bluuebunny/crossref_metadata_2025 huggingface dataset:
483. Use of Terbinafine in Combination with Other Systemic Anti-fungal Agents As Treatment for Invasive Mold Infections. Experience from A National Cancer Institute Designated Cancer Center.
Authors: Ajayi Eloho , Sikora Anna , Klinkova Olga , Cozzini Lisa , Pasikhova Yanina , Quilitz Rod , Morrison Austin R , Baluch Aliyah
Published: December 2022

Background

The severely Immunocompromised are at an increased risk of fatal infection caused by invasive molds. Amphotericin B and triazole agents with anti-mold activity are commonly used in treating invasive mold infections. There is some data from in-vitro experiments to suggest an enhanced killing of some molds when terbinafine is used in combination with certain azoles or amphotericin B. At our center, terbinafine is occasionally used in combination with other systemic anti-fungal agents in treating severely immunocompromised patients with invasive mold infections.

Methods

The study was a retrospective review of electronic medical records. Sixty-four patients treated for culture confirmed infection with mold isolates at the Moffitt Cancer Center from 1/1/2015 to 6/1/2021 were included in this study. There were 2 treatment groups: Group A comprised of those treated with a terbinafine containing regimen and Group B comprised of patients that were not treated with a terbinafine containing regimen.

Results

Treatment group A: Comprised of 14 patients. Twenty-nine percent (4/14) had skin/soft tissue infections, 21% (3/14) had rhinosinusitis, 21% (3/14) had pulmonary infections and 4 patients (29%) had disseminated infection. Thirty-six percent (5/14) were discharged with treatment response, 57% (8/14) did not respond to treatment or died due to the invasive mold infection and 7% (1/14) died as a result of malignancy.

Treatment group B: Had 50 patients. thirty-eight percent (19/50) had pulmonary infections, 28% (14/50) with skin/soft tissue infections, 16% (8/50) had rhinosinusitis, 2% (1/50) were diagnosed with central nervous system infection, 2% (1/50) had gastrointestinal infection, 14% (7/50) had an unclear source of infection. Forty-eight percent (24/50) were discharged with treatment response, 42% (21/50) had treatment failure or died due to the invasive mold infection and 10% (5/50) died as a result of malignancy. Table 1Figure 1

Conclusion

There was no statistically significant improvement in outcome observed in this study when terbinafine was used in addition to other systemic anti-fungal medications as treatment of invasive mold infections. There is a need for larger studies to determine if terbinafine has a role in the treatment of invasive mold infections.

Disclosures

All Authors: No reported disclosures.
485. A hypermutator strain of Pseudomonas aeruginosa in a COVID-19 patient with ventilator-associated pneumonia
Authors: Nozick Sophia , Ozer Egon A , Medernach Rachel , Mills Jori , Wunderink Richard , Hauser Alan R
Published: December 2022

Background

P. aeruginosa is a cause of hospital-acquired and ventilator-associated pneumonia. Hypermutator P. aeruginosa strains have been described in patients with cystic fibrosis and chronic respiratory infections but are rare in patients with acute P. aeruginosa infection. This case describes a hypermutator strain of P. aeruginosa found in a patient with COVID-19-associated acute respiratory distress syndrome (ARDS).

Methods

Serial respiratory and blood cultures were collected. Short-read sequencing libraries were prepared using the Illumina Nextera XT kit, and whole-genome sequencing was performed using the Illumina NextSeq platform. Long-read sequencing libraries were prepared from unsheared genomic DNA using ligation sequencing kit SQK-LSK109 and sequenced on the Oxford MinION platform. Single nucleotide variants were identified by aligning reads from each isolate to the complete genome of the first available clinical isolate. Hypermutator assays were performed by measuring the mutation frequency rate for rifampin resistance. Antibiotic minimal inhibitory concentrations (MICs) were performed. Growth curves were performed with a starting OD600 of 0.1 with measurements taken every 30 minutes for 24 hours.

Results

Seventeen respiratory and five blood isolates were obtained throughout 62 days of hospitalization. Fourteen of the 22 isolates exhibited hypermutator phenotypes by rifampin resistance assays, which demonstrated rapid accumulation of mutations. All five bloodstream isolates were hypermutators. MIC testing noted increased resistance to aminoglycosides, fluoroquinolones, and aztreonam in the hypermutator isolates. All bloodstream isolates descended from a single progenitor noted on whole-genome sequencing. Each hypermutator strain contained a mutation in the mismatch repair gene mutL, previously associated with the hypermutator phenotype.

Genetic Tree of Patient Isolates

The genetic tree highlights hypermutator versus non-hypermutator single nucleotide variants

Conclusion

This case was notable for multiple isolates of hypermutator P. aeruginosa that persisted over weeks. The patient’s COVID-19 infection and acute respiratory distress syndrome may have facilitated persistence of the P. aeruginosa lineage, allowing a hypermutator lineage to emerge.

Disclosures

All Authors: No reported disclosures.
487. Analysis of the Association between Specific Antibody Response against Respiratory Syncytial Virus Fusion Protein Conformations and Life-Threatening Infection in Previously Healthy Infants
Authors: Bonnin Florencia A , Talarico Laura B , Phung Emily , Kumar Azad , Ferolla Fausto M , Byrne Alana B , Acosta Patricio L , Toledano Analía , Caratozzolo Ana , Contrini María M , Graham Barney S , Ruckwardt Tracy , López Eduardo L
Published: December 2022

Background

Specific humoral response against pre-fusion (pre-F) conformation of respiratory syncytial virus (RSV) F protein has been proposed to play a role against severe infection. We aimed to analyze the association between serum IgG titers against pre-F and post-fusion (post-F) conformations of RSV F protein and life-threatening RSV disease (LTD) in previously healthy infants.

