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Abstract Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200).

Background: Invasive fungal infections are responsible for a large number of infections in hospitalized patients annually and are responsible for high morbidity and mortality. Familiarity with novel agents or strategies in this area can be challenging., Objectives: To identify the top 10 manuscripts on the treatment of invasive fungal infections from 2018 to 2023., Design: Modified Delphi consensus-building technique., Methods: A three-stage consensus-building approach was used comprised of (1) identifying relevant articles; (2) voting by a panel of experts to establish consensus on the importance of these articles; and (3) finalizing the list of top articles by a small group. Members of the Southeastern Research Group Endeavor network served as content experts. Publications from 2018 to 2023 were evaluated if articles met the following inclusion criteria: (1) published between 2018 and 2023, (2) contained content related to fungal infections, and (3) included an actionable intervention., Results: A total of 6518 potential publications were assessed. After applying inclusion and exclusion criteria, 82 articles were reviewed. The top 10 publications related to invasive fungal infections, selected by a panel of experts, are summarized in this manuscript and include publications related to the treatment of invasive aspergillosis, candidiasis, and cryptococcosis., Conclusion: This article highlights the selected publications and may serve as a key resource for teaching and training. Clinicians may also employ these reported interventions to identify new opportunities to optimize antifungal therapeutic strategies within one's institution., (© The Author(s), 2024.)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: This review explores the management of persistent methicillin-susceptible Staphylococcus aureus bacteremia (SAB), emphasizing the importance of timely intervention due to SAB's association with metastatic dissemination, relapse, and mortality., Summary: The literature analysis first delves into risk factors for persistent SAB, highlighting the need for effective treatment strategies. The subsequent focus is on combination strategies for persistent SAB. Daptomycin, ertapenem, ceftaroline, fosfomycin, rifampin, and gentamicin are explored as adjuncts to cefazolin or antistaphylococcal penicillins. Daptomycin combination therapy is assessed through in vivo and clinical studies, indicating potential benefits, especially with higher-risk sources of infection. Ertapenem combination therapy has been demonstrated to have a synergistic effect with cefazolin, presenting a viable salvage option. Rifampin's ability to penetrate biofilm is examined, with discussion of inconclusive evidence on mortality benefits. The review also considers stewardship implications, discussing concerns such as resistance emergence, adverse events, and increased costs associated with combination therapy. Mathematical models suggest combination therapy as an effective approach to prevent resistance. Adverse events vary with each combination, and duration of therapy remains diverse across studies in the absence of well-established dosing guidelines., Conclusion: The review provides a thorough exploration of the literature on treatment of persistent SAB, underscoring the need for evidence-based guidelines, further studies, and clinical judgment in tailoring treatment strategies. The multifaceted analysis contributes valuable insights for clinicians managing this challenging condition., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Trichotillomania (TTM) is associated with impairments in response inhibition and cognitive flexibility, but it is unclear how such impairments relate to treatment outcome. The present study examined pre-treatment response inhibition and cognitive flexibility as predictors of treatment outcome, change in these domains from pre-to post-treatment, and associations with TTM severity. Participants were drawn from a randomized controlled trial comparing acceptance-enhanced behavior therapy (AEBT) to psychoeducation and supportive therapy (PST) for TTM. Adults completed assessments at pre-treatment (n = 88) and following 12 weeks of treatment (n = 68). Response inhibition and cognitive flexibility were assessed using the Stop Signal Task and Object Alternation Task, respectively. Participants completed the MGH-Hairpulling Scale. Independent evaluators administered the NIMH-Trichotillomania Severity Scale and Clinical Global Impressions-Improvement Scale. Higher pre-treatment TTM severity was associated with poorer pre-treatment cognitive flexibility, but not response inhibition. Better pre-treatment response inhibition performance predicted positive treatment response and lower post-treatment TTM symptom severity, irrespective of treatment assignment. Cognitive flexibility did not predict treatment response. After controlling for age, neither neurocognitive variable changed during treatment. Response inhibition and cognitive flexibility appear uniquely related to hair pulling severity and treatment response in adults with TTM. Implications for treatment delivery and development are discussed., Competing Interests: Declaration of competing interest Ms. Barber, Dr. Deckersbach, Mr. Bauer, Dr. Compton, Dr. Robinson, Dr. Saunders, and Dr. Franklin declare that they have no conflicts of interest. Dr. Woods receives book royalties from Guilford Press, Springer Press, and Oxford University Press. Dr. Twohig has books with New Harbinger and Oxford University Press, and an online course with Praxis CET. Dr. Ricketts has received research funding from the National Institute of Mental Health (NIMH), and the TLC Foundation for Body-Focused Repetitive Behaviors. She has received honoraria from the Centers for Disease Control and Prevention and Springer Nature., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In tic disorders (TD), tic expression varies across the lifespan and as a function of contextual factors. This study explored connections between tic expression and contextual triggers across life periods in 74 adults (M age  = 23.2) with TDs. The Tic History and Coping Strategies form assessed retrospective self-reports of contextual antecedents, consequences, and tic severity during four life periods (middle school; 9th/10th grade; 11th/12th grade; college/work) and past month. Tics reportedly worsened during and after school in school-aged years and worsened in the evening during college/work years. Stress and anxiety were reported to consistently trigger tics across time. The impact of activities, places, and emotions did not differ across life periods. Attention-based consequences, most prevalent during middle school, were more common than escape- or avoidance-related consequences across all periods. Findings illuminate how contextual factors may influence tics across life periods and underscore the consistent impact of tic-triggering emotions and attention-related consequences., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Behavior therapy is a well-established and empirically supported treatment for tic disorders (TDs). However, concerns have been expressed about the negative effects of behavioral interventions, such as tic worsening, tic substitution, and excessive effort. This study explored perceived negative effects of tic management strategies in adults with TDs and predictors of these experiences. Participants ( N  = 72) completed semi-structured interviews 11 years after receiving behavior therapy or supportive therapy in a randomized clinical trial. We examined responses to interview questions about managing tics and predictors of reported negative effects. Most participants did not experience tic worsening (84%) or tic substitution (75%) from tic management strategies. The majority felt they could manage tics while participating in their environment (87%) and did not report life interference from tic management (77%). About half (45%) felt less present when managing tics. Treatment non-responders in the original trial were more likely to report negative effects of tic management strategies. No differences in reported negative consequences were found between those who received behavior therapy versus supportive therapy, suggesting that behavior therapy specifically does not lead to such adverse effects. These findings could reduce misconceptions about behavior therapy for TDs and enhance its acceptability and utilization., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ms. Barber, Mr. Pitts, Mr. Stiede, and Dr. Compton declare that they have no conflicts of interest. Dr. Espil has received research support from the Foundation for OCD Research and honoraria from Springer Nature. Dr. Woods receives royalties from Guilford Press, Springer Press, and Oxford University Press and royalties for www.tichelper.com. Dr. Woods also receives speaking fees from the Tourette Association of America. Dr. Specht receives research support and speaking honoraria from the Tourette Association of America. Dr. Bennett receives royalties from UpToDate for an entry on child anxiety, and honoraria from the Tourette Association of America for CBIT training/talks and Lyra Health for speakers’ bureau. Dr. Walkup has served on advisory boards for the TLC Foundation for Body-Focused Repetitive Behaviors, Tourette Association of America, and the Anxiety and Depression Association of America. He has received speaking fees from the Tourette Association of America and AACAP. Dr. Walkup receives research funding from the Tourette Association of America and royalties from Oxford Press, Guilford Press, and Wolters Kluwer. Dr. Ricketts has received research funding from the National Institute of Mental Health (NIMH), Brain and Behavior Research Foundation, and the TLC Foundation for Body-Focused Repetitive Behaviors. She has received honoraria and research funding from the Tourette Association of America (TAA). She has received honoraria from the Centers for Disease Control and Prevention and Springer Nature. Dr. McGuire has received research support from the American Academy of Neurology, American Brain Foundation, American Psychological Foundation, Hilda and Preston Davis Foundation, Misophonia Research Fund, Tourette Association of America, and National Institute of Health. Dr. McGuire has received royalties from Elsevier and serves as a consultant for Signant Health, Syneos Health, and Luminopia. He has received editorial honoraria from Springer Nature and speakers’ bureau from the International OCD Foundation Pediatric Behavior Therapy Training Institute, and Tourette Association of America Scientific Advisory Board. Dr. Peterson reports receiving royalties from Oxford University Press for treatment manuals on tic disorders and receiving honoraria for CME presentations from the Tourette Association of America. Dr. Scahill has received research support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the US Department of Defense, and the Marcus Foundation. He has served as a consultant to Janssen Pharmaceuticals, Impel NeuroPharma and Cogstate. Dr. Scahill has received licensing fees from Roche, Yamo Pharmaceuticals, and Abbvie. He has received royalties from Guilford Press, Oxford University Press, and American Psychiatric Association Publishing. Dr. Wilhelm is a presenter for the Massachusetts General Hospital Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies. She has received royalties from Guilford Publications, New Harbinger Publications, Springer, and Oxford University Press. Dr. Wilhelm has also received speaking honoraria from various academic institutions and foundations, including the International Obsessive Compulsive Disorder Foundation, the Tourette Association of America, and the Centers for Disease Control and Prevention. In addition, she received honoraria for her role on the Scientific Advisory Board for One-Mind (PsyberGuide), Koa Health, Inc., and Noom, Inc. Dr. Wilhelm has received research and salary support from Koa Health, Inc. Dr. Piacentini receives research support from NIMH, Patient-Centered Outcomes Research Institute (PCORI) and the TLC Foundation for BFRBs, advisor fees and equity from Lumate Health; publication royalties from Guilford Press, Oxford University Press, and Elsevier; and travel/speaking honoraria from the Tourette Association of America and International OCD Foundation.

