RESUMEN
The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin's permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.
Asunto(s)
Antibacterianos , Vancomicina , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Humanos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Aminoácidos/química , Aminoácidos/metabolismo , Staphylococcus aureus/efectos de los fármacos , Mucosa Bucal/metabolismo , Permeabilidad/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Línea Celular , Ácido Glutámico/metabolismoRESUMEN
Vancomycin, a first-line drug for treating methicillin-resistant Staphylococcus aureus infections, is associated with acute kidney injury (AKI). This study involved an evaluation of biomarkers for AKI detection and their comparison with traditional serum creatinine (SCr). We prospectively enrolled patients scheduled to receive intravenous vancomycin for methicillin-resistant S aureus infection. Blood samples for pharmacokinetic assessment and SCr and cystatin C (CysC) measurements were collected at baseline and on days 3, 7, and 10 from the initiation of vancomycin administration (day 1). Urinary biomarkers, including kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin, and clusterin, were collected from days 1 to 7 and adjusted for urinary creatinine levels. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Of the 42 patients, 6 experienced vancomycin-induced AKI. On day 7, the change from baseline eGFR using CysC (ΔeGFRCysC) showed a stronger correlation with vancomycin area under the curve (râ =â -0.634, Pâ <â .001) than that using SCr (ΔeGFRSCr; râ =â -0.437, Pâ =â .020). ΔeGFRSCr showed no significant correlation with vancomycin pharmacokinetic in patients with body mass indexâ ≥23. The median (interquartile range) level of KIM-1 (µg/mg) was significantly higher in the AKI group (0.006 [0.005-0.008]) than in the non-AKI group (0.004 [0.001-0.005]) (Pâ =â .039, Mann-Whitney U test), with area under the receiver operating characteristic curve (95% confidence interval) of 0.788 (0.587-0.990). Serum CysC, particularly in overweight individuals or those with obesity, along with urinary KIM-1 are important predictors of vancomycin-induced AKI. These results may aid in selecting better biomarkers than traditional SCr for detecting vancomycin-induced AKI.
Asunto(s)
Lesión Renal Aguda , Antibacterianos , Biomarcadores , Creatinina , Cistatina C , Receptor Celular 1 del Virus de la Hepatitis A , Vancomicina , Humanos , Vancomicina/efectos adversos , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/sangre , Biomarcadores/orina , Biomarcadores/sangre , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/orina , Lesión Renal Aguda/sangre , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano , Receptor Celular 1 del Virus de la Hepatitis A/análisis , Cistatina C/sangre , Cistatina C/orina , Creatinina/sangre , Creatinina/orina , Tasa de Filtración Glomerular , Lipocalina 2/orina , Lipocalina 2/sangre , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus Resistente a Meticilina , Clusterina/orina , Clusterina/sangreRESUMEN
Background and Objectives: The predicted serum concentrations of vancomycin are determined using population pharmacokinetic parameters. However, the accuracy of predicting vancomycin serum concentrations in the older population remains unclear. Therefore, this study aimed to investigate the accuracy of predicting vancomycin serum concentrations and identifying elements that diminish the prediction accuracy in older people. Materials and Methods: A total of 144 patients aged 75 years or older were included. The serum vancomycin concentrations in the patients were predicted based on population pharmacokinetic parameters common in Japan. We examined the accuracy of serum vancomycin concentration prediction in elderly individuals by comparing the predicted and measured serum vancomycin concentrations in each patient. The prediction accuracy was evaluated using the mean prediction error (ME) and mean absolute error of prediction (MAE) calculated from the measured and predicted serum vancomycin concentrations in each patient. Results: The ME for all patients was 0.27, and the 95% CI included 0, indicating that the predicted values were not significantly biased compared to the measured values. However, the predicted serum concentrations in the <50 kg body weight and serum creatinine (Scr) < 0.6 mg/dL groups were significantly biased compared to the measured values. The group with a history of intensive care unit (ICU) admission showed the largest values for the ME and MAE. Conclusions: Our prediction accuracy was satisfactory but tended to be lower in underweight patients, those with low creatinine levels, and patients admitted to the ICU. Patients with multiple of these factors may experience a greater degree of decreased predictive accuracy.