Methods

Prospective cohort study including previously healthy infants < 12 months, hospitalized with a first RSV infection, in 2017-2019. Patients were defined to have LTD when required intensive care and ventilatory support. Pre-F exclusive and post-F-specific antibody responses were determined by post-F competition and non-competitive immunoassays, respectively, and neutralizing activity was measured by plaque reduction neutralization test. Viral load (VL) was assessed by qRT-PCR from nasopharyngeal aspirates collected on admission. Serum samples were collected within 72 h from admission and in convalescence (between 14 to 60 days).

Results

Seventy-five patients were included, median age 3 months, 60% (n=45) were males; 21 patients developed LTD. Importantly, acute and convalescent post-F and pre-F exclusive IgG titers did not associate with LTD (Fig 1). There was a positive correlation between neutralizing antibody titers and pre-F exclusive IgG titers (p=0.016). Post-F and pre-F exclusive IgG titers negatively correlated with age in acute phase (p< 0.0001 and p= 0.0009). In acute phase, post-F and pre-F exclusive IgG titers were higher in patients ≤ 2 months (Fig 2). Patients > 2 months increased post-F and pre-F exclusive IgG titers in convalescence. Additionally, post-F and pre-F exclusive titers did not correlate with VL, and VL was not related to LTD.

Conclusion

-Pre-F exclusive and post-F IgG titers did not associate with LTD, even though pre-F exclusive IgG correlated with neutralizing antibody titers.

-Infants under two months of age developed a lower humoral response, likely due to an interference by maternal antibodies and/or immunological immaturity.

-These findings highlight the importance of fully characterizing the immune response against RSV and its association with disease severity for the development of preventive strategies.

Disclosures

Barney S. Graham, MD, PhD, BSG: BSG is an inventor on patents for the stabilization of the RSV F protein (WO2014160463A1, Prefusion RSV F proteins and their use).|National Institutes of Health: Inventor on patents for RSV vaccines|National Institutes of Health: inventor on patents for measles and other paramyxovirus vaccines.
492. Dectin-1 Stimulation Promotes a Distinct Inflammatory Signature in the Setting of Aging and HIV-infection
Authors: Zapata Heidi , Kumar Archit , Wang Jiawei , Shaw Albert , Zhou Haowen , Radcliffe Christopher , Barakat Lydia A , Wyk Brent Vander , Allore Heather , Zhao Hongyu , Tsang Sui , Manager Data , Mohanty Subhasis
Published: December 2022

Background

Dectin-1 is an innate immune pattern recognition receptor that recognizes and binds b-1,3/1,6 glucans on fungal pathogens.

Methods

We evaluated Dectin-1 function in innate immune cells (Monocytes and Dendritic cells) in a cohort of HIV-positive and HIV-negative young and older adults (n= 81). PBMCs were stimulated with whole glucan particles (1,3/1,6-b-glucan, WGP), a specific Dectin-1 agonist and analyzed via intracellular cytokine staining (ICS) and multicolor flow cytometry of monocytes and dendritic cells. Sorted CD14+ CD16+ monocytes stimulated with WGP and subjected to RNA-seq analysis.

Results

Stimulation of monocytes with β-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-a, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-a production. This increase in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-a and coagulation response that was already increased at baseline, and a persistent IFN-α and IFN-γ response. HIV-older adults also demonstrated an activated dendritic cell signature and M1 macrophage signature upon stimulation that was not seen in young individuals. Pathways upregulated in all cohorts were the signaling pathways MTORC-1, hypoxia pathway (pathways involved in trained immunity) and the unfolded protein response. Of note MTORC-1 signaling was upregulated at baseline in HIV-Older adults.

Conclusion

Overall, our study demonstrates that increased age and HIV-infection can affect the function of Dectin-1 and lead to a distinct inflammatory signature. Dectin-1 stimulation in HIV-Older adults led to a more pro-inflammatory phenotype that was demonstrated through both protein and gene expression. Dectin-1 induced inflammation in HIV-infected individuals may be contributing to the pro-inflammatory environment that is seen in the setting of both aging and HIV-infection.

Disclosures

All Authors: No reported disclosures.
506. Neonatal CD8+ T Cells Demonstrate PD-1 Dependent Impairment Following Human Metapneumovirus Infection
Authors: Eddens Taylor , Parks Olivia , Zhang Yu , Williams John
Published: December 2022

Background

Human metapneumovirus (HMPV) is a leading cause of pediatric acute respiratory illness, accounting for 14.2 million acute lower respiratory tract infections and 500,000 hospitalizations per year in children less than 5 years of age globally. Infants and neonates are particularly susceptible to severe HMPV disease. Our prior studies in adult mice demonstrated CD8+ T cells were critical for clearance of HMPV infection, although these cells show impaired function due to PD-1:PD-L1 signaling. However, the immune system in the neonatal lung skews towards an anti-inflammatory and tolerogenic response when compared to adults. We therefore sought to explore the roles CD8+ T cell and PD-1 signaling in neonatal mice to recapitulate the population at highest risk.

Methods

C57BL/6 or Pdcd1-/- pups were infected intranasally with 1.0x106 PFU/g of a clinical isolate of HMPV (TN94-49) on day of life 4-6. Viral burden was assessed via plaque assay and cellular responses were characterized by multispectral flow cytometry.

