bluuebunny/crossref_metadata_2025_split huggingface dataset:
1477. A Randomized Phase 2 Study of Cefepime Combined with the Novel Extended Spectrum β-Lactamase Inhibitor Enmetazobactam in Hospitalized Adults with Complicated Urinary Tract Infections (cUTI) Including Acute Pyelonephritis (AP)
Authors: Carmeli Yehuda , Knechtle Philipp , Hardenberg Jeff , Knecht Mathias 
Published: October 2019

Abstract

Background
Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae has been classified as critical priority pathogens. The novel extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (formerly AAI101; EMT) in combination with cefepime (FEP) is currently being developed as a carbapenem-sparing treatment of serious Gram-negative infections in settings with a high prevalence of 3GC-resistant Enterobacteriaceae. We report here the results from a phase 2 study that assessed safety, tolerability, and pharmacokinetics of FEP-EMT in patients with cUTI/AP.

Methods
Forty-five patients were enrolled in a randomized, multicenter, double-blind study of hospitalized adults with cUTI/AP. Patients received dosing regimens of FEP or FEP-EMT IV therapy q8h by 2 hours infusion (table) for 7 to 10 days with a 28-day follow-up. Efficacy was evaluated in the microbiological-modified ITT (µMITT) population. Safety was monitored in patients who received at least 1 dose of study drug. Clinical cure was designated as the resolution of cUTI symptoms present at study entry. Plasma and urine PK were determined from all patients.

Results
The study drugs were well tolerated in each cohort, with similar % adverse events and no new or unexpected safety concerns (table). Two discontinuations were due to allergic dermatitis. The microbiological- and clinical responses at test-of-cure for the combined FEP-EMT group were 83.3% (20/24) and 95.8% (23/24) compared with responses in the combined FEP group of 73.3% (11/15) and 93.3% (14/15), respectively (table). The most common baseline pathogens were Escherichia coli (66.7%) and Klebsiella pneumoniae (23.1%): 28.2% of isolates produced ESBLs with eradication rates for the combined FEP-EMT group of 85.7% (6/7) and for the combined FEP group of 75.0% (3/4). FEP and EMT PK were best described by a 2-compartment, linear PK model. Both agents exhibited half-lives of 2.3 hours. Creatinine clearance had a significant covariate effect on FEP and EMT, consistent with predominant renal excretion of both agents.

Conclusion
Results from this phase 2 study justify advancement to phase 3 studies to evaluate the safety and efficacy of FEP-EMT in patients with cUTI/AP.

Disclosures
All authors: No reported disclosures.
1480. Plasma and Urine Pharmacokinetic Analysis of Gepotidacin (GSK2140944) Following BID Oral Dosing in a Phase IIa Study for Treatment of Uncomplicated Urinary Tract Infections
Authors: Zimmerman Eric I , Dumont Etienne , Perry Caroline R , Tiffany Courtney , Scangarella-Oman Nicole , Raychaudhuri Aparna , Hossain Mohammad 
Published: October 2019

Abstract

Background
Uncomplicated urinary tract infections (uUTIs) are very common, with approximately 11% of women >18 years of age experiencing at least 1 episode of acute cystitis per year [Foxman, 2000]. Multidrug resistance has now emerged at the community level and has made treatment approaches for UTIs more difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. Gepotidacin (GEP), a first-in-class, novel triazaacenaphthylene antibacterial has demonstrated in vitro activity against uropathogens, including E. coli. With its unique ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, GEP warrants further study as a potential opportunity to address an unmet medical need by providing a new and effective oral treatment option for acute cystitis.

Methods
All participants received oral GEP 1500 mg BID for 5 days (total of 10 doses) and PK sampling was performed on Days 1–5.

Results
GEP was rapidly absorbed with median Tmax values of 1.50 to 1.92 hours. Steady-state was attained by Day 3 with moderate accumulation in plasma following BID dosing (1.4 fold), which is consistent with an effective elimination half-life of 6.6 hours. Steady-state urine trough levels were high and remained above an MIC of 4 µg/mL over 12 hours. Approximately 20% of the dose was excreted in urine over the 12-hour dosing interval on Day 1, which increased to 31% on Day 4. Urinary AUC24hr (11945 µg hours/mL) was higher than the free plasma AUC24hr (39.4 µg hours/mL). Slightly higher GEP plasma and urine exposures were observed in uUTI patients compared with Phase I healthy subjects.

Conclusion
Oral dosing of 1500 mg BID produces urine GEP exposures that exceed free plasma exposures by ~300-fold. Urine concentrations were also higher than the GEP MIC90 values for common UTI pathogens, such as E. coli (MIC90 = 4 µg/mL), suggesting that GEP warrants further clinical study for the treatment of uUTI.

