AUCs and 123s: a critical appraisal of vancomycin therapeutic drug monitoring in paediatrics.

The revised vancomycin guidelines recommend implementing AUC24-based therapeutic drug monitoring (TDM) using Bayesian methods in both adults and paediatrics. The motivation for this change was accumulating evidence showing aggressive dosing to achieve high troughs, as recommended in the first guidelines for adults and extrapolated to paediatrics, is associated with increased nephrotoxicity without improving clinical outcomes. AUC24-based TDM requires substantial resources that may need to be diverted from other valuable interventions. It can therefore be justified only after certain assumptions are shown to be true: (i) there is a clear relationship between vancomycin efficacy and/or toxicity and the proposed therapeutic range; and (ii) maintaining exposure within the target range with AUC24-based TDM improves clinical outcomes and/or decreases toxicity. In this review, we critically appraise the scientific basis for these assumptions. We find studies evaluating the relationship between vancomycin AUC24/MIC and efficacy in adults and children do not offer strong support for the recommended lower limit of the proposed therapeutic range (i.e. AUC24/MIC ≥400). Nephrotoxicity in children increases in a stepwise manner along the vancomycin exposure continuum but it is unclear if one parameter (AUC24 versus trough) is a superior predictor. Overall, evidence in children suggests good-to-excellent correlation between AUC24 and trough. Most importantly, there is no convincing evidence that the method of vancomycin TDM has a causal role in improving efficacy or reducing toxicity. These findings question the need to transition to resource-intensive AUC24-based TDM over retaining trough-based TDM with lower targets to minimize nephrotoxicity in paediatrics.

Long-Term Effects of Phased Implementation of Antimicrobial Stewardship in Academic ICUs: 2007-2015.

OBJECTIVES: Antimicrobial stewardship is advocated to reduce antimicrobial resistance in ICUs by reducing unnecessary antimicrobial consumption. Evidence has been limited to short, single-center studies. We evaluated whether antimicrobial stewardship in ICUs could reduce antimicrobial consumption and costs. DESIGN: We conducted a phased, multisite cohort study of a quality improvement initiative. SETTING: Antimicrobial stewardship was implemented in four academic ICUs in Toronto, Canada beginning in February 2009 and ending in July 2012. PATIENTS: All patients admitted to each ICU from January 1, 2007, to December 31, 2015, were included. INTERVENTIONS: Antimicrobial stewardship was delivered using in-person coaching by pharmacists and physicians three to five times weekly, and supplemented with unit-based performance reports. Total monthly antimicrobial consumption (measured by defined daily doses/100 patient-days) and costs (Canadian dollars/100 patient-days) before and after antimicrobial stewardship implementation were measured. MEASUREMENTS AND MAIN RESULTS: A total of 239,123 patient-days (57,195 patients) were analyzed, with 148,832 patient-days following introduction of antimicrobial stewardship. Antibacterial use decreased from 120.90 to 110.50 defined daily dose/100 patient-days following introduction of antimicrobial stewardship (adjusted intervention effect -12.12 defined daily dose/100 patient-days; 95% CI, -16.75 to -7.49; p < 0.001) and total antifungal use decreased from 30.53 to 27.37 defined daily doses/100 patient-days (adjusted intervention effect -3.16 defined daily dose/100 patient-days; 95% CI, -8.33 to 0.04; p = 0.05). Monthly antimicrobial costs decreased from $3195.56 to $1998.59 (adjusted intervention effect -$642.35; 95% CI, -$905.85 to -$378.84; p < 0.001) and total antifungal costs were unchanged from $1771.86 to $2027.54 (adjusted intervention effect -$355.27; 95% CI, -$837.88 to $127.33; p = 0.15). Mortality remained unchanged, with no consistent effects on antimicrobial resistance and candidemia. CONCLUSIONS: Antimicrobial stewardship in ICUs with coaching plus audit and feedback is associated with sustained improvements in antimicrobial consumption and cost. ICUs with high antimicrobial consumption or expenditure should consider implementing antimicrobial stewardship programs.

Use of a structured panel process to define antimicrobial prescribing appropriateness in critical care.