Results

HMPV infection led to stunted weight gain in pups compared to mock-infected controls. HMPV-infected neonatal mice had a robust innate immune response comprised of neutrophils, CD103+ dendritic cells, and interstitial macrophages, all of which demonstrated upregulation of PD-L1. From an adaptive perspective, neonatal mice mounted an antigen-specific CD8+ T cell response and resolved HMPV infection by day 8 post-infection. Similar to our prior studies in adult mice, neonatal CD8+ T cells upregulated expression of several inhibitory receptors, such as PD-1, LAG-3, and TIM-3. Neonatal CD8+T cells demonstrated limited effector cytokine production, such as IFN-γ and granzyme B, following ex vivo stimulation with a class I HMPV-specific peptide. Pdcd1-/- mice (lacking PD-1) also mounted an antigen-specific CD8+ T cell response, but had markedly increased production of IFN-γ and granzyme B.

Conclusion

These data demonstrate that PD-1 signaling on CD8+ T cells constrains the antiviral response in a novel model of neonatal respiratory viral infection. Understanding the mechanisms that inhibit neonatal anti-viral responses could present opportunities for novel therapeutic strategies for common infections with high morbidity and mortality in neonates and infants.

Disclosures

John Williams, MD, GlaxoSmithKline: Advisor/Consultant|Quidel: Advisor/Consultant.
508. Prevalence of nasopharyngeal colonization by Staphylococcus aureus in adults with chronic diseases in Colombia.
Authors: Lozada Julian , Ibáñez-Prada Elsa D D , Serrano-Mayorga Cristian C , Fuentes Yuli V , Bustos Ingrid G G , Mendez Lina , Crispin Ana M , Reyes Luis Felipe F
Published: December 2022

Background

Staphylococcus aureus is a significant cause of morbidity and mortality worldwide. It is responsible for many infections, especially soft tissues, and bacteremia. S. aureus is also a commensal microorganism in humans, usually found in the nasopharynx. Colonized subjects, especially adults with comorbidities, have a higher risk of developing clinical infections such as community-acquired pneumonia (CAP). Some researchers have hypothesized that nasopharyngeal colonization is the etiology that could predict the etiology of CAP. Therefore, the objective of this study was to establish the prevalence of nasopharyngeal colonization by S. aureus in adults with comorbidities in a Colombian cohort.

Methods

This was a multicenter prospective cohort study in 3 centers in Colombia, conducted between December 2020 and March 2021. Patients older than 18 years with a diagnosis of chronic disease were included. Subjects with evidence or diagnosis of CAP before 90 days and subjects admitted to hospitalization during the last seven days were excluded. Nasopharyngeal aspirate (NPA) sampling in each participant according to WHO guidelines. A seeding of 100 ¼L of NPA by counting method on blood agar. The colonies in these cultures were identified by MALDI-TOF.

Results

NPAs were obtained in 810 subjects. S. aureus was isolated in 16.9% [137/810] of participants, with an average concentration of 148 CFU/100 µL [IQR 1 – 5500]. All the obtained colonies were confirmed by MALDI-TOFF. Patients had a mean age of 61.4 years [IQR 26 – 98], and 48.7% [67/137] were women. All of the subjects presented at least one comorbidity (51,1% [70/137] Arterial hypertension, 21,9% [30/137] chronic kidney disease, 16,8% [23/137] Diabetes and Heart failure). Notably, only 5.8% [8/137] developed pneumonia during the first six months of follow-up.

Conclusion

Our results confirm that S. aureus is a prevalent microorganism that colonizes the nasopharynx in adults with comorbidities. We will follow up with the patients for two years to determine if the nasopharyngeal colonization due to S. aureus is a risk factor for developing CAP.

Disclosures

All Authors: No reported disclosures.
510. Secretory IgA in the Vaginal Mucosa Inhibits Herpes Simplex Virus Infection
Authors: Fong Valerie , Hunte Richard , Keller Marla J , Herold Betsy , Herold Betsy
Published: December 2022

Background

HSV2 increases HIV risk and is twice as common among women. We previously showed that cervicovaginal secretions exhibit innate anti-HSV2 activity that was lower in adolescents and women with HIV-- conditions associated with vaginal dysbiosis and increased HSV shedding. Our current study aims to test the hypothesis that vaginal dysbiosis is associated with low anti-HSV activity and to explore the molecules and mechanisms that contribute.

Methods

Cervicovaginal lavage (CVL) (10 ml normal saline wash) was collected from 20 women who presented with clinical bacterial vaginosis (BV) (Day 0) and then 1 and 4 weeks after completing a 7-day oral metronidazole course; parent study results were reported (PMID 34003290). Anti-HSV2 activity of CVL (diluted 1:4) was determined by plaque reduction assay. CVL IgG, IgA, cytokines and antimicrobial peptides were quantified by ELISA or multiplex Luminex and select microbiota by quantitative real-time PCR. CVL was enriched for IgA and IgG using protein L (binds all Ig) and Protein G (binds only IgG). HSV-specific antibodies in CVL were assessed by ELISA. Statistical analyses including Spearman correlation coefficients (SCC) were performed with GraphPad Prism version 9.1.2 software.

Results

Anti-HSV2 activity of CVL was highly variable at Day 0 (mean 18.6% SD 36.7) and trended to increase after treatment (mean 22.56% SD 33.8). The anti-HSV2 activity correlated positively with Nugent scores (SCC= -0.28, p= 0.03) and qPCR levels of BV-associated microbes (SCC = -0.2 to -0.3, p< -0.1) but positively with IgA (r= 0.49, p< 0.01) and IgG (r= 0.33, p= 0.01). IgA and IgG were isolated from pools of CVL with high inhibitory activity greater than 40% (n= 8). The anti-HSV2 activity mapped to the IgA fraction (56.5% inhibition) compared to the IgG or non-Ig fraction (0% inhibition) even though, as expected, the CVL concentration of IgG was higher than IgA (8.3μg/mL vs 4.9 μg/mL). The anti-HSV2 activity did not correlate with HSV-specific Ig in CVL.

