Biopsy-Proven Acute Tubular Necrosis due to Vancomycin Toxicity

Vancomycin (VAN) has been associated with acute kidney injury (AKI) since it has been put into clinical use in the 1950's. Early reports of AKI were likely linked to the impurities of the VAN preparation. With the advent of the more purified forms of VAN, the incidence of AKI related to VAN were limited to acute interstitial nephritis (AIN) or as a potentiating agent to other nephrotoxins such as Aminoglycosides. VAN as the sole etiologic factor for nephrotoxic acute tubular necrosis (ATN) has not been described. Here, we report a case of biopsy-proven ATN resulting from VAN

Trends in and predictors of carbapenem consumption across North American hospitals: Results from a multicenter survey by the MAD-ID research network

This Special Issue is dedicated to the late Dr. Charles (Charlie) D. Hufford, former Professor of Pharmacognosy and Associate Dean for Research and Graduate Studies at University of Mississippi [...]

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model-informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill

International survey of antibiotic dosing and monitoring in adult intensive care units

AVAILABILITY OF DATA AND MATERIALS : All data generated or analyzed during this study are included in this published article [and its supplementary information files].SUPPLEMENTARY INFORMATION : TABLE S1. Definition of infusion types and duration; TABLE S2. Online survey questions; TABLE S3. Exclusions; TABLE S4. Respondents as per Region and Economy; TABLE S5. Results according to Region and Economy; Table S6. TDM utilization and beta-lactam prolonged infusion administration according to hospital type.BACKGROUND : In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time. METHODS : A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides. RESULTS : A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%). CONCLUSION : We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Betalactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.Clinician Researcher Fellowship funding from Sunshine Coast Hospital, Health Service Study Education Research Trust Fund (SERTF), Wishlist, the Australian National Health and Medical Research Council, an Investigator Grant and an Advancing Queensland Clinical Fellowship.https://ccforum.biomedcentral.comam2024PharmacologySDG-03:Good heatlh and well-bein

A Component of Retinal Light Adaptation Mediated by the Thyroid Hormone Cascade

Analysis with DNA-microrrays and real time PCR show that several genes involved in the thyroid hormone cascade, such as deiodinase 2 and 3 (Dio2 and Dio3) are differentially regulated by the circadian clock and by changes of the ambient light. The expression level of Dio2 in adult rats (2–3 months of age) kept continuously in darkness is modulated by the circadian clock and is up-regulated by 2 fold at midday. When the diurnal ambient light was on, the expression level of Dio2 increased by 4–8 fold and a consequent increase of the related protein was detected around the nuclei of retinal photoreceptors and of neurons in inner and outer nuclear layers. The expression level of Dio3 had a different temporal pattern and was down-regulated by diurnal light. Our results suggest that DIO2 and DIO3 have a role not only in the developing retina but also in the adult retina and are powerfully regulated by light. As the thyroid hormone is a ligand-inducible transcription factor controlling the expression of several target genes, the transcriptional activation of Dio2 could be a novel genomic component of light adaptation

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Development of a pharmacy student research program at a large academic medical center

PURPOSE: A program to promote research by pharmacy students created through the collaboration of an academic medical center and a college of pharmacy is described. SUMMARY: In 2009, Midwestern University Chicago College of Pharmacy and Northwestern Memorial Hospital (NMH) expanded their existing partnership by establishing a program to increase opportunities for pharmacy students to conduct clinical-translational research. All professional year 1, 2, or 3 students at the college, as well as professional year 4 students on rotation at NMH, can participate in the program. Central to the program\u27s infrastructure is the mentorship of student leads by faculty- and hospital-based pharmacists. The mentors oversee the student research projects and guide development of poster presentations; student leads mentor junior students and assist with orientation and training activities. Publication of research findings in the peer-reviewed literature is a key program goal. In the first four years after program implementation, participation in a summer research program grew nearly 10-fold (mainly among incoming professional year 2 or 3 students, and student poster presentations at national pharmacy meetings increased nearly 20-fold; the number of published research articles involving student authors increased from zero in 2009 to three in 2012 and two in 2013. CONCLUSION: A collaborative program between an academic medical center and a college of pharmacy has enabled pharmacy students to conduct research at the medical center and has been associated with increases in the numbers of poster presentations and publications involving students

Characterization of Genetic Diversity of Carbapenem-Resistant Acinetobacter baumannii Clinical Strains Collected from 2004 to 2007▿

Genotypes of carbapenem-resistant Acinetobacter baumannii collected by the clinical microbiology laboratory of a university hospital in Chicago, IL, between 2004 and 2007 were analyzed by pulsed-field gel electrophoresis. A single genotype established predominance after being introduced in 2005. Analysis of carbapenemases by PCR revealed that imipenem resistance but not meropenem resistance was associated with the presence of blaOXA-23 and blaOXA-40 genes

Rational dosing of HCQ for COVID-19_pre-print

Background: Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2. However, data to inform optimal human dosing are limited. Methods: We conducted Monte Carlo simulations of HCQ sulfate using a published population pharmacokinetic model. The model informing our simulations described a 2-compartment linear model with first-order absorption with a lag, derived from plasma HCQ concentration data from 22 healthy adults and 69 patients with malaria. Using the final PK model, we performed 1000 simulations for the plasma concentrations of HCQ sulfate based on various approved dosages (i.e. acute malaria, autoimmune conditions) and proposed dosing regimens for treatment of COVID-19. The results of simulations were used to derive the area under the concentration-time curve (AUC), maximal concentration, and time to maximal concentration for each evaluated regimen. Results: The use of a loading dose, as with acute malaria dosing, resulted in rapid achievement of maximal concentrations early in the treatment course, which were maintained with daily dosing thereafter. The use of once or twice daily doses without a loading dose led to slowly increasing plasma concentrations through day 10. Simulated regimens that employed an 800 mg loading dose for adults (13 mg/kg for children) followed by 400 mg at 6 or 12 hours (6.5 mg/kg for children) achieved the greatest AUC0-24. Conclusions: Based on our findings, along with established safety data from malarial studies, we believe that approved dosing for treatment acute malaria is the most reasonable and safest approach if HCQ will be used to treat COVID-19