Disclosures
All authors: No reported disclosures.
1488. Effects of Clostridium difficile Infection in Hospitalized Patients with Inflammatory Bowel Disease, National Inpatient Sample Study 2016
Authors: Chen Bing , Mahmoud Omar , Liu Bolun 
Published: October 2019

Abstract

Background
Patients with inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) have been shown to have increased Clostridium difficile infection (CDI) rates. In this study, we aimed to determine the effects of concurrent CDI in the outcomes of hospitalized patients with IBD.

Methods
In this retrospective cohort study, we analyzed the 2016 National Inpatient Sample (NIS) database of hospitalized patients with a first or secondary diagnosis of IBD and CDI using their respective ICD-10 codes. Primary outcomes of interest were all-cause mortality, hospital length of stay, total cost for hospital stay, and rate of colectomy. Multivariate regression was used to adjust for age, gender, race, hospital bed size, and Charlson comorbidity index. We used STATA 14 for analysis.

Results
There were a total of 3,306 patients admitted with IBD and CDI, of which 1,864 had a diagnosis of UC and 1,460 had a diagnosis of CD. 58.02% of the cases were female and the mean age was 52.5 years old. The mean age of patients in the CD group (48.97 [47.79–50.15]) was lower than the UC group (55.16 [54.01–56.31]). The results of in-hospital outcomes are shown in Tables 1 and 2.

Conclusion
We observed a significant increase in all-cause mortality, hospital length of stay, and total cost for hospital stay in IBD patients with concurrent CDI. There was no statistical difference in the rate of colectomy. In the subgroup analysis, there was a statistically non-significant increase in all-cause mortality in the CD group and a statistically significant increase in all-cause mortality in the UC group. Thus, in our study, IBD patients, especially UC patients, with concurrent CDI had a worse prognosis but they did not have more colectomies.

Disclosures
All authors: No reported disclosures.
1491. Active Norovirus Surveillance in Children Under 5 Years with Diarrhea after Rotavirus Vaccine Introduction in Argentina (2017–2019)
Authors: Gentile Angela , Stupka Juan , Degiuseppe Juan I , del Valle Juárez María , Florencia Lucion Maria , Agustina Pirker María , Turco Marisa , Sabbaj Rosa Liliana , Soledad Areso María 
Published: October 2019

Abstract

Background
Acute diarrhea is one of the leading causes of infant morbidity and mortality. Argentina introduced massive rotavirus vaccination in 2015. In several countries, this introduction has changed the distribution of enteropathogens. The decrease in the prevalence of rotavirus has been described at the expense of an increase in Norovirus (NoV) activity worldwide. The aim of this study was to analyze the role of NoV in acute diarrhea cases in outpatient children under 5 years of age and their epidemiological profile.

Methods
A prospective and cross-sectional study in <5 years outpatients attended for acute diarrhea in Children’s Hospital “Dr. Ricardo Gutiérrez” in Buenos Aires, Argentina, between July 2017 and March 2019 was conducted. Active epidemiological surveillance was performed with a specific case reporting form. Stool samples were tested for NoV (RT-qPCR). Clinical and epidemiological data were recorded.

Results
A total of 252 patients were enrolled and 235 stools samples were tested. Median of age was 22.3 months (IQR: 11–30), 58.7% were male. The most frequent symptoms were fever and vomiting in 63.1% and 53%, respectively; 52% had watery diarrhea, 45.2% had moderate diarrhea according to Vesikari Scale, 95.6% were normohydrated and 22% had a household member with diarrhea. There were no immunocompromised children. A 72% had received rotavirus vaccine, 86% of them with full scheme. From samples tested, 27% (n = 63) were NoV positive. NoV was found throughout the year and the frequency of detection was higher in January and June (summer and winter in Argentina). Regarding genetic diversity the most frequent genogroup was GII (65%; 41/63) and genotype GII.P16-GII.4 Sydney (48%; 20/41). Bacterial co-infection was observed in 35%. Compared with negative cases, NoV were younger (18 vs. 20 months; P < 0.001) and were associated with higher prevalence of rotavirus vaccination (88% vs. 66%; P = 0.001). No statistically difference was found regarding to gender, clinical outcome and severity.

Conclusion
NoV was detected at high frequency (27%) in children presenting moderate acute diarrhea, mainly in those who received rotavirus vaccine. Regarding sporadic acute diarrhea cases in children, it is important to consider NoV as a frequent etiological agent.