Conclusion

Our findings suggest that secretory vaginal IgA contributes to innate anti-HSV2 activity and may trap viral particles to prevent viral entry. We speculate that sialidases, which cleave IgA and are elaborated by BV-associated microbiota, contribute to the low anti-HSV2 activity observed in high-risk cohorts.

Disclosures

Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl. Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl.
515. Comparing Different Delivery Methods of Fecal Microbiota Transplantation
Authors: Lee Eun Hwa , Lee Ki Hyun , Kim Jinnam , Ju Lee Se , Kim Jung Ho , Ahn Jin Young , Jeong Su Jin , Ku Nam Su , Yeom Joon-sup , Choi Jun Yong
Published: December 2022

Background

The increasing prevalence of multi-drug resistant organism (MDRO) carriage imposes significant medical challenges by increasing healthcare costs. Since MDRO carriage impacts treatment outcome and prognosis, many decolonization strategies were proposed but were not as effective as expected. Recently, fecal microbiota transplantation (FMT) has been discussed as a novel and effective method of MDRO decolonization. In this study, we compared the effectiveness of different FMT delivery methods to find suitable methods and optimize the success rate of decolonization for the patients with MDRO carriage.

Methods

In this prospective cohort study, we enrolled patients with MDRO carriage from 2018 to 2021. Patients received FMT via one of the four following methods; oral capsule, esophagogastroduodenoscopy, colonoscopy, or gastric tube. FMT delivery method was chosen according to the medical condition or eligibility for oral diet. The participants were followed up for one year. Decolonization and recolonization with MDRO were determined by the follow-up stool cultures. Microbiome analysis was done to assess the successful restoration of the gut microbiome.

Results

A total of 57 patients received FMT for MDRO decolonization. The number of patients who received FMT via oral capsule, EGD, colonoscopy, and gastric tubes was 14, 9, 23, and 11. The overall decolonization rate was 69.2%, and the recolonization rate was 19.3%. The colonoscopy group required the shortest time for decolonization, while the EGD group was the longest (24.9 vs. 190.4 days, p-value=0.022). The decolonization rate was the highest in the EGD group (85.7%) and the lowest in the gastric tube group (50.5%). The oral capsule group had a comparable decolonization rate to the EGD group (84.6% vs. 85.7%, p=0.730). The clinical factor associated with decolonization was antibiotic usage after FMT (Odds ratio= 6.810, p-value=0.008). Microbiome analysis data showed improvement in alpha index in the Oral capsule and the EGD group. All four groups showed a reduced proportion of MDRO species after FMT.

Comparison of ACE index of Taxonomic data with different FMT modalities

Conclusion

The oral capsule is an effective FMT method for patients who are tolerable to an oral diet compared to the other conventional methods. Discontinuation of antibiotics after FMT is critical in decolonization.

Disclosures

All Authors: No reported disclosures.
524. An Objective Measure of The Host Response Suggests Social Determinants, Rather than Pathobiology, as a Factor in Disparate Sepsis Outcomes Among Races
Authors: O’Neal Hollis R , Sheybani Roya , Mitchell Miranda , Tse Henry T , Shah Ajay M , Thomas Christopher B
Published: December 2022

Background

Sepsis is a common and costly condition encountered in United States hospitals and Emergency Departments (ED). Studies have shown that the incidence of sepsis and risk of sepsis morbidity and mortality increases with age. With increased efforts on early detection and process of care, in-hospital sepsis deaths have declined; however, racial disparities have been observed in sepsis-related outcomes. The objective of this study was to assess demographic, severity, and outcome differences among septic patients presenting to the ED self-reporting as White vs. Black, and evaluate the potential of an investigational cellular host response test in risk stratifying these subpopulations for risk of poor outcomes.

Methods

The IntelliSep test is an investigational in-vitro diagnostic that quantifies the state of immune activation by measuring the biophysical properties of leukocytes from a routine whole blood sample in under 10 minutes. The result is the IntelliSep Index (ISI), ranging between 0.1-10.0, stratified into three discrete interpretation bands of increasing disease severity risk: Green, Yellow, and Red.

Adult patients presenting to the ED with signs or suspicion of infection were prospectively enrolled in four discrete but similar cohorts at multiple sites in the USA (Feb. 2016 – Apr. 2020). All patients had ISI performed and were followed by retrospective chart review for outcome information and sepsis adjudication. Treating clinicians did not have access to assay results, and only those determined to be septic were included in the final analysis.

Results

Of the 150 patients included in the analysis, 92 (61%) were White and 58 (39%) Black. No significant differences were observed in biological sex or severity of illness (Fig). Black subjects were significantly younger (mean difference 8.9 years; p < 0.001) compared to Whites. Independent of race, the ISI correlated with increasing likelihood of adverse sepsis-related outcomes.

Biological sex and APACHE II scores by ISI Interpretation Band for White and Black Study subjects.

Conclusion

The ISI is an objective tool for the quantification of immune activation, and adequately risk-stratifies patients with sepsis for adverse outcomes, independent of race. This finding suggests that social determinants of health, rather than differences in immunobiology, contribute to racial disparities observed in sepsis-related outcomes.

Disclosures

Roya Sheybani, PhD, Cytovale: Employee|Cytovale: Stocks/Bonds Henry T. Tse, PhD, Cytovale: Stocks/Bonds Ajay M. Shah, PhD, Cytovale Inc: Board Member|Cytovale Inc: Ownership Interest|Cytovale Inc: Stocks/Bonds.
549. The Application of Nanopore Sequencing Technology to Characterize Rotavirus Genotypes from Young Children with Diarrhea in the United Arab Emirates
Authors: George Junu , Al-Marzooq Farah , Narchi Hassib , Alsuwaidi Ahmed R
Published: December 2022

Background

In the United Arab Emirates, rotavirus A (RVA) remains a major cause of gastroenteritis in young children despite the universal use of rotavirus vaccines. Monitoring the genetic diversity of circulating strains is essential to better understand the disease burden. Although semi-nested multiplex-PCR is a popular method for RVA genotyping, some clinically significant strains may not be accurately identified by this method. Nanopore sequencing is a third-generation single-molecule sequencing technology that allows for real-time identification of viral and bacterial isolates at competitive costs. This study aims to investigate the use of nanopore sequencing and multiplex-PCR methods to identify RVA genotypes.

