Pseudomonas aeruginosa; however, real-world comparative-effectiveness data are lacking.Ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) are front-line agents for treatment of multidrug-resistant (MDR) P. aeruginosa. CT and CZA patients were matched 1:1 within each study site by the presence/absence of septic shock/severe sepsis, infection site, and time to treatment initiation. The primary outcome was clinical success at day 30 defined as survival, resolution of signs/symptoms with the intended treatment course, and absence of recurrent infections. Patients with cystic fibrosis or COVID-19 infection within 90 days were excluded.CACTUS is a retrospective, matched, multicenter study to compare the efficacy of CT and CZA among patients with bacteremia or pneumonia due to MDR Table 1). The overall median age was 61 years, 61% were male, and the median Charlson score was 5. At study drug initiation, 77% of patients were in the ICU, 67% received mechanical ventilation and the median SOFA score was 7. 79% of patients were treated for pneumonia; 72% of which occurred in ventilated patients. The median time from index culture to treatment initiation was 72 hours in both groups; CT patients were more likely to receive a prolonged infusion of ≥3 hours . Clinical success occurred in 62% and 55% of patients receiving CT and CZA, respectively . Corresponding rates of success for pneumonia were 63% and 52%, respectively . All-cause, 30-day mortality rate was 20% and 19%, respectively. Microbiologic failures, recurrent infections, and development of resistance within 90 days were similar between groups. Time to a composite endpoint of recurrent infection or death within 90 days was similar between groups in the overall analysis and the subgroup of patients with pneumonia .234 patients were included from 20 sites. Patient demographics, severity of illness, infection types, and treatment durations were similar for patients treated with CT or CZA , Merck: Advisor/Consultant Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Honoraria|La Jolla (Entasis): Advisor/Consultant|LabSimply: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Christopher Polk, MD, ViiVHealthcare: Job change to work for ViiV as Medical Director Michael J. Satlin, MD, AbbVie: IDMC member|Biomerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Michael Veve, PharmD, MPH, National Institutes of Health: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant


Gut microbiome dysbiosis has been implicated in various gastrointestinal and extra-gastrointestinal diseases, but evidence on the efficacy and safety of fecal microbiota transplantation (FMT) for therapeutic indications remains unclear.The gutMDisorder database was used to summarize the associations between gut microbiome dysbiosis and diseases. We performed an umbrella review of published meta-analyses to determine the evidence synthesis on the efficacy and safety of FMT in treating various diseases. Our study was registered in PROSPERO (CRD42022301226).Firmicutes (phylum) was associated with 34 diseases. We identified 62 published meta-analyses of FMT. FMT was found to be effective for 13 diseases, with a 95.56% cure rate (95% CI: 93.88–97.05%) for recurrent Chloridoids difficile infection (rCDI). Evidence was high quality for rCDI and moderate to high quality for ulcerative colitis and Crohn’s disease but low to very low quality for other diseases.Gut microbiome dysbiosis was associated with 117 gastrointestinal and extra-gastrointestinal. Colorectal cancer was associated with 92 dysbiosis. Dysbiosis involving Gut microbiome dysbiosis may be implicated in numerous diseases. Substantial evidence suggests FMT improves clinical outcomes for certain indications, but evidence quality varies greatly depending on the specific indication, route of administration, frequency of instillation, fecal preparation, and donor type. This variability should inform clinical, policy, and implementation decisions regarding FMT. Clostridioides difficile infection (rCDI), inflammatory bowel disease (IBD), Crohn’s disease (CD), obesity and metabolic syndrome, among others  tract and significantly affect gut homeostasis and host health by producing various metabolites that influence the gut barrier and immunity . Pathogeg others . Severalg others . ElucidaFecal microbiota transplantation (FMT), which restores microbiome diversity and function by transferring screened feces from healthy donors to patient GI tracts, is gaining popularity for research and clinical use . NumerouWe aimed to systematically review relationships between gut microbiome dysbiosis and diseases and determine evidence on FMT efficacy and safety for various indications.We used gutMDisorder , a database cataloging relationships between diseases and the gut microbiome in humans, to examine associations . The gutClinicalTrials.gov for ongoing FMT trials and conducted an umbrella review following Cochrane living review guidelines  or observational studies on FMT through October 2021, updating in June 2022 without language restrictions. We searched reference lists of identified studies .Studies were eligible if: (1) study design: meta-analyses of RCTs and/or observational studies; (2) participants: any condition or subtype of the disease; (3) intervention: FMT by any route of administration, donor type, infusion frequency or bacterial fluid status; and (4) outcomes: clinical remission, response or adverse events. We excluded: (1) systematic reviews without meta-analysis; (2) pre/probiotic research; and (3) animal research.After eliminating duplicates, two reviewers independently screened the titles and abstracts and the full texts. Disagreements were resolved by consensus or appeal to a senior reviewer. We recorded reasons for exclusion.I2, P).Two reviewers extracted data independently and a third checked accuracy. For each study, we extracted: (1) characteristics: author, publication year, country, disease, studies, participants, age, sex, follow-up, adverse events; and (2) FMT details: participants, outcome measures including relative risk (RR), odds ratio (OR), mean difference (MD), weighted mean difference (WMD) and standardized mean difference (SMD), and heterogeneity  . If no remission rate was reported, we used another outcome. We chose the study with the highest number of RCTs or cohort studies if two or more studies for the same disease category and outcome were published within the same 24-month period. If two or more studies published in the same period had the same number of RCTs or cohort studies, we included the study with the highest AMSTAR-2 score. When both cohort studies and case series were included in a meta-analysis, and subgroup analysis was stratified by study design, the cohort design sub-analysis was selected for inclusion in the summary forest plots. We summarized subgroup analyses by administration route, donor type, frequency or bacterial fluid status.We synthesized data from the most recent meta-analysis for each disease, estimating heterogeneity  associated with the most (34) diseases, followed by Bacteroides , Bacteroidetes  and Prevotella . Firmicutes (34), Clostridiales (14), Enterobacteriaceae (22), Bacteroides (30), Faecalibacterium prausnitzii (13) and unclassified Lachnospiraceae (2).Dysbiosis of 479 gut microbes is associated with 117 gastrointestinal and extra-gastrointestinal diseases . Figure s nordii . Figure Analysis of 370 registered clinical trial entries presented an overview of FMT used for treating various digestive and non-digestive diseases since 2008 . Figure n = 24), UC (n = 14), IBD (n = 6), IBS (n = 4), CD (n = 3), AMR (n = 2), obesity (n = 1), metabolic syndrome (n = 1), functional gut disorders (n = 1), psychiatric outcomes (n = 1), chronic pouchitis (n = 1), functional constipation (n = 1) and GVHD (n = 1). We utilized an evidence mapping approach to visually present the reported efficacy, safety, and recurrence outcomes of FMT across 20 disease conditions after screening  had an overall final cure rate of 95.56%  for rCDI . CompareFMT also seemed beneficial for CDI subtypes. For severe or fulminant CDI, a single FMT had an overall successful resolution rate of 0.88  and preventing multiple rCDI recurrence (75%), while tolevamer also prevented recurrence (87%) . AnotherStudies largely found consistent results for FMT delivery via colonoscopy to the lower vs. upper gastrointestinal tract for outcomes such as clinical remission . Fresh FThere was evidence that FMT vs. placebo improved clinical outcomes in IBD , clinical response , and endoscopic remission  final remission rate and 71.7%  clinical response rate after FMT for CD . FMT impFew studies have examined FMT for chronic pouchitis. A meta-analysis of two studies with 14 patients reported a clinical remission rate of 7.4%  and for pediatric patients was 78%  . CDI curAmong patients with IBS, 57.8%  showed significant improvement . Fresh oAlthough the gut-brain axis suggests microbes could affect the central nervous system and neurological diseases, no meta-analysis has explored the clinical efficacy of FMT for these conditions. Available studies evaluating psychiatric outcomes have focused on patients with IBS. For the Fatigue Assessment Scale mental health subscale at 1 month, patients receiving 30 g of FMT vs. placebo showed significant improvement , including 43.7% complete response and 20.7% partial response. fter FMT .FMT vs. conventional treatment was associated with a lower rate of failing to achieve remission for decolonization of AMR bacteria  hemoglobin A1c  and early-stage high-density lipoprotein cholesterol  of patients with IBD had worsening symptoms after FMT . Rates oOf 94 patients with IBS receiving FMT, 29 (30.9%) reported at least one adverse event compared with 25 of 65 (38.5%) receiving placebo  for non-CDI indications need refinement. Finally, In summary, gut dysbiosis associates with at least 117 gastrointestinal and extra-gastrointestinal diseases. FMT provides a new modality to reshape the gut microbiome, virome, mycobiome and metabolome, benefitting patients with said diseases. Meta-analyses suggest FMT efficacy and safety in clinical practice, but higher-quality evidence is needed to strengthen recommendations.Future research should explore gut-disease causality, measure dysbiosis, identify disease mechanisms and FMT’s molecular effects. Improving FMT standardization, innovation and delivery will enhance its efficacy, safety and indications. However, large, rigorous studies are still needed to support expanded use.Several avenues remain unexplored: (1) Determine if dysbiosis causes or results from certain diseases. New techniques can quantify dysbiosis and its disease-specific nature. (2) Identify disease-associated microbes and FMT’s mechanisms of action. This can illuminate new therapeutic targets and applications . (3) OptXZ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. XLu: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. LT: Conceptualization, Data curation, Investigation, Validation, Visualization, Writing – review & editing. PY: Data curation, Formal analysis, Investigation, Resources, Validation, Visualization, Writing – review & editing. ML: Data curation, Formal analysis, Investigation, Validation, Visualization, Writing – review & editing. KL: Data curation, Investigation, Visualization, Writing – review & editing. DZ: Data curation, Visualization, Writing – review & editing. CH: Data curation, Writing – review & editing. QS: Data curation, Writing – review & editing. LY: Data curation, Writing – review & editing. ZX: Data curation, Writing – review & editing. JZ: Data curation, Writing – review & editing. ZM: Data curation, Writing – review & editing. JL: Data curation, Writing – review & editing. JWL: Conceptualization, Data curation, Formal analysis, Methodology, Resources, Visualization, Writing – review & editing. YL: Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Writing – review & editing. JY: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Visualization, Writing – review & editing. WM: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. XLi: Resources, Supervision, Writing – review & editing. YC: Conceptualization, Methodology, Project administration, Resources, Writing – review & editing.


