Variability in Antimicrobial Prescribing Across Five Ambulatory Settings Within a Large Integrated Health System.

Background: Lack of access to timely, detailed antibiotic use data has limited ambulatory antibiotic stewardship efforts. Antibiotic utilization is tracked across ambulatory care sites and emergency departments (ED) within a large integrated health system. Methods: This is a retrospective cohort analysis from June 1, 2019 to May 31, 2020 comparing antibiotic prescribing for all patients with ICD-10 diagnosis codes for cystitis, otitis media, pharyngitis, sinusitis, and upper respiratory tract infections (URTIs) among five ambulatory care departments across northeast Ohio and southeast Florida locations: ED, Urgent Care (UC), On-Demand Telehealth (TEL), Pediatrics (PED), and Primary Care (PC). Results: A total of 261,947 encounters were included (ED:56,766, UC:92,749, TEL:8,783, PED:29,151, PC:74,498) for the treatment of cystitis (30,932), otitis media (22,094), pharyngitis (59,964), sinusitis (53,693), or URTI (95,264). The population was 63% female with a median age of 34.2 years [12.8-56.3]. A total of 17% of patients had documented penicillin allergies and 18% of patients with pharyngitis received Group A Streptococcus (GAS) testing. Antibiotics were prescribed in 44% of encounters (ED:21,746 [38%], UC:45,652 [49%], TEL:4,622 [53%], PED:10,909 [37%], PC:33,547 [45%]; P < 0.001). Guideline concordant antibiotics were prescribed in 65% of encounters (ED:14,338 [66%], UC:31,532 [69%], TEL:3,869 [84%], PED:8,212 [75%], PC:17,263 [51%]; P < 0.001). Conclusions: Observed rates of antibiotic and guideline concordant antibiotic prescribing were similar to national published rates of antibiotic prescribing in the ambulatory setting. The variability in antibiotic prescribing demonstrates opportunities for targeted outpatient stewardship efforts. Timely antibiotic tracking tools can facilitate ambulatory antimicrobial stewardship activities.

Extraction of Unstructured Electronic Health Records to Evaluate Glioblastoma Treatment Patterns.

PURPOSE: Data on lines of therapy (LOTs) for cancer treatment are important for clinical oncology research, but LOTs are not explicitly recorded in electronic health records (EHRs). We present an efficient approach for clinical data abstraction and a flexible algorithm to derive LOTs from EHR-based medication data on patients with glioblastoma multiforme (GBM). METHODS: Nonclinicians were trained to abstract the diagnosis of GBM from EHRs, and their accuracy was compared with abstraction performed by clinicians. The resulting data were used to build a cohort of patients with confirmed GBM diagnosis. An algorithm was developed to derive LOTs using structured medication data, accounting for the addition and discontinuation of therapies and drug class. Descriptive statistics were calculated and time-to-next-treatment (TTNT) analysis was performed using the Kaplan-Meier method. RESULTS: Treating clinicians as the gold standard, nonclinicians abstracted GBM diagnosis with a sensitivity of 0.98, specificity 1.00, positive predictive value 1.00, and negative predictive value 0.90, suggesting that nonclinician abstraction of GBM diagnosis was comparable with clinician abstraction. Of 693 patients with a confirmed diagnosis of GBM, 246 patients contained structured information about the types of medications received. Of them, 165 (67.1%) received a first-line therapy (1L) of temozolomide, and the median TTNT from the start of 1L was 179 days. CONCLUSION: We described a workflow for extracting diagnosis of GBM and LOT from EHR data that combines nonclinician abstraction with algorithmic processing, demonstrating comparable accuracy with clinician abstraction and highlighting the potential for scalable and efficient EHR-based oncology research.

Socioeconomic disparities in lumbar fusion rates were exacerbated during the COVID-19 pandemic.

