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1337. SYN-004 (Ribaxamase) Protects the Gut Microbiome of Patients Treated With Ceftriaxone From Disruption and Reduces the Emergence of Antimicrobial Resistance

Abstract Background When β-lactam antibiotics are administered intravenously, a significant portion of each dose can be excreted through the bile into the intestine. This excess antibiotic disrupts the balance of the gut microbiome making the recipient more susceptible to certain infections and can lead to the emergence of antimicrobial resistance. SYN-004 (ribaxamase) is an orally administered β-lactamase designed to be given with IV β-lactam antibiotics (penicillins and cephalosporins) to degrade excess antibiotics excreted into the upper GI tract before they can disrupt the gut microbiome and resistome. Methods During a Phase 2b, clinical study with ribaxamase which demonstrated a significant reduction in Clostridium difficile infection in patients receiving ceftriaxone + ribaxamase, longitudinal fecal samples were collected from the patients. DNA extracted from these samples was 16S rRNA and whole genome sequenced, and the sequences were analyzed for changes in the gut microbiome and resistome. Statistical analyses were performed to determine correlations between changes in the gut microbiome and resistome and clinical study data. Results Sequence analyses revealed that ribaxamase protected the integrity of the gut microbiome, including preventing enterococcal mono-domination (defined as >30% of the microbiome being from one genus), and identified over 1,300 AMR genes in the gut resistome. LefSe analysis of the gut resistome identified a family of β-lactamases (CfxA) and vancomycin resistance genes which demonstrated a significant increase in placebo-treated vs. ribaxamase-treated patients from pre-to post-antibiotics. Analysis by qPCR supported both new acquisition of these genes and expansion of existing AMR pools. Further statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including β-lactamase gene frequency and study drug assignment, and efflux pump gene frequency and vancomycin resistance. Conclusion Taken together, these findings demonstrated that coadministration of ribaxamase with IV β-lactam antibiotics can protect the integrity of the gut microbiome and may help limit the emergence of AMR induced by these antibiotics. Disclosures J. Kokai-Kun, Synthetic Biologics, Inc.: Employee, Salary. C. Le, Synthetic Biologics, Inc.: Employee, Salary. K. Trout, Synthetic Biologics, Inc.: Employee, Salary. J. Sliman, Synthetic Biologics, Inc.: Employee, Salary.

Conclusion. HSR of WCK 5222 showed potent in vivo activity against CR-ACBN expressing OXA carbapenemases in the murine thigh model which is attributed to the β-lactam enhancing effect of ZID, driven by the complementary PBP binding of FEP and ZID. These results support the clinical evaluation of WCK 5222 for the management of infections due to CR-ACBN.
Disclosures. D. P. Nicolau, Wockhardt: Investigator, Research support. Background. When β-lactam antibiotics are administered intravenously, a significant portion of each dose can be excreted through the bile into the intestine. This excess antibiotic disrupts the balance of the gut microbiome making the recipient more susceptible to certain infections and can lead to the emergence of antimicrobial resistance. SYN-004 (ribaxamase) is an orally administered β-lactamase designed to be given with IV β-lactam antibiotics (penicillins and cephalosporins) to degrade excess antibiotics excreted into the upper GI tract before they can disrupt the gut microbiome and resistome.

SYN-004 (Ribaxamase) Protects the Gut Microbiome of Patients Treated
Methods. During a Phase 2b, clinical study with ribaxamase which demonstrated a significant reduction in Clostridium difficile infection in patients receiving ceftriaxone + ribaxamase, longitudinal fecal samples were collected from the patients. DNA extracted from these samples was 16S rRNA and whole genome sequenced, and the sequences were analyzed for changes in the gut microbiome and resistome. Statistical analyses were performed to determine correlations between changes in the gut microbiome and resistome and clinical study data.
Results. Sequence analyses revealed that ribaxamase protected the integrity of the gut microbiome, including preventing enterococcal mono-domination (defined as >30% of the microbiome being from one genus), and identified over 1,300 AMR genes in the gut resistome. LefSe analysis of the gut resistome identified a family of β-lactamases (CfxA) and vancomycin resistance genes which demonstrated a significant increase in placebo-treated vs. ribaxamase-treated patients from pre-to post-antibiotics. Analysis by This abstract has been withdrawn at the author's request. qPCR supported both new acquisition of these genes and expansion of existing AMR pools. Further statistical analyses demonstrated significant correlations between changes in the gut resistome and clinical study parameters including β-lactamase gene frequency and study drug assignment, and efflux pump gene frequency and vancomycin resistance.
Conclusion. Taken together, these findings demonstrated that coadministration of ribaxamase with IV β-lactam antibiotics can protect the integrity of the gut microbiome and may help limit the emergence of AMR induced by these antibiotics.
Disclosures. J. Kokai-Kun, Synthetic Biologics, Inc.: Employee, Salary. C. Le, Synthetic Biologics, Inc.: Employee, Salary. K. Trout, Synthetic Biologics, Inc.: Employee, Salary. J. Sliman, Synthetic Biologics, Inc.: Employee, Salary. Background. The objective of this evaluation was to provide an analysis of pooled efficacy data from two parallel Phase 3 trials of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, compared with vancomycin for the treatment of patients with wound infections including surgical site infections (SSI).

Methods.
A pooled analysis of patients with wound infections was conducted from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2), which included a total of 602 patients with wound infections. The data were analyzed separately and then pooled to determine the efficacy of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg. Both drugs were administered intravenously every 12 hours for 5 to 14 days according to the investigator assessment of clinical response. The primary endpoint of these studies was to determine whether iclaprim was noninferior (NI; 10% margin) to vancomycin in achieving a ≥20% reduction in lesion size (early clinical response [ECR] at 48 to 72 hours after initiation of the study drug (early time point [ETP]), compared with baseline in the intent-to-treat (ITT) population.
Results. Iclaprim had similar ECR rates at ETP compared with vancomycin among the subset of patients with wound infections (see table). The median treatment duration for both iclaprim and vancomycin was 7 days (range 5-14 days).