BACKGROUND: Antimicrobial prescribing is frequently reported as appropriate or inappropriate, particularly in the ICU. However, the definitions used are non-standardized and lack validity and reliability. OBJECTIVES: To develop standardized definitions of appropriateness for antimicrobial prescribing in the critical care setting. METHODS: We used consensus-based modified Delphi and RAND appropriateness methodology to develop criteria to define appropriateness of antimicrobial prescribing. A multiphased approach with an online questionnaire followed by a facilitated in-person meeting was utilized and included clinicians from a variety of practice areas (e.g. surgeons, infectious diseases specialists, intensivists, transplant specialists and pharmacists). RESULTS: There were a total of 23 criteria agreed upon to define the following categories of antimicrobial prescribing: appropriate; effective but unnecessary; inappropriate; and under-treatment. CONCLUSIONS: These standardized criteria for appropriateness may be generalizable to other patient populations and utilized with other tools to adjudicate prescribing practices.

A National Survey of Critical Care Physicians' Knowledge, Attitudes, and Perceptions of Antimicrobial Stewardship Programs.

OBJECTIVE: Antimicrobial stewardship is a process designed to optimize antimicrobial therapy by ensuring patients get the right antimicrobials at the right dose and at the right time. Antimicrobial stewardship programs (ASPs) are increasingly being implemented in health care institutions, are required by some accreditation bodies, and have the potential for maximum impact in intensive care units (ICUs). We administered a survey to critical care physicians across Canada to better understand their knowledge, attitudes, and perceptions on the utility of ASPs in improving patient care. DESIGN, SETTING, AND PATIENTS: We distributed a Web-based survey to physicians who attend in Canadian ICUs. Respondents were identified through the membership lists of multiple critical care organizations. Content validity, utility, clarity, and test-retest reliability were evaluated prior to distribution. Survey items assessed ASP knowledge, attitudes, and experiences. Attitudes toward ASPs were assessed on a 5-point Likert-type scale. MEASUREMENTS AND MAIN RESULTS: The survey was completed by 185 physicians, with a response rate of 29% (n = 185/634) for all physicians contacted. A majority (74%) of respondents reported that there was at least 1 component of an ASP at their institution. Most (86%) respondents agreed or strongly agreed that the patients in their ICU benefit from an ASP, with 81% reporting the ASP increases their knowledge of appropriate antimicrobial use in the ICU setting. Only 11% of respondents reported they felt that time spent interacting with the ASP team was an inefficient use of their time, and only 7% expressed concern that the ASP negatively affected their autonomy. CONCLUSION: Based on our survey results, Canadian intensivists are supportive of antimicrobial stewardship in ICUs and feel that ASPs provide a valuable service to both patients and clinicians.

Pathway to Prevention of Nosocomial Clostridium difficile Infection.

BACKGROUND: To address the significant morbidity and mortality rates associated with nosocomial Clostridium difficile-associated diarrhea (CDAD), a series of recommendations and a pathway to prevention were developed. METHODS: An expert panel of infectious disease (ID) specialists participated in a modified Delphi process with specific objectives: (1) conduct a review for CDAD and prevention; (2) develop statements based upon panel members' opinions; (3) hold a panel meeting during the 2012 IDWeek; and (4) review the final recommendations and prevention pathway prior to submission for publication. RESULTS: The panel voted on (1) antibiotic stewardship (7 of 8 panelists); (2) reduction of other potentially modifiable risk factors (variable); (3) utilization of specific probiotics to prevent C. difficile overgrowth (8/8); (4) staff education regarding CDAD preventive measures (8/8); (5) appropriate hand hygiene for everyone (7/8); (6) environmental cleaning (8/8); (7) medical equipment disinfection (7/8); (8) early detection of CDAD in symptomatic patients (7/8); (9) usage of protective clothing/gloves (8/8); (10) proper measures during outbreak (8/8); and (11) surveillance to monitor efficacy data of preventive measures (8/8). CONCLUSIONS: The panel members agreed with 11 of 17 recommendations presented. The additional recommendations by the panel were proton pump inhibitor use as a risk factor and the use of adjunctive therapy with specific probiotic, as it was approved by Health Canada for the risk reduction of CDAD in hospitalized patients.

Outpatient parenteral antimicrobial therapy for surgery patients: A comparison with previous standard of care.