Background: The COVID-19 pandemic disrupted healthcare access and utilization throughout the US, with variable impact on patients of different socioeconomic status (SES) and race. We characterize pre-pandemic and pandemic demographic and SES trends of lumbar fusion patients in the US. Methods: Adults undergoing first-time lumbar fusion 1/1/2004-3/31/2021 were assessed in Clinformatics® Data Mart for patient age, geographical location, gender, race, education level, net worth, and Charlson Comorbidity Index (CCI). Multivariable regression models were used to evaluate the significance of trends over time, with a focus on pandemic trends 2020-2021 versus previous trends 2004-2019. Results: The total 217,204 patients underwent lumbar fusions, 1/1/2004-3/31/2021. The numbers and per capita rates of lumbar fusions increased 2004-2019 and decreased in 2020 (first year of COVID-19 pandemic), with large variation in geographic distribution. There was overall a significant decrease in proportion of White patients undergoing lumbar fusion over time (OR=0.997, p<.001), though they were more likely to undergo surgery during the pandemic (OR=1.016, p<.001). From 2004-2021, patients were more likely to be educated beyond high school. Additionally, patients in the highest (>$500k) and lowest (<$25k) net worth categories had significantly more fusions over time (p<.001). During the pandemic (2020-2021), patients in higher net worth groups were more likely to undergo lumbar fusions ($150k-249k & $250k-499k: p<.001) whereas patients in the lowest net worth group had decreased rate of surgeries (p<.001). Lastly, patients' CCI increased significantly from 2004 to 2021 (coefficient=0.124, p<.001), and this trend held true during the pandemic (coefficient=0.179, p<.001). Conclusions: To the best of our knowledge, our work represents the most comprehensive and recent characterization of SES variables in lumbar fusion rates. Unsurprisingly, lumbar fusions decreased overall with the onset of the COVID-19 pandemic. Importantly, disparities in fusion patients across patient race and wealth widened during the pandemic, reversing years of progress, a lesson we can learn for future public health emergencies.

Demographic and Socioeconomic Trends in Cervical Fusion Utilization from 2004 Through 2021 and the COVID-19 Pandemic.

BACKGROUND: Cervical fusion rates increased in the U.S. exponentially 1990-2014, but trends leading up to/during the COVID-19 pandemic have not been fully evaluated by patient socioeconomic status (SES). Here, we provide the most recent, comprehensive characterization of demographic and SES trends in cervical fusions, including during the pandemic. METHODS: We collected the following variables on adults undergoing cervical fusions, 1/1/2004-3/31/2021, in Optum's Clinformatics Data Mart: age, Charlson Comorbidity Index, provider's practicing state, gender, race, education, and net worth. We performed multivariate linear and logistic regression to evaluate associations of cervical fusion rates with SES variables. RESULTS: Cervical fusion rates increased 2004-2016, then decreased 2016-2020. Proportions of Asian, Black, and Hispanic patients undergoing cervical fusions increased (OR = 1.001,1.001,1.004, P < 0.01), with a corresponding decrease in White patients (OR = 0.996, P < 0.001) over time. There were increases in cervical fusions in higher education groups (OR = 1.006, 1.002, P < 0.001) and lowest net worth group (OR = 1.012, P < 0.001). During the pandemic, proportions of White (OR = 1.015, P < 0.01) and wealthier patients (OR ≥ 1.015, P < 0.01) undergoing cervical fusions increased. CONCLUSIONS: We present the first documented decrease in annual cervical surgery rates in the U.S. Our data reveal a bimodal distribution for cervical fusion patients, with racial-minority, lower-net-worth, and highly-educated patients receiving increasing proportions of surgical interventions. White and wealthier patients were more likely to undergo cervical fusions during the COVID-19 pandemic, which has been reported in other areas of medicine but not yet in spine surgery. There is still considerable work needed to improve equitable access to spine care for the entire U.S.

Anabolic and Antiresorptive Osteoporosis Treatment: Trends, Costs, and Sequence in a Commercially Insured Population, 2003-2021.