Ab cause high mortality in hospitalized patients. Treatment options are limited, but now include FDC, a novel siderophore cephalosporin. Following clinical implementation, cases of treatment-emergent resistance have been reported. Proposed resistance mechanisms include alterations in iron transporters and amino acid substitutions in Acinetobacter-derived AmpC β-lactamase (ADC). Our objective was to define the relative contribution of ADC amino acid substitution to reduced FDC susceptibility against CRAb clinical strains.Infections due to CRAb isolates from the US and Italy. We compared common variants  to variants from FDC-resistant strains that had not been exposed to FDC , and variants from FDC-resistant strains collected following FDC treatment . blaADC-30 was used as a reference. The ADCbla genes with an upstream ribosomal binding site from pET24 were subcloned into pBCSK (-), transformed into E. coli Top10 cells, and selected on plates containing 100 µg/ml ampicillin and 30 µg/ml chloramphenicol. The constructs’ sequences were verified by Sanger sequencing. Minimum inhibitory concentrations (MICs) of FDC were determined by broth microdilution in iron-depleted media at least in duplicate.Variant ADCs were identified from whole genome sequencing analysis of clinical CRAmong studied ADC sequences, substitutions that were located in the Ω- or R2-loop regions, which accommodate the binding of cephalosporins, resulted in a 2- to 8-fold change in FDC MIC . When both regions were affected, there was an 8- to 16-fold increase in MIC. No significant MIC changes occurred among the studied mutations outside of these regions (Table 1). R2-loop substitutions were observed in FDC-exposed resistant strains, whereas Ω-loop mutations were observed in resistant strains that had not been exposed to FDC.Figure 1.Alignment of amino acid sequences in the ADC Ω- and R2- loop regions among studied isolates.We identified amino acid substitutions in Ω- and R2-loop regions of ADC that contribute to increased FDC MIC. Given the broad diversity of currently circulating ADC variants, it is crucial to study the impact of sequence variation on the activity of novel agents.Robert A. bonomo, MD, Entasis, Merck, VenatoRx, 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 Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support 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


Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. The association between prior hepatitis B virus (HBV), hepatitis A virus (HAV), and hepatitis E virus (HEV) infection and NAFLD has not been elucidated. The National Health and Nutrition Examination Survey (NHANES) aims to assess the health and nutritional status of the population across the United States.By using the 2017-2020 NHANES, we evaluated the age-adjusted prevalence of prior HBV, HAV and HEV infection among participants with NAFLD, as well as the age adjusted prevalence of NAFLD, high risk non-alcoholic steatohepatitis (NASH) and liver fibrosis among participants with prior HBV infection. We then performed multivariable logistic regression analyses using adjusted odds ratios (aOR) to examine the association of prior HBV, HAV and HEV infection with NAFLD, high risk NASH, and liver fibrosis.We identified 2565 individuals with anti-HBc serology results, 1480 unvaccinated participants with anti-HAV results, and 2561 participants with anti-HEV results. Among participants with NAFLD, the age-adjusted prevalence of prior HBV, HAV and HEV infection was 3.48%, 32.08% and 7.45%, respectively. The age-adjusted prevalence of NAFLD, high-risk NASH and fibrosis among participants with prior HBV infection was 33.59%, 3.36%, and 8.00%, respectively. Prior infection with HBV, HAV and HEV was not associated with NAFLD or high-risk NASH. Participants with anti-HBc and anti-HAV seropositivity were more likely to have significant fibrosis compared to participants with negative anti-HBc and anti-HAV serology .Age-adjusted prevalence of NAFLD, high-risk NASH and liver fibrosis among participants with positive anti-HBc serologyAdjusted odds ratio of prior viral hepatitis exposureParticipants with a history of HBV or HAV infection exhibit greater odds of significant liver fibrosis compared to those without HBV or HAV exposure. To limit disease-related outcomes, healthcare providers should prioritize vaccination efforts and use an individualized strategy for NAFLD in patients with prior viral hepatitis, including HBV or HAV infection.Eleftherios Mylonakis, MD, PhD, BARDA: Grant/Research Support|Basilea: Advisor/Consultant|Chemic Labs/KODA Therapeutics: Grant/Research Support|Cidara: Grant/Research Support|Leidos Biomedical Research Inc./NCI: Grant/Research Support|NIH/NIAID: Grant/Research Support|NIH/NIGMS: Grant/Research Support|Pfizer: Grant/Research Support|Regeneron Pharmaceuticals, Inc.: Grant/Research Support|SciClone Pharmaceuticals: Grant/Research Support


Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk , an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores.Treatment for first recurrent Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models.P>0.05). At Week 1, Shannon diversity  was greater vs baseline (P< 0.001); gains were not significantly different between subgroups (P>0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P< 0.001); similar gains were seen between subgroups (P>0.05) . Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups .At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment.Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds


Clostridioides difficile infection (CDI) following clinical treatment guideline updates placing it as first-line therapy. This puts a selection pressure on the development of fidaxomicin resistance, which has been associated with in vitro fitness costs compared to wildtype isolates. Here we aimed to assess the epidemiology of reduced susceptibility (RS) to fidaxomicin and prevalence of rpoB mutations in a clinical cohort.Fidaxomicin use is increasing to treat rpoB single nucleotide polymorphisms (SNPs).Stool samples from patients with CDI were collected from two different healthcare systems in Houston, TX between 2016-21. Fidaxomicin minimum inhibitory concentrations (MIC) were determined via agar dilution susceptibility testing following CLSI standards. RS was defined as MIC > 0.5 mg/L based on the EUCAST [T]ECOFF. A subgroup of 40 isolates with RS underwent Sanger sequencing to detect rpoB SNP mutations were detected in 12.5% (5/40) of isolates at 7 novel base positions; no SNPs were detected at previously reported position 3428.Of 535 patients included, 114 (21.3%) had infecting strains with fidaxomicin RS . Fidaxomicin RS was more common in RT 027  compared to non-027 strains . There were no differences in the proportions demonstrating RS across collection years (P=0.18) or based on location in or out of the Texas Medical Center (P=0.29). Mean MICs were similar between isolates collected before and after the IDSA/SHEA guideline update in 2018 (P =0.1). rpoB SNPs were observed in isolates with RS. Studies are needed to determine potential association(s) between fidaxomicin exposure and MIC changes.RS to fidaxomicin occurred in one fifth of clinical isolates with no changes in incidence between 2016-21. Several new Anne J. Gonzales-Luna, PharmD, BCIDP, Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Personal Fees|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin Garey, PharmD, MS, BCIDP, Acurx Pharmaceuticals: Grant/Research Support|Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Vedanta Therapeutics: Grant/Research Support


Little is known about the prevalence of respiratory symptoms and associated respiratory virus detection in students/ staff in primary and secondary schools.School KIDS is a prospective respiratory viral surveillance program in a large Missouri school district. Participating students/ staff complete a monthly electronic symptom survey that asks about respiratory symptoms (sx) in the preceding 7 days; participants are categorized based on the presence of any respiratory sx: ongoing (current), resolved, and no sx. Within 36 hours of survey completion, participants undergo surveillance respiratory viral testing at school. Self-administered nasal swabs are tested via multipathogen PCR assay (Table). Prevalence of respiratory viruses in participants with and without sx were calculated. A mixed-effect multivariable logistic regression model was used to compare odds of a sample testing positive based on surveillance sx and enrollee age.A total of 544 students (30 pre-kindergarten (preK), 320 elementary, 117 middle, and 77 high) and 224 staff enrolled. A total of 2,537 sx surveys with corresponding respiratory samples were collected from November 2, 2022–April 15, 2023 (Table). Of the samples provided, 1,138 were preK-elementary (45%), 368 middle (14%), 276 high (11%), and 755 staff (30%). Participants reported ongoing (20%), resolved (14%), and no sx (66%). Prevalence of commonly reported sx were congestion (21%), runny nose (17%), cough (16%), and fever (3%). Overall respiratory virus test positivity was 26%; 50% of positive samples came from participants without sx. Flu A, PIV, and RSV were more frequently detected in those with ongoing sx. AdV, HMPV, RV/EV, and SARS-CoV-2 were more frequently detected in those with no sx. Increased odds of a positive test were observed among enrollees who reported runny nose , congestion , cough , or sore throat  but not fever .More research is needed to understand if students with respiratory sx are more likely than asymptomatic students to shed transmissible respiratory viruses.Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, FAAM, Abbott: Honoraria|Altona Diagnostics: Grant/Research Support|Baebies Inc: Advisor/Consultant|BioMerieux: Advisor/Consultant|BioMerieux: Grant/Research Support|Bio-Rad: Grant/Research Support|Cepheid: Grant/Research Support|GSK: Advisor/Consultant|Hologic: Grant/Research Support|Lab Simply: Advisor/Consultant|Luminex: Grant/Research Support


