bluuebunny/crossref_metadata_2025 huggingface dataset:
685. An In Vitro Investigation of WCK 5222 (Cefepime/Zidebactam) and Currently Available Combination Antibiotic Regimens Against Enterobacteriaceae That Co-express Serine-β-Lactamase (SBL) and Metallo-β-Lactamase (MBL) Enzymes
Authors: Avery Lindsay M , Mullane Elias M , Nicolau David P
Published: October 2019

Background

Carbapenem-resistant Enterobacteriaceae (CRE) that simultaneously harbor SBLs and MBLs may demonstrate pan-drug resistance. Current therapeutic options include combinations of aztreonam (ATM), which is resistant to hydrolysis by MBLs, plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) for coverage of relevant SBLs. However, these selections add a level of complexity to clinical management compared with administration of a single antibiotic as monotherapy.

Methods

Minimum inhibitory concentrations (MICs) of WCK 5222 (cefepime/zidebactam), ATM, CZA, and M/V were determined with Liofilchem MIC Test Strips against SBL- and MBL-positive CRE (N = 15). The gradient diffusion strip (GDS) cross method was used to assess the activities of CZA+ATM and M/V+ATM. Additive interactions as defined by fractional inhibitory concentration indices ≤ 1 would be predicted based upon the known genotypic profiles; thus, the relative activities of the combination regimens were compared with the “zone of hope” (ZOH) test. The size of the ZOH (the zone of inhibited growth) was quantitated by multiplying the observed length of inhibited growth (in mm) adjacent to each GDS from the point of intersection. The Mann–Whitney rank-sum test was used to assess differences.

Results

All isolates (N = 15) contained one MBL and ≥1 SBL, and were resistant to ATM, CZA, and M/V with the exception of one isolate intermediate to M/V (MIC=8 mg/L). The WCK 5222 MIC50 (range) was 1 (0.19–2) mg/L. The median (interquartile range) ZOH product for CZA+ATM and M/V+ATM was 75.4 (62.8–93.7) and 23.5 (14.1–60.4), respectively (P = 0.002). In strains that produced OXA-type carbapenemases (n = 6), the median ZOH product for CZA+ATM and M/V+ATM was 78.1 and 20.7, respectively (P = 0.004). In the remaining 9 strains with a single carbapenemase (i.e., the MBL),the median ZOH product for CZA+ATM and M/V+ATM was 73.8 and 25.6, respectively (P = 0.052).

Conclusion

WCK 5222 displayed potent in vitro activity against SBL- and MBL-positive CRE, warranting further pre-clinical in vivo evaluation as a monotherapy option. When considering the co-expression of SBL and MBL, CZA+ATM appears to offer enhanced coverage compared with M/V+ATM.

Disclosures

All authors: No reported disclosures.
689. Therapeutic Efficacy of CB-012, a Novel Cloudbreak Antiviral Fc-Conjugate (AVC) in Lethal Mouse Models of Influenza A (H1N1) and Influenza B (Victoria)
Authors: Levin James , Borchardt Allen , Lam Thanh , Jiang Wanlong , Chen Zhi-Yong , Fortier Joanne , Akers-Rodriguez Suzanne , Amundson Karin , Donatelli Joanna , Döhrmann Simon , Cole Jason , Tari Les
Published: October 2019

Background

In 2018, the World Health Organization estimated up to 650,000 influenza-related respiratory deaths occur annually. Cidara therapeutics is developing a novel class of potent, long-acting antiviral Fc-conjugates (AVCs) against influenza that in a single molecule combine a surface-acting antiviral agent with the Fc domain of a human IgG1 antibody. AVCs function by inhibiting viral replication while simultaneously engaging the immune system, providing a multimodal mechanism of action. Here we present efficacy data on an AVC development candidate against influenza A and B.

