bluuebunny/crossref_metadata_2025 huggingface dataset:
Binary outflows from young stars: interaction of co-orbital jet and wind
Authors: Lynch Chris J R , Smith Michael D , Glover Simon C O
Published: October 2019

Jets from young stellar objects provide insight into the workings of the beating heart at the centre of star forming cores. In some cases, multiple pulsed outflows are detected such as the atomic and molecular jets from a proposed binary system in the T Tauri star HH 30. We investigate here the development and propagation of duelling atomic and molecular outflows stemming from the two stars in co-orbit. We perform a series of numerical experiments with the ZEUS-MP code with enhanced cooling and chemistry modules. The aim of this work is to identify signatures on scales of order 100 AU. The jet sources are off the grid domain and so it is the propagation and interaction from ∼ 20 AU out to 100 AU simulated here. We find that the molecular flow from the orbiting source significantly disturbs the atomic jet, deflecting and twisting the jet and disrupting the jet knots. Regions of high ionisation are generated as the atomic jet rams through the dense molecular outflow. Synthetic images in atomic and molecular lines are presented which demonstrate identifying signatures. In particular, the structure within the atomic jet is lost and Hα may trace the walls of the present CO cavity or where the walls have been recently. These results provide a framework for the interpretation of upcoming high resolution observations.
‘Drc’, a structurally novel ssDNA-binding transcription regulator of N4-related bacterial viruses
Authors: Boon Maarten , De Zitter Elke , De Smet Jeroen , Wagemans Jeroen , Voet Marleen , Pennemann Friederike L , Schalck Thomas , Kuznedelov Konstantin , Severinov Konstantin , Van Meervelt Luc , De Maeyer Marc , Lavigne Rob
Published: October 2019

Bacterial viruses encode a vast number of ORFan genes that lack similarity to any other known proteins. Here, we present a 2.20 Å crystal structure of N4-related Pseudomonas virus LUZ7 ORFan gp14, and elucidate its function. We demonstrate that gp14, termed here as Drc (ssDNA-binding RNA Polymerase Cofactor), preferentially binds single-stranded DNA, yet contains a structural fold distinct from other ssDNA-binding proteins (SSBs). By comparison with other SSB folds and creation of truncation and amino acid substitution mutants, we provide the first evidence for the binding mechanism of this unique fold. From a biological perspective, Drc interacts with the phage-encoded RNA Polymerase complex (RNAPII), implying a functional role as an SSB required for the transition from early to middle gene transcription during phage infection. Similar to the coliphage N4 gp2 protein, Drc likely binds locally unwound middle promoters and recruits the phage RNA polymerase. However, unlike gp2, Drc does not seem to need an additional cofactor for promoter melting. A comparison among N4-related phage genera highlights the evolutionary diversity of SSB proteins in an otherwise conserved transcription regulation mechanism.
Ring-shaped replicative helicase encircles double-stranded DNA during unwinding
Authors: Joo Sihwa , Chung Bong H , Lee Mina , Ha Tai H
Published: October 2019

Ring-shaped replicative helicases are hexameric and play a key role in cellular DNA replication. Despite their importance, our understanding of the unwinding mechanism of replicative helicases is far from perfect. Bovine papillomavirus E1 is one of the best-known model systems for replicative helicases. E1 is a multifunctional initiator that senses and melts the viral origin and unwinds DNA. Here, we study the unwinding mechanism of E1 at the single-molecule level using magnetic tweezers. The result reveals that E1 as a single hexamer is a poorly processive helicase with a low unwinding rate. Tension on the DNA strands impedes unwinding, indicating that the helicase interacts strongly with both DNA strands at the junction. While investigating the interaction at a high force (26–30 pN), we discovered that E1 encircles dsDNA. By comparing with the E1 construct without a DNA binding domain, we propose two possible encircling modes of E1 during active unwinding.
76. Validation of Systemic Inflammatory Mediators as Biomarkers for Severity and Adverse Outcomes in Clostridium difficile Infection
Authors: Dieterle Michael G , Putler Rosemary K B , Perry Donald A , Menon Anitha , Abernathy-Close Lisa , Perlman Naomi , Penkevich Aline , Standke Alexandra , Keidan Micah , Vendrov Kimberly , Bergin Ingrid L , Young Vincent B , Rao Krishna
Published: October 2019

Background

Clostridium difficile infection (CDI) can result in severe disease and death. We are currently unable to identify patients at risk for developing adverse outcomes. We previously showed multiple inflammatory mediators were associated with severity and adverse outcomes. Here, we set out to validate these findings in patients and a murine model of CDI.

