Case Western Reserve University
  • Cleveland, Ohio, United States
Recent publications
Background and Objectives Sentinel lymph node biopsy (SLNB) is an area of debate in the management of lentigo maligna melanoma (LMM). The utility of SLNB and its prognostic value in LMM have not yet been studied with large databases. Methods We performed a retrospective review of the National Cancer Database (2012−2020) and the Surveillance, Epidemiology, and End Results (2010−2019) database for patients with cutaneous nonmetastatic LMM with Breslow thickness >1.0 mm. Multivariable logistic regression identified factors associated with SLNB performance and sentinel lymph node (SLN) positivity. Univariable and multivariable analyses assessed overall survival (OS) and melanoma‐specific survival (MSS) based on SLNB performance and SLN status. Results Compared to other melanoma subtypes, LMM had lower rates of SLNB (66.6% vs. 80.0%−84.0%) and SLN positivity (11.3% vs. 18.6%−34.2%). Compared to patients who did not undergo SLNB, SLN status was significantly associated with improved OS in patients with SLN positive (HR = 0.64 [0.55−0.76]) and SLN negative (HR = 0.68 [0.49−0.94]), and worse MSS only in patients with positive SLN (HR = 3.93, p < 0.05). Conclusion The improved OS associated with SLNB likely implies surgical selection bias. Analysis of MSS confirms appropriate patient selection and suggests important prognostic value associated with SLN status. These results support continued SLNB for LMM patients according to standard guidelines.
Not only historians of mathematics but also working analysts know how seventeenth through nineteenth century mathematicians advanced from vaguer notions to the set theoretic idea of function. The celebrated Princeton Lectures in Analysis of Elias Stein and Rami Shakarchi are shaped around that history, and review it at some length in both volumes 3 and 4. Stein and Shakarchi take the set theoretic notion as their official definition of function, but the reason they review that history twice is explicitly to contrast it with the modern forms of two other classical notions of function that they use informally. Terence Tao studied with Stein in the 1990s and emphasizes an even wider view of the function concept. All these authors show both how and why these generalizations of the set theoretic notion of function suit the purposes of classical and current analysis.
Background Research is the scientific basis for the profession of dietetics, as it must be located and applied in evidence‐based practice (EBP). EBP is often presented as a foundational skill for research. CEAR – Core, Evidence Application, Research – is a newly proposed model that separates Research and Evidence Application skills into distinct domains, jointly supported by a set of Core skills, thus acknowledging that education and advancement in one domain neither requires nor precipitates education and advancement in the other. The goal was to investigate the content and construct validity of the new CEAR Model. Methods A cross‐sectional online survey of randomly selected dietitians in the United States was used to collect CEAR domain scores, validated measures of research or EBP skills and self‐reported characteristics. Exploratory factor analysis, Cronbach's α and Pearson correlation between various tools and CEAR domains were used to assess validity and reliability. Analysis of variance (ANOVA) and multiple linear regression between CEAR domains and participant characteristics were used to assess convergent and divergent validity. Results One hundred and fifty‐four responses with a valid CEAR score were received and led to a three‐factor solution, supporting the theorised differentiation of research from evidence application skills (content validity). Internal reliability for the CEAR Model overall and for each domain was high. The hypothesised correlations between existing research or EBP measurement tools and the relevant CEAR domains were found (construct validity). Known groups analysis demonstrated the expected differences in CEAR domain scores based on participant characteristics. Conclusions The CEAR Model demonstrates preliminary validity and internal reliability. It adds to the current literature by acknowledging the separateness of evidence application skills from research skills.
Background Introduction: Varicella-zoster virus (VZV) reactivation was not listed as a side effect of any vaccine until introduction of COVID-19 vaccines. Since COVID-19 vaccines were introduced, several case reports described the link between COVID-19 vaccination and VZV reactivation. In our study we aimed to investigate how often patients developed VZV reactivation after mRNA COVID-19 vaccine compared to influenza vaccine. Methods We used the TriNetX platform and its global health research network containing aggregated de-identified information of electronic health records on over 100 million patients from scores of healthcare organizations. Three patient groups were identified: Patients receiving their 1st mRNA COVID-19 vaccine 12/20/2020-12/20/2022 Patients receiving their 2nd mRNA COVID-19 vaccine 12/20/2020-12/20/2022 Patients receiving influenza vaccine 12/20/2018-12/20/2022 Propensity Score Matching was used for age, gender, and Zoster vaccine status. We examined the prevalence of VZV reactivation in each group during the first 21 days following vaccination. Results Out of 444,016 patients in each matched group receiving either their 1st mRNA COVID-19 vaccine or the Influenza vaccine, 0.04% in the COVID-19 vaccine group and 0.15% in the influenza group, odds ratio (OR) 0.24 (95% CI 0.20-0.29), were diagnosed with VZV reactivation within 21 days. Among 445,382 patients in each matched group receiving either their 2nd mRNA COVID-19 vaccine or their influenza vaccine, 0.04% in the COVID-19 vaccine group and 0.13% in the Influenza group, OR 0.27 (95% CI 0.22-0.32), were diagnosed with VZV reactivation within 21 days. There was a lower risk of VZV reactivation after 1st or 2nd dose of mRNA COVID-19 vaccine than influenza vaccine. Conclusion The risk of VZV reactivation after the 1st or 2nd dose of mRNA COVID-19 vaccination is smaller than VZX reactivation after influenza vaccine. The risk of VZV reactivation after mRNA COVID-19 vaccine is very low and hesitance to receive COVID-19 vaccine due to concern of VZV reactivation is not substantiated. Disclosures David C. Kaelber, MD, PhD, MPH, FAAP, FACP, FACMI, FAMIA, Becton, Dickinson and Company: Advisor/Consultant|Dynavax Technologies Corporation: Advisor/Consultant|Merck Sharp & Dohme Corporation: Advisor/Consultant
