bluuebunny/crossref_metadata_2025_split huggingface dataset:
2592. Lung Function as an Indicator of Vaccine Enhanced RSV Disease in Cotton Rats
Authors: Jones Crystal , Shen Xiaolan , Ping Xiaoli , Gallagher Catherine , Beech Jeremy , Douglas Cameron M , Citron Michael , Espeseth Amy 
Published: October 2019

Abstract

Background
Respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract infections in infants and young children. Seronegative children previously vaccinated with formalin-inactivated live RSV formulated with aluminum (FIRSV) developed vaccine enhanced RSV disease (VERD), which is characterized by fever, wheezing, bronchopneumonia, and airway hyperresponsiveness (AHR). We investigated whether impaired lung function can serve as a marker for VERD in an animal model of RSV infection.

Methods
Uninfected and RSV-infected cotton rats intranasally challenged with 106 pfu of RSV A2 were anesthetized with pentobarbital and tracheostomized. A cannula was placed in the trachea and animals were connected to flexiVent™ (Scireq), which is a computer-controlled piston ventilator that analyzes pressure and volume signals in response to an oscillatory waveform applied at the animal’s airways. Vecuronium bromide was administered to ventilated animals to prevent independent breathing. To measure AHR, animals were exposed to increasing doses of inhaled methacholine, and methacholine-induced bronchoconstriction was measured.

Results
Two independent studies showed that RSV-infected cotton rats (n = 4) exhibited increased total respiratory system resistance (Rrs) and airway resistance (Rn) following methacholine challenge on days 4 and 6 post-infection compared with uninfected cotton rats (n = 4).

Conclusion
RSV-induced impairment in lung function can be exploited for the development of a more robust and objective method for assessing vaccine safety in a cotton rat model of respiratory disease compared with traditional histopathological analysis.

Disclosures
All authors: No reported disclosures.
2594. Biofilm-Dispersed Staphylococcus aureus Exhibits a Distinct agr-Independent Host Interaction
Authors: Chang Spencer , Fowler Vance G , Sharma-Kuinkel Batu K , Medie Felix , Park Larry , Zheng Yue , Otto Michael , Horswill Alexander 
Published: October 2019

Abstract

Background
Staphylococcus aureus biofilms are a common cause of persistent, life-threatening infections. Dispersal of S. aureus cells from established biofilm-based infections is crucial for dissemination within the host, but is poorly understood. We tested the hypothesis that biofilm dispersed S. aureus cells have distinct physiology from planktonic cells and are better equipped to evade host immunity in an agr-dependent manner.

Methods
Primary murine bone marrow-derived macrophages (BMDMs) were infected with planktonic and biofilm dispersed cells from S. aureus USA300 LAC wild type (WT) and USA300 LAC-agr knockout (KO). Biofilm dispersed cells were collected via glucose deprivation. Gentamicin protection assays were used to enumerate phagocytosed bacteria and fluorescence microscopy to quantify macrophage viability. A 26-plex immunoassay was used to screen for cytokines and chemokines. Reversed phase high-performance liquid chromatography was used to measure relative phenol-soluble modulin (PSM) levels from macrophage co-cultures.

Results
Compared with planktonic cells, biofilm-dispersed cells in both S. aureus WT and KO backgrounds exhibited: (1) ~10-fold less phagocytosis by BMDMs (p = 0.0003; Figure 1); (2) increased macrophage killing (23% vs. 8%; p = 0.0038; Figure 2); (3) stronger pro- (e.g., IFN-y, IL-2, IL-6, IL-17; Figure 3A) and anti- (e.g., IL-10, IL-4, IL-22; Figure 3B) inflammatory cytokine responses from macrophages (P < 0.05 for all); (4) significantly higher δ toxin PSM production (P = 0.0090; Figure 4) in WT background only.

Conclusion
S. aureus biofilm dispersed cells are physiologically distinct from planktonic cells and have a unique interaction with the host immune system. Dispersed cells are more resistant to phagocytosis, have a greater propensity to kill macrophages, and mount stronger pro- and anti-inflammatory responses in an agr-independent manner. Dispersed cells also have the ability to produce more δ toxin PSM via well-known agr-dependent pathways.

Disclosures
All authors: No reported disclosures.
2601. Identification of Staphylococcus aureus Genetic Factors Associatiated with the Subversion of Macrophage Phagosomal Acidification
Authors: Morris Paul E R , Renshaw Stephen , Foster Simon J , Peden Andrew , Dockrell David 
Published: October 2019

Abstract

Background
S. aureus is a major medical pathogen contributing to healthcare-associated costs and mortality. Metastatic S. aureus infection is commonly associated with skin and soft-tissue infections. Macrophages as resident tissue phagocytes are essential for bacterial clearance and effectively phagocytose and kill S. aureus at low inocula. Formation of an intracellular reservoir develops when the capacity for macrophages to eradicate S. aureus is overwhelmed at increased inocula. Phagosomal maturation after bacterial ingestion involves sequential fusion with endosomes and lysosomes, reducing luminal pH, facilitating bacterial degradation. In the context of intracellular S. aureus, incomplete phagosomal maturation is demonstrable with impaired acidification and failure of lysosome fusion. Inhibition of phagosomal maturation is dependent upon bacterial factors as it is reversed in heat-killed bacteria. Intracellular survival of S. aureus is associated with reduced antimicrobial effectivity and increased complications. Within the intracellular environment, persistence of S. aureus is associated with adaptation of gene expression which confers greater resistance to antimicrobial effector mechanisms.

Methods
An ordered mutant library of S. aureus provides the opportunity to give a comprehensive evaluation of gene function. The Nebraska transposon (Tn) mutant library contains 1952 sequence-defined Tn insertion mutants derivative of USA300 LAC S. aureus, each with a single non-essential gene deletion. The mutants were labeled with a fluorescent stain activated at pH < 6 and challenged against differentiated human monocyte-derived macrophages for 4 hours. A high-content microscopy screen was developed to identify the bacterial genes associated with impairment of phagosomal acidification.

Results
The results of the high-throughput screen indicate the global regulators agr and saeR, hemolysin A and catalase are associated with the inhibition of phagosomal acidification.

Conclusion
The burden of S. aureus bacteremia and metastatic disease makes the targeting of intracellular S. aureus essential. Identification of bacterial factors associated with impaired phagosomal acidification and maturation offers targets to limit S. aureus infections.

Disclosures
All authors: No reported disclosures.
2615. Increased Severity of Lower Respiratory Tract Infection Among Native American Compared with Non-Native American Children
Authors: Cayetano. Lopez Santiago Manuel , Weber Zachary , Palmer Geralyn , Kooima Travis , Bula-Rudas Fernando , Chatterjee Archana , Chatterjee Archana 
Published: October 2019

Abstract

Background
Lower respiratory tract infection (LRTI) is the leading cause of pediatric hospitalizations in the United States, with significant morbidity and mortality. Native American children are at increased risk for severe illness during LRTI. Yet, the reasons for this increased risk are poorly understood. Socio-economic status and/or a genetic predisposition have been postulated as possible causes. In addition, the spectrum of LRTI presentations has not been adequately described in this patient population. The objective of this study was to define the clinical presentations of LRTI and highlight the differences between Native American and non-native American previously healthy patients under the age of 24 months.

Methods
We performed a retrospective chart review during the 2017–2018 respiratory season. We reviewed 357 medical records, and included 192 patients in the analysis that were full term, previously healthy, and met our inclusion criteria. We recorded demographic information, clinical and laboratory data, and outcomes.

Results
Of 192 patients, 39 were Native American and 153 were non-native American. We found no differences in gestational age, gender or age (median age was 5 and 7 months, respectively) between groups. We found no difference in rates of vaccination, upper respiratory symptoms, cough, wheezing, crackles, increased work of breathing or peripheral white blood cell count at presentation. In addition, we found no differences in antibacterial use or length of antimicrobial therapy during hospitalization. Native American children had a statistically significant higher length of hospitalization (P = 0.01) as well as days of oxygen supplementation (mean 4.9 vs. 3 days; P = 0.006) compared with non-native Americans. Furthermore, Native American children had a significantly higher percentage of PICU admissions (28% vs. 10.4%; P = 0.008) as well as intubation rate (26% vs. 8%; P = 0.04) compared with non-native Americans.

Conclusion
Native American children had increased length of hospitalization associated with severe illness including longer oxygen supplementation, higher PICU admission rate and need for mechanical ventilatory support.

Disclosures
All authors: No reported disclosures.
158. Invasive Group B Streptococcal Diseases in Adults: A Retrospective Study in Thailand (2013–2017)
Authors: Angkasekwinai Nasikarn , Pirogard Nantaporn , Phoompoung Pakpoom , Leelaporn Amornrut 
Published: October 2019

Abstract

Background
Group B Streptococcus (GBS) has been increasingly associated with invasive diseases in nonpregnant adults. This study aims to describe the epidemiology of invasive GBS (iGBS) diseases in adult patients.

Methods
A retrospective cohort study was conducted at Siriraj Hospital between January 1, 2013 and December 31, 2017. We included adult patients with a positive culture of GBS isolated from sterile sites.

Results
Among 224 patients recruited to the study, 170 patients (75.9%) had bacteremia. The median age of all patients was 63 years (IQR 53–73 years) and 52.7% were female. Approximately 80% of all patients had comorbid diseases. Diabetes mellitus (38.8%), cancer (18.8%) and heart disease (12.5%) were the three most common comorbidities. Skin and soft-tissue infection (30.8%), septic arthritis (21.4%), primary bacteremia (21%), and meningitis (7.1%) were the four most common presenting syndrome of iGBS diseases. Overall mortality within 30 days of infection was 12%. Non-survived patients were older, had chronic kidney disease, bacteremia, pneumonia and had at least one comorbidity than survived patients. However, only pneumonia was found independently associated with the 30-day overall mortality, with adjusted odd ratio (aOR) of 24.96 (95% confidence interval [CI]: 5.95–104.75). Antimicrobial susceptibility testing of 69 isolates demonstrated that 7 (10%) and 9 (13%) were resistant to erythromycin and clindamycin, respectively. All isolates remain susceptible to penicillin.

Conclusion
Invasive GBS is an emerging disease in non-pregnant adults particularly in elderly and diabetes mellitus patients. Two-thirds of iGBS patients have concomittant bacteremia. Even though the overall mortality was 12% but a significant morbidity was observed.

Disclosures
All authors: No reported disclosures.
2657. Clinical Prediction Tool for Multidrug-Resistant Organisms Among Deceased Donors at the Time of Donor Evaluation
Authors: Anesi Judith A , Anesi Judith A , Blumberg Emily , Han Jennifer , Lee Dong Heun , Clauss Heather , Climaco Antonette , Hasz Richard , Molnar Esther , Alimenti Darcy , West Sharon , Bilker Warren , Tolomeo Pam C , Lautenbach Ebbing 
Published: October 2019

Abstract

Background
Transplant guidelines recommend exercising caution when considering organs that may be infected or colonized with multidrug-resistant organisms (MDROs) and treating the organ recipient with perioperative antibiotics active against the donor MDRO. Unfortunately, donor MDROs are often identified only after transplantation. We developed a clinical prediction tool to stratify donors’ MDRO risk at the time of donor evaluation.

Methods
A retrospective cohort study was conducted at four transplant centers in Philadelphia between January1, 2015 and June 30, 2016. All deceased organ donors who donated ≥1 organ to one of the centers were included. Multivariate logistic regression was used to determine predictors of donor MDROs, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum cephalosporin-resistant (ESC-R) or carbapenem-resistant Enterobacteriaceae, multidrug-resistant (MDR) P. aeruginosa, or MDR Acinetobacter species. Manual forward selection was utilized to maximize the area under the receiver operating characteristic curve (AUC). A scoring system was developed based on the odds ratios for each covariate. Internal validity was assessed using the Hosmer–Lemeshow statistic, specificity, and negative predictive value (NPV).

Results
Of 440 total donors, 62 (14%) grew MDROs on culture. The majority were MRSA (40) or ESC-R Enterobacteriaceae (20). The most parsimonious model that predicted donor MDROs included: a terminal hospitalization ≥ 7 days (1 point), ≥ 2 antibiotics administered during the terminal hospitalization (1 point), receipt of extracorporeal membrane oxygenation (ECMO) (1 point), and presence of opacities on donor chest imaging concerning for lower respiratory tract infection (2 points). With this scoring system, the maximum attainable score is 5; any donor with a score of ≥ 2 points would be considered high risk for an MDRO, with an AUC of 0.71, specificity of 99%, and NPV of 86%. The Hosmer–Lemeshow P = 0.68.

Conclusion
The risk of an MDRO among deceased organ donors can be predicted using the above scoring system. This tool will inform decisions about organ utilization and perioperative prophylaxis for solid-organ transplant recipients.

Disclosures
All authors: No reported disclosures.
2667. Does Ceftazidime–Avibactam (CAZ-AVI) Improve Short- and Long-Term Outcomes Among Solid-Organ Transplant (SOT) Recipients with Carbapenem-Resistant Enterobacteriaceae (CRE) Infections?
Authors: Sun Jonathan , Clancy Cornelius J , Shields Ryan K , Nguyen Minh-Hong 
Published: October 2019

Abstract

Background
SOT recipients are an ideal population in which to study the impact of new antibiotics, since they are particularly dependent upon drug activity to clear infections. In 3/15, FDA approved CAZ-AVI, the first new anti-CRE agent to arrive in the clinic. Our objective was to determine whether CAZ-AVI improves short- and long-term outcomes of CRE-infected SOT recipients.

Methods
We performed a retrospective study of SOT recipients infected with CRE since 2012, who were treated with CAZ-AVI or salvage agents for ≥ 3 days.

Results
35 CRE-infected SOT recipients (14 liver, 11 lung, 6 kidney, 3 intestine, 1 heart) with bacteremia (20), pneumonia (11), intra-abdominal abscess (3) and soft-tissue infection/osteomyelitis (1) were enrolled. 16 and 19 patients (pts) were treated with CAZ-AVI and salvage agents, respectively. Types of infection or SOT, APACHE II and McCabe scores did not differ significantly between patients treated with CAZ-AVI or salvage agents. 30- and 90-d mortality rates were significantly lower among SOT recipients treated with CAZ-AVI (0% and 6%, respectively) compared with salvage agents (26% and 37%; P = 0.049 and 0.047). Among patients who survived 90 days, recurrent CRE infections were diagnosed in 53% and 17% of those treated with CAZ-AVI and a salvage regimen, respectively (P = 0.10). Median time from end of therapy for the 1st CRE infection to recurrent infection was 116 days (max 1,242) and 361 days (max 799) for CAZ-AVI and salvage regimens, respectively. Survival and recurrence-free survival were greater for treatment with CAZ-AVI and salvage agents, respectively, as measured by Kaplan–Meier (Figures). CAZ-AVI resistance developed in 37% (n = 3) of patients with recurrent infections. Recurrent isolates were genetically indistinguishable from parent isolates by core genome SNP phylogeny (< 15 SNP).

Conclusion
CAZ-AVI significantly reduced short-term mortality among SOT recipients with CRE infections compared with salvage regimens, but was limited by recurrent infections and emergence of resistance. The same strains caused recurrent and initial infections, suggesting that CAZ-AVI did not eliminate CRE from GI sites that serve as sources of recurrence. Optimizing outcomes in SOT recipients with CRE infections will require new agents like CAZ-AVI, and strategies to eliminate long-term colonization.

Disclosures
All authors: No reported disclosures.
2679. Factors Associated with Multidrug-resistant Gram-Negative Bacteremia in Acute Leukemia Patients with Neutropenic Fever, a Retrospective Study
Authors: Chaiittiporn Dudrudee , Prasongdee Klaorat , Kongkiatkamon Sunisa , Jutivorakool Kamonwan , Vanichanan Jakapat 
Published: October 2019

Abstract

Background
Gram--negative bacteremia in acute leukemia patients with neutropenia is associated with high morbidity and mortality rate. Appropriate antibiotic for empirical treatment is crucial; however, antibiotic selection is challenging especially in setting with high prevalence of infections with multidrug-resistant (MDR) organisms. Data on associated factors of MDR Gram-negative bacteremia in this population is limited.

Methods
A retrospective study was conducted in King Chulalongkorn Hospital, Bangkok, Thailand. Medical records of patients aged ≥15 years with acute leukemia who were hospitalized in our institute and had neutropenic fever between 1 January 2001 and 31 December 2016 were reviewed. Demographic data, causative organisms, treatment and outcomes were documented. Episodes of MDR Gram-negative bacteremia were compared with non-MDR group. Associated risk factor was assessed by multivariate logistic regression

Results
From total 405 admission records of 227 acute leukemia patients, 587 episodes of neutropenic fever occurred with 131 episodes of Gram-negative bacteremia. Majority (81.68%) were bacteremia without source of infection. Most common causative pathogens were E. coli, P. aeruginosa and K. pneumoniae, respectively. Sixty episodes of Gram-negative bacteremia (53.57%) were caused by MDR pathogen. Associated factor for MDR Gram-negative bacteremia was prior colonization or infection with MDR Gram-negative bacteria within 3 months (P = 0.049). Subgroup analysis in patients with non-lactose fermenter bacteremia showed higher rate of intensive care unit (ICU) admission and in-hospital death in MDR group (P = 0.03 and P = 0.004).

Conclusion
Prior colonization or infection by MDR Gram-negative bacteria within 3 months was associated with MDR Gram-negative bacteremia in acute leukemia patients with neutropenic fever. Thoroughly review of previous culture data and active screening for colonization may increase chance of appropriate empirical antibiotics.

Disclosures
All authors: No reported disclosures.
2696. Breakthrough Toxoplasmosis While on Atovaquone Prophylaxis Following Allogeneic Hematologic Stem Cell Transplantation
Authors: Chueng Teresa A , Raja Mohammed A , Morris Michele I , Komanduri Krishna V , Camargo Jose F 
Published: October 2019

Abstract

Background
The opportunistic parasite Toxoplasma causes life-threatening complications in immunocompromised hosts such as hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the agent of choice in preventing Pneumocystis jirovecii pneumonia and Toxoplasma, but bone marrow suppression often precludes its use. Broad-spectrum atovaquone also targets protozoan tachyzoite and cyst forms, but few studies examine its efficacy in prophylaxis among this vulnerable population. We present two HCT patients experiencing breakthrough toxoplasmosis despite compliance with atovaquone prophylaxis.

Methods
Review of literature and electronic medical records.

Results
Case 1. A 68-year-oldToxoplasma seropositive woman with myelodysplastic syndrome underwent Flu-Mel-ATG-matched unrelated donor HCT. On day +68 post HCT, she presented with encephalopathy. MRI brain revealed solid and ring-enhancing lesions correlating with positive CSF T. gondii PCR. Serum DNA PCR was negative. She received 12 weeks of sulfadiazine, pyrimethamine, and leucovorin with clinical and radiological improvement. Atovaquone prophylaxis was restarted given pancytopenia intolerance of TMP-SMX. Despite compliance, she experienced recurrent central nervous system toxoplasmosis. Her demise followed an unrelated ischemic cerebrovascular accident. Case 2. A 53-year-old Toxoplasma seropositive woman with CMV viremia and severe aplastic anemia limiting TMP-SMX use presented with pancytopenia on day +46 after HCT. Diagnosed with graft failure, routine screening revealed positive Toxoplasma PCR while on atovaquone prophylaxis. Toxoplasma PCR became negative after preemptive therapy. She underwent a second Flu-Cy-ATG-TBI-matched related donor HCT. 2 months later, medication noncompliance led to readmission with CMV viremia and culture-negative sepsis. Blood Toxoplasma PCR was positive at the time of death.

Conclusion
Toxoplasmosis prophylaxis failure can occur in allogeneic HCT recipients receiving atovaquone. When possible, TMP-SMX should remain first-line agent for this indication. In those unable to tolerate TMP-SMX, close clinical and Toxoplasma PCR monitoring may help identify reactivation and facilitate early initiation of therapy.

Disclosures
All authors: No reported disclosures.
2711. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in Older Adults
Authors: Lewis Ned , Hsiao Amber , Hansen John , Yee Arnold , Chao Charlie , Suaya Jose A , Alexander-Parrish Ronika , Isturiz Raul E , McLaughlin John M , Gessner Bradford D , Klein Nicola 
Published: October 2019

Abstract

Background
Routine use of 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for infants since early 2010 and for adults ≥65 years since 2014 when KPNC began routine use of PCV13 in adults. PCV13 vaccine effectiveness (VE) against vaccine-type invasive pneumococcal disease (IPD) has been demonstrated; however, recent surveillance data have been interpreted as showing limited population-level impact of PCV13 on serotype 3 IPD. We estimated PCV13 VE against IPD due to vaccine serotypes at Kaiser Permanente Northern California (KPNC).

Methods
The study period spanned September 2014 through September 2018. The cohort included KPNC members who were aged ≥65 years with no record of pneumococcal polysaccharide vaccine (PPV23) receipt before age 65 years. We compared IPD cases with KPNC members who were the same age on the date of the positive pneumococcal culture using conditional logistic regression, conditioned on age and date, and controlled for sex, race, KPNC service area and membership history, prior season influenza vaccine receipt, PPV23 receipt after age 65 years, risk factors for IPD, and healthcare utilization.

Results
From September 2014 to September 2018, PCV13 vaccine coverage among persons ≥65 years old increased from < 1% to 77%. During the same period, there was a total of 245 IPD cases. For a variety of reasons, we did not have serotype results for 57 (23%) IPD cases, which were excluded from the analysis. There were 61 (25%) PCV13-type IPD cases included in the analysis, of which 33 (14%) were serotype 3. PCV13 VE against PCV13-type serotypes was 68.0% (95% CI: 37.7%, 83.6%; P-value < 0.01), and 53.4% (95% CI: −10.0%, 80.3%; P = 0.08) against serotype 3.

Conclusion
During the first 4 years of PCV13 vaccination implementation in adults ≥65 years of age at KPNC, PCV13 provided significant protection against PCV13-type IPD. Further surveillance will allow for more precise estimation of PCV13 VE on overall and serotype 3 IPD over time.

Disclosures
All authors: No reported disclosures.