Methods

CDI was diagnosed by the clinical microbiology laboratory. Sera were collected ≤48 hours after diagnosis from pilot (October 2010–November 2012) and validation (January–September 2016) cohorts. Inflammatory mediators were measured with a custom multiplex assay. IDSA severity was defined as serum creatinine >1.5-fold above baseline or white blood cell count >15,000 cells/mL. The 30-day outcomes were all-cause mortality and disease-related complications (DRCs): ICU admission, colectomy, or death attributed to CDI. We sought to validate our patient findings in a murine model of CDI: 67 antibiotic-treated mice were infected with 630 g (37 mice), a low virulence strain, or VPI 10463 (30 mice), a highly virulent strain. Host responses were assessed with a murine version of the multiplex panel. Unadjusted and adjusted models were built using logistic and L1 regression, respectively.

Results

The pilot cohort had 156 CDI cases; 63 (40%) with IDSA severity. The inflammatory response in IDSA severe cases was distinct based on redundancy analysis of all measured analytes (P = 0.01). In unadjusted analysis, IL-2R, IL-6, and procalcitonin associated with severity (P < 0.001, P = 0.003, and P = 0.003, respectively). The same findings were seen in the validation cohort of 272 cases (Figure 1). Unadjusted analyses revealed several predictors of severity and outcomes (Table 1). Adjusted models performed well (Figure 2) with AUCs of 0.74 [0.67–0.81] (IDSA severity), 0.89 [0.83–0.95] (death), and 0.84 [0.74–0.95] (DRCs). Application of each model to the mouse cohort for high vs. low virulence infections revealed AUCs of 0.59 [0.44–0.74], 0.96 [0.90–1.0], and 0.89 [0.81–0.97] (Figure 3).

Conclusion

In both humans and a murine CDI model, a panel of biomarkers from sera associated with severe CDI and predicted adverse outcomes. Our results support the possibility of a serum-based biomarker panel to inform medical decision-making for patients with CDI.

Disclosures

All Authors: No reported Disclosures.
87. Heart and Lung Transplants From HCV-Viremic Donors to Uninfected Patients: Longer-Term Follow-Up
Authors: Woolley Ann E , Goldberg Hilary J , Singh Steve K , Mehra Mandeep R , Givertz Michael M , Coppolino Antonio , Cheng Vivien , Fanikos John , Harrington David P , Mallidi Hari R , Baden Lindsey R
Published: October 2019

Background

The DONATE HCV Trial demonstrated that hearts and lungs can be safely transplanted from HCV-infected donors using a shortened, 4-week, pre-emptive course of direct-acting antivirals (DAA). The 6-month results from that study of 35 patients are encouraging, but longer-term data from a larger cohort are needed to better define the risk–benefit profile.

Methods

We conducted a single-center trial to transplant thoracic organs from HCV viremic donors, irrespective of HCV genotype, to HCV-uninfected adults. Sofosbuvir/velpatasvir, a pan-genotypic DAA, was pre-emptively administered for 4 weeks, beginning within hours of transplant. The primary outcome was a composite of HCV clearance and graft survival at 6 months post-transplant. Secondary outcomes included graft survival and mortality at 12 months and the occurrence of grade 3 or higher adverse events (AEs). This protocol is IRB approved and all participants provided written informed consent (NCT03086044).

