bluuebunny/crossref_metadata_2025_split huggingface dataset:
1473. Structured Patient Interview in Complicated Urinary Tract Infections to Assess Clinical Outcomes vs. Investigator’s Evaluation in the APEKS-cUTI Study
Authors: Portsmouth Simon , Toyoizumi Kiichiro , Den Nagata Tsutae , Tillotson Glenn S , Echols Roger 
Published: October 2019

Abstract

Background
Based on the 2009 US FDA guidance, patient-reported outcome (PRO) measures are recommended in clinical study designs for certain indications to evaluate response to therapy from the patient’s perspective, and a PRO was recommended in the final complicated urinary tract infection (cUTI) guidance in 2014. Several PRO tools have been rigorously validated, but currently, no tool exists for evaluating cUTI. We included a “structured patient interview (SPI)“ while conducting a randomized, double-blind, study (NCT02321800) investigating cefiderocol (CFDC) vs. imipenem–cilastatin (IPM/CS) in cUTI patients to support the physician’s assessment of clinical response.

Methods
Patients, who were fully alert and oriented, were interviewed at randomization, end of treatment, test of cure (TOC), and follow-up (FUP) by the same interviewer. The questionnaire identified the presence or absence of relevant symptoms pertinent to cUTI. Responses were graded as none, or if present, mild, moderate, or severe. Investigator assessment included objective measures of clinical outcome(s) and was performed independently from the patient-reported symptoms collected in the SPI. Changes in the patient’s responses were compared with the investigator’s assessment at randomization and at each study visit. A kappa correlation coefficient comparing the SPI and physician’s clinical assessment was calculated at each evaluation time point.

Results
Based on investigator assessment, 89.7% (226 out of 252 patients) in the CFDC arm and 87.4% (104 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 2.39%; 95% CI: –4.66; 9.44) at TOC. Based on the SPI responses, 89.7% (226 out of 252 patients) in the CFDC arm and 84.9% (101 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 4.96%; 95% CI: –2.48; 12.39) in favor of CFDC. The correlation between SPI evaluation and physician’s assessment of clinical outcomes was very high at TOC and FUP visits (Kappa coefficients: 0.820 and 0.766, respectively).

Conclusion
The strong correlation between patients’ reported symptoms collected in the SPI and investigator assessment showed that SPI responses could be a useful alternative measure of clinical outcomes in cUTI studies.

Disclosures
All authors: No reported disclosures.
1484. Prevalence of Pyuria With and Without Bacteriuria in Healthy Pre-Menopausal Women
Authors: Stapleton Ann E , Roberts Pacita , Hooton Thomas M 
Published: October 2019

Abstract

Background
Pyuria has long been considered key to diagnosis of urinary tract infection in women, but there is a paucity of data on its prevalence and association with asymptomatic bacteriuria (ASB) in healthy women, even though pyuria and ASB often trigger inappropriate antimicrobial treatment.

Methods
We enrolled 104 healthy premenopausal women with a history of recurrent urinary tract infection (UTI) in an observational study and performed daily assessments of bacteriuria, pyuria (leukocyte esterase strips) and UTI symptoms over a 3-month period. These data enabled an evaluation of the prevalence of pyuria and ASB and associations between them.

Results
The mean age of participants was 22 and 74% were white. Pyuria occurred frequently in this cohort of women, with 72 (77%) of 94 evaluable subjects having pyuria on at least one day with no symptomatic UTI diagnosed. The median percent of days with pyuria reported was 7% (range, 0–100%). Asymptomatic bacteriuria (ASB, urine culture with colony count ≥105 CFU/mL of uropathogen on days with no symptomatic UTI diagnosed) occurred in 45 (45%) women on 159 (2.5%) of 6,283 days. ASB was most commonly caused by E. coli, which was present in 1.4% of days with median duration one day (range, 1–10). The positive predictive value of pyuria in detecting ASB was 4%. Five women had 11 transient episodes of pyuria, significant bacteriuria, and UTI symptoms (“preclinical UTI”) but did not seek medical attention.

