Dose-response of Ceftazidime–Avibactam Against K. pneumoniae in the COMBINE Pneumonia Model

Aim Efficacy evaluation and dose-response of ceftazidimeavibactam against KPC-producing K. pneumoniae in the murine COMBINE pneumonia model. Background Ceftazidime–avibactam is an important treatment option against lung infection caused by resistant K. pneumoniae, yet variability in drug exposure at the infection site mayinfluence therapeutic success. Preclinical infection models are essential for understanding the relationships between drug exposure and antibacterial response, which is important for optimizing treatment. Methods CD-1 mice were infected intranasally with K. pneumoniae 0978 (CAZ:AVI MIC = 16:4 μg/mL) and treated subcutaneously with CAZ and AVI either in combination at the registered 4:1 ratio, with avibactam fixed at 100 mg/kg, or as monotherapy (Q4h) at doses designed to achieve human-equivalent exposures. Treatment efficacywas evaluated as reduction in bacterial burden. Dose-response relationships were evaluated for the 24-hour bacterial response (ΔLog10 CFU) using the Sigmoidal-Emax model, and the resultant targets (corresponding to stasis, 1- and 2-log kills) were calculated. Results Combination therapy produced dose-dependent reductions in lung bacterial burden, decreasing counts from ~6 to ~3–4 log₁₀ CFU/lung at doses ≥ 25/6.25; both 4:1 and fixed-AVI regimens showed comparable efficacy across dose levels. Dose–response analysis showed a lower ED₅₀ with increased AVI exposure (fixed AVI 100 mg regimen). Dose targets for stasis, 1-log kill, and 2-log kill were 4.6, 18.2, and 83.1 for the fixed-ratio regimen and 2.7, 10.4, and 46.6 for the fixed AVI 100 mg regimen. COMBINE Pneumonia Model resources COMBINE preclinical repository with bacterial strains found to be reproducibly virulent and fulfilling performance criteria in the COMBINE standardised pneumonia mouse model. Data from the COMBINE Multicenter Study to Standardize a Mouse Pneumonia Model with Pseudomonas aeruginosa and Klebsiella pneumoniae for Antibiotic Development Arrazuria R, Kerscher B, Huber KE, Hoover JL, Lundberg CV, Hansen JU, Sordello S, Renard S, Aranzana-Climent V, Hughes D, Gribbon P, Friberg LE, Bekeredjian-Ding I (2022): Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections.Front Microbiol 13: 988725. Arrazuria R, Kerscher B, Huber KE, et al. Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents. Frontiers in Microbiology. 2022;13:988728.