New anabolic medications (abaloparatide and romosozumab) were recently approved for osteoporosis, and data suggest that prescribing antiresorptive medications after a course of anabolic medications offers better outcomes. This study aimed to characterize prescription trends, demographics, geographical distributions, out-of-pocket costs, and treatment sequences for anabolic and antiresorptive osteoporosis medications. Using a commercial claims database (Clinformatics Data Mart), adult patients with osteoporosis from 2003 to 2021 were retrospectively reviewed and stratified based on osteoporosis medication class. Patient demographics and socioeconomic variables, provider types, and out-of-pocket costs were collected. Multivariable regression analyses were used to identify independent predictors of receiving osteoporosis treatment. A total of 2,988,826 patients with osteoporosis were identified; 616,635 (20.6%) received treatment. Patients who were female, Hispanic or Asian, in the Western US, had higher net worth, or had greater comorbidity burden were more likely to receive osteoporosis medications. Among patients who received medication, 31,112 (5.0%) received anabolic medication; these were more likely to be younger, White patients with higher education level, net worth, and greater comorbidity burden. Providers who prescribed the most anabolic medications were rheumatologists (18.5%), endocrinologists (16.8%), and general internists (15.3%). Osteoporosis medication prescriptions increased fourfold from 2003 to 2020, whereas anabolic medication prescriptions did not increase at this rate. Median out-of-pocket costs were $17 higher for anabolic than antiresorptive medications, though costs for anabolic medications decreased significantly from 2003 to 2020 (compound annual growth rate: -0.6%). A total of 8388 (1.4%) patients tried two or more osteoporosis medications, and 0.6% followed the optimal treatment sequence. Prescription of anabolic osteoporosis medications has not kept pace with overall osteoporosis treatment, and there are socioeconomic disparities in anabolic medication prescription, potentially driven by higher median out-of-pocket costs. Although prescribing antiresorptive medications after a course of anabolic medications offers better outcomes, this treatment sequence occurred in only 0.6% of the study cohort. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Selective prediction for extracting unstructured clinical data.

OBJECTIVE: While there are currently approaches to handle unstructured clinical data, such as manual abstraction and structured proxy variables, these methods may be time-consuming, not scalable, and imprecise. This article aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction. MATERIALS AND METHODS: We trained selective classifiers (logistic regression, random forest, support vector machine) to extract 5 variables from clinical notes: depression (n = 1563), glioblastoma (GBM, n = 659), rectal adenocarcinoma (DRA, n = 601), and abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601) of adenocarcinoma. We varied the cost of false positives (FP), false negatives (FN), and abstained notes and measured total misclassification cost. RESULTS: The depression selective classifiers abstained on anywhere from 0% to 97% of notes, and the change in total misclassification cost ranged from -58% to 9%. Selective classifiers abstained on 5%-43% of notes across the GBM and colorectal cancer models. The GBM selective classifier abstained on 43% of notes, which led to improvements in sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier and when compared to structured proxy variables. DISCUSSION: We showed that selective classifiers outperformed both non-selective classifiers and structured proxy variables for extracting data from unstructured clinical notes. CONCLUSION: Selective prediction should be considered when abstaining is preferable to making an incorrect prediction.

Translational Models in Glioma Immunotherapy Research.

Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.

Trends, payments, and costs associated with BMP use in Medicare beneficiaries undergoing spinal fusion.

