bluuebunny/crossref_metadata_2025_split huggingface dataset:
1891. Invasive Group A Streptococcus Infections Among Residents of Multiple Nursing Homes—Denver, Colorado, 2017–2018
Authors: Idubor Osatohamwen , Alden Nisha B , Nanduri Srinivas , Ogundimu Abimbola , Tanwar Sukarma S S , Reese Heather , Odongo Wycliffe , Herlihy Rachel , Johnston Helen , Burakoff Alexis , Burdorf April , Dale Ariella P , Nichols Janell , Bamberg Wendy M , Cilwick Alana , Barter Devra , Brousseau Geoff , Chochua Sopio , Stone Nimalie D , Van Beneden Chris 
Published: October 2019

Abstract

Background
Older adults residing in nursing homes (NH) are at increased risk for invasive group A Streptococcus (GAS) infections due to advanced age, presence of wounds, and comorbidities; approximately one-third of infected patients die. Beginning in 2015, increasing numbers of GAS infections in NH residents and several NH clusters were reported from the Denver metropolitan area. Colorado Department of Public Health and Environment (CDPHE) and CDC investigated to characterize cases and assess if outbreaks resulted from interfacility transmission.

Methods
We reviewed data from Active Bacterial Core surveillance (ABCs) in the 5-county Denver area from January 2017 to June 2018. We defined a case as isolation of GAS from a normally sterile site in an NH resident. GAS isolates underwent whole-genome sequencing (WGS) at CDC’s Streptococcus Laboratory to determine emm types for genotyping. Among isolates with the same emm type, pairwise single-nucleotide polymorphism (SNP) distances were calculated using Nucmer software. In October 2018, a CDPHE-CDC team assessed infection control at NHs with cases of the most common emm type.

Results
Over 18 months, among >100 NHs in the Denver area, ≥1 GAS case was identified in 29 NHs, with 6 having ≥3 cases. During this period, 68 cases in NH residents were identified. WGS identified 17 emm types among isolates from these cases; most common was emm11.10 (34%, n = 22), a rare subtype in ABCs. All emm11.10 isolates had nearly identical genomes (average pairwise SNP distance: 3.2), and were isolated from 10 NHs, with 2 NHs having ≥ 4 cases. Multiple infection control lapses were noted during site visits to 8 NHs.

Conclusion
Multiple outbreaks due to GAS were noted in 5-county Denver area NHs in 2017–2018. WGS of surveillance isolates identified a rarely seen emm subtype 11.10 from multiple facilities with temporal and genomic clustering suggesting interfacility GAS transmission.

Disclosures
All Authors: No reported Disclosures.
1946. An Exploratory Study of the Therapeutic Reasoning Underlying Antimicrobial Selection
Authors: Abdoler Emily , O’Brien Bridget , Schwartz Brian , Schwartz Brian 
Published: October 2019

Abstract

Background
Clinical reasoning research has helped illuminate how clinicians make diagnoses but offers less insight into management decisions. The need to understand therapeutic choices is particularly salient within infectious diseases (ID), where antimicrobial prescribing has broad implications given increasing rates of resistance. Researchers have examined general factors underlying antibiotic prescribing. Our study advances this work by exploring the factors and processes underlying physician choice of specific antimicrobials.

Methods
We conducted individual interviews with a purposeful sample of Hospitalists and ID attendings. Our semi-structured interview explored the reasoning underlying antimicrobial choice through clinical vignettes. We identified steps and factors after 12 interviews then conducted 4 more to confirm and refine our findings. We generated a codebook through an iterative, inductive process and used Dedoose to code the interviews and facilitate analysis.

Results
We identified three antibiotic reasoning steps (Naming the Syndrome, Delineating Pathogens, Antimicrobial Selection) and four factors involved in the reasoning process (Host Features, Case Features, Provider and Healthcare System Factors, Treatment Principles) (Table 1). Participants considered host and case features when determining likely pathogens and antimicrobial options; the other two factors influenced only antimicrobial selection. From these data, we developed an antimicrobial reasoning framework (Figure 1). We also determined that participants seemed to have a “script” with specific content for each antimicrobial they considered, functioning much like the illness scripts common to diagnostic reasoning (Table 2).

Conclusion
Our antimicrobial reasoning framework details the cognitive processes underlying antimicrobial choice. Our results build on general therapeutic reasoning frameworks while elaborating factors specific to ID. We also provide evidence of the existence of “therapy scripts” that mirror diagnostic reasoning’s “illness scripts.” Our framework has implications for medical education and antimicrobial stewardship.