Stratified by infection type, the activity of CFDC and comparator agents was evaluated against Pseudomonas aeruginosa (PSA), Acinetobacter baumannii-calcoaceticus complex (ABC), and Stenotrophomonas maltophilia isolates, collected from US hospitals during 2020-2022 in the SENTRY antimicrobial surveillance program.Cefiderocol (CFDC) has broad Antimicrobial Activity of Cefiderocol and Comparator Agents Against Isolates of Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus species complex, and Stenotrophomonas maltophilia by Infection Type from United States HospitalsS. maltophilia isolates from US hospitals were tested for susceptibility (%S) using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) or iron-depleted CAMHB for CFDC. Comparator agents included: ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), and imipenem-relebactam (I-R) as well as ampicillin/sulbactam (SAM), meropenem (MEM), imipenem (IPM), minocycline (MIN) and trimethoprim-sulfamethoxazole (SXT). Carbapenem non-susceptible (CarbNS) was defined as non-susceptibility to IPM and MEM. Susceptibility was interpreted according to 2023 CLSI breakpoints.3,383 PSA, 910 ABC and 657 S. maltophilia isolates, CFDC and MIN were the most active agents across all infection types.The most common infection type from which isolates were collected was pneumonia , followed by skin and skin structure , bloodstream infection , urinary tract infection  and intra-abdominal infections . Among PSA, %S to CFDC was highest among comparators with >98%, across all infection types, including those caused by CarbNS isolates. In CarbNS-PSA, %S to CZA and C/T were lowest in BSI isolates while among PNA isolates, %S to CZA and I-R were the lowest. ABC %S to CFDC ranged from 97-100% and 91-100% in CarbNS-ABC across all infection types. In CarbNS-ABC, SAM and MIN %S in BSI and PNA was 19% and 66% and 8% and 53%, respectively. Against S. maltophilia, including Carb-NS, isolates from US hospitals, CFDC was the most active agent with >90% susceptibility across all infection types. CFDC represents a potential option for empiric antimicrobial therapy in US hospitals with high rates of Carb-NS non-fermenting Gram-negative pathogens.Against PSA, ABC, and Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Calbert Valencia, PharmD, Shionogi Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee


Millions of Americans are infected by influenza each year. Most experience mild and self-limited illness but a minority progress to severe disease and death. Emergency departments (ED) serve as a frontline for the US health system and must distinguish those at risk for clinical deterioration from those who can be safely discharged to the community.We developed random forest machine learning (ML) models to estimate risk for two severe outcomes in ED patients with influenza: need for inpatient care within 72 hours and need for critical care within 24 hours. Both were defined by multidisciplinary consensus using markers of cardiovascular and respiratory dysfunction captured in the electronic health record (EHR). Predictor data were limited to those recorded prior to ED disposition decision  and included patient demographics, ED complaint, active medical problems, vital signs and trends, supplemental oxygen use and selected laboratory results. Our cohort was comprised of adult patients who visited one of five EDs in our university health system between 01/01/2017 and 05/18/2022. A development cohort comprised of encounters that occurred before December 2019 was used for model derivation and 10-fold out of sample validation; models were externally validated in the cohort of encounters that occurred afterward.Among 8,032 patients with confirmed influenza, incidence of critical care needs at 24 hours was 6.2% (n = 502) and incidence of inpatient care needs at 72 hours was 16.1% (n = 1295). The most common reasons for ED visit were symptoms of upper or lower respiratory tract infection, fever, and shortness of breath. During external validation, models exhibited excellent predictive performance with AUCs of 0.90 (0.87 - 0.94) for critical and 0.89 (95% CI 0.86 -0.92) for inpatient care needs; both were well-calibrated (Brier scores 0.025 and 0.036). Important predictors of severe disease included shortness of breath, increasing respiratory rate and a high number of comorbid diseases.Predictive Model Performance During External Validation.Random forest models predicted risk for critical care needs within 24 hours (red) and inpatient care needs within 72 hours (blue). Overall predictive performance is shown using receiver operating characteristic curves with area under the curve (AUC) in panels A and B; model calibration curves with Brier scores are shown in C and D; predicted probability distributions are shown with kernel density estimation plots in E and F.These findings demonstrate that EHR data and ML can be used to risk-stratify patients with influenza early in their hospital course. An important future aim is to integrate ML-driven predictions into clinical decision support at the point of care.Jeremiah S. Hinson, MD, PhD, Beckman Coulter: Advisor/Consultant|Beckman Coulter: Grant/Research Support|Beckman Coulter: TriageGO Katherine ZJ Fenstermacher, PhD, Cepheid: Grant/Research Support Richard E. Rothman, MD, PhD, CEPHEID: Advisor/Consultant|Cepheid: Grant/Research Support|Danaher: Grant/Research Support Oluwakemi Badaki-Makun, MD, PhD, Beckman Coulter: Grant/Research Support Scott Levin, PhD, Beckman Coulter: Licenses|Beckman Coulter: Employment|Beckman Coulter: Stocks/Bonds


Correction: Zahedi et al. Diabetol Metab Syndr _#####################_10.1186/s13098-021-00637-4Following publication of the original article [1], the authors identified an error in affiliation. The correct affiliation of Maryam S. Daneshpour is given below.Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, POBox: 19,195 − 4763, Tehran, IranThe original article has been corrected.


Oseltamivir is the most common antiviral prescribed to treat influenza. There are limited data about oseltamivir receipt in uncomplicated influenza, including frequency of early discontinuation of oseltamivir.Individuals who tested positive for influenza were identified from outpatient clinics, emergency departments, or surveillance testing at seven sites in the United States from December 2021–March 2023. Index cases and their household contacts (HHC) enrolled ≤6 days after the first illness in the household, completed symptom/medication logs, and collected nasal swabs for influenza testing daily for 10 days. Oseltamivir receipt was classified by daily logs  among eligible persons (Methods 1). Addresses linked to the 2020 Social Vulnerability Index by census tract. Odds of oseltamivir receipt were estimated using binomial regression with household clustering.Methods upload 1: Analytic flow diagram for assessment of use and discontinuation of oseltamivir in household settings, United States 2021-22 and 2022-23 influenza seasons.Discontinuation was defined as use for 1-2 days, compared to use for 3-4 or ≥5 days. If the participant reported oseltamivir on the first or last day of follow-up and did not report use for at least 3 days, the duration of oseltamivir usage was considered “censored” and discontinuation was not described.Of 737 household members, 142 individuals  reported oseltamivir. Oseltamivir receipt was more common among those recruited in 2022–23 vs. 2021–22 and by participants who self-reported pre-existing conditions vs. those who did not. Oseltamivir receipt was less common among children 5–11 vs. adults 18–49 years (Results 1). Individuals from the most vulnerable census tracts were least likely to receive oseltamivir (Results 2). Among symptomatic infected persons, oseltamivir was typically initiated within 2 days of symptoms (76%). Of 126 individuals whose duration of oseltamivir was not censored by the start or end of follow-up, 19% reported receipt on only 1-2 days, 17% for 3-4 days, and 63% for ≥5 days. Compared to those who reported ≥5 days of oseltamivir receipt, people who took oseltamivir for 1–2 days had similar reported symptoms, including gastrointestinal symptoms, on the first day of illness and first day of oseltamivir (Results 3).Results upload 1: Characteristics of individuals who did and did not report use of oseltamivir among individuals in households with a known influenza case, United States, 2021-22 and 2023-24 influenza seasons.Results Upload 2. Social vulnerability of individuals who did and did not report use of oseltamivir among individuals in geocoded households with a known influenza case, United States, 2021-22 and 2023-24 influenza seasons.Over a third of index cases received oseltamivir, and receipt differed by age and social vulnerability status. In this analysis, early discontinuation was not associated with initial symptom burden or symptoms, including gastrointestinal side-effects, after initiating oseltamivir.Edward Belongia, MD, Seqirus: Grant/Research Support Yvonne A. Maldonado, MD, Pfizer: Grant/Research Support|Pfizer: Site Investigator, DSMB member Suchitra Rao, MBBS, MSCS, Sequiris: Advisor/Consultant Huong McLean, PhD, MPH, Seqirus: Grant/Research Support Joshua Petrie, PhD, CSL Seqirus: Grant/Research Support Edwin J. Asturias, MD, Hillevax: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Grant/Research Support Carlos G. Grijalva, MD, MPH, AHRQ: Grant/Research Support|CDC: Grant/Research Support|FDA: Grant/Research Support|Merck: Advisor/Consultant|NIH: Grant/Research Support|Syneos Health: Grant/Research Support


Escherichia coli reside as commensal intestinal microflora without harming human health. But some E. coli strains are pathogenic and can cause deadly infections. Antimicrobial resistant E. coli is associated with more than 1.5 million deaths globally. Here, we studied the prevalence of antimicrobial resistance in E. coli isolates from two cities based on the antimicrobial(AMR) genes and MIC values. By correlating genotypic and phenotypic antimicrobial resistance, we also examined the performance of whole genome sequencing (WGS) based prediction of phenotypic resistance.Most E. coli isolates from Detroit, MI and Cleveland, OH hospitals underwent WGS. Antibiotic susceptibility testing (AST) was performed using the gram-negative AST cards on the VITEK 2 system. WGS was performed with Nextseq 550 using Nextera flex kits. After de novo assembly, AMR genes were identified using AMR gene database, ResFinder.A total 109 st and 3rd generation cephalosporins were very high among the E. coli isolates. They were susceptible to penicillin combinations and 2nd generation cephalosporins. While resistance to quinolone antibiotics was high, resistance to aminoglycoside, tetracycline, and sulfonamide/trimethoprim were relatively low . As shown in Table 1, WGS-based method accurately predicted the majority of antimicrobial resistance phenotypes with accuracy of 0.89 ∼ 1.0. However, for cephalothin (0.36), piperacillin/tazobactam (0.69), and amikacin (0.63), the prediction accuracy was low which could potentially lead to false predictions of antimicrobial resistance. Extended Spectrum Beta-Lactamase (ESBL) genes such as blaCTX-M, blaOXA, and blaTEM were abundant, though subtle difference in the prevalence of AMR genes between two cities was observed .The resistance to beta-lactam antibiotics including 1E. coli isolates contained various ESBL genes and their gyrA genes were mutated to quinolone resistant forms. Therefore, most of the isolates were resistant to many beta-lactam and quinolone drugs. WGS based prediction of phenotypic resistance showed good predictive values but needs more studies to increase sensitivity and specificity.Most of the Keith S. Kaye, MD, MPH, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Entasis: Advisor/Consultant|Entasis: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|VenatoRx: Advisor/Consultant|VenatoRx: Honoraria


