bluuebunny/crossref_metadata_2025 huggingface dataset:
1493. Creation and External Validation of a Clinical Prediction Rule for Diarrheal Etiology Using Natural Language Processing
Authors: Howard Joel Iverson , Aoki Joni , Ferraro Jeffrey , Haaland Ben , Pavia Andrew , Leung, Daniel T
Published: October 2019

Background

Infectious diarrheal illness is a significant contributor to healthcare costs in the US pediatric population. New multi-pathogen PCR-based panels have shown increased sensitivity over previous methods; however, they are costly and clinical utility may be limited in many cases. Clinical Prediction Rules (CPRs) may help optimize the appropriate use of these tests. Furthermore, Natural Language Processing (NLP) is an emerging tool to extract clinical history for decision support. Here, we examine NLP for the validation of a CPR for pediatric diarrhea.

Methods

Using data from a prospective clinical trial at 5 US pediatric hospitals, 961 diarrheal cases were assessed for etiology and relevant clinical variables. Of 65 variables collected in that study, 42 were excluded in our models based on a scarcity of documentation in reviewed clinical charts. The remaining 23 variables were ranked by random forest (RF) variable importance and utilized in both an RF and stepwise logistic regression (LR) model for viral-only etiology. We investigated whether NLP could accurately extract data from clinical notes comparable to study questionnaires. We used the eHOST abstraction software to abstract 6 clinical variables from patient charts that were useful in our CPR. These data will be used to train an NLP algorithm to extract the same variables from additional charts, and be combined with data from 2 other variables coded in the EMR to externally validate our model.

Results

Both RF and LR models achieved cross-validated area under the receiver operating characteristic curves of 0.74 using the top 5 variables (season, age, bloody diarrhea, vomiting/nausea, and fever), which did not improve significantly with the addition of more variables. Of 270 charts abstracted for NLP training, there were 41 occurrences of bloody diarrhea annotated, 339 occurrences of vomiting, and 145 occurrences of fever. Inter-annotator agreement over 9 training sets ranged between 0.63 and 0.83.

Conclusion

We have constructed a parsimonious CPR involving only 5 inputs for the prediction of a viral-only etiology for pediatric diarrheal illness using prospectively collected data. With the training of an NLP algorithm for automated chart abstraction we will validate the CPR. NLP could allow a CPR to run without manual data entry to improve care.

Disclosures

All authors: No reported disclosures.
1497. Relapsing Clostridium difficile Infection: Resolution with Combined Patient Choice Fecal Microbiota Transplantation, Vancomycin Taper, and Vancomycin Suppression
Authors: Shadowen Rebecca D , Edds Steven A
Published: October 2019

Background

Clostridium difficile infection (CDI) results in approximately a half a million cases and 15,000 deaths annually in the United States. Relapse rates vary between 20 and 50% and account for frequent readmissions and morbidity. Application of treatment modalities for relapsing cases resulting in complete resolution is reported here.

Methods

An observational analytical cohort study was done from June 2014 to December 2018 by offering options to patients for treatment of their CDI relapse. Each chose between Fecal Microbiota Transplantation (FMT; N = 52), Vancomycin po 6-week taper (VTa; N = 4), or Vancomycin 125 mg po daily 6-month suppression (VSu; N = 18). The FMT was given either as a liquid NG instillation (FMT-L) twice 12–24 hours apart (N = 47) or 20 capsules (FMT-C) given over 90 minutes (N = 5). Patients were followed for at least 8 weeks after treatment with readmissions tracked for 6 months in all cases. Fisher exact test was used for statistical significance.

Results

No patient was readmitted to the hospital for CDI-associated problems during the term of this study. More men choose po Vancomycin with more women choosing FMT (VTa/VSu Female 38%: Male 62% and FMT Female 80%: Male 20%; P < 0.01). Overall, initial response rate was 90%. Resolution of CDI was highest among the FMT-L (95.7%; N = 45/47; P = 1) and the VSu (94%; N-17/18; P = 1). The VTa group had 75% resolution (N = 3/4; nsd). The FMT-C arm showed a 40% success rate (N = 2/5; nsd). Treatment failures (N = 7) chose re-treatment with 6 cases repeating VTa having one relapse responding to FMT-L. One relapse in the VSu group responded to a 6 months daily Vancomycin suppressive course. The only statistically significant difference was in male to female ratios. Cost of therapy was highest for FMT-L $2326, FMT-C $1870, VSu $965, and VTa $700 average per course.

Conclusion

This report integrates options in treatment that follows the relapsing CDI patient to complete resolution. This eliminated hospital readmission and further morbidity. Allowing the patient freedom of treatment option was well received. Of the treatment arms, FMT-L and VSu were equivalent in outcomes, followed by VTa and FMT-C. FMT-L as 2 instillations provides higher response rates than previously reported. This was a small sample size; however, primary study endpoints of no hospitalizations and complete resolution were attained.

Disclosures

All authors: No reported disclosures.
1499. Distribution and Clinical Implication of Isolation of Multidrug-Resistant Microorganisms in Patients with Intra-Abdominal Infections
Authors: Kyung Yoon Young , Yeon Kim Jeong , Lee Hojin , Bean Kim Sun , Hun Kim Jong , Wook Sohn Jang , Ja Kim Min
Published: October 2019

Background

The aim of this study was to determine the prevalence and the clinical significance of multidrug-resistant microorganisms (MDROs) isolated from patients with intra-abdominal infections.