Results

Between March 2017 and March 2019, 57 participants were enrolled: 46 received lung and 11 received heart transplants. The median donor HCV viral load (VL) was 889,817 IU/mL (IQR 212,062–4,641,078). Of the 57 recipients, 53 (93%) had detectable HCV VL immediately after transplant, with median VL of 1,460 IU/mL (IQR 463–6,618). HCV VL became negative by about 2 weeks and subsequently remained undetectable in all participants. Forty-nine of 49 (100%) and 34 of 35 (97%) participants were alive with excellent graft function and an undetectable HCV VL at 6 months and 1-year post-transplant, respectively. No treatment-related serious AEs were identified. Outcomes between transplant recipients from HCV donors vs. non-HCV donors were similar, including the occurrence of renal failure, respiratory failure, and non-HCV infections.

Conclusion

In patients who received thoracic organs from HCV viremic donors, a 4-week antiviral treatment course initiated within hours of transplant prevented the establishment of HCV infection. These data demonstrate that thoracic organs from HCV viremic donors can be transplanted safely with excellent graft and recipient survival at 12 months with a similar AE profile compared with transplant recipients who received thoracic organs from non-HCV donors. Two-year outcomes will be available in October 2019.

Disclosures

All Authors: No reported Disclosures.
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

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

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

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

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

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

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

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

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

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.
1825. Optimizing β-lactam Therapy in Surgical Intensive Care Unit Patients Using Therapeutic Drug Monitoring
Authors: Al-Shaer Mohammad H , Rubido Eric , Lee Daniel , Klinker Kenneth , Peloquin Charles
Published: October 2019

Background

Therapeutic drug monitoring (TDM) is a powerful tool to optimize antibiotic exposure. It seldom has been used for β-lactams (BLs). We present our BL data in patients admitted to the surgical intensive care unit (SICU).

Methods

This retrospective study included SICU patients at UF Health (2016 and 2018) who received BL therapy and had TDM. Data collected included demographics, APACHE scores, platelet count, serum creatinine (Scr), infection source, cultures/susceptibilities, BL regimens, and plasma concentrations. Clinical cure was defined as resolution of infection-related symptoms at the end of therapy. Microbiologic eradication was defined as eradication of causative organism from the primary source out to 30 days after therapy. Pharmacokinetic and statistical analyses were performed on Phoenix v8.0 and JMP Pro v14.

Results

A total of 127 patients were included. Table 1 shows the baseline characteristics. The median age was 55 years, and weight was 83 kg. Eighty-three (65%) were male. P. aeruginosa was the most common isolated bacteria (n = 38). Lung was the most common source of infection (n = 50). Table 2 summarizes the median (IQR) doses, infusion times, calculated free trough concentrations (fCmin) of common BLs, and the reported minimum inhibitory concentrations (MICs). Calculated median time above the MIC (fT > MIC) for 66 (52%) patients was 100%. A total of 99 (79%) patients had clinical cure and 67 (61%) patients had microbiologic eradication. For efficacy, the Cmin/MIC ratio predicted the microbiologic eradication in wound infections only (n = 15, OR 1.09 [95% CI 1.01–1.24]). Using stepwise regression, 1-unit increase fT > MIC and APACHE score was associated with 0.84 decrease (P = 0.03) and 0.62 increase (P = 0.004) in days of therapy, respectively. For safety, Figure 2 shows the increase in Scr vs. BL free area under the concentration–time curve from time zero to end of the dosing interval (fAUC0-tau). Cefepime fAUC0-tau predicted neurotoxicity (OR per 20 unit increase 1.08 [95% CI: 1.01–1.18]).

Conclusion

In SICU patients, increase in fT > MIC was associated with shorter treatment duration, and fAUC0-tau increase was associated with an increase in Scr and incidence of neurotoxicity. TDM is warranted in this population to optimize therapy.

Disclosures

All Authors: No reported Disclosures.
1837. Considerations for a Targeted Approach to Contact Precautions for Patients with MRSA in Hospitals: A Multicenter Cohort Study to Identify High-Risk Patient Characteristics and Healthcare Personnel Interactions
Authors: O’Hara Lyndsay M , Calfee David P , Miller Loren G , Harris Lisa , Magder Laurence S , Kristie Johnson J , Morgan Daniel , Harris Anthony
Published: October 2019

Background

Healthcare personnel’s (HCP) gloves and gowns are frequently contaminated with antibiotic-resistant bacteria in the intensive care unit (ICU). Guidelines recommend contact precautions for patients with methicillin-resistant Staphylococcus aureus (MRSA); however, this approach remains controversial. This study aimed to identify which patients are more likely to transfer MRSA to HCP gloves or gowns and to identify HCP interactions more likely to lead to glove or gown contamination.

