bluuebunny/crossref_metadata_2025 huggingface dataset:
2519. Urban vs Rural HIV-infected Persons Have Differential Gene Expression for Estrogen Signaling, Inflammation, and Cytokine Production Pathways
Authors: Schafer Katherine R , Piggott Damani A , Abadir Peter , Zimmerman Kip , Langefeld Carl , High Kevin P
Published: October 2019

Background

People aging with HIV (PAWH) are living longer with effective antiretroviral therapy and new HIV diagnoses are rising in older populations. Concurrent with trends in age, the epidemiology of HIV infection in the United States has shifted geographically and racially; the Southeast and African Americans now have the highest HIV incidence and prevalence. Although there are marked health disparities for rural and African American PAWH, limited data exist comparing aging phenotypes between rural and urban PAWH, and no data exist comparing mechanistic pathways between these populations. Among African American PAWH, we hypothesize that rural PAWH will be more likely than urban PAWH to have a molecular profile of advanced aging associated with chronic disease burden and shorter health span.

Methods

Demographics, clinical data, and RNA were collected from 14 matched pairs from rural (Wake Forest University, Winston-Salem, NC) and urban cohorts (ALiVE cohort, Johns Hopkins University, Baltimore, MD) matched on age, sex, Short Physical Performance Battery score, smoking status, and sample collection date. Raw sequences were examined for quality, aligned using STAR, and normalized using DESeq2. DESeq2 tested matched pair differential gene expression. Genes with an average read count threshold > 5, a genomic control adjusted P-value < 0.01 and a fold change > 1.3 were retained for further analysis using STRING, MCODE, and IPA to find functional and biological patterns.

Results

Of the 399 genes meeting significance criteria, 212 showed higher expression in the rural group; the remaining 187 genes showed lower expression in the rural group. Top enriched canonical pathways in the IPA analysis identified differential estrogen signaling (P < 0.0001), inflammation (P < 0.001), and cytokine production (p = 0.005). Protein–protein interactions involved in cell–cell signaling and intracellular trafficking were also differentially identified between the 2 populations.

Conclusion

Urban and rural PAWH have differential gene expression, particularly centered around estrogen signaling and inflammatory cytokine production. These findings merit further investigation to determine clinical significance, including correlation with phenotypes and healthspan between rural and urban PAWH.

Disclosures

All authors: No reported disclosures.
2521. Prevalence and Associated Factors of Protective Antibody Responses against Diphtheria, Tetanus, and Pertussis among HIV-Infected Thai Adolescents Stable on Combination Antiretroviral Treatment
Authors: Sudjaritruk Tavitiya , Kanjanavanit Suparat , Prasarakee Chanidapa , Sarachai Saowalak , Taweehorm Wanvisa , Aurpibul Linda , Sintupat Kamolrawee , Khampan Ratchaneekorn
Published: October 2019

Background

To assess the prevalence and associated factors of protective antibodies against diphtheria, tetanus, and pertussis among HIV-infected adolescents stable on combination antiretroviral treatment (cART).

Methods

A multicenter seroprevalence study was conducted. Perinatally HIV-infected Thai adolescents (11–25 years) who had previous evidence of severely immune suppression (CD4 < 15% or < 200 cells/mm3), were currently stable on cART (CD4 > 350 cells/mm3 for > 6 months or CD4 > 200 cells/mm3 with viral suppression [VS; HIV RNA < 50 copies/mL] for > 12 months) and had completed a 5-dose series of diphtheria, tetanus, whole cell pertussis (DTwP) vaccine during childhood were enrolled. Adolescents who received immunosuppressive agents or blood components within 6 months were excluded. Protective antibodies for diphtheria, tetanus, and pertussis were defined as diphtheria toxoid IgG ≥ 0.1 IU/mL, tetanus toxoid IgG ≥ 0.1 IU/mL, and anti-pertussis toxin IgG ≥ 5 IU/mL, respectively. Logistic regression analysis was performed to identify factors associated with protective antibody response to each antigen.

Results

Of 150 adolescents, 47% were male, a median age was 19 years. Forty (27%) and 0 (0%) adolescents had ever received tetanus, diphtheria (Td) or tetanus, diphtheria, acellular pertussis (Tdap) vaccine during adolescence, respectively. A median duration since the last dose of DTwP/Td vaccine was 12 years. At enrollment, 67% of adolescents were on NNRTI-based cART regimens, a median cART duration was 13 years. A median CD4 was 29%, and 90% had VS. Prevalence of protective antibodies against diphtheria, tetanus, and pertussis were 37%, 82%, and 52%, respectively. Proportion of adolescents with protective antibodies and geometric mean concentrations of antibodies to all antigens declined over time after the last immunization (Figures 1–3). Associated factors of protective antibodies to diphtheria, tetanus and pertussis are shown in Table 1.

Conclusion

Although having completed a 5-dose series of DTwP during childhood, significant proportion of our perinatally HIV-infected adolescents had no protective antibodies to those antigens, particularly diphtheria and pertussis, when entering adolescence. Tdap vaccination is a crucial strategy to prevent such diseases in the future.

Disclosures

All authors: No reported disclosures.
2524. Prevalence and Associated Factors of Seroprotection Against Japanese Encephalitis Virus Among HIV-Infected Thai Adolescents Stable on Combination Antiretroviral Treatment
Authors: Sudjaritruk Tavitiya , Kanjanavanit Suparat , Prasarakee Chanidapa , Sarachai Saowalak , Taweehorm Wanvisa , Aurpibul Linda , Saheng Jutamad , Sintupat Kamolrawee , Khampan Ratchaneekorn , Yoksan Sutee
Published: October 2019

Background

To determine the prevalence and associated factors of seroprotection against Japanese encephalitis (JE) virus among HIV-infected adolescents stable on combination antiretroviral treatment (cART).