Methods

This cohort study was conducted at a 1,051-bed university-affiliated hospital in the Republic of Korea, between 2016 and 2018. The subjects included patients with intra-abdominal infections who had identified causative organisms. Patients with spontaneous bacterial peritonitis were not included in our study. Identification and antimicrobial susceptibility testing were done by standard criteria as defined by the Clinical and Laboratory Standards Institute.

Results

During the study period, a total of 627 non-duplicated clinical isolates were collected from 430 patients. Among these patients, 196 patients (45.6%) were suffered from generalized peritonitis while 234 (54.4%) affected by localized peritonitis or abscesses. In total, 152 (35.3%) were affected by healthcare-associated infections. The overall mortality and the 28-day mortality rate were 6.3% and 5.8%, respectively. Distribution of causative microorganisms was as follows: aerobic gram-positive (40.5%), aerobic gram-negative (56.1%), anaerobic (1.9%), and fungal (1.4%) pathogens. Escherichia coli (24.2%) was isolated most frequently, followed by Enterococcus spp. (23.9%), Klebsiella spp. (16.3%), and Streptococcus spp. (11.8%). The MDROs represented 15.8% of the total of isolated micro-organisms (figure). In the multivariable logistic regression analysis, isolation of MDROs (odds ratio [OR], 3.72; 95% confidence interval [CI], 1.53–9.04), hypoalbuminemia (OR, 5.56; 95% CI, 1.25–24.75), immunosuppressant (OR, 6.29; 95% CI, 1.96–20.18), and underlying renal diseases (OR, 4.29; 95% CI, 1.66–11.11) were found as independent risk factors for 28-day mortality.

Conclusion

In conclusion, our study indicates that MDROs are widespread in the patients with intra-abdominal infections. Furthermore, the isolation of MDROs was associated with poor clinical outcomes. For the appropriate selection of empirical antibiotics, local epidemiology of causative microorganisms and patterns of antimicrobial resistance should be continuously monitored.

Disclosures

All authors: No reported disclosures.
1508. Carbapenem vs. Non-carbapenem as Empiric Regimens for Bacteremia Caused by ESBL Producing Escherichia coli and Klebsiella pneumoniae in Children: Preliminary Study
Authors: Park Saera , Lee Jina
Published: October 2019

Background

The clinical efficacy of non-carbapenem for the treatment of extended-spectrum β-lactamase (ESBL) bacteremia in children with underlying comorbidities is controversial. We aimed to compare clinical and microbiological outcomes between pediatric patients received carbapenem and non-carbapenem as empiric regimens for bacteremia caused by ESBL producing E. coli and K. pneumoniae.

Methods

Pediatric patients aged <19 years who hospitalized between January 2014 to Jun. 2018 at Asan medical center with monomicrobial ESBL producing E. coli and K. pneumoniae bacteremia were included. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. We compared outcomes between patients who had empirical therapy with a carbapenem to those who had empirical therapy with a non-carbapenem.

Results

Among total 161 E. coli and K. pneumoniae bacteremia, 46 (28.6%) fulfilled the criteria, of which 25 (54.3%) were caused by E. coli and 21 (45.7%) by K. pneumoniae. The most common underlying diseases were hemato-oncologic diseases (47.8%) and prematurity (23.9%). The main sources of bacteremia were vascular catheter (37.0%) and necrotizing enterocolitis (10.9%). 25 cases were treated with empiric carbapenem, and the remaining 21 cases with non-carbapenem agents. The all-cause 30-day fatality in the carbapenem group was 32% (8/25) and 5% (1/21) in the non-carbapenem group (P = 0.023). Microbiological cure rate at 3 days after the first culture positive day was 75.3% in the carbapenem group and 89.6% in the non-carbapenem group (P = 0.046). However, adjusting initial presentation with septic shock, the choice of initial empiric antibiotic was not a risk factor for the 30-day fatality and microbiological cure rate at 3 days (aHR 4.82, 95% CI 0.592–39.231; aHR 0.648, 95% CI 0.333- 1.259, respectively).

Conclusion

For the medically fragile pediatric patients with bacteremia caused by ESBL producing E. coli and K. pneumoniae, the impact of empiric antibiotics on clinical and microbiological outcomes was not significant if early transition to definitive carbapenem regimen is possible when susceptibility is proven. A large-scale multicenter study will be needed to select the most appropriate empiric antibiotics and minimize the spread of antibiotics resistance.

Disclosures

All authors: No reported disclosures.
1515. Distinguishing Kawasaki Disease Initially Presenting as Cervical Lymphadenopathy from Bacterial Cervical Lymphadenitis Using the Decision Tree Analysis
Authors: Kim Jihye
Published: October 2019

Background

Kawasaki disease (KD) can present initially with fever and cervical lymphadenopathy before other characteristic clinical signs appear. It is important to recognize KD at an early stage for appropriate treatment to be started and reduce cardiac complications. We sought to identify variables which distinguish early stage of node first presentation of KD from bacterial cervical lymphadenitis (BCL).

Methods

We retrospectively reviewed records of patients presenting with cervical lymphadenopathy and fever as primary diagnosis who discharged from the inpatient ward between January 2010 and December 2017. Only the patients who underwent radiologic studies (CT or US) were included. Patients were divided into 3 groups by their final diagnosis; CL with abscess (Group A), CL without abscess (Group B), and Node first presentation of KD (Group C). Initial clinical, laboratory, and imaging characteristics of the 3 groups were compared. Sequential laboratory data performed on the third hospital day was used to calculate their percentage differences. A clinical prediction model for KD in patients with CL was constructed using the decision tree analysis.