Eating disorders (ED) are serious psychiatric illnesses, with no everyday support to intervene on the high rates of relapse. Understanding physiological indices that can be measured by wearable sensor technologies may provide new momentary interventions for individuals with ED. This systematic review, searching large databases, synthesises studies investigating peripheral physiological (PP) indices commonly included in wearable wristbands (heart rate [HR], heart rate variability [HRV], electrodermal activity [EDA], peripheral skin temperature [PST], and acceleration) in ED. Inclusion criteria included: (a) full peer-reviewed empirical articles in English; (b) human participants with active ED; and (c) containing one of five wearable physiological measures. Kmet risk of bias was assessed. Ninety-four studies were included (Anorexia nervosa [AN; N = 4418], bulimia nervosa [BN; N = 916], binge eating disorder [BED; N = 1604], other specified feeding and eating disorders [OSFED; N = 424], and transdiagnostic [N = 47]). Participants with AN displayed lower HR and EDA and higher HRV compared to healthy individuals. Those with BN showed higher HRV, and lower EDA and PST compared to healthy individuals. Other ED and Transdiagnostic samples showed mixed results. PP differences are indicated through various assessments in ED, which may suggest diagnostic associations, although more studies are needed to validate observed patterns. Results suggest important therapeutic potential for PP in ED, and larger studies including diverse participants and diagnostic groups are needed to fully uncover their role in ED., (© 2024 Eating Disorders Association and John Wiley & Sons Ltd.)

Daptomycin use for gram-positive infections has increased. This cost minimization analysis aimed to determine cost and/or time savings of daptomycin over vancomycin. The estimated hospital cost savings was US$166.41 per patient, and pharmacist time saved of almost 20 minutes per patient. Daptomycin has the potential to save both time and money., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Acceptance-enhanced behavior therapy for trichotillomania (AEBT-TTM) is effective in reducing trichotillomania (TTM) symptoms, but the durability of treatment effects remains in question. This study analyzed 6-month follow-up data from a large randomized clinical trial comparing AEBT-TTM to an active psychoeducation and supportive therapy control (PST). Adults with TTM (N=85; 92% women) received 10 sessions of AEBT-TTM or PST across 12 weeks. Independent evaluators assessed participants at baseline, post-treatment, and 6 months follow-up. For both AEBT-TTM and PST, self-reported and evaluator-rated TTM symptom severity decreased from baseline to follow-up. TTM symptoms did not worsen from post-treatment to follow-up. At follow-up, AEBT-TTM and PST did not differ in rates of treatment response, TTM diagnosis, or symptom severity. High baseline TTM symptom severity was a stronger predictor of high follow-up severity for PST than for AEBT-TTM, suggesting AEBT-TTM may be a better option for more severe TTM. Results support the efficacy of AEBT-TTM and show that treatment gains were maintained over time. Although AEBT-TTM yielded lower symptoms at post-treatment, 6-month follow-up outcomes suggest AEBT-TTM and PST may lead to similar symptom levels in the longer term. Future research should examine mechanisms that contribute to long-term gain maintenance., Competing Interests: Declaration of competing interest Ms. Barber, Dr. Ely, Dr. Saunders, Dr. Compton, Dr. Neal-Barnett, Dr. Franklin, Dr. Capriotti, and Dr. Conelea declare that they have no conflicts of interest. Dr. Woods and Dr. Twohig are the authors of the treatment manual tested in this study and receive book royalties from Oxford University Press., (Copyright © 2024. Published by Elsevier B.V.)

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium . The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies ( n =260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8-62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections., Competing Interests: Disclosure and potential conflicts of interest: KS has served as an advisory panel member for Cidara Therapeutics, Inc. and is currently serving as the American College of Clinical Pharmacy Secretary. All other authors have nothing to disclose. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2023/12/dic.2023-9-1-COI.pdf, (Copyright © 2024 Stover KR, Jordan TE, Wagner JL, Barber KE.)

Keeping abreast of the antimicrobial stewardship-related articles published each year is challenging. The Southeastern Research Group Endeavor identified antimicrobial stewardship-related, peer-reviewed literature that detailed an actionable intervention during 2022. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight actionable interventions used by antimicrobial stewardship programs to capture potentially effective strategies for local implementation., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. The views and opinions expressed in this paper represent those of the authors and do not necessarily reflect the position or policy of any previous, current, or potential future employer., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Invasive fungal infections are a strong contributor to healthcare costs, morbidity and mortality, especially amongst hospitalized patients. Historically, Candida was responsible for approximately 15% of all nosocomial bloodstream infections. In the past 10 years, the epidemiology of Candida species has altered, with increasing prevalence of resistant species. With rising fungal resistance, especially in Candida spp., the demand for novel antifungal therapies has exponentially increased over the last decade. Newer antifungal agents have become an attractive option for patients needing long-term therapy for infections or those requiring antifungal prophylaxis. Despite advances in coverage of non- Candida pathogens with newer agents, clinical scenarios involving multidrug-resistant fungal pathogens continue to arise in practice. Combination antifungal therapy can lead to a host of side-effects, some of which can be drug limiting. Additional antifungal therapies with enhanced fungal spectrum of activity and decreased rates of adverse effects are warranted. Fosmanogepix, ibrexafungerp, olorofim and rezafungin may help fill some of these gaps in the antifungal armamentarium. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections., Competing Interests: Disclosure and potential conflicts of interest: KS has served as an advisory panel member for Cidara Therapeutics, Inc. and is soon to serve as the American College of Clinical Pharmacy Secretary (beginning November 2023). All other authors have nothing to disclose. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2023/09/dic.2023-7-1-COI.pdf, (Copyright © 2023 Stover KR, Hawkins BK, Keck JM, Barber KE, Cretella DA.)