During XBB variant dominance, there is still a lack of evidence describing phenotypes of acute respiratory infection (ARI) symptoms present at COVID testing and how clusters of symptoms are associated with COVID test positivity, COVID vaccination status, and vaccination timing.This observational cohort included 88,147 adult symptomatic individuals presenting for COVID testing at CVS Pharmacy® locations across the US during March and April of 2023. Individuals self-reported ARI symptoms, comorbid conditions, vaccination status, vaccination timing, and demographics when making an appointment for COVID testing. Latent class analysis (LCA) is a statistically robust method of cluster analysis and was adopted to examine patterns of ARI symptoms. COVID testing positivity was tabulated for each pattern by time from last dose of vaccine.Patients were 43.3 (SD: 16.6) years old on average and 37% male. The cohort was composed of 43% White or Caucasian, 21% Hispanic, 16% Black, 11% Asian, and 9% other race and/or ethnicities. About 20% of patients self-reported at least one comorbid condition. PCR and antigen tests were chosen by 79% and 21% of patients, respectively. Overall, 33% of patients tested positive for COVID. Of 87% vaccinated, 4% had been vaccinated within three months of testing, 21% within 4-6 months, 17% within 7-12 months, and 45% had been vaccinated over one year prior to testing.The number of months since vaccination was associated with an increased number of reported symptoms, presenting a marked uptick of symptoms at 6-months following the last vaccination dose . LCA identified four distinct phenotype groups of ARI symptoms described with prevalence (%) . Phenotype group positivity rates were also associated with time since last dose of vaccines, and yet unlike individual symptoms, appeared to stabilize six months post-vaccination.Four ARI symptom phenotypes having distinct responses to vaccine and COVID positivity were identified. Some phenotypes (such as P3 and P4) may present with symptom patterns consistent with seasonal influenza or RSV. More research is needed to validate these findings and understand the implications of possible COVID phenotypes.Xiaowu Sun, PhD, CVS Health: Employee|CVS Health: Stocks/Bonds Laura L. Lupton, MD, MHSA, CVS Health: employee|CVS Health: Stocks/Bonds Coetzer Henriette, MD, Astra Zeneca: Stocks/Bonds|CVS Health: Employee|GSK: Stocks/Bonds Alexandra Berk, PhD, CVS Health: employee|CVS Health: Stocks/Bonds Laura Anatale-Tardiff, MPH, CVS Health: employee|CVS Health: Stocks/Bonds


Antibiotic resistance in pediatrics, including neonates and infants, is increasing globally. Ceftazidime-avibactam (CAZ-AVI) is approved for use in pediatric patients (age ≥ 3 months) with Gram-negative bacterial infections. This study evaluated pharmacokinetics (PK), safety, and efficacy of CAZ-AVI in hospitalized neonates and young infants  with suspected/confirmed infections due to Gram-negative pathogens requiring intravenous (IV) antibiotic treatment (Tx).This Phase 2a study was conducted at 39 sites in 9 countries . Hospitalized neonates and infants received single (Part A) or multiple doses (Part B) of IV CAZ-AVI . PK (CAZ and AVI), safety , and efficacy  were assessed. The study was not powered for inferential statistical analysis, descriptive methods were used to summarize all data.Escherichia coli. Median duration of CAZ-AVI Tx in Part B was 7.0 days. Plasma concentrations of CAZ and AVI were similar to those in previous pediatric studies . Overall, 50% (n=23) of participants had treatment-emergent AEs (TEAEs); the majority were mild/moderate in severity. SAEs (n=8) and deaths  were not related to study Tx. Most participants had favorable clinical outcomes and microbiological response at test of cure.In total, 46 participants were administered CAZ-AVI, aged 2 to 89 days and 31 to ≥ 37 weeks gestation (Table 1). Overall, sepsis (39.1%) and urinary tract infection (15.2%) were the most common primary infectious diagnoses. In Part B, 60% of the baseline pathogens isolated were Plasma concentrations of CAZ and AVI after single and multiple doses of CAZ-AVI were similar to previous pediatric studies. Single and multiple doses of CAZ-AVI were safe and well tolerated in hospitalized neonates and young infants with suspected/confirmed bacterial infections. TEAEs were mild/moderate in severity and no new safety concerns were identified.Emmanuel Roilides, MD, PhD, Gilead: Advisor/Consultant|GSK: Grant/Research Support|MSD: Advisor/Consultant|MSD: Grant/Research Support|Mundipharma: Advisor/Consultant|Pfizer: Grant/Research Support|Scynexis: Grant/Research Support Richard England, MD, PhD, Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds Margaret Tawadrous, MD, MS, Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds Jean Yan, M.S., Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds Elena Soto, PhD, Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds Gregory Stone, PhD, Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds Shweta Kamat, MD, Pfizer: Employee of Pfizer|Pfizer: Stocks/Bonds


CHIKV remains a significant public health concern globally. We report the results of two phase 3 trials evaluating an aluminum hydroxide adjuvanted CHIKV VLP vaccine.80 serum neutralizing antibody (SNA) titers at selected timepoints. Seroresponse rate (SRR) was the percentage of participants who achieved NT80 SNA titer ≥ 100 (FDA/EMA agreed threshold). Safety outcomes were evaluated through monitoring adverse events (AEs) through Day 183.Two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were conducted: an adult/adolescent trial (NCT05072080) in ages 12-64 years and an older adult trial in ages ≥ 65 years (NCT05349617). Participants received CHIKV VLP vaccine or placebo as a single intramuscular dose. Immunogenicity objectives assessed anti-CHIKV NTStudy overview.Adult/adolescent trial: 3254 participants  were enrolled. Primary endpoints were met with a Day 22 SRR of 98% (2503/2559) for vaccine and 1% for placebo , as well as lot consistency, and superiority to placebo in geometric mean titer (GMT). A rapid antibody response was observed in the CHIKV VLP vaccine group with Day 8 SRR=47% (1169/2510) and Day 15 SRR=97% (2355/2434); responses were durable through Day 183 with SRR=86% (1967/2301).Older adult trial: 413 participants  were enrolled. Primary endpoints were met with a Day 22 SRR of 87% (167/191) for vaccine and 1% for placebo , as well as by GMT. At Day 15 a rapid antibody response was observed in the CHIKV VLP vaccine group with SRR=82% (150/182).CHIKV VLP vaccine demonstrated a favorable safety profile, and most AEs were mild to moderate in severity. The most common AEs were myalgia, fatigue, and headache.CHIKV VLP vaccine is the only VLP-based vaccine in clinical development for active immunization against CHIKV disease. Results demonstrate that CHIKV VLP vaccine induces a rapid and robust immune response in most people by Day 15 and through Day 183. These findings support the potential of this VLP-based vaccine to help protect individuals 12 years and older from CHIKV.Jason S. Richardson, PhD, Bavarian Nordic Canada Inc: Stocks/Bonds Debbie Anderson, MS, Bavarian Nordic: Employee|Emergent BioSolutions: Stocks/Bonds Sufia Muhammad, MD, Bavarian Nordic: Employee|Emergent BioSolutions: Stocks/Bonds Lauren Tindale, PhD, Bavarian Nordic: Employee Tobi Loreth, n/a, Emergent BioSolutions: Stocks/Bonds Sarah Royalty Tredo, MBA, Emergent Biosolutions: Employee|Emergent Biosolutions: Stocks/Bonds Victoria Jenkins, PhD, Bavarian Nordic: Employee Patrick Ajiboye, MD, Bavarian Nordic: Employee|Emergent BioSolutions: Stocks/Bonds Lisa Bedell, Director Biostatistic, Bavarian-Nordic: Advisor/Consultant|Emergent BioSolutions: Employee|Emergent BioSolutions: Stocks/Bonds


All panels use two assays for SARS-CoV-2 detection, each targeting a different gene. Positive detection in only one of the two assays is required for a positive SARS-CoV-2 result. As new variants of SARS-CoV-2 emerge, https://gisaid.org/) for SARS-CoV-2 variants deemed significant by the WHO and UKHSA are analyzed monthly. Assay primer regions are assessed for mismatches using Geneious Prime® as well as proprietary software tools. When primer mismatches with potential to affect the sensitivity of SARS-CoV-2 detection are identified , and meet the testing criteria, the BIOFIRE RP2.1 Panel is used to empirically evaluate the impact by comparing synthetic templates with mismatches of concern to synthetic template without mismatches.Sequence data  contain paired mismatches of concern. Wet testing showed < 10x lower projected sensitivity for 288 (72 unique) sequences, 10-100x lower sensitivity for 16 (10 unique) sequences, and only 1 sequence had 100-1000x lower projected sensitivity. Lineage defining mutations were seen within a SARS-CoV-2 assay primer region in 27 variants. However, most lack mutations in the second assay, indicating no major risk for SARS-CoV-2 detection. Wet testing shows that the inclusion of two SARS-CoV-2 assays in the panels helps to mitigate the effect of mismatches of concern.in silico analysis of available sequences and variants, BIOFIRE RP2.1 Panel, SPOTFIRE R Panel and SPOTFIRE R Panel Mini continue to function as intended with >99.99% detection of SARS-CoV-2 sequences.Based on the comprehensive Eleanor K. Horrocks, bioMerieux: employee|bioMerieux: Stocks/Bonds Toma Todorov, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Alexandra Debernardi, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Usha Spaulding, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Tanner Robinson, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Jeremiah Antosch, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Zhenmei Lu, n/a, bioMerieux: employee|bioMerieux: Stocks/Bonds Matthew Jones, MS, bioMerieux: employee|bioMerieux: Stocks/Bonds Joann Cloud, PhD, bioMerieux: employee|bioMerieux: Stocks/Bonds