Background Transrectal ultrasound-guided biopsy of the prostate (TRUBP), first described in the 1980s, remains a commonly performed procedure. Since approximately 2010, increasing infection rates due to fluoroquinolone-resistant E. coli have been reported. These data prompted a change in our recommended antibiotic prophylaxis in March 2014 from ciprofloxacin to ceftriaxone. Limited data are available on whether this strategy leads to improved outcomes or contributes to emergence of infections due to ceftriaxone-resistant organisms. Methods We conducted a retrospective, single-center cohort study comparing patients who received ciprofloxacin monotherapy from 1/1/2011 through 2/28/2014 and patients who received ceftriaxone monotherapy from 3/1/2014 through 12/31/2022 as prophylaxis for TRUBP. The primary outcomes were the percentage of procedures with positive blood cultures within 30 days after the procedure and the percentage of urinary tract infections (UTI), defined as a positive urine culture, within 30 days after the procedure. Secondary outcomes included the percentage of procedures with UTI due to specific organisms, including E. coli, fluoroquinolone-resistant E. coli, and extended-spectrum beta-lactamase producing (ESBL) E. coli within 30 days after the procedure. Results Of 2,910 total TRUBP procedures, ciprofloxacin was used for prophylaxis in 653 procedures in 578 patients, and ceftriaxone was used for 2,257 procedures in 1,794 patients. As shown in Table 1, patients receiving ceftriaxone prophylaxis had significantly fewer positive blood and urine cultures in the 30 days after the procedure and significant reductions in positive urine cultures with E. coli, fluoroquinolone-resistant E. coli, and non-E. coli Enterobacteriaceae. Conclusion Our findings suggest that in the setting of increasing rates of fluoroquinolone resistance in E. coli, switching from ciprofloxacin to ceftriaxone for TRUBP prophylaxis may result in fewer infectious complications without increasing the risk for emergence of infections due to ceftriaxone-resistant organisms. Disclosures All Authors: No reported disclosures
Background Stenotrophomonas maltophilia is a leading cause of carbapenem-resistant, Gram-negative bacterial bloodstream infections (BSI). Methods A retrospective, observational study was conducted at four centers in Italy and the United States. Patients who were treated for S. maltophilia BSI between 1/1/2015 through 12/31/2020 with available antimicrobial susceptibility testing (AST) as reported by the local clinical microbiology laboratories were included. Data extracted from the electronic medical record and collected in a central database. Acute critical illness was measured through the Pitt Bacteremia Score, and chronic comorbidities through the Charlson Comorbidity Index. Desirability of outcome ranking (DOOR) outcomes were determined as shown. Table. DOOR Outcomes Results Median age of 143 patients was 54 years (IQR 40-65 years), and 77/143 (54%) were women. The median Charlson Comorbidity Index and Pitt bacteremia score were 3 (IQR 2-5), and 1 (IQR 0-2). At time of culture, 22/143 (15%) patients were in the intensive care unit, and 15/143 (10%) patients were on mechanical ventilation. Of tested isolates, 4/142 (3%), 0/53 (0%), 17/140 (12%) were non-susceptible to trimethoprim/sulfamethoxazole, minocycline, and levofloxacin, respectively. In the first 14 days after culture, 68/143 (48%) received at least 2 different antibiotics either together or sequentially. Levofloxacin (84/143, 59%), trimethoprim/sulfamethoxazole (68/143, 48%), and tetracyclines (23/143, 16%) were most used. Novel treatment approaches were less commonly employed; cefiderocol in 5/143 (3%), and ceftazidime-avibactam & aztreonam in 6/143 (4%) of patients. Overall mortality at 30 days was 29/143 (20%); 30-day mortality was 8/17 (47%) in patients with fluoroquinolone-non-susceptible isolates, vs. 20/123 (16%) in patients with fluoroquinolone-susceptible isolates (p< 0.01). DOOR distribution of outcomes is shown in Figure 1. A randomly selected patient with a fluoroquinolone -susceptible isolate had a 74% (95% CI 61%-84%, p< 0.001) likelihood of a better outcome as compared to a randomly selected patient with a fluoroquinolone-non-susceptible isolate.Figure.DOOR Outcomes*Three isolates were not tested for fluoroquinolone (FQ) susceptibility Conclusion S. maltophilia BSI is associated with poor outcomes and high mortality, especially in patients with fluoroquinolone-non-susceptible isolates. Disclosures Giusy Tiseo, MD, Shionogi: Honoraria Robert A. Bonomo, MD, Entasis: Grant/Research Support|Merck: Grant/Research Support|venatorax: Grant/Research Support|Wockhardt: Grant/Research Support Marco Falcone, MD, PhD, Gilead: Board Member|Gilead: Honoraria|Menarini: Board Member|Menarini: Grant/Research Support|Menarini: Honoraria|MSD: Board Member|MSD: Grant/Research Support|MSD: Honoraria|Nordic Pharma: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Shionogi: Honoraria David van Duin, MD, PhD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Union: Advisor/Consultant|Utility: Advisor/Consultant
