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Abstract Background Small colony variants (SCVs) of Staphylococcus aureus (SA) have significant intracellular persistence. Fluoroquinolones demonstrate intracellular activity and are often utilized to treat SCVs. Delafloxacin is a fluroquinolone with increased potency at a low pH, which could lead to enhanced intracellular activity. This study evaluates delafloxacin activity against intracellular MSSA and MSRA SCV isolates.Figure 1.Illustration of SCV co-culture methods Methods Six clinical SCV-SA isolates were co-cultured with human macrophages for 1 hour, allowing for phagocytosis (Fig 1). The remaining extracellular bacteria were removed and antibiotic treatments of delafloxacin, levofloxacin, gentamicin, cefazolin, or vancomycin were added. After 5-hour and 24-hour incubation periods, supernatants were collected for extracellular colony forming unit (CFU) enumeration. Macrophages were washed, lysed, collected, and plated for intracellular bacterial CFU enumeration. All conditions were repeated in triplicate and compared using a Mann Whitney U test.Figure 2.Intracellular SCV-MSSA CFUs Results Delafloxacin resulted in a 1.9-log reduction in intracellular CFUs (p< 0.001) at 5 hours and a 3.4 log reduction (p< 0.001) at 24 hours compared to antibiotic-free control for MSSA strains (Fig 2). Similarly, levofloxacin resulted in a 1.6-log (p< 0.001) and 1.9-log (p< 0.001) reduction in CFUs after 5 and 24 hours, respectively. Delafloxacin was more effective at clearing intracellular bacteria than levofloxacin at 24 hours (p= 0.004). In MRSA-SCV isolates, delafloxacin demonstrated CFU reduction of 2.4-log (p< 0.001) at 5 hours and 4.7-log (p< 0.001) at 24 hours compared to antibiotic-free control (Fig 3). Levofloxacin demonstrated a 1.6-log (p< 0.001) reduction at 5 hours and 1.5-log (p= 0.034) reduction at 24 hours. In comparison to levofloxacin, delafloxacin led to greater reductions in MRSA CFUs at both 5 hours and 24 hours of incubation, 0.85-log (p= 0.028) and 3.2-log (p< 0.001) respectively.Figure 3.Intracellular SCV-MRSA CFUs Conclusion The results demonstrate delafloxacin having greater intracellular activity than levofloxacin and other comparator antibiotics against both MSSA and MRSA SCVs. These results support using delafloxacin to treat recurrent or chronic infections caused by either MSSA or MRSA SCVs and suggest that the observed efficacy may be a result of enhanced intracellular activity. Disclosures All Authors: No reported disclosures

Abstract Background The Rochester Epidemiology Project (REP) has been used to examine numerous infectious and non-infectious entities in a population-based approach in Olmsted County, Minnesota. To further investigate patterns of enterococcal bloodstream infection (BSI), we used the Expanded Rochester Epidemiology Project (E-REP) to include additional surrounding counties to conduct a retrospective population-based study of adult patients who developed enterococcal BSI, with or without infective endocarditis (IE). Methods The E-REP population under study included eight counties in southeastern Minnesota (including Olmsted County), representing a total population of over 250,000 individuals. Adults (age ≥ 18 years) diagnosed with an initial episode of enterococcal BSI with or without enterococcal IE between January 1, 2018 and December 31, 2022 were included; patients with either polymicrobial BSI with enterococci or a previous bout of enterococcal BSI before the study period were excluded. Cases of enterococcal BSI and IE were identified using ICD-10 codes and underwent complete medical record review. Patient characteristics, microbiology, antibiotic regimens, infectious complications, and outcomes were collected. Results A total of 113 cases of enterococcal BSI were identified over the five-year study period. The age- and sex-adjusted incidence rate of enterococcal BSI was 6.9 per 100,000 person-years, with a significantly higher rate among males than females (Figure 1). BSI incidence rate varied by age, with patients 80 years or older having the highest incidence rate (Figures 1 and 2). Twenty-two cases of enterococcal IE were identified, yielding an overall IE prevalence of 20.8% (Figure 3). The cumulative mortality rate at 12 months was high at 41.7% (Figure 3). Five patients (4.4%) had a relapse of enterococcal BSI, defined as recurrence of BSI after negative follow-up blood cultures and within 12 weeks of the initial BSI. Conclusion This is the first population-based investigation that has focused on the epidemiology and clinical profile of patients with enterococcal BSI and complicating IE in a US population. This included an IE prevalence of 20.8%, which should be considered when evaluating and managing patients with enterococcal BSI. Disclosures Larry M. Baddour, MD, UpToDate, Inc.: Royalty payments (authorship duties).