BACKGROUND: Current literature reports that outpatient parenteral antimicrobial therapy (OPAT) programs improve cure rates, and reduce length of hospitalization and costs. OPAT programs are still relatively new in Canada. OBJECTIVE: To evaluate the benefits of an OPAT program initiated at a multispecialty tertiary care facility in Toronto, Ontario, compared with the previous standard of care. METHODS: The present retrospective observational study was conducted using data from a group of surgical patients who were treated for active infections. Between February 1, 2010 and November 30, 2010, a total of 108 surgical patients were enrolled in the OPAT program. Patients were matched 1:1 with historical controls discharged between January 1, 2001 and January 1, 2010 according to age, sex, type of surgery, infection and comorbidities (Charlson Comorbidity Index). Cure rate, 30-day rehospitalization and length of stay were evaluated as primary end points. RESULTS: Of 108 eligible OPAT patients, 21 were matched to the control group using the prespecified criteria. For this cohort, the OPAT program was associated with improved cure rates (OPAT 61.7% versus control 57.1%; P>0.10), reduction in rehospitalization rate (14.3% versus 28.6%; P>0.10) and reduced length of stay (10.7 versus 13.9 days, P>0.10) compared with the control group. CONCLUSIONS: For this cohort of surgery patients, the OPAT program demonstrated a trend toward improved outcomes but did not achieve statistical significance. Due to the lack of statistical power, further evaluation is required to determine the full benefit of OPAT to patients and the health care system.

HISTORIQUE: D'après les rapports bibliographiques actuels, les programmes d'antibiothérapie parentérale ambulatoire (ATPA) améliorent les taux de guérison et réduisent la durée d'hospitalisation et les coûts. Les programmes d'ATPA sont encore relativement nouveaux au Canada. OBJECTIF: Évaluer les avantages d'un programme d'ATPA lancé dans un centre de soins tertiaires multidisciplinaire de Toronto, en Ontario, par rapport aux normes de soins antérieures. MÉTHODOLOGIE: Les chercheurs ont mené la présente étude d'observation rétrospective à l'aide des données d'un groupe de patients opérés traités en raison d'infections actives. Entre le 1er février et le 30 novembre 2010, 108 patients opérés ont été inscrits au programme d'ATPA. Les patients ont été jumelés 1:1 avec des sujets témoins historiques qui ont obtenu leur congé entre le 1er janvier 2001 et le 1er janvier 2010 d'après leur âge, leur sexe, le type d'opération, l'infection et les comorbidités (indice de comorbidité de Charlson). Les paramètres principaux étaient le taux de guérison, la réhospitalisation au bout de 30 jours et la durée d'hospitalisation. RÉSULTATS: Sur les 108 patients du programme d'ATPA admissibles, 21 ont été jumelés au groupe témoin au moyen des critères pré-définis. Dans cette cohorte, le programme d'ATPA s'associait à un meilleur taux de guérison (61,7 % pour l'ATPA par rapport à 57,1 % pour le groupe témoin; P>0,10), à une réduction du taux de réhospitalisation (14,3 % par rapport à 28,6 %; P>0,10) et à diminution de la durée d'hospitalisation (10,7 par rapport à 13,9 jours, P>0,10) que dans le groupe témoin. CONCLUSIONS: Auprès de cette cohorte de patients opérés, le programme d'ATPA démontrait une tendance vers de meilleures issues, sans pour autant avoir de signification statistique. En raison de l'absence d'efficacité statistique, il faudra approfondir l'évaluation afin de déterminer les avantages du programme d'ATPA pour les patients et le système de santé.

Pharmacokinetic Alterations Associated with Critical Illness.

Haemodynamic, metabolic, and biochemical derangements in critically ill patients affect drug pharmacokinetics and pharmacodynamics making dose optimisation particularly challenging. Appropriate therapeutic dosing depends on the knowledge of the physiologic changes caused by the patient's comorbidities, underlying disease, resuscitation strategies, and polypharmacy. Critical illness will result in altered drug protein binding, ionisation, and volume of distribution; it will also decrease oral drug absorption, intestinal and hepatic metabolism, and renal clearance. In contrast, the resuscitation strategies and the use of vasoactive drugs may oppose these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion. Metabolism is the main mechanism for drug clearance and is one of the main pharmacokinetic processes affected; it is influenced by patient-specific factors, such as comorbidities and genetics; therapeutic-specific factors, including drug characteristics and interactions; and disease-specific factors, like organ dysfunction. Moreover, organ support such as mechanical ventilation, renal replacement therapy, and extracorporeal membrane oxygenation may contribute to both inter- and intra-patient variability of drug pharmacokinetics. The combination of these competing factors makes it difficult to predict drug response in critically ill patients. Pharmacotherapy targeted to therapeutic goals and therapeutic drug monitoring is currently the best option for the safe care of the critically ill. The aim of this paper is to review the alterations in drug pharmacokinetics associated with critical illness and to summarise the available evidence.