Background Increased breakthrough infections among nursing home residents (NHR) are clinically consequential despite good vaccine coverage and substantial antibody titers. While vaccination blunted severe outcomes, breakthrough infections may arise from lower vaccine-induced antibody quality. We aimed to assess vaccine-induced antibody quality among NHR and younger healthcare workers (HCW) using antibody avidity. Methods We longitudinally sampled 50 NHR and 30 HCWs, with or without prior history of COVID-19, who received the BNT162b2 mRNA vaccine at 0-14 days before, 2 weeks, and 4-6 months after each vaccine dose up to the bivalent (BV) boosters. Primary outcomes included anti-spike, anti-Receptor Binding Domain (RBD), and avidity levels to the ancestral Wuhan, Delta, and Omicron BA.1 strains determined by bead-multiplex immunoassay and ability to bind after 6M urea vs. saline incubation. Results After the primary series, anti-spike and RBD titers increased significantly to all 3 strains in both NHR and HCW. Avidity levels progressively increased across all time points up to the 3rd dose. Interestingly, this increase continued 6-8 months after vaccination suggesting that affinity maturation continues to occur for many months after the primary vaccination series. NHRs without prior infection have the poorest avidity levels to Delta and Omicron, especially before the 3rd dose. The 3rd dose raised avidity levels substantially in all groups and for all strains. Avidity levels after boosting, across the 3rd and 4th doses, demonstrate evidence of durability. Preliminary findings after BV boost show a continuation of avidity maturation with a larger impact on prior infected individuals. Wuhan Spike Avidity Avidity index of the Wuhan spike antibody across different time points among naive and prior infected individuals. Prevax- before primary series; Postvax- 2 weeks after primary series; M6- 6 months after primary series; Postboost- 2 weeks after 1st monovalent booster; M3M6postboost- 3-6months post booster; Postboost 2- 2 weeks after 2nd monovalent booster. NH- Nursing home; HCW- Healthcare Workers Omicron BA.1 spike Avidity Avidity index of the BA.1 spike antibody across different time points among naive and prior infected individuals. Prevax- before primary series; Postvax- 2 weeks after primary series; M6- 6 months after primary series; Postboost- 2 weeks after 1st monovalent booster; M3M6postboost- 3-6months post booster; Postboost 2- 2 weeks after 2nd monovalent booster. NH- Nursing home; HCW- Healthcare Workers Conclusion This study underscores the importance of booster vaccination among NHR and HCWs. The booster dose increases avidity, adding to vaccine-induced antibody functional ability. Higher avidity antibodies have higher cross-reactivity to other SARS-CoV-2 strains, as Wuhan boosting improves Delta and Omicron avidity, and should improve protection from ever-evolving strains. Higher avidities may help explain how the vaccine’s protective effects persist even while antibody titers fade between vaccine doses. Disclosures Stefan Gravenstein, MD, MPH, CDC: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|GSK: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|NIH: Grant/Research Support|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Grant/Research Support|Seqirus: Honoraria David Canaday, MD, Pfizer: Grant/Research Support
Background Mycobacterium tuberculosis (Mtb) remains a leading cause of pediatric morbidity and mortality worldwide. As TB develops quickly following exposure in young children, identifying clinical, diagnostic, and epidemiologic factors associated with progression to pediatric TB is an important step towards early diagnosis, and prioritization for preventive therapy. Our objectives are to compare epidemiologic risk scores (ERS), and tests of immune-sensitization to Mtb, among young children with known Mtb exposure who did and did not develop TB. Methods Using a household contact (HHC) study in Kampala, Uganda, we recruited 75 children ≤ 5 years living with an adult with recently confirmed TB, performed a complete TB diagnostic evaluation, and assigned children into two baseline cohorts: asymptomatic with negative diagnostic studies (PedAS) versus symptomatic (PedTB). All children underwent tuberculin skin test (TST) and interferon gamma release assay (IGRA) testing at enrollment, and detailed epidemiologic and clinical characteristics were used to compute ERS for Mtb exposure (Figure 1). Comparisons were performed using chi-square test, T-test, Fisher’s exact test and Mann–Whitney U test.Figure 1.Epidemiologic Risk Score (ERS) The ERS includes 10 indicators of risk of Mtb infection. The score ranges from 0 to 10, and it is composed as a sum across all the above variables with 1 equaling the presence of each particular risk factor. A higher score indicates a higher risk. Results Of 75 children, 45 (60%) were classified as PedAS and 30 (40%) as PedTB. The two groups did not differ in terms of age, sex, ERS, or presence of BCG scar (Table 1). IGRA positivity also did not differ between groups (27.3% vs. 50%, p-value = 0.09), and when stratified by age, only 30% of PedTB participants < 2 years had a positive IGRA (Table 2). There was no difference in ERS by IGRA status. Indeterminate IGRA results occurred in 3/75 participants. Conversely, TST was more likely to be positive categorically (40% vs. 70%, p-value = 0.02) and quantitatively (0mm vs. 11.9mm, p-value = 0.02) among those in the PedsTB cohort. There was no difference in ERS by TST status.Table 1.Comparing baseline cohorts: Asymptomatic for TB (PedAS) vs. Symptomatic for TB (PedTB) Assignment of baseline cohorts was based on presence of signs and symptoms of TB disease, chest X-ray findings, and microbiologic testing (AFB smear and culture; GeneXpert Ultra) of two induced sputum samples. Counts (percentages), means [+/- standard deviation], or median [quartiles]. χ 2: Chi-squared test. MWU: Mann–Whitney U test. QFT: QuantiFERON-TB Gold. * Statistically significant at p<0.05.Table 2.Comparing immune-sensitization of Asymptomatic for TB (PedAS) and Symptomatic for TB (PedTB) cohorts stratified by age Assignment of baseline cohorts was based on presence of signs and symptoms of TB disease, CXR findings, and microbiologic testing (AFB smear and culture; GeneXpert Ultra) of two induced sputum samples. QFT: QuantiFERON-TB Gold. Conclusion In this cohort of young, Ugandan children with known Mtb-exposure, commonly used epidemiologic and clinical characteristics quantified as ERS, and IGRA testing, were not useful in distinguishing between children with TB diseases versus asymptomatic exposure. However, TST was significantly different between cohorts, suggesting that TST is valuable for detection of immune-sensitization to Mtb in young children who develop TB. Disclosures All Authors: No reported disclosures