Disclosures
All Authors: No reported Disclosures.
1952. Bacteriophage Treatment Improves Survival of Mice Infected with Carbapenem-Resistant Klebsiella pneumoniae
Authors: Hesse Shayla , Malachowa Natalia , Porter Adeline , Freedman Brett , Kobayashi Scott , Adhya Sankar , DeLeo Frank 
Published: October 2019

Abstract

Background
Bacteriophage (phage) therapy is being considered as a treatment option for patients with multi-drug-resistant bacterial infections. However, there is a dearth of controlled clinical data to support therapeutic phage efficacy. As a first step toward addressing this deficiency, we tested the ability of two well-characterized phages, alone and in combination, to kill carbapenem-resistant Klebsiella pneumoniae (ST258) in blood in vitro and rescue mice from lethal ST258 infection.

Methods
Wild-type C57BL/6J mice were infected with a lethal inoculum of ST258 by intra-peritoneal (IP) injection followed 1 hour later by IP administration of lytic phage P1, P2, or P1+P2 at a multiplicity of infection (MOI) estimated at 1. Survival of each group of mice was tracked for 10 days. In separate experiments, mice were sacrificed at 1 hour, 24 hours, and 48 hours post-phage treatment. Mouse blood and tissues were collected at each timepoint for enumeration of bacteria and phage, screening for phage resistance, and histopathology.

Results
ST258 survival in mouse blood in vitro was significantly less after 1 hour of incubation with P1 or P1+P2 (MOI 1) compared with the control group (no phage). Consistent with the in vitro data, none of the mice (0/15) in the control group (no phage) survived to 10 days post-infection, whereas 12/15, 14/15, and 15/15 mice survived in the P2, P1, and P1+P2-treated groups, respectively (P < 0.0001).

Conclusion
Prompt, systemic administration of lytic bacteriophages rescued mice from lethal ST258 infection. These data support the potential of phage therapy to effectively treat infections caused by ST258. It will be important to assess whether, for other phage-bacteria combinations, in vitro lysis in blood correlates with in vivo treatment efficacy and therefore may have predictive utility.

Disclosures
All Authors: No reported Disclosures.
1954. In vivo Efficacy of Delayed Therapy with the Novel Inositol Acyltransferase Inhibitor Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis
Authors: Wiederhold Nathan P , Najvar Laura K , Shaw Karen J , Jaramillo Rosie , Patterson Hoja P , Olivo Marcos , Catano Gabriel , Patterson Thomas F 
Published: October 2019

Abstract

Background
Candida auris is an emerging pathogen associated with antifungal resistance and high mortality. The novel antifungal manogepix (APX001A) prevents glycosylphosphatidylinositol-anchored protein maturation through inhibition of the inositol acyltransferase Gwt1 enzyme, and has demonstrated in vitro and in vivo activity against numerous pathogenic fungi, including C. auris. We evaluated the efficacy of the prodrug fosmanogepix (APX001) following delayed initiation of therapy in a murine model of C. auris invasive candidiasis.

Methods
Neutropenic outbred mice (10 per cohort) were inoculated intravenously with C. auris (minimum inhibitory concentrations [MICs]: manogepix 0.03 mg/mL, fluconazole >64 mg/mL, caspofungin 0.25 mg/mL).Treatment with placebo, fosmanogepix (104 or 130 mg/kg by intraperitoneal injection [IP] three times daily, or 260 mg/kg IP twice daily), fluconazole (20 mg/kg/day orally), or caspofungin (10 mg/kg/day IP) began 1 day later and continued for 7 days. Mice were followed post therapy until day 21 to assess survival. Kidneys and brains were collected on day 8, on the days that mice succumbed to infection, or on day 21. Fungal burden was assessed by colony-forming units (CFU).

Results
Survival was significantly improved at each dose level of fosmanogepix (median >21 days; 90–100%) and high dose caspofungin (>21 days; 90%) compared with placebo (5 days; 10%; P < 0.0001). On day 8 post-inoculation, kidney and brain fungal burdens were significantly reduced in mice treated with fosmanogepix 260 mg/kg BID compared with placebo and in kidneys of mice treated with caspofungin (Table 1). In the survival arm, fungal burden in kidneys and brains was significantly lower at each dose level of fosmanogepix and with high dose caspofungin compared with placebo. In contrast, no improvements in survival or reductions in fungal burden were observed with fluconazole.

