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

The gut microbiome, composed of the microflora that inhabit the gastrointestinal tract and their genomes, make up a complex ecosystem that can be disrupted by antibiotic use. The ensuing dysbiosis is conducive to the emergence of opportunistic pathogens such as Clostridium difficile. A novel approach to protect the microbiome from antibiotic-mediated dysbiosis is the use of beta-lactamase enzymes to degrade residual antibiotics in the gastrointestinal tract before the microflora are harmed. Here we present the preclinical development and early clinical studies of the beta-lactamase enzymes, P3A, currently referred to as SYN-004, and its precursor, P1A. Both P1A and SYN-004 were designed as orally-delivered, non-systemically available therapeutics for use with intravenous beta-lactam antibiotics. SYN-004 was engineered from P1A, a beta-lactamase isolated from Bacillus licheniformis, to broaden its antibiotic degradation profile. SYN-004 efficiently hydrolyses penicillins and cephalosporins, the most widely used IV beta-lactam antibiotics. In animal studies, SYN-004 degraded ceftriaxone in the GI tract of dogs and protected the microbiome of pigs from ceftriaxone-induced changes. Phase I clinical studies demonstrated SYN-004 safety and tolerability. Phase 2 studies are in progress to assess the utility of SYN-004 for the prevention of antibiotic-associated diarrhea and Clostridium difficile disease.

Multimedia distribution, partitioning, sources, comprehensive toxicity risk and co-occurrence network characteristics of trace elements in a typical Chinese shallow lake with high antibiotic risk.

Although the combined pollution of trace elements and antibiotics has received extensive attention, the fate and toxicity risk of trace elements with high antibiotic risk are still unclear. The multimedia distributions, partitioning, sources, toxicity risks and co-occurrence network characteristics of trace elements in surface water (SW), overlying water (OW), pore water (PW) and sediment (Sedi) samples of 61 sites from Baiyangdian (BYD) Lake were investigated. The trace elements in the SW and OW are derived mainly from traffic and agricultural sources, and those in PW and Sedi samples are primarily from lithogenic and industrial sources. The total toxicity risk index (TRI) of nine trace elements (ΣTRI) in Sedi samples showed a very high toxicity risk (18.35 ± 8.84), and a high combined pollution toxicity risk (ΣΣTRI) was observed in PW (149.17 ± 97.52) and Sedi samples (46.37 ± 24.00). The co-occurrence network from SW to PW became more vulnerable. Generally, total antibiotics and TP may be keystones of trace elements in water and sediment. The high antibiotic risk significantly influenced ΣΣTRI in water samples but not in Sedi samples. The findings provide new implications for the monitoring and control of combined antibiotic-trace element pollution in shallow lakes.

Heterotrophic bacteria in drinking water: evaluating antibiotic resistance and the presence of virulence genes.

Heterotrophic bacteria, impacting those with infections or compromised immunity, pose heightened health risks when resistant to antibiotics. This study investigates heterotrophic plate count bacteria in water from North West-C (NWC) and North West-G (NWG) facilities, revealing prevalent ß-hemolysis (NWC 82.5%, NWG 86.7%), enzyme production (98%), and antibiotic resistance, especially in NWC. NWG exhibits variations in hemolysin (P = 0.013), lipase (P = 0.009), and DNase activity (P = 0.006). Antibiotics, including ciprofloxacin, persist throughout treatment, with high resistance to ß-lactams and trimethoprim (47%-100%), predominantly in NWC. Multiple antibiotic resistance index indicates that 90% of values exceed 0.20, signifying isolates from high antibiotic usage sources. Whole genome sequencing reveals diverse antibiotic resistance genes in heterotrophic strains, emphasizing their prevalence and health risks in water.IMPORTANCEThis study's findings are a stark reminder of a significant health concern: our water sources harbor antibiotic-resistant heterotrophic bacteria, which can potentially cause illness, especially in individuals with weakened immune systems or underlying infections. Antibiotic resistance among these bacteria is deeply concerning, as it threatens the effectiveness of antibiotics, critical for treating various infections. Moreover, detecting virulence factors in a notable proportion of these bacteria highlights their elevated risk to public health. This research underscores the immediate need for enhanced water treatment processes, rigorous water quality monitoring, and the development of strategies to combat antibiotic resistance in the environment. Safeguarding the safety of our drinking water is imperative to protect public health and mitigate the spread of antibiotic-resistant infections, making these findings a compelling call to action for policymakers and public health authorities alike.

Optimization of sepsis therapy based on patient-specific digital precision diagnostics using next generation sequencing (DigiSep-Trial)-study protocol for a randomized, controlled, interventional, open-label, multicenter trial.

BACKGROUND: Sepsis is triggered by an infection and represents one of the greatest challenges of modern intensive care medicine. With regard to a targeted antimicrobial treatment strategy, the earliest possible pathogen detection is of crucial importance. Until now, culture-based detection methods represent the diagnostic gold standard, although they are characterized by numerous limitations. Culture-independent molecular diagnostic procedures represent a promising alternative. In particular, the plasmatic detection of circulating, cell-free DNA by next-generation sequencing (NGS) has shown to be suitable for identifying disease-causing pathogens in patients with bloodstream infections. METHODS: The DigiSep-Trial is a randomized, controlled, interventional, open-label, multicenter trial characterizing the effect of the combination of NGS-based digital precision diagnostics with standard-of-care microbiological analyses compared to solely standard-of-care microbiological analyses in the clinical picture of sepsis/septic shock. Additional anti-infective expert consultations are provided for both study groups. In 410 patients (n = 205 per arm) with sepsis/septic shock, the study examines whether the so-called DOOR-RADAR (Desirability of Outcome Ranking/Response Adjusted for Duration of Antibiotic Risk) score (representing a combined endpoint including the criteria (1) intensive/intermediate care unit length of stay, (2) consumption of antibiotics, (3) mortality, and (4) acute kidney injury (AKI)) can be improved by an additional NGS-based diagnostic concept. We also aim to investigate the cost-effectiveness of this new diagnostic procedure. It is postulated that intensive/intermediate care unit length of stay, mortality rate, incidence of AKI, the duration of antimicrobial therapy as well as the costs caused by complications and outpatient aftercare can be reduced. Moreover, a significant improvement in patient's quality of life is expected. DISCUSSION: The authors´ previous work suggests that NGS-based diagnostics have a higher specificity and sensitivity compared to standard-of-care microbiological analyses for detecting bloodstream infections. In combination with the here presented DigiSep-Trial, this work provides the optimal basis to establish a new NGS-driven concept as part of the national standard based on the best possible evidence. TRIAL REGISTRATIONS: DRKS-ID DRKS00022782 . Registered on August 25, 2020 ClinicalTrials.gov NCT04571801 . Registered October 1, 2020.