Viale Pierluigi, Sandrock Christian E, Ramirez Paula, Rossolini Gian Maria, Lodise Thomas P
Infectious Disease Unit, IRCCS Policlinico di Sant'Orsola, Bologna, Italy.
Department of Medical and Surgical Science, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
Ann Intensive Care. 2023 Jun 15;13(1):52. doi: 10.1186/s13613-023-01146-5.
Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug-drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS-NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE-CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.
对重症监护病房中患有严重革兰氏阴性菌感染的重症患者进行恰当的抗生素治疗对于将发病率和死亡率降至最低至关重要。几种新型抗生素已显示出对耐碳青霉烯类肠杆菌科细菌（CRE）和难以治疗的耐药铜绿假单胞菌具有体外活性。头孢地尔是首个获批的铁载体β-内酰胺类抗生素，对多重耐药、耐碳青霉烯类、难以治疗或广泛耐药的革兰氏阴性病原体具有强效活性，而针对这些病原体的治疗选择有限。头孢地尔的活性谱包括鲍曼不动杆菌、铜绿假单胞菌、嗜麦芽窄食单胞菌、无色杆菌属和伯克霍尔德菌属的耐药菌株以及产生丝氨酸和/或金属碳青霉烯酶的CRE。1期研究证实，头孢地尔在肺上皮衬液中能达到足够的浓度，并且需要根据肾功能调整剂量，包括肾清除率增加的患者和接受持续肾脏替代治疗（CRRT）的患者；预计不会出现具有临床意义的药物相互作用。在针对疑似或确诊革兰氏阴性菌引起的医院获得性肺炎患者的随机、双盲APEKS-NP 3期临床研究中，证实了头孢地尔在第14天的全因死亡率（ACM）方面不劣于高剂量、延长输注时间的美罗培南。此外，在针对患有严重耐碳青霉烯类革兰氏阴性菌感染的目标患者群体（包括患有医院获得性肺炎、血流感染/败血症或复杂性尿路感染的住院患者）的随机、开放标签、以病原体为重点的描述性CREDIBLE-CR 3期临床研究中，对头孢地尔的疗效进行了研究。然而，与最佳抗菌治疗（BAT）相比，头孢地尔的ACM率在数值上更高，这导致在美国和欧洲的处方信息中加入了一项警示。由于目前商业检测在准确性和可靠性方面存在问题，因此应仔细评估通过商业检测获得的头孢地尔药敏结果。自获批以来，针对多重耐药和耐碳青霉烯类革兰氏阴性菌感染患者的真实世界证据表明，头孢地尔在某些重症患者群体中可能有效，例如因COVID-19肺炎需要机械通气并随后发生革兰氏阴性菌二重感染的患者，以及接受CRRT和/或体外膜肺氧合的患者。在本文中，我们综述了头孢地尔的微生物谱、药代动力学/药效学、疗效和安全性概况以及真实世界证据，并探讨了其在治疗患有具有挑战性的革兰氏阴性菌感染的重症患者中作用的未来考量。