Methods

A multicenter seroprevalence study was conducted in Thailand. Perinatally HIV-infected adolescents who aged 11–25 years, had previous evidence of severely immune suppression (CD4 < 15% or < 200 cells/mm3), were currently stable on cART (CD4 > 350 cells/mm3 for > 6 months or CD4 > 200 cells/mm3 with viral suppression [VS; plasma HIV RNA < 50 copies/mL] for > 12 months), and had completed a 3- or 4-dose series of mouse brain-derived inactivated JE vaccine (MBDV) during childhood were enrolled. Adolescents who had clinically or serologically confirmed recent JE virus infections, or received immunosuppressive agents or blood components within 6 months were excluded. Plaque reduction neutralization (PRNT50) assay was conducted to assess neutralizing antibodies to JE virus, and titers of ≥ 10 were considered seroprotective. Logistic regression analysis was performed to identify associated factors of JE seroprotection.

Results

Of 98 eligible adolescents, 54% were female, a median age was 19 years, and 11% were overweight. Ninety-five percent and 5% of adolescents received 3 and 4 doses of MBDV during childhood, respectively. A median duration since the last dose of MBDV was 16 years. At enrollment, 71% were on NNRTI-based cART regimens, a median cART duration was 13 years. A median current CD4 was 29%, and 89% had VS. Seroprotection against JE virus was identified in 28 (29%) adolescents; of whom, the geometric mean titer (GMT) of neutralizing antibody was 64 (95% CI: 39–106). Proportion of adolescents with JE seroprotection and GMT of neutralizing antibodies to JE virus slightly decreased over time after the last immunization (Figure 1). In a multivariable logistic regression analysis, seroprotection against JE virus was associated with younger age and greater current CD4 count (Table 1).

Conclusion

The majority of our perinatally HIV-infected adolescents did not maintain seroprotection against JE virus although having completed a series of MBDV during childhood. JE revaccination is an important tool for disease prevention in these adolescents who live in JE endemic areas.

Disclosures

All authors: No reported disclosures.
2525. Understanding PrEP in Female Adolescents: A Parent/Adolescent Dyad Perspective
Authors: Shah Meera , Murray Ashley , Gillespie Scott , Camacho-Gonzalez Andres
Published: October 2019

Background

Adolescents aged 13–24 years account for 23% of HIV diagnoses in the Atlanta Metropolitan Area, indicating the need for new prevention strategies. Pre-Exposure Prophylaxis (PrEP), recently approved for adolescent use, is effective in HIV prevention and is often marketed to young men who have sex with men (MSM); however, problems with access, scalability and waning adherence have limited its use in this population and more broadly. A 2016 CDC HIV surveillance report showed 19.2% of new HIV diagnoses were attributed to heterosexual transmission in women aged 13–24, relative to 0% in their heterosexual male counterparts, and 5.4% in same-aged MSM. This study assesses parent and female adolescent knowledge on HIV risk and PrEP perception to inform potential implementation strategies.

Methods

PrEP acceptability and barrier surveys were administered to 102 adolescent-parent dyads attending an adolescent clinic and emergency room in Atlanta, Georgia. Eight female adolescent-parent pairs were randomly selected to participate in in-depth phone interviews. Responses were analyzed using computer-assisted thematic analyses.

Results

Of the 8 female adolescent participants (mean age = 18.9 years), all were African American, and 1 was sexually active. Of the 8 parent participants (mean age = 44.1 years), all were female and African American. None of the participants had ever used PrEP. Analysis indicated that both parents and adolescent females had poor HIV risk assessment and knowledge, as well as barriers to PrEP usage including concerns about side effects, cost, and desire for alternative PrEP delivery methods and/or schedules. Finally, adolescent females expressed reliance on self-efficacy to be able to discuss HIV protection methods with their partner.

Conclusion

Female adolescents use unreliable methods to ensure HIV prevention, and with poor HIV knowledge, are at risk of transmission. Thus, PrEP may be a viable option for adolescent females at high risk for infection. PrEP implementation strategies in adolescents needs to consider HIV risk assessment, PrEP education, potential options for alternative dosing and delivery, and continued implementation work, focused beyond just the young MSM community.

Disclosures

All authors: No reported disclosures.
2528. Inflammation and Plasma Selenium and Chromium in Ugandan Children Living with HIV
Authors: Dirajlal-Fargo Sahera , Sattar Abdus , Shan Lingpeng , Bowman Emily , Nazzinda Rashida , Musiime Victor , Funderburg Nicholas , McComsey, Grace A
Published: October 2019

Background

Selenium deficiency has been reported to be associated with HIV disease progression and chromium deficiency with insulin resistance and hyperlipidemia. Here, we assessed selenium and chromium status in a cohort of Ugandan HIV+, HIV exposed uninfected (HEU) and HIV negative (HIV−) children and their associations with markers of systemic inflammation, immune activation, and gut integrity.

Methods

This is a cross-sectional study in HIV+, HEU and HIV unexposed uninfected (HIV-) children aged 2–10 years old enrolled in Uganda. HIV+ children were on stable ART with undetectable viral load. We measured plasma concentrations of selenium and chromium as well as markers of systemic inflammation, monocyte activation, gut integrity and insulin resistance (HOMA-IR).