Aims The current American Joint Committee on Cancer (AJCC) staging manual and the College of American Pathologists (CAP) colorectal carcinoma (CRC) protocol specify use of a four‐tiered grading system (i.e. grades 1–4; well‐differentiated–undifferentiated) for CRC, based on percentage of gland formation. The World Health Organization (WHO) 5th edition grades CRC into low‐grade (well‐ and moderately differentiated) and high‐grade (poorly and undifferentiated), based on the least differentiated component. We studied interobserver agreement and practice patterns among pathologists when grading CRC by these two grading systems. Methods and results Five gastrointestinal pathologists reviewed 100 scanned CRC slides and graded the tumour on each slide, per provided criteria in (a) WHO 5th edition book, (b) AJCC manual/CAP CRC protocol and (c) their clinical practice. A questionnaire for grading selected CRC subtypes was also provided. Statistical analysis was performed using Pearson's χ 2 test and Fleiss multi‐rater kappa analyses. Overall, agreement among the five reviewers when grading via WHO and AJCC criteria for low‐grade and high‐grade CRC was moderate ( κ = 0.568, P < 0.001) and good ( κ = 0.611, P < 0.001), respectively. All reviewers graded significantly more tumours as high‐grade when using WHO (median = 46) versus AJCC/CAP criteria (median = 20). Conclusions Interobserver agreement was higher using the AJCC grading criteria as a two‐tiered system. Significantly more tumours were called high‐grade using the WHO criteria. This raises concerns regarding upgrading tumours, as well as potential differences in grading tumours among pathologists worldwide, based on regional preferred grading systems. Synchronisation of these two grading systems is necessary for uniform grading of CRCs throughout institutions.

62 Background: Both Regorafenib (R) and Trifluridine/Tipiracil (T) ± BEV are widely used treatments for mCRC in later lines. This RW study evaluated optimal sequencing and associated outcomes among patients who initiated R and T in sequential lines of therapy (LOT) between LOT1-LOT6 within community oncology settings in the US. Methods: A retrospective study utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated R and T ± BEV sequentially between 09/01/2015 and 11/30/2022 (index date), with follow-up until 05/31/2023. Treatment patterns, overall survival (OS) and time to next treatment (TTNT) after sequence were assessed overall, R first (R-T) and T first (T-R). Multivariable Cox regression adjusting for age, sex, ECOG, tumor stage, and prior medication, assessed the association of factors with OS and TTNT. Results: In total, 308 mCRC patients initiating R and T (R-T, 156 pts [140 R-T and 16 R-T+BEV]; T-R, 152 pts [136 T-R and 16 T+BEV-R]) met study criteria. Baseline demographic (mean age 63 yrs, males 55%) and clinical characteristics (70% colon cancer, 58% ECOG 0-1) were similar between the cohorts. Most patients initiated index therapies at the third line of therapy (LOT3) (49% R-T, 45% T-R). The median (IQR) sequence duration was 7.4 (5.6), 6.7 (4.4), and 7.0 (4.7) months, respectively in patients with R-T, T-R, and overall. The median (95% CI) OS was 12.8 (11.2, 14.1) months among R-T and 10.2 (8.8, 11.9) months among T-R patients. Compared to R-T, the adjusted HR for the T-R sequence was 1.2 (95% CI 0.9–1.6; p=0.2). The median (95% CI) TTNT was 9.3 (8.4, 10.3) and 8.6 (7.8, 9.4) months, for R-T and T-R, respectively; the adjusted HR was 1.1 (95% CI 0.8–1.4; p=0.62). Conclusions: Patients initiating R first appeared to have a longer duration of treatment and survival, although not statistically significant. The one-year median duration of survival in this real-world setting confirms the importance of access to these treatments in patients with mCRC and can inform physicians regarding the choice of medications while sequencing therapies in mCRC. Clinical outcomes among R-T and T-R mCRC patients. Variable Level R-T (± BEV)[N 1 = 156] T (± BEV) -R[N 1 = 152] Adjusted 3,4 HR 5 (95% CI)[R-T Reference] Effect OverallSurvival Months – median (95% CI) 12.8(11.2, 14.1) 10.2(8.8, 11.9) 1.20 (0.91, 1.58) 0.20 TTNT 2 Months – median (95% CI) 9.3(8.4, 10.3) 8.6(7.8, 9.4) 1.07 (0.83, 1.37) 0.62 1 Entire R-T and T-R cohorts are presented since 16 patients in each cohort initiated T+BEV. 2 Time To Next Treatment. 3 Overall Survival adjusting for age, gender, stage at diagnosis, ECOG, prior anti-VEGF treatment. 4 Time To Next Treatment adjusting for age, gender, stage at diagnosis, and line of therapy. 5 Hazard Ratio.

