bluuebunny/crossref_metadata_2025_split huggingface dataset:
673. Novel Delayed-Release Formulation of an Oral β-Lactamase Prevents Gut Microbiome Damage and Attenuates Antibiotic Resistance Caused by Oral Amoxicillin/Clavulanate without Interfering with Amoxicillin Systemic Absorption in Dogs
Authors: Connelly Sheila , Furlan-Freguia Christian , Fanelli Brian , Hasan Nur A , Colwell Rita R , Kaleko Michael 
Published: October 2019

Abstract

Background
Exposure of the gut microbiota to antibiotics can alter the composition of the microbiome and lead to the emergence and spread of antibiotic resistance. SYN-004 (ribaxamase) is a clinical-stage β-lactamase intended to degrade certain IV β-lactam antibiotics in the GI tract to preserve the gut microbiome. In a phase 2b clinical study, ribaxamase significantly reduced C. difficile infection in patients treated with IV ceftriaxone. A new delayed-release ribaxamase formulation, SYN-007, intended for use with oral β-lactams, was evaluated in dogs that received oral amoxicillin plus the β-lactamase inhibitor, clavulanate (amox/clav).

Methods
SYN-007 was engineered for release in the lower small intestine, distal to the site of antibiotic absorption. Dogs received amox/clav (40 mg/kg amox/5.7 mg/kg clav, PO, TID) +/- SYN-007 (10 mg, PO, TID) for 16 doses. Amoxicillin serum levels were measured by LC/MS/MS after the first and last doses. DNA, isolated from feces collected before and after antibiotic treatment, was analyzed by whole-genome shotgun sequencing using CosmosID, Inc. metagenomics software.

Results
Serum amoxicillin levels were not significantly different +/- SYN-007 after the first and last doses of amox/clav. Microbiome analyses revealed that amox/clav disrupted the gut microbiome resulting in loss of some species and overgrowth of other taxa. SYN-007 attenuated changes to gut microbiome composition. Amox/clav exposure resulted in the emergence of many, mainly TEM β-lactamase genes that was reduced with SYN-007.

Conclusion
Oral amox/clav disrupted the gut microbiome in dogs and resulted in the emergence of β-lactamase genes. SYN-007 diminished amox/clav-mediated microbiome disruption and attenuated emergence of β-lactamase genes. SYN-007 did not interfere with amox systemic absorption indicating that the β-lactamase was not released in the upper small intestine, the site of oral amoxicillin absorption. Antibiotic inactivation represents a potential new treatment paradigm for preservation of the gut microbiome and reduction of antibiotic resistance. SYN-007 has the potential to expand β-lactamase-mediated microbiome protection to oral as well as IV β-lactam antibiotics.

Disclosures
All authors: No reported disclosures.
686. Evaluation of Contezolid Activity to Anaerobic and Gram-positive-cocci Isolates from a Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial (MRX-I-06)
Authors: Yang Yang , Zhu Demei 
Published: October 2019

Abstract

Background
Contezolid (MRX-I) is an oxazolidinone in development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). In this study, in vitro susceptibility (S) for Contezolid and comparator agents for Gram-positive (GP) and anaerobic isolates from Phase 3 ABSSSI clinical trials were determined.

Methods
313 isolates were collected from 65 participated sites and sent to a central laboratory for MIC testing. Clinical isolates included 34 anaerobes (15 Finegoldia magna, 8 Actinomyces spp., 4 Prevotella spp., 3 Propionibacterium avidum, 2 Peptostreptococcus spp., 1 Veillonella spp. and 1 Bacteroides fragilis), 187 S. aureus (59.7%). 12 S. pyogenes, 5 Enterococcus, and 75 other Gram-positive organisms. Broth micro-dilution method was used to determine the MIC of contezolid, linezolid, and other comparators to facultative isolates. Agar dilution was carried out for the anaerobes.

Results
For both 33 MRSA and 154 MSSA MIC50/90 values of contezolid and linezolid were 2 mg/L. One E. faecalis showed decreased susceptibility to oxazolidinones (both MIC = 4). 1 mg/L contezolid and linezolid could inhibit 12 S. pyogenes. 2 mg/L contezolid and linezolid could inhibit 15 Finegoldia magna. 0.5 mg/L contezolid and linezolid could inhibit 8 Actinomyces spp. To one Bacteroides fragili, two Prevotella bivia and one Leuconostoc lactis (Intrinsic resistant to vancomycin) the MIC of contezolid were 4 or 8 mg/L. In general, Contezolid had lower or equal MIC50/90 values against both GP and ANA species compared with linezolid for all organisms.

