Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

Background Ceftazidime-avibactam (CAZ-AVI) is a safe and effective treatment option for carbapenem-resistant Enterobacterales (CRE). However, predictors of resistance to CAZ-AVI have not been well defined. Therefore, our study describes risk factors for resistance to CAZ-AVI in hospitalized patients with CRE infections. Methods This was a single-center, retrospective cohort study conducted at an urban community hospital including adults older than 18 years with at least 1 culture growing CRE. Results Among 36 adults who had at least 1 CRE culture, 30 had a CRE isolate that was susceptible to CAZ-AVI, and 6 had resistant isolates. Previous CAZ-AVI use was significantly associated with an increased risk of resistance to CAZ-AVI (odds ratio, 17.2; 95% confidence interval [CI], 1.157–255.688; P = 0.039). When 30-day, all-cause mortality was assessed based on susceptibility to CAZ-AVI, it was 36.7% (n = 11 of 30) and 50% (n = 3 of 6) in susceptible and resistant groups, respectively (P = 0.658). When it was based on the type of antibiotic therapy, it was 36.8% (n = 7 of 19) for the patients on CAZ-AVI and 41.2% (n = 7 of 17) on other antibiotic therapy (n = 0.791). Conclusions Emergence of resistance to CAZ-AVI is an evolving problem for patients with prolonged hospitalization in large urban hospital settings and is associated with prior receipt of CAZ-AVI. Further studies are warranted to confirm our data and assess for additional predictors of CAZ-AVI resistance.

Background Patients with COVID-19 disease often receive antibiotics to treat suspected bacterial coinfections. Procalcitonin (PCT) is a biomarker used for suspected bacterial infections. The objective of this study is to evaluate the association between PCT and the use of antimicrobials in COVID-19 patients. Methods This was a retrospective, cohort study of adult patients admitted with confirmed COVID-19 from March 30, 2020 to March 30, 2021. Data collected included demographics, baseline inflammatory markers including initial PCT and C-reactive protein (CRP) values, past medical history, initiation of empiric antibiotics, mechanical ventilation, in-hospital mortality, days of antibiotic therapy, and length of hospital stay (LOS). Univariate analyses were utilized to assess for any significant differences in demographics based on predefined initial PCT groupings (&lt; 0.25 ng/ml (group 1), 0.25-0.49 ng/ml (group 2), and ≥ 0.5 ng/ml (group 3)). Multivariate analyses were performed to evaluate for any differences between initial PCT values and in-hospital mortality, LOS, and days of antibiotic therapy. Results Out of 149 patients, 61.7% had an initial PCT value &lt; 0.25 ng/ml, 17.45% had an initial value of 0.25-0.49 ng/ml, and 20.8% had an initial value ≥ 0.5 ng/ml. A total of 145 patients (97%) received empiric antibiotics. Univariate analysis among the three groups displayed a difference in the initial CRP value, which was higher in groups 2 and 3 versus group 1 (p &lt; 0.001). Regression analysis controlling for initial CRP value found that patients in groups 2 and 3 had a higher duration of antibiotic therapy compared to group 1 (12 and 11 versus 8 days) (p &lt; 0.001) and a longer LOS (17 and 15 vs 12 days) (p = 0.009). More patients (34.6%) were mechanically ventilated in group 2 compared to group 1 (14.1%) and group 3 (22.6%) with a trend toward significance (p = 0.059). Multivariate analysis found no significant association between PCT levels and mortality. The rate of in-hospital mortality in patients receiving invasive ventilation was higher in groups 2 and 3 (78% and 86%, respectively) compared to group 1 (54%, p &lt; 0.001). Conclusion When controlling for CRP, an initial PCT value &gt; 0.25 ng/ml was associated with increased days of antibiotic therapy and longer duration of hospital stay in COVID-19 patients. Disclosures All Authors: No reported disclosures.