54 Background: The incidence of colorectal cancer is increasing rapidly, particularly amongst younger people. Despite a screening program being widely available, most patients are diagnosed with cancer through symptomatic presentation. Leveraging electronic medical records (EMRs) through clinical decision support platforms offers potential for identifying high-risk individuals before clinical suspicion develops. This study aims to explore the challenges associated with early colorectal cancer diagnosis and evaluate the effectiveness of the cancer case finding feature of a cancer management platform called C the Signs. Methods: A retrospective analysis was conducted using data from the Mayo Data Platform, comprising records of 894,275 patients, including 7,348 diagnosed with colorectal cancer. C the Signs was employed to identify patients at risk of colorectal cancer based on EMR data. Sensitivity and specificity analyses were performed to assess the platform's performance in identifying high-risk patients. Additionally, the study evaluated the temporal discrepancy in colorectal cancer diagnoses between those flagged by C the Signs and those detected by primary care physicians. Results: The C the Signs screening platform had a sensitivity of 93.8% and a specificity of 19.7% in identifying patients at risk of colorectal cancer. Notably, 29.4% of patients with colorectal cancer were identified as being at risk up to 5 years earlier by C the Signs compared to diagnoses made by primary care physicians, highlighting the platform's potential for early detection. Conclusions: Early identification of high-risk individuals holds promise for improving patient outcomes and reducing the burden of colorectal cancer. Whilst the specificity of the C the Signs platform for colorectal cancer is relatively low, the sensitivity is comparable to the most favorable rates reported for colonoscopy. In addition, if C the Signs was used in conjunction with a relatively cheap screening test such as Faecal Immunochemical Testing, this would significantly drive up the specificity whilst maintaining the sensitivity. Further studies are needed to assess its efficacy in conjunction with tests available in primary care.

Abstract Background Crohn’s disease (CD) treatment is associated with increased risks of infection and malignancies. Although the safety of certolizumab pegol (CZP) is well established, long-term data from community-based observational studies are lacking. Aim This study aimed to evaluate long-term safety outcomes of patients from the SECURE registry receiving CZP relative to other CD treatments, including corticosteroids, immunosuppressants, and biologics. The primary outcome of this observational study was the evaluation of malignancies. Methods Adult patients with CD were prospectively monitored for up to 8 years. Pre-specified data were collected for all enrolled patients. Adverse events of interest (AEoIs) were reported per 100 patient-years (PY) of exposure. Incidence rate ratios (IRRs) were calculated for AEoIs using multivariate regression analysis accounting for exposure to multiple treatments. Malignancies reported after any exposure to CZP were attributed to CZP. Post-hoc analyses were conducted to evaluate non-melanoma skin cancer (NMSC), lymphoma, and pregnancy outcomes. Results A total of 3072 patients were enrolled in the study. The risk of AEoIs was similar between patients with only CZP exposure versus comparator exposure. Among patients with any CZP exposure, there was a higher frequency of serious infections (IRR: 2.56 [95% confidence interval (CI): 2.00, 3.29]) and hypersensitivity or anaphylactic reactions (IRR: 4.11 [95% CI: 1.80, 9.38]) versus patients with comparator exposure. Malignancy rates were similar across groups; however, concomitant use of thiopurines was associated with higher odds of NMSC (odds ratio: 2.30 [95% CI: 1.09, 4.89]). Most cases of lymphoma (5/7) occurred in patients with exposure to thiopurines. Pregnancy outcomes were similar across groups. Conclusions No new safety signals were identified for CZP; the use of thiopurines was identified as a risk factor for NMSC. Trial registration NCT00844285.

Background Echocardiographic evaluation of vegetations is crucial in infective endocarditis ( IE ). Although several studies have noted a link between larger vegetations and an increased risk of embolization, a more comprehensive evaluation of vegetation characteristics in a contemporary cohort has not been conducted. Our study aimed to define the short‐term risk of symptomatic embolization in patients with IE . Methods and Results The Mayo Clinic IE registry was screened to identify patients from 2015 to 2021 who had undergone transesophageal echocardiography. Multivariable subdistribution hazards regression analysis was used to identify factors associated with the cumulative incidence of symptomatic embolism over 30 days accounting for the competing risk of death. Overall, 779 patients with IE were included, of whom 517 (66.4%) were men, median age was 65.0 ( interquartile range, 52.9–74.8) years, and 89.3% were White. In total, 234 patients had a symptomatic embolic event, a 30‐day cumulative incidence of 30.2%. In multivariable analysis, a highly mobile vegetation was the strongest predictor of embolism ( P <0.001). Vegetation length with interaction of IE type was also associated with embolic risk ( P <0.001), with a stronger effect in native valve IE ( P interaction=0.001). Other associated factors included multiple vegetations, younger age, and Staphylococcus aureus . A nomogram that incorporated these factors was constructed to facilitate the prediction of embolic risk. Conclusions Highly mobile, larger vegetations are associated with embolic events. Embolic risk could be assessed by evaluating length as a continuous variable, alongside other echocardiographic findings, using a newly developed scoring tool; external validation is warranted.