Conclusion
Contezolid demonstrated potent in vitro antibacterial activity against Gram-positive and anaerobic isolates tested. These data suggest that contezolid might be a beneficial supplement to the arena against MDR Gram-positive infection.

Disclosures
All authors: No reported disclosures.
697. Evaluation of Contezolid Activity to Anaerobic and Gram-positive-cocci Isolates from a Phase 3 Acute Bacterial Skin and Skin Structure Infection Clinical Trial (MRX-I-06)
Authors: Yang Yang , Hu Fupin , Zhu Demei 
Published: October 2019

Abstract

Background
Contezolid (MRX-I) is an oxazolidinone in development for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). In this study, in vitro susceptibility (S) for Contezolid and comparator agents for Gram-positive (GP) and anaerobic isolates from Phase 3 ABSSSI clinical trials were determined.

Methods
313 isolates were collected from 65 participated sites and sent to a central laboratory for MIC testing. Clinical isolates included 34 anaerobes (15 Finegoldia magna, 8 Actinomyces spp., 4 Prevotella spp., 3 Propionibacterium avidum, 2 Peptostreptococcus spp., 1 Veillonella spp. and 1 Bacteroides fragilis), 187 S. aureus (59. 7%). 12 S. pyogenes, 5 Enterococcus and 75 other Gram-positive organisms. Broth micro-dilution method was used to determine the MIC of contezolid, linezolid and other comparators to facultative isolates. Agar dilution was carried out for the anaerobes.

Results
For both 33 MRSA and 154 MSSA MIC50/90 values of contezolid and linezolid were 2 mg/L. One E. faecalis showed decreased susceptibility to oxazolidinones (both MIC = 4). 1 mg/L contezolid and linezolid could inhibit 12 S. pyogenes. 2 mg/L contezolid and linezolid could inhibit 15 Finegoldia magna. 0.5 mg/L contezolid and linezolid could inhibit 8 Actinomyces spp. To one Bacteroides fragili, two Prevotella bivia and one Leuconostoc lactis (Intrinsic resistant to vancomycin) the MIC of contezolid were 4 or 8 mg/L. In general, Contezolid had lower or equal MIC50/90 values against both GP and ANA species compared with linezolid for all organisms.

Conclusion
Contezolid demonstrated potent in vitro antibacterial activity against Gram-positive and anaerobic isolates tested. These data suggest that contezolid might be a beneficial supplement to the arena against MDR Gram-positive infection.

Disclosures
All authors: No reported disclosures.
711. Exebacase (Lysin CF-301) Activity Against Staphylococcus aureus (S. aureus) Isolates From Bacteremic Patients Enrolled in a Phase 2 Study (CF-301-102)
Authors: Anastasiou Diane , Cassino Cara , Schuch Raymond 
Published: October 2019

Abstract

Background
Exebacase (CF-301) is a novel, recombinantly-produced, bacteriophage-derived lysin (cell wall hydrolase) which is the first lysin to report Phase 2 (Ph2) results which demonstrated 42.8% higher clinical responder rates with a single dose of exebacase used in addition to standard of care antibiotics (SOC) vs. SOC alone for the treatment of methicillin-resistant S. aureus (MRSA) bacteremia including endocarditis. We examined exebacase activity by broth microdilution (BMD) against baseline methicillin-sensitive S. aureus (MSSA) and MRSA isolates from each of the 116 participants in the recently complete exebacase”first in-patient’ Ph2 study (NCT03163446).

Methods
Patients with complicated bacteremia or endocarditis caused by S. aureus were enrolled into Study CF-301-102 at study centers in the United States, EU, Latin America, Israel, and Russia from 2017 and 2018. Baseline isolates from blood cultures were collected prior to administration of exebacase. Exebacase MICs against 117 isolates of MSSA (n = 74) and MRSA (n = 43) were determined at a central laboratory using a modified BMD approved by the CLSI for exebacase AST.

Results
The exebacase MICs of baseline patient isolates from the Ph2 study ranged from 0.125 – 2 µg/mL and the MIC50/90 values for all MSSA and MRSA isolates were 0.5/1 µg/mL. Exebacase MICs reported in a recent surveillance study were similar, with MIC50/90 values of 0.5/1 µg/mL. Of the 6 total subjects with EXE MICs of 2, 3 were clinical responders, 2 were indeterminate (not available for assessment), and 1 was a clinical nonresponder at Day 14.