Asunto(s)
Antibacterianos , Vancomicina , Humanos , Anciano , Vancomicina/farmacocinética , Vancomicina/sangre , Vancomicina/uso terapéutico , Femenino , Masculino , Anciano de 80 o más Años , Estudios Retrospectivos , Antibacterianos/farmacocinética , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Japón , Creatinina/sangreRESUMEN
BACKGROUND: This study was conducted to evaluate the cost-benefit indicators of a vancomycin monitoring protocol based on area under the curve estimation using commercial Bayesian software. METHODS: This quasi-experimental study included patients who were aged >18 years with a vancomycin prescription for >24 hours. Patients who were terminally ill or those with acute kidney injury (AKI) ≤24 hours were excluded. During the preintervention period, doses were adjusted based on the trough concentration target of 15-20 mg/L, whereas the postintervention period target was 400-500 mg × h/L for the area under the curve. The medical team was responsible for deciding to stop the antimicrobial prescription without influence from the therapeutic drug monitoring team. The main outcomes were the incidence of AKI and length of stay. Cost-benefit simulation was performed after statistical analysis. RESULTS: There were 96 patients in the preintervention group and 110 in the postintervention group. The AKI rate decreased from 20% (n = 19) to 6% (n = 6; P = 0.003), whereas the number of vancomycin serum samples decreased from 5 (interquartile range: 2-7) to 2 (interquartile range: 1-3) examinations per patient ( P < 0.001). The mean length of hospital stay for patients was 26.19 days after vancomycin prescription, compared with 17.13 days for those without AKI ( P = 0.003). At our institution, the decrease in AKI rate and reduced length of stay boosted yearly savings of up to US$ 369,000 for 300 patients receiving vancomycin therapy. CONCLUSIONS: Even in resource-limited settings, a commercial Bayesian forecasting-based protocol for vancomycin is important for determining cost-benefit outcomes.
Asunto(s)
Antibacterianos , Área Bajo la Curva , Teorema de Bayes , Análisis Costo-Beneficio , Monitoreo de Drogas , Vancomicina , Humanos , Vancomicina/farmacocinética , Vancomicina/economía , Vancomicina/uso terapéutico , Vancomicina/sangre , Análisis Costo-Beneficio/métodos , Monitoreo de Drogas/métodos , Monitoreo de Drogas/economía , Masculino , Femenino , Antibacterianos/uso terapéutico , Antibacterianos/economía , Antibacterianos/farmacocinética , Antibacterianos/sangre , Persona de Mediana Edad , Anciano , Lesión Renal Aguda , Tiempo de Internación , Adulto , Configuración de Recursos LimitadosRESUMEN
AIMS: Although there are various model-based approaches to individualized vancomycin (VCM) administration, few have been reported for adult patients with periprosthetic joint infection (PJI). This work attempted to develop a machine learning (ML)-based model for predicting VCM trough concentration in adult PJI patients. METHODS: The dataset of 287 VCM trough concentrations from 130 adult PJI patients was split into a training set (229) and a testing set (58) at a ratio of 8:2, and an independent external 32 concentrations were collected as a validation set. A total of 13 covariates and the target variable (VCM trough concentration) were included in the dataset. A covariate model was respectively constructed by support vector regression, random forest regression and gradient boosted regression trees and interpreted by SHapley Additive exPlanation (SHAP). RESULTS: The SHAP plots visualized the weight of the covariates in the models, with estimated glomerular filtration rate and VCM daily dose as the 2 most important factors, which were adopted for the model construction. Random forest regression was the optimal ML algorithm with a relative accuracy of 82.8% and absolute accuracy of 67.2% (R2 =.61, mean absolute error = 2.4, mean square error = 10.1), and its prediction performance was verified in the validation set. CONCLUSION: The proposed ML-based model can satisfactorily predict the VCM trough concentration in adult PJI patients. Its construction can be facilitated with only 2 clinical parameters (estimated glomerular filtration rate and VCM daily dose), and prediction accuracy can be rationalized by SHAP values, which highlights a profound practical value for clinical dosing guidance and timely treatment.