Results

Patients with KD had a longer duration of fever after admission and longer duration of fever prior to final diagnosis compared with BCL patients. Compared with group A or B, group C patients had higher neutrophil counts, neutrophil-lymphocyte ratio, C-reactive protein (CRP), erythrocyte sedimentation rates (ESR), alanine transaminase (ALT), aspartate transaminase (AST). In radiologic studies, no differences were observed in node sizes or palatine tonsil enlargement among the 3 groups. Retropharyngeal edema was more commonly associated with group C than group A and B combined, but was not significantly different between group A and C. By decision tree analysis, factors contributing to classification included presence of abscess, CRP percentage change, and neutrophil percentage change (Figure 1). Strong predictivity of the decision tree was observed in classifying Group C, with an overall accuracy of 87.9% for Group A, 82.6% for Group B, and 91.4% for Group C.

Conclusion

Decision tree analysis showed that the presence of abscess, CRP percentage change, and neutrophil percentage change could classify KD from BCL with an accuracy of 91.4%.

Disclosures

All authors: No reported disclosures.
1519. Identification of Neisseria meningitidis (Nn) Nasopharyngeal Carriage Among Non-Vaccinated Children and Isolations in Invasive Disease (ID) Cases in Argentina 2017
Authors: Gentile Angela , Paula Della Latta Maria , Wisner Barbara , Bloch Mercedes , Martonelli Luisina , Sorohuet Cecilia , Regueira Mabel , del Valle Juárez María , Umido Veronica , Efron Adriana
Published: October 2019

Background

Neisseria meningitides (Nm) cause different types of invasive infections.Nm pharyngeal carriage is a necessary condition for invasive meningococcal disease. In 2017 Argentina introduced a tetravalent meningococcal conjugated vaccine (MenACYW) to the National Immunization Program.Aims To assess the rate of Nm carriage in healthy children and adolescents attending a public hospital in Buenos Aires city, to determine genogroup and clonal complex distribution,to describe genogroup distribution of Nm isolated from ID in Argentina, during the same period.

Methods

Between March and December 2017, a single-center, cross-sectional study was performed among 1,751 children 1–17 years old attending Ricardo Gutiérrez Children Hospital in Buenos Aires, Argentina. From oro-pharyngeal swabs, genogroup and clonal complex (CC) were identified. We analyzed Nm ID genogroups data reported to the Regional Surveillance Program (SIREVA II) in the same year. at the same period were relevated.

Results

114Nm were isolated from the carriage study, with an overall carriage of 6.5%.Genogroups distribution: B 25(21.9%), W 9(7.8%), Y 7(6.1%), Z 6(5.2%), C 4(3.5%), non-groupable 9(7.8%) and non-capsulated (NC)54 (47.3%). 105 Clonal complex (CC) were determined: Genogroup B isolates belonged to ST-41/44, ST-35, ST-32 and ST-865. Genogroup W was associated to ST-11 and ST-35. SIREVA reported 76 strains of Nminvasive infections in 2017, 53.9% meningitis, 11.8% meningitis and sepsis, 22.4% sepsis, and 11.8% others. Genogroupsdistribution: B59.2% (45), W 23.6% (18), C 10.5% (8), Y 6.5% (5).

Conclusion

Genogroup B is the most frequent cause of ID followed by W in our country. In the pharyngeal carriage study we found that NmNC was prevalent and genogroup B was the most frequent among the encapsulated.Genogroup B CCs detected in our carriage study coincided with those found previously in ID in Argentina. Genogroup W carriage was low and hypervirulent CC ST-11 was detected. Although genogroup Z does not cause ID in our country it was found in carriage.

Disclosures

All authors: No reported disclosures.
1528. Rates of Peripheral Blood Culture Contamination in an Urban Children’s Hospital
Authors: Tam Derek , Hengel Kyle , Arun Aparna
Published: October 2019

Background

Positive peripheral blood culture results are essential in guiding antimicrobial therapy in patients with bacteremia. However, false-positive results may frequently pose diagnostic issues in interpreting the test. These results can lead to increased costs and patient harm through the administration of unnecessary antibiotics and prolongation of hospital stay. The maximum acceptable contamination rate for peripheral blood cultures as suggested by the College of American Pathologists is 3%.

Methods

We initiated a longitudinal quality improvement project to monitor peripheral blood contamination rates at our children’s hospital in Brooklyn, NY. We reviewed positive blood culture results on a monthly basis and assessed whether they represented true infections vs. contamination based on review of patient charts. Residents and nurses in the pediatric emergency department (ED), neonatal intensive care unit (NICU), pediatric intensive care unit (PICU), inpatient unit, and newborn nursery were educated on proper skin sterilization techniques using video demonstration; the importance of avoiding palpating the venipuncture site after sterilization and the importance of cleaning the port on the blood culture bottle were reinforced.

Results

The pediatric ED and the PICU had the highest contamination rates in 2018 at 4.38% and 3.82%, respectively. The newborn nursery had the lowest contamination rate, at 0%. The NICU and pediatric inpatient units had contamination rates that met the goal as well, at 1.25% and 0.72%, respectively.

Conclusion

The departments in need of targeted interventions are the pediatric ED and the PICU, both of which had contamination rates greater than the 3% goal rate set for our project. Future interventions currently being considered include re-education of nursing and resident staff as well as the creation of equipment bundles to facilitate adequate skin preparation prior to venipuncture.