Results

Among HIV+ children (n = 57), 93% had viral load ≤ 20 copies/mL, mean CD4 was 34% and 77% were receiving a non-nucleotide reserve transcriptase regimen. Mean age of all participants was 7 years and 55% were girls. Mean selenium concentrations were higher in the HIV+ group (106 µg/L) compared with the HEU (84 µg/L) and HIV− (98 µg/L) groups (p . Mean chromium concentrations were 1 µg/L; 1 HIV+ child and 6 HEU children had chromium levels > 1 µg/L (p.

Conclusion

In this cohort of HIV+ children on ART in Uganda, plasma selenium and chromium concentrations appear sufficient. Higher plasma selenium concentrations were associated with lower systemic inflammation and higher gut integrity markers. Although our findings do not support the use of selenium supplementation broadly for HIV-infected children in Uganda, further studies are warranted to assess the role of selenium supplements in attenuating heightened inflammation.

Disclosures

All authors: No reported disclosures.
2534. Development of an Infectious Diseases Fellowship Well-Being Program
Authors: Budak Jehan , Brickman Cristina , Abdoler Emily , Wallender Erika , Mulliken Jennifer S , Kerkhoff Andrew D , Lampiris Harry , Babik Jennifer M , Koss Catherine , Schwartz Brian , Schwartz Brian
Published: October 2019

Background

Burnout in graduate medical education is common and reported in ~70% of Internal Medicine (IM) residents. Most studies have described interventions focused on residency training, but fellowship training suffers from similar challenges and likely similar levels of burnout. After conducting a needs assessment amongst fellows within our Infectious Diseases (ID) fellowship program, we developed a wellness program to address these issues.

Methods

In Spring 2018, we reviewed the existing literature and consulted with local experts on trainee well-being. Based on our findings, we designed a multi-tiered approach to enhance wellness amongst fellows. An ID Fellowship Well-Being Committee (WBC) was created in September 2018 to lead the intervention. The WBC includes an even mix of fellows and faculty at multiple levels at all three main teaching hospitals associated with the program. Meetings occur every other month, and co-chairs (one faculty and one fellow) report back to the program director quarterly. Topic areas and interventions are described in Table 1. Fellows were sent a qualitative survey to evaluate the impact of the well-being interventions to date.

Results

Four of 5 first year fellows responded to the survey, and all felt the retreat should be repeated yearly. Themes identified from the survey included benefits of having protected time together, convening in a low pressure and informal setting to provide feedback, and spending quality time in a non-clinical setting with co-fellows. Fellows cited the wellness retreat as a strength at our annual fellowship external program review.

Conclusion

Burnout is likely high among IM sub-specialty fellows, and interventions are needed to support the well-being of those trainees. We describe a roadmap for the development of a well-being program at a relatively large, academic ID fellowship program led by a mixed fellow and faculty committee. We will continue to monitor data on fellow burnout and make programmatic changes based on feedback. We are hopeful that our work will empower other programs to engage in developing their own well-being programs.

Disclosures

All authors: No reported disclosures.
2537. #IDDailyPearl: A Twitter Tool to Enhance Literature Engagement on Busy Infectious Diseases Consult Services
Authors: Cowell Annie N , Wooten Darcy
Published: October 2019

Background

Social media platforms enable on-demand, open-access learning which is attractive for busy clinicians and trainees. Additionally, teaching that occurs in a clinically contextualized, case-based setting in real time has the potential to be more effective than traditional didactics. We piloted a teaching tool to enhance learning and engagement with the literature for fellows on the infectious diseases (ID) consult service.

Methods

During a clinical service rotation, ID faculty posted a brief daily teaching point on Twitter under the hashtag “#IDDailyPearl” with a link to the relevant article. Tweets were required to be related to a patient case, associated with an article, and could not include patient identifiers.

Results

Over a 3-month period, there were 134 tweets that fit our criteria, with 103 tweets posted by UCSD faculty and 45 by faculty from other institutions. The most common topic was endocarditis and bacteremia (16.4%), followed by fungal infections (11%), tuberculosis (9.4%), and antimicrobials (9.4%) (Figure 1). Article types included review articles (21.6%), retrospective cohort studies (20.2%), case reports (13.5%), randomized controlled trials (12.1%), prospective cohort studies (9.4%), and guidelines (8.8%). Most articles cited were published after 2015 (61.6%), and were from infectious diseases journals (58.2%). The average journal impact factor was 13 (range 0.07–79), with Clinical Infectious Diseases as the most commonly mentioned journal (20.2%). Tweets were “liked” 14.5 times (range 0–80) and re-tweeted 4.6 times (range 0–33). The twitter engagement rate per tweet was 6.3% (range 2.2 to 12%) and article links were clicked 19 times (range 3–164). We are currently identifying Tweet characteristics associated with increased engagement rates.

Conclusion

Our study provides a snapshot of the literature used to teach while on the ID clinical service and lays the groundwork for identifying teaching points that receive the most engagement. This tool enables teaching points and high-yield articles to be shared within and across institutions. Future studies will examine the impact that this tool has on fellow and faculty learning, and engagement with and knowledge of the current literature.