Methods

Efficacy studies were conducted in female BALB/c mice (6–8 weeks) challenged intranasally with 3x the LD95 of influenza A/Puerto Rico/8/1934 (H1N1) or B/Malaysia/2506/04. CB-012 or CB-012b (CB-012 with slightly modified Fc) was administered as a single intravenous (IV) dose 2 hours after challenge. Oseltamivir was dosed orally, twice daily for 5 days in the influenza A study. Vehicle and appropriate Fc controls were included. Body weights (BW) and mortality were monitored for 2 weeks; animals with 20% BW loss, or moribund, were scored as a death.

Results

In an initial study of CB-012 against influenza A, a single IV dose of 0.4 mg/kg was fully protective and statistically significant compared with the Fc control (P = 0.0027). In contrast, mice treated with oseltamivir at 5 mg/kg twice daily for 5 days were not protected; only the higher 20 mg/kg dose was fully protective. Importantly, mice treated with CB-012 (0.4 mg/kg) showed a transient BW loss of 1% compared with 14% in mice of the oseltamivir (20 mg/kg) group, although treatment was initiated at the same time. In a second study against influenza B, CB-012b was fully protective with a single IV dose at 0.3 mg/kg (P = 0.0027). In contrast, vehicle and Fc control groups reached mortality by day 6. BW loss in the CB-012b 0.3 mg/kg group was transient and <4% overall during the study.

Conclusion

The novel AVCs CB-012 and CB-012b demonstrated robust efficacy in multiple influenza models. In conjunction with previous findings against influenza A (H3N2), the data on CB-012 support its potential as a candidate against seasonal influenza. The continued development of CB-012 for the prevention and treatment of influenza is warranted.

Disclosures

All authors: No reported disclosures.
698. In vitro Activity of a New Generation Oxopyrazole Antibiotic Against Multidrug-Resistant Gram-Negative Bacilli
Authors: Goldberg Joel , Bethel Christopher , Hujer Andrea M , Hujer Kristine , Marshall Steven , Papp-Wallace Krisztina M , Perez Federico , Spencer Elizabeth , Hoyer Denton , Plummer Mark , Bonomo Robert A
Published: October 2019

Background

Multidrug-resistant Gram-negative bacilli (MDRGNB) are emerging as a challenging cause of hospital-acquired infections and represent a critical need for innovative antibacterial development. New oxopyrazole agents targeting penicillin-binding proteins (PBPs) based on a non-β-lactam core and incorporating a siderophore moiety (Figure 1) which facilitates transport to the periplasm are being developed that show promise against Gram-negative organisms including multidrug-resistant strains of E. coli, K. pneumoniae and P. aeruginosa.

Methods

YU253434, an example of this new class of antibacterials, was investigated in vitro. Minimum inhibitory concentrations (MICs) were determined by broth microdilution against a representative panel comprising 15 strains each of E. coli, K. pneumoniae and P. aeruginosa, which contain extended-spectrum β-lactamase (ESBL) and/or carbapenemases genes.All studies were performed according to current Clinical & Laboratory Standards Institute (CLSI) guidelines using iron-depleted media. Ceftazidime breakpoints were arbitrability chosen as a reference for YU253434 (susceptibilities ≤4 μg/mL for Enterobacteriaceae and ≤8 μg/mL for P. aeruginosa).

Results

MIC testing (Figures 2–4) against E. coli showed 11 strains were YU253434 susceptible (compared with 6 for ceftazidime, and 3 for imipenem); against K. pneumoniae 13 strains were YU253434 susceptible (compared with 2 for ceftazidime and 6 for imipenem); against P. aeruginosa 10 strains were YU253434 susceptible (compared with 0 for both ceftazidime and imipenem). There appeared to be no correlation between YU253434 resistance and the presence of specific lactamase genes.

Conclusion

YU253434, a new generation oxopyrazole antibiotic, demonstrated promising in vitro potency against a panel of E. coli, K. pneumonia, and P. aeruginosa strains which contain ESBL and/or carbapenemases genes.