Disclosures

All authors: No reported disclosures.
1544. Efficacy of Human-Simulated Cefiderocol Exposure Against Gram-Negative Bacteria in an Iron-Overloaded Murine Thigh Infection Model
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P
Published: October 2019

Background

Cefiderocol (CFDC) is a siderophore-cephalosporin conjugate which exploits bacterial iron scavenging in reaction to the hypoferremic response of host immunity and achieves potent in vivo activity against various Gram-negative bacteria (GNB). In patients with hereditary or iatrogenic hemochromatosis, the hypoferremic response may be altered by iron overload, which could hypothetically suppress the bacterial iron scavenging that bolsters CFDC efficacy. We compared CFDC efficacy between iron-overloaded (Fe+) and normal iron (NFe) murine thigh infection models.

Methods

Female CD-1 mice received iron dextran 100 mg/kg/d for 14 d to induce iron overload (Fe+) (ASM Microbe 2019 abstract HMB-373); an equal number of same-age mice were not dosed (NFe). On day 15, both thighs of mice rendered neutropenic were inoculated with GNB suspensions of 107 CFU/mL. Twenty CFDC-susceptible isolates with previously determined CFDC MIC from 0.25 to 4 mg/L, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriales, were used. Two hours after inoculation, treatment mice were dosed with a CFDC regimen simulating the human plasma PK profile after doses of 2g q8h (3 h infusion), while control mice were sacrificed (0 h) or dosed with saline placebo on the same schedule as the CFDC regimen (24 h). All procedures were simultaneously performed in Fe+ and NFe mice. Efficacy was defined as a change in log10 CFU/thigh at 24 h vs. 0 h and was compared between Fe+ and NFe mice for individual isolates using Student’s t-test.

Results

Mean (SD) bacterial burdens at 0 h in Fe+ and NFe control mice were 5.77 (0.52) and 5.76 (0.52) and log10 CFU/thigh, respectively, and, at 24 h, increased by 3.49 (0.73) and 3.42 (0.96) log10 CFU/thigh, respectively. Mean (SD) efficacies of CFDC in Fe+ and NFe mice were -1.98 (0.83) and -1.98 (0.72) log10 CFU/thigh, respectively. For 17 of 20 individual isolates, no significant differences in efficacy between Fe+ and NFe mice were observed (P > 0.05); 2 of the 3 isolates with a difference had greater efficacy in Fe+ mice.

Conclusion

Human-simulated exposure of CFDC is equally efficacious in iron-overloaded and normal hosts against a variety of GNB susceptible to CFDC. The potential clinical use of CFDC to treat GNB infections in patients with iron overload is supported.

Disclosures

All authors: No reported disclosures.
1549. Impact of New Fluoroquinolone Breakpoints on Enterobacteriaceae Susceptibility Rates and Clinical Outcomes
Authors: Pettit Natasha N , Nguyen Cynthia T , Pisano Jennifer , Charnot-Katsikas Angella
Published: October 2019

Background

In January 2019, the Clinical and Laboratory Standards Institute (CLSI) lowered the Fluoroquinolone (FQ) susceptibility breakpoints for Enterobacteriaceae. The new breakpoints were updated primarily based on FQ pharmacodynamics, and only limited clinical data. We sought to evaluate clinical outcomes among patients who received an FQ for infection with Enterobacteriaceae with MIC values that would now be considered resistant, using the new interpretive criteria. We also assessed the potential impact of the new breakpoints on overall blood and urine Enterobacteriaceae susceptibility rates at our medical center.

Methods

All positive blood and urine cultures with Enterobacteriaceae between September 1, 2018 and February 28, 2019 were included. Enterobacteriaceae isolates with ciprofloxacin MICs of 0.5 and 1 µg/mL (based on new breakpoints, now considered non-susceptible) were identified. We assessed the length of stay (LOS), mortality, and 30-day readmissions among patients who received an FQ for treatment. The impact of the new breakpoints on overall Enterobacteriaceae susceptibilities from urine and blood isolates was also determined.

Results

A total of 1,761 cultures (191 blood, 1,570 urine) grew Enterobacteriaceae. One-hundred and twenty-five (7%) cultures grew isolates with a ciprofloxacin MIC of 0.5 or 1 µg/mL. Eighteen patients with Enterobacteriaceae isolated (4 blood, 14 urine) received an FQ. Among these patients, the median LOS was 4 days; one patient was readmitted within 30 days, and 0% mortality was observed. The patient readmitted within 30 days received an FQ for a blood isolate with MIC 0.5. Overall, with the revised breakpoints, we observed a 4.2% decrease in the number of Enterobacteriaceae that would be susceptible to ciprofloxacin (Figure 1).

Conclusion

The new FQ breakpoints for Enterobacteriaceae will have a marginal impact on overall FQ susceptibility rates at our medical center. In this single-center study, patients that received FQ antibiotics for Enterobacteriaceae with MIC values now considered intermediate or resistant did not appear to experience poor outcomes.

Disclosures

All authors: No reported disclosures.
1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia
Authors: Winchell Gregory A , de Greef Rik , Wrishko Rebecca E , Mangin Eric , Waskin Hetty , Bruno Christopher
Published: October 2019

Background

Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean Cavg and individual Cavg ≥500 ng/mL and <2500 ng/mL in ~90% of patients.

Methods

A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability.

Results

An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg was achieved for all but the 2–<7 years cohort receiving the PFS formulation.

Conclusion

This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food.

Disclosures

All authors: No reported disclosures.
1559. Ertapenem Plus Ceftriaxone or Ceftaroline Dual Β-Lactam Combination for Enterococcus faecalis
Authors: Cusumano Jaclyn A , Daffinee Kathryn E , LaPlante Kerry
Published: October 2019

Background

Ampicillin-ceftriaxone β-lactam therapy has become the standard of care for treating serious Enterococcus faecalis infections. Alternative regimens are of interest due to ceftriaxone’s association with C. difficile infections and VRE colonization, and ampicillin’s instability and inconvenient dosing schedule.

