Background

Ceftolozane–tazobactam and ceftazidime–avibactam are preferred treatment options for multidrug-resistant Pseudomonas aeruginosa infections; however, real-world comparative effectiveness studies are scarce. Pharmacokinetic and pharmacodynamic differences between the agents might affect clinical response rates. We aimed to compare the effectiveness of ceftolozane–tazobactam and ceftazidime–avibactam for treatment of invasive multidrug-resistant P aeruginosa infections.

Methods

This multicentre, retrospective, observational study was conducted at 28 hospitals in the USA between Jan 1, 2016, and Dec 31, 2023. Eligible patients were adults (age ≥18 years old) with microbiologically confirmed multidrug-resistant P aeruginosa pneumonia or bacteraemia treated with ceftolozane–tazobactam or ceftazidime–avibactam for more than 48 h. Patients were matched (1:1) by study site, severity of illness, time to treatment initiation (≤72 h or >72 h), and infection type. The primary outcome was clinical success at day 30, which was defined as survival, resolution of signs and symptoms of infection with the intended treatment course, and the absence of recurrent infection due to P aeruginosa. Secondary outcomes included all-cause mortality and development of resistance to study drug.

Findings

420 eligible patients were included (210 in each treatment group), of whom 350 (83%) had pneumonia and 70 (17%) had bacteraemia. Baseline demographics, comorbidities, and severity of illness indicators were similar between groups. On treatment initiation, 336 (80%) patients were in the intensive care unit, 296 (70%) were receiving mechanical ventilation, and 168 (40%) required vasopressor support. Clinical success was observed in 128 (61%) of 210 patients treated with ceftolozane–tazobactam and 109 (52%) of 210 patients treated with ceftazidime–avibactam. By conditional logistic regression analysis, the adjusted odds ratio (aOR) of success after treatment with ceftolozane–tazobactam compared with ceftazidime–avibactam was 2·07 (95% CI 1·16–3·70). For patients with pneumonia, clinical success was observed in 110 (63%) of 175 patients in the ceftolozane–tazobactam group and 89 (51%) of 175 patients in the ceftazidime–avibactam group (aOR 2·34 [95% CI 1·22–4·47]). Among patients with bacteraemia, rates of clinical success were 51% (18 of 35 patients) for patients treated with ceftolozane–tazobactam and 57% (20 of 35 patients) for those treated with ceftazidime–avibactam (0·76 [0·23–2·57]). There were no significant differences between groups in 30-day or 90-day mortality. Among patients whose baseline isolates were tested for susceptibility, resistance developed in 22% (38 of 173) of patients treated with ceftolozane–tazobactam and 23% (40 of 177) of patients treated with ceftazidime–avibactam.

Interpretation

Treatment with ceftolozane–tazobactam resulted in higher rates of clinical success compared with ceftazidime–avibactam for invasive infections due to multidrug-resistant P aeruginosa. Differences were driven by improved response rates for patients with pneumonia who were treated with ceftolozane–tazobactam. There were no significant differences between study groups with respect to all-cause mortality; treatment-emergent resistance was common with both agents.

Funding

Merck Sharp & Dohme.

中文翻译：

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头孢他啶-阿维巴坦与头孢洛扎-他唑巴坦治疗美国多重耐药铜绿假单胞菌感染的有效性 （CACTUS）：一项多中心、回顾性、观察性研究

 背景

头孢洛扎-他唑巴坦和头孢他啶-阿维巴坦是多重耐药铜绿假单胞菌感染的首选治疗选择;然而，现实世界的比较有效性研究很少。药物之间的药代动力学和药效学差异可能会影响临床反应率。我们旨在比较头孢洛扎-他唑巴坦和头孢他啶-阿维巴坦治疗侵袭性多重耐药铜绿假单胞菌感染的有效性。

 方法

这项多中心、回顾性、观察性研究于 2016 年 1 月 1 日至 2023 年 12 月 31 日期间在美国的 28 家医院进行。符合条件的患者是经微生物学证实的多重耐药铜绿假单胞菌肺炎或菌血症的成人 （≥18 岁），接受头孢洛扎-他唑巴坦或头孢他啶-阿维巴坦治疗超过 48 小时。根据研究地点、疾病严重程度、治疗开始时间 （≤72 h 或 >72 h） 和感染类型对患者进行匹配 （1：1）。主要结局是第 30 天的临床成功，定义为生存率、预期疗程感染体征和症状的消退以及没有铜绿假单胞菌引起的复发感染。次要结局包括全因死亡率和对研究药物耐药性的发展。

 发现

纳入 420 例符合条件的患者 （每个治疗组 210 例），其中 350 例 （83%） 患有肺炎，70 例 （17%） 患有菌血症。基线人口统计学、合并症和疾病严重程度指标在各组之间相似。治疗开始时，336 名 （80%） 患者在重症监护病房，296 名 （70%） 接受机械通气，168 名 （40%） 需要血管加压药支持。在接受头孢洛扎-他唑巴坦治疗的 210 名患者中有 128 名 （61%） 和接受头孢他啶-阿维巴坦治疗的 210 名患者中有 109 名 （52%） 观察到临床成功。通过条件 logistic 回归分析，与头孢他啶-阿维巴坦相比，头孢洛扎-他唑巴坦治疗后成功的校正比值比 （aOR） 为 2·07 （95% CI 1·16–3·70）。对于肺炎患者，头孢洛扎-他唑巴坦组的 175 例患者中有 110 例 （63%） 观察到临床成功，头孢他啶-阿维巴坦组的 175 例患者中有 89 例 （51%） 观察到临床成功 （aOR 2·34 [95% CI 1·22–4·47]）。在菌血症患者中，头孢洛扎-他唑巴坦治疗的患者的临床成功率为 51%（35 例患者中的 18 例），头孢他啶-阿维巴坦治疗的患者的临床成功率为 57%（35 例患者中的 20 例）（0·76 [0·23–2·57]）。组间 30 天或 90 天死亡率无显著差异。在进行基线分离株药敏试验的患者中，22% （173 例中的 38 例） 接受头孢洛扎-他唑巴坦治疗的患者和 23% （177 例中的 40 例） 接受头孢他啶-阿维巴坦治疗的患者产生耐药性。

 解释

与头孢他啶-阿维巴坦治疗多重耐药铜绿假单胞菌引起的侵袭性感染相比，用头孢洛扎-他唑巴坦治疗导致的临床成功率更高。差异是由接受头孢洛扎-他唑巴坦治疗的肺炎患者反应率的提高驱动的。研究组之间在全因死亡率方面没有显著差异;两种药物的治疗中出现的耐药性是共同的。

 资金

 默克夏普和多姆。