Objective: There is a strong association between sleep disturbance and negative affect. However, the day-to-day directional connections between sleep and negative affect remain unclear. We examined day-to-day relationships between sleep duration and negative affect in community adults., Methods: Participants were two subsamples of the Midlife in the United States Study (Sample 1: n = 2,022; Sample 2: n = 782). Daily negative affect and previous night sleep duration were assessed via end-of-day telephone interviews for eight days. Random intercept cross-lagged panel models tested sleep duration as a predictor of next-day negative affect and vice versa, controlling for age, gender, and race., Results: In both samples, shorter sleep duration predicted higher next-day negative affect, but daily negative affect was not a significant predictor of upcoming-night sleep duration. Follow-up analyses indicated that the relationship between sleep duration and negative affect was nonlinear. Sleeping fewer than 7.5 hours or more than 10.5 hours was associated with greater next-day negative affect than sleeping between 7.5 and 10.5 hours., Conclusions: In two large samples of community adults, sleep duration unidirectionally predicted higher next-day negative affect, and this relationship was nonlinear. Sleeping at least 7.5 hours and no more than 10.5 hours appeared to be an optimal range associated with lowest next-day negative affect., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: VRE infections increased in 2020. High-dose daptomycin (≥10 mg/kg) has shown mortality benefit over other regimens, though daptomycin resistance is increasing. Limited data exist on the practice patterns of ID pharmacists for VRE bloodstream infections (VRE BSIs)., Objectives: To describe practice patterns for VRE BSI in ID pharmacists., Methods: A 22-question REDCap survey was distributed to ID pharmacist members of the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (ID PRN) via e-mail listserv. The survey was distributed on 7 April 2022 and remained open for 4 weeks., Results: Sixty-eight pharmacists responded. All pharmacists completed additional training or certification in infectious diseases past their PharmD, and most (70.5%) had been practising for 10 years or less. Pharmacists at academic medical centres (80.0%) were more likely ( P  = 0.001) to have implemented the updated CLSI breakpoints than pharmacists at other types of institutions (55.2%). Daptomycin was the preferred drug for VRE BSI (92.6%), with 10 mg/kg (72.1%) being the preferred dose. Adjusted body weight was the most common weight (61.2%) used for obese patients. Fourteen days (76.1%) was the most common treatment duration for VRE BSI. Pharmacists defined persistent VRE BSI as 5 days (68.7%) after first blood culture., Conclusions: ID pharmacists overwhelmingly selected high-dose daptomycin for VRE BSI. There were variations in practice and response rate when selecting combination therapy, managing persistent bacteraemia, and treating patients with high daptomycin MICs or previous exposure to daptomycin., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Introduction: Staphylococcus aureus bacteremia (SAB) remains complex, in that optimal treatment for patients, including complicated or persistent infection, remains unclear. Two recent surveys have demonstrated practice variations in SAB among infectious diseases (ID) physicians. Objectives: The purpose of this survey was to examine practice variations in SAB among ID pharmacists. Methods: A thirty-five-question survey was electronically distributed to the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (IDPRN) in Fall 2019 to determine differences in SAB management. Data were analyzed utilizing Pearson's Chi-Square or Fisher's Exact Test. Results: A total of 106 ID pharmacists responded. Only 28% of pharmacists practiced at hospitals with mandatory ID consultation for SAB. A majority (75%) had rapid diagnostic technology (RDT) for identifying SABSI, but 32% of those facilities with RDT did not notify pharmacy with results. Anti-staphylococcal penicillins were preferred for MSSA blood stream infections (BSI) in patients with central nervous system infection and endocarditis, whereas cefazolin was favored for other MSSA BSI. For persistent MRSA BSI, 34% selected daptomycin alone while 38% elected to combine daptomycin and ceftaroline. Pharmacists at hospitals less than 500 beds were more likely to use daptomycin, while those at larger hospitals were more likely to use daptomycin and ceftaroline for persistent MRSA BSI ( P < .05). Conclusions: A survey of ID pharmacists showed variation in the management of SABs, as well as the definition and treatment of persistent SAB. Mandatory ID consultation and RDT use to improve SAB management have not been optimized.

Background: Generalized anxiety disorder (GAD) and major depressive disorder (MDD) often precede and predict one another. Heightened stress reactivity may be a mediation mechanism underlying the long-term connections between GAD and MDD. However, cross-sectional studies on this topic have hindered directional inferences., Method: The present study examined stress reactivity as a potential mediator of the sequential associations between GAD and MDD symptoms in a sample of 3,294 community-dwelling adults (M age = 45.6, range = 20-74). Participants completed three waves of measurement (T1, T2, and T3) spaced nine years apart. GAD and MDD symptom severity were assessed at T1, T2, and T3 (Composite International Diagnostic Interview-Short Form). Stress reactivity (Multidimensional Personality Questionnaire) was measured at T2., Results: Structural equation mediation modeling demonstrated that higher T1 GAD symptoms positively predicted more severe T3 MDD symptoms via T2 stress reactivity, controlling for T1 MDD (d = 0.45-0.50). However, T2 stress reactivity was not a significant mediator in the relationship between T1 MDD severity and T3 GAD symptoms after controlling for T1 GAD. Direct effects indicated that T1 GAD positively predicted T3 MDD 18 years later and vice versa (d = 1.29-1.65)., Limitations: Stress reactivity was assessed using a self-report measure, limiting conclusions to perceived (vs. physiologically indexed) stress reactivity., Conclusions: These findings indicate that stress reactivity may be one mechanism through which GAD leads to later MDD over prolonged durations. Overall, results suggest that targeting stress reactivity in treatments for GAD may reduce the risk of developing subsequent MDD., Competing Interests: Conflict of interest None of the authors, Kathryn E. Barber, Nur Hani Zainal, and Michelle Gayle Newman, have any conflicts to disclose. We do not have any financial relationships (regardless of amount of compensation) with any entity, grants, personal fees, non-financial support, or royalties, and neither have any patents, whether planned, pending or issued, broadly relevant to the work. We confirm that there no other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what we wrote in the submitted work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) co-occur at high rates, often preceding and predicting one another over long durations. Interpersonal theories propose that relationships with others may contribute to the longitudinal connections between MDD and GAD. Therefore, the current study examined the mediational effect of positive relations with others in these connections over 18 years., Methods: Community-dwelling adults (n = 3294) participated in data collection at three time-points (Time 1 [T1], Time 2 [T2], and Time 3 [T3]) spaced about nine years apart. MDD and GAD symptoms were assessed using the Composite International Diagnostic Interview-Short Form. Positive relations was measured with the Psychological Well-Being Scale-Positive Relations with Others subscale. Structural equation mediation modeling was used for data analysis., Results: Results indicated that lower T2 positive relations significantly mediated the relationship between higher T1 MDD severity predicting more severe T3 GAD symptoms (d = 0.375) and explained 10.7% of the variance. T2 positive relations also had a significant mediational effect in the association between T1 GAD symptoms positively predicting T3 MDD severity (d = 0.360), accounting for 12.2% of the variance of this connection. These mediational effects were significant after adjusting for age, gender, education, and T1 symptoms (d = 0.277-0.677)., Conclusions: Supporting interpersonal theories, lack of positive relations with others mediated the bidirectional connections between MDD and GAD symptoms across 18 years. Future research should continue to explore the influence of positive relations on mental health and whether treatments that enhance interpersonal functioning could improve treatment for depression and anxiety., Competing Interests: Conflict of interest None of the authors, Kathryn E. Barber, Nur Hani Zainal, and Michelle Gayle Newman, have any conflicts to disclose. We do not have any financial relationships (regardless of amount of compensation) with any entity, grants, personal fees, non-financial support, or royalties, and neither have any patents, whether planned, pending or issued, broadly relevant to the work. We confirm that there no relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what we wrote in the submitted work., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Delays in the treatment of proven invasive fungal disease have been shown to be harmful. However, empiric treatment for all patients at risk of infection has not demonstrated benefit. This study evaluates the effects of a micafungin stewardship initiative on the duration of therapy and clinical outcomes at the University of Mississippi Medical Center in Jackson, Mississippi. This single-center quasi-experiment evaluated patients who received micafungin. Adult inpatients who received at least one treatment dose of micafungin in the pre-intervention (1 October 2020 to 30 September 2021) or post-intervention (1 October 2021 to 30 April 2022) groups were included. Patients were placed on micafungin for prophylaxis and those who required definitive micafungin therapy were excluded. An algorithm was used to provide real-time recommendations in order to assess change in the treatment days of micafungin therapy. A total of 282 patients were included (141 pre-group versus 141 post-group). Over 80% of the patients included in the study were in an intensive care unit, and other baseline characteristics were similar. The median number of treatment days with micafungin was 4 [IQR 3-6] in the pre-group and 3 [IQR 2-6] in the post-group ( p = 0.005). Other endpoints, such as time to discontinuation or de-escalation, hospital mortality, and hospital length of stay, were not significantly different between the groups. An antifungal stewardship initiative can be an effective way to decrease unnecessary empiric antifungal therapy for patients who are at risk of invasive fugal disease., Competing Interests: The authors declare no conflict of interest.