Methods

In a multicenter cohort study of MRSA colonized patients, we observed HCP–patient interactions and cultured HCP’s gloves and gowns before doffing. We also assessed the association between bacterial burden and contamination by sampling patients’ anterior nares, perianal area, chest, and arm.

Results

We enrolled 402 MRSA-colonized patients and observed 3,982 HCP interactions. MRSA contamination of HCP gloves and gown occurred in 14.3% and 5.9% of interactions, respectively. Contamination of either gloves or gown occurred in 16.2% of interactions. Occupational/physical therapists had the highest rates of contamination (OR: 6.96 [95% CI: 3.51–13.79]), followed by respiratory therapists (OR: 5.34 [95% CI: 3.04–9.39]) when compared with the “Other” category. Touching the patient was associated with higher contamination (OR: 2.59 [95% CI: 1.04–6.51]) when compared with touching nothing in the room. Touching only the environment was not associated with glove or gown contamination (OR: 1.13 [95% CI: 0.43, 3.00]) when compared with touching nothing. Touching the endotracheal tube (OR: 1.75 [95% CI: 1.38–2.19]), bedding (OR: 1.43 [95% CI: 1.20–1.70]) and bathing a patient (OR: 1.32 [95% CI: 1.01–1.75]) increased odds of contamination when compared with not having such contacts (Figures 1 and 2). We found an association between increasing bacterial burden in the patient’s nares, perianal area, and chest skin and glove or gown contamination.

Conclusion

Contamination of HCP gloves and gowns with MRSA occurs frequently when caring for ICU patients. We identified interactions that are high-risk for transmission. Hospitals may consider optimizing contact precautions by using less precautions for low-risk interactions and more precautions for high-risk interactions.

Disclosures

All Authors: No reported Disclosures.
1895. Serious Antibiotic-Related Adverse Effects Following Unnecessary Dental Prophylaxis in the United States
Authors: Gross Alan E , Suda Katie J , Zhou Jifang , Calip Gregory , Rowan Susan A , Hershow Ronald , Perez Rose , Evans Charlesnika T , McGregor Jessina C
Published: October 2019

Background

Dentists prescribe 10% of outpatient antibiotics in the United States, with a significant portion of these being for prophylaxis. We previously found that 80% of prescriptions for prophylaxis prescribed prior to dental visits are unnecessary; however, the sequelae of these unnecessary antibiotics have not been characterized. Our objective was to assess the harms of unnecessary antibiotic prophylaxis using Truven, a national health claims database.

Methods

This was a retrospective cohort study of patients with dental visits from 2011 to 2015 linked to medical and prescription claims. Patients with commercial dental insurance without a hospitalization or extra-oral infection 14 days prior to antibiotic prophylaxis (≤2 days supply dispensed within 7 days before a dental visit) were assessed for inclusion. Patients with unnecessary antibiotic prophylaxis (defined as antibiotic prophylaxis in patients who both did not undergo a procedure that manipulated the gingiva/tooth periapex and did not have an appropriate cardiac diagnosis) were included and assessed for serious antibiotic-related adverse effects (AAE). The primary endpoint was the cumulative incidence of any AAE within 14 days post-prescription (composite of allergy, anaphylaxis, C. difficile infection, or ED visit). The secondary analyses were the cumulative incidence of each individual AAE and the risk difference of the primary endpoint between amoxicillin and clindamycin.

Results

Of the 168,420 dental visits with antibiotic prophylaxis, 136,177 (80%) were unnecessary and included for analysis. 3.8% of unnecessary prescriptions were associated with an AAE; primary and secondary endpoints are listed in the Table. ED visits (1.2%) and new allergies (2.9%) were most frequent. Clindamycin was associated with more AAE than amoxicillin (risk difference 322.1 per 1000 person-years, 95% CI: 238.5 - 405.8).

