Centre for Clinical Research, Faculty of Medicine, University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, Queensland, Australia.
Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Trials. 2021 Dec 7;22(1):889. doi: 10.1186/s13063-021-05870-w.
Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii. Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection.
This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient's treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5-14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The sample size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected.
With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent.
The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.
由于广泛存在的超广谱β-内酰胺酶（ESBL）、AmpC 酶的过度产生、碳青霉烯酶和其他耐药机制，革兰氏阴性菌中的抗生素耐药率不断上升，包括肠杆菌科、铜绿假单胞菌和鲍曼不动杆菌等常见医院和医疗保健相关病原体。头孢他啶-阿维巴坦是一种新型的铁载体头孢菌素抗生素，其 3-位侧链上有一个儿茶酚基团。头孢他啶-阿维巴坦在体外对广泛的革兰氏阴性菌具有强大的作用，包括耐碳青霉烯类肠杆菌科（CRE）和多药耐药（MDR）铜绿假单胞菌和鲍曼不动杆菌。最近的临床数据表明，头孢他啶-阿维巴坦在治疗复杂性尿路感染和医院获得性肺炎方面具有疗效，但尚未研究其治疗血流感染的效果。
本研究将采用多中心、开放标签、非劣效性试验设计，比较头孢他啶-阿维巴坦和标准治疗抗生素。符合条件的参与者将是被诊断为革兰氏阴性菌血流感染的成年住院患者，依据是阳性血培养结果，感染符合医疗保健相关或医院获得性的定义。它将根据患者的治疗医生，将头孢他啶-阿维巴坦与当前的标准治疗（SOC）抗生素方案进行比较。符合条件的参与者将以 1:1 的比例随机分配至头孢他啶-阿维巴坦或 SOC 组，并接受 5-14 天的抗生素治疗。试验招募将在至少 20 个国家的 10 个地点（澳大利亚、马来西亚、新加坡、泰国、土耳其和希腊）进行。样本量是根据对照组 14 天的全因死亡率估计为 10%，两组之间非劣效性差距为 10%得出的。总共需要至少 284 名患者，以实现双侧α水平为 0.05 的 80%功效。将收集描述人口统计学信息、风险因素、同时使用的抗生素、疾病评分、微生物学、多药耐药菌筛查、出院和死亡率的数据。
随着抗菌药物耐药性的增加，需要开发对革兰氏阴性病原体（如头孢他啶-阿维巴坦）具有广泛活性的新抗生素。通过选择具有多药耐药病原体风险的人群，并在临床疾病的早期（索引血培养后 48 小时内）开始研究治疗，可以为临床医生提供这种新型药物疗效的指导。
GAME CHANGER 试验在美国国立卫生研究院临床试验.gov 注册，注册号为 NCT03869437，于 2019 年 3 月 11 日注册。