Disclosures

All authors: No reported disclosures.
147. Non-Fermenting Gram-Negative Bloodstream Infection: A Multicenter Retrospective Cohort Study
Authors: Pascale Renato , Giannella Maddalena , Corcione Silvia , Roberto Giacobbe Daniele , Bussini Linda , Pancaldi Livia , Rosselli Del Turco Elena , Giuseppe De Rosa Francesco , Viscoli Claudio , Viale Pierluigi
Published: October 2019

Background

Few data exist on clinical characteristics, therapeutic management and outcome of patients with Non-Fermenting Gram-negative bloodstream infection (NFGN-BSI). Our aim is to describe a large cohort of patients with NFGN-BSI and to investigate risk factors for 30-day mortality. Further, the impact of the new difficult to treat resistance (DTR) definition will be investigated.

Methods

Retrospective multicenter study of patients diagnosed with NFGN-BSI at three large Italian hospitals (Bologna, Genova, Torino), over a 4-year period (2013–2016). Exclusion criteria: age <18 years, clinical data not available, polymicrobial BSI, death within 72 hours from drawing index blood cultures (BCs). Carbapenem resistance (CR) was defined according to 2015 CDC definitions, and DTR as resistance to all β-lactams and fluoroquinolones. Active empiric therapy (AET) was defined as at least one in vitro active drug administered within 24 hours from drawing index BCs. Endpoint was all-cause 30-day mortality.

Results

521 patients with NFGN-BSI were analyzed: 63.3% male, median age 67 (IQR 55–78) years, median Charlson index 6 (IQR: 3–7). Most episodes were hospital acquired 72.9%. Etiology distribution: Pseudomonas aeruginosa 69.9%, Acinetobacter baumannii 19.6%, and Stenotrophomonas maltophilia 10.6%. CR and DTR rates were 38.6% and 26.9%. Main infection sources were deemed as primary 50.7%, CVC-related 26.5%, and lower respiratory tract 16.3%. Source control and ID consultation were performed in 33.4% and 47.6% of cases. AET rate was 38.2%. Empiric and definitive antibiotic treatment cohorts consisted of 377 and 472 patients, respectively. There was high heterogeneity in antibiotic choice with 30 and 48 different regimens in empiric and definitive cohort, respectively. Combination therapy was administered in 22.3% of empiric cohort and in 37.3% of definitive cohort patients. Independent risk factors for 30-day mortality were age (HR 1.03, 95% CI 1.01–1.05, P = 0.001), SOFA (HR 1.25, 1.15–1.36, <0.001), DTR (HR 2.73, 1.60–4.65, <0.001), and AET (HR 0.50, 0.25–0.99, 0.05).

Conclusion

High heterogeneity in therapeutic management of patients with NF-GNBSI was observed. DTR was a strong predictor of mortality, AET was associated with improved outcome.

Disclosures

All authors: No reported disclosures.
2542. ID-Psych Addiction Rounds: A New Model to Address Opioid Use Disorder For Patients on the Infectious Disease Consult Service
Authors: West William , Eckhardt Benjamin , Cohen Gabriel M
Published: October 2019

Background

ID physicians often treat the infectious sequelae of opioid use disorder (OUD) and are uniquely poised to link hospitalized patients to substance use resources. In a large safety net hospital, we launched a multi-disciplinary initiative to ensure that patients on the ID consult service with OUD were always offered medication-assisted treatment (MAT). We used infections as “sentinel” events to identify patients with OUD and described the clinical characteristics of the high-risk patient population jointly consulted by ID and Psychiatry teams. This healthcare workforce initiative aimed to expand the role of ID providers in the opioid epidemic and decrease barriers to buprenorphine prescribing.

Methods

Every 2 weeks, ID fellows identified patients on their consult lists with infectious complications of OUD. Focused discussions were then held with the Psychiatry service and discussion of each patient continued at subsequent case conferences with attention paid to re-engaging those lost to follow-up. We performed chart abstraction of demographic and clinical characteristics as part of a quality improvement initiative.

Results

From October 2018 to March 2019, 23 patients were discussed at 10 case conferences with input from attendings, fellows, housestaff, social workers, and representatives from a novel Primary Care Safety Net program. The average patient age was 43 (range 24–50). Patients were predominantly male (65%), heroin users (90%) with high rates of HIV (22%) and untreated HCV (40%). ID-related infections included endocarditis (39%), osteomyelitis (31%), skin and soft-tissue infections (17%) and spinal abscesses (17%). The median time for a patient to be presented at an ID-Psych Addiction Rounds was 7 days (IQR 4.5–11.5). The mean length of hospitalization was 30 days (range 2–112). MAT was initiated in 75% of patients (41% buprenorphine; 59% methadone). The 30-day lost to follow-up rate was exceedingly high, with 80% of post-hospital appointments being missed.

Conclusion

ID physicians can effectively link hospitalized patients with OUD to substance use resources. A multi-disciplinary approach is key to addressing the opioid epidemic. Future work should explore how to create effective post-hospital transitions to decrease those lost to follow-up.

Disclosures

All authors: No reported disclosures.
2548. Provider Adherence to Cervical Cancer Screening in HIV Patient Populations
Authors: Brett Catherine , Puckett Hannah , Potter Devin , Ahuja Divya , Badmus Olabisis
Published: October 2019

Background

Antiretroviral therapy has nearly normalized the life expectancy of people living with HIV (PLWH). However, malignancies still remain a major cause of morbidity and mortality in PLWH, and thus an important part of the clinical visit is age appropriate screening and referral to care, from Lancet 2019 for the poster. Most cases of cervical cancer occur in women who were either never screened or were screened inadequately. Over-screening for cervical cancer, on the other hand, leads to unnecessary stress and procedures, adding increased costs to the patient and to the healthcare system. The central aim of this project is to evaluate provider adherence at the Immunology Center (IC) to cervical cancer screening guidelines and to identify factors associated with over and underscreening.