Conclusion

Even though antibiotic prophylaxis is prescribed for a short duration (≤2 days), it is not without risk. Since most AAE are diagnosed in medical settings, dentists may not be aware of these adverse effects. These data provide further impetus to decrease unnecessary prescribing of antibiotic prophylaxis prior to dental procedures.

Disclosures

All Authors: No reported Disclosures.
1947. Educational Impact of a Hybrid Infectious Diseases Rotation for Internal Medicine Residents
Authors: Cutrell James B , Cutrell James B , Le Binh-Minh , Wolfe Heather R , King Helen , Arasaratnam Reuben J , Nijhawan Ank E , Nijhawan Ank E , McKenna Megan , Lee Francesca
Published: October 2019

Background

Traditional infectious diseases (ID) rotations for internal medicine (IM) residents focus on inpatient consultation, potentially skewing trainees’ perspectives on ID. We report our experience with a hybrid inpatient–outpatient ID rotation which provides broader ID clinical exposure and an effective venue for educational innovation.

Methods

We included all IM residents completing an assigned ID rotation in the UT Southwestern IM residency since July 2013. From July 2013 to June 2017, a 4-week ambulatory ID (Amb ID) rotation, consisting of general and subspecialty ID clinics and weekly teaching sessions focused on ID board review, was offered in parallel to traditional inpatient ID consult rotations. From July 2017 to present, all assigned residents complete up to a 4-week ID hybrid rotation, consisting of 2 weeks of ambulatory ID and 2 weeks of inpatient ID consults, with all residents receiving weekly teaching sessions; in some cases, the 4 weeks were not completed sequentially. Data were collected on resident numbers and training level, quantitative and qualitative course evaluations, and program in-training examination scores in ID content areas.

Results

From July 2013 to June 2019, IM residents completed a total of 626 ID rotations, an average of 104 per year (Table 1). A sample ID hybrid schedule is shown in Table 2. Overall resident satisfaction with the ID hybrid rotation was 4.7 (std. dev. 0.7) on a 5-point Likert scale. This rotation has consistently been among the highest rated rotations by residents. In-training examination ID scores increased significantly with creation of the Amb ID rotation in 2013 and further increased since 2017 with creation of the ID hybrid, in which both inpatient and ambulatory residents receive the weekly teaching sessions (Figure 1). Pilot educational innovations through this rotation include an online web-based antibiotic stewardship curriculum (2014–2015) and a mobile app-based ID board review platform utilizing spaced interval learning (2018–2019).

Conclusion

A hybrid inpatient–outpatient ID rotation for IM residents has proven to be a highly effective platform for ID education and curriculum innovation at our institution. This concept could be exported to other institutions and increase IM resident interest and breadth of clinical exposure in ID.

Disclosures

Ank E. Nijhawan, MD, MPH, Gilead Sciences, Inc.: Research Grant.
1953. VE303, a Rationally Designed Bacterial Consortium for Prevention of Recurrent Clostridioides difficile (C. Difficile) infection (rCDI), Stably Restores the Gut Microbiota After Vancomycin (vanco)-Induced Dysbiosis in Adult Healthy Volunteers (HV)
Authors: Bobilev Dmitri , Bhattarai Shakti , Menon Rajita , Klein Brian , Reddy Shilpa , Olle Bernat , Roberts Bruce , Bucci Vanni , Norman Jason
Published: October 2019

Background

Gut microbiota alterations and resulting changes in metabolites involved in colonization resistance and host responses, including bile acids (BA) and short-chain fatty acids (SCFA), are hallmarks of C. difficile infection. Reduction in rCDI was shown with fecal microbiota transplants (FMT), but FMT has limitations for routine use and carries unforeseen risks. VE303 is a first-in-class drug being developed for prevention of rCDI consisting of a rationally defined bacterial consortium manufactured under GMP conditions. VE303 comprises 8 distinct species belonging to Clostridium clusters IV, XIVa, and XVII, the commensal bacteria associated with clinical response in FMT, suppress C. difficile growth in vitro and improve survival in vivo.