Asunto(s)
Antibacterianos , Aprendizaje Automático , Infecciones Relacionadas con Prótesis , Vancomicina , Humanos , Femenino , Masculino , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/sangre , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Persona de Mediana Edad , Anciano , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Adulto , Tasa de Filtración Glomerular , Estudios Retrospectivos , Modelos Biológicos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Vancomycin trough concentration is closely associated with clinical efficacy and toxicity. Predicting vancomycin trough concentrations in pediatric patients is challenging due to significant inter-individual variability and rapid physiological changes during maturation. AIM: This study aimed to develop a machine learning model to predict vancomycin trough concentrations and determine optimal dosing regimens for pediatric patients < 4 years of age using ML algorithms. METHOD: A single-center retrospective observational study was conducted from January 2017 to March 2020. Pediatric patients who received intravenous vancomycin and underwent therapeutic drug monitoring were enrolled. Seven ML models [linear regression, gradient boosted decision trees, support vector machine, decision tree, random forest, Bagging, and extreme gradient boosting (XGBoost)] were developed using 31 variables. Performance metrics including R-squared (R2), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) were compared, and important features were ranked. RESULTS: The study included 120 eligible trough concentration measurements from 112 patients. Of these, 84 measurements were used for training and 36 for testing. Among the seven algorithms tested, XGBoost showed the best performance, with a low prediction error and high goodness of fit (MAE = 2.55, RMSE = 4.13, MSE = 17.12, and R2 = 0.59). Blood urea nitrogen, serum creatinine, and creatinine clearance rate were identified as the most important predictors of vancomycin trough concentration. CONCLUSION: An XGBoost ML model was developed to predict vancomycin trough concentrations and aid in drug treatment predictions as a decision-support technology.
Asunto(s)
Antibacterianos , Monitoreo de Drogas , Aprendizaje Automático , Vancomicina , Humanos , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Vancomicina/sangre , Estudios Retrospectivos , Preescolar , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/sangre , Femenino , Lactante , Masculino , Monitoreo de Drogas/métodos , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.
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Antibacterianos , Área Bajo la Curva , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas , Vancomicina , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/uso terapéutico , Estudios Retrospectivos , Masculino , Femenino , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/mortalidad , Infecciones Estafilocócicas/microbiología , Persona de Mediana Edad , Anciano , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Adulto , Anciano de 80 o más AñosRESUMEN
An area-under-the-curve (AUC24)-based approach is recommended to guide vancomycin therapeutic drug monitoring (TDM), yet trough concentrations are still commonly used despite associated risks. A definitive toxicity target is lacking, which is important for hematology patients who have a higher risk of nephrotoxicity. The aims were to (1) assess the impact of trough-based TDM on acute kidney injury (AKI) incidence, (2) establish a vancomycin nephrotoxicity threshold, and (3) evaluate the proportion of hematology patients achieving vancomycin therapeutic targets. Retrospective data was collected from 100 adult patients with a hematological malignancy or aplastic anemia who received vancomycin between April 2020 and January 2021. AKI occurrence was determined based on serum creatinine concentrations, and individual pharmacokinetic parameters were estimated using a Bayesian approach. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pharmacokinetic indices to predict AKI occurrence. The proportion of patients who achieved target vancomycin exposure was evaluated based on an AUC24/MIC ≥400 and the determined toxicity threshold. The incidence of AKI was 37%. ROC curve analysis indicated a maximum AUC24 of 644 mg.h/L over the treatment period was an important predictor of AKI. By Day 4 of treatment, 29% of treatment courses had supratherapeutic vancomycin exposure, with only 62% of courses achieving AUC24 targets. The identified toxicity threshold supports an AUC24 target range of 400-650 mg.h/L, assuming an MIC of 1 mg/L, to optimize vancomycin efficacy and minimize toxicity. This study highlights high rates of AKI in this population and emphasizes the importance of transitioning from trough-based TDM to an AUC-based approach to improve clinical outcomes.