A national survey of antimicrobial stewardship content in Canadian entry-to-practice pharmacy programs.

Objective: To describe the current landscape of antimicrobial stewardship (AMS) instruction in Canadian entry-to-practice pharmacy programs and the perceived barriers and facilitators to optimizing teaching and learning. Design: Electronic survey. Participants: Faculty representatives from the 10 Canadian entry-to-practice pharmacy programs, including content experts and faculty leadership. Methods: A review of international literature pertaining to AMS in pharmacy curricula informed a 24-item survey, which was open for completion from March to May of 2021. Curriculum content questions were developed using AMS topics recommended by pharmacy educators in the United States, and professional roles described by the Association of Faculties of Pharmacy of Canada. Results: All 10 Canadian faculties returned a completed survey. All programs reported teaching AMS principles in their core curricula. Content coverage varied, with programs teaching, on average, 68% of the recommended AMS topics from the United States. Potential gaps were identified within the professional roles of "communicator" and "collaborator." Didactic methods of content delivery and student assessment, such as lectures and multiple-choice questions, were most frequently used. Three programs offered additional AMS content in their elective curricula. Experiential rotations in AMS were commonly offered, though teaching AMS in formalized interprofessional settings was rare. Curricular time constraints were identified by all programs as a barrier to enhancing AMS instruction. A course to teach AMS, a curriculum framework, and prioritization by the faculty's curriculum committee were perceived as facilitators. Conclusions: Our findings highlight potential gaps and areas of opportunity within Canadian pharmacy AMS instruction.

Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus.

BACKGROUND: The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA. METHODS: 40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 10(6) and 10(8) cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model. RESULTS: 15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 10(6) cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 10(8) cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log(10) CFU/ml for agr functional vs. 2.41 log(10) CFU/ml for agr dysfunctional MRSA (p = 0.0007). CONCLUSIONS: Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.

A Canadian perspective on the revised 2020 ASHP-IDSA-PIDS-SIDP guidelines for vancomycin AUC-based therapeutic drug monitoring for serious MRSA infections.

Background: A revised consensus guideline on therapeutic drug monitoring (TDM) of vancomycin for serious methicillin-resistant Staphylococcus aureus (MRSA) infections was recently published with endorsement of numerous American pharmacy and medical societies. Changing practice from trough TDM to area-under-the-curve-(AUC)-guided dosing was suggested. Methods: Recent literature was critically appraised to determine whether AUC TDM is appropriate for Canadian hospital practice. Results: Previous 2009 vancomycin consensus guidelines recommended trough levels of 15-20 mg/L for serious MRSA infections, based on relatively poor evidence for efficacy or safety. In the past decade, aggressive trough targets have led to unnecessary toxicity. Adoption of a TDM strategy using an alternative parameter (AUC) has been suggested, although the evidence for any outcome benefits is low quality. In addition, implementation would require greater resources at health care institutions in the forms of more frequent serum levels or acquisition of costly Bayesian software programs. Most studies on this subject have been observational and retrospective; therefore, relationships between TDM parameters and outcomes have not been convincingly and consistently demonstrated to be causal in nature. Despite claims to the contrary, based on few in silico experiments, available clinical data suggest correlation of trough levels and AUC is high. TDM with lower target trough levels is a simpler solution to reduce risk of toxicity. Conclusions: There are serious concerns with adoption of AUC TDM of vancomycin into routine practice in Canada. Trough-based monitoring with modest reduction in target levels remains the most evidence-informed practice at this time.