Methods

E. faecalis wild-type strain JH2-2 was utilized in a 48-hour in vitro pharmacodynamic model with a starting inoculum of 106 colony-forming units (CFU)/mL. Models were performed in duplicate to triplicate. Simulated doses of ertapenem 1g every 24 hours (fCmax 12.2 μg/mL; half-life 4 hours; MIC 4 μg/mL), ceftriaxone 2 g every 12 hours (fCmax 28.5 μg/mL; half-life 6.5 hours; MIC 512 μg/mL), and ceftaroline 600 mg every 8 hours (fCmax 27.1 μg/mL; half-life 2.7 hours; MIC 2 μg/mL) were tested. Ertapenem was also combined with ceftriaxone or ceftaroline. Bacterial counts were obtained at 0, 4, 8, 24, 32, and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum. MICs were assessed at 0, 24, and 48 hours using E-tests in accordance with CLSI.

Results

Ertapenem plus ceftriaxone, and ertapenem plus ceftaroline demonstrated bactericidal activity at 24 hours, but bacterial regrowth was observed at 48 hours (Table 1). An ertapenem MIC increase was only noted in one set of the ertapenem plus ceftriaxone models to 16mcg/mL at 48 hours, from 4mcg/mL at 0 hours. All other models did not have an increase in MIC.

Conclusion

Bactericidal activity of ertapenem-based dual β-lactam combinations may prove to be an alternative treatment for severe E. faecalis infections. Mechanistic understanding of penicillin-binding protein (PBP) saturation and optimization of antimicrobial pharmacodynamics must be explored.

Disclosures

All authors: No reported disclosures.
1565. Characterization of Tebipenem (SPR859) Pharmacokinetics–Pharmacodynamics (PK-PD) for Efficacy Against Enterobacteriaceae in a One-Compartment In Vitro Infection Model
Authors: VanScoy Brian D , Onufrak Nikolas J , Conde Haley , Caranco Ana I , Bhavnani Sujata M , Cotroneo Nicole , Critchley Ian A , Parr Thomas R , Ambrose Paul G
Published: October 2019

Background

SPR859 (tebipenem) is the active form of the orally bioavailable prodrug SPR994. Tebipenem is an oral carbapenem with a broad-spectrum activity against Gram-positive and -negative bacteria. SPR994 is being developed as an oral option for the treatment of complicated urinary tract infections (cUTI). The goal of these studies was to characterize the PK-PD of tebipenem against a diverse panel of Enterobacteriaceae.

Methods

24-hour dose-fractionation and dose-ranging studies were carried out utilizing the one-compartment in vitro infection model. Bacteria (1 × 106 CFU/mL) were exposed to tebipenem concentrations that mimicked human healthy volunteer free-drug plasma (f) concentration–time profiles following oral drug administration. For the dose-fractionation studies, 7 total daily dose levels (fAUC range, 0.11 to 19.0 mg hours/L) were fractionated in equal divided doses administered every 4, 8 or 12 hours (q4h, q8h and q12h, respectively). A single challenge isolate, E. coli ATCC 25922 (MIC = 0.015 mg/L), was evaluated in the dose-fractionation studies. In the dose-ranging studies, 13 Enterobacteriaceae clinical isolates (MIC values from 0.008 to 0.25 mg/L) were exposed to doses ranging from 4.69 to 1200 mg administered q8h (fAUC ranging from 0.14 to 37.2 mg hours/L). Relationships between change in log10 CFU from baseline at 24 h and each of fCmax:MIC ratio, f%T>MIC, and fAUC:MIC ratio, with and without adjustment for dosing interval tau for the latter (fAUC:MIC ratio·1/τ), were fit using Hill-type models.

Results

Dose-fractionation study results demonstrated the activity of tebipenem to be time-dependent, with both f%T>MIC and fAUC:MIC ratio·1/τ similarly describing the PK-PD of tebipenem. The relationship between change in log10 CFU from baseline at 24 hours and fAUC:MIC ratio·1/τ, as assessed using pooled data for 13 Enterobacteriaceae isolates evaluated in the dose-ranging studies, described the PK-PD of tebipenem well (Figure 1). The magnitude of fAUC:MIC ratio·1/τ associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline was 7.23, 13.1, and 32.4, respectively.

Conclusion

These data will be useful to design other pre-clinical studies and support tebipenem dose selection for clinical studies in patients with cUTI.

Disclosures

All authors: No reported disclosures.
1574. Predictive Ability and Bias of Vancomycin Population PK Models in an Obese Adult Population
Authors: Sabourenkov Paul E , McLeay Robert C
Published: October 2019

Background

Accurate dosing of vancomycin is difficult due to high inter-individual variability of vancomycin pharmacokinetics (PK), and is particularly challenging in obese patients. Vancomycin is hydrophilic, yet total body weight (TBW) has traditionally been used for dosing in the general population, and also into the obese population. The aim of this study was to evaluate the performance of published vancomycin PK models in a large set of routine clinical data obtained from an obese population.

Methods

De-identified data were available from 1717 courses of vancomycin administered to obese adults (BMI ≥ 30) from hospitals across the United States, EU, and Australia. Three population PK models, Buelga et al. (2005), Goti et al. (2018), and an obese-specific model, Adane et al. (2015), were used to predict plasma concentrations at the time of each recorded vancomycin assay, and their accuracy and bias were compared. Goodness of fit at both the population and individual level was assessed, and elastic net regression was used to identify any sources of predictive error in the obese-specific model. Model parameters for each model were then re-estimated, and a variety of body size metrics were evaluated.