Disclosures
All authors: No reported disclosures.
1498. Assess Risk Factors, Mortality, and Healthcare Utilization Associated with Clostridioides difficile Infection (CDI) in 4 Latin American Countries
Authors: Yu Holly , Flaster Nestor , Casanello Adrian , Curcio Daniel 
Published: October 2019

Abstract

Background
In contrast to Europe and North America, little is known about Clostridioides difficile infection (CDI) in Latin America, especially about risk factors, mortality, and healthcare utilization.

Methods
We conducted a retrospective, case–control study at eight hospital centers in Brazil, Mexico, Argentina, and Chile. Hospital databases and medical records were used to identify nosocomial CDI cases from January 1, 2014 to December 31, 2017. CDI cases were patients with diarrhea and a positive CDI testing ≥72 hours after hospital admission. Two controls with no CDI diagnosis and diarrhea were matched to each CDI case and were required to (1) have a length of hospital stay (LOS) ≥ 3 days, (2) be admitted ±14 days from the case, and (3) share the same ward. Risk factors associated with CDI were assessed by conditional logistic regression. Mortality and healthcare utilization were compared between cases and controls.

Results
A total of 1,443 patients (≥18 years old) who met eligibility criteria were selected (481 cases and 962 controls). Comparing cases to controls, the mean age and gender representation were similar (age: 58.7 vs. 56.7 years, P = 0.269; male: 56.3% vs. 53.4%, P = 0.293), but comorbidity was higher (mean Charlson Comorbidity index: 4.3 vs. 3.6, p

Conclusion
Antibiotic exposure, existing medical conditions, and recent hospital admission are CDI major risk factors in Latin America. CDI also increased in-hospital death risk and LOS. These findings are consistent with published literature in developed countries.

Disclosures
All authors: No reported disclosures.
1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)
Authors: Ford Christopher , Litcofsky Kevin , McGovern Barbara , Pardi Darrell , Nathan Richard , Hansen Val , Brennan Robert , Pullman John , Bernardo Patricia , Tomlinson Amelia , Horgan Kevin , Bryant Jessica , Walsh Emily , Rodriguez Michelle , Rogalin Henry , Wang Elaine , Henn Matt 
Published: October 2019

Abstract

Background
CDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance.

Methods
SERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks.

Results
SER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3).

Conclusion
In this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI.

Disclosures
All authors: No reported disclosures.
1505. Shorter-Course Antibiotic Treatment for Pediatric Ventilator-Associated Tracheitis Is Safe and Effective
Authors: Grabic Mirela , Lake Jason G , Debelnogich Jelena , Krucylak Christina , Newland Jason 
Published: October 2019

Abstract

Background
Ventilator-associated tracheitis (VAT) is a common infection in children cared for in pediatric intensive care units (PICU). Short-course antibiotic treatment (5 days) has been shown to be effective. In October 2016, we implemented a PICU VAT guideline for short-course therapy. We assessed the impact of this intervention.

Methods
We conducted a retrospective cohort study of PICU patients diagnosed with VAT from October 2016 to June 2018. The antimicrobial stewardship program (ASP) identified potential patients through daily chart review. Only those patients with a clinician diagnosis and who were receiving antibiotics for VAT, either enterally or parenterally, were included. Frequencies and proportions were calculated. Chi-square or Fisher exact tests were used to compare proportions.

Results
ASP identified 251 potential patients, 105 (42%) of whom met inclusion criteria. The median age was 7 years (range: 0–21). Twenty-eight (27%) were tracheostomy dependent. The most commonly prescribed antibiotics were cefepime (43%), ceftriaxone (17%), and vancomycin (14%). Median antibiotic duration was 13 days (range: 1–29); 57 (52%) received > 5 days and 48 (44%) received 5 days. Only 3 (6%) patients who received 5 days of antibiotics required retreatment within 10 days of their initial course vs. 11 (19%) who received > 5 days (P = 0.09). A diagnosis of ventilator-associated pneumonia (VAP) within 10 days of completing VAT treatment was made in 2 (4%) patients who received 5 days vs. 3 (5%) of patients who received > 5 days (P = 1.0). C. difficile infection within 90 days occurred in 2 (4%) patients who received > 5 days vs. 1 (2%) who received 5 days (P = 1.0).

Conclusion
Short-course antibiotic therapy for VAT was not associated with retreatment for VAT or subsequent diagnosis of VAP. Development of C. difficile was similar between groups. Adherence to the guideline was approximately 50%, perhaps due to physician perception of disease severity. Additional work is needed to refine the diagnosis of VAT and assess the interaction between illness severity and treatment duration.