Methods

Thirty-three RVA isolates, obtained from stool specimens collected from children less than 5 years old who presented with diarrhea between December 2017 and April 2019, were used for genotyping by PCR and nanopore sequencing. Sixteen isolates were genotyped by Taqman-based qRT-PCR based on VP7 (G) and VP4 (P) genes and genotypes were confirmed by nanopore sequencing in thirteen isolates; three isolates were excluded from nanopore sequencing due to poor RNA quality. Another fifteen isolates were genotyped by the nanopore method alone and two samples were excluded due to poor RNA quality.

Results

The majority of isolates genotyped by qRT-PCR (9 out of 16) were found to harbor VP7 gene of G9 genotype, whereas 5 isolates were of G3 genotype. G12 genotype was rare (2 isolates). For VP4 (P) genotypes, P8 was the most prevalent (8 isolates), followed by P4 (7 isolates), and P6 (1 isolate). When combinations of VP7 and VP4 genotypes are considered, G9P[8] and G9P[4] were the most common genotypes. Nanopore sequencing of 28 isolates revealed G3P8 (29%) as the most prevalent G-P combination, followed by G8P[8] (18%). G9P[8] and G2P[4] were present in 14% of samples. G12P[6] was present in 7% of tested samples. Further, G9P[4], G3P[4], G1P[4], and G4P[2] were detected in 4% of total specimens. One sample was non-typable.

Conclusion

Nanopore sequencing detected various RVA strains among the studied samples including the recently emerging strain, G8P[8]. Using this method in surveillance studies may advance our understanding of the origin, genetic recombination, and burden of disease.

Disclosures

All Authors: No reported disclosures.
569. Utility of the Meningoencephalitis Panel in Modifying Antimicrobial Use in Neonates with Temperature Instability
Authors: Player Brittany , Havens Peter , Mitchell Michelle L , Bushee Glenn , Pan Amy , Huppler Anna R
Published: December 2022

Background

Decisions to discontinue antibiotics in infants undergoing evaluation for central nervous system (CNS) infection can be difficult. Previous reports have associated the use of the meningoencephalitis (ME) PCR panel with decreased hospital stay and antimicrobial use in pediatric and adult patients. However, limited focus has been on infants ≤60-days-old with temperature instability (TI) who undergo evaluation for serious bacterial infection based on age and risk-stratification. We hypothesize use of the ME panel will decrease the duration of antimicrobial use in infants with TI and negative bacterial cultures undergoing evaluation for CNS infection.

Methods

The electronic medical record was queried for patients that met inclusion criteria. Infants ≤60-days-old evaluated for CNS infection due to TI between 1/1/12 – 1/31/22 were included. Exclusion criteria were history of intracranial (IC) devices, previous IC surgery, IC structural or neurovascular abnormalities, or head trauma. A retrospective chart review was performed. We compared length of stay and antimicrobial duration for the groups of patients with the ME panel done versus not done.

Results

A total of 1808 patients with negative bacterial cultures were identified, 96 of whom had the ME panel performed. Patient age, sex, and race were similar between groups. The median hospital length of stay for the patients that had the ME panel done was 64.7 hours as compared to 47.8 hours for those that did not have the ME panel done. The duration of antibacterial therapy was similar when the ME panel was done versus not done. The median duration of therapy for acyclovir was 8.5 when the ME panel was done versus 14.8 hours when it was not done.

Conclusion

When including all patients ≤60-days-old evaluated for TI, use of the ME panel did not lead to a shorter length of hospital stay or duration of empiric antibiotics. However, use of the ME panel decreased duration of therapy in the subset of patients empirically started on acyclovir. Further data analysis will seek to identify patient populations that may most benefit from the use of the ME panel.

Disclosures

All Authors: No reported disclosures.
571. A Report of the Postmarketing Spontaneous Safety Data over 24 Years for GSK’s Measles-Mumps-Rubella (MMR) Vaccine
Authors: Singh Tina , Casabona Giacomo , Abu-Elyazeed Remon , Vetter Volker , Hergibo Fanny
Published: December 2022

Background

GSK’s measles-mumps-rubella (MMR) vaccine is indicated for active immunization of individuals aged 12 months and older against these 3 serious illnesses. It is licensed in > 100 countries worldwide not including the US. In clinical trials, it elicited robust immune responses in children and was well tolerated. Monitoring the vaccine’s real-world safety profile in the general population continues, and rapid collection of data on its real-world use is a strength of passive safety surveillance. We provide an overview of the postmarketing spontaneous safety data over 24 years for GSK’s MMR vaccine.

Methods

Spontaneous adverse events (AE) reports following vaccination with GSK’s MMR vaccine were collected from GSK’s Global Safety Database from 4-December-1997 until 1-March-2022. Annual reporting trends for pyrexia, rashes (commonly reported in the pediatric population), and events of clinical interest like febrile convulsions and neurological conditions were analyzed from 1998 until 2021. The patient exposure was estimated by the number of doses distributed (DD).