California has the largest number of active tuberculosis (TB) cases in the US; more than 2 million Californians are estimated to have latent tuberculosis infection (LTBI), and 87% of TB cases in 2021 were attributed to LTBI reactivation. This study in a large California health system assessed missed opportunities for LTBI screening and treatment among patients with active TB.Kaiser Permanente Southern California patients who were ≥18 years with membership for ≥24 months from January 1, 2008 to December 31, 2019 were included. Receipt and result of prior LTBI test (tuberculosis skin test or interferon gamma release assay) or LTBI diagnosis code prior to active TB diagnosis was estimated among patients with observed active TB (confirmed by polymerase chain reaction and/or culture). LTBI testing/diagnosis < 60 days before observed active TB diagnosis was considered part of the active TB diagnostic process, and not part of LTBI screening. A range of hypothetical active TB cases prevented through current LTBI screening practices was estimated by multiplying literature supported LTBI reactivation rates by the number of treated LTBI positive patients. These hypothetical cases were categorized to have their first LTBI positive test/diagnosis ≥60 days prior to active TB.A total of 1,289 patients with observed active TB were identified during the study period. Among them, 148 patients had a positive LTBI test/diagnosis and 84 patients had a negative LTBI test ≥60 days before active TB onset. There were 1,057 patients who either never had an LTBI test/diagnosis, or had an LTBI test/diagnosis <60 days before active TB onset who made up 82.0% of observed active TB cases . Adding the maximum estimate for possible prevented cases decreased the percentage of patients with TB who had never been screened for LTBI to 44.9% .Less than a fifth of patients were screened for LTBI prior to their active TB diagnosis during the study period. Even assuming the highest number of cases prevented through current screening, almost 45% of active TB patients were never screened for LTBI. Future work to elucidate gaps in LTBI screening practices and to identify opportunities to improve LTBI screening guidelines are needed.Heidi Fischer, PhD, Pfizer: Grant/Research Support Lei Qian, PhD, Dynavax: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support Katia J. Bruxvoort, PhD, MPH, Dynavax: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Jacek Skarbinski, MD, Genentech: Grant/Research Support|Gilead Sciences: Grant/Research Support Jennifer H. Ku, PhD MPH, GlaxoSmithKline: Grant/Research Support|Moderna: Grant/Research Support Sara Y. Tartof, PhD MPH, Genentech: Grant/Research Support|GSK: Grant/Research Support|Pfizer: Grant/Research Support|SPERO: Grant/Research Support


There remains a need for pre-exposure prophylaxis against SARS-CoV-2 infection in vulnerable patients in whom response to vaccination is often sub-optimal. The PROTECT-V platform trial is testing pre-exposure prophylactic interventions for COVID-19 in vulnerable patient populations: transplant recipients, individuals with oncological/haematological diagnoses, immune deficiency, autoimmune diseases requiring immunosuppression, and individuals receiving dialysis.Sotrovimab is a dual-action monoclonal antibody and the second agent to be added to the PROTECT-V platform . Although a single sotrovimab 500mg intravenous (IV) dose has been widely used for early treatment, data on a 2000mg IV dose are limited. Tolerability data in the first 143 participants randomized to this arm of the trial are presently available. Patients are randomized 1:1 sotrovimab to placebo. Data remain blinded.Median age was 66 years (range 21 – 86) and 82 (57%) patients were female. 132 (96%) had received ≥3 doses of SARS-CoV-2 vaccine. Patient populations were: 82 (57%) autoimmune disease; 26 (18%) haematological/oncological diseases; 21 (15%) transplant recipients; 12 (8%) immunodeficiency; 2 (1%) on dialysis.Two (1%) participants experienced a mild infusion related reaction (IRR). The infusion was briefly interrupted, but completed. Thirty (21%) participants experienced at least one symptom in the 24 hours post-infusion, but none were severe or required hospital admission. The most common symptoms were dizziness (7 [5%]), headache (7 [5%]), rigors (5 [4%]) and fever (4 [3%]). No severe adverse events were reported within 72 hours of IMP infusion at the time of writing.The first 55 patients underwent routine hematological and biochemical blood test evaluation 72 hours post-infusion. Ten events from 9 participants exhibited worsening of laboratory parameters, meeting at least grade two DAIDS criteria or worse. None of these were clinically significant.A 2000mg IV dose of sotrovimab was tolerated well in this blinded analysis of immunocompromised participants, with no severe IRRs or significant change in haematological or biochemical markers up to 72 hours post infusion.Davinder Dosanjh, n/a, Astrazeneca: Honoraria|Astrazeneca: Employee|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Gilead: Advisor/Consultant|GSK: Grant/Research Support|Synairgen: Advisor/Consultant Louise Crowley, n/a, GSK: Grant/Research Support Michael Chen-Xu, n/a, GSK: Grant/Research Support Rona M. Smith, MD MRCP, GSK: Grant/Research Support|Union Therapeutics: Grant/Research Support


Central nervous system (CNS) symptoms are frequent after chimeric antigen receptor T-cell therapy (CARTx) and usually attributed to immune effector cell-associated neurotoxicity syndrome (ICANS). Cerebrospinal fluid (CSF) testing to rule out CNS infection is not routinely performed, although ICANS and viral encephalitis have overlapping presentations. Reports of viral encephalitis after CARTx are increasing, but no cohort studies have been performed to understand its epidemiology.This retrospective cohort study included all adults receiving first CARTx for B-cell malignancies at Fred Hutch Cancer Center from July 2013 to December 2022. We computed the cumulative incidence of CSF testing for viruses within 56 days after CARTx.Figure 1). ICANS was diagnosed in 29 (85.3%) of these 34 patients (ICANS grade ≥ 3 in 14), and 26 patients received immunosuppressive treatment. In the remaining five tested patients, the cause of CNS symptoms was vascular (n=1), CNS progressive disease (n=2), metabolic encephalopathy (n=1) or unknown (n=1). CSF testing practices evolved overtime, and testing was performed more frequently before 2018 ; after 2018, all tested patients had ICANS grade ≥ 3. Four patients had a positive CSF PCR test for EBV (n=3) occurring 8–39 days post-CARTx or HHV-6 (n=1) on day 32 post-CARTx. EBV detection in CSF was low-level, of unclear clinical significance, and not treated; all three patients were treated for ICANS. The patient with HHV-6 had low-level detection in CSF and blood; HHV-6 encephalitis was considered, but no antiviral therapy was administered, and symptoms resolved with treatment for ICANS grade 4.626 patients received CARTx during the study period; 552 (88.2%) received CD19 or CD20-targeted CARTx and 74 (11.8%) BCMA-targeted CARTx. Median age was 60.4 (IQR: 50.9–67.6) years, 232 (37.1%) identified as female, and 216 (34.5%) received prior hematopoietic cell transplantation. Thirty-four patients had CSF tested for viruses with PCR in the context of CNS symptoms for a cumulative incidence of 5.7%  : Grant/Research Support|Century Therapeutics: Independent Data Review Committee|Janssen: Advisor/Consultant|Janssen: Honoraria|Juno Therapeutics (a BMS company): Grant/Research Support|Kite Pharma: Advisor/Consultant|Kite Pharma: Honoraria|Legend Biotech: Advisor/Consultant|Legend Biotech: Honoraria|MorphoSys: Advisor/Consultant|MorphoSys: Honoraria|Sobi: Advisor/Consultant|Sobi: Grant/Research Support|Sobi: Honoraria David G. Maloney, MD, PhD, A2 Biotherapeutics: Membership with compensation: member of scientific advisory board|BMS: Advisor/Consultant|BMS: Grant/Research Support|BMS: Honoraria|BMS: Member (compensation): JCAR017 EAP-001 Safety Review Committee, CLL Strategic Council. Without compensation: JCAR017-BCM03 Scientific Steering Committ|Celgene: Advisor/Consultant|Celgene: Grant/Research Support|Celgene: Honoraria|Chimeric Therapeutics: Membership with compensation: member of scientific advisory board|Genentech: Advisor/Consultant|Genentech: Honoraria|Genentech: Membership with compensation: member and chair of the Lymphoma Steering Committee|Gilead Sciences: Membership with compensation: Member Scientific Review Committee, Research Scholars Program in Hematologic Malignancies|ImmPACT Bio: Membership with compensation: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program|Interius: Membership with compensation: member clinical advisory board|Juno Therapeutics: Advisor/Consultant|Juno Therapeutics: Grant/Research Support|Juno Therapeutics: Honoraria|Juno Therapeutics/BMS: Dr. Maloney has the rights to royalties from Fred Hutchinson Cancer Center for patents licensed to Juno Therapeutics/BMS|Kite: Advisor/Consultant|Kite: Grant/Research Support|Kite: Honoraria|Legend Biotech: Grant/Research Support|Navan Technologies: Membership with compensation: member of scientific advisory board Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Century Therapeutics: Advisor/Consultant|Covance/CSL: Advisor/Consultant|Deverra: Grant/Research Support|Eversana Life Science Services, LLC: Advisor/Consultant|GeoVax: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Moderna DSMB: Advisor/Consultant|Octapharma AG: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer (previously Amplyx/Medpace): Advisor/Consultant|Senti BioSciences, Inc: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Up-to-Date: Advisor/Consultant


