SYN-004, a clinical-stage, orally delivered beta-lactamase therapy that protects the gut microbiome from IV antibiotics is also efficacious with oral antibiotics in a pig model

Stroke is a major cause of death and long-term disability affecting seven million adults in the United States each year. Recently, it has been demonstrated that neurological diseases, associated pathology, and susceptibility changes correlated with changes in the gut microbiota. However, changes in the microbial community in stroke has not been well characterized. The acute stage of stroke is a critical period for assessing injury severity, therapeutic intervention, and clinical prognosis. We investigated the changes in the gut microbiota composition and diversity using a middle cerebral artery (MCA) occlusion ischemic stroke pig model. Ischemic stroke was induced by cauterization of the MCA in pigs. Blood samples were collected prestroke and 4 h, 12 h, 1 day, and 5 days poststroke to evaluate circulating proinflammatory cytokines. Fecal samples were collected prestroke and 1, 3, and 5 days poststroke to assess gut microbiome changes. Results showed elevated systemic inflammation with increased plasma levels of tumor necrosis factor alpha at 4 h and interleukin-6 at 12 h poststroke, relative to prestroke. Microbial diversity and evenness were reduced at 1 day poststroke compared to prestroke. Microbial diversity at 3 days poststroke was negatively correlated with lesion volume. Moreover, beta-diversity analysis revealed trending overall differences over time, with the most significant changes in microbial patterns observed between prestroke and 3 days poststroke. Abundance of the Proteobacteria was significantly increased, while Firmicutes decreased at 3 days poststroke, compared to prestroke populations. Abundance of the lactic acid bacteria Lactobacillus was reduced at 3 days poststroke. By day 5, the microbial pattern returned to similar values as prestroke, suggesting the plasticity of gut microbiome in an acute period of stroke in a pig model. These findings provide a basis for characterizing gut microbial changes during the acute stage of stroke, which can be used to assess stroke pathology and the potential development of therapeutic targets.

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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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.741 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S307-S307

Author(s):

Sheila Connelly ◽

Christian Furlan-Freguia ◽

Brian Fanelli ◽

Nur A Hasan ◽

Rita R Colwell ◽

...

Keyword(s):

Antibiotic Resistance ◽

Small Intestine ◽

Gut Microbiome ◽

Clinical Stage ◽

Serum Levels ◽

Systemic Absorption ◽

Release Formulation ◽

Microbiome Composition ◽

Delayed Release ◽

Oral Amoxicillin

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.

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Clinical-Stage, Oral β-Lactamase Enzyme to Prevent Clostridium difficile Infection Triggered by Antibiotic-Mediated Gut Microbiome Disruption

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw172.1769 ◽

2016 ◽

Vol 3 (suppl_1) ◽

Author(s):

Sheila Connelly ◽

Andrew Bristol ◽

Steve Hubert ◽

Christian Furlan-Freguia ◽

Poorani Subramanian ◽

...

Keyword(s):

Clostridium Difficile ◽

Clostridium Difficile Infection ◽

Gut Microbiome ◽

Clinical Stage

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An Orally Delivered Beta-Lactamase Protects the Gut Microbiome from Antibiotic-Mediated Damage and Mitigates the Propagation of Antibiotic-Resistance Genes in a Porcine Dysbiosis Model

Gastroenterology ◽

10.1016/s0016-5085(17)34350-0 ◽

2017 ◽

Vol 152 (5) ◽

pp. S1305-S1306

Author(s):

Sheila Connelly ◽

Christian Furlan Freguia ◽

Poorani Subramanian ◽

Nur A. Hasan ◽

Rita R. Colwell ◽

...

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Gut Microbiome ◽

Antibiotic Resistance Genes ◽

Beta Lactamase

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1267. Comparative activity of omadacycline against extended-spectrum beta-lactamase positive and negative Escherichia coli and Klebsiella pneumoniae strains recovered from urine specimens

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1451 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S650-S650

Author(s):

Tyler J Stone ◽

Abdullah Kilic ◽

John Williamson ◽

Elizabeth Palavecino ◽

Elizabeth Palavecino

Keyword(s):