The viridans group streptococci (VGS) are a large consortium of commensal streptococci that colonize the human body. Many species within this group are opportunistic pathogens causing bacteremia and infective endocarditis (IE), yet little is known about why some strains cause invasive disease. Identification of virulence determinants is complicated by the difficulty of distinguishing between the closely related species of this group. Here, we analyzed genomic data from VGS that were isolated from blood cultures in patients with invasive infections and oral swabs of healthy volunteers and then determined the best-performing methods for species identification. Using whole-genome sequence data, we characterized the population structure of a diverse sample of Streptococcus oralis isolates and found evidence of frequent recombination. We used multiple genome-wide association study tools to identify candidate determinants of invasiveness. These tools gave consistent results, leading to the discovery of a single synonymous single nucleotide polymorphism (SNP) that was significantly associated with invasiveness. This SNP was within a previously undescribed gene that was conserved across the majority of VGS species. Using the growth in the presence of human serum and a simulated infective endocarditis vegetation model, we were unable to identify a phenotype for the enriched allele in laboratory assays, suggesting a phenotype may be specific to natural infection. These data highlighted the power of analyzing natural populations for gaining insight into pathogenicity, particularly for organisms with complex population structures like the VGS. IMPORTANCE The viridians group streptococci (VGS) are a large collection of closely related commensal streptococci, with many being opportunistic pathogens causing invasive diseases, such as bacteremia and infective endocarditis. Little is known about virulence determinants in these species, and there is a distinct lack of genomic information available for the VGS. In this study, we collected VGS isolates from invasive infections and healthy volunteers and performed whole-genome sequencing for a suite of downstream analyses. We focused on a diverse sample of Streptococcus oralis genomes and identified high rates of recombination in the population as well as a single genome variant highly enriched in invasive isolates. The variant lies within a previously uncharacterized gene, nrdM , which shared homology with the anaerobic ribonucleoside triphosphate reductase, nrdD , and was highly conserved among VGS. This work increased our knowledge of VGS genomics and indicated that differences in virulence potential among S. oralis isolates were, at least in part, genetically determined.

Febrile neutropenia (FN) is associated with mortality rates as high as 40%, highlighting the importance of appropriate clinical management in this patient population. The morbidity and mortality of FN can be attributed largely to infectious processes, with specific concern for infections caused by pathogens with antimicrobial resistance. Expeditious identification of responsible pathogens and subsequent initiation of empiric antimicrobial therapy is imperative. There are four commonly used guidelines, which have variable recommendations for empiric therapy in these populations. All agree that changes could be made once patients are stable and/or with an absolute neutrophil count (ANC) over 500 cells/mcL. Diagnostic advances have the potential to improve knowledge of pathogens responsible for FN and decrease time to results. In addition, more recent data show that rapid de-escalation or discontinuation of empiric therapy, regardless of ANC, may reduce days of therapy, adverse effects, and cost, without affecting clinical outcomes. Antimicrobial and diagnostic stewardship should be performed to identify, utilize, and respond to appropriate rapid diagnostic tests that will aid in the definitive management of this population., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Fluoroquinolones are a widely used class of chemotherapeutics within veterinary medicine, prized for their broad-spectrum bactericidal activity. These drugs present a known risk of retinal phototoxicity in domestic cats ( Felis catus ); therefore, using lower doses and alternative antibiotic classes is encouraged in this species. This adverse drug effect of fluoroquinolones, and enrofloxacin specifically, has been determined to be species-specific in domestic felids. Four feline-specific missense variants in ABCG2 result in four amino acid changes (E159M, S279L, H283Q, and T644I) that are unique to the domestic cat compared with multiple other nonfeline mammalian species. These changes alter the ABCG2 protein involved with the cellular transmembrane transport of drugs, including fluoroquinolones, making the protein functionally defective in domestic cats. The predisposition to fluoroquinolone-mediated phototoxicity in nondomestic felids was explored in this study. At least eight nondomestic felids share the four ABCG2 missense variants with domestic cats, and eleven other felids shared at least three of the four domestic cat variants. Taken together, these results suggest the genetic potential for nondomestic felids to also experience fluoroquinolone-induced retinal phototoxicity; therefore, cautions similar to those for domestic cats should be followed for these drugs in the entire feline taxon.

The purpose of this study was to assess the clinical impact of the BioFire FilmArray Meningitis/Encephalitis (ME) panel on antimicrobial use and clinical outcomes. This retrospective, quasi-experiment evaluated adult and pediatric patients with suspected ME, evidenced by cerebrospinal fluid (CSF) culture. Hospital-acquired meningitis patients and patients who received antimicrobials >48 h prior to lumbar puncture were excluded. The primary endpoint was days of antimicrobial therapy pre- and post-implementation of the ME panel. Secondary endpoints included total length of stay, 30-day readmission, and individual days of antimicrobial therapy. Two hundred and sixty-four total adult and pediatric patients were included. Antimicrobial days of therapy had a median of 3 days (IQR 0−5) in the pre vs. post group with a median of 2 days (2−5) (p = 0.099). Days of therapy for acyclovir were significantly decreased in the post group (median 2 days [IQR 1−3] vs. 3 days [IQR 2.5−4.5], p = 0.0002). There were no significant differences in the secondary endpoints. Overall, implementation of the ME panel impacted the duration of antimicrobials, particularly acyclovir; however, opportunities for further education regarding antimicrobial de-escalation and utilization of the panel were identified. Antimicrobial stewardship program intervention is critical to maximize benefit of this rapid diagnostic test.

