A Prospective Multicenter Clinical Observational Study on Vancomycin Efficiency and Safety With Therapeutic Drug Monitoring.

Background: Vancomycin is a first-line antibiotic used for the treatment of severe gram-positive bacterial infections. Clinical guidelines recommend that the vancomycin trough concentration be 10-15 mg/L for regular infections and 15-20 mg/L for severe infections. We investigated whether increasing the vancomycin concentration would result in better clinical outcomes with sustainable adverse effects (AEs) in the Chinese population. Methods: A prospective, open, multicenter clinical observational study was performed in patients with gram-positive bacterial infections from 13 teaching hospitals. Patients received vancomycin therapeutic drug monitoring. Clinical, microbiological, and laboratory data were collected. Results: In total, 510 patients were enrolled, and 470 were evaluable, of whom 370 were adults and 100 were children; 35.53% had methicillin-resistant Staphylococcus aureus infections (vancomycin 50% minimum inhibitory concentration [MIC50] = 1, 90% minimum inhibitory concentration [MIC90] = 1), and 23.19% had Enterococcus species infections (vancomycin MIC50 = 1, MIC90 = 2). The average trough concentration was 10.54 ± 8.08 mg/L in adults and 6.74 ± 8.93 mg/L in children. The infection was eradicated in 86.22% of adults and 96% of children. Thirty-six vancomycin-related nephrotoxicity cases were reported in the enrolled population. No severe AEs or deaths were related to vancomycin therapy. Logistic regression analysis showed that trough concentration had no relationship with clinical outcomes (adults P = .75, children P = .68) but was correlated with adult nephrotoxicity (P < .0001). Vancomycin trough concentration had an applicable cut point at 13 mg/L. Conclusions: Our study shows that vancomycin trough concentration has no statistical correlation with clinical outcomes, and is an indicator of nephrotoxicity in the observed population. We found no evidence that increasing vancomycin trough concentration to 15-20 mg/L can benefit Chinese patients with complicated infections. Clinical Trials Registration: ChiCTR-OPC-16007920.

Combined Autodock and comparative molecular field analysis study on predicting 5-lipoxygenase inhibitory activity of flavonoids isolated from Spatholobus suberectus Dunn.

5-Lipoxygenase (5-LOX) plays a key role in the pathway of leukotriene biosynthesis. To predict the inhibitory activity of flavonoid inhibitors against 5-LOX from Spatholobus suberectus Dunn, Autodock 4.2 and comparative molecular field analysis (CoMFA) were employed. For the positive inhibitors (n=7), the value of the coefficient of determination (R2) between the binding free energy, calculated using Autodock 4.2, and the experimental pIC50 is 0.838. In the training set (n=21) of inhibitors against 5-LOX, the R2 of non-cross-validated partial least squares analysis between the actual and predicted pIC50 values, using the no-validation with the optimum number of components set to 6, is 0.997 (p=0.000). For the model generated by CoMFA, the contribution of electrostatic and steric factors are 0.522 and 0.478, respectively. Among the flavonoids of S. suberectus, liquiritigenin, catechin, butin, 3',4',7-trihydroxyflavone, plathymenin, and gallocatechin are the more potent inhibitors of 5-LOX based on the calculated binding free energy and the predicted pIC50 value.

Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome.

INTRODUCTION: Heparin-binding protein (HBP) is an antimicrobial protein stored in neutrophil granules and plays a role in endothelial permeability regulation. The aim was to assess the diagnostic and prognostic value of measuring HBP in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). METHODS: Plasma HBP was collected from 78 patients with ALI/ARDS, 28 patients with cardiogenic pulmonary edema (CPE) and 20 healthy volunteers at enrollment. Levels of HBP were measured by ELISA. RESULTS: Patients with ALI/ARDS had significantly higher median levels of HBP compared with patients with CPE (17.15 (11.95 to 24.07) ng/ml vs. 9.50 (7.98 to 12.18) ng/ml, P <0.001) at enrollment. There was no significant difference between CPE patients and healthy subjects in terms of HBP value (P = 0.372). The HBP levels of nonsurvivors was significantly higher than that of survivors (23.90 (14.81 to 32.45) ng/ml vs. 16.01 (10.97 to 21.06) ng/ml, P = 0.012) and multivariate logistic regression showed HBP (odds ratio =1.52, P = 0.034) was the independent predictor for 30-day mortality in patients with ALI/ARDS. CONCLUSIONS: Plasma HBP levels of ALI/ARDS patients were significantly higher than that of CPE patients. HBP was a strong prognostic marker for short-term mortality in ALI/ARDS.

