Data_Sheet_1_Evaluation of polymyxin B AUC/MIC ratio for dose optimization in patients with carbapenem-resistant Klebsiella pneumoniae infection.docx

Polymyxin B has been used as a last-line therapy for the treatment of carbapenem-resistant gram-negative bacterial infection. The pharmacokinetic/pharmacodynamic index (AUC/MIC) of polymyxin B has not been clinically evaluated, given that the broth microdilution method for polymyxin susceptibility testing is rarely used in hospitals. This study analyzed data from 77 patients with carbapenem-resistant Klebsiella pneumoniae infections. Among the samples, 63 K. pneumoniae isolates had MIC values of 1.0 mg/L as measured by broth microdilution but 0.5 mg/L as measured using the Vitek 2 system. Polymyxin B AUC/MIC was significantly associated with clinical response (p = 0.002) but not with 30-day all-cause mortality (p = 0.054). With a target AUC/MIC value of 50, Monte Carlo simulations showed that a fixed dose of 100 mg/12 h and three weight-based regimens (1.25 mg/kg/12 h for 80 kg and 1.5 mg/kg/12 h for 70 kg/80 kg) achieved a cumulative fraction of response >90% regardless of renal function, but the risk of nephrotoxicity was high. For patients with carbapenem-resistant K. pneumoniae infections, the underestimation of polymyxin resistance in automated systems need to be taken into account when optimizing polymyxin B dosing based on pharmacokinetic/pharmacodynamic principles.</p

Additional file 1 of An area under the concentration–time curve threshold as a predictor of efficacy and nephrotoxicity for individualizing polymyxin B dosing in patients with carbapenem-resistant gram-negative bacteria

Additional file 1: Figure S1. Scatterplot of polymyxin B AUCss,24h versus dosage. AUCss,24h, the area under the plasma concentration-time curve across 24 hours at steady state. Figure S2. Scatterplot of polymyxin B AUCss,24h (a) and C0h (b) stratified for different stages of acute kidney injury. AUCss,24h, the area under the plasma concentration-time curve across 24 hours at steady state; C0h, trough concentration. Figure S3. Kaplan-Meier estimates of survival to 30 days after administration of polymyxin B. Stratified by AUCss,24h (a) and C0h (b). AUCss,24h, the area under the plasma concentration-time curve across 24 hours at steady state; C0h, trough concentration

Data_Sheet_1_Effect of intravenous vitamin C on adult septic patients: a systematic review and meta-analysis.zip

BackgroundAn increasing number of studies indicate that vitamin C (VC) reduces the mortality of adult septic patients, while some articles suggest otherwise. We performed this systematic review and meta-analysis to resolve the discrepancies in reported results concerning the efficacy of VC in septic patients.MethodsWe comprehensively searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled trials for randomized controlled trials (RCTs) evaluating the efficacy of intravenous VC (IVVC) on adult septic patients published from inception to November 28, 2022. The quality of outcomes for eligible studies was assessed using the Recommendations Assessment, Development, and Evaluation methodology. The results were analyzed using the pooled mean difference (MD) or risk ratio (RR) and 95% confidence intervals (CIs).ResultsTwenty-two studies (3,570 adult septic patients) were included. IVVC treatment did not improve 28-day mortality compared to the control group (RR, 0.92; 95% CI, 0.81–1.04; I2 = 26%; evidence risk, moderate). IVVC monotherapy decreased mortality (RR, 0.69; 95% CI, 0.52–0.93; I2 = 57%), whereas combination therapy did not affect mortality (RR, 1.03; 95% CI, 0.90–1.17; I2 =0%). IVVC had a trend to decrease the mortality of septic patients (RR, 0.83; 95% CI, 0.69–1.00; I2 = 33%) but did not affect septic shock patients (RR, 1.01; 95% CI, 0.85–1.21; I2 = 18%). IVVC reduced the duration of vasopressor use (MD, −8.45; 95% CI, −15.43 to −1.47; evidence risk, very low) but did not influence the incidence of AKI, ICU length of stay, duration of mechanical ventilation.ConclusionsIVVC treatment did not improve the 28-day mortality in septic patients. Subgroup analysis indicated that VC had a trend to decrease the 28-day mortality in patients with sepsis but not septic shock. IVVC monotherapy, rather than combination therapy, decreased the 28-day mortality in septic patients. The findings imply that Hydrocortisone, Ascorbic acid, Thiamine (HAT) combination therapy is not superior to IVVC monotherapy for septic patients. These findings warrant further confirmation in future studies, which should also investigate the mechanisms underlying the enhanced efficacy of IVVC monotherapy in septic patients.Systematic review registrationhttps://inplasy.com/.</p

Table_1_Corticosteroids for Treating Sepsis in Adult Patients: A Systematic Review and Meta-Analysis.docx

