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Objectives Sitafloxacin is one of the newer generation fluoroquinolones with highly active against multidrug-resistant (MDR) bacteria. Our objectives were to identify the sitafloxacin pharmacokinetic/pharmacodynamic (PK/PD) index and breakpoints against MDR isolate in the urinary tract infection model. Methods Forty-eight MDR isolates underwent sitafloxacin and levofloxacin microdilution susceptibility testing. A 24 h in vitro model was established that simulated the healthy subjects urodynamics of sitafloxacin fumarate injection. Ten MDR isolates (four carbapenem-resistant Escherichia coli, three carbapenem-resistant P. aeruginosa and three vancomycin-resistant E. faecium) were selected. The drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid Emax model was fitted to the killing effect data. Monte Carlo simulations were performed to assess target attainment for the sitafloxacin fumarate doses of 100 and 200 mg q24h. Results Analysis indicated that the MICs of sitafloxacin were all significantly lower than that of levofloxacin (P < 0.01). The UAUC0–24h/MIC targets required to achieve stasis, 1-log10 killing and 2-log10 killing were 63.60, 79.49 and 99.45 (carbapenem-resistant E. coli), 60.85, 90.31 and 128.95 (carbapenem-resistant P. aeruginosa), 65.91, 77.81 and 103.11 (vancomycin-resistant E. faecium). Monte Carlo simulation showed the infusion of sitafloxacin fumarate 100 mg q24h was able to achieve 90% probability of target attainment against bacteria with MIC of 8 mg/L for the common complicated urinary tract infections. Conclusions Sitafloxacin fumarate injection is an alternative therapeutic agent for the treatment of UTIs caused by MDR isolates.

ObjectiveThis study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime‐avibactam (YK‐1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation.MethodsYK‐1169 single‐ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2‐h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2‐h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK‐1169 (2.5 g) to assess drug‐drug interactions. The minimum inhibitory concentrations (MICs) of YK‐1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens.ResultsCefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0‐∞,ss were 9.20 and 16.0 μg/mL, 407.2 and 659.45 μg·h/mL in the 2.5 and 3.75 g multiple‐dose groups, respectively. The avibactam Cmax,ss and AUC0‐∞,ss were 0.545 and 0.837 μg/mL, 53.31 and 79.55 μg·h/mL in the 2.5 and 3.75 g multiple‐dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2‐h infusion), 3.75 (q8h, 2‐, 3‐ and 4‐h infusions) and 7.5 g (24‐h continuous infusion) reached a 90% cumulative fraction of response.ConclusionYK‐1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.