ABSTRACT
Background: Exposing patients with a low probability of disease to diagnostic testing with poor test characteristics leads to false positive results. Providers often act on these false results, which can cause unnecessary evaluation and treatment. The treatment of asymptomatic bacteriuria is discouraged, but it still frequently occurs in the inpatient setting; it is less studied in the Emergency Department (ED). In this study, we examine associations between urine testing, inappropriate antibiotic use, and length of stay in discharged ED patients at risk of urinary tract infection (UTI) misdiagnosis. Methods: A cohort of discharged ED patients at risk of UTI misdiagnosis was created by pulling visit information for patients presenting with abdominal pain, chest pain, headache, vaginal bleeding in pregnancy, and elderly females with weakness or confusion. Predictors of urine testing, and urinary tract infection treatment were determined with logistic regression analysis. A chart review of a representative sample of this cohort was then completed screening for the presence of urinary tract symptoms and urine culture results. Linear regression analysis was then used to generate an adjusted mean difference in length of stay between patients who had urine testing compared to those who did not. Results: About a quarter of chest pain and headache patients had urine testing, while approximately 75% of abdominal pain patients, vaginal bleeding in pregnancy, and elderly females with weakness or confusion did. Except for chest pain patients, the UTI treatment rate was more than double the positive culture rate, indicating overtreatment. A diagnosis of UTI is based on a combination of UTI symptoms and positive urine cultures, yet only about 15% of patients treated for UTI met these criteria. Lastly, in all chief complaint groups, the length of stay was significantly longer-30 min or more-for those who had urine testing compared to matched controls. Conclusions: In this observational study of patients at risk of UTI misdiagnosis, urine testing was associated with inappropriate antibiotic use and delayed discharge. There is pressure on providers to perform diagnostic testing, but in patients without specific UTI symptoms, urine testing might cause more harm than benefit.
ABSTRACT
One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.
