bluuebunny/crossref_metadata_2025 huggingface dataset:
2546. The Mentor Model: Improving Fellow-Level Transitions of Patient Care
Authors: Modi Anita R , Isada Carlos M
Published: October 2019

Background

Our infectious disease fellows rarely see follow-up patients. Yet longitudinal patient care teaches the fellow how to approach chronic illnesses, continued clinical decline, and adverse effects of antimicrobial therapy. Fellows at our institution typically rotate with a different faculty member every 1–2 weeks. Follow-up visits are scheduled with the faculty member. While this model exposes the fellow to a variety of cases and management styles, it limits fellow follow-up opportunities. We developed a model to solve this problem.

Methods

The Mentor Model involves 12-week blocks during which the fellow and a faculty member share the same schedule, facilitating fellow participation in post-discharge visits, re-consultations, and repeat outpatient appointments. We queried our electronic medical record for a list of all consult notes written by fellows during both Mentor Model and traditional (non-Mentor Model) blocks. The number of repeat encounters, or evaluations of an established patient, were tallied and divided by the number of total encounters to determine each fellow’s follow-up rate. This value was compared between Mentor Model and non-Mentor Model blocks.

Results

Historically, our fellows have reported 1–2 follow-ups each over the course of his or her training. Four first-year fellows rotated through two Mentor Model blocks totaling 23 weeks and several non-Mentor Model blocks totaling 14 weeks within the study period. Fellow follow-up rates ranged from 5–12% during non-Mentor Model blocks. One fellow demonstrated increased rates during the first Mentor Model block (5% vs. 9%) and three demonstrated increased rates during the second Mentor Model block (5–11% vs. 9–18%). The most encounters noted for a single patient was five. The majority of repeat encounters occurred in the outpatient setting.

Conclusion

We describe a rotation model designed to improve continuity of patient care among first-year Infectious Disease fellows at our institution. Compared with our previous rotation schedule, the Mentor Model increased fellow follow-ups. Structural changes to promote longitudinal patient care experiences are described in outpatient-heavy training programs. Further interventions to improve fellow follow-up rates in all training programs are merited.

Disclosures

All authors: No reported disclosures.
2560. Assessing Resident Perspectives on Prescribing Pre-Exposure Prophylaxis for HIV
Authors: Shallal Anita , Boapimp Pimpawan , Patel Keshav , Melgar Thomas , Vaillant James
Published: October 2019

Background

Over 15,000 people were living with HIV in Michigan in 2017. Kalamazoo County is one of the ten counties with the highest prevalence rate. Despite the efficacy of pre-exposure prophylaxis (PrEP) and updated guidelines from CDC/USPSTF with daily dosing of oral tenofovir/emtricitabine, 35% of patients encounter a physician who is unwilling to prescribe PrEP. One-third of primary care providers (PCP) are unaware of it. We investigated the perspectives of residents in several primary care-focused residency programs regarding PrEP and barriers to its prescription.

Methods

We surveyed 108 residents at Western Michigan University Homer Stryker M.D. School of Medicine from the departments of Internal Medicine, Medicine-Pediatrics, Pediatrics, Family Medicine, and OB/GYN. An anonymous electronic seven-question survey was sent, accompanied by a brief PrEP guideline.

Results

Of 108 residents surveyed, 53 responded (49%). The majority (45%) were in their intern year (Figure 1). Most respondents (67%) felt somewhat to very comfortable with providing counseling on safe sex practices and HIV prevention (Figure 2). Over 80% of respondents were aware of PrEP prior to reviewing the accompanying guideline. More than 70% of respondents would prescribe PrEP to patients in commercial sex work and serodiscordant couples, but only 30% were willing to prescribe PrEP to heterosexual men or women, and 8% were unwilling to prescribe PrEP at all (Figure 3). The main reason reported for not prescribing PrEP was inadequate knowledge about medication monitoring and follow-up (Figure 4). Only one respondent reported religious or moral beliefs affecting their prescribing habits. The vast majority (98%) of respondents would be more willing to prescribe PrEP with further education.

Conclusion

The majority of residents were comfortable with sex education and counseling on HIV prevention, which could help identify at-risk patients. There was wide variation in willingness to prescribe PrEP among indications, but little variation in reasons why PrEP is not being prescribed. This suggests either limited knowledge about the indications or possibly subconscious bias. Our results are consistent with previous literature that additional medical education on PrEP is essential to its utilization by PCPs.

Disclosures

All authors: No reported disclosures.
2565. Initial and Recurrent Episodes of Clostridioides difficile: Online Education as a Tool to Improve Management Strategies
Authors: Hurst Simi Thomas , Martorano James , Gerding Dale N
Published: October 2019

Background

The most common cause of infectious diarrhea in hospitalized patients, C. difficile is responsible for nearly half a million infections annually. Among persons over the age of 65 years, 1 in 11 die within a month of diagnosis.

Methods

A CME-certified/ABIM MOC educational program was developed to evaluate and improve ID specialists’ application of the latest guideline recommendations for the diagnosis and management of individuals with C. difficile. Modeled on the interactive grand rounds approach, the activity blended case-based presentation with multiple-choice questions. Using a “test then teach” approach to elicit cognitive dissonance, the activity provided evidence-based feedback following each learner response. Educational effectiveness was assessed with a repeated-pairs pre-/post-assessment study design; each individual served as his/her own control. A chi-square test assessed changes pre- to post-assessment. P values < 0.05 are statistically significant. Effect sizes were evaluated using Cramer’s V (< 0.05 modest; 0.06–0.15 noticeable effect; 0.16–0.26 considerable effect; > 0.26 extensive effect). The activity launched on a website dedicated to continuous professional development on May 29, 2018. Data for this initial analysis were collected through March 27, 2019.