Conclusion
In this population of healthy women at high risk for UTI and ASB, asymptomatic pyuria was a frequent occurrence and ASB rarely lasted more than 2 days. Pyuria, whether associated with bacteriuria or not, was generally not accompanied by urinary symptoms and did not appear to be clinically meaningful. Young women with recurrent UTI are often advised by their providers to test their urine with dipsticks for pyuria or bacteriuria, and be treated if either are positive, regardless of absence of UTI symptoms. Such practices, which contribute to antimicrobial resistance, are not supported by our data.

Disclosures
All authors: No reported disclosures.
1489. Clinical Utility and Patterns of the use of the Gastrointestinal PCR Panel Over a 2-Year Period at a University Hospital
Authors: Cushman Teresa , Barron Michelle , Arbet Jaron , Weber Rachel , Zhuang Yaxu , Jeffers Alexiss , Huang Misha 
Published: October 2019

Abstract

Background
Up to 80% of cases of acute infectious gastroenteritis do not have an identifiable etiologic agent. Molecular syndromic diagnostic panels, such as the Biofire® Filmarray® gastrointestinal (GI) panel, can improve pathogen detection, including frequent causes of community-onset diarrhea. There are little data about the real-world use and test characteristics of the GI panel in the clinical setting. The objective of this study was to evaluate the patterns of use and clinical utility of the GI panel.

Methods
We conducted a retrospective cohort study of adults (age >18 years) admitted to the University of Colorado Hospital for whom a GI Panel was ordered from October 1, 2015 to August 31, 2017. Primary outcomes included patient demographics and co-morbidities, time since admission to test order, and cumulative test results. Descriptive statistics were utilized to summarize the frequencies of the primary outcome measures.

Results
1684 panels were ordered and completed during the study period compared with 1379 stand-alone C. difficile PCRs. Seventeen of the 22 components of the panel had been validated by our lab prior to the study period; therefore, results were only available for these pathogens. Most GI panels (78%) were ordered in the first 48 hours of admission, with 6% ordered between 48 and 72 hours after admission, and 16% >72 hours after admission. The GI panel yielded an organism 34% of the time. The most frequently identified organism was C. difficile (18.5%) followed by Norovirus (5.2%) and Enteropathogenic E. coli (5.1%).

Conclusion
Over a 2-year period at a University hospital, the GI panel only had a positive result in 20% of patients tested. Although most of the tests were ordered in the first 48 hours after admission, 22% were ordered after 48 hours, after which etiologies of hospital-onset diarrhea are expected to be more common. Among all GI Panel tests ordered, C. difficile was the most common organism identified, followed by Norovirus. Each of these organisms has an accurate and less costly alternative test. Stand-alone testing for C. difficile and Norovirus should be considered prior to the GI Panel for patients admitted to the hospital, particularly when admitted >48 hours.

Disclosures
All authors: No reported disclosures.
1529. Kawasaki Disease Shock Syndrome: Identifying Risks
Authors: Downey Quick Rachel , Sehgal Ila , Feldman Alexandra , Murphey Donald , Fernandez Mariosl , Bhaduri. Hauger Sarmistha 
Published: October 2019

Abstract

Background
Kawasaki disease shock syndrome (KDSS) is a severe and less common complication of Kawasaki disease (KD). KDSS may progress rapidly and mimic other types of shock. Limited data are available in the literature describing recognition, evaluation, and treatment of KDSS. This report compares children with KDSS with those with KD without shock syndrome in 149 consecutive patients over 4.5 years in Central Texas.

Methods
Inpatient medical records of children with ICD diagnosis code for KD who were hospitalized between January 2014 and July 2018 at one children’s hospital in Texas were identified and charts were manually reviewed for inclusion. Cases were categorized as having KDSS if they had a diagnosis of KD with sustained systolic hypotension for age or signs or symptoms of shock with poor perfusion including tachycardia with delayed capillary refill, change in mental status, or weak peripheral pulses. Information about each case was collected from the chart including demographics, presentation, medical treatments, laboratory data, and initial echocardiograms.

