Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.

Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation (FAO) and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-coenzyme A dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly up-regulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout (KO) animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged KO animals, including FAO proteins which led to improved FAO activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates FAO in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.

How does the antimicrobial stewardship provider role affect prospective audit and feedback acceptance for restricted antibiotics in a Canadian tertiary-care center?

Of 731 restricted antimicrobial prescriptions subject to antimicrobial stewardship program (ASP) prospective audit and feedback (PAF) over a 3-year period, 598 PAF recommendations (82%) were fully accepted. Physician auditors had an increased odds of PAF recommendation acceptance, reinforcing the complementary role of the ASP physician in the multidisciplinary ASP team.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalised with COVID-19 (COVASP): a pragmatic, cluster-randomised, non-inferiority trial.

BACKGROUND: The COVID-19 pandemic has been associated with increased antimicrobial use despite low rates of bacterial co-infection. Prospective audit and feedback is recommended to optimise antibiotic prescribing, but high-quality evidence supporting its use for COVID-19 is absent. We aimed to study the efficacy and safety of prospective audit and feedback in patients admitted to hospital for the treatment of COVID-19. METHODS: COVASP was a prospective, pragmatic, non-inferiority, small-unit, cluster-randomised trial comparing prospective audit and feedback plus standard of care with standard of care alone in adults admitted to three hospitals in Edmonton, AB, Canada, with COVID-19 pneumonia. All patients aged at least 18 years who were admitted from the community to a designated study bed with microbiologically confirmed SARS-CoV-2 infection in the preceding 14 days were included if they had an oxygen saturation of 94% or lower on room air, required supplemental oxygen, or had chest-imaging findings compatible with COVID-19 pneumonia. Patients were excluded if they were transferred in from another acute care centre, enrolled in another clinical trial that involved antibiotic therapy, expected to progress to palliative care or death within 48 h of hospital admission, or managed by any member of the research team within 30 days of enrolment. COVID-19 unit and critical care unit beds were stratified and randomly assigned (1:1) to the prospective audit and feedback plus standard of care group or the standard of care group. Patients were masked to their bed assignment but the attending physician and study team were not. The primary outcome was clinical status on postadmission day 15, measured using a seven-point ordinal scale. We used a non-inferiority margin of 0·5. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04896866, and is now closed. FINDINGS: Between March 1 and Oct 29, 2021, 1411 patients were screened and 886 were enrolled: 457 into the prospective audit and feedback plus standard of care group, of whom 429 completed the study, and 429 into the standard of care group, of whom 404 completed the study. Baseline characteristics were similar for both groups, with an overall mean age of 56·7 years (SD 17·3) and a median baseline ordinal scale of 4·0 (IQR 4·0-5·0). 301 audit and feedback events were recorded in the intervention group and 215 recommendations were made, of which 181 (84%) were accepted. Despite lower antibiotic use in the intervention group than in the control group (length of therapy 364·9 vs 384·2 days per 1000 patient days), clinical status at postadmission day 15 was non-inferior (median ordinal score 2·0 [IQR 2·0-3·0] vs 2·0 [IQR 2·0-4·0]; p=0·37, Mann-Whitney U test). Neutropenia was uncommon in both the intervention group (13 [3%] of 420 patients) and the control group (20 [5%] of 396 patients), and acute kidney injury occurred at a similar rate in both groups (74 [18%] of 421 patients in the intervention group and 76 [19%] of 399 patients in the control group). No intervention-related deaths were recorded. INTERPRETATION: This cluster-randomised clinical trial shows that prospective audit and feedback is safe and effective in optimising and reducing antibiotic use in adults admitted to hospital with COVID-19. Despite many competing priorities during the COVID-19 pandemic, antimicrobial stewardship should remain a priority to mitigate the overuse of antibiotics in this population. FUNDING: None.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalized with COVID-19: A protocol for a pragmatic clinical trial.