BACKGROUND CONTEXT: Bone morphogenic protein (BMP) promotes bony fusion but increases costs. Recent trends in BMP use among Medicare patients have not been well-characterized. PURPOSE: To assess utilization trends, complication, payments, and costs associated with BMP use in spinal fusion in a Medicare-insured population. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Total of 316,070 patients who underwent spinal fusion in a 20% sample of Medicare-insured patients, 2006 to 2015. OUTCOME MEASURES: Utilization trends across time and geography, complications, payments, and costs. METHODS: Patients were stratified by fusion type and diagnosis. Multivariable logistic and linear regression were used to adjust for the effect of baseline characteristics on complications and total payments or cost, respectively. RESULTS: BMP was used in 60,249 cases (19.1%). BMP utilization rates decreased from 23.1% in 2006 to 12.0% in 2015, most significantly in anterior cervical (7.5%-3.1%), posterior cervical (17.0%-8.3%), and posterior lumbar fusions (31.5%-15.8%). There are significant state- and region-level geographic differences in BMP utilization. Across all years, states with the highest BMP use were Indiana (28.5%), Colorado (26.6%), and Nevada (25.7%). States with the lowest BMP use were Maine (2.3%), Vermont (8.2%), and Mississippi (10.4%). After multivariate risk adjustment, BMP use was associated with decreased overall complications in thoracic (odds ratios [OR] [95% confidence intervals [CI]): 0.89 [0.81-0.99]) and anterior lumbar fusions (OR [95% CI]: 0.89 [0.84-0.95]), as well as increased reoperation rates in anterior cervical (OR [95% CI]: 1.11 [1.04-1.19]), posterior cervical (OR (95% CI): 1.14 (1.04-1.25)), thoracic (OR (95% CI): 1.32 (1.23-1.41)), and posterior lumbar fusions (OR (95% CI): 1.11 (1.06-1.16)). BMP use was also associated with greater total costs, independent of fusion type, after multivariate risk adjustment (p<.0001). Payments, however, were comparable between groups in anterior and posterior cervical fusion with or without BMP. BMP use was associated with greater total payments in thoracic, anterior lumbar, and posterior lumbar fusions. Notably, the difference in payments was smaller than the associated cost increase in all fusion types. CONCLUSIONS: BMP use has declined across all fusion types over the last decade, after a peak in 2007. While BMP is associated with greater costs, reimbursement does not increase proportionally with BMP cost.

Multidisciplinary Approach to Improve Human Immunodeficiency Virus and Syphilis Testing Rates in Emergency Departments.

Background: Best practice guidelines recommend that patients at risk for sexually transmitted infections (STIs), such as gonorrhea (GC) and chlamydia, should also be tested for human immunodeficiency virus (HIV) and syphilis. This prospective quality assurance study aimed to increase HIV and syphilis testing rates in emergency departments (EDs) across the Cleveland Clinic Health System from January 1, 2020 through January 1, 2022. Methods: A multidisciplinary team of emergency medicine, infectious diseases, pharmacy, and microbiology personnel convened to identify barriers to HIV and syphilis testing during ED encounters at which GC/chlamydia were tested. The following interventions were implemented in response: rapid HIV testing with new a workflow for results follow-up, a standardized STI-screening order panel, and feedback to clinicians about ordering patterns. Results: There were 57 797 ED visits with GC/chlamydia testing completed during the study period. Human immunodeficiency virus testing was ordered at 5% of these encounters before the interventions were implemented and increased to 8%, 23%, and 36% after each successive intervention. Syphilis testing increased from 9% before the interventions to 12%, 28%, and 39% after each successive intervention. In multivariable analyses adjusted for age, gender, and location, the odds ratio for HIV and syphilis testing after all interventions was 11.72 (95% confidence interval [CI], 10.82-12.71; P ≤.001) and 6.79 (95% CI, 6.34-7.27; P ≤.001), respectively. Conclusions: The multidisciplinary intervention resulted in improved testing rates for HIV and syphilis.

Updates in intraoperative strategies for enhancing intra-axial brain tumor control.

To ensure excellent postoperative clinical outcomes while preserving critical neurologic function, neurosurgeons who manage patients with intra-axial brain tumors can use intraoperative technologies and tools to achieve maximal safe resection. Neurosurgical oncology revolves around safe and optimal extent of resection, which further dictates subsequent treatment regimens and patient outcomes. Various methods can be adapted for treating both primary and secondary intra-axial brain lesions. We present a review of recent advances and published research centered on different innovative tools and techniques, including fluorescence-guided surgery, new methods of drug delivery, and minimally invasive procedural options.

Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review.

BACKGROUND AND OBJECTIVE: Immunotherapy has yielded significant improvements in survival for many cancer types, but its impact on glioblastoma (GBM) has been relatively muted. There is a growing interest in understanding the role of cancer metabolism and its role in tumor growth and therapeutic response. Thus, it is equally important to consider the clinical implications of immune cell metabolism on cancer progression and implications for therapeutic development. Our objective is to present new developments in immunometabolic research that are relevant to immunotherapy development for high-grade gliomas. METHODS: A literature search and review was conducted, regarding original research articles studying metabolic pathways of immune cells in high-grade gliomas. Searches were conducted in PubMed and Embase databases on May 15 and June 13, 2022. English-language original research articles were selected and prioritized based on their inclusion of findings related to metabolic changes in myeloid and lymphoid cells in the glioma tumor microenvironment. KEY CONTENT AND FINDINGS: There are many metabolic mechanisms by which immune cells in high-grade gliomas, like GBM, contribute to tumor growth and persistence via immunosuppression and high therapeutic resistance. There are also several ways that metabolic optimization has already been shown to improve immunotherapies already in clinical trials or in use, including dendritic cell vaccines and chimeric antigen receptor T cells. CONCLUSIONS: The implications of immunometabolic research presented here should be taken into consideration in future research and immunotherapy development of high-grade gliomas for our best chances at improving patient survival.

Relevance of Medullary Vein Sign in Neurosarcoidosis.

BACKGROUND: Central nervous system involvement is uncommon in patients with sarcoidosis. It remains a diagnostic challenge for clinicians, as there is a broad differential diagnosis that matches the presenting neurological signs. Often, the imaging findings also overlap with other disease entities. One understudied finding in patients with neurosarcoidosis is the presence of medullary vein engorgement on SWI imaging, termed the "medullary vein sign", which has been postulated to be a specific sign for neurosarcoidosis. This study aims to provide an understanding of the diagnostic potential of the medullary vein sign. METHODS: Thirty-two patients who presented with neurologic signs concerning for possible neurosarcoidosis were analyzed retrospectively for the presence of the medullary vein sign. RESULTS: Out of these cases, 7 cases of definitive neurosarcoidosis cases were found based on other imaging signs, biopsy and CSF analysis; the remaining were classified into groups as possible (16), probable (5) and (4) cases of other infectious meningoencephalitis including 2 cases of autoimmune encephalitis. Seven patients among all of these cases were found to have the medullary vein sign on imaging, with five cases with confirmed and two cases from possible neurosarcoidosis. The sensitivity of the medullary vein sign in this study was 71.4%, and the specificity was 92.3%. DISCUSSION: The benefits of improving diagnostic criteria for neurosarcoidosis include more rapid diagnosis leading to more prompt treatment, less exposure to potentially harmful antibiotics or antifungals, and less long-term neurological effects. Our results support that the medullary vein sign will potentially fill in the diagnostic gaps that have challenged the timely diagnosis of neurosarcoidosis. CONCLUSIONS: Our findings support that the medullary vein sign has a high specificity and should be included in the diagnostic criteria for neurosarcoidosis.

The Role of Myeloid Cells in GBM Immunosuppression.

Gliomas are intrinsic brain tumors that originate from glial cells. Glioblastoma (GBM) is the most aggressive glioma type and resistant to immunotherapy, mainly due to its unique immune environment. Dimensional data analysis reveals that the intra-tumoral heterogeneity of immune cell populations in the glioma microenvironment is largely made up of cells of myeloid lineage. Conventional therapies of combined surgery, chemotherapy and radiotherapy have achieved limited improvements in the prognosis of glioma patients, as myeloid cells are prominent mediators of immune and therapeutic responses-like immunotherapy resistance-in glioma. Myeloid cells are frequently seen in the tumor microenvironment (TME), and they are polarized to promote tumorigenesis and immunosuppression. Reprogramming myeloid cells has emerged as revolutionary, new types of immunotherapies for glioma treatment. Here we detail the current advances in classifying epigenetic, metabolic, and phenotypic characteristics and functions of different populations of myeloid cells in glioma TME, including myeloid-derived suppressor cells (MDSCs), glioma-associated microglia/macrophages (GAMs), glioma-associated neutrophils (GANs), and glioma-associated dendritic cells (GADCs), as well as the mechanisms underlying promotion of tumorigenesis. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in glioma patients.