Susceptibility Testing ◽

Uncomplicated Urinary Tract Infection ◽

Beta Lactamase ◽

Oral Antibiotics ◽

Research Support ◽

Extended Spectrum Beta Lactamase ◽

E Coli ◽

Extended Spectrum ◽

Urine Specimens ◽

Research Grant

Abstract Background Omadacycline (OMC) is a novel tetracycline (TET) derivative antibiotic with activity against TET-resistant Enterobacterales. OMC is available in both oral and intravenous formulations and is has been studied as a treatment of uncomplicated urinary tract infection (UTI) and acute pyelonephritis. The purpose of this study was to evaluate OMC activity against extended-spectrum beta-lactamase (ESBL) positive and negative Enterobacterales strains recovered from urine specimens. Methods Urine samples from patients with suspected UTI were quantitatively plated onto blood agar and MacConkey agar plates in the microbiology lab of Wake Forest Baptist Medical Center. After overnight incubation, colonies were identified to the species level by MALDI-TOF system. Susceptibility testing was performed for isolates of E. coli and K. pneumoniae. OMC and TET susceptibility testing was performed by disk diffusion and gradient strip methodologies. Results were interpreted in accordance with the Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration breakpoints. Isolates were tested in triplicate. ESBL screening and susceptibility testing to oral antibiotics commonly prescribed for UTI were performed by the MicroScan WalkAway System. Susceptibility rates and MIC50/90 were calculated and subsets of isolates were analyzed using descriptive statistics. Results A total of 204 isolates, including 102 E. coli and 102 K. pneumoniae, were tested. All but 1 isolate (99.5%) exhibited categorical agreement in results generated by the strip (Table 1) and disk (data not shown) methods and this was considered a minor error involving an intermediate result. OMC MIC90 for E. coli and K. pneumoniae were 6 µg/mL and >32 µg/mL, respectively. OMC displayed increased susceptibility rates compared to TET regardless of isolate species or ESBL positivity (Table 2). Table 1. Omadacycline Minimum Inhibitory Concentrations (MICs, µg/mL) Table 2. Susceptibilities of Oral Antibiotics Used to Treat UTI (% S) Conclusion OMC exhibits promising antimicrobial activity against TET-resistant and ESBL-positive E. coli and K. pneumoniae. OMC displays superior activity to ESBL positive E. coli when compared to ESBL positive K. pneumoniae. These data support the development of OMC as a much needed option in the treatment of UTI caused by resistant Enterobacterales. Disclosures Tyler J. Stone, PharmD, Paratek (Research Grant or Support) Abdullah Kilic, MD, Paratek (Grant/Research Support) John Williamson, PharmD, Paratek (Research Grant or Support) Elizabeth Palavecino, MD, Paratek (Grant/Research Support)Paratek (Grant/Research Support)

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Can Oral Antibiotics Be an Alternative to Carbapenems in The Treatment of Non-Complicated Urinary Tract Infections Caused by Extended Spectrum Beta-lactamase Positive Escherichia coli?

ANKEM Dergisi ◽

10.5222/ankem.2017.085 ◽

2017 ◽

Author(s):

Yeşim ALPAY ◽

Mehmet Tevfik YAVUZ ◽

Turan ASLAN ◽

Batıhan BÜYÜKZENGİN

Keyword(s):

Escherichia Coli ◽

Urinary Tract ◽

Urinary Tract Infections ◽

Beta Lactamase ◽

Oral Antibiotics ◽

Extended Spectrum Beta Lactamase ◽

Extended Spectrum ◽

Tract Infections

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A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00535-16 ◽

2016 ◽

Vol 60 (7) ◽

pp. 4264-4273 ◽

Cited By ~ 22

Author(s):

Jiangwei Yao ◽

Robert A. Carter ◽

Grégoire Vuagniaux ◽

Maryse Barbier ◽

Jason W. Rosch ◽

...

Keyword(s):

Antibiotic Treatment ◽

Broad Spectrum ◽

Gut Microbiome ◽

Bacterial Abundance ◽

Acyl Carrier Protein ◽

Control Group ◽

Oral Antibiotics ◽

Broad Spectrum Antibiotic ◽

Microbial Composition ◽

Selective Approach

ABSTRACTBroad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of negative health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clinical development and was used to determine whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and composition, with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4,000-fold decreases in gut bacterial abundance and severely altered the microbial composition. The gut bacterial abundance and composition of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut composition of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.

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