Disclosures

All authors: No reported disclosures.
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

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

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

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

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

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

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

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

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

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.
754. Evaluation of Standardized Dalbavancin Use to Facilitate Early Hospital Discharge for Patients Inappropriate for Outpatient Parenteral Antibiotic Therapy
Authors: Shihadeh Katherine C , Young Heather , Wyles David L , Jenkins Timothy C
Published: October 2019

Background

Patients frequently remain in the hospital for prolonged intravenous (IV) antibiotic therapy for serious infections when outpatient IV antibiotic therapy is unsafe or unfeasible. A protocol was developed to facilitate early discharge by administering one dose of dalbavancin 7 – 10 days prior to the planned end of treatment, allowing patient discharge the same day as the infusion. The purpose of this analysis was to describe the effectiveness, safety, and financial impact by using dalbavancin to facilitate early discharge.

Methods

This is a retrospective observational analysis of all inpatients who received dalbavancin at Denver Health Medical Center from April 2018 to April 2019. One dose of dalbavancin 1,500 mg was administered over 30 minutes to each patient. The medical record was reviewed 30 days after discharge to determine safety (adverse reaction to dalbavancin) and effectiveness (readmission or receipt of additional antibiotics). The estimated cost of one hospital day was $1,800; one dose of dalbavancin costs $3,000.

Results

Sixteen patients (69% male; average age 45 years) received dalbavancin. The majority of patients were homeless (81%), injection drug users (75%), and infected with HCV (56%). One patient was infected with HIV (6%) and none had diabetes, kidney disease, or cirrhosis. Antibiotics administered prior to dalbavancin were vancomycin or cefazolin, based on organism, for a median duration of 25 days (IQR 11–34). Patients were infected with methicillin-resistant S. aureus (n = 8), methicillin-susceptible S. aureus (n = 7), and one co-infection with S. epidermidis and S. pyogenes. The infections included complicated bacteremia (n = 6), uncomplicated bacteremia (n = 4), osteomyelitis (n = 2), right-sided endocarditis (n = 2), and osteomyelitis with bacteremia (n = 2). No adverse reactions were noted. Readmission 30 days from discharge occurred for two patients for reasons unrelated to the infection or dalbavancin. None received additional antibiotics. 115 hospital days were averted (average of 7 days per patient). Cost savings to the hospital were estimated to be $159,000.

Conclusion

A standardized approach to use dalbavancin for serious infections to facilitate early hospital discharge appears to be safe and effective and led to substantial cost savings.

Disclosures

All authors: No reported disclosures.
761. Sepsis Readmissions and Coding in Two Community Hospitals
Authors: Cheruranky Anita , Li Aldon , Faiad Graciela
Published: October 2019

Background

An estimated 1.7 million adults in the United States develop sepsis and nearly 270,000 Americans die because of sepsis annually. A diagnosis of sepsis increases hospitalization costs, antibiotic usage, and mortality. Admissions for sepsis account for a high proportion of 30-day readmissions, creating a major financial burden for the healthcare system. However, reliable measurement of sepsis incidence remains challenging given increasing clinical awareness, changes in diagnosis/coding practices and changing definitions. We thus sought to evaluate sepsis readmissions and coding practices at 2 community hospitals (226, 99 beds).

Methods

A total of 997 hospitalizations occurred at both institutions with a primary diagnosis of sepsis from January 30, 2018–December 31, 2018; out of which 130 were readmitted within 30 days.An Infectious Disease trained physician reviewed all 130 index admissions and readmissions. Sepsis was defined as per the Centers for Medicare and Medicaid Services (CMS) sepsis-1 mandate: 2 of 4 SIRS criteria + suspected infection.

Results

All 130/130 (100%) index hospital admissions had a primary discharge diagnosis of sepsis, out of which only 85/130 (65%) met criteria for sepsis. While coded as sepsis, in 45/130 (35%) cases no infectious etiology was found. Among 130 readmissions 51 (39%) truly met criteria for sepsis. The infectious etiologies of index admissions included urinary tract infections (UTI) (18), pneumonia (16), bacteremia (16), abscess (9), Clostridium difficile infection (CDI) (8), cellulitis (5), neutropenic fever (5), cholecystitis (4), meningoencephalitis (1), candidemia (1). Readmissions that met criteria for sepsis included pneumonia (10), UTI (8), abscess (7), CDI (5), bacteremia (5), osteomyelitis (4), cellulitis (4), neutropenic fever (3), candidemia (2), and cholecystitis (2).