Results

To date, 3274 HCPs, including 2946 physicians have participated in the activity. Data from the subset of ID specialists (n = 82) who answered all pre-/post-assessment questions during the initial study period were analyzed. Following activity participation, significant improvements were observed in the proportion of ID specialists who answered all assessment questions correctly (4% pre vs. 74% post; P < 0.0001; V = .555). Improvements were also observed in several specific areas of assessment (table). Additionally, 50% of ID specialists indicated they planned to modify their treatment approach and 18% planned to modify their diagnostic strategies for C. difficile.

Conclusion

Participation in this online, interactive, case-based, educational intervention significantly improved ID specialists’ management strategies for initial and recurrent episodes of C. difficile. These findings highlight the positive impact of well-designed online education.

Disclosures

All authors: No reported disclosures.
2567. Effect of Broad vs. Narrow-Spectrum Clostridioides difficile Treatment on Human Stool Bile Acid Composition Over Time
Authors: Thorpe Cheleste M , Qian Xi , Yanagi Karin , Kane Anne , Alden Nicholas , Snydman David R , Lee Kyongbum
Published: October 2019

Background

Secondary bile acid production by a diverse commensal flora may be a critical factor in preventing recurrence of Clostridioides difficile infection (CDI). Key enzymes involved are bacterial-encoded bile salt hydrolases (BSHs), felt to be “gatekeepers” to secondary bile acid synthesis. Ridinilazole, a novel narrow-spectrum drug for CDI, demonstrated superior sustained clinical response compared with vancomycin in Phase 2. Longitudinal sampling during this trial allowed for assessment of metabolites differentially present in stools during/after therapy with either broad or narrow-spectrum anti-CDI agent. Previous work characterizing subject’s fecal microbiota in this trial showed that unlike vancomycin, ridinilazole has little effect on commensal flora during and after therapy. We hypothesized that ridinilazole’s microbiota-preserving effect is associated with lack of accumulation of conjugated primary bile acids and/or reaccumulation/persistence of secondary bile acids over the course of CDI treatment, when compared with vancomycin-treated subjects. Furthermore, we hypothesized that we would observe correlations between bile acid profiles and predicted BSH gene abundances.

Methods

Sequential stool samples were obtained from 44 subjects treated with either ridinilazole or vancomycin (22 in each arm), ranging from time of CDI diagnosis, at end-of-therapy, and up to 40 days after diagnosis. Bile acids were quantitated by liquid chromatography-mass spectrometry. Using the PICRUSt algorithm, metagenomic predictions of BSH gene abundances were performed.

Results

Stool bile acid compositions differed between ridinilazole-treated and vancomycin-treated subjects at end-of-therapy. In vancomycin-treated subjects, stool composition became dominated by conjugated primary bile acids and decreased levels of secondary bile acids compared with baseline; the ratio of stool conjugated bile acids to secondary bile acids significantly predicted treatment arm. This ratio was also associated with predicted BSH gene abundance in ridinilazole-treated subjects.

Conclusion

Microbiota-preserving CDI treatment with ridinilazole preserves bile acid composition, which may decrease likelihood of recurrence.

Disclosures

All authors: No reported disclosures.
2569. The Gut Microbiome and Acute Graft vs. Host Disease Risk in Hematopoietic Stem Cell Transplantation Recipients
Authors: Ilett Emma E , Reekie Joanne , Jørgensen Mette , Murray Daniel D , Noguera Marc , Paredes Roger , Nørgaard Jens C , Daugaard Gedske , Helleberg Marie , Lundgren Jens , MacPherson Cameron , Sengeløv Henrik
Published: October 2019

Background

16S rRNA gene-based studies report that allogeneic hematopoietic stem cell transplant (aHSCT) recipients with low bacterial diversity and certain bacteria close to engraftment have increased risk of developing acute graft-vs.-host disease (aGvHD). Using shotgun metagenomic data, we aim to confirm and extend these observations in a larger cohort.

Methods

Adult aHSCT recipients with stool samples collected days −30 to +100 relative to aHSCT, but prior to aGvHD, were included. One sample was selected per patient and time point: pre-aHSCT (T1), post-aHSCT pre-engraftment (T2). Complete ascertainment of aGvHD (grades ≥ 2) until day +100 was performed. Bacterial microbiome factors (α-diversity, gene richness and 16 a priori bacteria) and clinical factors were tested for associations with aGvHD across T1:2 in univariable models. Significant factors (P < 0.1) were included in a multivariable model.

Results

Of 147 aHSCT recipients, 35 developed aGvHD a median of 35 days (IQR 24–51) post-aHSCT. We found that higher gene richness was significantly associated with lower aGvHD risk in T2, but not T1, samples (OR 0.65 (95% CI 0.42–1.00), P = 0.04 vs. OR 1.14 (95% CI 0.67–1.94), P = 0.64 per doubling of unique genes). A decreased abundance of Akkermansia muciniphila, Proteobacteria, Blautia and Gammaproteobacteria was observed in those that developed aGvHD, again in T2 samples only (Figure 1). Among clinical factors, donor sex, donor/recipient (related/unrelated) and conditioning regimen (adjusted OR = 0.34 for non-myeloablative vs myeloablative (95% CI 0.15–0.77)) were significantly associated with aGvHD. Conditioning regimen was also strongly associated with microbiome changes; myeloablative recipients had lower gene richness and differences in bacterial abundance, including decreased abundance of aforementioned bacteria, compared with non-myeloablative recipients at T2 (Figures 2and 3).

Conclusion

Post-aHSCT pre-engraftment was a crucial timepoint where microbial changes, including lower gene richness and abundance of certain bacteria, were associated with development of aGvHD. Myeloablative regimes were also associated with both aGvHD and microbiome changes, suggesting that intense conditioning may affect aGvHD risk through perturbation of the gut microbiome.