Candida auris is deemed an urgent threat because it spreads easily in healthcare facilities, can cause severe infections with high mortality rates, and is resistant to antifungal agents. Since the onset of the COVID-19 pandemic, we detected a rise in inpatient C. auris cases. We describe a series of C. auris cases at a tertiary hospital in Washington, DC.Cases of Candida auris by date of initial sample collection, GW Hospital, Washington, DC, March 2020 - April 2023.C. auris between 3/2020-4/2023. Patients transferred from a single long-term care acute hospital (LTACH) with high C. auris prevalence were placed in empiric isolation on admission and screened for C. auris colonization via axilla and groin surveillance swabs. C. auris was identified by MALDI-TOF MS and/or Biofire BCID Panel v2 and strain typing was performed by Fourier-Transform Infrared Spectroscopy. Antifungal susceptibility testing (AST) was performed via broth microdilution and interpreted using tentative breakpoints from CDC.We reviewed charts of inpatients with C. auris . 29 patients (71%) were transferred from the LTACH. 29 (71%) patients had either a tracheostomy or gastrostomy tube. 22 (54%) were identified through surveillance culture (21 from the LTACH) and 19 (46%) via clinical culture . 2/32 (6%) patients with C. auris detected initially via non-blood specimens later developed C. auris candidemia. 8/11 (73%) cases of candidemia were CLABSIs. Overall, 8/41 (20%) patients either died or were placed on comfort care during hospitalization. Among 23 isolates available for AST, 22 (96%) were resistant to fluconazole, 15 (65%) to amphotericin B, and 1 (4%) to anidulafungin. Preliminary strain typing suggested grouping of isolates into 2 main clusters denoting distribution into 2 distinct clades; further characterization is undergoing.We identified 41 cases of C. auris infection or colonization died/were placed on comfort care underscores the poor prognosis associated with C. auris. To combat the spread of C. auris, further development of antifungals, rapid diagnostics, and effective infection prevention strategies are needed.The COVID-19 pandemic placed healthcare systems under unprecedented strain which has accelerated the spread of antimicrobial resistant pathogens. The finding that 1 of 5 patients with Tara Palmore, MD, Abbvie: Grant/Research Support|Gilead: Grant/Research Support|Rigel: Grant/Research Support Jennifer Dien Bard, PhD, Abbott Molecular: Grant/Research Support|BioMerieux: Advisor/Consultant|BioMerieux: Grant/Research Support|BioMerieux: Honoraria|Genetic Signature: Advisor/Consultant|Genetic Signature: Grant/Research Support|Luminex: Grant/Research Support|Salve: Stocks/Bonds|Thermo Fisher: Honoraria


Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus species complex (ABC).Difficult to Treat Resistant (DTR) Gram-negative isolates show treatment-limiting resistance to all first-line agents; β-lactams and fluoroquinolones. Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with a unique mode of entry into bacteria, showing good activity against Gram-negative bacteria. Here, susceptibility of CFDC and comparator agents was determined against DTR isolates of Enterobacterales, Activity of Cefiderocol and Comparator Agents Against Difficult to Treat Resistance (DTR) Gram-negative IsolatesP. aeruginosa, and 2,479 ABC isolates, collected in 2020–2022 in Europe and the USA as part of the SENTRY program, using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparator agents and iron-depleted CAMHB for CFDC. Susceptibility was assessed according to CLSI, EUCAST and FDA breakpoints (BPs). DTR was defined as being non-susceptible, using CLSI BPs, to fluoroquinolones and β-lactams, except for CFDC and β-lactam/β-lactamase inhibitor (BL/BLI) combinations.Minimum inhibitory concentrations were determined according to CLSI guidelines against 24,084 Enterobacterales, 7,310 K. pneumoniae . The isolates showed high susceptibility to CFDC . Comparator agents, including novel BL/BLI combinations, showed susceptibility of < 80%, except for tigecycline . For P. aeruginosa 4.1% (n=299) showed the DTR phenotype, of which 98.3%, 97.7%, and 89.6% were susceptible to CFDC, according to CLSI, EUCAST and FDA BPs respectively. Colistin was also active  whereas other agents, including novel BL/BLI combinations, had susceptibility of < 65%. Amongst ABC, 47.1% (n=1167) showed the DTR phenotype, and 96.2%, 93.8%, and 89% were susceptible to CFDC according to CLSI, EUCAST and FDA BPs, respectively. Susceptibility to comparator agents was < 40%, except for colistin .1.6% (n=387) of the Enterobacterales isolates showed the DTR phenotype, the majority being DTR isolates remained susceptible to CFDC, indicative of a low degree of cross resistance with β-lactams, including BL/BLI combinations, and fluoroquinolones.Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi: Employee|Shionogi, Inc: Employee Jason J. Bryowsky, PharmD, MS, Shionogi Inc.: Employee Christopher M. Longshaw, PhD, Shionogi BV: Employee Joshua Maher, PhD, AbbVie: Grant/Research Support|Affinity Biosensors: Grant/Research Support|AimMax Therapeutics, Inc: Grant/Research Support|Alterity Therapeutics: Grant/Research Support|Amicrobe, Inc: Grant/Research Support|Arietis Pharma: Grant/Research Support|Armata Pharmaceuticals, Inc: Grant/Research Support|Astrellas Pharma, Inc.: Grant/Research Support|Basilea Pharmaceutica AG: Grant/Research Support|Becton Dickinson And Company: Grant/Research Support|bioMerieux, Inc: Grant/Research Support|Boost Biomes: Grant/Research Support|Diamond V: Grant/Research Support|Fedora Pharmaceuticals, Inc: Grant/Research Support|Iterum Therapeutics plc: Grant/Research Support|Johnson & Johnson: Grant/Research Support|Kaleido Biosciences, Inc.: Grant/Research Support|Meiji Seika Pharma Co. Ltd.: Grant/Research Support|National Institutes of Health: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Roche Holding AG: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Summmit Therapeutics, Inc.: Grant/Research Support|Zoetis Inc: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi & Co., Ltd.: Stocks/Bonds Yoshinori Yamano, PhD, Shionogi HQ: Employee


Mucormycosis is a fatal fungal infection, and there is limited information on its epidemiology and treatment practices, including the optimal dosage of liposomal amphotericin B.A retrospective nationwide analysis of 82 proven and probable cases of mucormycosis was performed. Cases were collected from 51 hospitals in Japan by hematologists and infectious disease specialists. Variables included annual incidence, site of infection, Mucorales genera, and patient and treatment characteristics. Comparison was made between patients who survived and those who died. Comparative analysis was performed between patients who received a liposomal amphotericin B dose of 5 mg/kg and those who received a dose of >5 mg/kg. Categorical variables were tested for differences using Fisher's exact test or χ-squared test. The association between liposomal amphotericin B dose and prognosis was evaluated using the Kaplan-Meier method, and differences were tested using the log-rank test. A Cox proportional hazards model was used to control for confounding.The lung was the most commonly involved organ (70.7%), and 35.4% of cases were disseminated. Rhizopus spp., Cunninghamella spp., and Mucor spp. were the most common organisms. No significant differences in infected organs or distribution of Mucorales were observed between the survival and death groups. Longer duration of neutropenia was more common among deaths (p = 0.007). Mortality within 120 days was 54.2%. More cases in the survival group started liposomal amphotericin B before confirmed diagnosis (p = 0.028). Survival did not differ between patients receiving liposomal amphotericin B at 5 mg/kg and those receiving >5 mg/kg (p=0.873). Using Cox proportional hazards models adjusting for confounders, such as age ( >65 years), prolonged neutropenia, and resection of infected lesions, the hazard ratio for the effect of >5 mg/kg liposomal amphotericin B on 120-day prognosis was 0.93  compared with 5 mg/kg.This study provides important insights into the precise epidemiology and treatment practices of mucormycosis among hematologists and infectious disease specialists. There was no difference in prognosis between the 5 mg/kg and >5 mg/kg liposomal amphotericin B groups.Masato Tashiro, MD, PhD, Asahi Kasei Pharma Corporation: Advisor/Consultant|Asahi Kasei Pharma Corporation: Honoraria|Sumitomo Pharma Co., Ltd.: Honoraria Hiroshi Kakeya, MD, PhD, Asahi Kasei Pharma Corporation: Honoraria|Merck Sharp & Dohme: Honoraria|Sumitomo Pharma Co., Ltd.: Honoraria Hiroshige Mikamo, M.D, Ph.D, Asahi Kasei Pharma Corporation: Grant/Research Support|Merck Sharp & Dohme: Honoraria|Pfizer Inc.: Grant/Research Support|Pfizer R&D Japan: Honoraria|Sumitomo Pharma Co., Ltd.: Grant/Research Support|Sumitomo Pharma Co., Ltd.: Honoraria Kazutoshi Shibuya, M.D., Ph.D., Sumitomo Pharma Co., Ltd.: Grant/Research Support Koichi Izumikawa, M.D., Ph.D., Asahi Kasei Pharma Corporation: Grant/Research Support|Asahi Kasei Pharma Corporation: Honoraria|Astellas Pharma Inc.: Honoraria|DAIICHI SANKYO COMPANY, LIMITED: Grant/Research Support|DAIICHI SANKYO COMPANY, LIMITED: Honoraria|KYORIN Pharmaceutical Co., Ltd.: Honoraria|Merck & Co., Inc.: Honoraria|Pfizer Japan Inc.: Honoraria|Shionogi & Co., Ltd.: Grant/Research Support|Shionogi & Co., Ltd.: Honoraria|Sumitomo Pharma Co., Ltd.: Grant/Research Support|Sumitomo Pharma Co., Ltd.: Honoraria|TAIHO PHARMACEUTICAL CO., LTD.: Grant/Research Support


The correct name is: Mirai So. The publisher apologizes for the error. The correct citation is: Ochi S, So M, Hashimoto S, Hashimoto Y, Sekizawa Y (2023) Impact of the COVID-19 pandemic on exercise habits and overweight status in Japan: A nation-wide panel survey. PLOS Glob Public Health 3(7): e0001732.