Conclusion

Shockingly 35% of the index admission cases were misdiagnosed as sepsis and as high as 61% on re-admissions. Increasing clinical awareness and compliance with CMS may have led to overdiagnosis and treatment of sepsis. Given the significant treatment and prevention initiatives that are being undertaken; reliable sepsis definition and coding is warranted for accurate surveillance purposes.

Disclosures

All authors: No reported disclosures.
762. Integrating Diagnostics of Tomorrow into Clinical Practice Today: One Infectious Disease Group’s First 90 Days Experience with the Karius® Test
Authors: Stetzler Trisha , Ahmad Sharjeel , Almoujahed Mohammad , Farrell John J , Hong David K , Kasper Douglas , Kim Joseph , Lin Rone , Patel Marlynn
Published: October 2019

Background

Infection disease (ID) groups covering inpatient and office, antimicrobial stewardship, and infection prevention duties may welcome an opportunity to streamline diagnostics via metagenomic next-generation sequencing (NGS). But the appropriate patient profile for NGS has yet to be defined. In 2019, we began using the Karius Test (KT), an NGS test that identifies and quantifies microbial cell-free DNA in plasma.

Methods

On January 10, 2019 our ID group (7 MDs and an APN covering 14 Illinois hospitals) began using the KT (Redwood City, CA). 5 ml of whole blood is collected, spun to plasma, and shipped to Karius for analysis. Following NGS, human sequences are removed and remaining sequences are aligned to a curated pathogen database of >1,000 organisms. Organisms present above a statistical threshold are quantified in DNA molecules per microliter (MPM) and reported.

Results

Over 90 days 45 KTs were ordered on 42 patients (mean age = 46); including 3 repeat tests. Thirty-six were inpatients (8 in the ICU) with a mean 4.7 days to ID consult and length-of-stay of 16 days. 31% (13/42) were immunocompromised: i.e., transplant, oncology, or HIV/AIDS. Fine needle or open biopsies were performed on 13 patients and 13 patients had bronchoscopy; 30.8% (8/26) were diagnostic of infection. A valid KT result was returned in 44/45 tests (mean 3.5 days from ID consult). 56.8% (25/44) of tests were positive for one or more organisms (a single pathogen was detected on 11 KTs). Among positive tests, 56% (14/25 - 10 bacterial and 4 fungal infections) were confirmed by culture, antigen, or PCR. Mean time to diagnosis for culture, PCR, antigen, and KT was 16.4, 3, 5.5, and 3.5 days, respectively. In 3 cases, the KT was the only positive test but correlated with the clinical scenario resulting in antimicrobial changes (Pneumocystis jirovecii pneumonia in AIDS, pulmonary aspergillosis in AIDS, and Fusobacterium nucleatum septic thrombophlebitis).

Conclusion

We identified 4 clinical scenarios where the KT provided value: patients with suspected invasive fungal infections, culture-negative endovascular infections/endocarditis, possible discitis or paravertebral infection, and pulmonary disease in AIDS. Future efforts will include outreach for prevention of invasive diagnostic procedures when a KT is pending or positive.

Disclosures

All authors: No reported disclosures.
778. ID Rocks It: Infectious Disease Remotely Offered Consultative Knowledge and Support via Inpatient Telehealth
Authors: Tande Aaron J , Berbari Elie , Ramar Priya , Ponamgi Shiva , Sharma Umesh , Philpot Lindsey , Ebbert Jon , O’Horo John C
Published: October 2019

Background

Infectious diseases (ID) consultation is associated with improved outcomes for patients hospitalized with infection. Provision of this service is not practical for many smaller hospitals, particularly critical access facilities. We sought to evaluate the impact of an electronic, asynchronous consultative service (“eConsults”) at two rural hospitals without on-site ID support.