Sequence Type 5 (ST5) as a Possible Predictor of Bacterial Persistence in Adult Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia Treated with Vancomycin.

Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.

Labetalol Prevents Intestinal Dysfunction Induced by Traumatic Brain Injury.

BACKGROUND: Beta-adrenergic blockade has been hypothesized to have a protective effect on intestinal dysfunction and increased intestinal permeability associated with the epinephrine surge after traumatic brain injury (TBI). METHODS: Wister rats were subjected to either a weight drop TBI, and intraperitoneally injected or not with labetalol, or a sham procedure (18 rats per group). After 3, 6, or 12h (6 rats per subgroup), intestinal permeability to 4.4 kDa FITC-Dextran and plasma epinephrine levels were measured as was intestinal tight junction protein ZO-1 expression at 12h. Terminal ileum was harvested to measure levels of intestinal tumor necrosis factor (TNF)-α and to evaluate histopathology. RESULTS: In TBI group vs. sham group, intestinal permeability (P<0.01) was significantly higher at all time-points, and intestinal ZO-1 expression was lower at 12h. In TBI with vs. without labetalol group, 1) intestinal permeability was significantly lower at 6 and 12h (94.31±7.64 vs. 102.16±6.40 µg/mL; 110.21±7.52 vs. 118.95±7.11 µg/mL, respectively); 2) levels of plasma epinephrine and intestinal TNF-α were significantly lower at 3, 6 and 12h; and 3) intestinal ZO-1 expression was higher at 3, 6 and 12h (p=0.018). Histopathological evaluation showed that labetalol use preserved intestinal architecture throughout. CONCLUSION: In a rat model of TBI, labetalol reduced TBI-induced sympathetic hyperactivity, and prevented histopathological intestinal injury accompanied by changes in gut permeability and gut TNF-α expression.

Pentraxin 3 in the assessment of ventilator-associated pneumonia: an early marker of severity.

OBJECTIVES: The aim was to assess the diagnostic and prognostic value of measuring pentraxin 3 (PTX3) together with C-reactive protein (CRP) in patients with ventilator-associated pneumonia (VAP). BACKGROUND: The PTX3 values increase rapidly during multiple inflammatory conditions, but little is known about its characteristics in VAP. METHODS: Measurement of PTX3 and CRP levels in plasma from 136 consecutive patients receiving mechanical ventilation > 48 h in a prospective single center study. RESULTS: A PTX3 threshold of >16.43 ng/ml provided a specificity of 74.0% and a sensitivity of 68.6% for the diagnosis of VAP. PTX3 correlated with severity of sepsis and peaked earlier than CRP in patients with confirmed VAP. Multivariate Cox regression analysis showed PTX3 was the independent predictor for mortality of VAP. CONCLUSIONS: PTX3 was not superior to CRP as a biomarker to diagnose VAP, but it was an early indicator of inflammation and had better prognostic value to predict mortality than CRP.

Copeptin in the assessment of acute lung injury and cardiogenic pulmonary edema.

BACKGROUNDS: Copeptin has been studied as an excellent predictor of outcome in a variety of diseases, its value is even superior to that of B-type natriuretic peptide (BNP) in heart failure, but little is known about its characteristics in acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). We sought to assess the diagnostic and prognostic value of copeptin together with N-terminal pro-BNP (NT-proBNP) in patients with ARDS/ALI or cardiogenic pulmonary edema (CPE). METHODS: Measurement of copeptin and NT-proBNP levels in plasma from 121 consecutive patients with either ARDS/ALI or CPE enrolled in a prospective single center study. RESULTS: In a derivation cohort of 87 patients with ARDS/ALI and 34 patients with CPE, a copeptin threshold of >40.11 pmol/L provided a specificity of 88.2% and a sensitivity of 60.9% for the diagnosis of ARDS/ALI, a NT-proBNP cut point of <2813 pg/ml had a specificity of 79.4% and sensitivity of 65.5% for it. Multivariate Cox regression analysis showed that copeptin was the strongest predictor for mortality in patients with ARDS/ALI [hazard ratio (HR) = 4.72, P < 0.001] and CPE (HR = 3.52, P = 0.019), the association between increasing copeptin and death was statistically significant in patients with ARDS/ALI (HR = 2.64, P = 0.035) and patients with CPE (HR = 1.62, P = 0.029). CONCLUSION: Copeptin of >40.11 pmol/L had a high specificity for the diagnosis of ARDS/ALI in patients presenting with ARDS/ALI or CPE. Compared to NT-proBNP, copeptin was a stronger prognostic marker for short-term mortality.