Cefoperazone/sulbactam trough concentration (Cmin ) varies widely in cirrhotic patients. The objective of this study was to describe the characteristics of Cmin and to identify factors associated with the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of cefoperazone/sulbactam in cirrhotic patients.Data were collected retrospectively from cirrhotic patients who received cefoperazone/sulbactam treatment. The Cmin was measured using a validated liquid chromatography-tandem mass spectrometry. The PK/PD target of 100% fT > MIC was used for cefoperazone/sulbactam. Multivariate logistic regression and classification and regression tree (CART) analysis were performed to identify the factors affecting the PK/PD target attainment in these patients.Cefoperazone and sulbactam Cmin were measured simultaneously in 103 plasma samples from 70 cirrhotic patients. Cefoperazone and sulbactam Cmin were 89.27 ± 44.38 mg/L and 10.09 ± 13.01 mg/L, respectively. The PK/PD target of 100% fT > MIC was achieved in 47.1% (33/70) patients for cefoperazone and in 28.6% (20/70) patients for sulbactam. The CART analysis revealed that cefoperazone Cmin was likely to reach the PK/PD target in patients with serum bilirubin levels between 26.15 μmol/L and 99.15 μmol/L. Inversely, lower cefoperazone Cmin was observed in patients with bilirubin levels ≤26.15 μmol/L and serum albumin >38.45 g/L or in patients with bilirubin levels >99.15 μmol/L and creatinine clearance (CrCl) >139.13 mL/min. Additionally, patients had higher sulbactam Cmin when CrCl was below 62.85 mL/min.This study shows that current cefoperazone/sulbactam dosage regimens may result in inadequate plasma concentrations in cirrhotic patients. We recommend monitoring the Cmin of cefoperazone/sulbactam to ensure efficacy of cefoperazone/sulbactam treatment.
Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients.Retrospective pharmacokinetics study.Two large, academic, tertiary-care medical center.Two hundred nineteen plasma trough concentrations (Cmin ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included.Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens.Voriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold Cmin for AE was 5.12 mg/L. A two-compartment model with first-order elimination adequately described the data. The Child-Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of voriconazole Cmin in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients.These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function.
Abstract 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.
Bacterial infections are common complications in patients with cirrhosis or liver failure and are correlated with high mortality. Clinical practice guideline (CPG) is a reference used to help clinicians make decisions. This systematic appraisal aimed to evaluate the methodological quality and summarize the recommendations of reported CPGs in these patients.We systematically searched CPGs published from 2008 to 2019. The methodological quality of the included CPGs was assessed using the AGREE II instrument. We extracted and compared recommendations for prophylactic and empirical treatment strategies.Fourteen CPGs with a median overall score of 56.3% were included. The highest domain score was Clarity of Presentation (domain 4, 85.4%), and the lowest was for Stakeholder Involvement (domain 2, 31.3%). Three CPGs had an overall score above 80%, and 6 CPGs had a score above 90% in domain 4. Prophylaxis should be strictly limited to patients with varicose bleeding, low ascites protein levels and a history of spontaneous bacterial peritonitis. Fluoroquinolones (norfloxacin and ciprofloxacin), third-generation cephalosporins (G3) (ceftriaxone and cefotaxime) and trimethoprim-sulfamethoxazole (SXT) are recommended for preventing infections in patients with cirrhosis or liver failure. G3, β-lactam/β-lactamase inhibitor combinations (BLBLIs) and carbapenems are recommended as the first choice in empirical treatment according to local epidemiology of bacterial resistance.The methodological quality of CPGs focused on patients with cirrhosis or liver failure evaluated by the AGREE II instrument is generally poor. Three CPGs that were considered applicable without modification and 6 CPGs that scored above 90% in domain 4 should also be paid more attention to by healthcare practitioners. Regarding recommendations, norfloxacin, ciprofloxacin, ceftriaxone, cefotaxime, and SXT are recommended for prophylactic treatment appropriately. G3, BLBLIs, and carbapenems are recommended for use in empirical treatment strategies.
The optimal regimens of novel β-lactam/β-lactamase inhibitors (BLBLIs), ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/vaborbactam, are not well defined in critically ill patients. This study was conducted to identify optimal regimens of BLBLIs in these patients. A Monte Carlo simulation was performed using the published data to calculate the joint probability of target attainment (PTA) and the cumulative fraction of response (CFR). For the target of β-lactam of 100% time with free drug concentration remains above minimal inhibitory concentrations, the PTAs of BLBLIs standard regimens were <90% at a clinical breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa. For ceftazidime/avibactam, 2000 mg/500 mg/8 h by 4 h infusion achieved >90% CFR for Escherichia coli; even for 4000 mg/1000 mg/6 h by continuous infusion, CFR for Klebsiella pneumoniae was <90%; the CFRs of 3500 mg/875 mg/6 h by 4 h infusion and 4000 mg/1000 mg/8 h by continuous infusion were appropriate for Pseudomonas aeruginosa. For ceftolozane/tazobactam, the CFR of standard regimen was >90% for Escherichia coli, however, 2000 mg/1000 mg/6 h by continuous infusion achieved <90% CFRs for Klebsiella pneumoniae and Pseudomonas aeruginosa. For meropenem/vaborbactam, standard regimen achieved optimal attainments for Escherichia coli and Klebsiella pneumoniae; 2000 mg/2000 mg/6 h by 5 h infusion, 2500 mg /2500 mg/6 h by 4 h infusion, 3000 mg/3000 mg/6 h by 3 h infusion and 4000 mg/4000 mg/8 h by 5 h infusion achieved >90% CFRs for Pseudomonas aeruginosa. The CFRs of three BLBLIs were similar for Escherichia coli, but meropenem/vaborbactam were superior for Klebsiella pneumoniae and Pseudomonas aeruginosa.
Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL−1β, IL−18, IL−6, and TNF−α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase−1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.
Sarcopenia is prevalent among the older population and severely affects human health. Tea catechins may benefit for skeletal muscle performance and protect against secondary sarcopenia. However, the mechanisms underlying their antisarcopenic effect are still not fully understood. Despite initial successes in animal and early clinical trials regarding the safety and efficacy of (−)-epigallocatechin-3-gallate (EGCG), a major catechin of green tea, many challenges, problems, and unanswered questions remain. In this comprehensive review, we discuss the potential role and underlying mechanisms of EGCG in sarcopenia prevention and management. We thoroughly review the general biological activities and general effects of EGCG on skeletal muscle performance, EGCG's antisarcopenic mechanisms, and recent clinical evidence of the aforesaid effects and mechanisms. We also address safety issues and provide directions for future studies. The possible concerted actions of EGCG indicate the need for further studies on sarcopenia prevention and management in humans.
Idiopathic membranous nephropathy (IMN) has a high incidence in the middle-aged and elderly population, and poses a great threat to the physical and mental health and quality of life of patients. Nephritis Rehabilitation Tablets have many potential effects, such as clearing residual toxins, tumefying the kidney and spleen, replenishing qi, and nourishing yin, and have played an important role in the treatment of a variety of kidney diseases.To investigate the efficacy and safety of Nephritis Rehabilitation Tablets combined with tacrolimus in the treatment of IMN.Eighty-four patients with IMN recruited from January 2017 to September 2020 were randomly divided into a study group (n = 42) and a control group (n = 42). On the basis of routine symptomatic treatment, both groups were treated with tacrolimus, and the study group was additionally treated with Nephritis Rehabilitation Tablets. Both groups were treated for 12 wk. The therapeutic effect, the levels of renal function indexes [serum creatinine (Scr), serum albumin, and 24-h urinary protein], urinary immunoglobulin (IgG4), membrane attack complex (C5b-9), and the incidence of adverse reactions were measured before and after 12 wk of treatment.The total effective rate in the study group was significantly higher than that of the control group. Before treatment, there was no significant difference in Scr, serum albumin, or 24 h urinary protein between the two groups. After 12 wk of treatment, the levels of Scr and 24-h urinary protein in both groups were significantly lower and serum albumin was significantly higher than those before treatment (P < 0.05), and the levels of Scr and 24-h urinary protein were significantly lower (P = 0.003 and 0.000, respectively), and the level of serum albumin was significantly higher (P = 0.00) in the study group than in the control group. Before treatment, there was no significant difference in urinary IgG4 and C5b-9 levels between the study group and the control group (P = 0.336 and 0.438, respectively). After 12 wk of treatment, the levels of urinary IgG4 and C5b-9 in the two groups were lower than those before treatment, and the levels of urinary IgG4 and C5b-9 in the study group were significantly lower than those in the control group (P = 0.000). There was no significant difference in the incidence of adverse reactions between the two groups (P = 0.710).Based on routine intervention, Nephritis Rehabilitation Tablets combined with tacrolimus in the treatment of IMN can effectively improve the renal function of patients and downregulate the expression of urinary IgG4 and C5b-9. In addition, they can improve the overall therapeutic effect while not increasing the risk of adverse reactions.
The beneficial effects of green tea polyphenols (GTPs) on D-galactose (D-Gal)-induced liver aging in male Kunming mice were investigated. For this purpose, 40 adult male Kunming mice were divided into four groups. All animals, except for the normal control and GTPs control, were intraperitoneally injected with D-galactose (D-Gal; 300 mg/kg/day for 5 days a week) for 12 consecutive weeks, and the D-Gal-treated mice were allowed free access to 0.05% GTPs (w/w) diet or normal diet for 12 consecutive weeks. Results showed that GTP administration improved the liver index and decreased transaminases and total bilirubin levels. Furthermore, GTPs significantly increased hepatic glutathione and total antioxidant levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase (GST). Furthermore, GTPs downregulated 8-hydroxy-2-deoxyguanosine, advanced glycation end products, and hepatic oxidative stress markers, such as malondialdehyde and nitric oxide. Additionally, GTPs abrogated dysregulation in hepatic Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene expression [heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and GST] and inhibited tumor necrosis factor-α, transforming growth factor-β, and interleukin (IL)-1β and IL-6 in the liver of treated mice. Finally, GTPs effectively attenuated D-Gal-induced edema, vacuole formation, and inflammatory cell infiltration. In conclusion, GTPs showed antioxidant and anti-inflammatory properties in D-Gal-induced aging mice, and may be considered a natural alternative to the effects of hepatic aging.
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