Methods

Beginning July 2018, ID physicians at Mayo Clinic, Rochester, began performing asynchronous eConsults for patients hospitalized at Mayo Clinic Health System (MCHS) Albert Lea and MCHS Austin Hospitals. The first 100 consecutive patients receiving eConsults (cases) were compared with patients admitted for infection at the same facilities prior to pilot initiation (controls). Cases were matched to controls using 1:3 propensity match based on age, gender, race, and weighted Charlson comorbidity index. The primary outcome was readmission or death within 30 days after hospital discharge.

Results

Cases (n = 100) were more likely to have been hospitalized in the 6 months prior to the index hospitalization than controls (n = 300) (P < 0.0001). Patients with ID eConsult had a significantly decreased odds of death at 30 days (OR 0.3, 95% CI 0.2–0.7, P = 0.003) and there was a trend toward decreased readmission at 30 days (OR 0.4, 95% CI 0.2–1.1, P = 0.07). The mean length of stay was significantly longer for cases (5.7 days vs. 3.8 days, P =0.003). However, ID eConsult did not occur until 2.6 days into hospitalization, on average.

Conclusion

ID eConsultation was associated with lower odds of 30-day mortality. The increased length of stay may be mitigated by encouraging ID eConsults earlier during hospitalization. Inpatient ID eConsults represent a high-value proposition for patients and providers and a feasible means of expanding the reach of ID physicians. This novel care delivery model warrants further investigations.

Disclosures

All authors: No reported disclosures.
780. Inpatient Addiction Medicine Consultations at the Urban/Rural Frontier: Improving Quality of Care and Linkage to Outpatient Services for Patients with Substance Use Disorder in Central Kentucky
Authors: Fanucchi Laura , Oller Devin
Published: October 2019

Background

When persons with opioid use disorder (OUD) are hospitalized with medical complications (e,g. endocarditis, viral hepatitis) they frequently do not receive medications for the underlying OUD. In recent years, a number of hospitals have implemented addiction medicine consultation (AMC) services to help address this treatment gap, though these are all in large urban centers. AMCs provide comprehensive substance use disorder (SUD) assessments, manage SUDs, initiate pharmacotherapy for OUD, and arrange linkage to ongoing treatment. The aim of this study was to describe the initial implementation and outcomes of a new AMC at the University of Kentucky Hospital, a 945-bed tertiary referral center with a large rural catchment.

Methods

The Addiction Consultation and Education Service(ACES) began October, 2018 and was comprised of several physicians and an APRN. A patient navigator assisted with prior authorizations and outpatient linkage. ACES referred to a new bridge clinic at the University for ongoing office-based opioid treatment as well as to community programs and licensed opioid treatment programs. Patient demographics, SUD diagnoses, and comorbidities (including details of the injection-related infections) are collected from the electronic health record, as well as key process metrics including: time-to-consultation and medication initiation, length of stay(LOS), discharge against medical advice(AMA), and details of linkage to outpatient services.

Results

From October-December, 91 patients were seen, 73 met DSM-5 criteria for OUD, 82 had a medical complication of SUD, and 53 lived in rural counties (Rural-Urban Continuum Codes 4–9). Average LOS was 19.5 days. Among OUD patients, 71% underwent buprenorphine/naloxone induction, 9% were started on methadone. Less than 6% of patients started on buprenorphine or methadone left against medical advice.

Conclusion

AMCs are a key part of providing comprehensive care for persons hospitalized with infectious complications of substance use. Initiating medication for OUD likely decreases rates of discharge against medical advice. Compared with other AMCs, a greater percentage of patients seen by ACES resided in rural counties. Establishing a bridge clinic prior to starting an AMC is critical to ensure ongoing care.