The scope of antimicrobial stewardship programs has expanded beyond the acute hospital setting. The need to optimize antimicrobial use in emergency departments, urgent, primary, and specialty care clinics, nursing homes, and long-term care facilities prompted the development of core elements of stewardship programs in these settings. Identifying the most innovative and well-designed stewardship literature in these novel stewardship areas can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network evaluated antimicrobial stewardship-related, peer-reviewed literature published in 2021 that detailed actionable interventions specific to the nonhospital setting. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for expansion of antimicrobial stewardship programs beyond the acute hospital setting., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Pharmacy residency recruitment and interviews have been significantly impacted by the COVID-19 pandemic. Many traditional recruitment events and interviews were transitioned from in-person to virtual, and new approaches to recruitment, such as virtual open houses, were developed. There are limited data on how these changes impacted pharmacy residency applicants and programs, and the future of virtual events is currently unknown. We highlight recommendations for virtual recruitment and interviews and provide suggestions for residency programs and national organizations to improve virtual processes in the future., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Introduction: Due to the COVID-19 pandemic, most pharmacy residency programs changed to an all-virtual format for recruitment and interviews for the 2020-2021 application cycle. There are no data evaluating the experiences and perceptions of these changes from the perspective of pharmacy residency programs and applicants., Methods: An electronic cross-sectional survey was distributed via email to post-graduate year 1 (PGY1) and post-graduate year 2 (PGY2) pharmacy residency programs and applicants across the Southeastern United States. Results have been reported according to the Checklist for Reporting of Survey Studies (CROSS) guidelines (Enhancing the QUAlity and Transparency Of health Research [EQUATOR] Network)., Results: 142 residency applicants and 104 residency programs responded to the survey. Most respondents participated in virtual recruitment and interviews. In 2020-2021, less residency programs participated in local/regional showcases and personal placement services, but social media engagement increased. Of the applicants who responded, over half felt the need to apply to more programs during this application cycle, and a corresponding increase in applications were seen by residency programs. Residency interviews appeared shorter than previous years, and less programs offered an informal time to get to know the applicants. Overall, applicants and residency programs preferred on-site interviews, but both parties reported feeling confident creating rank lists after virtual interviews., Conclusion: These results highlight the impact of COVID-19 on residency recruitment and the interview process. Residency programs should implement feedback for improving the virtual experience, as able. The ongoing pandemic may affect the 2022-2023 application cycle, and pharmacy leadership organizations should consider developing guidance for applicants and residency programs on navigating another year of virtual events.This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Diabetes mellitus continues to be an increasingly common comorbidity. Diabetic foot infections are one of the most common causes of hospitalization in this population, and account for a significant portion of increased hospitalization and healthcare expenditure. Complications, such as osteomyelitis, can necessitate the use of multiple, prolonged antibiotic courses. These courses often consist of broad-spectrum, empiric therapy determined by organisms considered to be commonly associated with these types of infections. Extended periods of broad-spectrum antibiotic regimens can contribute to antibiotic resistance and ultimately limit future treatment options. Furthermore, patient specific risk factors can impact the microbiologic diversity found in these infections. As a result, it is difficult to determine if a single empiric regimen is appropriate for all instances of diabetic foot infections., Objectives and Methods: This review analyzes global literature relating to the culture methods, incidence, risk factors, resistance patterns, and geographic distribution of the microorganisms isolated from diabetic foot infections using the PRISMA statement for systematic review and meta-analysis reporting., Results: Staphylococcus aureus remains a significant pathogen, with a growing incidence of Pseudomonas aeruginosa and MDR gram-negative bacilli., Conclusions: Though some individualized risk factors can be useful, local epidemiology and resistance patterns remain essential for antibiotic treatment considerations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Burn patients have numerous risk factors for multidrug-resistant organisms (MDROs) and altered pharmacokinetics, which both independently increase the risk of treatment failure. Data on appropriate antimicrobial dosing are limited in this population and therapeutic drug monitoring (TDM) for beta-lactams is impractical at most facilities. Technology is available that can detect genetic markers of resistance, but they are not all encompassing, and often require specialized facilities that can detect less common genetic markers. Newer antimicrobials can help combat MDROs, but additional resistance patterns may evolve during treatment. Considering drug shortages and antimicrobial formularies, clinicians must remain vigilant when treating infections. This case report describes the development of resistance to ceftazidime-avibactam in a burn patient. The patient was a 54-year-old burn victim with a 58% total body surface area (TBSA) thermal burn who underwent multiple courses of antibiotics for various Pseudomonal infections. The initial Pseudomonal wound infection was sensitive to cefepime, aminoglycosides, and meropenem. A subsequent resistant pseudomonal pneumonia was treated with ceftazidime-avibactam 2.5 g every 6 hours due to the elevated MIC to cefepime (16 mcg/mL) and meropenem (>8 mcg/mL). Although the patient improved over 7 days, the patient again spiked fevers and had increased white blood counts (WBC). Repeat blood cultures demonstrated a multidrug-resistant (MDR) Pseudomonas with a minimum inhibitory concentration (MIC) to ceftazidime-avibactam of 16 mcg/mL, which is above the Clinical and Laboratory Standards Institute (CLSI) breakpoint of 8 mcg/mL. At first, resistance was thought to have occurred due to inadequate dosing, but genetic work demonstrated multiple genes encoding beta-lactamases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Limited data are available regarding optimal antimicrobial therapy for Staphylococcus aureus bacteremia (SAB) in pediatric patients. The purpose of this study was to assess clinical characteristics and outcomes associated with intravenous (IV) versus oral step-down treatment of pediatric SAB. This study evaluated patients aged 3 months to 18 years that received at least 72 h of inpatient treatment for SAB. The primary endpoint was 30-day readmission. Secondary endpoints included hospital length of stay and inpatient mortality. One hundred and one patients were included in this study. The median age was 7.9 years. Patients who underwent oral step-down were less likely to be immunocompromised and more likely to have community-acquired SAB from osteomyelitis or skin and soft tissue infection (SSTI). More patients in the IV therapy group had a 30-day readmission (10 (25.6%) vs. 3 (5.3%), p = 0.006). Mortality was low (5 (5%)) and not statistically different between groups. Length of stay was greater in patients receiving IV therapy only (11 vs. 7 days, p = 0.001). In this study, over half of the patients received oral step-down therapy and 30-day readmission was low for this group. Oral therapy appears to be safe and effective for patients with SAB from osteomyelitis or SSTIs.