BACKGROUND: The use of broad-spectrum antibiotics is widespread in patients with COVID-19 despite a low prevalence of bacterial co-infection, raising concerns for the accelerated development of antimicrobial resistance. Antimicrobial stewardship (AMS) is vital but there are limited randomized clinical trial data supporting AMS interventions such as prospective audit and feedback (PAF). High quality data to demonstrate safety and efficacy of AMS PAF in hospitalized COVID-19 patients are needed. METHODS AND DESIGN: This is a prospective, multi-center, non-inferiority, pragmatic randomized clinical trial evaluating AMS PAF intervention plus standard of care (SOC) versus SOC alone. We include patients with microbiologically confirmed SARS-CoV-2 infection requiring hospital admission for severe COVID-19 pneumonia. Eligible ward beds and critical care unit beds will be randomized prior to study commencement at each participating site by computer-generated allocation sequence stratified by intensive care unit versus conventional ward in a 1:1 fashion. PAF intervention consists of real time review of antibacterial prescriptions and immediate written and verbal feedback to attending teams, performed by site-based AMS teams comprised of an AMS pharmacist and physician. The primary outcome is clinical status at post-admission day 15 measured using a 7-point ordinal scale. Patients will be followed for secondary outcomes out to 30 days. A total of 530 patients are needed to show a statistically significant non-inferiority, with 80% power and 2.5% one-sided alpha assuming standard deviation of 2 and the non-inferiority margin of 0.5. DISCUSSION: This study protocol presents a pragmatic clinical trial design with small unit cluster randomization for AMS intervention in hospitalized COVID-19 that will provide high-level evidence and may be adopted in other clinical situations. TRIAL REGISTRATION: This study is being performed at the University of Alberta and is registered at ClinicalTrials.gov (NCT04896866) on May 17, 2021.

Comparison of risk-scoring systems for heparin-induced thrombocytopenia in cardiac surgery patients.

OBJECTIVES: Several risk-scoring tools have been developed to exclude heparin-induced thrombocytopenia (HIT) in patients with thrombocytopenia, but these scores have not been reproduced or compared in the cardiac surgery population. The objective of this study was to validate and compare the modified 4T's (m4T) and Lillo-Le Louet (LLL) scores for HIT screening in the cardiac surgery population. METHODS: In this nested case-control study, we retrospectively calculated the m4T and the cardiac surgery-specific score by LLL for 18 cases (HIT-positive) and 54 matched controls (HIT-negative) using characteristics known at the time the HIT assay was ordered post-cardiac surgery and compared their performances by their c-statistic (area under the receiver operating characteristic curve), sensitivity and specificity. RESULTS: The median time from surgery to HIT assay order was 9.5 days (IQR 3.75-11.0) in the HIT-positive group and 2 days (IQR 2.0-3.0) in the HIT-negative group (p < 0.0001). The c-statistics for the m4T and the LLL scores were 0.76 (95% CI 0.64-0.85) and 0.63 (95% CI 0.51-0.74), respectively (p = 0.051). Sensitivity and specificity were 61% and 91% for the m4T, and 94% and 32% for the LLL score. CONCLUSION: Performance of the m4T and LLL scores in discriminating HIT-positive from HIT-negative patients was modest among patients post-cardiac surgery. However, differences between the sensitivities of these scores suggest that the LLL score may be a safer tool for ruling out HIT in this population.

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.

The case for 'conservative pharmacotherapy'.

In the modern era of rapid advances in the field of antimicrobial 'precision dosing' through therapeutic drug monitoring (TDM), there is growing pressure to adopt new technologies and expand the number of antimicrobials managed with TDM and/or the complexity of TDM methods. For many clinicians, it may seem inevitable that TDM must improve patient outcomes. However, based on the evidence to date, this concept remains largely a hypothesis. Conversely, it is plausible that focusing on TDM may distract from careful clinical monitoring of the patient for efficacy and drug-related toxicities and shift finite resources from other valuable interventions. In this article we make the case for embracing critical appraisal of precision dosing, remaining skeptical until persuaded by compelling evidence, and adopting new technologies only when they have proven their value over competing priorities; that is, we make the case for using 'conservative pharmacotherapy'.

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.