Asunto(s)
Lesión Renal Aguda , Antibacterianos , Área Bajo la Curva , Monitoreo de Drogas , Neoplasias Hematológicas , Vancomicina , Humanos , Vancomicina/efectos adversos , Vancomicina/farmacocinética , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Anciano , Adulto , Monitoreo de Drogas/métodos , Neoplasias Hematológicas/tratamiento farmacológico , Anemia Aplásica , Teorema de Bayes , Creatinina/sangre , Anciano de 80 o más Años , Adulto Joven , Incidencia , Pruebas de Sensibilidad Microbiana , Curva ROCRESUMEN
OBJECTIVE: Individual differences challenge the treatment of vancomycin, linezolid and voriconazole in severe infections. This study aimed to build a simple and economical method for simultaneous determination of the three antibiotics in human plasma by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and provided a reference for therapeutic drug monitoring (TDM) of infected patients. METHODS: The plasma samples were precipitated by acetonitrile and detected and separated on a shim-pack GIST C18 column following the gradient elution within 5 min. Mass quantification was performed on multiple reaction monitoring mode under positive electrospray ionization. RESULTS: The linear ranges of vancomycin, linezolid and voriconazole were 1.00-100.00, 0.10-15.00 and 0.10-20.00 µg·mL-1, respectively, with good linearity (R2 > 0.99). The accuracy and precision, matrix effect, extraction recovery and stability were validated, and the results all meet the acceptance criteria of China Food and Drug Administration (CFDA) guidelines. CONCLUSION: The UHPLC-MS/MS method was established and validated for the simultaneous determination of vancomycin, linezolid and voriconazole in human plasma and successfully applied to routine TDM for individualized treatment.
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Monitoreo de Drogas , Linezolid , Espectrometría de Masas en Tándem , Vancomicina , Voriconazol , Humanos , Voriconazol/sangre , Linezolid/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Vancomicina/sangre , Vancomicina/farmacocinética , Monitoreo de Drogas/métodos , Reproducibilidad de los Resultados , Modelos Lineales , Límite de DetecciónRESUMEN
BACKGROUND: Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity. METHODS: Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m 2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using Pmetrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset. RESULTS: In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m 2 (range: 40-70.3 kg/m 2 ). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients). CONCLUSIONS: Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.
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Antibacterianos , Índice de Masa Corporal , Obesidad , Mejoramiento de la Calidad , Vancomicina , Humanos , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Persona de Mediana Edad , Femenino , Adulto , Masculino , Anciano , Obesidad/tratamiento farmacológico , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Anciano de 80 o más Años , Adulto Joven , Modelos BiológicosRESUMEN
BACKGROUND: The standard vancomycin regimen for term neonates is 45 mg/kg/day. However, the optimal starting vancomycin dosing for achieving therapeutic levels in young infants in cardiac intensive care units remains unknown. Moreover, data on the association of supratherapeutic vancomycin levels with acute kidney injury (AKI) are limited. METHODS: Retrospective study of infants ≤3 months old, receiving vancomycin following congenital heart surgery at postoperative intensive care unit admission. Assessed were vancomycin dosing, achievement of therapeutic trough concentration of 10-20 mg/L and development of AKI, based on the modified Kidney Disease Improving Global Outcomes criteria. RESULTS: Inclusion criteria were met by 109 patients with a median age of 8 days (IQR: 6-16). The mean (SD) vancomycin dose required for achieving therapeutic concentration was 28.9 (9.1) mg/kg at the first postoperative day. Multivariate logistic regression identified higher preoperative creatinine levels and shorter cardiopulmonary bypass time as predictors of supratherapeutic vancomycin concentrations (c-index 0.788). During the treatment course, 62 (56.9%) developed AKI. Length of stay and mortality were higher in those who developed AKI as compared with those who did not. Multivariate logistic regression identified higher vancomycin concentration as a predictor for postoperative AKI, OR, 3.391 (95% CI: 1.257-9.151), P = 0.016 (c-index 0.896). CONCLUSION: Our results support a lower starting vancomycin dose of ~30 mg/kg/day followed by an early personalized therapeutic approach, to achieve therapeutic trough concentrations of 10-20 mg/L in cardiac postoperative term infants. Supratherapeutic concentrations are associated with an increased risk for AKI, which is prevalent in this population and associated with adverse outcomes.