Methods

A retrospective chart review from January 1, 2015, to December 31, 2017 was performed. Study included HIV-seropositive women seen at the IC between April 2014 and June 2018. Exclusion criteria includes prior hysterectomy, abnormal cytology, cervical excision procedures, or other causes of immunosuppression.

Results

Of the 803 HIV-positive women identified, n = 262 met criteria for inclusion in the study. Overall adherence was 48%, with statistical significance found in cervical cancer screening between MDs and NPs, with an OR = 2.51 (P < 0.01). In regard to gender of provider, statistical significance in over screening was found between male and female providers, with an OR = 4.3 (P < 0.01), and in under screening between male and female providers, with an OR = 0.43 (P < 0.05). Over screening led to 44 excess pap smears over a 2-year period, yielding an excess cost of $6461. HPV co-testing was underutilized, with only one-third of encounters having HPV testing performed.

Conclusion

This project gives us the opportunity to reeducate and retrain the clinical staff and practitioners providing cervical cancer screening at the Immunology Center. This is an ongoing quality improvement project, where adherence will be reassessed on a continuous basis at one-year intervals to ensure compliance with guidelines-based cervical cancer screening among female HIV seropositive patients at the Immunology Center.

Disclosures

All authors: No reported disclosures.
2549. Variance Between Clinicians and Guidelines in Management of HIV/HCV Coinfection
Authors: Naggie Susanna , Sulkowski Mark , Schulz Jenny , King Edward , Schwartz Zachary
Published: October 2019

Background

Clinicians often encounter patients requiring simultaneous treatment for both HIV and HCV. Although several resources help clinicians identify potential drug interactions, these resources do not account for other factors that should be considered when selecting HIV and HCV regimens, such as renal function, HLA-B*5701 status, and HCV genotype. We developed an online decision support tool based on HIV and HCV guideline recommendations. We report data comparing guideline recommendations with the initial treatment plans of clinicians using the tool.

Methods

In May 2018, American Association for the Study of Liver Diseases (AASLD)/IDSA and DHHS treatment recommendations were applied to 304 unique HIV/HCV coinfection case scenarios based on a simplified set of patient variables: current ART/HCV therapy, HIV and HCV genotypes, liver histology, renal function, HLA-B*5701 status. We then developed an online decision support tool that enables clinicians to specify a patient scenario using these variables. After clinicians select their currently intended HIV and HCV treatment from among the guideline-recommended first-line options, guideline recommendations for that specific patient case are shown, and clinicians are asked if this information changed their treatment plan.

Results

From August 2018 to March 2019, 505 participants (n = 303 ID/HIV, n = 68 hepatology/GI, n = 58 IM/FP/GP/addiction, n = 76 other; n = 229 North America, n = 118 Europe) entered 694 patient case scenarios in the HIV/HCV coinfection tool. In 36% of patient case scenarios (248/694), clinicians were unsure or were planning a treatment not recommended by guidelines. All treatment choices that were inconsistent with guidelines are shown in the table. Not all clinicians self-identified the impact of the tool, but in the subset of 174 patient case scenarios where they did, 47 identified their initial treatment plan as different from the guidelines. Of these, 32% (15/47) changed their treatment plan based on the recommendations, 40% (19/47) had barriers to implementing the recommendations, 23% (11/47) were still undecided, 4% (2/47) disagreed with the recommendations.

Conclusion

This online treatment decision support tool shows substantial variability between clinicians’ treatment plans and HIV and HCV treatment guidelines for 36% of case scenarios.

Disclosures

All authors: No reported disclosures.
2570. A Randomized Controlled Trial of Lactobacillus rhamnosus GG on Multidrug-Resistant Organism (MDRO) Colonization
Authors: Rauseo Adriana M , Hink Tiffany , Reske Kimberly , Seiler Sondra , Bommarito Kerry , Fraser Victoria J , Burnham Carey-Ann D , Dubberke Erik R
Published: October 2019

Background

MDRO present a greater threat to public health than ever before, and antimicrobial options are decreasing. Altered colonic microbiota following antimicrobial exposure allows for subsequent colonization by MDRO. Ingestion of prophylactic Lactobacillus rhamnosus GG (LGG) could be an approach to prevent the spread of, and subsequent infection due to MDRO, by promoting a healthy bacterial milieu within the colon.

Methods

This is a prospective, double-blinded, randomized clinical trial in which a total of 87 subjects on broad-spectrum antibiotics were randomized to receive LGG twice daily (n = 43) vs placebo (n = 44). Stool or rectal swab specimens were collected for culture at enrollment, every 3 days during admission, and at discharge. Selective media were used to detect the following MDRO: Clostridioides difficile (CD), vancomycin-resistant Enterococcus (VRE), and antibiotic-resistant Gram-negatives (GN). The primary outcome was MDRO acquisition. Secondary outcomes included analysis for loss of any MDRO if colonized at enrollment, and acquisition or loss of individual MDRO.

Results

Subjects in both groups had similar prevalence of colonization with any MDRO at study enrollment (LGG 40% vs. placebo 39%), with similar colonization prevalence for individual MDRO (Figure 1). There was no difference in any MDRO acquisition (LGG 27%, placebo 33%, OR 1.36, 95% CI 0.42–4.41) or any individual MDRO acquisition (Figure 2). There was also no difference in loss of any MDRO (LGG 18%, placebo 24%, OR 1.44, 95% CI 0.27–7.68) or any individual MDRO (Figure 2).

