bluuebunny/crossref_metadata_2025_split huggingface dataset:
701. Comparison of MIC Results for Gepotidacin by Agar Dilution and Broth Microdilution Methods
Authors: Arends S J Ryan , Canino Michele A , Roth Brieanna M , Rhomberg Paul R , Flamm Robert K , Scangarella-Oman Nicole 
Published: October 2019

Abstract

Background
Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study tested the equivalency of minimal inhibitory concentrations (MICs) obtained by 2 reference susceptibility testing methods, agar dilution (AD) and broth microdilution (BMD), for gepotidacin against Gram-positive and Gram-negative organisms.

Methods
Susceptibility testing for both methods was performed on a total of 733 clinical isolates recovered largely in 2016 from over 120 medical centers worldwide. For N. gonorrhoeae, only the AD method is recommended by CLSI, therefore BMD was performed using Fastidious Broth for comparison purposes. Essential agreement (EA) based on evaluable results was calculated as the number of isolates with MICs within one 2-fold dilution of the reference method divided by the total number of results. Equivalency was defined using the 95% criteria from the FDA’s class II controls document.

Results
The EA observed for gepotidacin with these 2 methods was 85.8% overall and 98.3% when H. influenzae and N. gonorrhoeae isolates were excluded. Slightly higher gepotidacin MICs were observed when tested by BMD for each of these species/groups; this trend was especially prominent for E. coli and S. pyogenes. Gepotidacin tested against H. influenzae (73.1%) or N. gonorrhoeae (28.6%) species had much lower EAs.

Conclusion
Equivalency (EA >95%) was established between AD and BMD methods for determining gepotidacin susceptibility results against Staphylococcus spp., Streptococcus spp. and E. coli. However, for N. gonorrhoeae and H. influenzae, equivalency between the 2 methods was not established; therefore, future antimicrobial susceptibility testing for gepotidacin against these organisms should adhere to the methods for which quality control ranges and breakpoints are approved.

Disclosures
All authors: No reported disclosures.
703. In Vitro Activity of Lefamulin Against Bacterial Pathogens Causing Community-Acquired Bacterial Pneumonia (CABP): SENTRY Surveillance 2017–2018 Results From the United States (US)
Authors: Sader Helio S , Paukner Susanne , Arends S J Ryan , Gelone Steven P 
Published: October 2019

Abstract

Background
Lefamulin (LEF), a novel pleuromutilin protein synthesis inhibitor in development for use as an empiric IV and oral monotherapy for CABP, recently demonstrated safety and efficacy in two phase 3 trials in adults with CABP (PORT II–V). LEF IV or IV/oral (5–7 days; 10 days for methicillin-resistant Staphylococcus aureus [MRSA]) and LEF oral (5 days) were noninferior to MOX IV or IV/oral (7 days; 10 days for MRSA) and MOX oral (7 days) in patients with CABP caused by the most prevalent typical and atypical bacterial pathogens. This study investigated the in vitro activity of LEF and comparators against bacterial respiratory pathogens collected in the United States in 2017 and 2018.

Methods
As part of the SENTRY Surveillance Programme, isolates (n = 2299, 1/patient) were collected from 39 medical centers in the United States from patients with community-acquired respiratory tract infections (1812/2299 [78.8%]) and pneumonia in hospitalized patients (487/2299 [21.2%]). LEF and comparators were tested by broth microdilution and CLSI (2019) breakpoints were applied.

Results
LEF demonstrated potent antibacterial activity against all pathogens tested and was unaffected by resistance to other antibiotic classes (table). Streptococcus pneumoniae isolates were largely susceptible ( >80%) to most comparators; however, 45.6% and 20.4% were resistant (R) to macrolides and tetracycline, respectively. LEF exhibited a MIC50/90 of 0.12/0.25 mg/L for S. pneumoniae, including all R subsets. Among S. aureus isolates, and particularly MRSA, resistance to macrolides was high (48.5% and 81.2% R, respectively). LEF showed a MIC50/90 of 0.06/0.12 mg/L for S. aureus, including all R subsets. Haemophilus influenzae isolates were susceptible to all comparators except for ampicillin (31.4% R) and trimethoprim-sulfamethoxazole (35.3% R). LEF displayed a MIC50/90 of 0.5/2 mg/L for H. influenzae isolates. Moraxella catarrhalis isolates, which were largely β-lactamase positive (98%), were susceptible to all comparators.