Results

Over the reviewed period, ∼445 million doses of GSK’s MMR vaccine were distributed worldwide, and 29,504 cases were spontaneously reported (rate: 6.63 cases reported/100,000 DD). Of all spontaneous AE reports, 9,960 (33.76%) were considered as serious. For the period analyzed, pyrexia and rash were the most frequently reported AEs following vaccination with GSK’s MMR vaccine (Table). Reports of febrile convulsions had a mean frequency of 0.27 cases/100,000 DD (Table); reports of neurological conditions (encephalitis and/or panencephalitis and/or meningitis and/or meningism) had a mean frequency of 0.07 cases/100,000 DD (Table) and did not show a trend of increased incidence over time.

Conclusion

The postmarketing safety data analyzed showed that the safety profile of GSK’s MMR vaccine is consistent with that observed in clinical trials and remains supportive of its overall safety profile in routine use. GSK continues monitoring the safety of its MMR vaccine.

Funding

GlaxoSmithKline Biologicals SA

Acknowledgment: Adina Truta/Julie Mellery provided medical writing/editorial support (Modis c/o GSK)

Disclosures

Tina Singh, MD physician, GSK: Employee of the GSK group of companies and having restricted GSK shares in the GSK group of companies Giacomo Casabona, MD, GSK: I’m an employee of the GSK group of companies and shareholder in the GSK group of companies Remon Abu-Elyazeed, MD, PhD, GSK: Employee of the GSK group of companies and having GSK stocks in the GSK group of companies Volker Vetter, MD, GSK: I’m an employee of the GSK group of companies and hold shares in the GSK group of companies Fanny Hergibo, Pharm.D., GSK: Employee of the GSK group of companies.
572. Adverse Events Following Live Immunization in Patients with DiGeorge Syndrome: A Retrospective, Single Center Study in Korea
Authors: Lim Sung Min , Shin Je Hee , Baek Jee Yeon , Lee Ji Young , Kang Ji-Man , Ahn Jong Gyun
Published: December 2022

Background

DiGeorge syndrome (DGS) is a syndrome accompanied by congenital heart defect, hypoparathyroidism and immunodeficiency of varying severity. Live vaccination is generally contraindicated in patients with DGS. However, in real clinical practice, there are cases in which live vaccines are immunized before the diagnosis of DGS or are incidentally immunized. We collected these cases and investigated adverse events (AEs), especially infections caused by the vaccine strains.

Methods

This retrospective study included all patients diagnosed with DGS at Severance Hospital Seoul, Korea, between November 2005 and June 2021. We extracted patients with ICD-10 code (D82.1) and then excluded subjects without genetic confirm. According to the immune status, subjects were categorized into three groups: group A [CD3 < 500 or CD8 < 200 (cells/mm3)], group B [CD3 ≥500 and CD8 ≥ 200 (cells/mm3)] and group C (unknown).

Results

Of a total 94 DGS patients, approximately 40% of subjects (38/94) underwent immunological test, of which 21% (8/38) belonged to group A and 79% (30/38) were in group B. Approximately 80% of study subjects (73/94) had a record of at least one live vaccination. By vaccine type, measles-mumps-rubella accounted for the most at 70% (66/94), followed by varicella, bacillus Calmette–Guérin, rotavirus, and live-attenuated Japanese encephalitis virus vaccine. A total of 50 AEs were observed (Figure 1): fever (n=29), URI (n=9), diarrhea (n=4), rash (n=3), thrombocytopenia (n=3), injection site pus (n=1) and febrile convulsion (n=1). Among them 26% (13/50) occurred in group A and no significant difference in the incidence rate of AEs between group A and B was observed (P = 0.14). Six cases of them turned out to be consistent with live vaccination by WHO 2009 causality analysis. Moreover, there were no serious reactions, including ICU hospitalization or death, and there was no emergence of disease caused by vaccine strains.

Conclusion

Our data show that live vaccines were often given without immunologic screening and generally well tolerated in our study population.

Disclosures

All Authors: No reported disclosures.
580. Influenza, SARS-CoV-2, and routine childhood vaccines – trends in vaccine hesitancy in hospitalized children before and during the COVID-19 pandemic
Authors: Orbea Marisa , Cunningham Rachel , Mary Healy C , Boom Julie A , Bocchini Claire
Published: December 2022

Background

Vaccine hesitancy (VH) is adversely affecting the public health response to the COVID-19 pandemic. Similarly, influenza vaccine uptake is suboptimal. We aimed to monitor trends in VH with respect to influenza, SARS-CoV-2, and routine childhood vaccines.

Methods

We conducted a repeated cross-sectional survey in English and Spanish of caregiver influenza and SARS-CoV-2 knowledge, attitudes, behaviors, and associated VH among hospitalized children 6 mo-18 yrs at a large pediatric medical institution. Caregivers were enrolled over 3 influenza seasons (S); 2019-2020 (S1), 2020-2021 (S2), and 2021-2022 (S3). VH was assessed using the Parent Attitudes about Childhood Vaccines (PACV) survey; PACV score ≥ 50 denoted VH. Descriptive statistics were used.

Results

During 3 influenza seasons, 269/282 (95%), 295/307 (96%), and 384/418 (92%) of approached caregivers were enrolled in S1, S2, and S3 respectively. Most parents (45%) identified as Hispanic/Latino, 35% as White, and 20% as Black/African American. By report, 94% of children in S1, 91% in S2, and 91% in S3 were up-to-date with routine childhood vaccines. Based on PACV score, 13% of parents were VH in 19-20 compared to 17% in 20-21 and 19% in 21-22.

Approximately 70% of caregivers gave or planned to give their child the influenza vaccine across seasons. Following the COVID-19 pandemic, caregivers were less likely to believe that the “flu can be a dangerous infection in children,” and to agree that “all children over 6 months of age should receive the flu shot every year”. Decreased concern persisted or did not recover during the pandemic (Table 1).