Background Lipohypertrophy (central adipose tissue (AT) accumulation) is a common and significant problem in people with HIV (PWH). Pathogenesis remains elusive; yet, AT abnormalities are key drivers of cardiometabolic co-morbidities in HIV. We aimed to assess effects of semaglutide, a glucagon-like peptide-1 receptor agonist, on AT in PWH with lipohypertrophy. Methods We conducted a randomized, double-blinded, placebo-controlled trial of virologically-suppressed, non-diabetic PWH ≥ 18 years of age on stable antiretroviral therapy (ART) with body mass index (BMI) ≥ 25 kg/m2, increased waist circumference/waist-to-hip ratio, and subjective increased abdominal girth after ART initiation. Participants were randomized 1:1 to 32 weeks semaglutide (8-week titration + 24 weeks 1.0 mg weekly subcutaneous injection) or matching placebo. Computed tomography and whole-body dual-energy X-ray absorptiometry were used to measure area/density in abdominal AT [total (TAT), visceral (TAT), and subcutaneous (SAT)] and body composition [lean body mass (LBM), limb/trunk/total body fat (TBF)], resp. Semaglutide effects were estimated using generalized estimating equations or simultaneous quantile regressions on outcome variables. Results 108 participants were enrolled (N = 54 semaglutide: median age = 52 years, 70% male, 61% Black, 83% integrase inhibitor). Groups were well-matched at baseline. In unadjusted models, semaglutide group had greater reductions (P < 0.05) in BMI, homeostatic model of insulin resistance (HOMA-IR), trunk fat, TBF (at quantile ≥ 75th), TAT, and SAT with trends (P < 0.1) for limb fat and VAT (Fig 1/Table 1). Semaglutide effects remained significant for BMI, HOMA-IR, trunk fat, TAT, and VAT after adjusting for age, sex, CD4, and ART duration (Table 2); caloric intake was also significant at ≤ 50th quantile. No differences were seen in LBM, AT density, or VAT/TAT ratio. Semaglutide was well-tolerated; serious adverse events were rare. Conclusion Semaglutide significantly decreased central fat in PWH with lipohypertrophy, primarily driven by reductions in VAT. Semaglutide may offer an effective treatment to decrease visceral adiposity and reduce co-morbidity risk. Further investigation is needed to determine mechanisms by which reductions in visceral adiposity occur. Disclosures Grace A. McComsey, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support
Background The Infectious Diseases Society of America (IDSA) developed and disseminated a Core Antimicrobial Stewardship (AS) Curriculum intended to formalize AS training in infectious diseases (ID) fellowship programs in 2018. This study identified individual program approaches to curriculum implementation and intended to use this information to develop an implementation guide tailored to specific program needs. Methods We distributed surveys to all fellowship program directors (PDs) who had previously implemented the Core AS Curriculum. Questions were designed to identify ID program structure, curriculum participants, curriculum sections and materials utilized, and resources and barriers to implementation. Both structured and qualitative responses were captured. The results were summarized descriptively and organized into a framework connecting barriers to proposed solutions. Results PDs from 34 unique programs who had administered the Core Curriculum to an estimated 405 ID fellows responded to the survey, out of the 159 institutions invited (21.4%). Most represented adult programs which had administered the curriculum for at least 2 years (Table 1). Additional learners often included ID faculty and pharmacy trainees, and teachers were mostly AS program leadership. Most PDs reported limited faculty time as a barrier to implementation, whereas dedicated AS curricular time was a resource available to most programs (Figure 1). Approaches to curriculum implementation based on survey responses relating to each fellowship program feature were suggested, some of which applied to multiple program features (Figure 2). Qualitative feedback was generally positive, and most PDs indicated that they intended to continue to implement the curriculum. Additional materials such as a facilitator guide and demonstrations were proposed as other components which could assist with curriculum implementation.Table 1.Descriptive characteristics of infectious diseases fellowship programs participating in the survey.Figure 1.Self-reported barriers and resources described within each infectious diseases fellowship program.Figure 2.Roadmap for infectious diseases fellowship program features. Roadmap with infectious diseases fellowship program features (rounded green boxes) connected to identified potential approaches to curriculum implementation (rectangular blue boxes). Program features are categorized as relating to conference structure, program resources, or program barriers. Suggested approaches with potential application to multiple program features are highlighted in orange. Conclusion The IDSA Core AS curriculum provides an effective means of formalizing basic AS education into ID fellowship training. Curriculum implementation can be optimized by tailoring to training program resources and unique features. An implementation roadmap may be a useful tool to assist ID fellowship PDs with this task. Disclosures Payal K. Patel, MD MPH, qiagen: Honoraria Julie Ann Justo, PharmD, MS, FIDSA, BCPS, Gilead Sciences: Advisor/Consultant|Shionogi: Advisor/Consultant|Vaxart: Stocks/Bonds Erica J. Stohs, MD, MPH, bioMerieux: Grant/Research Support|Merck: Grant/Research Support Zachary Willis, MD, MPH, Merck Sharp & Dohme Corp: Grant/Research Support|Pfizer Inc: Grant/Research Support Trevor C. Van Schooneveld, MD, FSHEA, FACP, AN2 Therapeutics: Grant/Research Support|Biomeriuex: Advisor/Consultant|Biomeriuex: Grant/Research Support|Insmed: Grant/Research Support|Thermo-Fischer: Honoraria Amy Y. Kang, Pharm.D., BCIDP, Paratek: Grant/Research Support Kartik Cherabuddi, MD, FACP, FIDSA, Contrafect Corporation: Grant/Research Support|Labcorp Drug Development: Grant/Research Support|Merck Sharp & Dohme: Grant/Research Support Gary Fong, PharmD, Critical Innovations, LLC: Advisor/Consultant Molly L. Paras, MD, Angiodynamics: Honoraria David Gaston, MD PhD, American Association of Clinical Chemistry: Honoraria|BioMerieux, Inc: Advisor/Consultant|IDbyDNA, Inc.: Grant/Research Support|Illumina, Inc.: Grant/Research Support
