Multi-drug resistant (MDR) is emerging as a pathogen of increasing prevalence and concern. Infections associated with this Gram-negative pathogen are often associated with increased morbidity and mortality and few therapeutic options. The β-lactamase inhibitor sulbactam used commonly in combination with ampicillin demonstrates intrinsic antibacterial activity against acting as an inhibitor of PBP1 and PBP3, which participate in cell wall biosynthesis. The production of β-lactamases, particularly class D oxacillinases, however, has limited the utility of sulbactam resorting to increased doses and the need for alternate therapies. Durlobactam is a non-β-lactam β-lactamase inhibitor that demonstrates broad β-lactamase inhibition including class D enzymes produced by and has shown potent activity against MDR , particularly carbapenem-resistant isolates in susceptibility and pharmacodynamic model systems. The objective of this study is to evaluate the exposure-response relationship of sulbactam and durlobactam in combination using neutropenic thigh and lung models to establish PK/PD exposure magnitudes to project clinically effective doses. Utilizing established PK/PD determinants of %T>MIC and AUC/MIC for sulbactam and durlobactam, respectively, non-linear regressional analysis of drug exposure was evaluated relative to the 24-hour change in bacterial burden (log CFU/g). Co-modeling of the data across multiple strains exhibiting a broad range of MIC susceptibility suggested net 1-log CFU/g0 reduction can be achieved when sulbactam T>MIC exceeds 50% of the dosing interval and durlobactam AUC/MIC is 10. These data were ultimately used to support sulbactam-durlobactam dose selection for Phase 3 clinical trials.
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http://dx.doi.org/10.1128/aac.00800-23 | DOI Listing |
iScience
January 2025
CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, France.
Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in are associated with an autoinflammatory syndrome termed ROSAH and with spiradenoma (skin cancers with sweat gland differentiation).
View Article and Find Full Text PDFJ Clin Exp Hepatol
December 2024
Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Giza, Egypt.
Background: Liver fibrosis is a serious global health issue, but current treatment options are limited due to a lack of approved therapies capable of preventing or reversing established fibrosis.
Aim: This study investigated the antifibrotic effects of a synthetic peptide derived from α-lactalbumin in a mouse model of thioacetamide (TAA)-induced liver fibrosis.
Methods: analyses were conducted to assess the physicochemical properties, pharmacophore features, and docking interactions of the peptide.
Lancet Reg Health West Pac
January 2025
Division of Nephrology, National Clinical Research Centre for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Background: Early diagnosis of chronic kidney disease (CKD) is crucial for timely intervention to delay disease progression and improve patient outcomes. However, data for clinical characteristics of Chinese patients with undiagnosed, early-stage CKD are lacking.
Methods: REVEAL-CKD is a multinational, observational study using real-world data in selected countries to describe factors associated with undiagnosed stage 3 CKD, time to diagnosis, and CKD management post diagnosis.
Clin Cosmet Investig Dermatol
January 2025
Western University, London, ON, Canada.
Acne vulgaris is a globally prevalent dermatological condition associated with substantial physical and psychological burden. Although acne typically presents during adolescence, it is a chronic condition that also affects many adults. Despite the spectrum of treatments available for acne, limitations in tolerability and safety concerns can present challenges for the use of conventional medications in clinical practice.
View Article and Find Full Text PDFJ Inflamm Res
January 2025
Precision Medicine Laboratory, School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, People's Republic of China.
Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, largely due to its late-stage diagnosis and high recurrence rates. Chronic inflammation is a critical driver of OC progression, contributing to immune evasion, tumor growth, and metastasis. Inflammatory cytokines, including IL-6, TNF-α, and IL-8, as well as key signaling pathways such as nuclear factor kappa B (NF-kB) and signal transducer and activator of transcription 3 (STAT3), are upregulated in OC, promoting a tumor-promoting environment.
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