Parents were consistently scared of their child getting COVID-19 but fewer (49% versus 38%) were scared of their child getting the SARS-CoV-2 vaccine in S3. More (50% versus 71%) caregivers in S3 were willing to receive the SARS-CoV-2 vaccine themselves and 46% in S2 and 54% of caregivers in S3 had or planned to vaccinate their child against COVID-19 (Table 2). Table 1.Influenza comparison of study population, 2019-2020 versus 2020-2021 versus 2021-2022

Table 2. SARS-CoV-2 comparison of study population, 2020-2021 versus 2021-2022

Conclusion

Our results suggest a trend that VH may be increasing. During the COVID-19 pandemic, caregivers of hospitalized children were less concerned about influenza than pre-pandemic. Intention to vaccinate children against COVID-19 remains suboptimal.

Disclosures

C. Mary Healy, MD, Dexcom: Stocks/Bonds|Emmes Corporation: Advisor/Consultant|Intuitive: Stocks/Bonds|Quidel Corporation: Stocks/Bonds|Up to Date: Honoraria|Vapotherm: Stocks/Bonds.
596. Anti-Biofilm Activity of Isolated Bacteriophages Targeting Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Brodsky Julia R
Published: December 2022

Background

A rise in the prevalence of antibiotic-resistant infections has prompted a search for alternative methods to combat bacteria in the human body. People with cystic fibrosis are especially vulnerable because their lung environment provides a habitable environment for chronic infection, biofilm formation, and antibiotic-resistant mutations. The difficulty associated with finding bacteriophages targeted to a specific infection is one reason the treatment is used relatively infrequently, even when antibiotics have failed. This study aimed to isolate phage species for strains of Pseudomonas aeruginosa and Staphylococcus aureus, the most common causes of chronic infections in patients with cystic fibrosis.

Methods

Phages targeting multidrug-resistant strains of S. aureus and P. aeruginosa were isolated from samples of fecal matter and soil; stocks were enumerated with the double agar overlay method. The potency of the Pseudomonas-hosted isolates in eradicating biofilms was compared to the efficacy of an antibiotic cocktail and the enzyme cellulase through an in vitro resazurin cell viability assay. Each treatment was performed in sextuplicate. Metabolic reduction of resazurin to resorufin was quantified at 24 and 48 hours of growth using a microplate reader.

Results

Six phage stocks (four targeting Pseudomonas bacteria [from human & feline fecal matter and from soil], two targeting Staphylococcus [from human & feline fecal matter]) contained bacteriophages at concentrations ranging from 3.9x104 pfu/mL to 2.8x107 pfu/mL. The most effective treatments in the assay were found to be cellulase alone and the three inhibitors together.

Conclusion

Feline fecal matter is a potential source of Pseudomonas and Staphylococcus bacteriophages. Enzymes were found to be a critical component of biofilm treatment. The isolated bacteriophages were not the most potent treatment alone, but when combined with cellulase and antibiotics, bacterial growth was markedly slowed.

Disclosures

All Authors: No reported disclosures.
599. Association between Vancomycin AUC and Clinical Failure in Patients with Streptococcal Bacteremia
Authors: Aycock Anna C , Smith Jessica M , Coe Kelci E , Wang Shu-Hua , Reed Erica E
Published: December 2022

Background

Vancomycin (VAN) is an efficacious therapy against Streptococcus. VAN area under the curve to minimum inhibitory concentration (AUC/MIC) is the preferred monitoring strategy for serious methicillin-resistant S. aureus infections but is not well elucidated for other bacterial pathogens such as Streptococcus.

Methods

This was a retrospective cohort study evaluating adult inpatients with streptococcal bacteremia treated with VAN definitive therapy from Jan 1, 2011 to Sept 30, 2021 at a tertiary care academic medical center. VAN AUC was retrospectively calculated using Bayesian software (ClinCalc). The primary outcome was treatment failure, defined as a composite of recurrent or persistent streptococcal bacteremia, 60-day all-cause readmission, or 60-day all-cause mortality. Secondary outcomes included time to bacteremia clearance, hospital length of stay (LOS), and nephrotoxicity. Data collected included demographics; comorbidities; severity of illness; streptococcal species and source; VAN initial trough and duration; and clinical outcomes. Classification and regression tree analysis (CART) was conducted to identify the AUC threshold predictive of clinical failure. Wilcoxon rank sum, Chi Square, or Fisher’s exact tests were utilized as appropriate to compare groups stratified by the CART-identified AUC threshold.

Results

Forty-six patients met inclusion criteria during the study timeframe. Eleven patients had a VAN AUC < 329 of which 8 (73%) experienced clinical failure, while 35 patients had a VAN AUC > 329 of which 12 (34%) experienced clinical failure (p=0.04). No significant differences in baseline or clinical characteristics were identified between groups. Median VAN initial trough was higher in the VAN AUC > 329 group (13.2 vs 6.2, p< 0.001). Median hospital LOS was longer in the VAN AUC > 329 group (15 vs 8 days, p=0.05) while median time to bacteremia clearance (29 vs 25 hrs, p=0.15) and nephrotoxicity incidence (13% vs 4%, p=1) were not significantly different.

Conclusion

Vancomycin AUC < 329 was predictive of clinical failure in patients with streptococcal bacteremia. Larger studies are needed before VAN AUC monitoring can be recommended for implementation in the management of streptococcal bacteremia.