Conclusion
LEF displayed potent in vitro activity against contemporary CABP pathogens collected in the United States. LEF activity was unaffected by resistance to other antibiotic classes, including fluoroquinolones, macrolides, β-lactams, and tetracyclines.

Disclosures
All authors: No reported disclosures.
722. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Hepatic Function
Authors: Wicha Wolfgang , Marbury Thomas C , Dowell James A , Lykens Lori , Leister Cathie , Ermer James , Gelone Steven P 
Published: October 2019

Abstract

Background
Patients with chronic liver disease (CLD) have impaired immune function, are prone to community-acquired bacterial pneumonia (CABP), and experience greater morbidity/mortality and healthcare costs than CABP patients without CLD. LEF, a novel pleuromutilin antibiotic (IV/oral) with primary liver elimination, was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with hepatic impairment.

Methods
In this open-label study, subjects were allocated to 1 of 3 groups based on hepatic function level; Moderate (Child-Pugh score 7–9) or Severe subjects (Child-Pugh score ≥10) were matched (gender, age, and weight) to subjects in the Normal group (normal hepatic function, no liver cirrhosis). Subjects received a single 1-hour 150 mg LEF infusion. Blood and urine samples were collected predose and over a 48-hour period postdose for PK analysis; plasma and urine were assayed for LEF and BC-8041 using validated assays. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms.

Results
27 subjects enrolled in and completed the study (n = 11, Normal; n = 8, Moderate; n = 8, Severe). Mean LEF and BC-8041 plasma concentration profiles were comparable across all hepatic function groups through the first 12 hours following the start of infusion. Subjects with hepatic impairment had slightly slower rates of elimination in the later elimination phases. LEF and BC-8041 exposures were similar across all hepatic function groups (table), and the majority of LEF and BC-8041 were excreted nonrenally. TEAEs were reported in 2 (18.2%) subjects in the Normal group, 2 (25%) in the Moderate group, and 1 (12.5%) in the Severe group. None of the TEAEs were serious or led to study drug discontinuation. No subject met Hy’s law criteria. Within 4 hours postdose, the maximum mean change from baseline in the QTcF interval was 12.4, 19.2, and 14.1 msec in the Normal, Moderate, and Severe groups, respectively.

Conclusion
No dosage adjustment for LEF appears to be required when treating subjects with hepatic impairment. LEF was generally well tolerated in all subjects regardless of hepatic functional status.

Disclosures
All authors: No reported disclosures
724. The In Vitro Activity of Gepotidacin and Comparator Agents Against Anaerobic Bacterial Isolates
Authors: Hackel Meredith , Canino Michele A , Sahm Daniel F , Scangarella-Oman Nicole 
Published: October 2019

Abstract

Background
Gepotidacin (GSK2140944) is a first in class novel triazaacenaphthylene bacterial type II topoisomerase inhibitor in clinical development for the treatment of gonorrhea and uncomplicated UTI (acute cystitis). Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism not utilized by any currently approved therapeutic agent and demonstrates in vitro activity against most target pathogens resistant to established antibacterials, including fluoroquinolones. This study assessed the in vitro activity of gepotidacin and comparators against a collection of 649 Gram-positive and Gram-negative anaerobic bacterial clinical isolates.

Methods
A total of 649 clinically significant Gram-negative (333) and Gram-positive (316) anaerobic clinical isolates previously collected and frozen at −70°C were tested. Isolates came from North America (315/48.5%) and Europe (334/51.5%) and were collected between 2000 and 2017. Minimum inhibitory concentrations (MICs) for gepotidacin and 6 comparators were determined by agar dilution (AD) for all isolates, and by both AD and broth microdilution (BMD) for Bacteroides spp. according to CLSI guidelines (CLSI M11-A8). Most Lactobacillus spp. tested in this study require anaerobic conditions for growth and were tested by anaerobic AD.