Conclusion
Fosmanogepix demonstrated potent in vivo activity against invasive candidiasis caused by C. auris even with delayed initiation of treatment. Improvements in both survival and reductions in fungal burden within the kidneys and brains were observed. These data demonstrate the potential utility of fosmanogepix against C. auris infections.

Disclosures
All Authors: No reported Disclosures.
2851. Impact of Antimicrobial-Resistant Gram-Negative Bloodstream Infections on Outcomes Among Pediatric Hospitalizations in the United States, 2009–2016
Authors: Spaulding Alicen B , Watson David , Dreyfus Jill , Heaton Phillip , Kharbanda Anupam 
Published: October 2019

Abstract

Background
Antimicrobial-resistant (AMR) Gram-negative bloodstream infections (GNBSIs) are more challenging to treat and may be associated with higher rates of morbidity and mortality. However, no recent studies have assessed the impact of pediatric AMR GNBSIs on outcomes. This study’s objective was to analyze the impact of AMR GNBSIs on mortality, length of stay (LOS), and costs among pediatric hospital admissions in the United States.

Methods
We conducted a retrospective cohort study of patients ages < 19 from the Premier Healthcare Database (2009–2016) limited to hospitals reporting ≥4 years of blood culture data and to encounters with susceptibility testing among the five most common laboratory-confirmed GNBSIs. AMR was defined per pathogen according to Centers for Disease Control and Prevention criteria. Outcomes mortality, LOS, and total patient encounter costs were compared between AMR and susceptible GNBSIs using Bayesian hierarchical regression modeling, which allowed us to analyze outcomes at the pathogen-level and to incorporate adjustment for confounding factors in order to produce risk-adjusted average differences or risk ratios (RR), and corresponding 95% credible intervals (CrI).

Results
Among 1,279 GNBSI encounters with susceptibility testing from 104 hospitals, 153 (12%) were AMR, but varied by pathogen. AMR GNBSI occurred more often among non-neonates (62% vs. 51%); non-neonates more often had hospital-acquired infections (27% vs. 13%) or were transferred from a healthcare facility (16% vs. 10%) vs. susceptible GNBSIs. The adjusted RR for mortality was 1.31 (95% CrI 0.62, 3.07) and adjusted average differences for LOS were 6.8 days (95% CrI: −0.3, 16.3) and for cost $23800 (95% CrI $400, $53900) comparing AMR to susceptible GNBSIs.

Conclusion
This study analyzed the impact of AMR GNBSIs, which were rare, on pediatric patient outcomes using laboratory-confirmed GNBSIs with susceptibility results and advanced statistical methods, finding the greatest impact of pediatric AMR on costs. Knowing the impact of AMR GNBSIs can help improve management of these serious infections, increase clinician and patient awareness of the issue, and further strengthen evidence for justifying pediatric antimicrobial stewardship.

Disclosures
All Authors: No reported Disclosures.
2857. A Statistical Model to Predict Invasive Fungal Disease in Pediatric Cancer and Hematopoietic Stem Cell Transplantation Patients
Authors: Alali Muayad , Kumar Madan 
Published: October 2019

Abstract

Background
Invasive fungal diseases (IFDs) are devastating opportunistic infections that result in significant morbidity and death in pediatric cancer and hematopoietic stem cell transplantation (SCT) patients. Identification of risk factors for IFD will help clinical decisions relevant to the diagnosis and management of IFD in a timely manner. Despite this, data evaluating prediction risk tools for IFD in pediatric cancer are limited.

Methods
We conducted a retrospective review of pediatric oncology patients with a diagnosis of febrile neutropenia (FN) at UChicago Comer Children’s Hospital from July 2009 to December 2016. We analyzed 13 clinical, laboratory, and treatment-related risk factors for IFD including (age, gender, underlying diagnosis, SCT status, graft vs. host disease, chemotherapy in the last 2 weeks, temperature, height, fever duration, presence of hypotension, absolute neutrophil count, duration of neutropenia, absolute monocyte count, and the absolute lymphocyte count (ALC)). IFD was stratified as possible, probable, and proven according to the latest EORTC/MSG criteria (2008). Multivariable logistic regression risk prediction models were developed with separate analyses for all suspected IFD cases and only proven and probable cases.