Vancomycin-resistant enterococci (VRE) account for a large proportion of hospital-acquired infections. Determining optimal treatment of VRE urinary tract infections (UTIs) is challenging. The purpose of this study was to determine if a difference in efficacy or safety exists between linezolid and non-linezolid treatments for VRE UTIs. This retrospective cohort evaluated patients admitted between 1 June 2012-30 November 2017 who were treated for VRE UTI. Patients must have had at least one sign, symptom, or laboratory confirmation of UTI to be included. The primary endpoint of this study was difference in clinical cure between linezolid and non-linezolid treatment options. Secondary endpoints included 30-day recurrence, 30-day infection-related readmission, inpatient mortality, infection-related hospital length of stay (LOS), and time to appropriate therapy. A total of 45 patients (33 linezolid and 12 non-linezolid) were included. Clinical cure occurred in 71.4% linezolid and 58.3% non-linezolid ( p = 0.476). No patients had a 30-day infection-related readmission or 30-day recurrence. Of the 45 patients, 6 (13.3%) patients died during admission, and 5 of those deaths were in the linezolid group ( p = 1.000). No significant difference was found for clinical cure between linezolid and non-linezolid treatment options for VRE UTIs.

Introduction: The goal of this initiative was to provide a meaningful introductory pharmacy practice experience (IPPE) to third-year students when opportunities for direct patient interaction are limited., Methods: A single, pretest/posttest quasi-experiment was used to evaluate the impact of a structured pharmacy-based education series (intervention 1) and an interprofessional simulation (intervention 2) during combined internal medicine (IM) and infectious diseases (ID) IPPEs. Intervention 1 consisted of five, three-part pharmacy-based educational sessions, while intervention 2 consisted of an interprofessional simulated rounding experience. Pre- and post-rotation examinations were given to evaluate the impact of the interventions on student knowledge. Confidence was measured in 11 or 12-question pre- and post-surveys using a four-point Likert scale: strongly disagree, disagree, agree, strongly agree., Results: Thirty-six students (30 in intervention 1 and six in intervention 2) were included. In intervention 1, there was a 19% improvement in IM knowledge (45% vs. 64%) and 10% improvement in ID knowledge (40% vs. 50%). In intervention 2, there was a significant improvement in both IM (30% vs. 40%) and ID (50% vs. 65%) and knowledge questions (10% and 15% improvements, respectively). In both interventions, most students reported increased confidence., Conclusions: Knowledge and confidence improved in both intervention groups, demonstrating that there are ways to enhance IPPEs without direct patient interaction., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antimicrobial resistance remains a high global concern, as it is associated with prolonged hospitalizations, increased morbidity and mortality, and escalating healthcare-related costs. Rapid diagnostic technology (RDT) has become the cornerstone in achieving prompt blood culture results providing a quicker initiation of optimal therapy, decreased mortality, and decreased spread of resistance. To maximize the benefits of RDTs, antimicrobial stewardship programs must implement a diagnostic stewardship (DS) subgroup to optimize communication, education, and interpretation of RDT results within the healthcare system. The DS subgroup is necessary to evaluate the technologies available, better integrate the selected technologies into the healthcare system, and develop innovative and appropriate use to improve patient outcomes., (© 2021 Pharmacotherapy Publications, Inc.)

Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium , 9.5% of E. faecalis ). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis ., Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis . Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm 2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm 2 reduction., Results: Daptomycin bMICs were 2-8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981., Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response.

Rationale: Major depressive episodes are severe mood episodes which occur both in major depressive disorder and bipolar I and II disorder. Major depressive episodes are characterized by debilitating symptoms that often persist and interfere with typical daily functioning. Various treatments exist for major depressive episodes; however, most primary pharmacologic treatments may take weeks to months to provide relief from depressive symptoms. Ketamine is a demonstrated treatment for major depressive episodes, as relief from depressive symptoms can occur rapidly following treatment., Objectives: Prior meta-analyses have been conducted to analyze the effectiveness of ketamine for the treatment of major depressive episodes, but at the time of this writing, no meta-analysis had been conducted to observe ketamine treatment efficacy beyond 2 weeks., Methods: The present meta-analysis evaluated the efficacy of ketamine for the treatment of major depressive episodes; observations of depressive episode severity were analyzed at 2, 4, and 6-weeks post-treatment., Results: The present meta-analysis observed large effects at 2 weeks (g = -1.28), 4 weeks, (g = -1.28), and 6 weeks (g = -1.36) post-treatment., Conclusions: The results from the present meta-analysis indicate that ketamine can be an effective pharmacologic intervention for major depressive episodes, with treatment effects lasting up to 6 weeks post-ketamine administration, which has many positive implications for treatment.

Background: Epidemiology and risk factors for bacteremia in pediatric and adolescent patients have not been fully elucidated., Objective: The purpose of this study was to identify primary causative agents of bacteremia in pediatric and adolescent patients and associated risk factors. We hypothesized that these would be different than those seen in adults., Patients and Methods: This retrospective cohort, epidemiologic evaluation included patients admitted to a tertiary referral center from January 01, 2013, to December 31, 2015. Patients <18 years old with a confirmed positive blood culture were included; the first positive culture per organism per patient was analyzed. The primary outcome was to determine the most frequent causative organisms of bacteremia; the secondary outcome was an evaluation of risk factors for acquiring staphylococcal bacteremia., Results: A total of 913 isolates were evaluated, including 92 unique organisms. The most frequently identified were Staphylococcus epidermidis (238/913, 26.1%), followed by Staphylococcus aureus (136/913, 14.9%). Methicillin resistance was observed in 60.3% of S aureus . Two hundred thirty-six patients were included in the risk factor analysis. Prematurity, previous antibiotics, and intubation/ventilation were more likely associated with S epidermidis ( P < .001, P < .001, and P = .032, respectively). Patients with a recent or previous hospitalization and those with dermatitis/eczema were statistically more likely to grow S aureus ( P < .001, P = .029, respectively)., Conclusions: Although epidemiology of organisms associated with pediatric and adolescent bacteremia was similar to adults, risk factors were different than seen in that population. Further understanding of these risk factors may be helpful in developing preemptive infection control strategies in patients at risk.

