Introduction Proton pump inhibitors (PPI) are commonly prescribed in the primary care setting. While generally considered to be safe, there is growing evidence suggesting that PPI misuse is associated with a variety of significant adverse outcomes and unnecessary cost. The goal of this quality improvement project was to identify patients with non-guideline recommended PPI prescriptions in our internal medicine residency clinics and implement a process to de-prescribe or reduce the dose of PPIs across this patient population. Methods PPI prescription rates, dosage, and indication were extracted from the medical records of all 854 patients empaneled to the internal medicine residency clinics at a multicenter closed referral military hospital system. Appropriate PPI indication was consensus based upon published guidelines, and patients without an appropriate indication were targeted for intervention. These patients were directly contacted by their primary care physicians, via phone or during a clinic visit, to discuss the risks and benefits of ongoing PPI use as well as alternative therapies or tapering regimens at the physician's discretion. For moderate to high dose PPI, the dose was decreased by 50% every week until the lowest tolerated dose was achieved or until discontinuation. For low dose PPI, discontinuation was recommended as the initial intervention. Six months following the intervention, the empanelment was reevaluated for ongoing PPI usage, tapered dosage, or discontinuation. Results Of a total of 854 patient records reviewed at the initiation of the project, 322 patients were noted to be prescribed PPIs. Of this subset, 66% (217/322) did not meet a guideline recommended indication for their use. At the completion of the six-month intervention period, 44% (96/217) of patients were successfully weaned to a reduced dose or were no longer using a PPI. Conclusions PPIs are widely used and generally considered to be a well-tolerated therapy for acid-secretion disorders. PPI overprescription and the associated adverse effects and economic burden are increasingly recognized. We show that a simple, focused, resident-driven quality improvement intervention can be effective in deprescribing efforts to reduce inappropriate PPI use in the outpatient primary care setting.

Many bacteria regulate gene expression in response to phosphate availability using a two-component signal transduction system, the activity of which is controlled by interaction with the Pst phosphate specific transporter and a cytoplasmic protein PhoU. Mycobacterium tuberculosis, the causative agent of tuberculosis, requires its phosphate sensing signal transduction system for virulence and antibiotic tolerance, but the molecular mechanisms of phosphate sensing remain poorly characterized. M. smegmatis serves as a model for studying mycobacterial pathogens including M. tuberculosis. M. smegmatis encodes two proteins with similarity to PhoU, but it was unknown if both proteins participated in signal transduction with the phosphate-responsive SenX3-RegX3 two-component system. We constructed phoU single and double deletion mutants and tested expression of genes in the RegX3 regulon. Only the ΔphoU1ΔphoU2 mutant exhibited constitutive activation of all the RegX3-regulated genes examined, suggesting that M. smegmatis PhoU1 and PhoU2 have overlapping functions in inhibiting activity of the SenX3-RegX3 two-component system when phosphate is readily available. The ΔphoU1ΔphoU2 mutant also exhibited decreased tolerance to several anti-tubercular drugs. However, a complex plasmid swapping strategy was required to generate the ΔphoU1ΔphoU2 mutant, suggesting that either phoU1 or phoU2 is essential for in vitro growth of M. smegmatis. Using whole-genome sequencing, we demonstrated that all five of the ΔphoU1ΔphoU2 mutants we isolated had independent suppressor mutations predicted to disrupt the function of the Pst phosphate transporter, suggesting that in the absence of the PhoU proteins phosphate uptake by the Pst system is toxic. Collectively, our data demonstrate that the two M. smegmatis PhoU orthologs have overlapping functions in both controlling SenX3-RegX3 activity in response to phosphate availability and regulating phosphate transport by the Pst system. Our results suggest that M. smegmatis can serve as a tractable model for further characterization of the molecular mechanism of phosphate sensing in mycobacteria and to screen for compounds that would interfere with signal transduction and thereby increase the efficacy of existing anti-tubercular antibiotics.

OBJECTIVES: A significant proportion of patients with coronavirus disease 2019 requiring venovenous extracorporeal membrane oxygenation at our institution demonstrated heparin resistance, which in combination with a heparin shortage resulted in the transition to argatroban with or without aspirin as an alternative anticoagulation strategy. The optimal anticoagulation strategy for coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation is unknown, and therefore, we sought to evaluate the efficacy and safety of argatroban with or without aspirin as an alternative anticoagulation strategy in this patient population. DESIGN: Retrospective cohort. SETTING: Single-center tertiary-care facility in Fort Sam Houston, TX, from 2020 to 2021. PATIENTS: Twenty-four patients who were cannulated for venovenous extracorporeal membrane oxygenation due to respiratory failure secondary to coronavirus disease 2019. INTERVENTIONS: Argatroban, with or without aspirin, was substituted for heparin in coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Eighty percent of our coronavirus disease 2019 patients requiring venovenous extracorporeal membrane oxygenation demonstrated heparin resistance, and patients who were initially started on heparin were significantly more likely to require a change to argatroban than vice versa due to difficulty achieving or maintaining therapeutic anticoagulation goals (93.4% vs 11.1%; p < 0.0001). The time to reach the therapeutic anticoagulation goal was significantly longer for patients who were initially started on heparin in comparison with argatroban (24 vs 6 hr; p = 0.0173). Bleeding and thrombotic complications were not significantly different between the two cohorts. CONCLUSIONS: Argatroban, with or without aspirin, is an effective anticoagulation strategy for patients who require venovenous extracorporeal membrane oxygenation support secondary to coronavirus disease 2019. In comparison with heparin, this anticoagulation strategy was not associated with a significant difference in bleeding or thrombotic complications, and was associated with a significantly decreased time to therapeutic anticoagulation goal, likely as a result of high rates of heparin resistance observed in this patient population.