Results
The in vitro activity results of gepotidacin and comparators are shown in the table below. The gepotidacin MIC90 for all Gram-negative anaerobic isolates tested in this study was 4 µg/mL and for the comparators tested was as follows: ceftriaxone 512 μg/mL, clindamycin >8 μg/mL, imipenem 0.5 μg/mL, metronidazole 2 μg/mL, moxifloxacin 8 μg/mL and piperacillin–tazobactam 16 μg/mL. Gepotidacin had the lowest MIC90 (2 μg/mL) for the Gram-positive anaerobic isolates compared with the other antibiotics tested, with the exception of metronidazole (MIC90 = 0.5 µg/mL).

Conclusion
Gepotidacin showed in vitro activity against a collection of 649 anaerobic Gram-negative and Gram-positive clinical isolates, with an MIC90 value against all Gram-negative anaerobic isolates of 4 µg/mL, and against all Gram-positive anaerobic isolates of 2 µg/mL.

Disclosures
All authors: No reported disclosures.
729. Comparing Length of Stay and Clinical Outcomes for Hospitalized Patients at Bridgeport Hospital who Received Baloxavir Marboxil (BM) or Oseltamivir Phosphate (OP) During the 2018–2019 Influenza Season
Authors: Nachiappan Arun C , Yang Wei-Teng 
Published: October 2019

Abstract

Background
BM has been approved for the management of acute uncomplicated influenza in otherwise healthy individuals between age 12 and 64, and found to have a greater reduction in viremia. The original trial excluded hospitalized patients and those with co-morbidities.

Methods
This is a single-center, retrospective analysis of hospitalized patients diagnosed with influenza between October 1, 2018 and March 31, 2019. This study excluded those diagnosed before the addition of BM to the hospital formulary; those who were not treated with antivirals, treated before admission, or treated with both antivirals; those younger than 12 years old; and those who remain hospitalized. The relationship between length of stay and antiviral used was ascertained using t-test and multivariate linear regression. Due to heterogeneity in reasons for hospitalization, analysis was stratified by the main reasons for hospitalization. T-test and Wilcoxon’s rank-sum test were used for continuous variables, and Pearson’s chi-squared test was used for categorical variables. The significance level was 0.05.

Results
The study population (n = 145) has a mean age of 66.5 years; of whom, 43% are male. In terms of patient characteristics, those treated with BM (n = 105) vs. OP (n = 40) were older, less frequently admitted to ICU and of differing ethnic composition. The length of stay was similar in those treated with BM vs. OP in both univariate and multivariate linear regression (5.5 (5.3) vs. 8.2 (11.4) days, P = 0.33). In addition, the length of stay was similar in those treated with BM vs. OP when stratified by reasons for hospitalization: pneumonia/bronchitis (6.6 (7.1) vs. 8.2 (9.2) days, P = 0.43), obstructive airway disease exacerbation (5.5 (4.8) vs. 4.8 (8.0) days, P = 0.56), elderly with multiple co-morbidities (5.0 (4.0) vs. 3.4 (6.8) days, P = 0.63), reactive airway disease (4.1 (4.8) vs. 7.4 (1.5) days, P = 0.27) or congestive heart failure exacerbation (9.8 (9.0) vs. 5.6 (5.0) days, P = 0.43).

Conclusion
In hospitalized patients with co-morbidities diagnosed with influenza, there was no difference in length of stay in those who received BM vs. OP. This highlights the need to clarify the role of BM in this population, particularly given its comparable symptom reduction, greater cost, and the emergence of PA138T viral mutant.

Disclosures
All authors: No reported disclosures.
732. Posaconazole Serum Drug Levels Associated with Pseudohyperaldosteronism
Authors: Nguyen Minh-Vu Hoang , Davis Matthew R , Wittenberg Rebecca , Mchardy Ian , Baddley John W , Young Brian , Odermatt Alex , Thompson George R 
Published: October 2019

Abstract

Background
Posaconazole is an extended-spectrum triazole used in the treatment and prophylaxis of many fungal diseases. There have been case reports of posaconazole-induced pseudohyperaldosteronism; however, its occurrence and association with serum posaconazole drug levels need further investigation.

Methods
In this single-center retrospective observational study, we examined the occurrence of posaconazole-induced pseudohyperaldosteronism (PIPH), diagnosed either clinically or via laboratory abnormalities, and evaluated differences in serum posaconazole concentration and clinical characteristics between those with and without this syndrome.