Disclosures

All authors: No reported disclosures.
2576. The Microbiome of Recurrent Bacterial Vaginosis Compared with Asymptomatic Controls
Authors: Shay Elizabeth O , Goje Oluwatosin , Padmanabhan Roshan , Eng Charis
Published: October 2019

Background

Bacterial vaginosis (BV) affects nearly 1 in 3 women in the United States and is poorly understood. The study of the vaginal microbiome, using 16S rRNA-gene amplicon sequencing, has increased our knowledge of BV. We aimed to characterize the vaginal microbiome of women with recurrent BV firstly in comparison to controls, and secondly in comparison to a sub-population of our asymptomatic controls, positive for Gardnerella vaginalis via a vaginal pathogens DNA direct probe test (DNA probe).

Methods

Women aged 18–40 years, with recurrent BV, and asymptomatic controls were prospectively enrolled. Vaginal samples were collected from each participant. DNA was extracted, amplified using primers targeting the V3-V4 variable region of the 16S rRNA-gene, and then sequenced and processed through a hybrid Qiime MICCA bioinformatics pipeline. We also tested for G. vaginalis using the DNA probe.

Results

Seventeen recurrent BV patients and 46 controls were enrolled. Β diversity (P = 0.045), but not alpha diversity (P = 0.076) differed between groups. The genera Gardnerella and Prevotella were relatively more abundant, while Lactobacillus was relatively less abundant in recurrent BV vs. control groups. Of the patients for whom results of the DNA probe for Gardnerella vaginalis were available, 11 (69%) recurrent BV patients and 14 (35%) controls were positive. Control patients, negative by the DNA probe test, showed decreased alpha diversity (P = 0.0001) and significantly different β diversity (P = 0.001) compared with recurrent BV patients. Neither alpha (P = 0.31) nor β (P = 0.096) diversity differed between recurrent BV patients and controls that were G. vaginalis positive.

Conclusion

The microbiome of recurrent BV patients is distinct from that of asymptomatic controls; recurrent BV patients exhibit different β diversity, less Lactobacillus and more Gardnerella and Prevotella. Asymptomatic Gardnerella vaginalis-colonized controls demonstrate similar microbiome profiles to those of recurrent BV patients. These findings suggest that individual factors may influence whether or not a patient with a BV microbiomic profile experiences symptoms. Further investigation into these mechanisms could yield insights into the treatment of recurrent BV.

Disclosures

All authors: No reported disclosures.
2584. Effects of Fecal Microbiota Transplantation for Decolonizing Multidrug-Resistant Organism
Authors: Seong Hye , Lee Sang kil , Cheon Jae hee , Yong Dong eun , Koh Hong , Kang Yoon gu , Lee Woon Ji , Kim Jung Ho , Choi Heun , Ahn Jin young , Ku Nam su , Jeong Su Jin , Yeom Joon-Sup , Choi Jun yong
Published: October 2019

Background

Increasing prevalence of multidrug-resistant microorganisms (MDRO) results in poor clinical outcomes, longer hospitalizations and higher healthcare costs. It is likely that MDRO colonization can lead infections to vulnerable patients. Currently, however, MDRO decolonization strategies are lacking. The purpose of this study was to prove the efficacy of FMT on decolonization of carbapenemase-producing Enterobacteriaceae (CPE) and vancomycin-resistant enterococci (VRE) carriers.

Methods

This study was a prospective, open-label, uncontrolled, single-center pilot study of FMT for digestive tract colonized CPE, VRE, or CPE/VRE patients between March 2018 and February 2019. Fecal solution obtained from healthy unrelated donors was infused to recipient’s gut. Fecal samples of recipients were collected before and after FMT until 1year.We compared characteristics of subjects succeed in decolonization during study period (responders) with subjects who failed to decolonize MDRO by FMT (non-responders). Furthermore, microbiome analyses were performed to investigate the influence of microbial characteristics of recipients on the outcome of FMT.

Results

Decolonization was achieved in 12/23 (52.2%) during study period. Hemoglobin (11.0 vs. 10.0, P = 0.018), low-density lipoprotein cholesterol (102.0 vs. 89.0, P = 0.049), and albumin (3.4 vs. 3.2, P = 0.006) levels were higher in responders. Antibiotic treatment(ATB) within 1 week after FMT were less common in responders (41.7% vs. 90.9%, P = 0.027). Patients with no ATB approached frequent decolonization at 1(75.0% vs. 26.7%; P = 0.037) and 3 months (87.5% vs. 33.3%; P = 0.027). The rates of decolonization were significantly different between CPE, VRE and CPE/VRE colonizer (75.0% vs. 38.5% vs. 66.7%; P = 0.018). Gut microbiome of responders showed a higher richness and diversity than non-responders before(294 vs. 274 by Ace; 2.6 vs. 1.8 by Shannon) and after (345 vs. 260 by Ace; 2.9 vs. 2.1 by Shannon) FMT. The microbiota composition analysis revealed increasing abundance of Bacteroidetes and decreasing abundance of Proteobacteria at 1 month after FMT in responders. However, those changes of microbial composition did not occur in non-responders.

Conclusion

FMT is an effective way to decolonize CPE and VRE by restoration of the gut microbiome.

Disclosures

All authors: No reported disclosures.
2585. Changing Epidemiological Profile of Infantile Parechovirus-A3 Infection in Japan
Authors: Aizawa Yuta , Izumita Ryohei , Yamanaka Takayuki , Habuka Rie , Ikuse Tatsuki , Watanabe Kanako , Otsuka Taketo , Saitoh Akihiko
Published: October 2019

Background

Parechovirus-A3 (PeV-A3) causes severe disease, including sepsis and meningoencephalitis in young infants. The first case of PeV-A3 was reported in Japan in 1999 and, although epidemics have been reported every 2 to 3 years in more than 20 countries, no major epidemic has occurred in Japan since 2014.

