Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection

Kaleko, Michael; Bristol, J. Andrew; Hubert, Steven; Parsley, Todd B.; Widmer, Giovanni; Tzipori, Saul; Subramanian, Poorani; Hasan, Nur A.; Koski, Perrti; Kokai‐Kun, John F.; Sliman, Joseph; Jones, Annie; Connelly, Sheila

doi:10.1016/j.anaerobe.2016.05.015

Cited by 59 publications

(66 citation statements)

References 41 publications

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“…The pellets, confirmed by electron microscopy to be uniform spheres of approximately 1 mm diameter, contained approximately 15% ribaxamase (Kaleko et al . ). Hard capsules suitable for oral delivery were filled with the pellets for total ribaxamase content of 75 mg per capsule.…”

Section: Methodsmentioning

confidence: 97%

“…Ribaxamase is intended for oral use with IV beta‐lactam antibiotics, including CRO, and is formulated into enteric‐coated pellets that release the enzyme into the upper small intestine at pH >5·5 (Kaleko et al . ).…”

Section: Introductionmentioning

confidence: 97%

“…SYN‐004 (ribaxamase), originally named SYN‐004 (Kaleko et al . ), was engineered from the P1A enzyme to broaden its antibiotic degradation profile to include cephalosporins, such as CRO, while maintaining penicillinase activity (Kaleko et al . ).…”

Section: Introductionmentioning

confidence: 99%

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SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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Aim: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. Methods and Results: SYN-004 (ribaxamase) is an orally delivered betalactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg À1, SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. Conclusion: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. Significance and Impact of the Study: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

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Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

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SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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“…Another more novel approach is to “protect” the intestinal microbiome from antibiotic effects by selectively inactivating antibiotics in the intestines. Concurrent administration of an intravenous beta lactam or cephalosporin antibiotic with an enteral beta lactamase that is not systemically absorbed prevents parenteral antibiotic from disrupting the intestinal microbiome 90 . This approach, which cleverly utilizes bacterial antibiotic resistance to our benefit, is undergoing phase II clinical trials 90 .…”

Section: Antibiotic-induced Diarrheamentioning

confidence: 99%

Impact of Antibiotics on Necrotizing Enterocolitis and Antibiotic-Associated Diarrhea

Silverman

Konnikova

Gerber

2017

Gastroenterology Clinics of North America

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Summary Antibiotics induce changes or dysbiosis of the intestinal microbiome. These antibiotic-induce changes may contribute to the pathogenesis of necrotizing enterocolitis (NEC) and antibiotic-associated diarrhea (AAD). Studies are beginning to unravel the contribution of specific groups of microbes to these diseases—most notably Gammaproteobacteria for NEC and bile acid- and carbohydrate-metabolizing microbes for AAD. Antibiotic-associated diarrhea occurs when antibiotic treatment induces diarrhea by altering the metabolic function of the patient’s intestinal microbiota leading to either an osmotic or infectious diarrhea, most notably Clostridium difficile infection (CDI). Antibiotic therapy impairs the host microbiota’s ability to resist colonization or expansion of pathogenic bacteria. In the case of CDI, there is growing evidence that microbiota-mediated bile acid metabolism is critical in the pathogenesis of this infection. Probiotics or other microbiota-targeted therapies may provide effective strategies to prevent and treat NEC and AAD.

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“…[40][41] This agent degrades unmetabolised antibiotic in the host intestine in order to protect the gut microbiota from dysbiosis and is well tolerated. 42 Animal studies have demonstrated safety without interference with the systemic pharmacokinetics of ceftriaxone.…”

Section: Difficile Infection Prophylaxismentioning

confidence: 99%

New and emerging therapies for Clostridium difficile infection

Martin

Wilcox²

2016

Current Opinion in Infectious Diseases

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(max 200 words)Purpose of review: Clostridium difficile infection has attained high prominence given its prevalence and impacts on patients and healthcare institutions. Multiple new approaches to the prevention and treatment of CDI are undergoing clinical trials. Recent findings:Bezlotoxumab is a monoclonal antibody against toxin B that has successfully completed phase three studies, demonstrating a significant reduction in recurrent CDI when given with standard of care antibiotics. Antibiotics under development include cadazolid and ridinilazole, while surotomycin has had disappointing phase 3 results. Multiple live biotherapeutics are being developed, including freeze thawed and encapsulated versions of faecal microbiota transplantation to improve the practicality of treating patients with recurrent CDI. Alternatives to faecal microbiota transplantation, that aim to improve safety, including a microbial suspension, RBX2660, and a complex spore formulation, SER-109, have progressed to phase 2 studies. A non-toxigenic C. difficile strain has also shown promise to prevent recurrent CDI. In addition, three C. difficile vaccines have progressed to phase 2/3 clinical trials. Summary:The diverse approaches to treating and preventing CDI offer substantial promise that new treatment options will soon emerge, particular ones that reduce the risk of recurrences.3

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Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection

Cited by 59 publications

References 41 publications

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

Impact of Antibiotics on Necrotizing Enterocolitis and Antibiotic-Associated Diarrhea

New and emerging therapies for Clostridium difficile infection

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