Conclusion

LGG administration did not prevent acquisition of MDRO or accelerate loss of MDRO colonization.

Disclosures

All authors: No reported disclosures.
2578. Narrow-Spectrum Antibiotic Treatment of Clostridium difficile Infection Improves Preservation of Intestinal Metabolic Profile
Authors: Park Seoyoung , Yanagi Karin , Kane Anne , Snydman David R , Vickers Richard , Thorpe Cheleste M , Lee Kyongbum
Published: October 2019

Background

Commensal gut bacteria are thought to protect against C. difficile infection (CDI) by producing metabolites that inhibit C. difficile germination and growth. Alternatively, the protective effect could reflect nutrient competition or other mechanisms of chemical communication that also involve the host. CDI treatment using a broad-spectrum antibiotic such as vancomycin (VAN) dramatically depletes commensal bacteria. This dysbiosis can persist for several weeks after end-of-therapy (EOT), and is associated with increased recurrence risk. In this study, we investigate the hypothesis that treating CDI with a more selective antibiotic reduces collateral damage to the intestinal microbiota, preserving or restoring a CDI-inhibitory metabolic profile.

Methods

Stool samples were collected from CDI patients treated with either a narrow- (RDZ) or broad-spectrum antibiotic (VAN) at days 1, 10 (EOT), 25, and 40. Global metabolite profiles were measured by untargeted LC-MS.

Results

Untargeted metabolite analysis showed broad differences in the metabolic activity of intestinal microbiota of RDZ- and VAN-treated subjects (Figure 1). At EOT, 28% of LC-MS features detected in both RDZ and VAN samples were differentially present (FDR corrected P-value <0.05). Over 80% of the differentially present features were elevated in the RDZ group, indicating diminished capacity of microbiota from VAN subjects to generate diverse metabolic products. Pathway analysis found significant differences in purine, taurine, tyrosine, and bile acid metabolites. The VAN group showed a 5-fold decrease in free taurine, a major conjugation substrate of primary bile acids released by bacterial bile salt hydrolases. VAN treatment also decreased fermentation products of aromatic amino acids and amino sugars derived from mucin degradation. Oligosaccharides were the major metabolite class elevated in VAN subjects.

Conclusion

Our data suggest that RDZ treatment correlates with enhanced preservation of bacteria-derived ligands regulating intestinal immune function and substrates of bacterial metabolism. These metabolic profile differences between a narrow- and broad-spectrum antibiotic may contribute to their varying efficacy in preventing CDI recurrence.

Disclosures

All authors: No reported disclosures.
2582. The Association Between Dietary Fiber and Diet and Gut Colonization with Clostridium difficile
Authors: Sethi Ajay , Eggers Shoshannah , Mares Julie , Christensen Krista , Gangnon Ronald , Suen Garret , Watson Lauren , Shirley Daniel , Shukla Sanjay , Poulsen Keith , Malecki Kristen , Peppard Paul , Safdar Nasia
Published: October 2019

Background

There is little research on the relationship between diet and Clostridium difficile infection. Animal studies have shown potential benefits of dietary fiber in modulating C. difficile infection.

Methods

In 2016–2017, we carried out a microbiota study among adults in the Survey of the Health of Wisconsin, a population-based health survey collecting data on a wide range of health determinants and outcomes. We administered the Dietary History Questionnaire and asked about risk factors for C. difficile and collected fecal samples for 16S rRNA sequencing of gut microbiota and cultured for C. difficile. Dietary components were standardized to 1,000 kcal energy intake. Logistic regression was used to examine diet factors associated with C. difficile colonization. The quasi-conditional association test (QCAT) was performed to identify taxa that were significantly associated with fiber intake.

Results

In our general population sample of adults [(N = 238; 58% female; mean (range) age = 54 (18–94)], the prevalence of gut colonization with C. difficile was 9.2% (18 toxigenic/3 non-toxigenic). After adjusting for age, sex, and antibiotic use, C. difficile colonization was associated with usual daily fiber consumption over the last year. ORs (95% CI) in the highest vs. lowest quartile were 0.18 (0.03, 0.89) for total fiber, 0.09 (0.01, 0.77) for soluble fiber, and 0.10 (0.1, 0.80) for insoluble fiber. Lower odds of C. difficile colonization were associated with greater consumption of dark green vegetables and less consumption of solid fats, total saturated fats, and added sugar, but not significantly. Omega 3 fatty acids and fruit consumption were either non-monotonically or not associated with C. difficile colonization. Higher levels of total dietary fiber intake were also associated with increased colonization by bacteria within the order Clostridiales, the families Coriobacteriaceae, Lactobacillaceae, and Veillonellacea, and the genera Bifidobacterium, and Lactobacillus.

Conclusion

Higher average daily dietary fiber (total, soluble, and insoluble) appears to be associated with lower odds of gut colonization with C. difficile. Future research should examine the impact of dietary interventions on C. difficile colonization and infection.

Disclosures

All authors: No reported disclosures.
2590. Streptolysin O Enhances Binding of the Group A Streptococcal NAD+-Glycohydrolase Toxin to Oropharyngeal Keratinocytes
Authors: Velarde Jorge J , Lynskey Nicola , Piai Alessandro , Chou James , Wessels Michael
Published: October 2019

Background

Streptolysin O (SLO) and the NAD+-glycohydrolase (NADase) are co-toxins secreted by group A Streptococcus (GAS) that play a significant role in virulence. NADase requires SLO for translocation into the host cell cytoplasm, a process termed cytolysin-mediated translocation (CMT). Recently, we noted that interaction of the two toxins mutually increased their stability. Although NADase is predicted to bind to the host cell surface, this interaction is incompletely understood. Here, we investigate potential mechanisms by which NADase binds to oropharyngeal keratinocytes.

