-
Journal of Global Antimicrobial... Mar 2021To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC) could be optimised for...
OBJECTIVES
To determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration-time curve (AUC) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin.
METHODS
We determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway.
RESULTS
Vancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log CFU/mL Mtb. The EC was calculated as AUC/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log CFU/mL kill was achieved by AUC/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase.
CONCLUSION
Our proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.
Topics: Antitubercular Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Vancomycin
PubMed: 33508482
DOI: 10.1016/j.jgar.2021.01.005 -
Journal of Advanced Research Jan 2023High-dose drug administration for the conventional treatment of inflammatory bowel disease induces cumulative toxicity and serious side effects. Currently, few reports...
INTRODUCTION
High-dose drug administration for the conventional treatment of inflammatory bowel disease induces cumulative toxicity and serious side effects. Currently, few reports have introduced smart carriers for intestinal inflammation targeting toward the treatment of inflammatory bowel disease.
OBJECTIVES
For the unique lysozyme secretory microenvironment of the inflamed intestine, vancomycin-loaded chitosan-polyaniline microgels (CH-PANI MGs) were constructed for lysozyme-triggered VM release.
METHODS
Aniline was first grafted to chitosan to form polymers that were crosslinked by glutaraldehyde to achieve CH-PANI MGs using the inverse (water-in-oil) miniemulsion method. Interestingly, CH-PANI MGs exhibit polyampholyte behaviour and display charge-reversible behaviour (positive to negative charges) after treatment with a NaCl solution.
RESULTS
The formed negatively charged N-CH-PANI MG aqueous solution is employed to load cationic vancomycin with a satisfactory loading efficiency of 91.3%, which is significantly higher than that of chitosan-based MGs. Moreover, N-CH-PANI MGs present lysozyme-triggered biodegradation and controllable vancomycin release upon the cleavage of glycosidic linkages of chitosan. In the simulated inflammatory intestinal microenvironment, vancomycin is rapidly released, and the cumulative release reaches approximately 76.9%. Remarkably, N-CH-PANI@VM MGs not only exhibit high resistance to harsh gastric acidity but also prevent the premature leakage of vancomycin in the healthy gastrointestinal tract. Encouragingly, the N-CH-PANI@VM MGs show obvious antibacterial activity against Staphylococcus aureus at a relatively low concentration of 20 μg/mL.
CONCLUSION
Compared to other pH-responsive carriers used to treat inflammatory bowel disease, the key advantage of lysozyme-responsive MGs is that they further specifically identify healthy and inflammatory intestines, achieving efficient inflammatory bowel disease treatment with few side effects. With this excellent performance, the developed smart MGs might be employed as a potential oral delivery system for inflammatory bowel disease treatment.
Topics: Chitosan; Inflammatory Bowel Diseases; Microgels; Muramidase; Vancomycin; Drug Delivery Systems
PubMed: 36585117
DOI: 10.1016/j.jare.2022.02.014 -
Scientific Reports Jan 2021Management of vancomycin administration for intensive care units (ICU) patients remains a challenge. The aim of this study was to describe a population pharmacokinetic... (Clinical Trial)
Clinical Trial Observational Study
Management of vancomycin administration for intensive care units (ICU) patients remains a challenge. The aim of this study was to describe a population pharmacokinetic model of vancomycin for optimizing the dose regimen for ICU patients. We prospectively enrolled 466 vancomycin-treated patients hospitalized in the ICU, collected trough or approach peak blood samples of vancomycin and recorded corresponding clinical information from July 2015 to December 2017 at Tai Zhou Hospital of Zhejiang Province. The pharmacokinetics of vancomycin was analyzed by nonlinear mixed effects modeling with Kinetica software. Internal and external validation was evaluated by the maximum likelihood method. Then, the individual dosing regimens of the 92 patients hospitalized in the ICU whose steady state trough concentrations exceeded the target range (10-20 μg/ml) were adjusted by the Bayes feedback method. The final population pharmacokinetic model show that clearance rate (CL) of vancomycin will be raised under the conditions of dopamine combined treatment, severe burn status (Burn-S) and increased total body weight (TBW), but reduced under the conditions of increased serum creatinine (Cr) and continuous renal replacement therapy status; Meanwhile, the apparent distribution volume (V) of vancomycin will be enhanced under the terms of increased TBW, however decreased under the terms of increased age and Cr. The population pharmacokinetic parameters (CL and V) according to the final model were 3.16 (95%CI 2.83, 3.40) L/h and 60.71 (95%CI 53.15, 67.46). The mean absolute prediction error for external validation by the final model was 12.61% (95CI 8.77%, 16.45%). Finally, the prediction accuracy of 90.21% of the patients' detected trough concentrations that were distributed in the target range of 10-20 μg/ml after dosing adjustment was found to be adequate. There is significant heterogeneity in the CL and V of vancomycin in ICU patients. The constructed model is sufficiently precise for the Bayesian dose prediction of vancomycin concentrations for the population of ICU Chinese patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; China; Female; Hospitalization; Humans; Intensive Care Units; Male; Middle Aged; Models, Biological; Prospective Studies; Vancomycin
PubMed: 33514803
DOI: 10.1038/s41598-021-82312-2 -
Emergence of Clinical Clostridioides difficile Isolates With Decreased Susceptibility to Vancomycin.Clinical Infectious Diseases : An... Jan 2022Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few...