Methods

This prospective study included febrile infants (<4 months of age) admitted at Niigata University and its affiliated hospitals, which serve about 2.5 million people, during the period from 2014 to 2018. Neonates and infants younger than 4 months presenting with fever and suspected of having viral sepsis underwent serum and/or cerebrospinal fluid (CSF) testing by real-time PCR for parechovirus-A (PeV-A) and enteroviruses (EVs), and for herpes simplex viruses, if suspected. Bacterial infection was excluded on the basis of the results of bacterial culture of blood, urine, and/or CSF. PeV-A genotype was identified by examining the viral protein 1 (VP1) sequence, and the phylogenetic tree of the VP1 sequence was constructed.

Results

Of the 277 patients evaluated, 135 (49%) were positive for PeV-A (n = 74, 27%) or EVs (n = 61, 22%). Among PeV-A patients, most had PeV-A3 (n = 69; 93%), followed by PeV-A4 (n = 4; 5%). There was a PeV-A3 epidemic in 2014 (n = 43); however, no cases were reported in 2015. In 2016–2018, small numbers of PeV-A3 cases were reported: 10 in 2016, 7 in 2017, and 9 in 2018. In contrast, EV cases were reported throughout this period: 8 in 2014, 22 in 2015, 10 in 2016, 5 in 2017, and 16 in 2018. When data were analyzed by season, the PeV-A3 detection rate in summer (June-August) was 93% (40/43) in 2014 and 65% (17/26) during 2016–2018, indicating an increase in the number of PeV-A3 cases in seasons other than summer. Phylogenetic analysis showed that PeV-A3 strains during 2016–2018 were part of a cluster of epidemics in 2011 and differed from those in 2014.

Conclusion

After the major PeV-A3 epidemics in 2014, we observed changes in the PeV-A3 epidemic profile, namely, a small, but constant, number of cases every year in Niigata, Japan. A future study should investigate if this trend has continued in Japan and other countries and identify the causes of this change in epidemic profile.

Disclosures

All authors: No reported disclosures.
2588. Acute Toxoplasmosis among Pregnant Arab Women in Northern Israel: to Screen or Not?
Authors: Paz Alona , Potasman Asala , Stam Tamar , Potasman Israel
Published: October 2019

Background

The seroprevalence of toxoplasmosis among Israeli Arabs is high. Yet, the regulation of the Israeli Ministry of Health suggests not screening pregnant women for toxoplasmosis. During 2017/8 we have seen a surge in cases of acute toxoplasmosis in pregnancy in Northern Israel. We aimed to explore this surge and compare the rates of acute toxoplasmosis in pregnancy in Northern Israel among Jews and Arabs.

Methods

The database of the lab of Meuhedet HMO (Northern Israel only) was retrospectively screened for all tests for Toxoplasma serology during 2013–2017. We focused on women of childbearing age and compared rates of seropositivity in Jews and Arabs. IgG and IgM were carried out using Abbott Architect, and IgG avidity by Vidas, BioMerieux. Birth rates were retrieved from the central computer of Meuhedet HMO.

Results

: In 2017, Northern Israel had 1,397,833 citizens of whom 53% were Arabs. Of this population, 13% were insured by Meuhedet HMO, and of these 60% were Arabs (Muslims or Christians). During the 5-year period 16,044 Toxoplasma serology tests have been requested (both sexes), of which 26% returned IgG positive. 88% of the positive ones were of Arab citizens (P < 0.0001). Excluding duplicates, we found 118 women of childbearing age with a positive IgM test (2.8%). Of the latter, 37 had a low/medium avidity test (31.4%). 112 of the women were Arabs, while only 6 were Jews (P < 0.0001). Two-thirds of the women had a positive βHCG test at the same time. During this 5-year period there were 23,074 live births in this HMO (11,512 Arab newborns). Thus, had all these women delivered an infected newborn, the rate of congenital toxoplasmosis in the Arab population (97.2/10,000) was 19-fold higher than among the Jewish (5.2/10,000; P < 0.00001). Interview of 35 acute cases during 2017/8 revealed that most of the women had consumed raw meat called “Kibbe Niyye”—a popular dish unique to Northern Israeli Arabs (Galilee) and served on festive occasions.

Conclusion

We found that Northern Israeli Arab women are at a high risk to contract toxoplasmosis during pregnancy due to consumption of traditional raw meat. This finding calls for awareness among women as well as doctors. We believe that the regulation not to screen pregnant women in the Arab sector should be reevaluated.

Disclosures

All authors: No reported disclosures.
2591. The Role of Neutralizing Antibodies (nAb) Against Cytomegalovirus (CMV) Epithelial Cell-entry in Patients with Self-limited (SL) CMV infection after Hematopoietic Cell Transplantation (HCT)
Authors: Zamora Danniel , Green Margaret , Tono Jo , Blazevic Rachel , Edmison Bradley , Stevens-Ayers Terry , Geballe Adam , Boeckh Michael
Published: October 2019

Background

CMV transmission after HCT occurs in 20–30% of CMV-seronegative recipients with CMV-seropositive donors (i.e., CMV D+/R−) and a distinct subset develop transient CMV DNAemia without progression to culture positivity in the absence of antivirals (BMT 1992; 9:221; J Med Virol 2019; 91:1128). The mechanism of SL CMV infection is unknown but may involve nAb, which have been implicated in primary viral clearance, including nAb that inhibit viral epithelial and endothelial cell-entry via CMV pentameric complex (PC). We aimed to describe viral kinetics and the influence of nAb on CMV infection progression in SL CMV-infected patients and controls within a unique cohort from the pre-antiviral era.

Methods

Weekly serum samples from 456 CMV D+/R− allogeneic HCT patients collected between 1978–95 were screened using quantitative CMV DNA PCR. Patients with CMV DNAemia in the first 100 days after HCT followed by a sustained return to undetectable levels without positive surveillance CMV cultures were defined as having SL CMV infection. SL CMV-infected patients were matched 1:1:1 to CMV-infected controls (patients with CMV infection by culture in the same period after HCT ± 14 days) and non-infected controls (patients without CMV DNA or culture positivity) to compare viral kinetics and nAb. A modified nAb assay was used to evaluate serum nAb activity against CMV PC-mediated cell entry (Vaccine 2008; 26:5760; JID 2019; in press).