Background Double anaerobic coverage (DAC) is often used for intra-abdominal infections (IAIs) post-operatively. The primary objective of the study was evaluating length of hospital stay (LOS), in-hospital post-operative complications, and re-admission within 30 days of discharge due to post-operative complications in patients who received piperacillin/tazobactam plus metronidazole versus piperacillin/tazobactam for IAIs post-operatively. The secondary objective was comparing in-hospital mortality and hospital-acquired Clostridioides difficile infections (CDI) between the two groups. Methods This was a retrospective, cohort study including adults with surgically managed IAIs at an urban community hospital between January 1, 2016 and June 30, 2019. The following data were collected: age, sex, body mass index, comorbidities, Charlson Comorbidity Index (CCI), 5-day post-operative body temperature, American Society of Anesthesiologists (ASA) pre-operative assessment score, surgical wound classification, and IAI diagnosis. Multivariate analysis and aggregate resampling of the sampling distribution were conducted. An alpha of &lt; 0.05 was considered statistically significant. Results Out of 163 patients, 96 patients received piperacillin/tazobactam plus metronidazole and 67 patients received piperacillin/tazobactam. The patients who received DAC were sicker with higher CCI (p=0.021) and 5-day post-operative body temperature (p=0.013). They were also at a higher risk for surgical site infections (p=0.002). Double anaerobic coverage was more often used for acute cholecystitis (p=0.0001) and gastrointestinal perforations (&lt; 0.0001). After adjusting for these variables, DAC was associated with longer LOS (median 9 days vs. 4 days, p&lt; 0.0001) and in-hospital post-operative complications (23% vs. 9%, p&lt; 0.0001). There were more re-admissions within 30 days of discharge due to post-operative complications in the single anaerobic coverage group (4% vs. 1%, p=&lt; 0.0001). In-hospital mortality (4% vs. 0%) and hospital-acquired CDI (1% vs. 0%) were only observed in DAC group. Conclusion Double anaerobic coverage was associated with no clinical benefit in surgically managed IAIs and in some cases may produce worse outcomes. Disclosures All Authors: No reported disclosures

Background:The role of therapeutic intervention, particularly antibiotics, for Shiga toxin-producing Escherichia coli (STEC) related infection is controversial.Methods: We performed a population based matched case-control study to assess the association between treatment (antibiotics, antidiarrheal agents and probiotics) for STEC related infections and HUS development. We identified all STEC HUS patients as cases and matched five non-HUS patients as controls using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017, and December 31, 2018. Further medical information was obtained by standardized questionnaires answered by physicians who registered each patient. We used multivariate conditional logistic regression model to evaluate the association between exposures (use of antibiotics, use of antidiarrheal agents, days between disease onset and fosfomycin administration [within two or three days]) and the development of HUS, by matched odds ratios (OR) and 95% confidence intervals (CI). Covariates we used were sex, age group, area code, presence of diarrhea and other factors. We also performed subgroup analyses using age (adults and children) as a stratification factor.Results: 7,760 STEC related patients were registered in the NESID. We selected patients who had a record of HUS diagnosis (n=182) and matched controls without HUS (n=910). After collecting standardized paper-based questionnaires, we enrolled 90 HUS patients and 371 non-HUS patients for analysis. In the main analysis, matched OR of fosfomycin was 0.75(0.47-1.20) in all ages, 1.41(0.51-3.88) in adults and 0.58(0.34-1.01) in children. Matched OR of antidiarrheal agents was 2.07(1.07-4.03) in all ages, 1.84(0.32-10.53) in adults, 2.65(1.21-5.82) in children. Matched OR of probiotics was 0.86(0.46-1.61) in all ages, 0.76(0.21-2.71) in adults, 1.00(0.48-2.09) in children. There was no significant association between the timing of fosfomycin use in the first two or five days of illness and HUS development in any age group.Conclusion: Our results suggest that fosfomycin might decrease the risk of HUS in children younger than 15 years of age with STEC confirmed bacterial gastroenteritis.