BACKGROUND
Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population.
METHODS
Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, and in vivo testing in a CDI mouse model.
RESULTS
Of the Houston stool samples, 114/438 (26%) had vancomycin nonsusceptible C. difficile isolates and 128/438 (29%) were metronidazole nonsusceptible. Similarly, 66 out of 98 (67%) and 83/98 (85%) of the Nairobi patients harbored vancomycin and metronidazole nonsusceptible isolates, respectively. Vancomycin treatment of a CDI mouse model infected with a vancomycin nonsusceptible isolate failed to eradicate the infection. Whole-genome sequencing analyses did not identify vanA genes, suggesting a different mechanism of resistance.
CONCLUSIONS
C. difficile strains exhibiting reduced susceptibility to vancomycin are currently circulating in patient populations. The spread of strains resistance to vancomycin, a first-line antibiotic for CDI, poses a serious therapeutic challenge. Routine susceptibility testing may be necessary.
Topics: Animals; Anti-Bacterial Agents; Clostridioides; Clostridioides difficile; Clostridium Infections; Humans; Kenya; Mice; Vancomycin
PubMed: 35016207
DOI: 10.1093/cid/ciaa912 -
Clinical Microbiology and Infection :... Feb 2018Vancomycin is currently the primary option treatment for methicillin-resistant Staphylococcus aureus (MRSA). However, an increasing number of MRSA isolates with high... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Vancomycin is currently the primary option treatment for methicillin-resistant Staphylococcus aureus (MRSA). However, an increasing number of MRSA isolates with high MICs, within the susceptible range (vancomycin MIC creep), are being reported worldwide. Resorting to a meta-analysis approach, this study aims to assess the evidence of vancomycin MIC creep.
METHODS
We searched for studies in the PubMed database. The inclusion criteria for study eligibility included the possibility of retrieving the reported data values of vancomycin MIC and information concerning the applied MIC methodology.
RESULTS
The mean values of vancomycin MICs, of all 29 234 S. aureus isolates reported in the 55 studies included in the meta-analysis, were 1.23 mg/L (95% CI 1.13-1.33) and 1.20 mg/L (95% CI 1.13-1.28) determined by Etest and broth microdilution method, respectively. No significant differences were observed between these two methodologies. We found negative correlation between pooled mean/pooled proportion and time strata.
CONCLUSIONS
We have found no evidence of the MIC creep phenomenon.
Topics: Anti-Bacterial Agents; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin
PubMed: 28648858
DOI: 10.1016/j.cmi.2017.06.017 -
Critical Care (London, England) Aug 2002Following intravenous administration, vancomycin is poorly metabolized and is mainly excreted unchanged in urine. Total body clearance is thus dependent on the kidney,... (Review)
Review
Following intravenous administration, vancomycin is poorly metabolized and is mainly excreted unchanged in urine. Total body clearance is thus dependent on the kidney, and is correlated with glomerular filtration rate and creatinine clearance. Accumulation of vancomycin in patients with renal insufficiency may therefore occur, and this may lead to toxic side effects if dosage is not modified according to the degree of renal failure. Furthermore, vancomycin easily diffuses through dialysis membranes. The aim of the present review is to establish guidelines for handling this drug in such patients. We indicate how and when plasma concentrations of vancomycin should be determined in dialysis patients.