Results
A total of 667 FN episodes (FNEs) were identified in 265 patients. IFD was diagnosed in 62 episodes (9.2%) of which 13 (1.9%) were proven, 27 (4%) probable, and 22 (3.3%) possible. Five variables obtained were signiﬁcantly more common in IFD. Patients presenting with hypotension and fever >5 days were highly associated with IFD (P < 0.001). SCT receipts (P < 0.01), neutropenia longer than 10 days (P = 0.02), and ALC <300 mm3 at time of presentation (P = 0.03) were additional risk factors. The final model performs very well compared with other published models with a receiver operating characteristic–area under the curve (ROC-AUC) of 86.5 for all IFD cases and ROC-AUC of 84.5 for proven, probable IFD cases.

Conclusion
Our findings showed important clinical markers for the development of IFD in pediatric oncology patients. A predictive regression model including identified significant factors has been created. Risk stratification with prospective external validation using this model can be used to refine the clinical approach.

Disclosures
All Authors: No reported Disclosures.
2888. STAT4 Mutation in Three Generations with Disseminated Coccidioidomycosis (DCM) also Exhibits Increased Susceptibility to Coccidioidal Infection in Transfected Mice
Authors: Powell Daniel A , Shubitz Lisa F , Hsu Amy , Davis Joie , Holland Steven M , Berghout Joanne , Lussier Yves A , Frelinger Jeffrey A , Galgiani John N 
Published: October 2019

Abstract

Background
Reported coccidioidomycosis has increased with case rates of 198/100,000 in Arizona (2012). In California alone, 2000–2011 hospitalizations were $2.2B. Dissemination occurs in 8% of reports with significant morbidity and occasional deaths. DCM was found in 3 generations: grandmother (skin), mother (skin), and son (bone). Whole exome sequencing identified a heterozygous (het) STAT4 mutation (p.E626G) in all three. This mutation alters the phosphotyrosine binding pocket and is predicted to impair STAT4 function, interfering with (i) receptor binding and phosphorylation, (ii) nuclear localization, and/or (iii) transcription. Expression profiling of antigen-stimulated peripheral blood mononuclear cells from one patient showed dampening of known STAT4 targets compared with controls.

Methods
STAT4 p.E626G was generated and confirmed in C57BL/6NJ (WT) mice using CRISPR-Cas9. With continued breeding, neither homozygous (hom) nor het mice had gross abnormalities. There were normal spleen and lung lymphoid cell numbers. Thymus and bone marrow had normal development of lymphoid subsets. We performed intranasal infection with reduced virulence C. posadasii strain 1038 or with F. tularensis live vaccine- strain (LVS). Naïve or Δcps1-vaccinated mice were tested for resistance to C. posadasii strain Silveira.

Results
At day 21 post Cp 1038 infection, hom, het, and WT mice had similar lung fungal burdens (~104.7 cfu). All p.E626G mice died between days 31 and 39 with lung burden significantly higher (~9 × 106 cfu) than WT sacrificed on day 44 (7 × 105 cfu, P = 0.015). After LVS infection, p.E626G mice had increased lung bacterial cfu and all had dissemination to the spleen compared with WT lung bacterial burden and no splenic dissemination. Immunized het and WT mice all had significantly reduced lung cfu 14 days following C. posadasii infection compared with unvaccinated WT mice.

Conclusion
The STAT4 p.E626G mutated mouse recapitulated patients’ increased susceptibility to coccidioidal infection. The decreased fungal burdens seen in Δcps1-vaccinated mice suggest that vaccination may be effective in those persons genetically susceptible to DCM. Given the increasing frequency and economic burdens of coccidioidomycosis, pursuit of vaccination strategies should continue.

Disclosures
All Authors: No reported Disclosures.
1145. Reducing Antibiotic Use In Children With Respiratory Syncitial Virus-related Bronchiolitis: Implementation of TeamSTEPPS® 2.0 to Improve Pharmacy-Physician Communication in a Community Hospital Antibiotic Stewardship Program
Authors: Dutta Ankhi , Moffett Brady , Mobeen Samrah , Singh Amrita 
Published: October 2019

Abstract

Background
Overuse of antibiotics in Respiratory Syncytial virus (RSV) bronchiolitis in children has been reported between 29–80%. Our antibiotic stewardship program (ASP) utilized a validated communication tool using TeamSTEPPS ® 2.0 principles to improve pharmacy-physician communication and improve audit-feedback technique (AFT).