Historique: De nombreuses sociétés pharmaceutiques et médicales américaines ont récemment publié et avalisé des lignes directrices consensuelles révisées sur le suivi thérapeutique pharmacologique (STP) de la vancomycine en cas de graves infections par le Staphylococcus aureus résistant à la méthicilline (SARM). Ces lignes directrices préconisent de passer de la STP des creux à une posologie déterminée par l'aire sous la courbe (ASC). Méthodologie: Les chercheurs ont procédé à une évaluation critique des publications récentes pour déterminer si la STP selon l'ASC est adaptée à la pratique hospitalière au Canada. Résultats: Les lignes directrices consensuelles de 2009 sur la vancomycine recommandaient un creux de 15 mg/L à 20 mg/L en cas d'infection grave par le SARM, en fonction de données probantes d'efficacité et d'innocuité relativement faibles. Depuis dix ans, des creux cibles trop ambitieux ont été responsables de toxicités inutiles. Il est proposé de revoir la stratégie du STP d'après un autre paramètre (l'ASC), même si les données probantes en démontrant les bienfaits sont de faible qualité. De plus, sa mise en œuvre exigerait des ressources plus importantes dans les établissements de santé, soit le dosage plus fréquent des concentrations plasmatiques ou l'acquisition de logiciels bayésiens coûteux. La plupart des articles sur le sujet sont des études d'observation et des études rétrospectives. Par conséquent, la nature causale des relations entre les paramètres et les résultats du STP n'a pas été démontrée de manière convaincante ni systématique. Malgré les prétentions contraires, selon quelques expériences in silico, les données cliniques disponibles font foi d'une corrélation élevée entre les concentrations minimales et l'ASC. Il serait plus simple d'assurer le STP par des concentrations minimales cibles plus basses pour réduire le taux de toxicité. Conclusions: L'adoption du STP de la vancomycine selon l'ASC dans la pratique quotidienne soulève de vives préoccupations au Canada. Pour l'instant, la surveillance des creux assortie à de modestes réductions des concentrations cibles demeure la pratique la plus respectueuse des données probantes.

Development and evaluation of a primary care antimicrobial stewardship program (PC-ASP) in Toronto, Ontario, Canada.

Background: Effective community-based antimicrobial stewardship programs (ASPs) are needed because 90% of antimicrobials are prescribed in the community. A primary care ASP (PC-ASP) was evaluated for its effectiveness in lowering antibiotic prescriptions for six common infections. Methods: A multi-faceted educational program was assessed using a before-and-after design in four primary care clinics from 2015 through 2017. The primary outcome was the difference between control and intervention clinics in total antibiotic prescriptions for six common infections before and after the intervention. Secondary outcomes included changes in condition-specific antibiotic use, delayed antibiotic prescriptions, prescriptions exceeding 7 days duration, use of recommended antibiotics, and emergency department visits or hospitalizations within 30 days. Multi-method models adjusting for demographics, case mix, and clustering by physician were used to estimate treatment effects. Results: Total antibiotic prescriptions in control and intervention clinics did not differ (difference in differences = 1.7%; 95% CI -12.5% to 15.9%), nor did use of delayed prescriptions (-5.2%; 95% CI -24.2% to 13.8%). Prescriptions for longer than 7 days were significantly reduced (-21.3%; 95% CI -42.5% to -0.1%). However, only 781 of 1,777 encounters (44.0%) involved providers who completed the ASP education. Where providers completed the education, delayed prescriptions increased 17.7% (p = 0.06), and prescriptions exceeding 7 days duration declined (-27%; 95% CI -48.3% to -5.6%). Subsequent emergency department visits and hospitalizations did not increase. Conclusions: PC-ASP effectiveness on antibiotic use was variable. Shorter prescription durations and increased use of delayed prescriptions were adopted by engaged primary care providers.

Historique: Des programmes de gestion antimicrobienne (PGA) communautaires efficaces doivent exister, parce que 90 % des antimicrobiens sont prescrits dans la communauté. Des chercheurs ont évalué un PGA en première ligne (PGA-PL) afin d'en déterminer l'efficacité à réduire les prescriptions d'antibiotiques pour six infections courantes. Méthodologie: Les chercheurs ont évalué un programme de formation polyvalent au moyen d'une méthodologie avant-après dans quatre cliniques de soins de première ligne entre 2015 et 2017. Le résultat clinique primaire était la différence entre les cliniques de contrôle et d'intervention pour ce qui est du total de prescriptions antibiotiques contre six infections courantes avant et après l'intervention. Les résultats cliniques secondaires incluaient des modifications à l'utilisation des antibiotiques propres au trouble de santé, le report des prescriptions d'antibiotiques, des prescriptions de plus de sept jours, l'utilisation des antibiotiques recommandés et les visites à l'urgence ou les hospitalisations dans les 30 jours. Les chercheurs ont utilisé des méthodes multimodèles tenant compte de la démographie, du mélange de cas et du regroupement par médecin pour évaluer l'effet des traitements. Résultats: Les prescriptions totales d'antibiotiques dans les cliniques de contrôle et d'intervention ne différaient pas (différences des différences = 1,7 %; IC à 95 %, ­12,5 % à 15,9 %), ni l'utilisation de prescriptions reportées (­5,2 %; IC à 95 %, ­24,2 % à 13,8 %). Les prescriptions de plus de sept jours étaient très peu courantes (­21,3 %; IC à 95 %, ­42,5 % à ­0,1 %). Cependant, seulement 781 des 1 777 rencontres (44,0 %) avaient eu lieu avec des dispensateurs qui avaient suivi la formation sur le PGA. Lorsque les dispensateurs avaient suivi la formation, les reports de prescriptions augmentaient de 17,7 % (p = 0,06) et les prescriptions de plus de sept jours diminuaient (­27 %; IC à 95 %, ­48,3 % à ­5,6 %). Les visites subséquentes à l'urgence et les hospitalisations n'ont pas augmenté. Conclusions: L'efficacité du PGA-PL pour l'utilisation d'antibiotiques était variable. Les dispensateurs de soins de première ligne qui y avaient participé préparaient des prescriptions de moins longue durée et reportaient davantage leurs prescriptions.

