The Oral ß-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.

SYN-004 (ribaxamase) is a ß-lactamase designed to be orally administered concurrently with intravenous ß-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess ß-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).

Automatic Population of the Case Report Forms for an International Multifactorial Adaptive Platform Trial Amid the COVID-19 Pandemic.

OBJECTIVES: To automatically populate the case report forms (CRFs) for an international, pragmatic, multifactorial, response-adaptive, Bayesian COVID-19 platform trial. METHODS: The locations of focus included 27 hospitals and 2 large electronic health record (EHR) instances (1 Cerner Millennium and 1 Epic) that are part of the same health system in the United States. This paper describes our efforts to use EHR data to automatically populate four of the trial's forms: baseline, daily, discharge, and response-adaptive randomization. RESULTS: Between April 2020 and May 2022, 417 patients from the UPMC health system were enrolled in the trial. A MySQL-based extract, transform, and load pipeline automatically populated 499 of 526 CRF variables. The populated forms were statistically and manually reviewed and then reported to the trial's international data coordinating center. CONCLUSIONS: We accomplished automatic population of CRFs in a large platform trial and made recommendations for improving this process for future trials.

The impact of preoperative oral nutrition supplementation on outcomes in patients undergoing gastrointestinal surgery for cancer in low- and middle-income countries: a systematic review and meta-analysis.

Malnutrition is an independent predictor for postoperative complications in low- and middle-income countries (LMICs). We systematically reviewed evidence on the impact of preoperative oral nutrition supplementation (ONS) on patients undergoing gastrointestinal cancer surgery in LMICs. We searched EMBASE, Cochrane Library, Web of Science, Scopus, WHO Global Index Medicus, SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) databases from inception to March 21, 2022 for randomised controlled trials evaluating preoperative ONS in gastrointestinal cancer within LMICs. We evaluated the impact of ONS on all postoperative outcomes using random-effects meta-analysis. Seven studies reported on 891 patients (446 ONS group, 445 control group) undergoing surgery for gastrointestinal cancer. Preoperative ONS reduced all cause postoperative surgical complications (risk ratio (RR) 0.53, 95% CI 0.46-0.60, P < 0.001, I2 = 0%, n = 891), infection (0.52, 0.40-0.67, P = 0.008, I2 = 0%, n = 570) and all-cause mortality (0.35, 0.26-0.47, P = 0.014, I2 = 0%, n = 588). Despite heterogeneous populations and baseline rates, absolute risk ratio (ARR) was reduced for all cause (pooled effect -0.14, -0.22 to -0.06, P = 0.006; number needed to treat (NNT) 7) and infectious complications (-0.13, -0.22 to -0.06, P < 0.001; NNT 8). Preoperative nutrition in patients undergoing gastrointestinal cancer surgery in LMICs demonstrated consistently strong and robust treatment effects across measured outcomes. However additional higher quality research, with particular focus within African populations, are urgently required.

Performance Evaluation of Nasal Prong Interface for CPAP Delivery on a Critical Care Ventilator: A Bench Experiment.

BACKGROUND: The RAM cannula (Neotech, Valencia, CA) has become a commonly used interface for CPAP in neonatal intensive care. Performance characteristics of this interface used with a critical care ventilator are not well described. METHODS: This was a bench study utilizing a lung simulator configured as an actively breathing infant (weights of 800 g, 1.5 kg, and 3 kg) with moderate lung disease and a critical care ventilator in CPAP mode with leak compensation on. Three sizes of the RAM cannulae (preemie, newborn, and infant) were compared to 3 BabyFlow nasal prongs (Dräger Medical, Lübeck, Germany) (medium, large, and extra-large). Fabricated nasal models produced a 70% occlusive fit for the RAM cannula and an occlusive fit with the Dräger prongs. Delivered flow and pressure levels were recorded at 9 CPAP levels between 5 and 20 cm H2O. RESULTS: The Dräger prongs produced a mean airway pressure ([Formula: see text]) within 0.20 cm H2O (range -0.10 to 0.35) of the set CPAP across all evaluated prong sizes and CPAP levels. In contrast, the RAM cannula produced [Formula: see text] values that averaged 8.5 cm H2O (range -15 to -3.5) below the set CPAP levels. The deficit in delivered versus target CPAP level for the RAM cannula increased with greater set CPAP. Set CPAP of 5 cm H2O delivered [Formula: see text] values that ranged from 0.6 to 1.5 cm H2O (difference of 3.5-4.4 cm H2O). Set CPAP of 20 cm H2O delivered [Formula: see text] values that ranged from 5.0 to 8.4 cm H2O (difference of 11.7-15 cm H2O). Inspiratory flow required to achieve set CPAP levels did not differ between interfaces, suggesting high resistance in the RAM cannula device masks the delivered CPAP levels. CONCLUSIONS: Use of the RAM cannula with a 30% leak on a critical care ventilator delivered [Formula: see text] values lower than set CPAP. This may be clinically meaningful and should be considered when choosing a nasal interface.

Use of ribaxamase (SYN-004), a ß-lactamase, to prevent Clostridium difficile infection in ß-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial.