Results

We identified 9 patients with SL CMV infection and baseline demographics are shown (Table 1). SL CMV-infected patients had a median of 21 days (range 7–54 days) until first positive CMV DNAemia. The median peak CMV DNAemia was 94.2 IU/mL (range 40.2–225.9 IU/mL) and 46,118 IU/mL (range 1,132–284,362 IU/mL) in SL CMV-infected and CMV-infected controls respectively. There was no difference in nAb titers between groups at infection day 0 or in the preceding 4 weeks (Figure 1, Figure 2).

Conclusion

nAb against CMV PC-mediated cell entry did not appear to play a critical role in viral clearance in SL CMV infection after CMV D+/R- allogeneic HCT. Our study illustrates the potential for clearance of relatively low CMV DNAemia after HCT without the addition of antivirals. CMV-specific T-cell immunity or innate immune mechanisms may be more important in early viral control.

Disclosures

All authors: No reported disclosures.
2597. Dolichos biflorus Agglutinin Binds to Pneumococcal Teichoic Acid and Lipoteichoic Acid
Authors: Zhou Meng-Lan , Frost Michael R , Nahm Moon H
Published: October 2019

Background

Dolichos biflorus agglutinin (DBA) is a lectin with a binding specificity toward α-linked N-acetylgalactosamine (α-GalNAc). While DBA is known to bind some, but not all, pneumococci, its target molecule has not been identified. Pneumococcus teichoic acid (TA) and lipoteichoic acid (LTA) have repeating units with α-GalNAc-(1→3)β-GalNAc decorated with phosphorylcholine (PC) at the O-6 positions. Two PC transferases, LicD1 and LicD2, mediate the attachment of PC to GalNAc residues while phosphorylcholine esterase (Pce) removes PCs attached to the terminal GalNAcs. We examined if DBA binds to the terminal α-GalNAc-(1→3)β-GalNAc created by Pce.

Methods

Fifteen pneumococcus strains expressing 14 different serotypes, including one non-encapsulated strain (R36A), were studied with flow cytometry (FC) and confocal fluorescence microscopy (CFM) for DBA binding. Pce enzyme activity was detected with a colorimetric assay using p-nitrophenyl-phosphorylcholine as the substrate. Mutant strains with pce knocked-out were constructed in R36A and D39 by replacing pce with Janus cassette. Both licD genes were sequenced for some of the strains.

Results

Ten of the 15 strains had Pce activity and all of them bound DBA (Table 1). When the pce gene was inactivated in two normally Pce-positive strains (R36A△pce and D39△pce), the strains did not show DBA binding by CFM (Figure 1). Thus, expression of Pce appears to be sufficient for expressing the DBA antigen. Of the five strains that had no Pce activity, two bound DBA. Sequencing of the licD genes in these two strains with positive DBA binding and negative Pce activity revealed one SNP in licD1 and four SNPs in licD2, resulting in a single amino acid difference each for LicD1 and LicD2, compared with R36A and D39.

Conclusion

DBA can bind to the terminal α-GalNAc-(1→3)β-GalNAc of pneumococcal TA and LTA, which is created by Pce. DBA binding is independent of capsule type. The unexpected binding of DBA to the two Pce-negative strains suggests that there is a Pce-independent mechanism for generating the target for DBA binding. Since LicD1 and LicD2 are involved in attaching PC to α-GalNAc-(1→3)β-GalNAc, we are now investigating their role in creating DBA targets independent of Pce.

Disclosures

All authors: No reported disclosures.
2599. Studying the Effects of Altering Histone Modification on Aspergillus fumigatus Virulence
Authors: Lee Pam , Liu Hong , Filler Scott
Published: October 2019

Background

As there are few drugs for treating invasive aspergillosis, there is an urgent need for new antifungal agents. Enzymes involved in histone modification are possible antifungal drug targets. We set out to investigate whether genes whose products are involved in histone modifications influence the virulence of Aspergillus fumigatus (Af).

Methods

Genes whose products were likely involved in histone modification were deleted in strain Af293 using CRISPR-Cas9. Virulence was assessed in a triamcinolone-treated mouse model of invasive pulmonary aspergillosis. The extent of Af-induced damage to the A549 pulmonary epithelial cell line was determined by Cr51 release assay.

Results

Af genes were selected for investigation based on their homology to genes encoding known histone modifying proteins and their high expression level in vivo. The genes were predicted to encode members of the COMPASS histone methyltransferase complex (cclA/bre2, set2/Afu5g06000), the SAGA histone acetyltransferase complex (spt3, spt8), and the RPDL histone deacetylase complex (hosA). The ΔcclA and Δset2 mutants had significant growth defects on rich media and were not tested further. The Δspt3 and Δspt8 mutants grew normally and had mild conidiation defects. The ΔhosA mutant had wild-type (WT) growth and conidiation in vitro. Mice infected with the WT strain had 100% mortality within 9 days whereas mice infected the Δspt3, Δspt8, and ΔhosA mutants had only 40% mortality by 21 days. The ΔhosA mutant also had impaired capacity to damage pulmonary epithelial cells in vitro.

Conclusion

Ccla and Set2, components of the COMPASS complex, are required for normal growth in vitro. Spt3 and Spt8, members of the SAGA complex, are required for normal conidiation and virulence. HosA, part of the RPD3L complex, is necessary for maximal virulence and induction of host cell damage. Our results suggest that the HosA histone deacetylase may be a promising drug target for treating invasive aspergillosis.