Conclusion
Exebacase was highly active against all baseline S. aureus isolates from blood cultures obtained from bacteremic patients enrolled in the Ph2 study. Based on data from previously presented exposure target attainment animal studies, PK/PD modeling and preliminary nonclinical breakpoint assessments, we expected that strains with MIC values of ≤2 µg/mL will have been susceptible to the Ph2 clinical exebacase dose determined based on target attainment studies under study in Ph2.

Disclosures
All authors: No reported disclosures.
713. Preventive Administration of MEDI6389, a Combination of Monoclonal Antibodies (mAbs) Targeting Alpha-Toxin (AT), Panton-Valentine Leukocidin (PVL), Leukocidin ED (LukED), Gamma-Hemolysin and Clumping Factor A (ClfA), in a Rabbit Model of USA300 MRSA Prosthetic Joint Infection (PJI)
Authors: Yanjie Mao , Valour Florent , Vu Vi Tran Giang , Vu Trang , Delaye Thomas , Quynh Nhu Nguyen Tran , Tkaczyk Christine , Cheng Li , Sellman Bret R , An Diep Binh 
Published: October 2019

Abstract

Background
mAbs targeting staphylococcal virulence factors could represent an interesting preventive strategy in PJI. We evaluate here MEDI6389 compared with isotype-matched control IgG (c-IgG) in a rabbit model of USA300 MRSA PJI.

Methods
Rabbits were randomized for prophylaxis with either c-IgG (n = 13; 30 mg/kg; controls) or MEDI6389 (n = 13; 30 mg/kg of each mAb) administered intravenously 12h before infection. A cemented screw and ultrahigh-molecular-weight polyethylene washer were placed intraarticularly in the external femoral condyle. After suturing the joint capsule and musculocutaneous layers, 300 µL of a standardized bacterial inoculum containing 5 × 105 CFU of a USA300 MRSA clinical isolate were injected intraarticularly. Animals were euthanized on day 8 and the knee joint was harvested for bacteriological analysis (synovial bacterial counts, and enumeration of screw-adherent bacteria after sonication) and histology (conventional pathology, and transmission electron microscopy [TEM] for neutrophils analysis). In vivo observations made on neutrophils were confirmed by TEM analysis of human neutrophils incubated in vitro with purified PVL, LukED, and gamma-hemolysin with or without the corresponding mAb.

Results
In comparison with the control group, the average amount of pus (1.7 ± 1.8 vs. 3.1 ± 1.2 g, P = 0.026) and the number of bacteria in the synovial pus (5.9±1.5 vs. 7.2±1.4 log10 CFU, P = 0.031) and on the screw (2.7 ± 1.5 vs. 4.1 ± 1.6 log10 CFU, P = 0.035) were decreased in animals pretreated by MEDI6389. Conventional pathological examination showed a marked reduction in synovitis of MEDI6389-pretreated animals. TEM of synovitis harvested from infected knee joints of control animals showed significant greater number of abnormal neutrophils that appeared rounded, with condensed nucleus and no granules, compared with those pretreated with MEDI6389 (P = 0.002). This classical leukocidin-induced neutrophilic killing phenotype could be neutralized with anti-leukocidin mAbs using ex vivo human neutrophils incubated with PVL, LukED, HlgAB, or HlgCB.

Conclusion
The preventive administration of MEDI6389 allows a reduction of local inflammation and bacterial burden in this USA300 MRSA rabbit PJI model.

Disclosures
All authors: No reported disclosures.
726. APX001 (Fosmanogepix) Is Effective in an Immunosuppressed Mouse Model of Rhizopus oryzae Infection
Authors: Gebremariam Teklegiorgis , Alkhazraji Sondus , Gu Yiyou , Alqarihi Abdullah , Mamouei Zeinab , Shaw Karen J , Ibrahim Ashraf S 
Published: October 2019

Abstract

Background
Mucormycosis is a life-threatening infection that predominantly occurs in immunocompromised hosts. The antifungal APX001A (manogepix) inhibits Gwt1, an enzyme required for the conserved glycosylphosphatidyl inositol (GPI) post-translational modification in eukaryotes. We previously reported the activity of APX001 (fosmanogepix, the prodrug of APX001A) against Rhizopus delemar (minimum effective concentration [MEC] = 0.25 µg/mL). Here we assessed the activity against R. oryzae, which has an elevated MEC value.

