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A Rapid Allele-Specific Assay for HLA-A*32:01 to Identify Patients at Risk for Vancomycin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms.
Rwandamuriye FX, Chopra A, Konvinse KC, Choo L, Trubiano JA, Shaffer CM, Watson M, Mallal SA, Phillips EJ
(2019) J Mol Diagn 21: 782-789
MeSH Terms: Alleles, Anti-Bacterial Agents, Base Sequence, Drug Hypersensitivity Syndrome, Eosinophilia, Genetic Testing, HLA-A Antigens, Humans, Polymerase Chain Reaction, Sequence Homology, Vancomycin
Show Abstract · Added March 30, 2020
Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.
Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.
Konvinse KC, Trubiano JA, Pavlos R, James I, Shaffer CM, Bejan CA, Schutte RJ, Ostrov DA, Pilkinton MA, Rosenbach M, Zwerner JP, Williams KB, Bourke J, Martinez P, Rwandamuriye F, Chopra A, Watson M, Redwood AJ, White KD, Mallal SA, Phillips EJ
(2019) J Allergy Clin Immunol 144: 183-192
MeSH Terms: Adolescent, Adult, Aged, Anti-Bacterial Agents, Drug Hypersensitivity Syndrome, Female, HLA-A Antigens, Humans, Male, Middle Aged, Molecular Docking Simulation, Vancomycin, Young Adult
Show Abstract · Added March 30, 2020
BACKGROUND - Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs.
OBJECTIVE - We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS.
METHODS - Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele.
RESULTS - Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks.
CONCLUSIONS - HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Incidence of Nephrotoxicity Among Pediatric Patients Receiving Vancomycin With Either Piperacillin-Tazobactam or Cefepime: A Cohort Study.
Cook KM, Gillon J, Grisso AG, Banerjee R, Jimenez-Truque N, Phillips EJ, Van Driest SL
(2019) J Pediatric Infect Dis Soc 8: 221-227
MeSH Terms: Acute Kidney Injury, Anti-Bacterial Agents, Cefepime, Child, Child, Preschool, Cohort Studies, Combined Modality Therapy, Female, Humans, Incidence, Infant, Infant, Newborn, Male, Multivariate Analysis, Piperacillin, Tazobactam Drug Combination, Regression Analysis, Vancomycin
Show Abstract · Added March 30, 2020
BACKGROUND - Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime.
METHODS - We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group.
RESULTS - Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results.
CONCLUSION - Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime.
© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.
Van Driest SL, McGregor TL, Velez Edwards DR, Saville BR, Kitchner TE, Hebbring SJ, Brilliant M, Jouni H, Kullo IJ, Creech CB, Kannankeril PJ, Vear SI, Brothers KB, Bowton EA, Shaffer CM, Patel N, Delaney JT, Bradford Y, Wilson S, Olson LM, Crawford DC, Potts AL, Ho RH, Roden DM, Denny JC
(2015) PLoS One 10: e0127791
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, Aged, Chromosomes, Human, Chromosomes, Human, Pair 6, Connexin 43, Creatinine, Female, GTPase-Activating Proteins, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Vancomycin
Show Abstract · Added February 22, 2016
Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
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16 MeSH Terms
Validation of two vancomycin nomograms in patients 10 years of age and older.
Gillon JE, Cassat JE, Di Pentima MC
(2014) J Clin Pharmacol 54: 35-8
MeSH Terms: Adolescent, Adult, Anti-Bacterial Agents, Body Weight, Child, Creatine, Female, Guidelines as Topic, Humans, Male, Reproducibility of Results, Vancomycin, Young Adult
Added January 20, 2015
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13 MeSH Terms
An intervention to improve the timing of vancomycin levels.
Melanson SE, Mijailovic AS, Wright AP, Szumita PM, Bates DW, Tanasijevic MJ
(2013) Am J Clin Pathol 140: 801-6
MeSH Terms: Blood Specimen Collection, Drug Monitoring, Education, Medical, Humans, Nurses, Time, Vancomycin
Show Abstract · Added November 7, 2019
OBJECTIVES - Blood samples for vancomycin levels are often drawn too early, leading to potential misinterpretation of results. However, only a few studies describe interventions to reduce mistimed vancomycin levels.
METHODS - We implemented an information technology (IT)-based intervention that provided educational instructions to nurses and determined the percentage of levels drawn too early for 27 months before (n = 6,291) and 14 months after (n = 3,608) the intervention. In addition, we conducted nurse interviews (n = 40) and dataset analysis to assess the root causes of mistimed levels.