Risk Factors for Trimethoprim and Sulfamethoxazole-Resistant Escherichia Coli in ED Patients with Urinary Tract Infections.

BACKGROUND: While trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as one of the first-line empiric therapies for treatment of acute uncomplicated cystitis, institutions that observe resistance rates exceeding 20% for Escherichia coli (E. coli) should utilize alternative empiric antibiotic therapy per the Infectious Diseases Society of America (IDSA). Identifying risk factors associated with TMP-SMX resistance in E. coli may help guide empiric antibiotic prescribing for urinary tract infections (UTIs). METHODS: This multicenter, retrospective study included adult patients who were discharged from 12 emergency departments (EDs) with a urine culture positive for E. coli between January 1, 2019 and December 31, 2019. Logistic regression was used to assess the relationship between potential risk factors and TMP-SMX resistance. The overall institutional antimicrobial resistance rates for E. coli were compared to the rates seen in the study population of ED urinary isolates. RESULTS: Among 427 patients included from a randomized sample of 500 with a urine culture positive for E. coli, 107 (25.1%) were resistant to TMP-SMX. Three predictors of TMP-SMX resistance were identified: recurrent UTI (OR 2.27 [95% CI 1.27-3.99]), genitourinary abnormalities (OR 2.31 [95% CI 1.17-4.49]), and TMP-SMX use within 90 days (OR 8.77 [95% CI 3.19-28.12]). When the antibiotic susceptibilities for this ED cohort were compared to the institutional antibiogram, the TMP-SMX resistance rate was found to be higher in the ED population (25.1% vs 20%). CONCLUSIONS: TMP-SMX should likely be avoided as first-line therapy for UTI in patients who have recurrent UTIs, genitourinary abnormalities, or have previously received TMP-SMX within the past 90 days. The use of an ED-specific antibiogram should be considered for assessing local resistance rates in this population.

Implementation of a Leeches + Antimicrobial Prophylaxis Order Panel to Optimize Medicinal Leech Use at a Tertiary Care Academic Medical Center.

Medicinal leech therapy promotes vascular flow and can be used to salvage grafts. Medicinal leeches have a symbiotic relationship with Aeromonas species and can therefore present a risk of bacterial transmission to patients. Antimicrobial prophylaxis is warranted for the duration of leech therapy, however, an institutional evaluation of 40 patients receiving medicinal leech therapy demonstrated poor adherence with recommendations. An electronic medical record order panel for antimicrobial prophylaxis with medicinal leech therapy was implemented, leading to a subsequent improvement in adherence to prophylaxis use, including significant increases in the ordering of antibiotics and the appropriate timing of initiation in the subsequent 10 patients receiving medicinal leech therapy after panel implementation. Aeromonas infections were rare before and after panel implementation, and developed only in the patient subset with non-optimized prophylaxis.

Periprosthetic Joint Infection: A Review of Antibiotic Treatment.

A team approach among orthopaedic surgeons, infectious disease specialists, and patients is of paramount importance when treating periprosthetic joint infections (PJIs). Treatment usually includes various surgical approaches along with antibiotic treatment. Antibiotic selection requires a multifactorial decision that depends on the organism that is identified, its antibiotic-resistance profile, the extent of the infection, and factors associated with the host. Antibiotic duration is dependent on surgical intervention and the type of organism. Typically, patients are treated for 6 weeks after debridement, antibiotics, and implant retention (DAIR) and for 4 to 6 weeks after single-stage and 2-stage revision arthroplasty. Levofloxacin in combination with rifampin has shown favorable outcomes for Staphylococcus PJI treatment. Quinolones have excellent bioavailability and bone and joint concentrations. Ciprofloxacin can be used for sensitive gram-negative infections. Evidence is emerging that supports the use of oral antibiotics after 7 days of intravenous antibiotics for the treatment of PJI. Although this should be considered carefully, it can potentially alleviate the burden on patients and caregivers, with fewer intravenous lines and the potential for fewer complications.

Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma.

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces ß-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of ß-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/ß-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms.

Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many ß-lactamases, including extended spectrum ß-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactose-fermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

Evaluation of a health system-wide pharmacist-driven emergency department laboratory follow-up and antimicrobial management program.

BACKGROUND: Emergency Department (ED) follow-up programs ensure that cultures, laboratory studies, and empiric antimicrobials are appropriately managed post-discharge. We sought to provide a comprehensive assessment of a pharmacist-driven laboratory follow-up process in a large, integrated health system. METHODS: A retrospective, observational review of 13 EDs was conducted. Patients were included if they had a laboratory study sent from the ED between December 1, 2017 and May 31, 2018 that did not result while the patient was in the ED. Microbiology results analyzed were urine, wound, respiratory, stool, throat, bacterial vaginosis, vaginal candidiasis, and sexually transmitted infections (STI). Examples of laboratory results assessed were metabolic panels and drug levels. The primary objective was to quantify the number of interventions made by pharmacists. RESULTS: During a 6-month period, pharmacists reviewed 9107 microbiology results and 6211 laboratory results. The majority of results were urine cultures (3998, 50.6%) followed by STI results (1198, 15.2%). Of 7663 encounters, 39.8% required interventions and/or follow-up with a total of 3049 interventions made and 3333 patients educated. The most common interventions were initiation of therapy (1629, 53.4%), change in medication (505, 16.6%), and follow-up with a clinician (322, 10.6%). Pharmacists reviewed microbiology results and completed interventions in a median of 25.3 h from the time the result was received in the electronic health record. CONCLUSION: Almost 40% of ED encounters required an intervention after discharge. A pharmacist led laboratory follow-up program is an important adjunct to facilitating stewardship and culture management in the ED.

Implementation of a Pharmacist-Driven Detailed Penicillin Allergy Interview.

Background: Self-reported penicillin allergies may be outdated or inaccurate, leading to the use of alternative antimicrobials that may be less effective, more toxic, and/or more expensive. Although penicillin skin tests can provide accurate assessments of penicillin allergies, these procedures are not feasible at all institutions. Another solution is to conduct a detailed penicillin allergy interview (DPAI), which can potentially lead to optimization of antimicrobial therapy. Objective: The purpose of this study was to assess the impact of a pharmacist-driven DPAI protocol. The primary objective was to measure the number of patients requiring a change to their allergy profile following DPAI. Secondary objectives included characterizing allergy profile updates and measuring the number of recommendations to switch to a ß-lactam agent, provider acceptance rate, and patient tolerance. Methods: Standardized pharmacist-driven DPAIs were conducted prospectively on adult patients admitted with a documented penicillin allergy. The allergy profile within the electronic health record (EHR) was updated and a recommendation to switch to noncarbapenem ß-lactam therapy was made when indicated by a decision algorithm. Results: A total of 175 (37.5%) patients received a DPAI. Of these, 133 (76.0%) required a change to their allergy profile. Additionally, 135 (77.1%) patients interviewed were on antimicrobial therapy, with 42 (31.1%) meeting criteria to switch to noncarbapenem ß-lactam therapy; of which 31 (73.8%) patients were successfully transitioned, with no signs or symptoms of intolerance. Conclusions and Relevance: Implementation of pharmacist-driven DPAIs can provide updated and corrected allergy information within the EHR, allowing for de-escalation and/or optimization of antimicrobial therapy.