Methods
We trained pharmacists and physicians in TeamSTEPPS ® 2.0 using simulation-based training. The key component of the training was: closed-loop communication and using a scripted pharmacy communication tool. The scripted pharmacy communication tool was modified from the “DESC” script used in TeamSTEPPS ® 2.0, which includes (1) Describing the situation, (2) Expressing concern, (3) providing Solutions, (4) stating Consequences and coming to an agreement. We incorporated this to improve the audit-feedback technique. We aimed to: (1) Reduce overall percentage of antibiotic (abx) use in RSV bronchiolitis by 25%, (2) reduce use of ceftriaxone, (3) reduce average antibiotic days of therapy (DOT).

Results
Our baseline data from 2017–18 RSV season showed a 42% (48/113) use of abx, of which 10% were deemed inappropriate. When compared with the 2018–2019 season, no differences were noted in patient demographics. The median length of stay between the two time periods was similar (2.9 days, IQR 1.9–4.8 days vs. 3.1 days, IQR 2.1–5.1 days, P = 0.17). More patients were admitted to the pediatric intensive care unit (PICU) in the 2018–2019 period: 35/96 (36.4%) as compared with 17/113 (15%) in the previous season. Although similar proportions of patients received abx (42% vs. 41%) in the two groups (Figure 1), average abx DOT, significantly decreased in the 2018–2019 period as compared with 2017–2018 (Figure 2). There was also a decrease in the use of ceftriaxone during the 2018–2019 (Figure 3). All physicians and pharmacists were satisfied with the communication technique and thought that it improved their interaction and understanding of the ASP process.

Conclusion
Though we did not reduce the overall abx use in RSV bronchiolitis, we did reduce the average abx DOT and use of ceftriaxone in our institution. The use of a validated communication tool to improve prospective AFT was crucial to the success of the ASP program.

Disclosures
All authors: No reported disclosures.
1146. Antibiotic Use in Infants Predicts Asthma Rate in Children 1–4 years at Fine Geographic Scale
Authors: Mamun Abdullah A , Sbihi Hind , Turvey Stuart , Dai Darlene , Rose Caren , Rasali Drona , Marra Fawziah , Patrick David M 
Published: October 2019

Abstract

Background
Early-life exposure to antibiotics is associated with childhood asthma. We previously reported that a dramatic drop in infant antibiotic use is correlated with a decline in asthma incidence in children in British Columbia (BC). This study aims to see whether antibiotic exposure predicts asthma at a fine geographic scale after adjustment for known covariates.

Methods
We used prescribing data from BC PharmaNet, a population-based database capturing all outpatient prescribing for BC population (n = 4.7 million). Prescribing rates for infants <1 year were calculated as prescriptions per 1000 population per year using age and sex-specified denominator estimates. Age-adjusted aggregate asthma incidence data for children 1–4 years were obtained from the BC Ministry of Health Chronic Disease Registry. The disease identification uses a standard case definition making using of diagnostic codes (ICD9-493 and ICD10-J45) in BC’s universal hospital and physician billing databases and relevant asthma-specific drug data from BC PharmaNet. We modeled the association between antibiotic prescribing rate and asthma incidence in 91 Local Health Areas using multivariable Poisson regression employing a generalized linear mixed-effects model adjusting for covariates.

Results
Between 2000 and 2014, the annual asthma incidence (ages 1–4 years) fell 26% from 27.3 (95% CI: 26.5–28.0) to 20.2 (95% CI: 19.5–20.8) per 1000 population. For children aged 1–4 years in 2000, the average proportion of infants exposed to one or more courses of antibiotics fell from 66.9 to 32.1% over the same interval. Antibiotic was a significant predictor of asthma rate (IRR=1.24 per 10% absolute increase in antibiotic prescribing; 95% CI: 1.19–1.27). Other covariates that remained significant in the model included male sex (IRR=1.56; 95% CI: 1.53–1.58), and atmospheric particulate matter PM 2.5 (IRR=1.08 per interquartile increase; 95% CI: 1.06–1.10).

Conclusion
Our findings suggest that antibiotic exposure in the first year of life increases the risk of being diagnosed with asthma later in childhood. This is congruent with similar findings at the individual level in a prospective cohort of Canadian children that also points to a pathway through altered gut microbiota.

Disclosures
All authors: No reported disclosures.