RESULTS - The percentage of vancomycin timing errors decreased from 39% (2,438/6,291) to 32% (1,137/3,608), though in a time series analysis this decrease was not statistically significant (P = .64). Four common causes of mistimed levels were found: (1) unclear provider orders, (2) scheduling levels to be drawn with morning laboratory tests, (3) lack of communication between providers, and (4) failure to adjust the blood draw in relation to the previous dose.
CONCLUSIONS - A real-time, IT-based intervention that links the timing of levels with medication administration might have a more substantial impact.
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Incidence of catheter-related bloodstream infections in neonates following removal of peripherally inserted central venous catheters.
Casner M, Hoesli SJ, Slaughter JC, Hill M, Weitkamp JH
(2014) Pediatr Crit Care Med 15: 42-8
MeSH Terms: Anti-Bacterial Agents, Apnea, Birth Weight, Bradycardia, Catheter-Related Infections, Catheterization, Peripheral, Catheters, Indwelling, Central Venous Catheters, Device Removal, Female, Gestational Age, Humans, Incidence, Infant, Newborn, Infant, Very Low Birth Weight, Male, Prevalence, Sepsis, Time Factors, Vancomycin
Show Abstract · Added February 27, 2014
OBJECTIVES - Catheter-associated bloodstream infections are a significant source of morbidity and healthcare cost in the neonatal ICU. Previous studies examining the prevalence of bloodstream infections after removal of peripherally inserted central venous catheters in neonates are equivocal.
DESIGN - A retrospective cohort study.
PATIENTS - All infants with peripherally inserted central venous catheters treated at the Vanderbilt neonatal ICU between 2007 and 2009.
MEASUREMENTS AND MAIN RESULTS - We evaluated the following outcomes: 1) bloodstream infections, 2) culture-negative sepsis, 3) number of sepsis evaluations, and 4) number of significant apnea/bradycardia events comparing odds ratios between 72 hours before and 72 hours after peripherally inserted central venous catheter removal. We analyzed a total of 1,002 peripherally inserted central venous catheters in 856 individual infants with a median (interquartile range) gestational age of 31 weeks (28-37 wk) and a median birth weight of 1,469 g (960-2,690 g). Comparing 72 hours before with 72 hours after peripherally inserted central venous catheter removal did not show a difference in the prevalence of bloodstream infections (9 vs 3, p = 0.08), prevalence of culture-negative sepsis (37 vs 40, p = 0.73), number of sepsis evaluations (p = 0.42), or number of apnea/bradycardia events (p = 0.32). However, in peripherally inserted central venous catheter not used for delivery of antibiotics, there was a 3.83-fold increase in odds for culture-negative sepsis following peripherally inserted central venous catheter removal (95% confidence interval, 1.48-10.5; p = 0.001). For infants less than 1,500 g birth weight (very low birth weight), odds for culture-negative sepsis increased to 6.3-fold following removal of peripherally inserted central venous catheters not used for antibiotic delivery (95% confidence interval, 1.78-26.86; p < 0.01).
CONCLUSIONS - Although these data do not support the routine use of antibiotics for sepsis prophylaxis prior to peripherally inserted central venous catheter removal, they suggests that very low birth weight infants not recently exposed to antibiotics are at increased odds for associated adverse events following discontinuation of their peripherally inserted central venous catheter.
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20 MeSH Terms
Prevalence and outcomes of antimicrobial treatment for Staphylococcus aureus bacteremia in outpatients with ESRD.