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Lesión Renal Aguda , Antibacterianos , Vancomicina , Humanos , Vancomicina/administración & dosificación , Vancomicina/efectos adversos , Vancomicina/farmacocinética , Lesión Renal Aguda/inducido químicamente , Estudios Retrospectivos , Femenino , Masculino , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Recién Nacido , Lactante , Unidades de Cuidado Intensivo Pediátrico , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/complicacionesRESUMEN
Purpose: Surgical site infections pose a significant challenge for medical services. Systemic antibiotics may be insufficient in preventing bacterial biofilm development. With the local administration of antibiotics, it is easier to minimize possible complications, achieve drugs' higher concentration at the injured site, as well as provide their more sustained release. Therefore, the main objective of the proposed herein studies was the fabrication and characterization of innovative hydrogel-based composites for local vancomycin (VAN) therapy. Methods: Presented systems are composed of ionically gelled chitosan particles loaded with vancomycin, embedded into biomimetic collagen/chitosan/hyaluronic acid-based hydrogels crosslinked with genipin and freeze-dried to serve in a flake/disc-like form. VAN-loaded carriers were characterized for their size, stability, and encapsulation efficiency (EE) using dynamic light scattering technique, zeta potential measurements, and UV-Vis spectroscopy, respectively. The synthesized composites were tested in terms of their physicochemical and biological features. Results: Spherical structures with sizes of about 200 nm and encapsulation efficiencies reaching values of approximately 60% were obtained. It was found that the resulting particles exhibit stability over time. The antibacterial activity of the developed materials against Staphylococcus aureus was established. Moreover, in vitro cell culture study revealed that the surfaces of all prepared systems are biocompatible as they supported the proliferation and adhesion of the model MG-63 cells. In addition, we have demonstrated significantly prolonged VAN release while minimizing the initial burst effect for the composites compared to bare nanoparticles and verified their desired physicochemical features during swellability, and degradation experiments. Conclusion: It is expected that the developed herein system will enable direct delivery of the antibiotic at an exposed to infections surgical site, providing drugs sustained release and thus will reduce the risk of systemic toxicity. This strategy would both inhibit biofilm formation and accelerate the healing process.
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Antibacterianos , Quitosano , Hidrogeles , Staphylococcus aureus , Vancomicina , Vancomicina/química , Vancomicina/farmacología , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Hidrogeles/química , Hidrogeles/farmacología , Staphylococcus aureus/efectos de los fármacos , Humanos , Quitosano/química , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Portadores de Fármacos/química , Colágeno/química , Colágeno/farmacología , Tamaño de la Partícula , Liberación de Fármacos , Infección de la Herida Quirúrgica/prevención & control , Infección de la Herida Quirúrgica/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Biopelículas/efectos de los fármacosRESUMEN
Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.
Asunto(s)
Digoxina , Monitoreo de Drogas , Tacrolimus , Vancomicina , Humanos , Monitoreo de Drogas/métodos , Estudios Retrospectivos , Masculino , Femenino , Tacrolimus/uso terapéutico , Tacrolimus/sangre , Vancomicina/sangre , Vancomicina/uso terapéutico , Vancomicina/farmacocinética , Persona de Mediana Edad , Anciano , Digoxina/sangre , Digoxina/uso terapéutico , Unidades de Cuidados Intensivos , Adulto , Creatinina/sangre , Nitrógeno de la Urea Sanguínea , Péptido Natriurético Encefálico/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Precision dosing requires selecting the appropriate population pharmacokinetic model, which can be assessed through external evaluations (EEs). The lack of understanding of how different study design factors influence EE study outcomes makes it challenging to select the most suitable model for clinical use. This study aimed to evaluate the impact of sample size, sampling strategy, and handling of concentrations below the lower limit of quantification (BLQ) on the outcomes of EE for four population pharmacokinetic models using vancomycin and tobramycin as examples. METHODS: Three virtual patient populations undergoing vancomycin or tobramycin therapy were simulated with varying sample size and sampling scenarios. The three approaches used to handle BLQ data were to (1) discard them, (2) impute them as LLOQ/2, or (3) use a likelihood-based approach. EEs were performed with NONMEM and R. RESULTS: Sample size did not have an important impact on the EE results for a given scenario. Increasing the number of samples per patient did not improve predictive performance for two out of the three evaluated models. Evaluating a model developed with rich sampling did not result in better performance than those developed with regular therapeutic drug monitoring. A likelihood-based method to handle BLQ samples impacted the outcomes of the EE with lower bias for predicted troughs. CONCLUSIONS: This study suggests that a large sample size may not be necessary for an EE study, and models selected based on TDM may be more generalizable. The study highlights the need for guidelines for EE of population pharmacokinetic models for clinical use.