Background Negative influenza-associated outcomes disproportionately impact non-White individuals. Targeted influenza vaccine coverage could improve outcomes in minority groups. This study examined the role of race-ethnicity and resource inequity in vaccine coverage. Methods We analyzed data from all outpatient visits at University Hospitals CMC from October 01, 2022 to February 28, 2023. Race, ethnicity, age, sex, income, home address, ICD diagnosis, and influenza immunization records were collected. Patients who received an influenza vaccine between July 01, 2022 and February 28, 2023 were considered immunized. A 9-digit patient zip code was used to obtain state Area Depravity Index (ADI) data provided by University of Wisconsin School of Medicine and Public Health. The state ADI ranges from 1 to 10, with group 1 being the least disadvantaged and 10 being the most disadvantaged. We used logistic regression analysis to estimate the odds for being vaccinated predicted by race-ethnicity, state ADI, age, and sex. Results Out of 301,572 hospitalizations, 59.0% were women, 81.2% were White non-Hispanic, 16.0% were Black non-Hispanic, and 2.7% were Hispanic. Black non-Hispanics were most disadvantaged with a mean State ADI of 7.54, followed by Hispanics at 5.64. White non-Hispanics were least disadvantaged with a mean State ADI of 3.99 (p< 0.001)(Table 1). Black non-Hispanics were disproportionately represented in the most disadvantaged areas (27.93%). Black non-Hispanics were 38% less likely to be vaccinated than White non-Hispanics. After ADI, sex, and age adjustment, Black non-Hispanics were 11% less likely to be vaccinated (OR: 0.89; 95% CI: 0.868 - 0.912). With each point increase in State ADI, vaccination rate decreased by 7% (OR: 0.93; 95% CI: 0.928 – 0.933)(Table 3). Regression analysis suggested significant interaction between race-ethnicity and State ADI. Influenza Vaccination by individual characteristics within overall population and race-ethnicity Influenza vaccination by race-ethnicity adjusting for State ADI, age, and sex Influenza vaccination by race-ethnicity adjusting for State ADI and sex, and stratified by age groups Conclusion This cross-sectional study found racial and ethnic disparities in rates of influenza vaccination. The effect of race-ethnicity on vaccination rate is dependent on ADI. These data identified subgroups on which to focus future influenza prevention efforts. The generalization of the study is limited and similar analysis from other areas and vaccines would be beneficial. Disclosures Elie Saade, MD, MPH, FIDSA, Envision Pharma: Speaker, Presenter|Johnson and Johnson: Speaker, Travel, Lodging|Protein Sciences Corp: Grant/Research Support|Sanofi Pasteur: Speaker, Travel and Lodging
Background This study describes clinical decisions on switching to B/F/TAF or DTG/3TC. Methods Sequential explanatory design was used in this mixed methods study. Retrospective EMR analysis of Trio HIV Network data characterized people living with HIV (PWH) ≥18 yrs prescribed B/F/TAF or DTG/3TC (4/2019-6/2022). Informed by retrospective analyses, interviews among selected clinicians were summarized through thematic analyses. Qualitative responses were then quantified to describe regimen choice. Results In EMR analysis, of 6996 eligible PWH, 84% were prescribed B/F/TAF, 16% DTG/3TC. B/F/TAF prescription was associated with HIV clinical parameters (detectable viral load [VL], CD4< 200 cells/μL) and substance use, while prescribing DTG/3TC was associated with renal toxicity and obesity. In qualitative analysis, 27 clinicians (44% MDs, 33% NPs, 22% PAs) participated in interviews. Factors influencing regimen switch endorsed by ≥50% of providers included resistance, HBV coinfection, eGFR, PWH views, VL, mental health, and weight [Figure 1]; only 22% felt CD4 count was relevant in decisions to switch. Over 89% of providers reported B/F/TAF or DTG/3TC switch discussions were related to development/anticipation of new symptoms or comorbidities. All providers had patient-initiated switch discussions motivated by individual concerns, advertisements, or social influences [Table 1]. In differential choice analysis, PWH were more likely to be prescribed B/F/TAF if they were viremic, had HBV co-infection, inconsistent clinic attendance, non-adherence, or substance use; providers were more likely to prescribe DTG/3TC when there were concerns about weight or eGFR < 30 [Table 2].Figure 1.Factors influencing switch to either B/F/TAF or DTG/3TC regimen.Table 1.Themes in decisions to consider a switch to B/F/TAF or DTG/3TC.Table 2.Differential choice based on individual profile. Conclusion This mixed methods approach highlights discordance between beliefs and evidence in clinical decision making. CD4 count was not a consideration for ≥75% of providers in interviews, although CD4 < 200 cells/μL was significantly associated with prescribing B/F/TAF in EMR analysis. Provider beliefs surrounding B/F/TAF and DTG/3TC suggested general preferences for B/F/TAF for a broader population, including those with possible adherence challenges, substance use, or resistance, while DTG/3TC was preferred when weight gain or eGFR was a concern. Disclosures Rick A. Elion, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Proteus: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Megan Dunbar, PhD, Gilead: Employment Joshua Gruber, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Grace A. McComsey, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Peter Shalit, MD, PhD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support Janna Radtchenko, MBA, Trio Health: Employee