Results
Sixty-nine patients receiving posaconazole were included; of whom, 16 (23.2%) met the definition of PIPH. Patients with PIPH were significantly older (61.1 vs. 44.7 years, P = 0.007), more frequently had hypertension prior to starting posaconazole (68.8% vs. 32.1%, P = 0.009), and were more frequently prescribed posaconazole for active treatment instead of prophylaxis compared with patients without PIPH (62.5% vs. 24.5%, P = 0.005). Patients with PIPH had a significantly higher median serum posaconazole level than those without PIPH (3.0 vs. 1.2 µg/mL, P = 0.0001). There was a positive correlation between serum posaconazole level and change in systolic blood pressure (r = 0.37, P = 0.01), a negative correlation between serum posaconazole level and change in serum potassium (r = −0.39, P = 0.006), and a positive correlation between serum posaconazole level and serum 11-deoxycortisol (r = 0.69, P < 0.0001).

Conclusion
Posaconazole is associated with secondary hypertension and hypokalemia, consistent with pseudohyperaldosteronism, and development is associated with higher serum posaconazole concentrations, older age, and baseline hypertension. Management may include dose reduction, the addition of an aldosterone antagonist, or an alternative triazole agent.

Disclosures
All authors: No reported disclosures.
733. Pharmacokinetic–Pharmacodynamic (PK–PD) Analyses for Alanine Aminotransferase (ALT) Using Phase 3 Data From Omadacycline (OMC)-Treated Patients
Authors: Bhavnani Sujata M , Trang Michael , George Darryl R , Liolios Kathryn , McGovern Paul C , Friedrich Lawrence , Steenbergen Judith N , Rubino Christopher M , Tzanis Evan , Ambrose Paul G , Hammel Jeffrey P 
Published: October 2019

Abstract

Background
OMC, an aminomethylcycline structurally related to tetracycline agents, was recently approved by the US FDA for the treatment of adult patients with ABSSSI (IV-to-PO and PO regimens) and CABP (IV-to-PO regimen). To better understand exposure-related concerns for ALT increase, PK-PD relationships for ALT were evaluated using data from OMC-treated patients enrolled in three Phase 3 studies.

Methods
Repeated-measures multiple linear regression was used to evaluate factors predictive of ALT, including different OMC total-drug AUC measures prior to each ALT, with interactions and covariates selected stepwise. Using a final AIC-optimized model, predicted percent probabilities of ALT elevation >1, 1.5, 2, 3, 5, and 10 × upper limit of normal (ULN) at any time post-baseline and up to 2 days after the end of therapy were calculated among analysis patients for fixed post-baseline OMC AUC measures, and among simulated patients after IV-to-PO and PO dosing regimens.

Results
The final model, developed using data from 327 patients with PK, included increased prior cumulative AUC among males, increased baseline gamma-glutamyl transferase, and study (ABSSSI, PO only) as factors predictive of increased ALT (P < 0.0001). However, the model-predicted impact of OMC across fixed average daily AUC values on ALT elevation endpoints of >1, 1.5, 2, 3, 5, and 10 × ULN was minimal (Figure 1), even for males despite the interaction with AUC (Figure 2). Among all patients, the estimated increases in percent probabilities for the 90th percentile of AUC relative to zero AUC were 5.81, 5.20, 1.53, 0.61, 0.31, and 0%, respectively, and ≤11.5, 7.76, 8.33, 1.31, 1.31, and 0%, respectively, across single variable patient subsets. Percent probabilities of ALT elevation endpoints were within 2.84% when comparing simulated and observed patients after administration of OMC IV-to-PO and PO dosing regimens (Figure 3).

Conclusion
A statistically significant relationship between an increase in ALT and increase in OMC AUC for males in the presence of other factors was found. However, increases in model-predicted ALT elevation endpoints across fixed OMC AUC values, or among simulated patients after administration of OMC IV-to-PO and PO dosing regimens relative to observed patients, were minimal.

