Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
Antimicrob Agents Chemother. 2023 Aug 17;67(8):e0041423. doi: 10.1128/aac.00414-23. Epub 2023 Jul 10.
Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM). Isolates CW41, CW35, and CW44 (ceftolozane-tazobactam MICs of 4, 4, and 2 mg/L, respectively) from adults with CF were exposed to simulated representative epithelial lining fluid pharmacokinetics of ceftolozane-tazobactam in the HFIM. Regimens were continuous infusion (CI; 4.5 g/day to 9 g/day, all isolates) and 1-h infusions (1.5 g every 8 hours and 3 g every 8 hours, CW41). Whole-genome sequencing and mechanism-based modeling were performed for CW41. CW41 (in four of five biological replicates) and CW44 harbored preexisting resistant subpopulations; CW35 did not. For replicates 1 to 4 of CW41 and CW44, 9 g/day CI decreased bacterial counts to <3 log CFU/mL for 24 to 48 h, followed by regrowth and resistance amplification. Replicate 5 of CW41 had no preexisting subpopulations and was suppressed below ~3 log CFU/mL for 120 h by 9 g/day CI, followed by resistant regrowth. Both CI regimens reduced CW35 bacterial counts to <1 log CFU/mL by 120 h without regrowth. These results corresponded with the presence or absence of preexisting resistant subpopulations and resistance-associated mutations at baseline. Mutations in , , and were identified following CW41 exposure to ceftolozane-tazobactam at 167 to 215 h. Mechanism-based modeling well described total and resistant bacterial counts. The findings highlight the impact of heteroresistance and baseline mutations on the effect of ceftolozane-tazobactam and limitations of MIC to predict bacterial outcomes. The resistance amplification in two of three isolates supports current guidelines that ceftolozane-tazobactam should be utilized together with another antibiotic against P. aeruginosa in CF.
铜绿假单胞菌仍然是囊性纤维化（CF）慢性呼吸道感染的一个挑战。头孢洛扎他唑巴坦尚未在中空纤维感染模型（HFIM）中针对多药耐药高突变铜绿假单胞菌分离株进行评估。从 CF 成人中分离出的 CW41、CW35 和 CW44（头孢洛扎他唑巴坦 MIC 分别为 4、4 和 2mg/L），在 HFIM 中暴露于模拟的代表性上皮衬里液头孢洛扎他唑巴坦药代动力学下。方案为连续输注（CI；所有分离株 4.5 克/天至 9 克/天）和 1 小时输注（1.5 克每 8 小时和 3 克每 8 小时，CW41）。对 CW41 进行全基因组测序和基于机制的建模。CW41（在五个生物重复中的四个）和 CW44 携带预先存在的耐药亚群；CW35 没有。对于 CW41 和 CW44 的重复 1 到 4，9 克/天 CI 将细菌计数减少至<3 对数 CFU/mL 持续 24 到 48 小时，随后出现细菌生长和耐药性扩增。CW41 的重复 5 没有预先存在的亚群，9 克/天 CI 抑制其生长至<3 对数 CFU/mL 持续 120 小时，随后出现耐药性生长。两种 CI 方案在 120 小时内将 CW35 的细菌计数减少至<1 对数 CFU/mL 而没有细菌生长。这些结果与基线时预先存在的耐药亚群和耐药相关突变的存在或不存在相对应。在 CW41 暴露于头孢洛扎他唑巴坦 167 至 215 小时后，发现了 、 和 中的突变。基于机制的建模很好地描述了总细菌计数和耐药细菌计数。这些发现强调了异质性耐药性和基线突变对头孢洛扎他唑巴坦作用的影响以及 MIC 预测细菌结果的局限性。在三个分离株中的两个中观察到耐药性扩增，这支持了当前的指南，即头孢洛扎他唑巴坦应与另一种针对 CF 中的铜绿假单胞菌的抗生素联合使用。