Disclosures
All authors: No reported disclosures.
1511. Effect of Discharge Antibiotic Route on Clinical Outcomes in Children with Methicillin-Resistant Staphylococcus aureus (MRSA) Osteomyelitis with Bacteremia
Authors: Olson Jared , Hamdy Rana F , Hsu Alice J , Tamma Pranita , Tamma Pranita , Gerber Jeffrey , Dona Daniele , Hersh Adam 
Published: October 2019

Abstract

Background
Children with osteomyelitis transitioned to oral step-down therapy experience similar outcomes to those treated with outpatient parenteral antibiotic therapy (OPAT). Compared with OPAT, oral therapy has lower costs and avoids catheter complications. However, few studies have specifically compared patient outcomes between those receiving oral therapy vs. OPAT for osteomyelitis with associated bacteremia caused by MRSA.

Methods
We performed a retrospective cohort study comparing early oral therapy (EOT), defined as transition to oral therapy at or prior to discharge vs. use of OPAT at discharge. We identified hospitalized children <19 years of age with MRSA osteomyelitis with bacteremia between 2007 and 2014 from three children’s hospitals. The primary outcome was treatment failure within 6 months of discharge, defined as unplanned change in antibiotic after discharge, development of chronic osteomyelitis, need for an operative procedure after discharge, or recrudescence of bacteremia. The secondary outcome was treatment-related events, defined as documented adverse drug events in the medical record and/or central venous catheter complications. Between-group comparisons were made using Fisher exact test for binomial distributions and the Wilcoxon rank-sum test for continuous variables.

Results
We included 61 patients with MRSA osteomyelitis with bacteremia. Twenty-five patients (41%) received EOT and 36 (59%) received OPAT. Duration of bacteremia and hospital length of stay was similar between groups (Table 1). Clindamycin was the most commonly used antibiotic in both the EOT (24/25; 96%) and OPAT (22/36; 61%) groups. Clinical failure occurred in 1/25 (4%) children receiving EOT and in 5/36 (14%) in the OPAT group (95% CI of difference: −29 to 6%; P = 0.38, Table 1). Treatment-related adverse events occurred in 1/25 (4%) children receiving EOT compared with 9/36 (25%) receiving OPAT (95% CI of difference: −49 to –7%; P = 0.04, Table 1).

Conclusion
Children receiving EOT for MRSA osteomyelitis with bacteremia did not experience higher rates of clinical failure and had fewer treatment-related complications compared with OPAT. Oral step-down therapy can be considered for children with MRSA osteomyelitis with bacteremia.

Disclosures
All authors: No reported disclosures.
1514. Factors Associated with an Infectious Diseases Consultation for Pediatric Staphylococcus aureus Bacteremia
Authors: Curley Tara E , Ansusinha Emily , Hamdy Rana F 
Published: October 2019

Abstract

Background
Staphylococcal aureus bacteremia is associated with substantial morbidity in children. An infectious diseases consultation is associated with decreased mortality in adults with S. aureus bacteremia, but this has not yet been shown in a pediatric population.

Methods
This was a retrospective cohort study of children <18 years old hospitalized at Children’s National Medical Center with S. aureus bacteremia between January 1, 2012 and December 31, 2016. We excluded children with polymicrobial infections, those with a concurrent culture-proven infection, and those transferred with incomplete records. Structured manual chart review was used to collect demographic information, underlying comorbidities, type of admission (ICU or non-ICU), epidemiologic classification (hospital- or community-onset), primary source of infection, and methicillin resistance (MRSA or MSSA). A multivariable logistic regression analysis was performed to identify factors associated with having an infectious diseases consultation.

Results
We identified 171 episodes of S. aureus bacteremia; 27.5% occurred in infants <12 months old, 65.5% occurred in males, 38% occurred in ICU patients, and 18.1% were methicillin-resistant S. aureus (MRSA). The most common primary sources of infection were musculoskeletal (38%), catheter-related (18.1%), and skin/soft-tissue infections (17%). The majority (70.2%) received an infectious diseases consultation. In univariable analysis, ID consultation was more frequent among infections with the following characteristics: non-neonates (74.2% vs. 45.8%; P = 0.007), community-acquired (78.7% vs. 45.5%; P < 0.01), no underlying comorbidities (97.0% vs. 53.3%; P < 0.001), musculoskeletal (98.5%) or endovascular (100%) source of infection, and MRSA (100%). In a multivariable logistic regression analysis, musculoskeletal infections, endovascular infections, and MRSA had significantly higher odds of receiving an infectious diseases consultation.

Conclusion
Children with S. aureus bacteremia were more likely to receive an infectious diseases consultation if presenting with musculoskeletal infections, endovascular infections, or MRSA.

Disclosures
All authors: No reported disclosures.