Disclosures
All authors: No reported disclosures.
740. A Comparison of Process Outcomes Among Patients Receiving Outpatient Parenteral Antibiotic Therapy in Different Settings: A Quality Improvement Project
Authors: Brady Daniel , Zheng Crystal , Orner Jonathon , Bourgeois Camille , Luk Alfred , Widmer Kyle 
Published: October 2019

Abstract

Background
Outpatient parenteral antibiotic therapy (OPAT) is an effective way to provide long-term antibiotic therapy and simultaneously decrease hospital length of stay, minimize costs and improve patient satisfaction. However, OPAT is not always an efficient process and there are systemic challenges to providing adequate care and ensuring close follow-up. The aims of this project are to define the OPAT process at three New Orleans hospitals staffed by the Tulane Infectious Diseases Section and to determine process outcomes among patients receiving OPAT in different settings.

Methods
We utilized the knowledge of medicine residents, infectious diseases (ID) fellows and social workers to create a process map defining the current OPAT system [Figure 1]. We performed a retrospective chart review identifying patients who were discharged with OPAT from August 1, 2018 to November 30, 2018. The patients received OPAT in a variety of settings: long-term acute care facilities (LTACs), infusion centers, home, hemodialysis centers and prison. We measured the following process outcomes: if the patient arrived to an ID appointment, if safety laboratory results were available for review and if the patient completed the pre-specified antibiotic course. These outcomes were compared amongst the OPAT delivery settings.

Results
Our retrospective analysis identified 62 patients discharged with OPAT, although 2 patients were excluded due to lack of availability of records. Only 42% completed the pre-specified antibiotic course, 54% arrived to ID follow-up, and 38% had laboratory results available. We compared the completion of antibiotic course amongst the different OPAT settings (Figure 2). The highest rates of incompletion were amongst LTAC patients (n = 19, 73%) and prisoners (n = 3, 75%). Given that the highest number of patients who did not complete antibiotics were discharged to LTACs, we plan further investigation and intervention to target this population.

Conclusion
Patient outcomes among OPAT patients discharged from three New Orleans hospitals are poor, as evidenced by 58% failing to complete their pre-specified antibiotic course. The highest number of patients who failed were LTAC patients. We propose a further investigation into this population in order to improve the efficacy of the OPAT system.

Disclosures
All authors: No reported disclosures.
753. Outpatient Parenteral Antibiotic Therapy (OPAT) in a Large Urban Safety Net Hospital Setting: Therapy for Vulnerable Populations at Home
Authors: Ashley Appa Ayesha , Marquez Carina , Jain Vivek 
Published: October 2019

Abstract

Background
Adoption of outpatient parenteral antibiotic therapy (OPAT) is accelerating due to proven safety and value, but experience in safety-net settings remains limited, especially in those with history of illicit drug use. Emerging reports from safety-net settings have featured OPAT delivered in nursing facilities, respite care centers, and infusion centers (including some persons who inject drugs [PWID]), but literature is sparse on home-based OPAT for vulnerable patients. In a new home antibiotics program at San Francisco General Hospital, we sought to describe early safety and efficacy outcomes among adults without active injection drug use but with high rates of substance use and comorbid illnesses.

Methods
We conducted a cohort study of patients discharged from a large urban county medical center and enrolled in an outpatient IV antibiotics program from September 2017 to January 2019. We collected demographic and clinical data and computed outcomes of safety (30- and 90-day readmission for infection, vascular access complications, and death) and efficacy (completion of antibiotic therapy).

Results
Overall, 47 courses of antibiotics were given to 45 patients. Of these, 39/47 (83%) of antibiotic courses were administered in a residential setting, and 8/47 (17%) via the hospital outpatient infusion center. Comorbid conditions were common, including 9/45 (20%) with hepatitis B/C and 8/45 (18%) with HIV (Table 1). Present or prior illicit drug use was seen in 17/45 patients (38%), including recent or active illicit drug use in 11/45 (24%) (Table 1). Most common indications for antibiotics were osteomyelitis and bacteremia (Table 2). Efficacy in the OPAT program was high: overall, 44/47 (94%) courses of outpatient IV antibiotics were completed, and the 30-day and 90-day readmission rates were 13% and 20% respectively, with zero 30-day readmissions related to OPAT (Table 3).

Conclusion
An OPAT program embedded within a safety net hospital system delivering care in patients’ homes had high completion rate and low readmission rate, despite patients’ high prevalence of underlying comorbid conditions and noninjection illicit drug use. Home-based OPAT should be considered for broader adoption in safety-net hospital systems.

Disclosures
All authors: No reported disclosures.