Objectives: The purpose of this study was to identify risk factors for initial complicated Clostridioides difficile infection (CDI)., Methods: This retrospective cross-sectional study included adult patients with initial episodes of CDI who received ≥72 h of CDI-active antimicrobials. Patients were categorised into one of two groups: complicated CDI or uncomplicated CDI. A total of 513 patients were screened for inclusion, with complicated CDI patients exhibiting abnormal abdominal CT findings or experiencing death within 30 days post-CDI diagnosis., Results: A total of 203 patients met the inclusion criteria, comprising 143 (70.4%) with uncomplicated CDI and 60 (29.6%) with complicated CDI. Complicated CDI patients were more likely to have been exposed to fluoroquinolones (48.3% vs. 30.8%; P = 0.017) and to carbapenems for a longer duration prior to CDI diagnosis (7 days vs. 3 days; P = 0.019). They were more likely to receive oral vancomycin (65.0% vs. 46.9%; P = 0.018) and rectal vancomycin (5.0% vs. 0%; P = 0.025) compared with uncomplicated CDI patients. Logistic regression identified previous fluoroquinolone exposure increased the risk of complicated CDI, while previous abdominal surgery decreased the risk., Conclusion: Almost one-third of included patients experienced a complicated episode of CDI as their initial episode. Further research is warranted to elucidate the extent of influence of prior antibiotics on the development of complicated CDI., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Altered pharmacokinetics in obese patients raise concerns over worse clinical outcomes. This study assessed whether obese patients receiving a β-lactam have worse clinical outcomes compared to nonobese patients and to identify if therapeutic drug monitoring may be beneficial., Methods: This multicenter, retrospective cohort included hospitalized adults admitted from July 2015 to July 2017 treated with a β-lactam as definitive monotherapy against a gram-negative bacilli for ≥72 hours. Patients were excluded if there was lack of source control or if polymicrobial infections required >1 antibiotic for definitive therapy. Patients were classified based on body mass index (BMI): nonobese (BMI ≤29.9 kg/m 2 ) and obese (BMI ≥30.0 kg/m 2 ). The primary outcome was clinical treatment failure, and secondary outcomes were hospital length of stay, inpatient all-cause mortality, and 30-day all-cause readmission., Results: There were 257 (43.6%) obese patients and 332 (56.4%) nonobese patients included. The most common infections were urinary (50.9%) and respiratory (31.4%). Definitive treatment was driven by third-generation cephalosporins (46.9%) and cefepime (44.7%). Treatment failure occurred in 131 (51%) obese patients and 109 (32.8%) nonobese patients ( P  < .001). Obesity and respiratory source were independently associated with increased likelihood of treatment failure. Obese patients were hospitalized longer than nonobese patients ( P  = .002), but no differences were found for all-cause mortality ( P  = .117) or infection-related readmission (0 = 0.112)., Conclusions: Obese patients treated with β-lactams have higher rates of treatment failure and longer hospitalization periods than nonobese patients. Future studies are needed to assess the impact of therapeutic drug monitoring and specific dosing recommendations for targeted infection types., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Significant mortality is associated with delays in appropriate antibiotic therapy in Pseudomonas aeruginosa infections. The impact of empiric dosing on clinical outcomes has been largely unreported., Methods: This retrospective cohort compared treatment failure in patients receiving guideline-concordant or guideline-discordant empiric therapy with cefepime, meropenem, or piperacillin/tazobactam. Patients with culture-positive P. aeruginosa between 1 July 2013 and 31 July 2019 were eligible for inclusion. Patients with cystic fibrosis, polymicrobial infection, and urinary or pulmonary colonization were excluded. The composite primary outcome was treatment failure, defined as (1) therapy modification due to resistance/perceived treatment failure, (2) increased/unchanged qSOFA, or (3) persistent fever 48 h after initiating appropriate therapy. Secondary outcomes included rate of infectious diseases consultation, all-cause inpatient mortality, mechanical ventilation requirement, and infection-related intensive care unit and hospital lengths of stay., Results: In total, 198 patients were included: 90 guideline-concordant and 108 guideline-discordant. Baseline characteristics were balanced. Treatment failure was more common in the guideline-discordant than the guideline-concordant group (62% versus 48%; p  = 0.04). This remained significant when adjusting for supratherapeutic dosing ( p  = 0.02). Infectious diseases consultation was higher in the guideline-discordant group (46% versus 29%, p  = 0.01), while intensive care unit length of stay was longer in the guideline-concordant group (4.5 versus 3 days, p  = 0.03). Additional secondary outcomes were similar., Conclusion: Treatment failure was significantly higher in patients receiving guideline-discordant empiric antipseudomonal dosing. Guideline-directed dosing, disease states, and patient-specific factors should be assessed when considering empiric antipseudomonal dosing., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Introduction. Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat in the USA and are associated with adverse clinical and economic outcomes. Several studies have evaluated risk factors for acquiring CRE versus carbapenem-susceptible Enterobacteriaceae , identifying antibiotic use and length of hospital stay as major players. However, no studies have compared risk factors for CRE colonization versus infection. Hypothesis/Gap Statement. Patients with CRE infection will have different risk factors and worse clinical outcomes than patients with CRE colonization. Aim. To assess clinical outcomes in patients with CRE infection versus CRE colonization. Methodology. A retrospective cohort of adult patients admitted between 1 June 2013 and 31 July 2018 with the first positive CRE culture from any source was performed. Patients were divided into two groups: CRE infection versus CRE colonization. Data collected included demographics, comorbidities, past antimicrobial usage and clinical outcomes (length of stay, in-hospital mortality). The primary outcome was infection-related length of stay. Data analysis was performed utilizing SPSS with a two-sided P value of less than 0.05 considered statistically significant. Results. A total of 56 patients were included (32 with infection; 24 with colonization). Baseline characteristics were similar between both groups. Infected patients were more likely to have higher actual body weight compared to colonized patients ( P =0.03). CRE-infected patients had a longer infection-related hospital stay [12 days (5-20) and 7.5 days (1-13), respectively; P =0.08], but in-hospital mortality was similar between infected and colonized patients (37.5 and 29.2 %, respectively; P =0.30). Patients with infection were more likely to have previous exposure to levofloxacin ( P =0.02) and trimethoprim/sulfamethoxazole ( P =0.03) for a median of 9 days compared to those with colonization. The most common source of CRE in infected patients was the blood compared to respiratory sources in colonized patients. Conclusion. CRE infection as opposed to colonization was more common in patients with previous exposure to levofloxacin and trimethoprim/sulfamethoxazole and those with higher actual body weight.

Background: As the prevalence of obesity climbs, dosing of antimicrobials, particularly cephalosporins, is becoming a greater challenge for clinicians. Data are lacking for appropriate dosing of cefepime, an anti-pseudomonal cephalosporin that is widely used as an empiric anti-pseudomonal agent. Objective: The purpose of this study was to determine the rate of clinical treatment failure in obese patients compared with nonobese patients receiving cefepime as definitive monotherapy. Methods: Adult inpatients treated with cefepime monotherapy for ≥72 hours were included. Patients were excluded if they (1) were not able to achieve culture clearance within 72 hours and (2) had polymicrobial infections requiring more than one antibiotic for definitive therapy. Results: Fifty-eight obese patients and 56 nonobese patients were included. Pseudomonas aeruginosa , Escherichia coli , and Enterobacter spp were the most prevalent organisms isolated. Most organisms had a minimum inhibitory concentration of ≤1 µg/mL to cefepime with no differences in minimum inhibitory concentration distributions between groups. Definitively, 60% of patients received cefepime 1 g, while almost 40% received cefepime 2 g. Clinical failure occurred in 52% of patients (67% obese vs 36% nonobese; P = .001), with study group (odds ratio = 1.057, 95% confidence interval = 1.008-1.109) and respiratory source (odds ratio = 3.251, 95% confidence interval = 1.378-7.667) being independent predictors of failure. There were no differences in hospital length of stay, all-cause mortality, or 30-day readmissions. Conclusions: Obese patients treated with cefepime are more likely to experience treatment failure than nonobese patients. Larger trials examining the reasons for clinical failure in obese patients treated with cefepime are needed to confirm the findings from this preliminary work., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ARM, JTL, and KRS declare that they have no conflict of interest. JLW has received research grants from MAD-ID unrelated to this work. KEB serves as a speaker for Paratek Pharmaceuticals., (© The Author(s) 2020.)

