Compass for antibiotic stewardship: using a digital tool to improve guideline adherence and drive clinician behaviour for appendicitis treatment in the emergency department.

BACKGROUND: Antibiotic stewardship in the ED is important given the increasing prevalence of multidrug resistance associated with poorer patient outcomes. The use of broad-spectrum antibiotics in the ED for infections like appendicitis is common. At baseline, 75% of appendicitis cases at our institution received broad-spectrum ertapenem rather than the recommended narrower-spectrum ceftriaxone/metronidazole combination. We aimed to improve antibiotic stewardship by identifying barriers to guideline adherence and redesigning our appendicitis antibiotic guideline. METHODS: Using the 'Fit between Individuals, Task and Technology (FITT)' framework, we identified barriers that preventclinicians from adhering to guidelines. We reformatted a clinical guideline and disseminated it using our ED's clinical decision support system (CDSS), E*Drive. Next, we examined E*Drive's user data and clinician surveys to assess utilisation and satisfaction. Finally, we conducted a retrospective chart review to measure clinician behaviour change in antibiotic prescription for appendicitis treatment. RESULTS: Data demonstrated an upward trend in the number of monthly users of E*Drive from 1 April 2021 to 30 April 2022, with an average increase of 46 users per month. Our clinician survey results demonstrated that >95% of users strongly agree/agree that E*Drive improves access to clinical information, makes their job more efficient and that E*Drive is easy to access and navigate, with a Net Promoter Score increase from 26.0 to 78.3. 69.4% of patients treated for appendicitis in the post-intervention group received antibiotics concordant with our institutional guideline compared with 20.0% in the pre-intervention group (OR=9.07, 95% CI (3.84 to 21.41)). CONCLUSION: Antibiotic stewardship can be improved by ensuring clinicians have access to convenient and up-to-date guidelines through clinical decision support systems. The FITT model can help guide projects by identifying individual, task and technology barriers. Sustained adherence to clinical guidelines through simplification of guideline content is a potentially powerful tool to influence clinician behaviour in the ED.

Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production.

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

Lactic Acid Inhibits Lipopolysaccharide-Induced Mast Cell Function by Limiting Glycolysis and ATP Availability.

Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-κB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.

Efficacy of Single-Dose Azithromycin for Ocular Chlamydial Infection: A Longitudinal Study.

Millions of doses of azithromycin are distributed each year for trachoma, yet the treatment efficacy of a single dose of azithromycin for ocular Chlamydia infection has not been well characterized. In this study, four villages in Niger received a mass azithromycin distribution for trachoma. All 426 children aged 0-5 years residing in the study villages were offered conjunctival swabbing every 6 months to test for ocular Chlamydia trachomatis. Among the children infected with ocular Chlamydia before treatment, 6% (95% CI: 2-15%) tested positive for ocular Chlamydia infection 6 months later, and 15% (95% CI: 7-28%) tested positive 12 months later. The most important predictor of post-treatment ocular Chlamydia infection was pretreatment ocular Chlamydia infection (relative risk: 3.5, 95% CI: 1.3-9.4). Although the 6-monthly monitoring schedule was suboptimal for testing the treatment efficacy of an antibiotic, these findings are nonetheless consistent with high treatment efficacy of a single dose of azithromycin and suggest that additional interventions might be most effective if targeted to those children infected prior to treatment.

Designing clinical guidelines that improve access and satisfaction in the emergency department.

Clinical guidelines are evidence-based clinician decision-support tools that improve health outcomes, reduce patient harm, and decrease healthcare costs, but are often underused in emergency departments (EDs). This article describes a replicable, evidence-based design-thinking approach to developing best practices for guideline design that improves clinical satisfaction and usage. We used a 5-step process to enhance guideline usability in our ED. First, we conducted end-user interviews to identify barriers to guideline usage. Second, we reviewed the literature to identify key principles in guideline design. Third, we applied our findings to create a standardized guideline format, incorporating rapid cycle learning and iterative improvements. Fourth, we ensured the clinical validity of our updated guidelines by using a rigorous process for peer review. Lastly, we evaluated the impact of our guideline conversion process by tracking clinical guidelines access per day from October 2020 to January 2022. Our end-user interviews and review of the design literature revealed several barriers to guideline use, including lack of readability, design inconsistencies, and guideline complexity. Although our previous clinical guideline system averaged 0.13 users per day, >43 users per day accessed the clinical guidelines on our new digital platform in January 2022, representing an increase in access and use exceeding 33,000%. Our replicable process using open-access resources increased clinician access to and satisfaction with clinical guidelines in our ED. Design-thinking and use of low-cost technology can significantly improve clinical guideline visibility and has the potential to increase guideline use.

Fluoxetine restrains allergic inflammation by targeting an FcɛRI-ATP positive feedback loop in mast cells.

There is a clinical need for new treatment options addressing allergic disease. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that have anti-inflammatory properties. We tested the effects of the SSRI fluoxetine on IgE-induced function of mast cells, which are critical effectors of allergic inflammation. We showed that fluoxetine treatment of murine or human mast cells reduced IgE-mediated degranulation, cytokine production, and inflammatory lipid secretion, as well as signaling mediated by the mast cell activator ATP. In a mouse model of systemic anaphylaxis, fluoxetine reduced hypothermia and cytokine production. Fluoxetine was also effective in a model of allergic airway inflammation, where it reduced bronchial responsiveness and inflammation. These data show that fluoxetine suppresses mast cell activation by impeding an FcɛRI-ATP positive feedback loop and support the potential repurposing of this SSRI for use in allergic disease.

Inhibiting Glycolysis and ATP Production Attenuates IL-33-Mediated Mast Cell Function and Peritonitis.

Cellular metabolism and energy sensing pathways are closely linked to inflammation, but there is little understanding of how these pathways affect mast cell function. Mast cells are major effectors of allergy and asthma, and can be activated by the alarmin IL-33, which is linked to allergic disease. Therefore, we investigated the metabolic requirements for IL-33-induced mast cell function, to identify targets for controlling inflammation. We found that IL-33 increases glycolysis, glycolytic protein expression, and oxidative phosphorylation (OX PHOS). Inhibiting OX PHOS had little effect on cytokine production, but antagonizing glycolysis with 2-deoxyglucose or oxamate suppressed inflammatory cytokine production in vitro and in vivo. ATP reversed this suppression. Glycolytic blockade suppressed IL-33 signaling, including ERK phosphorylation, NFκB transcription, and ROS production in vitro, and suppressed IL-33-induced neutrophil recruitment in vivo. To test a clinically relevant way to modulate these pathways, we examined the effects of the FDA-approved drug metformin on IL-33 activation. Metformin activates AMPK, which suppresses glycolysis in immune cells. We found that metformin suppressed cytokine production in vitro and in vivo, effects that were reversed by ATP, mimicking the actions of the glycolytic inhibitors we tested. These data suggest that glycolytic ATP production is important for IL-33-induced mast cell activation, and that targeting this pathway may be useful in allergic disease.