Disclosures

All Authors: No reported disclosures.
626. Tebipenem Pharmacokinetics and Soft-Tissue Distribution in Diabetic Patients with Lower Extremity Infections using In Vivo Microdialysis
Authors: Abouelhassan Yasmeen , Fratoni Andrew J , Shepard Ashley , Nicolau David P , Asempa Tomefa E
Published: December 2022

Background

Administration of the oral carbapenem, tebipenem along with its broad spectrum of activity against anaerobic, Gram-positive and Gram-negative pathogens including extended-spectrum β-lactamase-producing Enterobacterales, offers clinicians a potential new option and route to treat a range of infections. Lower extremity infections in diabetic patients are associated with high rates of hospitalization and amputation. Given the microvascular dysfunction and poor peripheral circulation in this population, the aim of this study was to assess tebipenem soft tissue pharmacokinetics (PK) and interstitial fluid distribution among diabetic patients with lower extremity infections using in vivo microdialysis.

Methods

This was a single-center, open-label, observational PK study in diabetic patients with foot infections who were enrolled and received tebipenem (600 mg) orally q8 hrs for a total of 3 doses. A microdialysis catheter was inserted within 4-8 cm of the wound margin to allow for dialysate sampling. Ten concurrent plasma and dialysate samples over an 8 hr period starting immediately prior to the last dose of tebipenem were obtained. Protein binding was determined by ultracentrifugation at 1 hr post-third dose. Plasma and dialysate samples were assayed via a validated LC/MS/MS assay. Non-compartmental analyses for free plasma and soft-tissue concentration were used to obtain PK parameters.

Results

Four male diabetic patients with an age of 70 ± 7 years and a hemoglobin A1C of 10 ± 2% were consented. All patients had an active complicated skin and soft tissue infection as defined by PEDIS Grade 2 or 3. Mean ± standard deviation (SD) plasma protein binding was 50% ± 1%. Mean ± SD tebipenem PK parameters in plasma were: maximum free concentration (fCmax), 2.34 ± 0.94 mg/L; time to Cmax (Tmax), 2.99 ± 1.40 hr; half-life (t1/2), 2.23 ± 1.65 hr and free area under the concentration-time curve (fAUCp(0-8)): 8.37 ± 1.63 mg.h/L. Mean ± SD parameters in tissue were: Cmax, 2.50 ± 1.04 mg/L; Tmax, 2.99 ± 1.40 h; t1/2 1.99 ± 1.42 hr; and AUCt(0-8), 8.01 ± 0.76 mg.h/L.

Conclusion

This study demonstrates that tebipenem has excellent distribution into interstitial fluid and lower extremity tissue of diabetic patients with ongoing foot infections.

Disclosures

Yasmeen Abouelhassan, PhD, Pfizer: spouse salary David P. Nicolau, PharmD, Shionogi: Grant/Research Support.
652. Ceftazidime-avibactam Alone or as Combination Therapy? Multicenter Retrospective Cohort Analysis of Clinical Outcomes in Patients with Carbapenem-resistant Gram-negative Infection
Authors: Mishuk Ahmed Ullah , Strich Jeffrey R , Warner Sarah , Sun Junfeng , Malik Seidu , Lawandi Alexander , Kondo Maiko , Satlin Michael J , Chandorkar Aditya , Heil Emily L , Morales Megan K , Mathur Anisha , Timpone Joseph , Wooten Darcy , Sweeney Daniel , Pan Jonathan , Raybould Jillian , Bonne Stephanie , Colindres Roberto , Boucher Helen W , Buckman Sara , Furukawa Daisuke , Uslan Daniel , Hohmann Samuel F , Kadri Sameer S
Published: December 2022

Background

Ceftazidime-avibactam (caz-avi), a novel β-lactam/β-lactamase inhibitor, is commonly utilized for carbapenem-resistant gram-negative infections (CR-GNI). However, the benefits vs risks of combining caz-avi with other agents are unclear.

Methods

In this retrospective cohort study, inpatients with CR-GNI treated with caz-avi were identified at 9 U.S. hospitals. The impact of caz-avi monotherapy (MT) or combination therapy (CT; i.e., any concomitant use of gram-negative-active antibiotics) was studied using logistic regression, controlling for baseline patient and hospital factors. The primary outcome was in-hospital mortality or discharge to hospice (death), and secondary outcomes were length of stay (LOS), resolution of infectious signs and symptoms (clinical response), 90-day recurrent infection and future caz-avi–resistant organism. An adjusted odds ratio (aOR) with 95% confidence interval (CI) was used to assess the primary and secondary outcomes.

Results

328/499 (65.7%) patients received caz-avi as targeted therapy for a CR-GNI. Overall patients treated with MT and CT were similar at baseline and had comparable baseline demographics although patients treated with CT were more likely to be in the ICU and receive a concomitant empiric in vitro-concordant antibiotic (table 1). The most common organism was Klebsiella spp. (44.6%) followed by Pseudomonas aeruginosa (27.7%) (table 2). Concomitant gram-negative agents are shown in table 3. Overall, 92 (28.1%) patients died and CT (vs MT) displayed similar adjusted mortality risk (27.7% vs 28.7%; aOR [95%CI]: 0.67 [0.34-1.33]) and LOS (19 [9, 37] and 20 [9, 42.5] days). CT (vs MT) was associated with greater odds of clinical response (aOR: 2.25 [95%CI:1.15-4.41]). Among survivors, similar rates of 90-day recurrent infection (50/154 (32.5%) were observed in CT vs 18/82 (22.0%) in MT group (p=0.09) and 5 (2.19%) patients had future infection with a caz-avi–resistant pathogen (3 in CT and 2 in MT group).

Conclusion

Compared to patients with CR-GNI treated with caz-avi alone, those who received CT including caz-avy had similar survival and LOS but higher clinical response. The role of CT in the era of novel antibiotics warrants additional study.

Disclosures

Helen W. Boucher, MD, American Society of Microbiology: Honoraria|Elsevier: Honoraria|Sanford Guide: Honoraria.