Cefiderocol：用於多重抗藥的革蘭氏陰性菌感染的新型機轉抗生素

Cefiderocol: A New Antibiotic with Novel Mechanism for Multidrug-Resistant Gram-Negative Bacterial Infections

抗生素的出現無疑是醫療史上的重大進展，擔任著治療細菌感染的關鍵角色，然而也無法避免的伴隨著細菌抗藥性的問題產生，尤其廣效抗生素的過度使用更加重了此惡性循環鍊。抗生素抗藥性(antimicrobial resistance, AMR)一直以來都是全球性的健康議題，世界衛生組織(world health organization, WHO)更將其視為全球十大公共衛生危機之一，而這當中又以多重抗藥的革蘭氏陰性菌(multidrug-resistant Gram-negative bacteria, MDRGNB)感染最為棘手。台灣本土抗藥性菌株的流行病學依據「醫院感染管制與抗藥性監測管理系統」（Taiwan healthcare-associated infection and antimicrobial resistance surveillance system，THAS系統）的資料，近十年來對碳青黴烯類(carbapenem)抗生素具抗藥性的革蘭氏陰性菌感染有顯著的上升。為因應日益棘手的抗藥性細菌感染，近年來陸續研發了可對抗多重抗藥的革蘭氏陰性菌的新抗生素，cefiderocol便是其中之一。Cefiderocol是新一代含鐵載體結構的頭孢菌素(siderophorecephalosporin)，擁有新的抗菌機轉，對於帶有超廣效乙內醯氨酶(extended-spectrumβ-lactamases, ESBLs)、AmpC乙內醯氨酶(AmpCβ-lactamase)、絲胺酸-碳青黴烯酶(serine-carbapenemases)與金屬輔助因子-碳青黴烯酶(metallo-carbapenemases,MβLs)等抗藥性革蘭氏陰性菌，在研究中皆顯現其良好的生體外活性。此外，對於臨床上重要的多重抗藥的革蘭氏陰性菌，如鮑氏不動桿菌(Acinetobacter baumannii complex)、綠膿桿菌(Pseudomonas aeruginosa)、腸桿菌(Enterobacterales)、嗜麥芽窄食單胞菌(Stenotrophomonas maltophilia)及洋蔥伯克氏菌群(Burkholderia cepacia complex, BCC)等等皆具敏感性，是迄今具有最廣效抗菌能力的藥物。Cefiderocol於2019年11月已通過美國食品藥物管理局(U.S. Food and Drug Administration, U.S. FDA)核准用於無可替代治療藥物的多重抗藥性的革蘭氏陰性菌造成的成人複雜性泌尿道感染（包括腎盂腎炎），於隔年更將治療範圍擴至院內肺炎與呼吸器相關肺炎，隨後也陸續於歐洲、日本等國核准上市。台灣食品藥物管理署(Taiwan food and drug administration, TFDA)也於2024年2月核准Cefiderocol使用於上述的適應症，未來勢必成為治療多重抗藥的革蘭氏陰性菌感染的有力選擇。本篇文章主要介紹關於Cefiderocol的相關機轉、給予方式、臨床試驗、治療成效及國內臨床菌株的感受性報告，作為將來使用此藥物的參考。

The discovery and revolution of antibiotics represents a significant advancement in medical history. However, this progress has also led to the development of bacterial resistance, and the overuse of broad-spectrum antibiotics further fuels this vicious cycle. Antimicrobial resistance (AMR) is an important global health issue, and the World Health Organization has listed it as one of the top ten public health crises worldwide. During an AMR storm, the emergence of multidrug-resistant Gram-negative bacteria (MDRGNB) presents a challenging dilemma. According to the Taiwan Healthcare-associated Infection and Antimicrobial Resistance Surveillance System, carbapenem-resistant Gram-negative bacterial infections have significantly increased over the past decade. To address AMR, pharmaceutical companies have been developing new antibiotics, including cefiderocol, to combat MDRGNB. Cefiderocol is a next-generation siderophore cephalosporin with a novel mechanism of action. It demonstrates good in vitro activity against Gramnegative bacteria withβ-lactamases such as extended-spectrumβ-lactamases, AmpC , serine-carbapenemases, and even metallo-β-lactamases (MβLs). It also exhibits sensitivity to major clinical MDRGNB such as Acinetobacter baumannii complex, Pseudomonas aeruginosa, Enterobacterales, Stenotrophomonas maltophilia, and Burkholderia cepacia complex. Consequently, in November 2019, cefiderocol was approved by the U.S. Food and Drug Administration for the treatment of complicated urinary tract infections (including pyelonephritis) caused by MDRGNB when no alternative treatment options are available for adults. In the following year, its indications were expanded to include hospital-acquired and ventilator-associated pneumonia. The Taiwan Food and Drug Administration also approved cefiderocol for the treatment of these infections in February 2024. This new drug is poised to play a crucial role in the treatment of MDRGNB infections, especially for the infamous MβL-producing bacteria or CRAB infections, owing to very limited treatment options. This study describes the mechanisms, administration, clinical trials, therapeutic efficacy, and susceptibility of MDRGNB isolates in Taiwan.