Remdesivir: Review of Pharmacology, Pre-clinical Data, and Emerging Clinical Experience for COVID-19.

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic ß-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.

Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID-19.

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.

Barriers and facilitators to the uptake of an antimicrobial stewardship program in primary care: A qualitative study.

The overuse of antimicrobials in primary care can be linked to an increased risk of antimicrobial-resistant bacteria for individual patients. Although there are promising signs of the benefits associated with Antimicrobial Stewardship Programs (ASPs) in hospitals and long-term care settings, there is limited knowledge in primary care settings and how to implement ASPs in these settings is unclear. In this context, a qualitative study was undertaken to explore the perceptions of primary care prescribers of the usefulness, feasibility, and experiences associated with the implementation of a pilot community-focused ASP intervention in three primary care clinics. Qualitative interviews were conducted with primary care clinicians, including local ASP champions, prescribers, and other primary health care team members, while they participated in an ASP initiative within one of three primary care clinics. An iterative conventional content analyses approach was used to analyze the transcribed interviews. Themes emerged around the key enablers and barriers associated with ASP implementation. Study findings point to key insights relevant to the scalability of community ASP activities with primary care providers.

Protecting Frontline Health Care Workers from COVID-19 with Hydroxychloroquine Pre-exposure Prophylaxis: A structured summary of a study protocol for a randomised placebo-controlled multisite trial in Toronto, Canada.

OBJECTIVES: Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome TRIAL DESIGN: The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. PARTICIPANTS: Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. INTERVENTION AND COMPARATOR: Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day MAIN OUTCOMES: The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. RANDOMISATION: Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. BLINDING (MASKING): All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. TRIAL STATUS: This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 TRIAL REGISTRATION: ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Outpatient gatifloxacin therapy and dysglycemia in older adults.

BACKGROUND: Gatifloxacin has been associated with both hypoglycemia and hyperglycemia. We examined dysglycemia-related health outcomes associated with various antibiotics in a population of approximately 1.4 million Ontario, Canada, residents 66 years of age or older. METHODS: We conducted two population-based, nested case-control studies. In the first, case patients were persons treated in the hospital for hypoglycemia after outpatient treatment with a macrolide, a second-generation cephalosporin, or a respiratory fluoroquinolone (gatifloxacin, levofloxacin, moxifloxacin, or ciprofloxacin). In the second, case patients were persons who received hospital care for hyperglycemia. For each case patient, we identified up to five controls matched according to age, sex, the presence or absence of diabetes, and the timing of antibiotic therapy. RESULTS: Between April 2002 and March 2004, we identified 788 patients treated for hypoglycemia within 30 days after antibiotic therapy. As compared with macrolide antibiotics, gatifloxacin was associated with an increased risk of hypoglycemia (adjusted odds ratio, 4.3; 95 percent confidence interval, 2.9 to 6.3). Levofloxacin was also associated with a slightly increased risk (adjusted odds ratio, 1.5; 95 percent confidence interval, 1.2 to 2.0), but no such risk was seen with moxifloxacin, ciprofloxacin, or cephalosporins. We then identified 470 patients treated for hyperglycemia within 30 days after antibiotic therapy. As compared with macrolides, gatifloxacin was associated with a considerably increased risk of hyperglycemia (adjusted odds ratio, 16.7; 95 percent confidence interval, 10.4 to 26.8), but no risk was noted with the other antibiotics. Risks were similar in the two studies regardless of the presence or absence of diabetes. CONCLUSIONS: As compared with the use of other broad-spectrum oral antibiotics, including other fluoroquinolones, the use of gatifloxacin among outpatients is associated with an increased risk of in-hospital treatment for both hypoglycemia and hyperglycemia.