Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug‐Resistant Gram‐Negative Pathogens

Abstract

Cefiderocol (CFDC), (formerly S-649266), is a novel injectable siderophore cephalosporin developed by Shionogi & Co., Ltd., with potent in vitro activity against Gram-negative pathogens including multidrug-resistant (MDR) Enterobacteriaceae and non-fermenting organisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, and Stenotrophomonas maltophilia. Characterized by its siderophore catechol-moiety, CFDC uses a "trojan-horse approach" to navigate through the bacterial periplasmic space, thus evading various beta-lactam degrading enzymes and other mechanisms of resistance present in Gram-negative bacteria. More specifically in carbapenem-resistant Enterobacteriaceae, CFDC has been shown to have activity against extended spectrum beta-lactamases (ESBLs), such as CTX-type, SHV-type, and TEM-type, as well as the Ambler classes of beta-lactamases, including class A (KPC), class B (NDM, IMP, and VIM), class C (AmpC), and class D (OXA, OXA-24, OXA-48, and OXA-48-like). In addition to the strong activity that CFDC has been shown to have against MDR P. aeruginosa, it has also displayed activity against the OXA-23, OXA-24, and OXA-51, beta-lactamases commonly found in MDR A. baumannii. Cefiderocol was recently approved by the US Food and Drug Administration (FDA) for use in complicated urinary tract infections (cUTI), including pyelonephritis, for use in patients 18 years or older with limited or no alternative options for treatment, and is currently being evaluated in a phase III trial for use in nosocomial pneumonia caused by Gram-negative pathogens. The unique features and enhanced activity of CFDC suggest that it is likely to serve as a viable therapeutic option in the treatment of MDR Gram-negative infections. The purpose of this review is to provide an overview of previously published literature explaining CFDC's pharmacology, pharmacokinetic / pharmacodynamic (PK / PD) properties, microbiologic activity, resistance mechanisms, safety parameters, dosing and administration, clinical data, and potential place in therapy. KEY WORDS siderophore, multidrug-resistant Gram-negative pathogens, Acinetobacter baumannii, Pseudomonas aeruginosa, trojan horse, cefiderocol, enterobacterales.

Contemporary Perspective on the Treatment of Acinetobacter baumannii Infections: Insights from the Society of Infectious Diseases Pharmacists

“…In vitro data demonstrate excellent activity against both colistin-resistant and CR A. baumannii [ 64 ]. The nuances of cefiderocol pharmacology and in vitro activity are well described in a 2020 review by Abdul-Mutakabbir and colleagues [ 81 ]. Unfortunately, clinical data among patients treated with cefiderocol for A. baumannii infections have not been as encouraging [ 5 , 65 ].…”

Escalating antimicrobial resistance among Enterobacteriaceae: focus on carbapenemases

“…Cefiderocol is a siderophore cephalosporin with unique ability to enter the bacterial periplasmic space that has enhanced stability against -lactamases including ESBLs and CPases; its activity appears equal to or superior to CAZ-AVI against CPase-producing Enterobacteriaceae 224 . Cefiderocol has potent activity against GNB including MDR Enterobacteriaceae and non-fermenters [225][226][227]…”

“…Cefiderocol is active against -lactamases including ESBLs (CTX, SHV, TEM) as well as KPC, NDM, IMP, VIM, OXA-24, OXA-48 type225 . Cefiderocol is FDA-approved to treat c-UTIs225 but data for other serious nosocomial infections are limited. In a non-randomized study, 10 critically ill patients with either BSI or VAP caused by CPR-GNB were treated with cefiderocol.…”

Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions

“…Furthermore, its unique structure makes it resistant to hydrolysis by all classes of β-lactamases, including metallo-β-lactamases; cefiderocol is stable against ESBLs, KPC (Class A), NDM, VIM, IMP (Class B), AmpC (Class C) and OXA-48 like (Class D) β-lactamases. It has been approved for complicated urinary tract infections, hospital acquired pneumonia and ventilator-associated pneumonia [ 113 , 114 , 115 ].…”