Methods

The amino terminal region of NADase has been implicated in CMT, but the structure of the putative translocation domain has not been characterized. We determined the solution structure of this domain by NMR spectroscopy. We used flow-cytometry and confocal microscopy to investigate whether NADase could interact directly with oropharyngeal keratinocytes. Finally, since we expect that NADase and SLO are co-expressed from the same operon, are secreted in a coordinated fashion, and interact in solution, we tested whether SLO affects NADase binding to host cells.

Results

The solution structure of the NADase translocation domain revealed a β-sandwich fold with an elongated N-terminal intrinsically disordered region. Structural homology searches (DALI) identified a potential carbohydrate binding module, suggesting the translocation domain could play a role in glycan binding. We also demonstrated by flow-cytometry that purified recombinant NADase toxin is able to independently interact with the cell surface of oropharyngeal keratinocytes. Importantly, interaction with SLO significantly enhanced the association of NADase with the cell surface, resulting in a 5-fold increase of the geometric mean fluorescence intensity.

Conclusion

The structure of the NADase translocation domain reveals a potential carbohydrate binding module, which may mediate binding of the toxin to a cell-surface glycan. Binding of NADase to host cells is markedly enhanced by its interaction with SLO. We conclude that interaction of the two toxins contributes to the CMT process by functionally increasing the local concentration of NADase at the cell surface.

Disclosures

All authors: No reported disclosures.
2593. Human Monoclonal Antibodies Potently Neutralize Enterovirus D68 in both a Clade-Specific and -Independent Manner
Authors: Vogt Matthew R , Kose Nurgun , Williamson Lauren , Bochkov Yury A , Gern James E , Crowe James E
Published: October 2019

Background

Enterovirus D68 (EV-D68) causes worldwide outbreaks of human respiratory illness with spacio-temporally related outbreaks of acute flaccid myelitis (AFM), a polio-like illness. Numerous seroepidemiology studies show that nearly all humans older than 2 years have EV-D68-neutralizing antibodies in their serum, even in serum collected prior to large outbreaks. However, little else is known about the human antibody response to this virus. We sought to isolate human monoclonal antibodies (mAbs) from B cells in peripheral blood mononuclear cells (PBMCs) of immune subjects, induced by natural infection, to understand human humoral immunity to EV-D68.

Methods

We obtained PBMCs from donors with known infection during the largest ever recorded outbreak, which occurred in the United States in 2014. We used EV-D68 virus isolates from this outbreak in an indirect ELISA to screen immortalized PBMCs for antigen-specificity, then fused them with myeloma cells to create hybridomas.

Results

To date, we have isolated > 60 naturally occurring anti-EV-D68 human mAbs from the B cells of subjects with documented infection. These mAbs exhibit diverse binding affinities when compared across different clades of recent EV-D68 isolates. Many mAbs neutralize EV-D68 quite potently in vitro, with [ng/mL] half maximal effective concentrations. Some mAbs neutralize diverse clades of EV-D68, whereas others are highly clade-specific. Binding of antibodies to at least three, but likely more, major antigenic sites on the virus leads to neutralization.

Conclusion

We observed a qualitative difference among antibodies isolated from patients who had natural infection. These differences could contribute to certain individuals being susceptible to respiratory disease and AFM. Our studies of humoral immunity are especially important for a disease with nearly universal apparent seroprotection, in which the virus somehow persistently causes outbreaks across the world. Furthermore, no licensed vaccines or treatments exist for EV-D68. Given the ability of human intravenous immune globulin to protect mice from AFM, these mAbs are being tested for therapeutic benefit in vivo, and may have promise in the prevention and/or treatment of EV-D68-related diseases.

Disclosures

All authors: No reported disclosures.
2595. Murine Models for the Host Response to Typical and Atypical Pneumonia
Authors: Khan Kirin , Betancourt-Quiroz Marisol , Zaas Aimee K , Treece Amy E , Que Loretta G , Henao Ricardo , Suchindran Sunil , McClain Micah T , Woods Chris W , Ginsburg Geoffrey S , Tsalik Ephraim L , Tsalik Ephraim L
Published: October 2019

Background

The etiology of pneumonia is difficult to diagnose, with typical bacterial, atypical bacterial, and viral infections being the most common. However, diagnostics that discriminate these infectious etiologies are limited. We, therefore, focused on the host response to identify possible diagnostic markers and better understand these infections. However, atypical bacterial pneumonia is challenging to identify in humans precisely because of this diagnostic difficulty. Therefore, we utilized murine models to define host response differences between typical bacterial, atypical bacterial, and viral pneumonia.

Methods

Mice were intranasally inoculated with S. pneumoniae (n = 38), M. pneumoniae (n = 27), H1N1 pr8 (n = 19), or saline as a control (n = 42). RNA was extracted from peripheral blood collected at 24, 48, 72, 120, or 168 hours and subjected to microarray analysis. Diagnostic signatures were generated using lasso logistic regression and accuracy was assessed using nested leave-one-out cross-validation with feature selection repeated within each iteration. Differentially expressed genes were used to perform gene set enrichment analysis. These murine-derived signatures were externally validated in silico in 487 human subjects found across 5 publicly available data sets.