Disclosures

All authors: No reported disclosures.
2604. Changes in a Fatty Acid Kinase Associated with Daptomycin (DAP) Resistance Lead to Increased Collagen Binding and Biofilm Formation in Enterococcus faecalis
Authors: Miller William R , Singh Kavindra V , Reyes Jinnethe , Murray Barbara E , Arias Cesar A
Published: October 2019

Background

Enterococci are a major cause of healthcare-associated infections with limited treatment options. We previously identified that mutations in dak (a gene encoding a putative fatty acid kinase), ace (a collagen adhesin) and the YxdJK stress response system are associated with DAP resistance (DAP-R) in E. faecalis (Efs) in the absence of a functional LiaFSR system. Here, we examined the role of DAK in pathogenesis by examining the ability of the mutants to produce biofilm and bind to collagen, an important protein of the extracellular matrix.

Methods

Previously, the Efs strain OG1RFΔliaR (inactive LiaFSR system, DAP susceptible) was adapted to make a DAP-R derivative (mutations in yxdK, dak, and ace), and the mutant OG1RFΔliaRΔc-dak, lacking the C-terminal domain of dak, and its complement OG1RFΔliaRΔc-dak::c-dak were constructed to study the dak mutation in isolation. Biofilm formation (BF) for the above strains was assayed after growth in tryptic soy broth with glucose in 96-well plates at 37° C for 24 hours. Bacteria were fixed with Bouin’s fixative, stained with crystal violet, and biofilm was quantitated by absorbance at 570 nm. For collagen adherence, 96-well plates were coated with 10 μg/well type I collagen, with 2% bovine serum albumin (BSA) as a control. Bacteria grown at 46° C (to induce ace expression) were added at OD 600 nm of 1.0 and allowed to bind for 2 hours. Non-adherent bacteria were removed by washing, cells were fixed, stained, and quantified as above.

Results

When compared with OG1RFΔliaR, the DAP-R derivative exhibited a significant increase in BF (4.6 vs. 2.4, P < 0.001). This enhanced biofilm phenotype was also seen in the OG1RFΔliaRΔc-dak mutant (6.1 vs. 2.4, P < 0.001), and reverted on complementation of the full-length dak in its native chromosomal location (2.4 vs. 2.6, p = 0.72). DAK was also found to impact adherence to collagen, with OG1RFΔliaRΔc-dak showing increased binding to collagen when compared with OG1RFΔliaR (7.9 vs. 3.4, P < 0.001), a phenotype which reverted on complementation (7.9 vs. 1.2, P < 0.001).

Conclusion

Changes in an enzyme involved in DAP adaptation lead to biofilm formation and adherence to extracellular matrix proteins, potentially enhancing virulence in the setting of DAP-R.

Disclosures

All authors: No reported disclosures.
2607. Establishment of a Novel High-Throughput Fungal Infection Model in Zebrafish Larvae by Controlled Ablation of Epithelial Cells
Authors: Wurster Sebastian , Ruiz Oscar E , Tatara Alexander M , Samms Krystin M , Kim Nguyen Anh , D. Albert Nathaniel , H. Kahan Philip , Mikos Antonios G , Eisenhoffer George T , Kontoyiannis Dimitrios P
Published: October 2019

Background

Efficient animal models are needed in order to investigate fungal pathogenicity and antifungal therapy in the context of epithelial injury, e.g., due to anticancer chemotherapy. Using a Gal4 enhancer trap (GET) zebrafish line facilitating metronidazole (MTZ)-inducible ablation of epithelial (periderm) cells, we aimed to establish a mucositis model predisposing larvae for fungal invasion.

Methods

4 days post-fertilization Et(Gal4-VP16)zc1044A;Tg(UAS-1b:nfsB-mCherry)c264 zebrafish larvae were exposed to 10 mM MTZ in E3 medium for 5 h. After washing, larvae were incubated in Candida albicans or Rhizopus arrhizus spore suspensions (5 × 105–5 × 107/mL) for 16 h. Thereafter, larvae were washed again and survival was monitored until 72 h post-infection. Fungal burden was assessed by 18S qPCR and histopathology. For drug protection studies, 5 µg/mL amphotericin B (AMB) or posaconazole (PCZ) was added to the medium of R. arrhizus-infected larvae at 16 h post-infection.

Results

In MTZ-treated GET larvae, inoculum-dependent mortality was found for both R. arrhizus (panel A) and C. albicans (panel B). High inter-experiment reproducibility of survival rates was seen (CV < 0.3). Using a GFP-expressing R. arrhizus strain, fungal invasion of the larval tissue was verified by fluorescence microscopy (panel C). PCZ and AMB improved survival rates of R. arrhizus-infected (5 × 106/mL) larvae from 46% to 85% and 51% to 86%, respectively (P < 0.001). Similarly, significantly reduced fungal burden in AMB and PCZ-treated larvae was documented by qPCR (panel D) and histopathology. In additional validation experiments, the hypo-virulent phenotypes of a CotH-depleted R. arrhizus strain and filamentation-defective C. albicans mutants (Δefg1 and Δcph1) were recapitulated in zebrafish larvae with epithelial cell loss.

Conclusion

We have established a robust and reliable model of invasive mycoses by controlled ablation of epithelial cells in zebrafish larvae, allowing for rapid immersion-based interrogation of different infection and treatment options. Our proof-of-concept experiments suggest that GET zebrafish larvae are positioned as an appealing high-throughput in vivo system for antifungal drug screening or comparative virulence studies.

Disclosures

All authors: No reported disclosures.
2628. Nasopharyngeal Microbiome in the First Weeks of Life Distinguishes Infants Who Subsequently Develop Lower Respiratory Tract Infections
Authors: Lapidot Rotem , Faits Tyler , Arshad Ismail , Mushal Allam , Macleod William , Kwenda Geoffrey , Mupila Zacharia , Murphy Caitriona , Nakazwe Ruth , Johnson Evan , Thea Donald M , Mwananyanda Lawrence , Gill Christopher
Published: October 2019

Background

Colonization of the nasopharynx (NP) is the initial event in the pathogenesis of lower respiratory tract infections (LRTI). Evidence is accumulating that the NP microbiome influences host immune responses and whether colonization progresses to disease or not. We hypothesized that infants who experience LRTI early in life display distinct NP microbiome characteristics prior to infection, and potentially as early as the newborn period.