Results

The Buelga et al. one-compartment model had the best predictive ability (Table 1). In all models, bias (calculated as MME; mean per-patient mean predictive error) by obesity class was observed at both the population and individual levels, and unexpectedly was largest in the obese-specific model. In the obese-specific model, predictive error correlated with the use of TBW as a model covariate. A set of models derived from Adane et al. model were then developed to correct for weight. Using ideal body weight (IBW) on Vd and no correction for weight on CL provided the best fit. The derived model accounted for 81% of variance in plasma concentration and exhibited negligible bias by obesity class (population MME = -0.75 (i), -0.06 (ii), and -0.50 (iii) mg/L; individual MME = −0.20 (i), −0.02 (ii), and −0.02 (iii) mg/L).

Conclusion

Existing vancomycin population PK models for use in the obese population are biased in higher obesity classes due to the use of total body weight. A novel population PK model developed using ideal body weight exhibits negligible bias across obesity classes as well as improved predictive ability.

Disclosures

All authors: No reported disclosures.
1583. Eight Years of Sustained Potency and Activity of Oritavancin against Gram-Positive Isolates Causing Bacteremia and Endocarditis in the USA, Including Enterococcal Infections Requiring an Optimized Dosing Strategy for Daptomycin
Authors: Carvalhaes Cecilia G , Sader Helio S , Streit Jennifer M , Flamm Robert K , Mendes Rodrigo E
Published: October 2019

Background

Oritavancin (ORI) is a potent lipoglycopeptide with desirable PK/PD parameters for treating serious gram-positive infections. This study assessed the activity of ORI against Staphylococcus aureus (SA), Enterococcus faecalis (EF), and E. faecium (EFM) causing bloodstream infection (BSI), including infective endocarditis (IE) and daptomycin (DAP)- susceptible dose-dependent (SDD) vancomycin-resistant (VRE) subsets. We also evaluated the longitudinal activity of ORI.

Methods

A total of 5,469 SA, 1,157 EF, and 721 EFM were recovered from BSI in 35 US sites (2011–2018). Subsets of SA isolates causing IE (84) and EFM displaying DAP-SDD-VRE phenotypes (230) were included. Identification was confirmed by MALDI-TOF MS and isolates were tested for susceptibility (S) according to CLSI.

Results

Overall, ORI showed similar MIC50 (0.03 mg/L) and MIC90 results (0.06 mg/L) against MRSA and MSSA (figure) and the SA EC subset (41.7% MRSA; data not shown). Similar findings were noted for ORI tested against EF DAP-S (MIC50/90, 0.015/0.06 mg/L) and DAP-SDD (MIC50/90, 0.015/0.06 mg/L). ORI MIC values against DAP- and VAN-S EFM (MIC50/90, ≤0.008/0.015 mg/L) were at least 8-fold lower than those from DAP-SDD-VRE isolates (MIC50/90, 0.06/0.12 mg/L; 31.9% of all EFM), and all EFM were inhibited by ORI at ≤0.25 mg/L. The longitudinal analysis showed MRSA rates varying from 39.7% (2017) to 46.8% (2011), while the annual ORI MIC50 and MIC90 results were 0.015–0.06 mg/L and 0.03–0.12 mg/L, respectively, against MRSA during the 8-year period. ORI yearly MIC50 and MIC90 results were 0.015–0.03 mg/L and 0.03–0.12 mg/L against EF, respectively. MIC50 and MIC90 results of 0.008–0.03 mg/L and 0.03–0.12 mg/L, respectively, were obtained for ORI against the DAP-SDD EF subset each year. ORI MIC50 and MIC90 results of 0.03–0.06 and 0.06–0.12 mg/L were obtained annually against DAP-SDD-VRE (EFM), respectively.

Conclusion

ORI showed a potent activity against this collection of isolates causing BSI and IE in the USA, including resistant subsets requiring higher dosage regimens when treating serious infections. In addition, ORI maintained a stable potency throughout the 8-year study period with no apparent temporal trends.

Disclosures

All authors: No reported disclosures.
1595. Comparative In Vitro Activity of Imipenem–Relebactam Against Drug-Resistant Gram-Negative Isolates from Pediatric Patients
Authors: Banerjee Dithi , Harrison Christopher J , Pence Morgan , Selvarangan Rangaraj
Published: October 2019

Background

Drug resistance in Gram-negative bacteria is of particular concern in children. Relebactam, a novel diazabicyclooctane inhibitor, coupled with imipenem has broad-spectrum activity against β-lactamase producing organisms. Here, we compare the in vitro activity of imipenem-relebactam to 10 standard comparator drugs against resistant Gram-negative isolates from two US pediatric hospitals.

Methods

We tested 100 isolates (50 per site) from pediatric clinical specimens tested during 2015–2017. All isolates were extended-spectrum cephalosporin-resistant (ESC-R); more than half were multidrug resistant (67%). Selected ESC-R isolates included Escherichia coli (90), Klebsiella pneumoniae (8), Klebsiella oxytoca (1), and Enterobacter cloacae (1) that were resistant or intermediate to ≥1 cephalosporins and/or aztreonam. A 0.5 McFarland suspension was prepared from colonies grown on blood agar plates (Thermo Scientific) at 35 ± 1°C for 18–24 hours. A final inoculum of 5 × 105 CFU/mL was prepared in Mueller–Hinton broth. Sensititre plates (Thermo Fisher Scientific) containing graded concentrations of imipenem/relebactam and 10 comparator drugs were inoculated and incubated at 35 ± 1°C for 18–24 hours. The minimum inhibitory concentration (MIC) was determined using the Sensititre Vizion system (Thermo Fisher Scientific) and endpoints were interpreted using CLSI (2019) breakpoint criteria, with the exception of colistin (EUCAST 2019).