Methods
R. oryzae 99–892 MIC and MEC values were 0.125 µg/mL and 4.0 µg/mL for isavuconazole (ISAV) and APX001A, respectively. ICR mice were immunosuppressed with cyclophosphamide (200 mg/kg) and cortisone acetate (500 mg/kg) on Days -2, +3, and +8 relative to intratracheal infection with 2.5 × 105 cells of R. oryzae 99–892. For survival studies, treatment with 104 mg/kg APX001 was compared with ISAV (110 mg/kg TID). Oral treatment started on Day +1 through Day +7, relative to infection for survival studies, and through Day +4 for tissue fungal burden studies (assessed by conidial equivalent [CE] using qPCR). Placebo mice received vehicle control. To extend the half-life of APX001, mice were administered 50 mg/kg of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) 2 h prior to APX001 administration.

Results
APX001 and ISAV equally prolonged median survival time of mice (n = 20) vs. placebo (12 and 14 days for APX001 and ISAV, respectively, vs. 8 days for placebo). Furthermore, APX001 and ISAV treatment both resulted in 30% 21-day survival vs. 0% survival of placebo mice (P < 0.05 by log-rank test). Both drug treatments resulted in ~1.5 log10 reduction in lung and brain CE vs. placebo-treated mice (n = 10, P < 0.005 by Wilcoxon rank-sum test).

Conclusion
Despite a higher MEC value, APX001 showed significant efficacy against R. oryzae that was as protective as ISAV in immunosuppressed mice. Given the previously reported activity of APX001 against a strain of R. delemar with a lower MEC value,APX001 has now been shown to be efficacious against both species of Rhizopus, which together are responsible for ~60–70% of isolates causing lethal mucormycosis. Thus, continued investigation of APX001 against mucormycosis is warranted.

Disclosures
All authors: No reported disclosures.
750. Serious Bacterial Infections: Successful Outpatient Management by Infectious Disease Physicians in Office Infusion Centers
Authors: Adams John S , Metzger Brian S , Mandel Richard M , Sleweon Thomas K , Dretler Robin H , Statner Barry , Bernett Jorge R , Schroeder Claudia P , Hardin Thomas C , Van Anglen Lucinda J 
Published: October 2019

Abstract

Background
Patients with serious bacterial infections (SBI), identified as bone and joint infections (BJI), bacteremia/endocarditis, and central nervous system (CNS) infections are frequently discharged on outpatient parenteral antimicrobial therapy (OPAT). They account for 48% of all infections treated in our network of Infectious Disease (ID) physician office infusion centers (POICs). Care for these patients poses risks and challenges to ensure safe and successful outcomes while avoiding hospitalizations. This study examines clinical outcomes and complications of our SBI patients receiving OPAT in ID POICs.

Methods
All patients were identified with SBI receiving OPAT in 2017 from 14 POICs. A group of 250 patients were randomly selected by incidence of diagnosis and a retrospective chart review performed. Demographics, treatment regimen, clinical outcomes, adverse drug reactions (ADRs) and unplanned hospitalizations during OPAT were collected. Clinical success was defined as clinical cure or improvement at completion of OPAT. Patients were included who were hospitalized for <7 days and subsequently completed OPAT. ADRs leading to hospitalization or discontinuation of OPAT were deemed serious. Descriptive statistics were used for distribution of variables.

Results
SBI patients included BJI (n = 175), bacteremia/endocarditis (n = 60) and CNS infections (n = 15) as described in Table 1. Successful clinical outcomes were reported in 224 patients (89.6%) after a mean duration of OPAT of 32±20 days. Of these, 15 patients (6.7%) were hospitalized during OPAT and returned to the POIC for a successful clinical outcome. Clinical success rates for BJI, bacteremia/endocarditis and CNS infections were 89.1%, 91.6% and 86.7%, respectively. The primary reason for nonfavorable outcomes was worsening of infection (15/26, 58%). Serious ADRs were reported in 12 patients (4.8%) with 6 (2.4%) leading to hospitalization. Unplanned hospitalizations during OPAT occurred in 33 patients (13.2%) with the majority (21/33, 64%) related to disease. ADRs and hospitalizations compare favorably to data previously reported. (Schmidt et al. OFID 16.4, 2017).

Conclusion
Patients with serious bacterial infections had high success rates when treated by an ID physician in infusion centers. Adverse events and unplanned hospitalization rates were low.