Background Mycobacterium avium Complex (MAC) are nontuberculous mycobacteria (NTM) responsible for chronic and debilitating diseases, with rising global prevalence. Clinical relapse/reinfection rates of MAC following treatment with first-line therapies range from 25% to 45%. β-lactam antibiotics are not utilized for the treatment of MAC due to clinically high minimum inhibitory concentrations (MICs). Recent studies have explored the effect of combining β-lactam antibiotics to reduce the MICs of other NTMs by inactivating multiple targets in the peptidoglycan synthesis pathway. Our hypothesis is that the cell wall of MAC is similar to that of other NTMs and thus, interrupting the peptidoglycan synthesis pathway using β-lactam combinations would result in lower MICs. In this study, we aim to determine the MICs of meropenem (MEM) in combination with ceftaroline (CPT), cefdinir (CDR), and cefuroxime (CXM) against MAC. Methods A total of 31 clinical MAC isolates underwent susceptibility testing using broth microdilution method. MICs were tested for MEM, CPT, CDR, and CXM, alone, as well as combination of MEM plus either CPT, CDR, or CXM. Results The susceptibility of MAC isolates to MEM was significantly enhanced when combined with CPT, CDR, and CXM. This effect was most prominent with the addition of CPT, with MIC50/MIC90 of < 0.125/1 µg/mL (compared to 16/64 µg/mL for MEM alone and 16/128 µg/mL for CPT alone), and CDR, with MIC50/MIC90 of < 0.125/2 µg/mL (compared to 16/ >128 µg/mL for CDR alone) (Table 1). The distribution of MICs of β-lactams alone and in combination demonstrates a “left shift” towards lower MIC values for the latter. A Wilcoxon signed-rank analysis confirmed that the change in MIC values for all β-lactam combinations compared to β-lactams alone reached statistical significance (p-value < 0.001, Figure 2). Conclusion In this study, we demonstrate that the susceptibility of MAC to MEM is restored with the addition of CPT and CDR. Our data support further exploration of β-lactam combinations as a therapeutic strategy against resistant MAC infections, refractory cases, and when first-line agents are poorly tolerated. Furthermore, our observations suggest that MAC and other NTMs share cell-wall synthetic pathways and that β-lactam combinations can overcome resistance. Disclosures Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
Background Targeted antimicrobial regimens rely on prompt isolation and identification of the pathogen. When conventional gold standard culture-based methods fail to identify a pathogen, broad range PCR and next-generation 16S rRNA sequencing has emerged as a clinically useful and increasingly frequent diagnostic tool. However, its impact in clinical decision making and effect on outcomes, particularly with negative results, remains poorly elucidated. This study aims to evaluate the clinical impact of 16S rRNA in adult infections. Methods A retrospective analysis was performed on clinical specimens analyzed by 16S rRNA from August 2016 to December 2021 in our institution. Electronic medical records were reviewed to determine if 16S rRNA results had clinical utility, defined as prompting a change or stop of therapy or confirming the prescribed antimicrobial regimen. Antimicrobial-related events, readmission and infection-related mortality at 90 days were the outcomes of interest and were compared between groups using the Fisher's exact test. Results Three hundred fifty-nine samples were included in the analysis. Clinical utility was identified in 108 (30.1%) specimens including 45 (41.7%) with negative 16S rRNA results (Figure 1). The most common pathogens identified were skin flora (19.4%) and Streptococci spp. (13.9%). Body fluid specimens yielded the most clinical utility (62.5%) followed by cranial samples (60%) and valve/endovascular graft samples (52%) (Figure 2). Readmissions were significantly lower in the clinical utility group compared to the no clinical utility group (10.5% vs 19.8%, p=0.04, 95% confidence interval 0.21-0.99) (Table 1). Mortality and adverse events were not statistically different between the two groups.Figure 1.Proportion of clinical specimens stratified by clinical impact of 16S rRNA sequencing.De-escalation of antibiotics = narrowing coverage or shortening course. Confirmation of antibiotic regimen = confirming current coverage, escalation of coverage, or lengthening course. Infectious process ruled out = low baseline suspicion for infection. No change = negative 16S rRNA result or those lost to follow-up (true negative utility). Inapplicable 16S rRNA = positive culture result before 16S rRNA result or intended therapy less than or equal to 14 days.Figure 2.The clinical utility of 16S rRNA sequencing results by clinical specimen type.Body fluid included pericardial fluid, peritoneal fluid, middles ear fluid, and cyst/seroma fluid. LN: lymph node, BAL: bronchoalveolar lavage, CSF: cerebrospinal fluid.Table 1.Comparison of outcomes between clinical utility and no clinical utility groups.LTFU: lost to follow-up, CI: confidence interval. Conclusion Both positive and negative 16S rRNA results have clinical utility in our study with body fluid specimens having the highest clinical utility. Readmissions were statistically lower in cases with clinical utility, while adverse events and mortality were numerically lower but not statistically significant. To our knowledge, this is the first study to demonstrate the impact of negative 16S rRNA results in adult infections, and further studies are needed to determine the most effective application for patient care. Disclosures Lisa M, Stempak, MD, Cytovale Inc: Advisor/Consultant