ObjectiveCorticosteroids are a common option used in sepsis treatment. However, the efficacy and potential risk of corticosteroids in septic patients have not been well assessed. This review was performed to assess the efficacy and safety of corticosteroids in patients with sepsis.MethodsPubMed, Embase, and Cochrane library databases were searched from inception to March 2021. Randomized controlled trials (RCTs) that evaluated the effect of corticosteroids on patients with sepsis were included. The quality of outcomes in the included articles was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The data were pooled by using risk ratio (RR) and mean difference (MD). The random-effects model was used to evaluate the pooled MD or RR and 95% confidence intervals (CIs).ResultsFifty RCTs that included 12,304 patients with sepsis were identified. Corticosteroids were not associated with the mortality in 28-day (RR, 0.94; 95% CI, 0.87–1.02; evidence rank, moderate) and long-term mortality (>60 days) (RR, 0.96; 95% CI, 0.88–1.05) in patients with sepsis (evidence rank, low). However, corticosteroids may exert a significant effect on the mortality in the intensive care unit (ICU) (RR, 0.9; 95% CI, 0.83–0.97), in-hospital (RR, 0.9; 95% CI, 0.82–0.99; evidence rank, moderate) in patients with sepsis or septic shock (evidence rank, low). Furthermore, corticosteroids probably achieved a tiny reduction in the length of hospital stay and ICU. Corticosteroids were associated with a higher risk of hypernatremia and hyperglycemia; furthermore, they appear to have no significant effect on superinfection and gastroduodenal bleeding.ConclusionsCorticosteroids had no significant effect on the 28-day and long-term mortality; however, they decreased the ICU and hospital mortality. The findings suggest that the clinical corticosteroids may be an effective therapy for patients with sepsis during the short time.Systematic Review Registrationhttps://inplasy.com/wp-content/uploads/2021/05/INPLASY-Protocol-1074-4.pdf</p

Table_1_Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats.docx

BackgroundNeutrophil elastase (NE) is associated with sepsis occurrence and progression. We hypothesized that the NE inhibitor Sivelestat might modulate abnormal gut microbiota and metabolites during sepsis.MethodsSixty Sprague-Dawley (SD) rats were randomly divided into sham control (SC), sepsis (CLP), and sepsis+Sivelestat (Sive) groups. The rats’ survival status was monitored for 24 hours postoperatively, and feces were collected for microbiome and non-targeted metabolomics analyses.ResultsSivelestat administration significantly improved the survival of septic rats (80% vs 50%, P = 0.047). Microbiome analysis showed that the microbiota composition of rats in the CLP group was significantly disturbed, as potential pathogens such as Escherichia-Shigella and Gammaproteobacteria became dominant, and the beneficial microbiota represented by Lactobacillus decreased. These changes were reversed in Sive group, and the overall microbial status was restored to a similar composition to SC group. Differential analysis identified 36 differential operational taxonomic units and 11 metabolites between the Sive and CLP groups, such as 6-Aminopenicillanic acid, gamma-Glutamyl-leucine, and cortisone (variable importance in projection>1and PConclusionSivelestat administration in septic rats improved survival, gut microbiota composition and associated metabolites, which could provide new options for sepsis treatment.</p

Table_1_A Machine Learning Model for Accurate Prediction of Sepsis in ICU Patients.DOCX

Background: Although numerous studies are conducted every year on how to reduce the fatality rate associated with sepsis, it is still a major challenge faced by patients, clinicians, and medical systems worldwide. Early identification and prediction of patients at risk of sepsis and adverse outcomes associated with sepsis are critical. We aimed to develop an artificial intelligence algorithm that can predict sepsis early.Methods: This was a secondary analysis of an observational cohort study from the Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University. A total of 4,449 infected patients were randomly assigned to the development and validation data set at a ratio of 4:1. After extracting electronic medical record data, a set of 55 features (variables) was calculated and passed to the random forest algorithm to predict the onset of sepsis.Results: The pre-procedure clinical variables were used to build a prediction model from the training data set using the random forest machine learning method; a 5-fold cross-validation was used to evaluate the prediction accuracy of the model. Finally, we tested the model using the validation data set. The area obtained by the model under the receiver operating characteristic (ROC) curve (AUC) was 0.91, the sensitivity was 87%, and the specificity was 89%.Conclusions: This newly established machine learning-based model has shown good predictive ability in Chinese sepsis patients. External validation studies are necessary to confirm the universality of our method in the population and treatment practice.</p