The 20-valent pneumococcal conjugate vaccine (PCV20), developed to expand protection against pneumococcal disease, is approved for adults in several countries and for pediatric use in the United States. Tolerability and safety data from PCV20 pediatric studies are described.Five randomized studies in infants  assessing the safety of PCV20 relative to 13-valent PCV (PCV13) receiving a 3- or 4-dose series (2 or 3 primary series doses and a toddler dose) were conducted in North America, Europe, South America, and Japan. Study vaccines were given intramuscularly in all studies except in Japan, where a subcutaneous (SQ) route was also evaluated. A single-arm Phase 3 study of 1 PCV20 dose was performed in US children 15 months to 17 years old; children < 5 years old had received ≥ 3 doses of PCV13. All studies assessed local reactions and systemic events within 7 days of vaccination. Adverse events (AEs) were collected through 1 month after the primary series (infant studies) and 1 month after the toddler or single vaccine dose. Serious AEs (SAEs) were collected throughout study participation.The safety population across 6 studies totaled 6654 participants; 3276 infants and 831 children received PCV20 and 2547 infants received PCV13. Overall, the most common local reaction was injection site pain, except in the infant study in Japan, where redness was most common, particularly in SQ groups. In the infant studies, the most common systemic events were irritability and drowsiness. The most common systemic events in older children were fatigue (≥ 2- to < 5-year-old age group) and muscle pain (≥ 5- to ≤ 17-year-old age group). Fever > 40°C was uncommon . AE and SAE rates were similar to the PCV13 group in the infant studies and low in the study in children. Events were consistent with illnesses and medical conditions that may occur in pediatric populations.In 6 studies conducted globally, PCV20 was safe and well tolerated in infants and children through 17 years of age. The PCV20 tolerability and safety profile was similar to PCV13 controls in infant studies and consistent with PCV13 studies in children.FUNDING BY PFIZER INCLaurence Flint, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kathleen McElwee, MD, MDH, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds G. Laissa Ouedraogo, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Noor Tamimi, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Mary J. Kline, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kimberly J. Center, M.D, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Allison Thompson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Richard de Solom, MBBS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Masako Yamaji, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James Trammel, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Lanyu Lei, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Yahong Peng, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Daniel Scott, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Wendy Watson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds


The US has experienced a significant decrease in CLABSI rates over time but is stalling. NHSN has rigid definitions for secondary BSI attribution. We reviewed CLABSIs in a large tertiary acute care hospital to determine the frequency and trends of potential misattribution.We reviewed 282 CLABSIs cases from 2019 to 2023 at a large tertiary hospital. A team of infection preventionists with high inter-rate reliability adjudicated each case strictly following NHSN methodology. A clinical review was performed by two hospital ID-trained epidemiologists to explore misattributed with an alternative primary infection.Of 282 CLABSI cases, 65% occurred in adults and 35% in children. 122 cases (43%) had a potential primary infection. The potential primary infections included: 33 (27%) pneumonia, 28 (23%) gastrointestinal infections, 6 (5%) urinary infections, 4 (3%) surgical infections, 13 (11%) skin and soft tissue infections, 11 (9%) vascular infections, 5 (4%) bacterial translocation, 8 (6.5%) infections that were present on admission, 4 (3%) CNS infections, 2 (1.6%) NEC infections, 2 (1.6%) musculoskeletal, 2 (1.6%) contaminates and 4 (3%) other non-NHSN specified sites. Pneumonia was the most frequent misattribution failing to meet imaging, laboratory, or documentation requirements within the infection window period (IWP). Intra-abdominal infection was the second most frequent cause of misattribution due to not meeting the imaging or matching site culture within the IWP. For the other categories, the most frequent reasons for not meeting the primary criteria included lack of matching culture, lack of clinical symptoms (often in intubated patients), or in the endocarditis category, the complexity of the criteria even with positive blood cultures and presence of vegetations. The graph shows an increasing proportion of misclassification over time.Percent of Misattributed CLABSI by Fiscal YearNHSN definitions and rules are becoming too prescriptive and may no longer be applicable to the complexity of cases, overestimating CLABSIs. As hospitals commit to CLABSI reduction, accurate and specific definitions are key in focusing efforts and attention and avoiding unfair penalties.Luis Ostrosky-Zeichner, MD, FACP, FIDSA, FSHEA, FECMM, CMQ, Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Advisor/Consultant|F2G: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Pulmocide: Grant/Research Support|Scynexis: Grant/Research Support|T2 Biosystems: Grant/Research Support|Viracor: Advisor/Consultant


Whether pharmacokinetic (PK)/pharmacodynamic (PD) target attainment for meropenem measured in plasma is a clinically reliable surrogate for target attainment in the epithelial lining fluid (ELF) in pneumonia is unclear. The objective of the current study was to characterize target attainment in plasma and ELF using prospectively collected samples and to define predictors of optimal target attainment.vs. PK/PD goals of 100% T>1xMIC and 100% T>4xMIC for a susceptible MIC of 2 mg/L.Individual Bayesian meropenem plasma and ELF profiles were generated using Pmetrics for the first 24 hours of treatment. First 24-hr PK/PD target attainment was evaluated plasma, and VELF estimates were 6.2 L/hr, 45.7, and 28.3 L. For the 100% T>4xMIC goal the following target attainment groups were identified: optimal (≥95%) in plasma and ELF , near-optimal ( >50% and < 95%) in both plasma and ELF , suboptimal (< 50%) in ELF only , suboptimal (< 50%) in plasma only , and suboptimal (< 50%) in both ELF and plasma . Loading doses significantly improved the likelihood of optimal vs. suboptimal target attainment in ELF and plasma  but did not reliably discriminate other groups.Sixty-seven patients contributed ELF and plasma PK data (range: 1-3 samples/patient for each matrix). Mean population CL, VIndividual observed meropenem (ordinate) and model predicted meropenem (abscissa) concentrations in plasma (A) and ELF (B) in patients with pneumonia.Optimal target attainment was achieved in only 40% of patients while nearly 20% of patients had suboptimal attainment in both plasma and ELF. Use of plasma as a surrogate for ELF would miss up to 20% of patients with suboptimal ELF attainment, suggesting that therapeutic monitoring of ELF may be required in some patients to optimize PK/PD attainment.Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|ASHP: Honoraria|Chambless, Higdon, Richardson, Katz & Griggs, LLP: Expert Testimony|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Guidepoint Global: Honoraria|Hall, Booth, Smith, P.C.: Expert Testimony|Merck: Advisor/Consultant|Reminger Co., L.P.A: Expert Testimony|Spero: Advisor/Consultant|Takeda: Advisor/Consultant|Taylor, English, Duma, LLP: Expert Testimony|Third Pole Therapeutics: Advisor/Consultant Michael N. Neely, MD, Astellas Pharma Global Development, Inc.: Advisor/Consultant|Astellas Pharma Global Development, Inc.: Support for the present publication Richard G. Wunderink, MD, bioMerieux: Honoraria|Kariius: Clinical Evaluation Committee|LaJolla: Advisor/Consultant|Pfizer, Inc: Clinical Evaluation Committee|Shionogi: Advisor/Consultant Nathaniel J. Rhodes, PharmD MS, Third Pole Therapeutics: Advisor/Consultant


Lenacapavir (LEN) is currently approved for multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced individuals. Mean trough concentrations >15.5 ng/mL, which is the inhibitory quotient-4  are associated with high rates of HIV-1 suppression. LEN dosing regimens consist of a subcutaneous (SC) 927 mg injection (2 x 1.5 mL) every 6 months along with oral loading. With SC injections, it is common practice to rotate injection sites (within the same or at a different body site) to mitigate injection site reactions while also providing flexibility in dosing. However, SC LEN is approved to be administered in the abdomen only. This study investigated the impact of alternate injection sites on the pharmacokinetics (PK) and safety/tolerability of SC LEN.This was a Phase 1, open-label, parallel design, single dose, multicohort study in healthy participants. Participants were enrolled into a thigh (TH), upper arm (UA), or abdomen (AB) cohort (N=10 per cohort) and received a single approved SC dose of 927 mg. Plasma PK samples were collected on Day 1 over 0–216 hours post dose, followed by a weekly or biweekly sample over Days 15–210, then monthly until Day 270 and were analyzed for LEN using validated bioanalytical methods. PK of LEN was characterized by noncompartmental analysis, and LEN plasma exposures in the TH and UA cohorts were descriptively compared to AB as the reference.max and AUCtau (tau = 6 months) were similar between TH vs AB . For UA, mean Cmax (86.0 [56%] ng/mL) and AUCtau (7760 [42%] days*ng/mL) were higher than AB by 42% and 22% respectively, which were not considered clinically significant. Mean Ctau [CV%] for TH, UA, and AB were higher than IQ4 . SC LEN was well-tolerated in TH, UA, and AB with no serious adverse events.Mean [CV%] Ctau exceeding the efficacy target of IQ4. This study supports TH and UA as potential alternate administration sites for SC LEN in future studies.TH and UA cohorts achieved similar or higher overall exposures compared to the reference AB, with mean CAllen K. Lat, PharmD, Gilead Sciences, Inc: Grant/Research Support Aryun Kim, PharmD, Gilead Sciences, Inc: Company employee|Gilead Sciences, Inc: Stocks/Bonds Haeyoung Zhang, PharmD, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Stephen Lin, BA, Aurinia Pharmaceuticals Inc: Stocks/Bonds|Biodexa Pharmaceuticals: Stocks/Bonds|Clearside Biomedical: Stocks/Bonds|Gilead Sciences, Inc: Company employee|Gilead Sciences, Inc: Stocks/Bonds Eva Mortensen, MD, MS, Ascendis: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Merck: Stocks/Bonds|Moderna: Stocks/Bonds|Novartis: Stocks/Bonds|Pfizer: Stocks/Bonds|Teva: Stocks/Bonds Ramesh Palaparthy, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Renu Singh, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds|Pfizer: Stocks/Bonds


Enterobacterales with significant AmpC production due to concerns for inducible resistance. We aimed to determine if dose-optimized TZP is as effective for bloodstream infections (BSI), and to establish rates of tx-emergent resistance in an era of β-lactam (BL) dose optimization.Cefepime (FEP) and carbapenems (CB) are preferred over piperacillin-tazobactam (TZP) for treatment (tx) of E. cloacae, K. aerogenes and C. freundii from 2017 to 2022 at two hospitals were included. We excluded patients surviving < 48 hours or if polymicrobial BSI due to a Gram-negative organism resistant to BLs. Primary outcome was 30-day success, defined as survival, clinical improvement, completion of definitive tx and absence of recurrent infection. Development of resistance was assessed over 90 days.Patients with BSI due to Table 1). Median (IQR) time to in-vitro active tx was 7.6 (1.4-20.7) hours. 48%, 30%, and 11% of patients received TZP, FEP, and CB as empiric tx, respectively. By comparison, 15%, 47%, and 22% received TZP, FEP, and CB as definitive tx, respectively (n=344). Patients tx’d with definitive CB were more likely to receive inactive empiric tx (p=0.0004) and have complicated BSI (p=0.015). Dose optimization was more common for TZP than FEP or CB (p=0.02). Early clinical failure was more common for CB than other agents, but similar for TZP and FEP (Table 2). 30-day clinical success rates ranged 58-85%, were lower for patients tx’d with CB , and comparable for TZP and FEP (p=0.25). By empiric tx, there were no differences in early clinical failures, microbiologic relapse, 30-day success, or all-cause mortality between patients tx’d with TZP or FEP (Table 3). Overall, 226, 279, and 117 patients received TZP, FEP, and CB as empiric or definitive tx. Corresponding rates of resistance development within 90 days were 2%, 1%, and 3%, respectively.429 patients were identified; 362 met inclusion criteria. The median age was 65 years, 61% were male and median Pitt Bacteremia score was 2 (Results Table 1. Patient demographics, severity of illness, infection and treatment characteristics based on definitive therapyResults Table 2Results Table 3Definitive tx with dose-optimized TZP did not lead to worse clinical or microbiologic outcomes compared to FEP, CB and FQ. There were no cases of tx-emergent resistance among patients who received TZP as definitive tx, and overall rates of resistance development were low.Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support