Background Mycobacterium abscessus (Mab) represents a significant clinical challenge, with a rising incidence in recent times. The current therapeutic approach, which involves prolonged IV administration of amikacin, is associated with notable toxicities. Consequently, there is a pressing need to explore safe alternatives in antibiotic therapy. This study aimed to evaluate the in-vitro synergistic effect of a double β-lactam (DBL) combination which is safe for all ages. Methods We conducted static concentration time-kill (SCTK) studies utilizing Mab strain ATCC19977 over 10 days in duplicate. SCTK evaluated the impact of imipenem (IPM) and ceftaroline (CFT) in both monotherapy and combination therapy on bacterial killing (inoculum: 6 log10 CFU/mL). To counteract the recognized extent of thermal degradation of β-lactams, predetermined quantities of IPM and CFT were added every 24 hours. Synergistic killing was estimated in the S-ADAPT software. In addition, the post-antibiotic effect (PAE) was measured following a 2-hour exposure to β-lactams. The β-lactams were removed by exchange with drug-free broth after centrifugation. Results DBL of IPM+CFT exhibited synergistic bactericidal activity, surpassing that of monotherapy with rapid regrowth observed in 1-3 days. Monotherapy demonstrated up to ∼1.5 log10 killing followed by near-complete regrowth over a period of 10 days. DBL demonstrated significant synergistic killing, resulting in rapid and the most extensive reduction (∼3.5 Log10 CFU/mL) and suppression of regrowth over 10 days. The addition of a β-lactamase inhibitor reduced the CFT concentration required for bacterial killing, resulting in synergistic bacterial killing at an achievable concentrations in-vivo mouse studies and clinical trials in the future. Furthermore, PAE were 4 minutes for IPM and 2 hours for CFT. Strikingly, the DBL at a concentration of 1xMIC demonstrated noteworthy bacteriostatic activity, with the suppression of bacterial growth lasting up to 14 h. Conclusion DBL therapy yielded the most rapid and extensive killing of Mab with limited regrowth. The β-lactamase inhibitor was efficacious in inhibiting a broad-spectrum β-lactamase (blaMab). The prolonged PAE observed in the DBL of IPM plus CFT may prove beneficial for intermittent dosing regimen. Disclosures Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
Background M. abscessus (Mab) is among the most clinically challenging pathogens. There are significant gaps remaining in mechanism of β-lactams action in Mab. β-Lactams preferentially inactivate one or multiple different L,D-Transpeptidases (LDTs) and penicillin-binding proteins (PBPs). Founded on our LDT binding data and in vitro synergistic efficacy of imipenem (IPM), ceftaroline (CFT), and amoxicillin (AMX) in Mab, this study aimed to identify binding affinities, conformational changes and the thermal stability of five LDTs and PBPs via β-lactam binding for further structure-activity relationship. Methods Binding affinity was measured by kinetic studies, MS analysis, or Bocillin-FL inhibition assay. We investigated changes in the secondary structure of five LDTs (LDT1-5), d,d-carboxypeptidase, PBPB, and PBP-lipo in response to bind of IPM, CFT, and AMX using circular dichroism (CD) spectroscopy in the far-UV region. To assess the thermal stability of these LDTs, we employed a Differential Scanning Fluorimetry (DSF) assay. Results CD analysis revealed a significant negative shift of LDT1, LDT2, and PBPB upon binding with either single or combination of imipenem (IPM) and ceftriaxone (CFT), particularly in the 210-220 nm range. Using DSF, IPM and CFT binding to LDTs, DDC and PBPB were found to alter the thermal stability of these protein enzymes. IPM induced a decrease in the melting temperature (Tm) in the range of 2.6-6.8 ˚C for LDTs and PBPB, while caused an increase in Tm for DDC. CFT caused decrease in Tm in the range of 1.4-3 ˚C for LDTs but increase in Tm for DDC and PBPB. In contrast, amoxicillin (AMX) only targeted DDC, PBPB, and PBP-lipo and caused changes in Tm. The magnitude of the change in Tm varied between combinations and single β-lactams. Although there was no evidence of a correlation between changes in protein stability upon ligand binding and ligand binding affinity, IPM with high binding affinity (lower value of Ki,app) resulted in larger decreases in Tm compared to CFT. Conclusion β-Lactam binding in single and combination leads to distinct structural changes of LDTs and PBPs, likely reflecting synergistic interactions between the two β-lactams. Further crystallography will be required to gain a better understanding of the induced structural changes. Disclosures Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
Background Highly Resistant (including ceftriaxone-resistant and carbapenem-resistant) Enterobacterales (HRE) are a major and growing public health threat. Community spread of HRE is poorly understood. Methods Monthly stool samples were obtained from patients who were discharged home after a hospitalization at one of 6 participating US medical centers with a clinical culture positive for HRE based on local laboratory antimicrobial susceptibility testing. Stool samples were also collected from community and household contacts they referred, and any contacts referred by those contacts. Samples were screened by culture on selective media for HRE, and with PCR for presence of extended-spectrum β-lactamase (ESBL), AmpC, and carbapenemase genes. Whole genome sequencing was performed on selected isolates. Results Of 1,923 patients with positive HRE cultures from healthcare settings, 943/1,923 (49%) were discharged home. 65/943 (7%) were consented into the study, and 31/65 (48%) returned at least one sample (median of 6 samples; IQR 5-10). The index HRE species was isolated from stool samples from 19/31 (61%) participants; the median duration of detected carriage was 391 days (range 84-662 days). Screening for resistance genes was performed on 477 sample-derived isolates (Table 1); ESBL/AmpC and carbapenemase genes were present in 221/447 (49%) and 17/447 (4%), respectively. Stool samples (median of 7 samples; IQR 5-11) were collected from 11 contacts of 9 participants, and 1 contact of a contact. Index HRE were isolated from samples from 10/12 contacts (83%); the median duration from date of positive index culture to last positive sample in a contact was 400 days (range 146-588). Whole genome analysis confirmed genetic similarity (< 21 single nucleotide polymorphism difference) between ceftriaxone-resistant blaSHV and blaCTX-M-15 carrying K. pneumoniae isolates in a cluster of 4 participants, which included secondary transmission between a contact of the index patient and one of their contacts over a period of 555 days.Table.Resistance genes Conclusion Patients with a clinical culture positive for HRE are at risk for prolonged intestinal HRE carriage after hospitalization. Upon returning home, community spread of HRE was very common in this cohort. Disclosures Robert A. Bonomo, MD, Entasis: Grant/Research Support|Merck: Grant/Research Support|venatorax: Grant/Research Support|Wockhardt: Grant/Research Support David van Duin, MD, PhD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Union: Advisor/Consultant|Utility: Advisor/Consultant
