Pharmacokinetics of YK-1169 in healthy subjects and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation.

OBJECTIVE: This 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. METHODS: YK-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. RESULTS: Cefepime 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. CONCLUSION: YK-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.

Sitafloxacin pharmacokinetics/pharmacodynamics against multidrug-resistant bacteria in a dynamic urinary tract infection in vitro model.

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.

Evaluation of the in vitro synergy of polymyxin B-based combinations against polymyxin B -resistant gram-negative bacilli.

OBJECTIVES: This study aimed to evaluate the in vitro synergy of polymyxin B (PMB) combined with 11 other antibiotics against PMB-resistant gram-negative bacilli (GNBs). METHODS: Thirty-six clinical isolates of PMB-resistant GNBs were used. The MICs of all the antimicrobials tested were determined by the broth microdilution method and the checkerboard assay method. Carbapenemase genes were detected by PCR. In vitro synergy results were interpreted using the fractional inhibitory concentration index (FICI). Four combinations that showed positive interactions were subsequently evaluated in a time-kill study. RESULTS: Among the 36 strains, 15 harboured the carbapenemase gene, and blaKPC was the predominant carbapenemase. The resistance rates of the 36 strains to tigecycline, meropenem, ceftazidime, and cefepime were 100% (36/36), 97% (35/36), 94% (34/36), and 97% (35/36), respectively. For Enterobacteriaceae and Pseudomonas aeruginosa, the resistance rates to aztreonam and ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L) were 95% (19/20) and 25% (5/20), respectively. The PMB-based combinations exhibited synergism to a certain degree. The most synergistic combinations were PMB plus meropenem-avibactam (avibactam at a fixed concentration of 4 mg/L) and PMB plus tigecycline, with the synergy rates of 83.3% and 80.6%, respectively. Compared to tazobactam- and sulbactam-based ß-lactam-ß-lactamase inhibitor combinations (BL-BLIs), PMB with avibactam-based BL-BLIs exhibited a better synergistic effect. For Acinetobacter baumannii, PMB plus sulbactam exhibited a strong synergism with a 2∼7-fold MIC reduction of PMB. In time-kill studies, the highest degree of synergism was observed for PMB with cefepime-avibactam on all the tested isolates. For isolates with low-level resistance to PMB, PMB combined with other partner antimicrobials also showed a certain degree of synergism. CONCLUSIONS: PMB in combination with tigecycline and avibactam-based BL-BLIs could be a potential clinical option for clinical treatment of infections caused by PMB -resistant GNBs.