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Antibacterianos , Monitoreo de Drogas , Modelos Biológicos , Tobramicina , Vancomicina , Humanos , Tamaño de la Muestra , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Tobramicina/farmacocinética , Tobramicina/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Monitoreo de Drogas/métodos , Simulación por Computador , Límite de DetecciónRESUMEN
Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection following cardiac surgery via median sternotomy. Controlled release of suitable antibiotics could allow maximizing drug efficacy and safety, and therefore achieving a desired therapeutic response. In this study, we have developed a vancomycin laden PEGylated fibrinogen-polyethylene glycol diacrylate (PF-PEGDA) hydrogel system that can release vancomycin at a controlled and predictable rate to be applied in SSI prevention. Two configurations were developed to study effect of the hydrogel on drug release, namely, vancomycin laden hydrogel and vancomycin solution on top of blank hydrogel. The relationship between the rigidity of the hydrogel and drug diffusion was found to comply with a universal power law, i.e., softer hydrogels result in a greater diffusion coefficient hence faster release rate. Besides, vancomycin laden hydrogels exhibited burst release, whereas the vancomycin solution on top of blank hydrogels exhibited lag release. A mathematical model was developed to simulate vancomycin permeation through the hydrogels. The permeation of vancomycin can be predicted accurately by using the mathematical model, which provided a useful tool to customize drug loading, hydrogel thickness and stiffness for personalized medication to manage SSI. To evaluate the potential of hydrogels for bone healing applications in cardiovascular medicine, we performed a proof-of-concept median sternotomy in rabbits and applied the hydrogels. The hydrogel formulations accelerated the onset of osteo-genetic processes in rabbits, demonstrating its potential to be used in human.
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Antibacterianos , Preparaciones de Acción Retardada , Fibrinógeno , Hidrogeles , Polietilenglicoles , Vancomicina , Vancomicina/administración & dosificación , Vancomicina/química , Vancomicina/farmacocinética , Polietilenglicoles/química , Fibrinógeno/química , Animales , Hidrogeles/química , Preparaciones de Acción Retardada/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacocinética , Liberación de Fármacos , Conejos , Infección de la Herida Quirúrgica/prevención & control , Infección de la Herida Quirúrgica/tratamiento farmacológico , HumanosRESUMEN
This retrospective chart review evaluated whether 20 mg/kg vancomycin loading doses increase early area under the curve (AUC) target attainment within 48 hours in comparison to non-loading dose regimens. There were no differences between groups for the primary outcome (46â¯% vs. 50â¯%; P = 0.58).
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Antibacterianos , Área Bajo la Curva , Vancomicina , Vancomicina/administración & dosificación , Vancomicina/farmacocinética , Humanos , Estudios Retrospectivos , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Masculino , Femenino , Persona de Mediana Edad , Anciano , AdultoRESUMEN
INTRODUCTION: Based on the recent guidelines for vancomycin therapeutic drug monitoring (TDM), the area under the curve to minimum inhibitory concentration ratio was to be employed combined with the usage of population pharmacokinetic (popPK) model for dosing adaptation. Yet, deploying these models in a clinical setting requires an external evaluation of their performance. OBJECTIVES: This study aimed to evaluate existing vancomycin popPK models from the literature for the use in TDM within the general patient population in a clinical setting. METHODS: The models under external evaluation were chosen based on a review of literature covering vancomycin popPK models developed in general adult populations. Patients' data were collected from Charles-Le Moyne Hospital (CLMH). The external evaluation was performed with NONMEM® (v7.5). Additional analyses such as evaluating the impact of number of samples on external evaluation, Bayesian forecasting, and a priori dosing regimen simulations were performed on the best performing model. RESULTS: Eight popPK models were evaluated with an independent dataset that included 40 patients and 252 samples. The model developed by Goti and colleagues demonstrated superior performance in diagnostic plots and population predictive performance, with bias and inaccuracy values of 0.251% and 22.7%, respectively, and for individual predictive performance, bias and inaccuracy were -4.90% and 12.1%, respectively. When limiting the independent dataset to one or two samples per patient, the Goti model exhibited inadequate predictive performance for inaccuracy, with values exceeding 30%. Moreover, the Goti model is suitable for Bayesian forecasting with at least two samples as prior for the prediction of the next trough concentration. Furthermore, the vancomycin dosing regimen that would maximize therapeutic targets of area under the curve to minimum inhibitory concentration ratio (AUC24/MIC) and trough concentrations (Ctrough) for the Goti model was 20 mg/kg/dose twice daily. CONCLUSION: Considering the superior predictive performance and potential for Bayesian forecasting in the Goti model, future research aims to test its applicability in clinical settings at CLMH, both in a priori and a posteriori scenario.