BACKGROUND: Infections with Clostridium difficile are a health threat, yet no products are currently licensed for prevention of primary C difficile infections. Intravenous ß-lactam antibiotics are considered to confer a high risk of C difficile infection because of their biliary excretion into the gastrointestinal tract and disruption of the gut microbiome. ribaxamase (SYN-004) is an orally administered ß-lactamase that was designed to be given with intravenous ß-lactam antibiotics to degrade excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. We therefore aimed to determine whether administration of ribaxamase could prevent C difficile infection in patients being treated with intravenous ceftriaxone for a lower respiratory tract infection, thereby supporting continued clinical development. METHODS: In this parallel-group, double-blind, multicentre, phase 2b, randomised placebo-controlled trial, we recruited patients who had been admitted to a hospital with a lower respiratory tract infection with a pneumonia index score of 90-130 and who were expected to be treated with ceftriaxone for at least 5 days. Patients were recruited from 54 clinical sites in the USA, Canada, Bulgaria, Hungary, Poland, Romania, and Serbia. We randomly assigned patients older than 50 years to groups (1:1) in blocks of four by use of an interactive web portal; these groups were assigned to receive either 150 mg ribaxamase or placebo four times per day during, and for 72 h after, treatment with ceftriaxone. All patients, clinical investigators, study staff, and sponsor personnel were masked to the study drug assignments. The primary endpoint was the incidence of C difficile infection, as diagnosed by the local laboratory, in patients who received at least one treatment dose, and this outcome was assessed during treatment and for 4 weeks after treatment. This study is registered with ClinicalTrials.gov, number NCT02563106. FINDINGS: Between Nov 16, 2015, and Nov 10, 2016, we screened 433 patients for inclusion in the study. Of these patients, 20 (5%) patients were excluded from the study (16 [4%] patients did not meet inclusion criteria; four [1%] patients because of dosing restrictions). We enrolled and randomly assigned 413 patients to groups, of whom 207 patients were assigned to receive ceftriaxone plus ribaxamase and 206 patients were assigned to receive ceftriaxone plus placebo. However, one (<1%) patient in the ribaxamase group withdrew consent and was not treated with ribaxamase. During the study and within the 4 weeks after antibiotic treatment, two (1·0%) patients in the ribaxamase group and seven (3·4%) patients in the placebo group were diagnosed with an infection with C difficile (risk reduction 2·4%, 95% CI -0·6 to 5·9; one-sided p=0·045). Adverse events were similar between groups but more deaths were reported in the ribaxamase group (11 deaths vs five deaths in the placebo group). This disparity was due to the higher incidence of deaths attributed to cardiac-associated causes in the ribaxamase group (six deaths vs one death in the placebo group). INTERPRETATION: In patients treated with intravenous ceftriaxone for lower respiratory tract infections, oral ribaxamase reduced the incidence of C difficile infections compared with placebo. The imbalance in deaths between the groups appeared to be related to the underlying health of the patients. Ribaxamase has the potential to prevent C difficile infection in patients treated with intravenous ß-lactam antibiotics, and our findings support continued clinical development of ribaxamase to prevent C difficile infection. FUNDING: Synthetic Biologics.

Tolerability and Pharmacokinetics of SYN-004, an Orally Administered ß-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies.

BACKGROUND: SYN-004 is an orally administered ß-lactamase enzyme, designed to be given concurrently with certain intravenous ß-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas. METHODS: Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75-750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75-300 mg SYN-004, administered every 6 h for 7 days and was conducted in 24 subjects (three cohorts of six active and two placebo subjects). The safety and tolerability of SYN-004 was assessed and serial plasma and serum samples were collected to assess the pharmacokinetics and potential immunogenicity of SYN-004. RESULTS: Minimal and mild adverse events were reported in ~30 % of the subjects who received active drug and placebo and no antidrug antibodies were detected in any subject. Analysis of serial plasma samples demonstrated negligible systemic bioavailability of SYN-004 with most plasma concentrations being below the lower limit of quantitation (0.8 ng/mL) for the assay. SYN-004 was well tolerated in the 48 subjects who received active drug, and adverse events in those subjects were comparable to the 16 subjects who received placebo, up to the maximum doses administered in each study. CONCLUSION: SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.

Peripatetic intravenous service for metabolic bone disease: case study in patient centred-care for new NHS.

OBJECTIVE: To develop a 'close to patient' peripatetic intravenous service (PIVS) for delivery of specialist osteoporosis care in a community setting without increasing cost and with a reduced carbon footprint. RESEARCH DESIGN AND METHODS: Cost and feasibility of a PIVS for intravenous (i.v.) bisphosphonate treatment were modelled using UK National Health Service costings and then tested in the field for 1 year. Average patient mileage to peripatetic sites was compared with mileage travelled if treated at the base hospital (current practice). The method of travel to hospital (current practice) or peripatetic sites (new study) was ascertained together with patients' preference for the new or the current system. Peripatetic sites were researched and those with suitable facilities selected. Data for fuel consumption were based on a usage of 1 litre per 14.5 km. MAIN OUTCOME MEASURES: The main outcome measure was cost comparison between hospital and peripatetic services. Others included patient satisfaction, miles saved, method of travel to the clinic and changes in CO(2) emissions. RESULTS: Cost per patient, including drugs, lies between pound557 and pound622 annually for 1000 and 500 patients, respectively which is cost-neutral compared with hospital attendance. PIVS was rated more convenient by 98% of patients. Hospital transport was significantly reduced and the total monthly saving of 2000 miles has reduced CO(2) emission by 6072 kg p.a. No medical emergency occurred in 410 infusions. CONCLUSIONS: PIVS is cost neutral compared with a conventional service, leads to a better patient experience, a significant cutback in hospital transport costs and a reduction of the NHS carbon footprint. However not all drugs may be suitable for this service: the area served was rural with large distances and poor public transport and mileage savings may not accrue in urban areas. Insurance was not included in the calculation of costs.