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British Journal of Clinical Pharmacology Feb 2021The 2019 update to the US consensus guideline for vancomycin therapeutic monitoring advocates using Bayesian-guided personalised dosing to maximise efficacy and minimise... (Observational Study)
Observational Study
AIMS
The 2019 update to the US consensus guideline for vancomycin therapeutic monitoring advocates using Bayesian-guided personalised dosing to maximise efficacy and minimise toxicity of vancomycin. We conducted an observational cohort study of the implementation of bed-side Bayesian-guided vancomycin dosing in vascular surgery patients.
METHODS
Over a 9-month prospective study period, vascular surgery patients were dosed vancomycin using Bayesian-guided dosing decision tool (DoseMeRx) and compared retrospectively with a control group admitted to the same ward in the 14 months prior to the study and dosed using a standard algorithmic approach. Primary endpoints were proportion of patients achieving mean area under the curve in 24 hours (AUC ) in the acceptable range 350-450 mg/L• h and percentage time in acceptable range (%TTR). Secondary endpoints focused on clinical outcomes including incidence of acute kidney injury.
RESULTS
A significantly higher proportion of DoseMeRx patients achieved mean AUC values in the acceptable range compared to the control group; 71/104 (68.3%) vs 58/139 (41.7%), P < .005. The median %TTR was also greater in DoseMeRx patients compared to the control group (57.1 vs 30.0%, P < .00001). Patients in the DoseMeRx group missed an average of 0.23 doses per course compared to 1.04 doses in the control group (P < .00001). No difference was observed in secondary (clinical) outcomes between the 2 groups.
CONCLUSION
Bedside Bayesian-guided personalised dosing of vancomycin increases the proportion of patients achieving target AUC and the %TTR.
Topics: Anti-Bacterial Agents; Area Under Curve; Bayes Theorem; Drug Monitoring; Humans; Prospective Studies; Retrospective Studies; Vancomycin
PubMed: 32495366
DOI: 10.1111/bcp.14411 -
PloS One 2022The purpose of this study was to investigate the effect of incorporating chitosan (Ch) and chitosan oligosaccharides (ChO) into the commercially premixed...
BACKGROUND AND PURPOSE
The purpose of this study was to investigate the effect of incorporating chitosan (Ch) and chitosan oligosaccharides (ChO) into the commercially premixed antibiotic-loaded bone cement (ALBC). We compare antibiotic release profiles, antibacterial activity, and mechanical properties among different ALBC formulations. The hypothesis was that increasing the amount of Ch and ChO in the cement mixture would increase the antibiotics released and bacterial control. ALBC mixed with Ch or ChO may create a greater effect due to its superior dissolving property.
MATERIALS AND METHODS
The bone cement samples used in this project were made from Copal® G+V composed of vancomycin and gentamicin. To prepare the Ch and the ChO mixed bone cement samples, different amounts of Ch and ChO were added to the polymethylmethacrylate matrix with three concentrations (1%, 5%, and 10%). Drug elution assay, antimicrobial assay, in vitro cytotoxicity, and mechanical properties were conducted.
RESULTS
Bone cement samples made from Copal® G+V alone or combined with Ch or ChO can release vancomycin and gentamicin into the phosphate-buffered saline. Mixing ChO into the bone cements can increase the amount of drug released more than Ch. ChO 10% gave the highest amount of antibiotics released. All samples showed good antibacterial properties with good biocompatibility in vitro. The microhardness values of the Ch and ChO groups increased significantly compared to the control group. In all groups tested, the microhardness of bone cements was reduced after the drug eluted out. However, this reduction of the Ch and ChO groups was in line with the control.
INTERPRETATION
Various attempts have been made to improve the ALBC efficacy. In our study, the best bone cement formulation was bone cement mixed with ChO (10%), which had the highest drug release profiles, was biocompatible, and contained antibacterial properties with acceptable mechanical properties. This phenomenon could result from the superior water solubility of the ChO. When ChO leaves the bone cement specimens, it generates pores that could act as a path that exposes the bone cement matrix to the surrounding medium, increasing antibiotic elution. From all above, ChO is a promising substance that could be added to ALBC in order to increase the drug elution rate. However, more in vitro and in vivo experiments are needed before being used in the clinic.