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Antibacterianos , Teorema de Bayes , Monitoreo de Drogas , Modelos Biológicos , Vancomicina , Humanos , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Monitoreo de Drogas/métodos , Adulto , Masculino , Femenino , Persona de Mediana Edad , Pruebas de Sensibilidad Microbiana , Área Bajo la Curva , AncianoRESUMEN
BACKGROUND: Therapeutic drug monitoring (TDM) is an effective method for individualising antimicrobial therapy in critically ill patients. The 2021 ADMIN-intensive care unit survey studied a wide range of intensive care unit clinicians worldwide to gain their perspectives on antimicrobial TDM. This article reports the responses from this survey relating to TDM access, utilisation, and barriers. METHODS: An online survey consisted of multiple-choice questions and 5-point Likert scales. The survey examined respondent's access to minimum inhibitory concentration (MIC) results, drug assays, and dosing software, as well as barriers to TDM. RESULTS: The survey included 538 clinicians from 409 hospitals in 45 countries, with 71% physicians and 29% pharmacists. Despite most respondents having access to assays, 21% and 26% of respondents lacked access to vancomycin and aminoglycosides, respectively. In lower-income countries, almost 40% reported no access. Delayed drug assay turnaround time was the most significant barrier to TDM, particularly in lower-income countries. Routine access to MIC results was unavailable for 41% of respondents, with 25% of lower-income country respondents having no access to MIC or susceptibility reports. CONCLUSIONS: This global survey indicated that consistent TDM usage is hindered by assay access in some sites and the timeliness of assay results in others. Addressing barriers to TDM, particularly in low-income countries, should be a priority to ensure equitable access to affordable TDM.
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Antibacterianos , Enfermedad Crítica , Monitoreo de Drogas , Pruebas de Sensibilidad Microbiana , Humanos , Monitoreo de Drogas/métodos , Monitoreo de Drogas/estadística & datos numéricos , Encuestas y Cuestionarios , Antibacterianos/uso terapéutico , Unidades de Cuidados Intensivos , Adulto , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Vancomicina/uso terapéutico , Vancomicina/farmacocinética , Salud GlobalRESUMEN
Numerous studies have suggested that intra-articular administration of antibiotics following primary revision surgery may be one of the methods for treating prosthetic joint infection (PJI). Vancomycin and meropenem are the two most commonly used antibiotics for local application. Determining the concentrations of vancomycin and meropenem in the serum and synovial fluid of patients with PJI plays a significant role in further optimizing local medication schemes and effectively eradicating biofilm infections. This study aimed to establish a rapid, sensitive, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining the concentrations of vancomycin and meropenem in human serum and synovial fluid. Serum samples were processed using acetonitrile precipitation of proteins and dichloromethane extraction, while synovial fluid samples were diluted before analysis. Chromatographic separation was achieved in 6 min on a Waters Acquity UPLC BEH C18 column, with the mobile phase consisting of 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Quantification was carried out using a Waters XEVO TQD triple quadrupole mass spectrometer with an electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) mode was employed to detect the following quantifier ion transitions: 717.95-99.97 (norvancomycin), 725.90-100.04 (vancomycin), 384.16-67.99 (meropenem). The method validation conformed to the guidelines of the FDA and the Chinese Pharmacopoeia. The method demonstrated good linearity within the range of 0.5-50 µg/ml for serum and 0.5-100 µg/ml for synovial fluid. Selectivity, intra-day and inter-day precision and accuracy, extraction recovery, matrix effect, and stability validation results all met the required standards. This method has been successfully applied in the pharmacokinetic/pharmacodynamic (PK/PD) studies of patients with PJI.
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Antibacterianos , Meropenem , Infecciones Relacionadas con Prótesis , Líquido Sinovial , Espectrometría de Masas en Tándem , Vancomicina , Humanos , Espectrometría de Masas en Tándem/métodos , Vancomicina/sangre , Vancomicina/análisis , Vancomicina/farmacocinética , Líquido Sinovial/química , Meropenem/análisis , Meropenem/sangre , Meropenem/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/sangre , Antibacterianos/sangre , Antibacterianos/análisis , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Reproducibilidad de los Resultados , Masculino , Límite de Detección , Persona de Mediana Edad , Cromatografía Líquida con Espectrometría de MasasRESUMEN
We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 µg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 µg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.