No abstract

Microtubule-based active matter provides insight into the self-organization of motile interacting constituents. We describe several formulations of microtubule-based 3D active isotropic fluids. Dynamics of these fluids is powered by three...

Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%fT > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of fT > MIC exposure needed for successful clinical response. While pre-clinical animal based studies, such as the neutropenic thigh infection model, have been widely used to support dosing regimen selection for clinical development and susceptibility breakpoint evaluation, pharmacodynamic based studies in human patients are used validate exposures needed in the clinic and for guidance during therapeutic drug monitoring (TDM). For the majority of studied beta-lactams, pre-clinical animal studies routinely demonstrated the fT > MIC should exceed approximately 40–70% fT > MIC to achieve 1 log reductions in colony forming units. In contrast, clinical studies tend to suggest higher exposures may be needed, but tremendous variability exists study to study. Herein, we will review and critique pre-clinical versus human-based pharmacodynamic studies aimed at determining beta-lactam exposure thresholds, so as to determine which targets may be best suited for optimal dosage selection, TDM, and for susceptibility breakpoint determination. Based on our review of murine and clinical literature on beta-lactam pharmacodynamic thresholds, murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

Background Imipenem (IPM)/XNW4107 is a novel β-lactam/β-lactamase inhibitor with in vitro activity against serine carbapenemase-producing Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales. Herein, we evaluated the in vivo activity of an IPM/XNW4107 human-simulated regimen (HSR) against clinical OXA-23- and OXA-24-producing A. baumannii as well as KPC- and GES-producing P. aeruginosa using a neutropenic murine thigh infection model. Methods Seven A. baumannii and 4 P. aeruginosa isolates were included. IPM and IPM/XNW4107 MICs (XNW4107 fixed at 8 mg/L) were tested in triplicate by broth microdilution. One thigh of neutropenic ICR mice (6 mice per group) was inoculated with ∼107 CFU/mL bacterial suspensions. HSR that mimicked the clinical exposures of IPM 500 mg q6h alone or in combination with XNW4107 250 mg q6h each as 1 h infusion were developed in the murine model. In efficacy studies, two hours after inoculation, placebo, IPM 500 mg q6h 1 h infusion HSR, or IPM/XNW4107 500/250 mg q6h 1 h infusion HSR were administered subcutaneously. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Results Isolates were IPM resistant (MICs 16 - > 64 mg/L). IPM/XNW4107 A. baumannii and P. aeruginosa MIC ranges were 1-16 and 1- 8 mg/L, respectively. Across all examined isolates, 0 h mean ± SD bacterial burden was 5.86 ± 0.32 log10 CFU/thigh. The 24 h increase in bacterial burden was 2.68 ± 0.91 log10 CFU/thigh in the sham controls. IPM HSR monotherapy groups showed mean increase in bacterial burden of 2.34 ± 0.95 log10 CFU/thigh. Bacterial kill with IPM/XNW4107 500/250 mg q6h 1 h infusion HSR ranged from -0.46 ± 1.69 to -3.77 ± 0.15 and -2.33 ± 0.25 to -3.76 ± 0.57 among A. baumannii and P. aeruginosa isolates, respectively. IPM/XNW4107 500/250 mg q6h 1 h infusion HSR produced > 1-log kill against 6/7 examined A. baumannii with the exception of A. baumannii 160 (IPM/XNW4107 MIC 16 mg/L) and 4/4 P. aeruginosa as well as > 2-log kill against 4/7 A. baumannii and 4/4 P. aeruginosa. Conclusion IPM/XNW4107 500/250 mg q6h 1 h infusion HSR showed potent in vivo activity against serine carbapenemase-producing A. baumannii and P. aeruginosa. These data support the consideration of IPM/XNW4107 for the treatment of serious infections due to these organisms in clinical trials. Disclosures Haitao Yuan, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xiao Liu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Xi Chen, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds Yuchuan Wu, PhD, Evopoint Biosciences Co., Ltd: Stocks/Bonds David P. Nicolau, PharmD, Shionogi: Grant/Research Support Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support.