Disclosures
All authors: No reported disclosures.
779. Impact of updated IDSA practice guidelines on the treatment of Clostridium difficile infections in the United States
Authors: Clancy Cornelius J , Nguyen Minh-Hong 
Published: October 2019

Abstract

Background
IDSA published updated practice guidelines for C. difficile infections (CDI) in February 2018. Since publication of previous CDI guidelines in2010, randomized clinical trials (RCTs) have demonstrated benefit of oral (po) vancomycin or fidaxomicin over metronidazole in at least some types of CDI. Updated guidelines endorsed vancomycin or fidaxomicin as recommended treatment for initial and recurrent nonfulminant CDI episodes, and vancomycin as treatment for fulminant CDI. We studied the use of po vancomycin, fidaxomicin and metronidazole in the United States before and after publication of updated guidelines.

Methods
We obtained US antibiotic prescription data (IQVIA, Durham, NC) since 2013, and used standard dosing regimens for treatment of initial CDI to estimate numbers of infections treated with different agents. Po vancomycin and fidaxomicin are used exclusively against known or suspected CDI. Metronidazole is used to treat CDI and other infections. IQVIA data do not capture indications for prescriptions.

Results
Treatment courses of po vancomycin and fidaxomicin increased by 45% (n = 126,729 increase) and 44% (n = 11,243 increase), respectively, over the 12 months after publication of the updated CDI guidelines compared with 12 months before publication (Figure, second arrow; Table). Increased use of both agents was evident in the first month after guidelines were published. Over the same 12 month periods, treatment courses of po metronidazole decreased by 3% (190,430 decrease). In comparison, treatment courses of po vancomycin increased by 24% (n = 47,219 increase) over the 12 months after publication of the multi-national PACT study in August 2014 (Figure, first arrow), which demonstrated superiority of vancomycin over metronidazole. Since 2013, there were no significant increases in the use of fidaxomicin until publication of the updated guidelines.

Conclusion
Updated IDSA guidelines have had a major impact on treatment of CDI in the US. RCT data used for guideline updates have been available since 2007–14 and 2011–12 for po vancomycin and fidaxomicin, respectively. IDSA should provide more timely updates to practice guidelines as new data emerge. Annual or bi-annual updates posted in electronic or other nontraditional formats may be more efficient than publishing long-form articles.

Disclosures
All authors: No reported disclosures.
785. Identifying Opportunities to Improve Adherence to Sepsis Care Guidelines Compliance
Authors: Balankura Tonnam , Odom Ashley 
Published: October 2019

Abstract

Background
Sepsis—a life-threatening organ dysfunction caused by a dysregulated host response to infection—is a major public health burden and is considered a leading cause of preventable death. Although sepsis care guidelines have been established by the Surviving Sepsis Campaign, improved compliance monitoring and analytics are required for sustainable improvement in clinical processes and patient outcomes. Using the Optum Pan-Therapeutic (PanTher) electronic medical record database, we developed granular process measures and a data analytics toolkit to measure compliance with sepsis care guidelines and provide insight into areas for improvement.

Methods
We identified 15,421 episodes of adult patients in January-June, 2017 with sufficient evidence of suspected sepsis. Episodes qualified if they: (1) met at least two of the quick Sequential Organ Failure Assessment (qSOFA) clinical criteria, (2) had a blood culture order initiated, and (3) had a serum lactate order. For these 15,421 episodes, we obtained the timestamps of antibiotics order and administration, blood culture order and collection, and when at least two of the qSOFA criteria were first met. Based on Surviving Sepsis Campaign care protocols for suspected Sepsis, we measured compliance for the timeliness of antibiotics administration and blood culture collection using a threshold of 3 hours after when the qSOFA criteria were first met.

Results
Compliance of the antibiotics administration and blood culture collection measures were found in 7,647/10,343 (74%) episodes and 1,219/1,530 (80%) episodes, respectively. The median times from when the qSOFA criteria were first met to antibiotics administration and blood culture collection were 77 minutes and 5 minutes, respectively.

Conclusion
We have developed new process measures and a data analytics toolkit to monitor compliance rates and identify episodes where sepsis protocols are not followed according to sepsis care guidelines. These noncompliant episodes are opportunities for care providers to identify root causes of noncompliance and proactively work toward improved adherence to sepsis care guidelines.

Disclosures
All authors: No reported disclosures.