Results
KD was identified in 149 patients; 22 were categorized as KDSS (14.8%). Among cases of KDSS, sustained systolic hypotension for age was observed in 19 patients; 3 patients had other signs of hemodynamic instability. Select details for each cohort are in Figure 1. Patients with KDSS were overall older on admission (6.2 vs. 2.3 years; P <0.001), and more likely to have anemia, neutrophilia, bandemia, thrombocytopenia, hypoalbuminemia, or hyponatremia. On acute echocardiogram, 5 of the 22 patients had coronary artery changes including ectasia, and dilation, and highest Z-score between 2.2–4.24. Patients with KDSS were more likely to receive steroids or adjunctive medications and had a longer length of stay (6 vs. 3.7 days; P < 0.001).

Conclusion
The current literature has relatively few cases of KDSS and suggests risk of misdiagnosis of KDSS initially as other types of shock. We demonstrate a higher incidence of KDSS; 14.8% compared with between 1.5 and 7% at KD diagnosis reported in the literature. The cause of this is unclear but may indicate regional or genetic differences in disease course. Patients with KD should be monitored for KDSS to avoid unexpected decompensation or delay in treatment. Lab abnormalities may indicate risk for KDSS.

Disclosures
All authors: No reported disclosures.
1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications
Authors: Koshimichi Hiroki , Retout Sylvie , Cosson Valérie F , De Buck Stefan , Tsuda Yoshiyuki , Ishibashi Toru , Wajima Toshihiro 
Published: October 2019

Abstract

Background
Baloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients.

Methods
The population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients.

Results
A 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately.

Conclusion
The results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil.

Disclosures
All authors: No reported disclosures.
1546. Efficacy of Daptomycin Combinations Against Daptomycin-Resistant Enterococcus faecium Differs by β-lactam
Authors: Kebriaei Razieh , Stamper Kyle , Rice Seth , Maassen Philip , Singh Kavindra V , Dinh An Q , Rios Rafael , Diaz Lorena , Murray Barbara E , Khan Ayesha , Tran Truc T , Arias Cesar A , Rybak Michael J 
Published: October 2019

Abstract

Background
We have previously demonstrated that daptomycin (DAP) combinations with β-lactams offer enhanced bactericidal activity and prevent the emergence of resistance in Enterococcus faecium infections. Although the mechanisms of DAP resistance in enterococci are not fully comprehended, they are associated with alterations in cell envelope phospholipids assembly which leads to either repulsion of the drug from cell exterior or diversion from the cell septum. In this context, we sought to evaluate combinations of DAP with a panel of β-lactams including ampicillin (AMP), amoxicillin (AMX), ceftaroline (CPT), ceftriaxone (CRO) and ertapenem (ERT).

Methods
E. faecium R497 harboring liaSFR mutations (DAP MIC of 16 mg/L) was evaluated in a simulated endocardial vegetation (SEV) pharmacokinetic and pharmacodynamic model over 336 h at a starting inoculum of 109 log10 CFU/g. DAP 10 mg/kg/day combinations with AMP, AMX (2 g continuous infusion), CPT 600 mg q 12 h, CRO 2g q 24 h or ERT 1 g q 24 h were evaluated. The emergence of DAP resistance was determined daily over the course of treatment.

Results
DAP alone was not bactericidal and high-level DAP resistance was observed (MIC increase from 16 to 64 µg/mL). Combination of DAP+AMP offered a significant reduction in log10CFU/g amounts (Up to 7 log10 CFU/g and to detection limits) in 24h in with no emergence of DAP resistance. DAP 10+ AMX caused 6–6.5 log10 CFU/g reduction and counts were maintained around the detection limit while demonstrating no increased resistance. Dose de-escalation with AMP indicated that even DAP 4 mg/kg/d with AMP (2g) combination, reached detection limit at 168 h with no further resistance. None of the CPT, CRO or ERT regimens in combination with DAP was effective against R497 and elevated DAP MICs (>64 µg/mL) was observed during the 14-day model.