Image_4_Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats.tif

BackgroundNeutrophil elastase (NE) is associated with sepsis occurrence and progression. We hypothesized that the NE inhibitor Sivelestat might modulate abnormal gut microbiota and metabolites during sepsis.MethodsSixty Sprague-Dawley (SD) rats were randomly divided into sham control (SC), sepsis (CLP), and sepsis+Sivelestat (Sive) groups. The rats’ survival status was monitored for 24 hours postoperatively, and feces were collected for microbiome and non-targeted metabolomics analyses.ResultsSivelestat administration significantly improved the survival of septic rats (80% vs 50%, P = 0.047). Microbiome analysis showed that the microbiota composition of rats in the CLP group was significantly disturbed, as potential pathogens such as Escherichia-Shigella and Gammaproteobacteria became dominant, and the beneficial microbiota represented by Lactobacillus decreased. These changes were reversed in Sive group, and the overall microbial status was restored to a similar composition to SC group. Differential analysis identified 36 differential operational taxonomic units and 11 metabolites between the Sive and CLP groups, such as 6-Aminopenicillanic acid, gamma-Glutamyl-leucine, and cortisone (variable importance in projection>1and PConclusionSivelestat administration in septic rats improved survival, gut microbiota composition and associated metabolites, which could provide new options for sepsis treatment.</p

DataSheet_1_Corrigendum: Corticosteroids for Treating Sepsis in Adult Patients: A Systematic Review and Meta-Analysis.zip

The full text of this article can be freely accessed on the publisher's website

Table_3_Corticosteroids for Treating Sepsis in Adult Patients: A Systematic Review and Meta-Analysis.doc

ObjectiveCorticosteroids are a common option used in sepsis treatment. However, the efficacy and potential risk of corticosteroids in septic patients have not been well assessed. This review was performed to assess the efficacy and safety of corticosteroids in patients with sepsis.MethodsPubMed, Embase, and Cochrane library databases were searched from inception to March 2021. Randomized controlled trials (RCTs) that evaluated the effect of corticosteroids on patients with sepsis were included. The quality of outcomes in the included articles was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation methodology. The data were pooled by using risk ratio (RR) and mean difference (MD). The random-effects model was used to evaluate the pooled MD or RR and 95% confidence intervals (CIs).ResultsFifty RCTs that included 12,304 patients with sepsis were identified. Corticosteroids were not associated with the mortality in 28-day (RR, 0.94; 95% CI, 0.87–1.02; evidence rank, moderate) and long-term mortality (>60 days) (RR, 0.96; 95% CI, 0.88–1.05) in patients with sepsis (evidence rank, low). However, corticosteroids may exert a significant effect on the mortality in the intensive care unit (ICU) (RR, 0.9; 95% CI, 0.83–0.97), in-hospital (RR, 0.9; 95% CI, 0.82–0.99; evidence rank, moderate) in patients with sepsis or septic shock (evidence rank, low). Furthermore, corticosteroids probably achieved a tiny reduction in the length of hospital stay and ICU. Corticosteroids were associated with a higher risk of hypernatremia and hyperglycemia; furthermore, they appear to have no significant effect on superinfection and gastroduodenal bleeding.ConclusionsCorticosteroids had no significant effect on the 28-day and long-term mortality; however, they decreased the ICU and hospital mortality. The findings suggest that the clinical corticosteroids may be an effective therapy for patients with sepsis during the short time.Systematic Review Registrationhttps://inplasy.com/wp-content/uploads/2021/05/INPLASY-Protocol-1074-4.pdf</p

Image_3_Positive Effects of Neutrophil Elastase Inhibitor (Sivelestat) on Gut Microbiome and Metabolite Profiles of Septic Rats.tif

BackgroundNeutrophil elastase (NE) is associated with sepsis occurrence and progression. We hypothesized that the NE inhibitor Sivelestat might modulate abnormal gut microbiota and metabolites during sepsis.MethodsSixty Sprague-Dawley (SD) rats were randomly divided into sham control (SC), sepsis (CLP), and sepsis+Sivelestat (Sive) groups. The rats’ survival status was monitored for 24 hours postoperatively, and feces were collected for microbiome and non-targeted metabolomics analyses.ResultsSivelestat administration significantly improved the survival of septic rats (80% vs 50%, P = 0.047). Microbiome analysis showed that the microbiota composition of rats in the CLP group was significantly disturbed, as potential pathogens such as Escherichia-Shigella and Gammaproteobacteria became dominant, and the beneficial microbiota represented by Lactobacillus decreased. These changes were reversed in Sive group, and the overall microbial status was restored to a similar composition to SC group. Differential analysis identified 36 differential operational taxonomic units and 11 metabolites between the Sive and CLP groups, such as 6-Aminopenicillanic acid, gamma-Glutamyl-leucine, and cortisone (variable importance in projection>1and PConclusionSivelestat administration in septic rats improved survival, gut microbiota composition and associated metabolites, which could provide new options for sepsis treatment.</p