Results

We generated pathogen-specific murine disease signatures that performed with 91–100% accuracy. Pathway analysis revealed that animals with pneumococcal pneumonia had a robust immune response by 48 hours that continued to 72 hours post-infection. In contrast, animals infected with M. pneumoniae did not show evidence of a strong immune response until 72-hours post-infection. Additionally, the immune response to M. pneumoniae bared greater similarity to the viral response than it did to the host pneumococcal response. H1N1-infected mice showed an anti-viral response at 120 hours that resolved by 168 hours post-infection. The AUC values resulting from independent human validation of our murine signatures ranged from 89 to 98%.

Conclusion

There are discrete host responses to typical bacterial, atypical bacterial, and viral etiologies of pneumonia in mice. These signatures validate well in humans, highlighting the conserved nature of the host response to these pathogen classes.

Disclosures

Ephraim L. Tsalik, MD MHS PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.
2598. Macrophage Migration Inhibitory Factor May Contribute to Disseminated Coccidioidomycosis Susceptibility
Authors: Odio Camila D , Leng Lin , Siu Edwin , Piecychna Marta , Galgiani John N , Holland Steven M , Bucala Richard
Published: October 2019

Background

Disseminated coccidioidomycosis occurs in <1% of cases, and genetic polymorphisms may account for some of the variability in infection severity. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with two promoter polymorphisms linked to variability in expression. High expression MIF polymorphisms have been associated with granulomatosis with polyangitis (GPA), sarcoidosis and tuberculosis. Despite the overlap between MIF and Coccidioides immunity, MIF has never been studied in coccidioidomycosis.

Methods

A549 cells transfected with MIF promoter/luciferase plasmids of 0 or 8 CATT repeats were stimulated with 50 µg/mL of inactivated C. posadasii spherule lysate, and luciferase expression was measured as relative units (RU) of luminescence. Genomic DNA from patients with disseminated coccidioidomycosis (n = 37) and healthy controls (n = 371) was analyzed for the 794 CATT5-8 microsatellite and the -173 G/C SNP. Cohorts were divided into self-identified African Americans and Caucasians, and allele frequencies were compared using Fisher exact test. Plasma MIF levels were analyzed by enzyme-linked immunosorbant assay using specific antibodies, and levels were compared by T-test.

Results

Human lung epithelial cells exposed to Coccidioides spherules had significantly higher MIF expression than unexposed cells (3.94 ± 0.44 vs. 3.02 ± 0.24 RU, P = 0.0162). Among Caucasians (n = 26), the high MIF expression −173C containing genotype was present in 50% of the coccidioidomycosis patients vs. 40% of healthy controls (P = 0.396). The -794 CATT7 containing genotype was present in 40% of patients vs. 27% of controls (p = 0.240). Plasma MIF levels were higher in coccidoidomycosis patients with high- vs. low-expression alleles (P = 0.008), but lower in patients vs. controls (P < 0.0001).

Conclusion

Coccoidioides spherules stimulated MIF expression in human lung epithelial cells supporting the hypothesis that MIF is involved in immunity against this pathogen. In Caucasian subjects, the higher MIF expression genotypes were more common in patients with disseminated coccidioidomycosis when compared with healthy controls, although significance was limited by sample size. This is consistent with high expression MIF alleles associated with other granulomatous diseases, and may reflect destruction of the granuloma with pathogen dissemination.

Disclosures

All authors: No reported disclosures.
153. A Review of Ten Cases of Pulmonic Valve Infective Endocarditis
Authors: Hicklin Harry E , Huang Glen , Davis Kyle A , Barnes Erin W , Peacock James E
Published: October 2019

Background

Pulmonic valve (PV) infective endocarditis (IE) is a rare entity, accounting for ~1.5–2% of all cases of IE. As a result, published literature describing the diagnosis and management of patients with PVIE is limited.

Methods

A retrospective review of patients ≥18 years old admitted to Wake Forest Baptist Medical Center from 2012 to 2017 with a diagnosis of PVIE based on the modified Duke criteria was performed.

Results

Ten patients were identified as having PVIE, 9 of whom had isolated PV involvement and 1 of whom had concurrent aortic valve involvement. The diagnosis of IE was definite per the modified Duke criteria in 8 patients. The median age was 41 years and 30% were female. Two patients had pacemakers, 1 had a prosthetic PV, and 1 had congenital heart disease. Six patients were identified as persons who inject drugs (PWID). On admission, 5 patients manifested fever and 5 had a documented murmur. Seven patients had septic pulmonary emboli with 4 of 7 patients manifesting pulmonary hypertension. Transthoracic echocardiography (TTE) revealed vegetations in 4 of 10 patients whereas PV vegetations were demonstrated in all 8 patients undergoing transesophageal echocardiography (TEE). S. aureus was the most common causative organism, accounting for 5 of the cases of PVIE with four of the five isolates being methicillin-resistant. Bacteremia persisted for a median of 3 days. One patient underwent PV replacement. The planned median duration of antimicrobial therapy was 6 weeks. The median length of stay was 18 days. Three patients died during the index hospitalization, 1 of whom was a PWID. No episodes of repeat PVIE occurred within 1 year.

Conclusion

PVIE is a rare disease. Only 40% of our patients had vegetations on TTE in contrast to a reported diagnostic yield of >90% in the literature. As such, PVIE may be underdiagnosed. S aureus was the most common organism isolated, which is in keeping with prior reports. PWID appear to be at high risk for PVIE. In view of the worsening opioid epidemic, more research on PVIE is warranted.

Disclosures

All authors: No reported disclosures.