Methods

A first-in-human Phase 1 dose-escalation study assessed safety and tolerability of VE303 in HV after vanco-induced dysbiosis. PK (strain colonization and durability) and PD (restoration of the resident microbiota, SCFA pool, and BA pool) were evaluated by metagenomic sequencing and metabolomics analysis of fecal material.

Results

HV (N = 23) received oral vanco 125 mg QID for 5 days followed by VE303 capsules at escalating single then multiple doses (total dose range 1.6 × 109 to 1.1 × 1011 CFU). VE303-related AEs, mostly gastrointestinal, all Grade 1 and transient, were observed in 35% of HV. Colonization with VE303 strains was abundant, durable (detected at 24 weeks), and dose-dependent. VE303 rapidly expanded 10- to 100-fold and each strain was detectable within 2 days after dosing. VE303 enhanced subjects’ microbiota and metabolic recovery after vanco treatment. When compared with the vanco-only cohort (N = 5), VE303 led to earlier and more complete recovery of beneficial taxa (eg, Bacteroidetes, Firmicutes), reduction in inflammatory taxa (e.g., Proteobacteria) (Figure 1.), and recovery of the secondary BA and SCFA pools.

Conclusion

VE303, a rationally designed microbial consortium, was safe, well tolerated, and efficiently restored microbiome composition after antibiotic-induced dysbiosis in a dose-dependent manner. VE303 was associated with early recovery of key PD markers of response, including microbiota composition, bile acid, and SCFA pools. A Phase 2 study of VE303 for prevention of rCDI is underway (NCT03788434).

Disclosures

All Authors: No reported Disclosures.
1958. Assessment of Guideline-Concordant Antimicrobial Prescribing in Urgent Care Centers
Authors: Wu Janet , Rivard Kaitlyn R , Neuner Elizabeth A , Athans Vasilios , Sabella Camille , Estridge Robert , Curtis Robert , Fraser Thomas G
Published: October 2019

Background

In the United States in 2014, 266 million outpatient antibiotic prescriptions were dispensed. The Center for Disease Control and Prevention estimates that 30% of outpatient antibiotic prescriptions are inappropriate. These inappropriate prescriptions contribute to increased resistance, adverse events, and healthcare costs.

Methods

This was a retrospective study of patients presenting to 22 urgent care centers within a large healthcare system between September 1, 2018 and February 28, 2019. Data were collected from a dashboard designed to track antimicrobial prescribing data by indication, location, and provider. ICD-9 and -10 codes associated with otitis media, pharyngitis, sinusitis, cystitis, and upper respiratory infections (URI) were included. Guideline-concordant antimicrobial prescribing was determined based on compliance with national guideline recommendations, after taking patient allergies into account. The URI category includes disease states in which antimicrobials are rarely appropriate (e.g., acute rhinitis, nasopharyngitis, and acute bronchitis).

Results

A total of 57,799 encounters were included in this analysis (19,242 pediatric and 38,557 adult) and 60% of patients received an antibiotic prescription. Overall antimicrobial guideline concordance was higher in pediatrics (84%) than adults (62%). Rates of guideline-concordant antimicrobial selection are shown in Table 1. The most common guideline-discordant prescriptions were tetracyclines (39%), amoxicillin/clavulanate (26%), and macrolides (17%) in adult patients with sinusitis, pharyngitis, or otitis media. In pediatric patients, the most common discordant prescriptions were macrolides (32%), third-generation cephalosporins (30%), and amoxicillin/clavulanate (19%). Unnecessary antimicrobial prescribing for URI occurred in 23% of pediatric patients and 36% of adult patients.

Conclusion

Guideline-discordant antimicrobial prescribing is common in urgent care centers, particularly in adult patients. In addition to encouraging utilization of order sets, emphasis on education and feedback may be important to improve and sustain guideline-concordant prescribing rates and reduce prescribing for URI.

Disclosures

All Authors: No reported Disclosures.