance for dantrolene, it eliminated extra dantrolene by a mere 4% of the area under the curve (AUC). We made no recommendation with respect to adjusting dantrolene dosing for MH adolescents with a 4-h PE.

Severe Thrombocytopenia Caused by Vancomycin in the Intensive Care Unit: A Case Report.

Thrombocytopenia can cause substantial morbidity and mortality in critically ill patients. There are multiple etiology factors and various mechanisms associated with thrombocytopenia, of which drug-induced thrombocytopenia (DITP) deserves attention. Herein, we describe a case of severe thrombocytopenia during intensive care unit (ICU) hospitalization that was likely to be associated with vancomycin. By revealing the process of identifying this case of DITP and reviewing relevant clinical studies, a risk alert of vancomycin-related severe hematotoxicity should be considered.

Optimizing Antimicrobial Dosing for Critically Ill Patients with MRSA Infections: A New Paradigm for Improving Efficacy during Continuous Renal Replacement Therapy.

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30-35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6-8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8-10 mg/kg every 24 h was optimal under 30-35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin.

Reversible domain closure modulates GlnBP ligand binding affinity.

Glutamine binding protein (GlnBP) is an Escherichia Coli periplasmic binding protein, which binds and carries glutamine to the inner membrane ATP-binding cassette (ABC) transporter. GlnBP binds the ligand with affinity around 0.1µM measured by isothermal titration calorimetry (ITC) and ligand binding stabilizes protein structure shown by its increase in thermodynamic stability. However, the molecular determinant of GlnBP ligand binding is not known. Electrostatic and hydrophobic interaction between GlnBP and glutamine are critical factors. We propose that the freedome of closure movement is also vital for ligand binding. In order to approve this hypothesis, we generate a series of mutants with different linker length that has different magnitude of domain closure. Mutants show different ligand binding affinity, which indicates that the propensity of domain closure determines the ligand binding affinity. Ligand binding triggers gradual ensemble conformational change. Structural changes upon ligand binding are monitored by combination of small angle x-ray scattering (SAXS) and NMR spectroscopy. Detailed structure characterization of GlnBP contributes to a better understanding of ligand binding and provides the structural basis for biosensor design.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis.

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance.

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400-650 mg·h/L, trough concentration: 10-20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

Application of a Physiologically Based Pharmacokinetic Model to Characterize Time-dependent Metabolism of Voriconazole in Children and Support Dose Optimization.

Background: Voriconazole is a potent antifungal drug with complex pharmacokinetics caused by time-dependent inhibition and polymorphisms of metabolizing enzymes. It also exhibits different pharmacokinetic characteristics between adults and children. An understanding of these alterations in pharmacokinetics is essential for pediatric dose optimization. Objective: To determine voriconazole plasma exposure in the pediatric population and further investigate optimal dosage regimens. Methods: An adult and pediatric physiologically based pharmacokinetic (PBPK) model of voriconazole, integrating auto-inhibition of cytochrome P450 3A4 (CYP3A4) and CYP2C19 gene polymorphisms, was developed. The model was evaluated with visual predictive checks and quantitative measures of the predicted/observed ratio of the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax). The validated pediatric PBPK model was used in simulations to optimize pediatric dosage regimens. The probability of reaching a ratio of free drug (unbound drug concentration) AUC during a 24-h period to minimum inhibitory concentration greater than or equal to 25 (fAUC24h/MIC ≥ 25) was assessed as the pharmacokinetic/pharmacodynamic index. Results: The developed PBPK model well represented voriconazole's pharmacokinetic characteristics in adults; 78% of predicted/observed AUC ratios and 85% of Cmax ratios were within the 1.25-fold range. The model maintained satisfactory prediction performance for intravenous administration in pediatric populations after incorporating developmental changes in anatomy/physiology and metabolic enzymes, with all predicted AUC values within 2-fold and 73% of the predicted Cmax within 1.25-fold of the observed values. The simulation results of the PBPK model suggested that different dosage regimens should be administered to children according to their age, CYP2C19 genotype, and infectious fungal genera. Conclusion: The PBPK model integrating CYP3A4 auto-inhibition and CYP2C19 gene polymorphisms successfully predicted voriconazole pharmacokinetics during intravenous administration in children and could further be used to optimize dose strategies. The infectious fungal genera should be considered in clinical settings, and further research with large sample sizes is required to confirm the current findings.

Good abdominal drainage fluid penetration and pharmacokinetics analysis of vancomycin for severe acute pancreatitis: A case report.

WHAT IS KNOWN AND OBJECTIVE: The antibiotic concentration in abdominal drainage fluid is very important for the treatment of patients with severe acute pancreatitis (SAP). Previous studies show that quinolones and carbapenems have high abdominal tissue levels, whereas aminoglycosides fail to penetrate into abdominal tissue in sufficient concentrations. However, there are limited data with respect to vancomycin. This case aims to investigate the penetration of vancomycin to abdominal drainage fluid in a 44-year-old SAP patient. CASE SUMMARY: We report a case of a 44-year-old female with SAP, on treatment of vancomycin. The time courses of vancomycin concentration in plasma and abdominal drainage fluid of the patient were described. Simultaneous measurement of abdominal drainage fluid and serum concentrations demonstrated that vancomycin can rapidly penetrate into abdominal tissue in acceptable amounts. WHAT IS NEW AND CONCLUSION: This case demonstrated that it took about 30 minutes for vancomycin to get from plasma to abdominal drainage fluid and about 76% of vancomycin could move into abdominal drainage fluid for SAP patients.