The 2023 Duke-ISCVID criteria for IE were recently introduced to improve classification of IE for research and clinical purposes (Table 1). We compared the diagnostic accuracy of the new criteria with the 2000 modified Duke criteria, the 2015 European Society of Cardiology (ESC) criteria and a clinically adjudicated reference standard by a panel of international experts on IE.The study population consisted of consecutively enrolled patients suspected to have IE and discussed by the IE team of the Amsterdam University Medical Center (AMC) between October 2016 and March 2021. A panel of international experts on IE assigned a final diagnosis, which served as the reference standard. We compared the definite classification of the 2023 Duke-ISCVID criteria against this reference standard. We also evaluated accuracy of the new criteria, excluding data obtained from cardiac surgery and pathology . Lastly, we quantified the added value of the proposed changes to the criteria, and compared the 2023 Duke-ISCVID to previous criteria using the McNemar test. We performed sensitivity analyses in patients who underwent cardiac surgery and patients who underwent TEE.595 patients with suspected IE were included, of whom 399 (67%) were adjudicated as having IE. 111 patients (19%) had prosthetic valve IE, 48 (8%) had cardiac implantable electronic device IE. The 2023 Duke-ISCVID criteria were more sensitive than the modified Duke or ESC criteria  without significant loss of specificity (Table 2). After excluding cardiac surgery/pathology results, the 2023 Duke-ISCVID Clinical Criteria also had significantly better sensitivity than the modified Duke and ESC criteria, again without losing specificity. The changes in the 'major microbiological' and 'imaging' criteria had the most impact . Findings were robust in sensitivity analyses (Table 3). When classifying ‘definite’ and ‘possible’ IE as a positive test, the 2023 Duke-ISCVID criteria had 99% sensitivity compared to the reference standard, but specificity decreased to 21%.Sensitivity and specificity are against the reference standard (adjudication panel). The Clinical Criteria classification is the Duke-ISCVID classification when results from surgery or post-mortem studies are not used to determine classification.In the Definite + Possible analysis, patients with possible IE according to the Duke-ISCVID criteria were also considered as having IE. All comparisons are against the reference standard (adjudication panel).In this cohort, the 2023 Duke-ISCVID criteria represent a significant advance in the diagnostic classification of patients suspected of IE.Added value of new Duke-ISCVID criteria compared to modified Duke criteriaEach point  provides the diagnostic accuracy measure for the 2000 modified Duke Criteria with addition of a specific change from the Duke-ISCVID criteria. The horizontal bars represent the 95% confidence interval for the point estimate. The top points represent the modified Duke criteria without addition, the bottom points are the complete Duke-ISCVID criteria.Larry M. Baddour, MD, Boston Scientific: Advisor/Consultant|Roivant Sciences: Advisor/Consultant Arnold S. Bayer, MD, Akagera Medicines: Grant/Research Support|ContraFect Corporation: Grant/Research Support Emanuele Durante Mangoni, MD,, PhD, Advanz pharma: Advisor/Consultant|Advanz pharma: Grant/Research Support|Advanz pharma: Honoraria|Angelini: Grant/Research Support|Angelini: Honoraria|Genentech: Advisor/Consultant|Genentech: Board Member|Genentech: Honoraria|Infectopharm: Grant/Research Support|Menarini: Board Member|Menarini: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Board Member|Roche: Honoraria Thomas L. Holland, MD, Aridis: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|Karius: Advisor/Consultant|Lysovant: Advisor/Consultant Adolf W. Karchmer, MD, Karius: Grant/Research Support|Up To Date: Honoraria 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


Humoral immune responses to respiratory syncytial virus (RSV) infection in hematopoietic cell transplant (HCT) recipients have not been well characterized. We measured RSV pre-fusion F antibody (RSVpreF) titers in HCT recipients in 3 groups: upper respiratory tract infections (URTI) only, lower respiratory tract infections (LRTI) only, and those who progressed from URTI to LRTIs (progressors).10 RSVpreF titers among groups using linear mixed effect models with restricted cubic splines.We evaluated adult and pediatric allogeneic HCT recipients who acquired RSV from 12/2011 to 12/2019. Prospective and leftover clinical serum specimens were collected from the Fred Hutchinson Cancer Center. Samples included baseline prior to infection, at RSV URTI or LRTI diagnosis, and after infection (both 4-6 and >8 weeks). Quantitative RSVpreF titers were determined using the MesoScale Discovery electrochemiluminescence assay. We compared longitudinal logA total of 129 samples from 39 patients were analyzed; 24 with URTI only, 8 progressors, and 7 with LRTI only. The median age at infection was 45 years, but HCT recipients with LRTI only had an overall higher median age of 54 (range 23-63) (Table 1). Most had acute leukemia  and received peripheral blood stem cells  as their cell source (Table 1). Median RSVpreF values were similar across the 3 different groups at each timepoint (Table 2). Trajectories of RSVpreF titers over time for each patient trended towards an increase following RSV diagnosis in all groups . Predicted curves in RSVpreF titers over time did not differ significantly by group .(A) RSVpreF titers for allogeneic HCT recipients with RSV infection. Each line represents a patient. The top panel shows patients with RSV URTI only, the middle panel shows patients who progressed from URTI to LRTI, and the bottom panel shows patients who presented with RSV LRTI. Open circles represent time points prior to RSV diagnosis, filled circles represent time points just prior to, on or after URTI, and asterisks represent time points just prior to, on, or after LRTI. (B) RSVpreF titers plotted by days from RSV diagnosis. Open circles represent observed values and lines represent model predicted trajectories. Black circles and lines correspond to patients with RSV URTI only, blue corresponds to patients who progressed from RSV URTI to LRTI, and dark orange represents patient who presented with RSV LRTI at diagnosis. An outlying observation at day -53 was excluded.Among allogeneic HCT recipients with RSV infection, RSVpreF titers increased in response to RSV infection, but did not differ among patients with URTI only, progressors, or those with LRTI only across pre and post infection time points. Our novel immunoassay results are similar to those from previously described RSV neutralization assays, but extended the observation period beyond 4 weeks after infection, revealing a modest increase in RSVpreF titers. Further characterization of RSV humoral immunity, including mucosal immunity, is needed.chikara Ogimi, MD, bioMerieux Japan Ltd.: Honoraria|Horiba: Honoraria|Pfizer: Honoraria Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Emily T. Martin, PhD, MPH, Merck: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Symbio: Advisor/Consultant Alpana Waghmare, MD, Allovir: Grant/Research Support|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|GlaxoKlineSmith/Vir: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Pfizer: Grant/Research Support|Vir Biotechnology: Advisor/Consultant


The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection against pneumococcal disease. PCV20 contains conjugates for serotype 6A, which is also in 13-valent PCV (PCV13) and appears to have had a clinical impact on 6C disease, and the additional serotype 15B. An exploratory assessment of cross-reactive functional antibodies to serotypes 6C and 15C elicited by PCV20 in two phase 3 infant studies is described.Two randomized phase 3 studies evaluated immunogenicity and safety of PCV20 relative to PCV13 in infants receiving a 4-dose series  or a 3-dose series . In each study, immunoglobulin G (IgG) concentrations and opsonophagocytic activity (OPA) titers to serotypes 6C and 15C were measured in a randomly selected subset of infants 1 month after the infant doses, and before and 1 month after the toddler dose. IgG geometric mean concentrations, OPA geometric mean titers (GMTs), and percentage of participants with predefined IgG concentrations, and OPA titers greater than or equal to the lower limit of quantitation were calculated with 95% confidence intervals.PCV20 elicited IgG and OPA responses to serotype 6C that were generally similar for most endpoints to PCV13 after the 3 infant and toddler doses in the 4-dose series study and after the toddler dose in the 3-dose series study. PCV20 also elicited both IgG and OPA responses to 15C after the infant and toddler doses that were well differentiated from the PCV13 group in both studies. After the toddler dose, OPA GMTs to serotype 6C in the PCV20 and PCV13 groups were 422 and 995, respectively, following a 3-dose series, and 824 and 1090 following a 4-dose series. OPA GMTs to serotype 15C were 67 and 38 and 117 and 38 at the same timepoint in the PCV20 and PCV13 groups, respectively.PCV20 elicits cross-reactive IgG and cross-functional OPA responses to serotypes 6C and 15C. The responses to serotype 6C after PCV20 are generally similar to those of PCV13. The epidemiology of disease due to the vaccine-type and vaccine-related serotypes will be monitored after introduction of PCV20 into infant immunization programs.Funded by Pfizer IncNoor Tamimi, MD, Pfizer: Employee|Pfizer: Stocks/Bonds Mary J. Kline, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Kimberly J. Center, M.D., Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Allison Thompson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Gary Baugher, PharmD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jelena Drozd, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Ingrid L. Scully, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Peter Giardina, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds James Trammel, MS, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Lanyu Lei, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Yahong Peng, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Daniel Scott, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds William C. Gruber, MD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Wendy Watson, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds