bluuebunny/crossref_metadata_2025_split huggingface dataset:
97. Competition Experiments for the Baloxavir-Resistant I38T Influenza A Mutant
Authors: Checkmahomed Liva , Mhamdi Zeineb , Carbonneau Julie , Baz Mariana , Abed Yacine , Boivin Guy 
Published: October 2019

Abstract

Background
Baloxavir marboxil (BXM), a cap-dependent endonuclease inhibitor, has been recently approved in the United States for the treatment of influenza infections. It is superior to oseltamivir for reducing the time of viral shedding but is reported to have a low barrier of resistance. We sought to evaluate the viral fitness of the predominant BXM-resistant I38T PA mutant in the A/H1N1 and A/H3N2 viral backgrounds.

Methods
Recombinant A/Quebec/144147/2009 (H1N1) and A/Switzerland/9715293/2013 (H3N2) influenza viruses and their respective I38T PA mutants were generated by reverse genetics. Standardized inoculums (500 PFUs) of wild-type (WT) and mutant mixtures were inoculated on α2,6 MDCK cells. On day 3 post-infection (pi), the supernatants were collected and the ratios of WT/mutant viruses were determined by droplet digital PCR using specific LNA probes. Single infections and competitive experiments were also performed in C56/BL6 mice with quantification of lung viral titers on days 3 and 6 pi.

Results
In vitro A/H1N1 studies showed similar total copy numbers for the WT and mutant viruses on day 3 pi (1.2 × 109 and 1.3 × 109 copies/mL, respectively). The initial 50%/50% mixture became 70%/30% (WT/mutant) after one passage in cells. For A/H3N2, the total copy numbers were 8.1 × 109 and 1.0 × 109 copies/mL for the WT and mutant viruses. The initial 50%/50% mixture became 94%/6% (WT/mutant) after one passage. The I38T mutants remained stable after 4 passages in α2,6 MDCK cells. In mice, the A/H1N1 WT and I38T mutant induced similar weight loss and generated comparable lung titers on days 3 and 6 pi. In contrast, the weight loss of the A/H3N2 mutant was greater than that of the WT between days 3 and 7 pi with comparable lung titers on days 3 and 6. Following infection with 50%/50% mixtures, the mutant virus predominated over the WT on day 3 pi (73% A/H1N1 and 58% A/H3N2).

Conclusion
The BXM-resistant I38T PA mutant replicates well both in vitro and in vivo in the A/H1N1 and A/H3N2 backgrounds. Surveillance for the emergence and transmission of such mutant in the community is required.

Disclosures
All Authors: No reported Disclosures.
850. Outcomes of Patients Discharged on Parenteral Ceftriaxone Compared with Oxacillin or Cefazolin in Methicillin-susceptible Staphylococcal aureus (MSSA) Bloodstream Infections
Authors: Erik Connor Lee , Hamad Yasir , George Ige 
Published: October 2019

Abstract

Background
MSSA is a leading cause of bloodstream infection (BSI) and its incidence is on the rise. Standard of care (SOC) is prolonged parenteral therapy with nafcillin, oxacillin, or cefazolin. Ceftriaxone is active against MSSA and can be given conveniently as a daily infusion.

Methods
We conducted a retrospective analysis of hospitalized adults with MSSA BSI from December 2014 to May 2018, defined as ≥1 blood cultures positive for MSSA and discharged on outpatient parenteral antimicrobial therapy (OPAT) on either ceftriaxone, cefazolin, or oxacillin. We excluded patients with ESRD and polymicrobial infections. We collected demographics, comorbidities, outcome data, and treatment-related adverse events. The primary outcome was 90-day mortality with secondary outcomes of clinical failure and microbiologic failure. Clinical failure was defined as readmission for any infection within 90 days of discharge or a change in antibiotics from the planned course of therapy after discharge. Microbiologic failure was defined as reinfection with MSSA within 90 days of discharge from any site.

Results
In total, 167 patients had a BSI with MSSA. Of those patients, 66 (39.5%) were discharged on SOC and 101 (60.5%) on ceftriaxone. The two groups were similar in terms of their demographics (Table 1). The SOC group had more cases of endocarditis with 34 (51.5%) than ceftriaxone with 25 (24.8%) (P = 0.001). LOS for the SOC group had a median of 14.05 days whereas the ceftriaxone group had a median length of stay of 7.88 (P = 0.004). In the SOC group, 5 (7.6%) patients died compared with 8 (7.9%) patients in the ceftriaxone group within 90 days of the onset of bacteremia which was not statistically significant (P = 0.94) (Figure 1). There were 4 (6.1%) cases of microbiologic failure in SOC and 7 (6.9%) cases in the ceftriaxone group (P = 0.83). For clinical failures, the SOC had 6 (9.1%) cases compared with the 19 (18.8%) cases in the ceftriaxone group (P = 0.13).

Conclusion
Ceftriaxone was not statistically different when compared with SOC in terms of mortality, microbiologic failure, or clinical failure. Though clinical failures numerically were more frequent in the ceftriaxone group. Ceftriaxone maybe a reasonable and convenient option to SOC for patients with uncomplicated MSSA BSI discharged on OPAT, but further studies are needed.

Disclosures
All Authors: No reported Disclosures.
852. The Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children: Does It Matter?
Authors: McNeil Jonathan C , Sommer Lauren , Boyle Mary G , G. Hogan Patrick , G. Vallejo Jesus , Hulten Kristina G , Kaplan Sheldon L , Fritz Stephanie 
Published: October 2019

Abstract

Background
Select methicillin-susceptible Staphylococcus aureus (MSSA) strains may produce β-lactamases with an affinity for first-generation cephalosporins (1GC). In the setting of a high inoculum, these β-lactamases may promote clinically meaningful cleavage of 1GCs, potentially resulting in antibiotic failure, a phenomenon known as the cefazolin inoculum effect (CIE). Acute hematogenous osteoarticular infections (AHOAIs, including osteomyelitis and septic arthritis) are the most common manifestation of invasive S. aureus infection in children. We evaluated the prevalence and potential impact of CIE among MSSA AHOAI isolates at two children’s hospitals.

Methods
MSSA AHOAI isolates were obtained through surveillance studies at Texas Children’s and St. Louis Children’s Hospitals from January 2011 to December 2018. Isolates were tested for CIE via a macrobroth dilution assay with an inoculum of 107 CFU/mL; CIE was defined as a cefazolin MIC ≥16 µg/mL. Isolates were characterized by accessary gene regulator group (agr). The subsequent development of chronic osteomyelitis (CO) was regarded as a clinically important outcome.

Results
A total of 287 cases were included and the median patient age was 8.6 years. 14.3% of isolates exhibited CIE; CIE prevalence was similar across study sites. 74.6% of patients received a 1GC as definitive therapy. CIE isolates were more often resistant to clindamycin, belonged to agr III and associated with CO (Figure 1); a numerically higher rate of CO was observed with CIE isolates regardless of definitive antibiotic choice (Figure 2). In multivariable analyses, bone abscesses, agr III, positive blood cultures, multiple surgeries, and delayed source control but not CIE were independently associated with CO (Figure 3); similar results were seen if analyses were restricted to only those receiving 1GC.

Conclusion
CIE is exhibited by 14.3% of MSSA AHOAI isolates in children. CIE is associated with agr III and clindamycin-resistant strains. agr III strains are independently associated with CO; thus negative outcomes reported with CIE may more accurately reflect strain-dependent virulence factors rather than true antibiotic failure. Further studies are necessary to better understand the clinical significance of these findings.

Disclosures
All Authors: No reported Disclosures.
856. Invasive Haemophilus influenzae Disease in Children: A Canadian MultiCenter Study on Emerging Serotypes
Authors: Frankel Craig , Alghounaim Mohammad , McDonald Jane , Gunawan John , Robinson Joan , Khan Sarah , Wong Jacqueline K , Lopez Alison , Fanella Sergio , Comeau Jeannette L , Bowes Jennifer , Slinger Robert , Kalia Angela , Roberts Ashley , Leifso Kirk , Barton Michelle 
Published: October 2019

Abstract

Background
Our objective was to describe the serotype distribution and clinical spectrum of invasive Haemophilus influenza (Hi) disease in children admitted to participating centers within the Paediatric Investigator’s Collaborative Network on Infections in Canada (PICNIC).

Methods
All cases of Hi bacteremia were identified from the PICNIC Database of Gram-negative bacteremia (2013–2017). Disease was defined as complicated if the following occurred: (a) >2 sites were affected, (b) surgical intervention was required, (c) organ failure, (d) ICU admission, (e) seizures, (f) sensory or motor deficits, (g) treatment-related complications, or (h) death.

Results
There were 98 cases of Hi bacteremia. Male to female ratio was 64:34 and median age was 12 (IQR: 7–48; range 0–216) months. Hi serotypes included: a (N = 31; 32%), b (N = 9; 9%), f (N = 15; 13%), c (N = 1;1%), e (N = 1; 1%), nontypeable (N = 34; 35%) and unknown (N = 7; 7%). Clinical foci included: bacteremia without a focus (N = 19; 19%), meningitis (N = 29; 30%), cellulitis (N = 8; 8%), septic arthritis (N = 6; 6%), pneumonia (n = 33; 34%), epiglottitis (N = 1; 1%), and endovascular infection (n = 3; 3%). Complicated disease occurred in 29 (30%) cases; there was one (1%) death. Where serotyping was available, complication rates were: 42%, 22%, 100%, 0%, 33%, and 21% for Hia, Hib, Hic, Hie, Hif and nontypeable Hi, respectively. Factors associated with complicated disease were: age <5 years (P = 0.009), bacteremia without a focus (P = 0.006) and a CNS focus (P < 0.001). Hia was the leading serotype in meningitis (55%; P = 0.022). Nontypeable Hi was most frequent in pneumonia cases (56%; P = 0.003) and never caused cellulitis (0% vs. 14%; P = 0.023). Neonatal disease (N = 5) was predominantly caused by nontypeable Hi (80%; P = 0.040). Of note, 26 (27%) of our Hi isolates were ampicillin resistant.

Conclusion
In the era of efficacious conjugate Hib vaccines, serotype has emerged as the leading cause of typeable Hi disease in Canada and is highly associated with meningitis, especially in young children. Strategies for preventing Hi disease need to target this emerging serotype and efforts should be focused toward developing an effective vaccine for serotype a disease.

Disclosures
All Authors: No reported Disclosures.
888. Impact of Mandatory Infectious Diseases Consult on All-cause In-patient Mortality and 30-Day Readmission in Patients with Severe Sepsis
Authors: Hou Cindy , Levin Todd P , Vyas Nikunj M , Deangelo Stefanie , Klepka Jean , Piotrowicz Dawne 
Published: October 2019

Abstract

Background
Severe sepsis is associated with high mortality and readmission rates. Infectious diseases (ID) consultations (IDC) improve clinical outcomes in patients with severe infections. In March 2016, a mandatory ID consultation (MIDC) policy for this patient population was implemented. This study’s goal was to determine the impact of MIDC on clinical outcomes.

Methods
In efforts to reduce mortality and complications from sepsis at our institution, multidisciplinary intervention led to a policy for MIDC for patients with sepsis. This intervention was monitored daily by the clinical initiatives team to ensure compliance. We conducted a retrospective chart review of patients with severe sepsis from all sources in Pre-MIDC group from January 2015 to February 2016 and Post-MIDC group from March 2016 to December 2017. The primary endpoint of the study was to evaluate the impact of MIDC on all-cause inpatient mortality (ACIM) and 30-day readmission in patients with severe sepsis. Secondary endpoint focused on the impact of MIDC on time to IDC and patient seen by ID physician. Subgroup analysis evaluated the impact of early vs. late IDC on ACIM.

Results
There was a total of 511 patients in Pre-MIDC and 635 patients in Post-MIDC groups. No differences were seen in the demographics between the groups. Overall a difference was not seen in ACIM between the two groups (9.2% vs. 8%, P = 0.52); however, Post-MIDC group had lower rates of 30-day readmission due to sepsis/infection (12.1% vs. 4.9%, P = 0.01) and shorter length of stay (8.5 vs. 6.7 days, P = 0.001). We did observe an association with early IDC from admission to a decrease in ACIM compared with late IDC (7.8% vs. 9.4%, P = 0.03). Times to IDC from admission (33.5 hours vs. 16.75 hours, P = 0.001) and patient seen by ID physician from time of IDC order (23 hours vs. 8.75 hours, P = 0.0001) was faster in Post-MIDC group. A decline was observed in sepsis mortality by 16% since MIDC implementation compared with Pre-MIDC.

Conclusion
Implementation of MIDC led to faster time to IDC and patients seen by ID physicians which was directly associated with a decrease in ACIM. MIDC did not show a difference in overall ACIM; however, it decreased 30-day readmission due to sepsis/infection and shorter LOS. We also observed a consistent decline in overall sepsis mortality through this intervention.

Disclosures
All Authors: No reported Disclosures.
892. Risk Factors for Adverse Events in Children Receiving Outpatient Antibiotic Therapy
Authors: Gillon Jessica , Townsley Elizabeth , Jimenez-Truque Natalia , Garguilo Kathryn , Banerjee Ritu , Banerjee Ritu 
Published: October 2019

Abstract

Background
Outpatient parenteral antibiotic therapy (OPAT) can decrease the length of hospital stay but is associated with adverse events (AEs). The purpose of this study was to quantify and identify risk factors for OPAT-associated AEs in children.

Methods
This is a retrospective, single-center study of patients aged ≤21 years discharged on OPAT from January 2016 to April 2019. Only patients with OPAT overseen by the infectious disease service were included. Medication AE’s included: rash, neutropenia, hepatitis, diarrhea, C. difficile infection, increased serum creatinine, or others. Central line AEs included: central line dysfunction, infection, rash around line site, or other. Wilcoxon rank-sum test, Pearson’s χ2 test, Fisher’s exact test, and multivariable logistic regression models were used for analyses.

Results
Demographic information can be found in Table 1. Among 176 patients included in the study, an AE occurred in 69 (39%). In a multivariable logistic regression model adjusting for age, county of residence, duration of OPAT, and duration line was in place, each additional day of antibiotics increased the odds of having a medication or line-related AE by 3% (OR 1.03; 95% CI 1.01–1.06; P = 0.005; Table 2). Medication AEs occurred in 30 patients (17%). The most frequent medication AEs were neutropenia (24%), rash (15%), and increased liver function tests (15%). Patients residing in a Large Fringe Metro area (suburb) had 33% lower odds of having a drug-related AE compared with those in a Large Central Metro area (OR 0.67; 95% CI 0.50 to 0.90; P = 0.008). Line AEs occurred in 46 patients (26%), with 10 patients (21%) experiencing >1 line AE. The most common line AEs were line malfunction (56.5%) and line infection (13%). Seven patients experienced both a medication AE and a central line AE. Of the 176 patients, 20 (11%) were readmitted to the hospital due to medication or line AE and an additional 25 (14%) had a healthcare visit for an AE although did not require admission.

Conclusion
In our region, nearly 40% of children experienced an OPAT-associated AE and line AEs were more common than medication AEs. Longer durations of IV therapy was an independent risk factor for AEs. Converting to oral antibiotic therapy as soon as feasible may reduce OPAT-associated AEs.

Disclosures
Ritu Banerjee, MD, PhD, Accelerate Diagnostics: Grant/Research Support; BioFire: Research Grant; Biomerieux: Research Grant; Roche: Research Grant.
964. Journey to Zero Harm: Eliminating Catheter-Associated Urinary Tract Infections (CAUTIs) for 12 Consecutive Months at Two Community Hospitals
Authors: Girio-Herrera Leonardo , Clay Colleen M , Younus Faheem , Ahmed Zafir , Zimand Paul 
Published: October 2019

Abstract

Background
Many US hospitals have implemented CAUTI prevention bundles (CPB) but few have achieved the goal of zero CAUTIs for 12 consecutive months. We report our journey to zero harm at two community hospitals that have each successfully eliminated CAUTIs from all their units, including the intensive care unit (ICU), for over 12 consecutive months.

Methods
From April 2015 to March 17 (Period A), CPB was implemented at University of Maryland-Upper Chesapeake Medical Center (UM-UCMC) and University of Maryland-Harford Memorial Hospital (UM-HMH), each with 195 and 128 beds, respectively. UM-UCMC has a 15-bed ICU while UM-HMH has a 5-bed ICU. The CPB included placement of urinary catheters only for approved indications, use of two persons (buddy system) for catheter insertion, Nurse Driven Protocol for catheter removal, and silver-impregnated cloths for perineal care. A massive frontline engagement campaign “You can’t have a CAUTI if you don’t have a foley” was launched from April 2017 to March 2019 (Period B). The focus was intensified on reducing catheter utilization rates. Real-time feedback on new CAUTIs cases was provided to leadership at the daily safety briefs and to nurses and physicians at the unit-based huddles. The number of CAUTIs and “days without a CAUTI” was shared with team members via small posters and whiteboards.

Results
A statistically significant decrease in utilization of urinary catheters was observed (Table 1). Both hospitals and their respective ICUs remained CAUTI free for >12-consecutive months (Figure 1).

Conclusion
Eliminating CAUTIs for 12 consecutive months in acute care community hospitals is possible and serves as a step toward the journey to zero harm. Reducing catheter utilization is a key strategy. Humanizing each infection and providing real-time feedback to the frontline staff and leadership in whole numbers (instead of the old paradigm of reporting CAUTI rates) may have resulted in greater engagement.

Disclosures
All Authors: No reported Disclosures.
974. PD-1 Immune Checkpoint Blockade Improves Survival and Promotes Fungal Clearance in an Immunosuppressed Murine Invasive Pulmonary Aspergillosis (IPA) Model
Authors: Wurster Sebastian , Robinson Prema , Albert Nathaniel D , Lionakis Michail S , Kontoyiannis Dimitrios P 
Published: October 2019

Abstract

Background
Checkpoint blockade (CPB) has brought a revolution in modern oncology and may offer new strategies for antifungal immunotherapy. In vitro studies have demonstrated that blockade of the PD-1/PDL-1 interaction increased IFN-γ secretion in response to Aspergillus antigens, suggesting a potential role for anti-PD-1 therapy in promoting anti-Aspergillus immunity. We sought to evaluate the therapeutic efficacy of low-dose anti-PD-1 therapy in a murine IPA model.

Methods
Eight- to twelve-week-old female BALB/c mice were immunosuppressed with cyclophosphamide and cortisone acetate and infected intra-nasally with 5 × 104 of A. fumigatus Af293 conidia (panel A). Mice were then treated intraperitoneally with 4 doses of either 200 µL PBS (PBS control), 250 µg/kg BW IgG antibody (isotype control), or a monoclonal PD-1 antibody (anti-PD-1). Survival was monitored daily until day 8 post-infection. 24–28 mice per treatment were assessed in 3 independent experiments. Pulmonary fungal burden was determined by 18S qPCR either on day 8 post-infection or upon death. Additional mice were sacrificed on day 1 and 4 post-infection to assess serum concentrations of selected cytokines by ELISA.

Results
Infected mice receiving treatment with either PBS or the isotype antibody exhibited 8 day survival rates of 33% and 36%, respectively. In contrast, 68% of the mice in the PD-1 antibody treatment group survived (panel B). Accordingly, pulmonary fungal burden was significantly reduced in anti-PD-1 vs. isotype-treated infected mice (median spore equivalent: 0.39 vs. 2.06 × 109, P = 0.015). No signs of toxicity or early mortality were seen in anti-PD-1-treated mice, and no elevated serum levels of pro-inflammatory cytokines TNF-α and INF-γ were found in those mice (compared with isotype-treated infected mice).

Conclusion
We found that anti-PD-1 immune checkpoint blockade has independent beneficial effects in untreated immunosuppressed mice with IPA. We are in the process of measuring pulmonary cytokines to deepen our understanding of protective anti-Aspergillus immunity conferred by low-dose CPB. In addition, future studies would address the combined application of CPB and conventional antifungal drugs that have immune-regulatory activity such as echinocandins.

Disclosures
All Authors: No reported Disclosures.
1823. Incidence of Meningoencephalitis in the Absence of CSF Pleocytosis
Authors: Upadhyayula Shankar 
Published: October 2019

Abstract

Background
Cerebrospinal fluid (CSF) pleocytosis, defined here as ≥5 white blood cells (WBC)/high power field (HPF) suggests inflammation of brain parenchyma /meninges or both. However, the absence of pleocytosis does not rule out meningoencephalitis. The frequency with which infectious targets are identified in the absence of CSF pleocytosis is not well known. Traditional diagnostic methods based on culture and single target polymerase chain reaction (PCR) assay were inadequate to answer this question. However, the availability of multiplex (PCR) panels opens up the opportunity.

Methods
Starting June of 2016 Akron children’s hospital adopted the Biofire® Meningitis encephalitis panel (MEP). The panel is run routinely on all CSF specimens obtained from patients presenting with a clinical picture consistent with meningoencephalitis irrespective of their CSF biochemistry and cell count Results. We retrospectively collected laboratory data for all the MEP positive patients. The data were filtered based on CSF WBC count, pathogens identified as well as by patient age.

Results
A total of 133 positive results were identified from June 2016 to March 2019. Due to unclear significance, 22 positive Human herpes virus (HHV) 6 results were excluded, One VZV positive result was also excluded (Figure 1). Of the remaining 110 positives, 29% had CSF WBC count < 5/HPF. Parecho and Enterovirus were the most common. Three isolates were positive for Herpes simplex 1 (HSV 1) and one for Herpes simplex 2 (HSV 2). Haemophilus influenzae was detected in one patient (Figure 2).

Conclusion
Our observations suggest that viral meningoencephalitis may occur frequently in the absence of CSF pleocytosis. Bacterial meningitis seems less likely. Several centers have a policy to restrict multiplex PCR panel testing based on CSF WBC cut-offs, citing increased costs. However, this approach may lead to missed diagnosis. As a direct result of this additional investigations and/or treatment may be pursued leading to increased overall costs as well as exposing the patient to potential harm. Additionally making a diagnosis could lend itself to monitoring outcomes—an area where there is paucity of high-quality data.

Disclosures
All Authors: No reported Disclosures.