Topics: Bone Cements; Chitosan; Anti-Bacterial Agents; Vancomycin; Sulindac; Gentamicins; Glass Ionomer Cements; Dental Materials; Oligosaccharides
PubMed: 36449553
DOI: 10.1371/journal.pone.0276604 -
Journal of Medical Microbiology Mar 2021There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Synergistic...
There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Synergistic combinations of existing antimicrobials show promise due to their enhanced efficacies and reduced dosages which can mitigate adverse effects, and therefore can be used as potential antibacterial therapy. In this study, we sought to characterize the interaction of 5-nitrofurans, vancomycin and sodium deoxycholate (NVD) against pathogenic bacteria. The synergy of the NVD combination was investigated in terms of growth inhibition and bacterial killing using checkerboard and time-kill assays, respectively. Using a three-dimensional checkerboard assay, we showed that 5-nitrofurans, sodium deoxycholate and vancomycin interact synergistically in the growth inhibition of 15 out of 20 Gram-negative strains tested, including clinically significant pathogens such as carbapenemase-producing , and , and interact indifferently against the Gram-positive strains tested. The time-kill assay further confirmed that the triple combination was bactericidal in a synergistic manner. This study demonstrates the synergistic effect of 5-nitrofurans, sodium deoxycholate and vancomycin against Gram-negative pathogens and highlights the potential of the combination as a treatment for Gram-negative and Gram-positive infections.
Topics: Anti-Bacterial Agents; Deoxycholic Acid; Drug Resistance, Multiple, Bacterial; Drug Synergism; Gram-Negative Bacteria; Nitrofurans; Vancomycin
PubMed: 33448923
DOI: 10.1099/jmm.0.001304 -
PloS One 2023We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of...
OBJECTIVES
We developed a rat model of prosthetic vascular graft infection to assess, whether the fibrinolytic tissue plasminogen activator (tPA) could increase the efficacy of antibiotic therapy.
MATERIALS AND METHODS
Rats were implanted a polyethylene graft in the common carotid artery, pre-inoculated with approx. 6 log10 colony forming units (CFU) of methicillin resistant Staphylococcus aureus. Ten days after surgery, rats were randomized to either: 0.9% NaCl (n = 8), vancomycin (n = 8), vancomycin + tPA (n = 8), vancomycin + rifampicin (n = 18) or vancomycin + rifampicin + tPA (n = 18). Treatment duration was seven days. Approximately 36 hours after the end of treatment, the rats were euthanized, and grafts and organs were harvested for CFU enumeration.
RESULTS
All animals in the control group had significantly higher CFU at the time of euthanization compared to bacterial load found on the grafts prior to inoculation (6.45 vs. 4.36 mean log10 CFU/mL, p = 0.0011), and both the procedure and infection were well tolerated. Vancomycin and rifampicin treatment were superior to monotherapy with vancomycin, as it lead to a marked decrease in median bacterial load on the grafts (3.50 vs. 6.56 log10 CFU/mL, p = 0.0016). The addition of tPA to vancomycin and rifampicin combination treatment did not show a further decrease in bacterial load (4.078 vs. 3.50 log10 CFU/mL, p = 0.26). The cure rate was 16% in the vancomycin + rifampicin group vs. 37.5% cure rate in the vancomycin + rifampicin + tPA group. Whilst interesting, this trend was not significant at our sample size (p = 0.24).
CONCLUSION
We developed the first functional model of an arterial prosthetic vascular graft infection in rats. Antibiotic combination therapy with vancomycin and rifampicin was superior to vancomycin monotherapy, and the addition of tPA did not significantly reduce bacterial load, nor significantly increase cure rate.
Topics: Animals; Rats; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Prosthesis-Related Infections; Rifampin; Staphylococcal Infections; Tissue Plasminogen Activator; Vancomycin
PubMed: 37463137
DOI: 10.1371/journal.pone.0287671 -
Hepatology International Apr 2022Gut microbiota and microbe-derived metabolites are involved in the development of HCC. Bile acids (BAs) are the most important gut microbiota-modulated endogenous...
BACKGROUND
Gut microbiota and microbe-derived metabolites are involved in the development of HCC. Bile acids (BAs) are the most important gut microbiota-modulated endogenous signaling molecules.
METHODS
We tested serum bile acid levels and gut microbiome compositions in patients with HCC, chemical-induced HCC mouse models (DEN-HCC mice) and mouse orthotopic implanted liver tumor models with vancomycin treatment (vancomycin-treated mice). Then, we screened an important kind of HCC-related BAs, and verified its effect on the growth of HCC in vivo and in vitro.