Conclusion
Combination of DAP+AMP offered the most encouraging results against E. faecium R497, while DAP+AMX caused enhanced reduction. The reason for this discrepancy in various β-lactam activity may be related to diverse β-lactam targeting or affinity toward PBP proteins. Further dissection of our observations is warranted to understand the optimized DAP-β-lactam combination and consequently improve patient outcomes and prevention of resistance.

Disclosures
All authors: No reported disclosures.
1554. Nebulized Liposomal Amphotericin B for Treatment of Murine Pulmonary Mucormycosis
Authors: Sandoval Adilene , Adler-Moore Jill 
Published: October 2019

Abstract

Background
Pulmonary mucormycosis, a life-threatening infection of immunocompromised individuals, can have a 95% mortality rate, even with treatment. Intravenous (IV) liposomal amphotericin B (AmBisomeâ, AmBi) is used to treat the infection, but rapid growth of the pathogen can limit the drug’s effectiveness. In the present study we investigated whether nebulized (nebz) AmBi could improve treatment outcome using a neutropenic murine model of pulmonary mucormycosis.

Methods
Rhizopus oryzae (ATCC MYA4621) was grown on Potato Dextrose Agar for 3–7 days, followed by spore harvesting, and determination of spore viability. Male ICR mice were immunosuppressed with 200 mg/kg of cyclophosphamide d-2, d0, d+2, d+4, and d0 challenged intranasally with 1 × 106 spores. In Study 1, mice (n = 16 mice/gp) were given AmBi at 7.5 or 10 mg/kg IV for 6 days, or nebz AmBi for 20 minutes (1.33 mg/mL AmBi in reservoir) for 4 days. In Study 2, 16 mice/gp were given AmBi at 15 mg/kg IV for 6 days or nebz AmBi for 7 days. PBS was the control. Lungs and kidneys were collected d+6 to determine drug concentration by a bioassay (n = 7–8 mice/gp) and morbidity (n = 8 mice/gp) monitored to d+21.

Results
In Study 1, survival was significantly better with nebz AmBi for 4 days (50%) or 10 mg/kg IV AmBi (33%) vs. 7.5 mg/kg IV AmBi (0%) (P < 0.003). In Study 2 with 13% survival in the PBS mice, 7 days of nebz AmBi produced 100% survival and 15 mg/kg IV AmBi gave 83% survival (P < 0.02 vs. PBS), underscoring the need for more intensive treatments. In Study 2, we also observed that average lung drug levels with nebz AmBi were significantly lower (3 μg/g lung) than with 15mg/kg AmBi IV (19 μg/g lung) (P = 0.003), even though both treatments were comparably effective. Kidney drug levels with 15 mg/kg AmBi IV were 13 μg/g and in comparison, nebz AmBi produced no detectable drug.

Conclusion
Daily nebulization of AmBi for one week or a high dose of IV AmBi at 15 mg/kg for 6 days protected the mice from severe pulmonary mucormycosis caused by R. oryzae, delivering effective drug levels to the lungs. The IV treatment yielded elevated levels of drug in the kidneys, while nebulization with AmBi produced no detectable drug in the kidneys. This indicated that nebz AmBi would be a less nephrotoxic, but still very effective route for drug delivery.

Disclosures
All authors: No reported disclosures.
1555. Risk of Developing Acute Kidney Injury in Patients Receiving Piperacillin–Tazobactam and Vancomycin Compared with Those on Piperacillin–Tazobactam and Telavancin
Authors: Reilly Joseph , Nhan Ethan , Erb Rebecca , Whittaker Cristen A , Trivedi Manish 
Published: October 2019

Abstract

Background
The combination of piperacillin–tazobactam (PIP-TAZO) and vancomycin is associated with an increased frequency of acute kidney injury (AKI) in patients when compared with either agent alone. Like vancomycin, telavancin is also used for gram-positive infections and has been reported to cause AKI, but there is a paucity of data regarding the development of AKI with the combination of PIP-TAZO and telavancin. The purpose of this study was to compare the incidence of AKI in patients receiving PIP-TAZO with concomitant vancomycin or telavancin.