Results

Selected ESC-R isolates had high rates of resistance to cephalosporins (64%–97%), aztreonam (80%), and levofloxacin (61%). All isolates were susceptible to imipenem/relebactam, imipenem and meropenem (MIC, ≤1 μg/mL for all). The imipenem/relebactam MIC50 (0.06 μg/mL) and MIC90 (0.12 μg/mL) values for ESC-R isolates were within one dilution of MICs of imipenem alone (0.12 μg/mL and 0.25 μg/mL). Among the comparators, colistin, amikacin, and piperacillin/tazobactam demonstrated comparable activities with 100%, 99%, and 94% susceptibilities, respectively.

Conclusion

Meropenem, imipenem alone and in combination with relebactam exhibited 100% susceptibilities against ESC-R Enterobacteriaceae isolated from pediatric specimens, demonstrating the high potency of carbapenems.

Disclosures

All authors: No reported disclosures.
1600. Susceptibility of β-Lactam-Resistant Pseudomonas aeruginosa to Other β-Lactams: Is There Truly a Lack of Cross-Resistance?
Authors: Patel Twisha S , Marshall Vince , Kaye Keith S , Smith Aaron , Young Carol , Lephart Paul , Pogue Jason M
Published: October 2019

Background

Resistance to β-lactams in P. aeruginosa is complex with multiple mechanisms contributing. Since different mechanisms impact different β-lactams to differing degrees, a common dogma is that resistance to one β-lactam does not lead to resistance to others. The purpose of this analysis was to assess the frequency of β-lactam cross-resistance in P. aeruginosa.

Methods

Unique P. aeruginosa isolated in 2017 at Michigan Medicine were included. Overall, susceptibility (using CLSI breakpoints) and MIC distributions of β-lactams were assessed in all isolates and those with β-lactam resistance.

Results

3,836 unique P. aeruginosa isolates were included. Resistance to traditional anti-pseudomonal β-lactams ranged from 15–23%, whereas ceftolozane/tazobactam resistance was 6%. Overall, cross-resistance between β-lactams was common. The table displays select β-lactam MIC distributions for all isolates and in those resistant to ≥1 β-lactam. When resistance of one agent was present susceptibility to other β-lactams was generally <40% with the majority of susceptible isolates having MICs at or near the breakpoint. Ceftolozane/tazobactam provided the best activity in this setting with 65–77% susceptibility.

Conclusion

Cross-resistance between β-lactams in P. aeruginosa is common. In patients at risk for resistant P. aeruginosa, ceftolozane/tazobactam should be considered for empiric coverage.

Disclosures

All authors: No reported disclosures.
1606. Legionellosis Cluster Associated with Direct and Indirect Hot Tub Exposure—West Virginia, 2018
Authors: Rispens Jared R , Edens Chris , Barskey Albert , Mercante Jeffrey , Ritter Troy , Martin Stephen B , Hast Marisa , Siegel Miriam , Thomasson Erica , Huff Jackie L , Baker Carolyne A , Everly Chelsea
Published: October 2019

Background

In October 2018, the West Virginia Bureau for Public Health (BPH) notified CDC of one Legionella urinary antigen test (UAT)-positive case of Legionnaires’ disease (LD) in a worker at a racetrack facility. Following investigation by BPH and the county health department, five additional LD cases were identified among facility workers within a one-month period. Our objective was to determine the extent of the outbreak and identify potential sources of exposure.

Methods

We interviewed the previously identified patients and conducted case-finding among racetrack workers. Our case definitions included confirmed LD (pneumonia with a positive UAT), suspected LD (pneumonia without a UAT completed), and Pontiac fever (PF) (self-limited, nonspecific flu-like symptoms) among employees with exposure to the facility within 14 days prior to symptom onset. We conducted an environmental assessment of the facility and the surrounding area for sources of potential Legionella exposure.

Results

We identified 17 cases (71% in men, 35% in current smokers, median age 55 years): six confirmed LD, four suspected LD, and seven suspected PF cases. Our environmental assessment revealed a poorly maintained hot tub in the first floor jockey area. All samples collected from the hot tub (which was chlorinated before our arrival) tested negative for Legionella. Two employees with confirmed LD (33%), three with suspected LD (75%), and six with suspected PF (86%) had direct exposure to the hot tub or adjacent hallway; the remaining six were exposed only to a second floor office suite. Further investigation identified deficiencies in the facility’s ventilation systems and a crack in the floor between the hot tub and office areas. These factors created a pathway for Legionella-containing aerosols from the hot tub to pass into the second floor office space and air-handling unit for recirculation to occupied areas.

Conclusion

Our investigation suggests that both direct and indirect exposure to a Legionella reservoir can cause illness. This finding supports analysis of ventilation systems and airflow dynamics in future LD outbreak investigations. Clinicians should consider LD in pneumonia patients with direct or indirect exposure to suspected Legionella sources to ensure appropriate testing and treatment.