RESULTS
We found that the remarkably decreasing percentages of serum secondary BAs in the total bile acids of patients and DEN-HCC mice, especially, conjugated deoxycholic acids (DCA). The relative abundance of the bile salt hydrolase (BSH)-rich bacteria (Bifidobacteriales, Lactobacillales, Bacteroidales, and Clostridiales) was decreased in the feces of patients and DEN-HCC mice. Then, in vancomycin-treated mice, vancomycin treatment induced a reduction in the BSH-rich bacteria and promoted the growth of liver tumors. Similarly, the percentage of conjugated DCA after vancomycin treatment was significantly declined. We used a kind of conjugated DCA, Glyco-deoxycholic acid (GDCA), and found that GDCA remarkably inhibited the growth of HCC in vivo and in vitro.
CONCLUSIONS
We conclude that the remarkably decreasing percentages of serum conjugated DCA may be closely associated with HCC, which may be induced by the reducing gut BSH-rich bacteria. The mechanisms may be correlated with conjugated DCA directly inhibiting the growth and migration of HCC cells.
Topics: Animals; Bile Acids and Salts; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mice; Microbiota; Vancomycin
PubMed: 35211843
DOI: 10.1007/s12072-022-10299-7 -
British Journal of Clinical Pharmacology Nov 2019Vancomycin 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...
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.
Topics: Administration, Intravenous; Adolescent; Age Factors; Anti-Bacterial Agents; Child; Child, Preschool; Critical Illness; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Female; Gestational Age; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Intensive Care Units, Neonatal; Kidney; Kidney Diseases; Male; Medical Records; Retrospective Studies; Sepsis; Vancomycin
PubMed: 31378957
DOI: 10.1111/bcp.14084 -
Drug Design, Development and Therapy 2021This study aimed to establish an optimal model to predict vancomycin trough concentrations by using machine learning.
PURPOSE
This study aimed to establish an optimal model to predict vancomycin trough concentrations by using machine learning.
PATIENTS AND METHODS
We enrolled 407 pediatric patients (age < 18 years) who received vancomycin intravenously and underwent therapeutic drug monitoring from June 2013 to April 2020 at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. The median (interquartile range) age and weight of the patients were 2 (0.63-5) years and 12 (7.8-19) kg. Vancomycin trough concentrations were considered as the target variable, and eight different algorithms were used for predictive performance comparison. The whole dataset (407 cases) was divided into training group and testing group at the ratio of 80%: 20%, which were 325 and 82 cases, respectively.
RESULTS
Ultimately, five algorithms (XGBoost, GBRT, Bagging, ExtraTree and decision tree) with high (0.657, 0.514, 0.468, 0.425 and 0.450, respectively) were selected and further ensembled to establish the final model and achieve an optimal result. For missing data, through filling the missing values and model ensemble, we obtained =0.614, MAE=3.32, MSE=24.39, RMSE=4.94 and a prediction accuracy of 51.22% (predicted trough concentration within ±30% of the actual trough concentration). In comparison with the pharmacokinetic models ( =0.3), the machine learning model works better in model fitting and has better prediction accuracy.
CONCLUSION
Therefore, the ensemble model is useful for the vancomycin concentration prediction, especially in the population of children with great individual variation. As machine learning methods evolve, the clinical value of the ensemble model will be demonstrated in the clinical practice.
Topics: Algorithms; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Machine Learning; Male; Vancomycin
PubMed: 33883878
DOI: 10.2147/DDDT.S299037 -
Microbiology Spectrum Feb 2023Enterococci can cause various infectious diseases, including urinary tract infection, wound infection, and life-threatening endocarditis and meningitis. The emergence...