Background Several randomized controlled trials (RCT) have shown that short-course (∼7 days) antibiotic treatment is non-inferior to longer antibiotic courses (∼14 days) in patients with uncomplicated bloodstream infection (BSI) with mostly susceptible Gram-negative bacteria. Here, we evaluate short-course therapy in ceftriaxone-resistant E. coli BSI. Methods In a prospective cohort of 300 patients with E. coli BSI at 14 United States hospitals between November 2020 and April 2021, each patient with ceftriaxone-R E. coli BSI, and the next consecutive patient with a ceftriaxone-S E. coli BSI was included. Patients who received 5-8 days (“short”) or 9-21 days (“long”) of antibiotics were included in this analysis. Patients who died before day 9 were excluded. Primary outcome was a Desirability of Outcome Ranking (DOOR, Table 1) based on disposition at day 30 after collection of the index blood culture. Ceftriaxone susceptibility was centrally determined using broth microdilution for all bacterial isolates. Desirability of outcome ranking (DOOR) categories Results Of 300 patients in the original cohort, 227 were included; 44 patients (24 ceftriaxone-S, 20 ceftriaxone-R) received short (median 8 days, range 5-8 days), and 183 patients (96 ceftriaxone-S, 87 ceftriaxone-R) received long duration (median 15 days, range 9-21 days). Age (median 68 years, IQR 57-77 years), sex (125/227 [55%] female), and Charlson comorbidity index (median 2, IQR 1-4) were similar between groups. Notably, almost all patients (18/19, 95%) with solid organ or stem cell transplant were in the long duration group. The median Pitt bacteremia score was 2 (IQR 1-3) in the short duration group vs. 1 (IQR 0-3) in the long duration group (Wilcoxon Rank Sum p=0.07). DOOR outcomes were similar in both groups (Figure and Table 2). Numerically more patients in the ceftriaxone-resistant group on short treatment were in category 3; 4/20 (20%) vs 5/87 (6%) in the long duration group. These 4 patients all had unsuccessful discharge combined with renal failure (n=2), and/or lack of clinical response (n=3). Desirability of outcome ranking (DOOR) analysesFigure.DOOR outcomes Shown are the percentages of patients in each group with a specific DOOR category outcome. Conclusion Short duration of therapy was less frequently used than long duration of therapy in this prospective cohort of E. coli BSI. Further studies are needed to determine whether short-course therapy is appropriate for ceftriaxone-R E. coli BSI. Disclosures Yohei Doi, MD, PHD, bioMerieux: Advisor/Consultant|FujiFilm: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Honoraria|GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Moderna: Advisor/Consultant|Moderna: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria Owen Albin, MD, Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant Elie Saade, MD, MPH, FIDSA, Envision Pharma: Speaker, Presenter|Johnson and Johnson: Speaker, Travel, Lodging|Protein Sciences Corp: Grant/Research Support|Sanofi Pasteur: Speaker, Travel and Lodging Loren G. Miller, MD MPH, ContraFect: Grant/Research Support|GSK: Grant/Research Support|Medline: Grant/Research Support|Merck: Grant/Research Support|Paratek: Grant/Research Support Michael J. Satlin, MD, AbbVie: IDMC member|Biomerieux: Grant/Research Support|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|SNIPRBiome: Grant/Research Support Martin Krsak, MD, MSc, FASAM, AbbVie: Grant/Research Support|Melinta: Honoraria W. Charles Huskins, MD, MSc, ADMA Biologics: Advisor/Consultant|Bristol Myers Squibb: Stocks/Bonds|Pfizer: Advisor/Consultant|Pfizer: Stocks/Bonds|Zimmer Biomet: Stocks/Bonds Robin Patel, MD, Abbott Laboratories: Advisor/Consultant|Adaptive Phage Therapeutics: Grant/Research Support|Adaptive Phage Therapeutics: Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics.|BIOFIRE: Grant/Research Support|CARB-X: Advisor/Consultant|ContraFect: Grant/Research Support|Day Zero Diagnostics: Advisor/Consultant|HealthTrackRx: Advisor/Consultant|Mammoth Biosciences: Advisor/Consultant|Netflix: Advisor/Consultant|Oxford Nanopore Technologies: Advisor/Consultant|PhAST: Advisor/Consultant|See details: Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic|See details: continued, patent on an anti-biofilm substance issued|TenNor Therapeutics Limited: Grant/Research Support|Torus Biosystems: Advisor/Consultant|Trellis Bioscience, Inc.: Advisor/Consultant Vance G. Fowler, MD, MHS, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, Astra Zeneca: Advisor/Consultant|Genentech, Regeneron, Deep Blue, Basilea, Janssen;: Grant/Research Support|Infectious Diseases Society of America: Honoraria|MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius;: Grant/Research Support|Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny,: Advisor/Consultant|Sepsis diagnostic: Patent pending|UpToDate: Royalties|Valanbio and ArcBio: Stock Options David van Duin, MD, PhD, Entasis: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Union: Advisor/Consultant|Utility: Advisor/Consultant
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Muhammad Noman Hasan
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Sami Ullah
  • Department of Physical Medicine and Rehabilitation (MetroHealth Medical Center)
Marzieh Ayati
  • Department of Electrical Engineering and Computer Science
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Barbara R. Snyder