Topics: Anti-Bacterial Agents; Creatinine; Glomerular Filtration Rate; Humans; Metabolic Clearance Rate; Practice Guidelines as Topic; Renal Dialysis; Vancomycin
PubMed: 12225605
DOI: 10.1186/cc1516 -
The American Journal of Medicine Feb 2010Vancomycin-associated nephrotoxicity was reported in 0% to 5% of patients in the 1980s. This has been confirmed by numerous clinical trials comparing novel... (Review)
Review
Vancomycin-associated nephrotoxicity was reported in 0% to 5% of patients in the 1980s. This has been confirmed by numerous clinical trials comparing novel anti-methicillin-resistant Staphylococcus aureus agents with vancomycin at the Food and Drug Administration-approved dosage of 1 g every 12 hours. Treatment failures of vancomycin in patients with methicillin-resistant S. aureus infections have been reported despite in vitro susceptibility. These failures have led to the use of vancomycin doses higher than those approved by the Food and Drug Administration. Higher doses are being administered to achieve goal vancomycin trough concentrations of 10 to 20 microg/mL recommended by several clinical practice guidelines endorsed by the Infectious Diseases Society of America. Recent studies suggest that increased rates of nephrotoxicity are associated with aggressive vancomycin dosing. These increased rates are confounded by concomitant nephrotoxins, renal insufficiency, or changing hemodynamics. These studies also have demonstrated that vancomycin's nephrotoxicity risk is minimal in patients without risk factors for nephrotoxicity. Clinicians unwilling to dose vancomycin in accordance with clinical practice guidelines should use an alternative agent because inadequate dosing increases the likelihood of selecting heteroresistant methicillin-resistant S. aureus isolates.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Kidney Diseases; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Treatment Outcome; Vancomycin
PubMed: 20103028
DOI: 10.1016/j.amjmed.2009.05.031 -
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 -
Antimicrobial Agents and Chemotherapy Apr 2013A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥ 400 has been associated with clinical success when treating Staphylococcus...
A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥ 400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a "real-world" context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥ 400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥ 400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods.
Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Female; Humans; Male; Microbial Sensitivity Tests; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Vancomycin
PubMed: 23335735
DOI: 10.1128/AAC.01485-12 -
Journal of Clinical Pharmacology Feb 2021Published vancomycin dosing recommendations for patients receiving maintenance hemodialysis were not designed to meet newly recommended 24-hour area under the...
Published vancomycin dosing recommendations for patients receiving maintenance hemodialysis were not designed to meet newly recommended 24-hour area under the curve/minimum inhibitory concentration (AUC /MIC) pharmacokinetic/pharmacodynamic targets. The aims of this study were to predict pharmacokinetic/pharmacodynamic target attainment rates with a commonly used vancomycin regimen and to design a new dosing scheme incorporating therapeutic drug monitoring (TDM) to maximize target attainment in patients receiving vancomycin and hemodialysis with high- or low-flux hemodialyzers. Vancomycin pharmacokinetic- and dialysis-specific parameters were incorporated into Monte Carlo simulations (MCS). A commonly used vancomycin regimen was modeled to determine its likelihood of attaining AUC /MIC targets for 1 week of thrice-weekly hemodialysis treatments. MCS was then used to develop optimal initial vancomycin dosing for patients receiving intradialytic or postdialytic vancomycin administration with either high- or low-flux hemodialyzers. Finally, a new MCS model incorporating TDM was built to further optimize the probability of pharmacokinetic/pharmacodynamic target attainment. Traditional vancomycin dosing methods are unlikely to meet AUC /MIC targets. Vancomycin doses necessary to attain AUC /MIC targets are significantly influenced by hemodialyzer permeability and whether vancomycin is administered intradialytically or after hemodialysis. Depending on dialyzer type and whether vancomycin is administered during or after hemodialysis, loading doses of 25 to 35 mg/kg followed by maintenance doses of 7.5 to 15 mg/kg are necessary to reach minimum AUC /MIC targets in 90% of virtual patients. For a 3-day interdialytic period, a 30% higher maintenance dose is required to maintain target attainment. Dosing based on a single vancomycin serum concentration obtained prior to the second dialysis session greatly enhances the probability of target attainment.
Topics: Anti-Bacterial Agents; Area Under Curve; Body Weight; Computer Simulation; Half-Life; Humans; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Renal Dialysis; Vancomycin
PubMed: 32851685
DOI: 10.1002/jcph.1727