Enterococci can cause various infectious diseases, including urinary tract infection, wound infection, and life-threatening endocarditis and meningitis. The emergence and transmission of vancomycin-resistant enterococci (VRE) have presented a challenge to clinical treatment. There is an urgent need to develop new strategies to fight against this pathogen. This study investigated the antibacterial and anti-biofilm activity of celastrol (CEL), a natural product originating from against enterococci, and its adjuvant capacity of restoring the susceptibility of VRE to vancomycin and . CEL inhibited all enterococcus strains tested, with MICs ranging from 0.5 to 4 μg/mL. More than 50% of biofilm was eliminated by CEL at 16 μg/mL after 24 h of exposure. The combination of CEL and vancomycin showed a synergistic effect against all 23 strains tested in checkerboard assays. The combination of sub-MIC levels of CEL and vancomycin showed a synergistic effect in a time-kill assay and exhibited significant protective efficacy in Galleria mellonella larval infection model compared with either drug used alone. The underlying mechanisms of CEL were explored by conducting biomolecular binding interactions and an enzyme inhibition assay of CEL on bacterial cell-division protein FtsZ. CEL presented strong binding and suppression ability to FtsZ, with K and IC values of 2.454 μM and 1.04 ± 0.17 μg/mL, respectively. CEL exhibits a significant antibacterial and synergic activity against VRE and and has the potential to be a new antibacterial agent or adjuvant to vancomycin as a therapeutic option in combating VRE. The emergence and transmission of VRE pose a significant medical and public health challenge. CEL, well-known for a wide range of biological activities, has not previously been investigated for its synergistic effect with vancomycin against VRE. In the present study, CEL exhibited antibacterial activity against enterococci, including VRE strains, and restored the activity of vancomycin against VRE and . Hence, CEL has the potential to be a new antibacterial adjuvant to vancomycin and could provide a promising therapeutic option in combating VRE.
Topics: Vancomycin; Anti-Bacterial Agents; Pentacyclic Triterpenes; Vancomycin-Resistant Enterococci; Microbial Sensitivity Tests
PubMed: 36622182
DOI: 10.1128/spectrum.03699-22 -
Comparative Immunology, Microbiology... Jul 2022The objective of this study was to evaluate local antimicrobial delivery from temperature-responsive hydrogels for preventing infection in a rat model of intra-abdominal...
The objective of this study was to evaluate local antimicrobial delivery from temperature-responsive hydrogels for preventing infection in a rat model of intra-abdominal infection (IAI), and to determine whether delivery of tobramycin and vancomycin in combination is effective against IAI pathogens. Rats received intraperitoneal inoculation of E. coli, rat cecal contents, or cecal contents supplemented with E. coli, and received either no treatment, subcutaneous cefoxitin, or local delivery from hydrogels containing vancomycin, tobramycin, or both antimicrobials. Only the hydrogel with tobramycin and vancomycin significantly increased the infection free-rate compared to no treatment for all inocula (E. coli: 13/17, p < 0.0001; cecal contents: 11/17, p = 0.0013; cecal contents + E. coli: 15/19, p < 0.0001). Additionally, tobramycin and vancomycin displayed no synergy or antagonism against clinical isolates in vitro. Local delivery of tobramycin and vancomycin from temperature-responsive hydrogels provides broad coverage and high antimicrobial concentrations for several hours that may be effective for preventing IAIs.
Topics: Animals; Anti-Bacterial Agents; Escherichia coli; Hydrogels; Incidence; Intraabdominal Infections; Rats; Temperature; Tobramycin; Vancomycin
PubMed: 35636372
DOI: 10.1016/j.cimid.2022.101823 -
Gastroenterology Feb 2021The increasing incidence of primary and recurring Clostridioides difficile infections (CDI), which evade current treatment strategies, reflects the changing biology of C...
The increasing incidence of primary and recurring Clostridioides difficile infections (CDI), which evade current treatment strategies, reflects the changing biology of C difficile. Here, we describe a putative plasmid-mediated mechanism potentially driving decreased sensitivity of C difficile to vancomycin treatment. We identified a broad host range transferable plasmid in a C difficile strain associated with lack of adequate response to vancomycin treatment. The transfer of this plasmid to a vancomycin-susceptible C difficile isolate decreased its susceptibility to vancomycin in vitro and resulted in more severe disease in a humanized mouse model. Our findings suggest plasmid acquisition in the gastrointestinal tract to be a possible mechanism underlying vancomycin treatment failure in patients with CDI, but further work is needed to characterize the mechanism by which plasmid genes determine vancomycin susceptibility in C difficile.
Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Disease Models, Animal; Drug Resistance, Bacterial; Germ-Free Life; Humans; Mice; Microbial Sensitivity Tests; Plasmids; Vancomycin; Whole Genome Sequencing
PubMed: 33197449
DOI: 10.1053/j.gastro.2020.10.046