ImportanceChronic obstructive pulmonary disease (COPD) is often undiagnosed. Although genetic risk plays a significant role in COPD susceptibility, its utility in guiding spirometry testing and identifying undiagnosed cases is unclear.ObjectiveTo determine whether a COPD polygenic risk score (PRS) enhances the identification of undiagnosed COPD beyond a case-finding questionnaire (eg, the Lung Function Questionnaire) using conventional risk factors and respiratory symptoms.Design, Setting, and ParticipantsThis cross-sectional analysis of participants 35 years or older who reported no history of physician-diagnosed COPD was conducted using data from 2 observational studies: the community-based Framingham Heart Study (FHS) and the COPD-enriched Genetic Epidemiology of COPD (COPDGene) study.ExposuresModified Lung Function Questionnaire (mLFQ) scores and COPD PRS.Main Outcomes and MeasuresThe primary outcome was spirometry-defined moderate to severe COPD (forced expiratory volume in the first second of expiration/forced vital capacity [FEV1/FVC] &amp;lt;0.7 and FEV1 [percent predicted] &amp;lt;80%). The performance of logistic models was assessed using the PRS, mLFQ score, and PRS plus mLFQ score for predicting spirometry-defined COPD.ResultsAmong 3385 FHS participants (median age, 52.0 years; 45.9% male) and 4095 COPDGene participants (median age, 56.8 years; 55.5% male) who reported no history of COPD, 160 (4.7%) FHS and 775 (18.9%) COPDGene participants had spirometry-defined COPD. Adding the PRS to the mLFQ score significantly improved the area under the curve from 0.78 to 0.84 (P &amp;lt; .001) in FHS, 0.69 to 0.72 (P = .04) in COPDGene non-Hispanic African American, and 0.75 to 0.78 (P &amp;lt; .001) in COPDGene non-Hispanic White participants. At a risk threshold for spirometry referral of 10%, the addition of the PRS to the mLFQ score correctly reclassified 13.8% (95% CI, 6.6%-21.0%) of COPD cases in FHS, but not in COPDGene.Conclusions and RelevanceA COPD PRS enhances the identification of undiagnosed COPD beyond a conventional case-finding approach in the general population. Further research is needed to assess its impact on COPD diagnosis and outcomes.

Abstract Background Histologic inflammation persists in up to 1/4 of patients with Crohn’s disease (CD) despite endoscopic mucosal healing. Histologic and combined endoscopic-histologic endpoints are evolving measures of treatment efficacy in CD; however, the impact of histologic healing on long-term outcomes and disease progression is unknown. Week (W) 52 data comparing mirikizumab (Miri) vs placebo (PBO) in the randomized, double-blind, placebo- and active-controlled, treat-through Phase 3 VIVID-1 trial in patients with moderately-to-severely active CD (NCT03926130) were reported previously.1 Methods The main objective was to evaluate the association of W12 histologic response and W12 histologic remission with W52 clinical and endoscopic outcomes in VIVID-1. Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized patients at screening, W12, and W52. All analyses were post hoc and among patients with active histologic disease (defined as a Robarts Histopathology Index &gt;0 and a Global Histologic Disease Activity Score &gt;0) at baseline. Results At W12, treatment with Miri resulted in statistically significantly higher rates of achieving histologic response and histologic remission vs. PBO (Figure). At W12, 62.1% of patients had agreement (k=0.27 [fair]) between histologic response and endoscopic response, with a greater percentage achieving histologic over endoscopic response (59.0% vs. 38.8%)*. Significantly greater proportions of patients who achieved histologic response at W12 also achieved histologic response, histologic remission, endoscopic response, endoscopic remission, combined CDAI (Crohn’s Disease Activity Index) remission and endoscopic response, and normalisation of faecal calprotectin levels ≤250 µg/g and ≤150 µg/g at W52 (Table). Similar associations were observed between W12 histologic remission and W52 outcomes. Conclusion Histologic response seems to be an early objective sign of anti-inflammatory response and was significantly associated with one-year endoscopic and histologic outcomes, as well as biomarker normalisation. *Observed data References 1.Jairath V, et al. Presented at: UEGW 2024. OP131.