Methods

As part of the “Southern Africa Mother Infant Pertussis Study” in Zambia, NP samples were prospectively collected approximately every 2 weeks beginning at birth, through 3 months of age, in conjunction with clinical data. Samples were also collected when an infant experienced respiratory symptoms. We identified infants from the cohort with LRTI and matched with asymptomatic controls. We performed 16S ribosomal DNA amplicon sequencing on DNA extracted from the NP samples using Illumina MiSeq, and analyzed the data using Qiime2 and PathoScope2. We described the NP microbiome characteristics of asymptomatic infants and infants with LRTI and their changes over time and compared between the two populations at each 2-week interval using the R package DESeq2.

Results

Ten infants who had LRTI during the study period were matched with 17 healthy asymptomatic controls, together contributing 183 samples with high-quality reads. In asymptomatic infants, Dolosigranulum, Haemophilus and Moraxella’s relative abundance increased over the first 3 months of life, while Corynebacterium and Staphylococcus relative abundance decreased in the NP microbiome (Figure 1). In contrast, infants who developed LRTI had increased abundance of Staphylococcus, Anaerobacillus, and Bacillus, and decreased relative abundance of Dolosigranulum and Moraxella compared with asymptomatic controls (Figure 2). These differences were already present at the time of first sample collection (age 1 week).

Conclusion

Infants who develop LRTI early in life demonstrate altered NP microbial composition as early as the first week of life. These differences could potentially lead to early identification of at-risk infants. If confirmed, interventions to prevent LRTI in infancy could be evaluated to reduce respiratory mortality and morbidity.

Disclosures

All authors: No reported disclosures.
159. Comparing Clinical Cure and Patient Outcomes Between Intravenous Therapy and Intravenous (IV)-to-Oral (PO) Step-down Therapy for Treatment of Gram-Negative Bloodstream Infections
Authors: Williams Kelsey , Ghamrawi Riane , Takieddine Sheila , Grubbs Peter , Powers-Fletcher Maggie , Liao Siyun
Published: October 2019

Background

There is a paucity of evidence surrounding optimal prescribing practices for the treatment of Gram-negative bloodstream infections (GNBSI). This study aimed to assess the appropriateness of IV-to-PO step-down therapy in the treatment of GNBSI.

Methods

A retrospective cohort study was conducted at the University of Cincinnati Medical Center and West Chest Hospital and included subject’s ≥18 years of age with GNBSI caused by Enterobacteriaceae spp. or Pseudomonas aeruginosa. The primary objective was to compare clinical cure rates between IV-only and IV-to-PO therapy, and to further assess differences in clinical cure rates amongst oral antibiotics of high, moderate, and low bioavailability. The study also aimed to identify factors associated with clinical cure, hospital length of stay, and emergence of multi-drug-resistant organisms (MDRO).

Results

Amongst 215 subjects screened, 99 subjects were included and 64 subjects met criteria for clinical cure. In the univariate analysis, the IV-to-PO group had a higher percentage of clinical cure than IV only therapy (82% vs. 48%, P = 0.001). Of note, the two study groups were significantly different in regards to intensive care status, Pitt bacteremia score, and primary site of infection. Upon further analysis, data from the multivariate logistic regression revealed that critical illness was the only significant factor that negatively impacted clinical cure (OR = 0.208; 95% CI 0.04–0.99; P = 0.049). A total of 49 subjects received oral antibiotics. Majority of patients (82%) in the IV-to-PO group received a moderately bioavailable oral antibiotic. No difference in respect to clinical cure rate was found between the three PO antibiotic bioavailability groups (P = 0.346). The median duration of hospital stay was shorter in the IV-to-PO compared with IV alone group (4 days vs. 9.5 days, respectively, P ≤ 0.001). There was a trend in emergence of MDROs with IV therapy compared with IV-to-PO therapy (10% vs. 2%, P = 0.204).

Conclusion

IV-to-PO stepdown therapy compared with IV therapy alone was noninferior in clinical cure rates in the treatment of GNBSI and may result in fewer hospital days and less emergence of multidrug-resistant organisms. These conclusions are limited by significant differences in severity of illness between groups in this study.

Disclosures

All authors: No reported disclosures.
2676. Effect of β-Lactam Allergy on Appropriateness of Antibiotic Use in Patients with Febrile Neutropenia
Authors: Yetmar Zachary A , Vijayvargiya Prakhar , Tosh Pritish , Kasten Mary J
Published: October 2019

Background

Over 80% of patients with hematologic malignancies develop some form of infectious complication, most commonly febrile neutropenia. Patients with febrile neutropenia have 10% mortality, which increases if antibiotic administration is delayed past 30 minutes. Studies have suggested β-lactam allergy may delay administration of antibiotic while putting patients at greater risk for inappropriate antibiotic choice and adverse effects stemming from this. We sought to describe the risks associated with β-lactam allergy in the neutropenic population.

Methods

We conducted a retrospective, descriptive study from January 2016 to December 2017 identifying patients with febrile neutropenia and a reported history of β-lactam allergy. Baseline characteristics, allergy data, treatment data, and outcomes were collected and analyzed.

Results

We identified 31 patients with febrile neutropenia and β-lactam allergy during this time period. Etiologies of neutropenia were hematologic malignancy (61.2%), stem cell transplantation (12.9%), solid-organ malignancy (22.6%), and autoimmune (3.3%). Reported reactions to β-lactams were rash (41.9%), hives (9.7%), anaphylaxis (3.2%), other (9.7%), and unknown (35.5%). Average time to antibiotic administration was 142.5 minutes. Antibiotic choice was cefepime (61.3%), piperacillin–tazobactam (6.5%), carbapenem (22.6%), fluoroquinolone (6.5%), cefepime and fluoroquinolone (3.2%), and vancomycin (58.1%). 51.6% received initial antibiotics consistent with the 2010 IDSA guidelines. Six patients underwent penicillin skin testing, all negative. 1 patient developed C. difficile infection, 1 developed MRSA colonization, and 3 developed VRE colonization. Mortality was 3.2% at 30 days and 16.1% at 90 days.

Conclusion

Our study estimated the antibiotic usage patterns and outcomes in patients with febrile neutropenia and reported β-lactam allergy. This showed low adherence to an established guideline for antibiotic choice in these patients. With rising antimicrobial resistance, there is a need to develop strategies to reduce inappropriate antimicrobial use, especially in patients with febrile neutropenia. Preemptive β-lactam allergy evaluation warrants further evaluation in the neutropenic population.

Disclosures

All authors: No reported disclosures.
2677. Infection-Related Outcomes in Patients With Malignancy-Related Febrile Neutropenia: A National Perspective
Authors: Noor Arish , Desai Aakash , Tandon Varun , Siddappa Pradeep K , Balakumaran Kathir , Diez-morales Luis F
Published: October 2019

Background

Febrile neutropenia (FBN) is a life-threatening oncological emergency requiring hospitalization and early treatment with broad-spectrum antibiotics. We aimed to study differences in infection-related outcomes for febrile neutropenia in various malignancies.

Methods

The National Inpatient Sample (NIS) data set was queried from 2007 to 2014 to identify all patients with a diagnosis of neutropenic fever (ICD-9: 780.6x and 288.5x or 288.0x or 284.1x). Diagnoses for various cancers were determined via their respective Clinical Classification Software (CCS) codes. Diagnoses of pneumonia (481.x, 482x), bacterial meningitis (320.x), Clostridium difficile (008.45), infectious colitis due to neoplastic agents (009.x), urinary tract infection (599.0x), pyelonephritis (590.1x, 590.80), skin and soft-tissue infection (682.x, 684.x, 686.8x, 686.9x), mucositis (528.01), influenza (CCS 487), sepsis (995.91), severe sepsis (995.92), septic shock (785.52), E. coli septicemia (038.42), Pseudomonas septicemia (038.43), MRSA septicemia (038.12) and Streptococcal septicemia (038.0) were identified using their respective ICD/CCS codes. Variables were analyzed via multivariate analysis using the program SAS.

Results

We studied 381,043 patients with FBN. Leukemia was the most common malignancy associated with FBN (140,190, patients, 36.8%). Meningitis was found to be significantly associated with brain cancer, while other infections were associated with a range of malignancies. (Table.1) Methicillin-resistant Staphylococcus aureus was associated with cancers of the bone, breast, uterus and non- hodgkins lymphoma, while other microorganisms varied across different malignancies (Table 2). Septic Shock was associated with cancer of the pancreas, lung, bone, breast, leukemia, bladder, kidney, thyroid, myeloma, prostate, testis, cervix, brain, melanoma, non-hodgkins lymphoma, compared with other malignancies (Table 3).

Conclusion

Pathogen-specific and targeted antibiotic therapy is the cornerstone of treatment in FBN. Our study provides evidence of specific presentations and organisms causing infections in various malignancies. We hope that further outcomes-based research will provide objective evidence of certain high-risk infections, improving patient outcomes and minimizing redundant testing.

Disclosures

All authors: No reported disclosures.
2689. Stenotrphomonas maltophilia, The Hidden Threat Among Pediatric Cancer Patients
Authors: Madney. Said Youssef , Abdelaziz Riham , Samir Shimaa , Elanany Mervat
Published: October 2019

Background

Stenotrophomonas maltophilia is an emerging nosocomial pathogen in immunocompromised patients. Although S. maltophilia exhibits limited pathogenicity in immunocompetent hosts, it has been shown to cause fatal infections in patients with malignancies. The objective of this study to analyze the clinical characteristics, susceptibility pattern, and treatment outcome of S. maltophilia among pediatric cancer patients.

Methods

Retrospective analysis including all pediatric cancer patients treated at children cancer hospital Egypt (CCHE) with S. maltophilia bloodstream infection from June 2013 till June 2018.

Results

281 isolates among 135 pediatric cancer patients. Most are hematological malignancies 67(50%), solid tumors 55 (40%) and post-transplant 13(10%). Most common hematological malignancies were acute lymphoblastic leukemia 34 patients (25%) while brain tumor was the most common solid tumors 20 patients (15%). The spectrum of infections includes bacteremia in 61 patients (45%) catheter-related in 34 (25%), pneumonia in 22 (16%), skin and soft-tissue infection in 11(8%) meningitis in 5 (3%) and disseminated infections with multiorgan involvement in 4(3%) patients. 46 patients (34%) was admitted in intensive care unit (ICU), 67 inpatient (50%), 11 (8%) stem cell transplant unit and 11 patient (8%) from emergency and outpatient department. The isolates revealed 80% susceptibility to Trimethoprim-Sulfamethoxazole (TMP-SMX), 77% to ciprofloxacin, 50% to cefepime and ceftazidime, 63% to amikacin, 48% to piperacillin–tazobactam, 93% to colistin, 97% to tigecycline. Day 30 mortality (Crude mortality rate) 33 patients (25%) while S. maltophilia attributable mortality (died within 7 days of culture isolation) was 17 patients (13%). Patients with pneumonia, (TMP-SMX) resistance and ICU admission were associated with a significant risk of mortality.

Conclusion

Stenotrphomonas bloodstream is a serious pathogen and hidden threat among pediatric cancer patients associated with high mortality rate.

Disclosures

All authors: No reported disclosures.