Methods
This retrospective cohort study included patients admitted between November 2016 and March 2019 who received at least 2 days of either vancomycin or telavancin in combination with PIP-TAZO. Patients were excluded if they had a baseline calculated creatinine clearance of less than 20 milliliters per minute or were receiving renal replacement therapy. Any cases of AKI were defined as a serum creatinine increase of 0.3 milligrams per deciliter (mg/dL) or an increase in creatinine of 1.5 times baseline when observed within 7 days of the studied antibiotic combinations. Statistical analysis was performed to compare baseline characteristics and the development of AKI between the two groups.

Results
Ninety-four patients with an average age of 55 years met the inclusion criteria. Forty-seven patients were included in both treatment arms. There were no statistically significant differences observed between study group baseline characteristics. All patients received PIP-TAZO 3.375 grams every 8 hours as a 4-hour infusion and the average telavancin dose was 7.5 mg/kg. Seventeen of 94 (18%) patients developed AKI, 8(17%) in the vancomycin and PIP-TAZO group and 9 (19%) in the telavancin and PIP-TAZO group (P = 1.0). No patients required dialysis.

Conclusion
The development of AKI appears to be similar when comparing vancomycin and PIP-TAZO to telavancin and PIP-TAZO in our population. It is noteworthy that PIP-TAZO was given as an extended infusion and telavancin dosing was lower than the manufacturer recommendations in this evaluation. Additional studies are warranted to further examine the occurrence of AKI with these antibiotic combinations.

Disclosures
All authors: No reported disclosures.
1560. Pharmacokinetics–Pharmacodynamics (PK-PD) of Gepotidacin (GEP) Against Escherichia coli in Murine Pyelonephritis and Thigh Infection Models
Authors: Barth Aline , Mininger Cindy l , Lewandowski Thomas , Hossain Mohammad , Rittenhouse Stephen , Hoover Jennifer 
Published: October 2019

Abstract

Background
GEP, a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens implicated in a range of infections, including drug-resistant strains of E. coli associated with acute cystitis.

Methods
PK and PD studies were conducted in murine (male CD-1 mice) thigh and kidney infections. The administered doses ranged from 1 to 200 mg/kg SC every 6 hours starting 1-hour post-infection. Infected tissues were evaluated for bacterial burden at 24-h post-infection (baseline controls at 1-hour post-infection). Plasma and tissue samples (kidney or thigh homogenates) were collected at 15, 30, 60, 120, 240 and 360 minutes. A population PK (PopPK) model was built in NONMEM using plasma exposures. Efficacy was determined against E. coli ALL, 997577, ATCC25922, IR5 and NCTC13441 (MICs of 1 to 4 µg/mL) in thigh-infected neutropenic (I-) mice and against E. coli ALL in kidney-infected immunocompetent (I+) and I- mice. The PopPK model was used to determine GEP exposures associated with efficacy. PK-PD analyses were conducted using Phoenix WinNonLin 6.3 (Pharsight). The change in log10 colony-forming units (CFU) from baseline were correlated with free drug (f) AUC:MIC using an inhibitory model from the Phoenix library, and model parameter values for each isolate were used to calculate the plasma fAUC:MIC associated with stasis, 1- or 2-log10 reductions in CFU.

Results
Plasma PK data were best fit by a 1-compartment IV model with first-order elimination and were similar in I+ vs. I- and thigh- vs. kidney-infected mice. The AUC0-6 of GEP in kidney was approximately 4- to 5-fold higher than in plasma while the AUC0-6 in thigh was approximately half of plasma. In the I- thigh model, median plasma fAUC:MIC ratios for stasis, 1- or 2-log10 reductions in CFU were 11, 16, and 25 (ranges 3–17, 4–25 and 7–40), respectively. Efficacy vs. E. coli ALL was similar in I- mice infected in thigh or kidney. In I+ mice, the PK-PD target was reduced by half.

Conclusion
Median plasma fAUC:MIC targets ranged from 11 to 25. Higher drug levels in kidney vs. plasma or thigh did not translate into improved efficacy in pyelonephritis vs. thigh-infection models.

Disclosures
All authors: No reported disclosures.