Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Antimicrob Agents Chemother. 2012 Dec;56(12):6137-46. doi: 10.1128/AAC.00851-12. Epub 2012 Sep 17.
The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P. aeruginosa isolates with ceftazidime MICs of 8 to 128 mg/liter and ceftazidime-avibactam MICs of 4 to 32 mg/liter were utilized in neutropenic mouse studies; 15 of the isolates were also evaluated in immunocompetent mice. Six isolates were studied in both the hollow-fiber system and the neutropenic mouse. In both systems, the free drug concentration-time profile seen in humans given 2 g of ceftazidime every 8 h (2-h infusion), with or without avibactam at 500 mg every 8 h (2-h infusion), was evaluated. In vivo activity was pharmacodynamically predictable based on the MIC. Ceftazidime decreased bacterial densities by ≥0.5 log unit for 10/27 isolates, while ceftazidime-avibactam did so for 22/27 isolates. In immunocompetent animals, enhancements in activity were seen for both drugs, with ceftazidime achieving reductions of ≥0.3 log unit for 10/15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates. In vitro, ceftazidime resulted in regrowth by 24 h against all isolates, while ceftazidime-avibactam achieved stasis or better against 4/7 isolates. Mutants with elevated ceftazidime-avibactam MICs appeared after 24 h from 3/7 isolates studied in vitro; however, no resistant mutants were detected in vivo. Against this highly ceftazidime-nonsusceptible population of P. aeruginosa, treatment with human simulated doses of ceftazidime-avibactam resulted in pharmacodynamically predictable activity, particularly in vivo, against isolates with MICs of ≤16 mg/liter, and this represents a potential new option to combat these difficult-to-treat pathogens.
头孢他啶和阿维巴坦的联合具有针对耐药革兰氏阴性病原体的强大活性，包括铜绿假单胞菌。我们使用中空纤维系统和中性粒细胞减少和免疫功能正常的鼠大腿感染模型比较了人模拟剂量的头孢他啶和头孢他啶-阿维巴坦的疗效。在中性粒细胞减少症小鼠研究中使用了 27 株临床分离的铜绿假单胞菌，其头孢他啶 MIC 值为 8 至 128 mg/L，头孢他啶-阿维巴坦 MIC 值为 4 至 32 mg/L；其中 15 株也在免疫功能正常的小鼠中进行了评估。在中空纤维系统和中性粒细胞减少症小鼠中研究了 6 株分离株。在这两种系统中，评估了给予每 8 小时 2 克头孢他啶（2 小时输注）和/或每 8 小时 500 毫克阿维巴坦（2 小时输注）的人类的游离药物浓度-时间曲线。基于 MIC，体内活性具有预测性。头孢他啶使 27 株分离株中的 10 株的细菌密度降低≥0.5 对数单位，而头孢他啶-阿维巴坦使 27 株分离株中的 22 株降低。在免疫功能正常的动物中，两种药物均显示出活性增强，头孢他啶使 15 株分离株中的 10 株的细菌密度降低≥0.3 对数单位，而头孢他啶-阿维巴坦则使所有 15 株分离株降低。体外，所有分离株在 24 小时内头孢他啶导致再生长，而头孢他啶-阿维巴坦对 7 株分离株中的 4 株达到稳定或更好的效果。在体外研究的 7 株分离株中，有 3 株在 24 小时后出现头孢他啶-阿维巴坦 MIC 值升高的突变体；然而，在体内未检测到耐药突变体。对于这种高度头孢他啶不敏感的铜绿假单胞菌群体，用人类模拟剂量的头孢他啶-阿维巴坦治疗可产生可预测的药效学活性，特别是在体内，对 MIC 值≤16 mg/L 的分离株，这代表了对抗这些难以治疗的病原体的潜在新选择。