Disclosures

All authors: No reported disclosures.
994. Effect on Β-lactam Usage Following Implementation of Clinical Pharmacy Services to Improve Β-lactam Allergy History Documentation
Authors: Harrington Nicole , Drews Victoria , Laude Jillian , Care Julianne , Walsh Donna
Published: October 2019

Background

The purpose of this study was to implement a pharmacy-initiated β-lactam allergy assessment and to determine its impact on antibiotic prescribing patterns. Avoiding the use of β-lactams due to a documented allergy may lead to inferior treatment outcomes, particularly for indications where β-lactams are preferred.

Methods

This performance improvement study was conducted at a large community-based academic healthcare system in Delaware. A β-lactam allergy algorithm was developed to guide allergy assessments and categorize patients as low risk for possible reaction, possible type 1 reaction or insufficient information. Pharmacy residents and clinical pharmacists were educated on how to conduct the assessments, which were then performed on inpatients with a β-lactam allergy that were prescribed a non-β-lactam antibiotic from December 2018 through March 2019. The primary outcome of this study was the percentage of patients ordered a β-lactam antibiotic pre- and post-implementation of the assessment. Secondary outcomes included: allergy assessment classifications, number of patients with an allergy discrepancy, percentage of patients switched to a β-lactam antibiotic, development of a reaction, and the number of allergy consultations ordered. The primary endpoint was analyzed using a Chi-square test.

Results

The percentage of patients prescribed a β-lactam pre- and post-implementation was 59% and 63%, respectively (P = 0.055). A total of101 patients had an allergy assessment performed. Assessments resulted in 45% of patients categorized as low risk, 45% as possible type 1 reaction and 10% as insufficient information. In summary, 33% of patients were changed to a β-lactam following completion of an assessment and zero patients experienced a reaction. Additionally, 69% of patients had an allergy discrepancy in their electronic medical record, and four patients received an allergy consultation.

Conclusion

The use of clinical pharmacy services to perform β-lactam allergy assessments was successful, as the majority of patients with a low-risk allergy classification were changed to a β-lactam antibiotic. The next steps for this project include engagement of infectious diseases and allergy specialists to further optimize clinical practice.

Disclosures

All authors: No reported disclosures.
995. A quality improvement initiative to increase penicillin allergy clarification and decrease aztreonam usage
Authors: rahbani Peggy
Published: October 2019

Background

Penicillin (PCN) allergy is a serious adverse reaction that prevents the use of first-line therapy. 10% of the population reports a PCN allergy; however, less than 1% is truly allergic. Elimination of false allergies significantly impacts patient’s lives and decreases antimicrobial resistance and cost. Inova Mount Vernon Hospital (IMVH) has reported lack of pharmacist’s interventions in allergy clarification and counseling thus leading to an increase in aztreonam usage.

The primary objective of the study was to increase pharmacist’s interventions in patient allergy clarification and counseling. The secondary objective was to decrease aztreonam duration of therapy (DOT) by 10%.

Methods

This project was conducted and monitored M-F on the pharmacy true north board March-December 2018. The initial step was to create a standard work and educate pharmacists on individualized PCN allergy patients interviewing and counseling. Pharmacist’s interventions tracking were made using the electronic reporting system. To quantify aztreonam usage, duration of therapy (DOT/1000) was collected during the study period and compared with data from 2017.

Results

During the study implementation, a total of 551 interventions pertaining to PCN allergy were documented by pharmacists between March-November 2018, compared with only 72 interventions made in March-November 2017 (7x increase, P < 0.005). Pharmacists while intervening clarified the allergy added the severity of the reaction, documented whether patients recently tolerated any PCN-based antibiotics, and de-labeled patients when appropriate. Allergy assessments lead to a decrease in aztreonam DOT/1000 by 12% in 2018 compared with 2017 and the overall antimicrobial stewardship goal was achieved.

Conclusion

Pharmacists interventions in allergy clarification helped with antibiotic de-escalation, improved safety, and de-labeled patients when appropriate. This initiative also increased physician and nursing awareness of the importance of clarifying PCN allergies. After successfully hardwiring this practice the pharmacy is partnering with nursing to implement PCN skin testing service at IMVH.

Disclosures

All authors: No reported disclosures.