Background : Ceftriaxone has standard, set dosing regimens that may not achieve adequate serum concentrations in obese patients compared to non-obese patients. The purpose of this study was to evaluate the effect of obesity on ceftriaxone efficacy when used as definitive monotherapy to treat infections. Methods : This retrospective cohort included adult inpatients treated with ceftriaxone monotherapy for ≥72 h between July 01, 2015-July 31, 2017. Patients were excluded if their infection lacked source control within 72 h or if they had polymicrobial infections requiring more than one antibiotic for definitive therapy. The primary outcome was the rate of clinical failure between obese versus non-obese patients, defined as a composite of (1) change in definitive therapy > 72 h due to clinical worsening; (2) residual leukocytosis (white blood cell count (WBC) > 10 × 10 9 /L) > 72 h after treatment initiation; (3) presence of a fever (single temperature > 100.9 °F) > 72 h after treatment initiation; or (4) readmission within 30 days due to re-infection with the same organism. Results : A total of 101 patients were included in the study: 39 obese and 62 non-obese. The most common indications for ceftriaxone were urinary tract (52.5%), respiratory tract (24.8%), and bloodstream (24.8%) infections. The most commonly isolated organisms were Escherichia coli (48.5%) and Klebsiella species (15.8%). Most patients received 1g every 24 h. Clinical failure was observed in 61.5% of obese patients versus 40.3% of non-obese patients ( p = 0.038). Conclusion : Obese patients treated with ceftriaxone were more likely to experience clinical failure when compared to non-obese patients. Further analyses are warranted to determine if weight-based dosing is required in obese patients treated with ceftriaxone.

Objectives: Chromosomally mediated AmpC-producing Enterobacteriaceae (CAE) display high susceptibility to fluoroquinolones; minimal clinical data exist supporting comparative clinical outcomes. The objective of this study was to compare treatment outcomes between fluoroquinolone and nonfluoroquinolone definitive therapy of bloodstream infections caused by CAE., Methods: This retrospective cohort assessed adult patients with positive blood cultures for CAE that received inpatient treatment for 48 hours. The primary outcome was difference in clinical failure between patients who received fluoroquinolone (FQ) versus non-FQ treatment. Secondary endpoints included microbiological cure, infection-related length of stay, 90-day readmission, and all-cause inpatient mortality., Results: 56 patients were included in the study (31 (55%) received a FQ as definitive therapy; 25 (45%) received non-FQ). All non-FQ patients received a beta-lactam (BL). Clinical failure occurred in 10 (18%) patients, with 4 (13%) in the FQ group and 6 (24%) in the BL group ( p = 0.315). Microbiological cure occurred in 55 (98%) patients. Median infection-related length of stay was 10 (6-20) days, with a significantly longer stay occurring in the BL group ( p = 0.002). There was no statistical difference in 90-day readmissions between groups (7% FQ vs. 17% BL; p = 0.387); one patient expired., Conclusion: These results suggest that fluoroquinolones do not adversely impact clinical outcomes in patients with CAE. When alternatives to beta-lactam therapy are needed, fluoroquinolones may provide an effective option., Competing Interests: The authors declare no conflicts of interest.

Background: Candida species are responsible for 15% of bloodstream infections, leading to prolonged hospitalizations and increased mortality. With the rise in obesity, antifungal dosing is unclear. The purpose of this study was to determine differences in clinical outcomes between obese versus non-obese patients with Candida bloodstream infections., Methods: This retrospective cohort included adult patient's first episode of Candida bloodstream infection treated with ≥ 48 h of antifungal therapy between 1 June 2013 and 31 August 2019. Patients were excluded for: dual systemic antifungal therapy, polymicrobial infections, or chronic candidiasis. The primary outcome was infection-related length of stay. Secondary outcomes included: time to candidemia resolution, 30-day readmission rates, and in-hospital mortality., Results: Eighty patients were included (28 obese; 52 non-obese). Most were male (55%); median age was 54 years. Median BMI and weight were 36.3 kg/m 2 and 103 kg versus 20.4 kg/m 2 and 61 kg, respectively (p < 0.01). Baseline characteristics were comparable. C. albicans was isolated in 37.5% of cultures and C. glabrata in 30%. Micafungin was utilized empirically in 72.5% of patients; obese patients received definitive micafungin more frequently (57.1% vs. 21.2%; p < 0.01) and were treated longer (13 versus 10 days; p = 0.04). Infection-related length of stay was 19 days in the obese patients and 13 days in the non-obese patients (p = 0.05). Non-obese patients had a shorter duration of candidemia (5 versus 6 days; p = 0.02). In-hospital mortality was numerically higher in obese patients (21.4% versus 13.5%; p = 0.36). There were no differences in 30-day readmissions between groups., Conclusions: Worse clinical outcomes were observed for obese versus non-obese patients. Further clinical research is warranted.

Background: Inpatient HIV-related medication errors occur in up to 86% of patients. Objective: To evaluate the number of antiretroviral therapy (ART)- and opportunistic infection (OI)-related medication errors following the implementation of pharmacist-directed interventions. Methods: This quasi-experiment assessed adult patients with HIV who received ART, OI prophylaxis, or both from December 1, 2014, to February 28, 2017 (pre-intervention) or December 1, 2017, to February 28, 2018 (post-intervention). Pre-intervention patients were assessed retrospectively; verbal and written education were provided (intervention); prospective audit and feedback was conducted for post-intervention patients. The primary outcome was rate of ART errors between groups. Secondary outcomes included rate of OI errors, time to resolution of ART and OI errors, types of errors, and rate of recommendation acceptance. Results: Sixty-seven patients were included in each group. ART errors occurred in 44.8% and 32.8% ( P = .156), respectively. OI prophylaxis errors occurred in 11.9% versus 9% ( P = .572), respectively. Medication omission decreased significantly in the post-intervention group (31.3% vs 11.9%; P = .006). Pharmacist-based interventions increased in the post-intervention group (6.3% vs 52.9%; P = .001). No statistical difference was found in time to error resolution (72 vs 48 hours; P = .123), but errors resolved during admission significantly increased (50% vs 86.8%; P < .001). No difference was found in rate of intervention acceptance (100% vs 97%). Conclusion and Relevance: ART and OI prophylaxis errors resolved a day faster in the pharmacist-led, post-intervention period, and there was a trend toward error reduction. Future interventions should target prescribing errors on admission using follow-up education and evaluation of medication reconciliation practices in HIV-infected patients., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Medicating animals poses unique challenges that are often best dealt with via compounding. Pharmacists receive compounding training while in pharmacy school, but this training is not veterinary specific. Pharmacists are expected to have enough knowledge to properly verify prescriptions that are received at their practice site while keeping with the most up-to-date guidelines related to animal and human health. Whether pharmacists have the proper training to verify and/or compound veterinary specific medications is unknown. A self-administered survey was distributed electronically to 4,550 email addresses on record with the American College of Veterinary Pharmacists, the International Academy of Compounding Pharmacists, and the Society of Veterinary Hospital Pharmacists. The survey asked questions about regulations and standards associated with the use of prescription or compounded medications. Of the 4,550 distributed surveys, 153 were received, for a 3.4% response rate. Of the responses received, only 131 were used in the final data analysis. Most respondents correctly answered the assessment question regarding the ability to compound backordered, commercially available products. A majority of respondents incorrectly answered the question regarding the proper flavoring for a medication for a ferret. Those with more training perceived themselves to have a higher level of skill (r = 0.41, P<0.001). Similarly, those with formal veterinary training had better scores on Question 4 of the assessment questions, which requires knowledge of feline toxicities (P=0.029). The most common compounded medications dispensed in practice by pharmacists are methimazole, metronidazole, and gabapentin. Pharmacists mostly recognized that compounding backordered, commercially available products is permitted. Formal training improves familiarity with current compounding rules, regulations, and best practices. Formal training in veterinary pharmacy and veterinary compounding should be promoted and encouraged. Efforts should also be made at improving pharmacists' understanding of both veterinary and compounding laws and regulations., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)