Disclosures

All authors: No reported disclosures.
1620. Effectiveness of the 2016 California Policy Eliminating Non-Medical Exemptions on Vaccine Coverage: A Synthetic Control Analysis
Authors: Nyathi Sindiso , Karpel Hannah , Sainani Kristin L , Maldonado Yvonne , Hotez Peter J , Bendavid Eran , Lo Nathan C
Published: October 2019

Background

Vaccine hesitancy in low vaccine coverage “hot spots” has led to recent outbreaks of vaccine-preventable diseases across the United States. State policies to improve vaccine coverage by restricting non-medical (personal belief) exemptions are heavily debated and their effectiveness is unclear due to limited rigorous policy analysis. In 2016, a California policy (SB 277) eliminated non-medical exemptions from kindergarten requirements. To address the ongoing debate on such policies, we performed a quasi-experimental, controlled analysis of the policy’s impact on vaccine and exemption outcomes.

Methods

We used state vaccine coverage and exemption data (2011–2017) from the CDC and health data from public sources. We prespecified a primary outcome of MMR coverage (%) and secondary outcomes of medical and non-medical exemptions (%). We included covariates related to socioeconomic and health measures (e.g., insurance, well child visits) and pre-2016 mean coverage. Using the synthetic control method, with 2016 as the treatment year and a 2-year post-policy period, we constructed a “control” California, from a weighted sum of states. We used permutation testing to repeat the process for each of the other states and their unique synthetic control, to determine whether there was a meaningful difference in California (i.e., a change in California’s coverage relative to its control in the top 5th percentile of states). We tested the model’s sensitivity to various analytical assumptions.

Results

Of 43 control states, synthetic California was predominantly comprised of Idaho, Mississippi, and Arkansas, and had a good pre-policy match on outcomes. MMR coverage in California increased by 3.2% relative to synthetic California in the post period (Top 1 of 44 states, Figure 1). Medical exemptions increased by 0.4%, while non-medical exemptions decreased by 2.2% in the post-period (Top 1 of 43 states). The model was robust to changes in covariates and control states.

Conclusion

The policy resulted in a meaningful increase in MMR coverage and reduction in non-medical exemptions. We measured a modest increase in medical exemptions, but this was offset by the larger reduction in non-medical exemptions. State policies removing non-medical exemptions can be effective in increasing vaccination coverage.

Disclosures

All authors: No reported disclosures.
1656. Klebsiella pneumoniae Antimicrobial Susceptibility to Carbapenems in Latin America Between 2000 and 2014
Authors: Sati Hatim , Bruinsma Nienke , Hsieh Jenny , Galas Marcelo F , Ramon-Pardo Pilar
Published: October 2019

Background

Antimicrobial resistance (AMR) to carbapenems in Enterobacteriaceae such as Klebsiella pneumoniae (KPN) is a major global public health concern. Infections caused by these pathogens are associated with high morbidity and mortality and perpetuated by limited safe alternative treatment options. This study aims to describe the antimicrobial susceptibility patterns amongst KPN to the carbapenems Latin America.

Methods

Surveillance laboratory data from 2000 to 2014 were obtained through the ReLAVRA network from 19 countries in Latin America. Longitudinal trends of mean percentage non-susceptibility for the region were conducted and evaluated with a significance level of P < 0.05.

Results

A total of 209,972 and 181,128 KPN isolates were reported from 2000 to 2014 for antibiotic susceptibility to imipenem and meropenem, respectively. From 2000 to 2014 an increasing trend was observed in the reported % KPN NS to imipenem (P < 0.0001) from 0.6% to 11.6% with an average annual percentage increase (AAPI) of 36.3% [95% CI: 39.8%–33%]. (Figure 1). Similarly, the % KPN NS to meropenem increased (P < 0.0001) from 0% in 2000 to 12.3% in 2014 with an AAPI of 49.5% [95% CI: 54%–44.6%] (Figure 2). For both antibiotics, the last 5 years of the timeframe (2010 to 2014) showed the highest rate of increase in NS. NS to carbapenems varied significantly between reporting countries, with the highest % KPN NS to imipenem and meropenem reported by Brazil, Guatemala, Nicaragua, and Peru.

Conclusion

The increase in KPN NS to carbapenems observed in Latin America threatens effective treatment of infections caused by this pathogen. The extremely limited treatment options could lead to further increases in morbidity and mortality. Strengthening health systems and core country capacity to identify and deal with these emerging high-risk pathogens and resistance mechanisms, through surveillance is vital to inform public health actions, control measures, mitigate outbreaks and support further development of Public health actions against AMR at country and regional level.

Disclosures

All authors: No reported disclosures.
1690. Risk Factors of Invasive Aspergillosis in Systemic Lupus Erythematosus Patients
Authors: Kunawathanakul Sithichai , Meesing Atibordee , Foocharoen Chingching
Published: October 2019

Background

Invasive aspergillosis (IA) has been reported in systemic lupus erythematosus (SLE) patients. We assessed the risk factors of invasive aspergillosis in SLE patients.

Methods

A retrospective age- and sex-matched case–control study with ratio 3:1 in adult SLE patients from January 2002- December 2017 at Srinagarind Hospital, Khon Kaen University, KhonKaen, Thailand has been conducted. We excluded the patients who were overlap with other immunocompromised condition.

Results

Of 1,585 SLE patients, 22 patients (1.4%) had invasive aspergillosis and 66 controls were included in the study. The mean age was 36.9 ± 11.8 years and 76 (86.4%) patients were female. SLE patients who developed IA had statistically significant lower median total absolute lymphocyte count than control (503 vs. 1342 cells/mm3, P = 0.05) and history of steroid treatment (adjusted OR 21.43, P = 0.006) were the risk factor of IA.

Conclusion

There was a low prevalence of IA in SLE patients. Low total lymphocyte count, renal impairment and history of steroid treatment were significantly associated with invasive aspergillosis in SLE patients.

Disclosures

All authors: No reported disclosures.