Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.
Methods: A dilutional pharmacokinetic system was used for in vitro experiments. In vivo experiments were conducted in the neutropenic murine thigh infection model. Three Escherichia coli and two Klebsiella pneumoniae strains were used. NOSO-502 pharmacokinetics (PK) in mice were described in a population PK model. Dose fractionation and escalation exposures were performed and bacteriostatic and 1 log10 and 2 log10 kill effects were determined using an Emax model. The coefficient of determination (R2) was used to estimate the variance that might be due to regression with various PDIs (fAUC/MIC, fCmax/MIC, %fT>MIC and fAUC/MIC per length of dosing interval fAUC/MIC·1/tau).
Results: Exposure fractionation in both in vitro and in vivo studies indicated that 6-hourly dosing resulted in a greater reduction in K. pneumoniae bacterial burden compared with either 12- or 24-hourly dosing. Similar observations were made with three E. coli strains in vitro and a single strain of E. coli in vivo. For K. pneumoniae, R2 for fAUC/MIC·1/tau was 0.8376 in vitro and 0.6001 in vivo, which was greater than R2 with other PDIs. Analysis of pooled in vitro data from three strains of E. coli produced an R2 of 0.7073 for fAUC/MIC and 0.6100 for fAUC/MIC·1/tau.
Conclusions: NOSO-502 exhibits both dose- and time-dependent in vitro and in vivo activity against both E. coli and K. pneumoniae.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1093/jac/dkae469 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A Multicellular In Vitro Model of the Human Intestine with Immunocompetent Features Highlights Host-Pathogen Interactions During Early Salmonella Typhimurium Infection.
Adv Sci (Weinh)
January 2025
Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany.
Studying the molecular basis of intestinal infections caused by enteric pathogens at the tissue level is challenging, because most human intestinal infection models have limitations, and results obtained from animals may not reflect the human situation. Infections with Salmonella enterica serovar Typhimurium (STm) have different outcomes between organisms. 3D tissue modeling of primary human material provides alternatives to animal experimentation, but epithelial co-culture with immune cells remains difficult.
View Article and Find Full Text PDFA review on the effects of flavan-3-ols, their metabolites, and their dietary sources on gut barrier integrity.
Food Funct
January 2025
Nutrition Innovation Centre for Food and Health (NICHE), Ulster University, Coleraine, UK.
Impairment of gut barrier integrity is associated with the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease, colorectal cancer, and coeliac disease. While many aspects of diet have been linked to improved barrier function, (poly)phenols, a broad group of bioactive phytochemicals, are of potential interest. The (poly)phenolic sub-class, flavan-3-ols, have been investigated in some detail owing to their abundance in commonly consumed foods, including grapes, tea, apples, cocoa, berries, and nuts.
View Article and Find Full Text PDFPhotothermal Coating on Zinc Alloy for Controlled Biodegradation and Improved Osseointegration.
Adv Sci (Weinh)
January 2025
Department of Prosthodontics, Peking University School and Hospital of Stomatology, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
Zinc (Zn) and its alloys are promising biomaterials for orthopedic applications due to their degradability and mechanical properties. Zn plays a crucial role in bone formation, but excessive early release may cause cytotoxicity and inhibit osseointegration. To solve this, we developed a near-infrared (NIR) light-controlled polycaprolactone/copper-sulfur (PCL/CuS) coating that slows degradation and enhances osseointegration of Zn alloys.
View Article and Find Full Text PDFEffects of therapy in experimental models of Peyronie's disease: a scoping review.
Sex Med
December 2024
Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.
Background: Peyronie's disease (PD) is a fibrotic disorder affecting the penile tunica albugínea, with unclear pathophysiology despite centuries of recognition.
Aim: This scoping review maps the effects of interventions in basic PD research, synthesizing evidence from in vivo and in vitro studies to guide future investigation.
Methods: In October-November 2023, a systematic search was conducted across PubMed, Embase (Ovid), Science of Web, and Scopus, following SRYCLE's guidelines.
Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy.
Acta Pharm Sin B
December 2024
School of Pharmacy, Institute of Hepatology and Metabolic Diseases, Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 () expression plasmid onto the surface of VNP20009, an attenuated strain with well-documented anti-cancer activity, and constructed a TME-targeted delivery system named /ZIF-8@.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!