Chan KE, Warren HS, Thadhani RI, Steele DJ, Hymes JL, Maddux FW, Hakim RM
(2012) J Am Soc Nephrol 23: 1551-9
MeSH Terms: Anti-Bacterial Agents, Bacteremia, Cefazolin, Comorbidity, Female, Humans, Kidney Failure, Chronic, Longitudinal Studies, Male, Methicillin-Resistant Staphylococcus aureus, Middle Aged, Outpatients, Prevalence, Renal Dialysis, Retrospective Studies, Risk Factors, Staphylococcal Infections, Staphylococcus aureus, Treatment Outcome, United States, Vancomycin
Show Abstract · Added May 20, 2014
Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection. In the study population, the overall rate of bacteremia was 15.4 per 100 outpatient-years; the incidence rate for methicillin-sensitive (MSSA) was 2.1 per 100 outpatient-years, and the incidence rate for methicillin-resistant (MRSA) S. aureus was 1.9 per 100 outpatient-years. One week after the collection of the index blood culture, 56.1% of outpatients with MSSA bacteremia were receiving vancomycin, and 16.7% of outpatients with MSSA were receiving cefazolin. Among MSSA-bacteremic patients who did not die or get hospitalized 1 week after blood culture collection, use of cefazolin was associated with a 38% lower risk for hospitalization or death compared with vancomycin (adjusted HR=0.62, 95% CI=0.46-0.84). In conclusion, vancomycin is commonly used to treat MSSA bacteremia in outpatients receiving chronic dialysis, but there may be more risk of treatment failure than observed among those individuals who receive a β-lactam antibiotic such as cefazolin.
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21 MeSH Terms
What proportion of vancomycin trough levels are drawn too early?: frequency and impact on clinical actions.
Morrison AP, Melanson SE, Carty MG, Bates DW, Szumita PM, Tanasijevic MJ
(2012) Am J Clin Pathol 137: 472-8
MeSH Terms: Anti-Bacterial Agents, Drug Monitoring, Female, Hospitals, Teaching, Humans, Male, Middle Aged, Retrospective Studies, Time Factors, Vancomycin
Show Abstract · Added November 7, 2019
Vancomycin trough levels are recommended to predict vancomycin efficacy, and inaccurate levels may lead to inappropriate clinical actions. However, the frequency of timing errors and associated clinical impact is unknown. We retrospectively analyzed vancomycin levels (n = 2,597) measured during 13 months at a large academic medical center. Of the specimens, 41.3% were drawn too early. These samples yielded significantly higher average ± SD vancomycin concentrations than correctly timed samples (22.1 ± 11.7 mg/L vs 15.5 mg/L ± 8.6 mg/L; P < .001), and, consequently, clinicians were more likely to decrease, discontinue, or hold a patient's vancomycin dose (25.6% vs 21.4%; P < .02) or repeat the vancomycin level (29.2% vs 20.0%; P < .001). A substantial proportion of specimens collected to assess vancomycin efficacy were drawn too early, leading to overestimation of patients' true trough level and possible underdosing of vancomycin or a high rate of repeat tests for vancomycin.
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Dual-purpose bone grafts improve healing and reduce infection.
Guelcher SA, Brown KV, Li B, Guda T, Lee BH, Wenke JC
(2011) J Orthop Trauma 25: 477-82
MeSH Terms: Animals, Anti-Bacterial Agents, Bone Morphogenetic Protein 2, Bone Transplantation, Combined Modality Therapy, Delayed-Action Preparations, Femoral Fractures, Fracture Healing, Guided Tissue Regeneration, Osteitis, Rats, Tissue Scaffolds, Treatment Outcome, Vancomycin
Show Abstract · Added February 23, 2016
OBJECTIVE - To determine if a dual-purpose bone graft can regenerate bone and reduce infection in highly contaminated bone critical size defects in rats.
METHODS - Biodegradable polyurethane (PUR) scaffolds were loaded with recombinant human bone morphogenetic protein-2 (BMP-2) and vancomycin (Vanc). The release kinetics of the BMP-2 were tuned to take advantage of its mechanism of action (ie, an initial burst to recruit cells and sustained release to induce differentiation of the migrating cells). The Vanc release kinetics were designed to protect the graft from contamination until it is vascularized by having a burst for a week and remaining well over the minimum inhibitory concentration for Staphylococcus aureus for 2 months. The bone regeneration and infection reduction capability of these dual-purpose grafts (PUR+Vanc+BMP-2) were compared with collagen sponges loaded with BMP-2 (collagen+BMP-2) and PUR+BMP-2 in infected critical size rat femoral segmental defects.
RESULTS - The dual-delivery approach resulted in substantially more new bone formation and a modest improvement in infection than PUR+BMP-2 and collagen+BMP-2 treatments.
CONCLUSIONS - The PUR bone graft is injectable, provides a more sustained release of BMP-2 than the collagen sponge, and can release antibiotics for more than 8 weeks. Thus, the dual-delivery approach may improve patient outcomes of open fractures by protecting the osteoinductive graft from colonization until vascularization occurs. In addition, the more optimal release kinetics of BMP-2 may reduce nonunions and the amount of growth factor required.
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14 MeSH Terms