Cefiderocol

Cefiderocol's defining feature is its dual mechanism: it binds to penicillin-binding proteins (PBPs) and, unlike other β-lactams, it is actively transported into the periplasm via the bacterial iron-uptake system. The catechol moiety mimics siderophores, chelating ferric iron and hijacking the TonB-dependent transporters, which are overexpressed under iron-limiting conditions. Once inside, it resists hydrolysis by serine and metallo-β-lactamases, including NDM, VIM, and KPC, due to its compact side chain and low affinity for these enzymes. This Trojan-horse strategy is unique among approved cephalosporins and provides activity against a broad spectrum of Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales.

Cefiderocol is approved for complicated urinary tract infections (cUTI) and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia, in adults with limited treatment options. In the APEKS-cUTI trial, it was non-inferior to imipenem-cilastatin for the composite outcome of clinical and microbiological eradication. The APEKS-NP trial demonstrated non-inferiority to meropenem for all-cause mortality at day 14 in HAP patients.¹ It is also used off-label for bloodstream infections and sepsis caused by carbapenem-resistant organisms, though randomized data are limited. The drug is administered intravenously, with dose adjustment required for renal impairment.

Resistance to cefiderocol can emerge through mutations in the iron-transport genes (e.g., cirA, fiu) or by the production of β-lactamases that slowly hydrolyze the drug, such as NDM variants.² In A. baumannii, resistance has been linked to the loss of the PiuA/PiuD transporters. Clinical failures have been reported, particularly in immunocompromised patients with high-burden infections. The drug is not active against Gram-positive or anaerobic bacteria, and its spectrum is limited to aerobic Gram-negative pathogens. Combination therapy with other agents is sometimes used empirically, but synergy data are mixed.

Cefiderocol was developed by Shionogi & Co., Ltd., and its siderophore concept dates back to the 1980s, but it was the first to reach clinical use. It is stable in the presence of the newly emerging Klebsiella pneumoniae carbapenemase (KPC) variants, yet some isolates with OXA-48-like enzymes show reduced susceptibility. The drug's activity is pH-dependent, being more potent at acidic pH, which is relevant in infected tissues. It also has a low propensity for resistance development in vitro compared to other β-lactams. In 2024, the WHO included it on the Model List of Essential Medicines as a reserve antibiotic.³ Its use is restricted to settings with high rates of carbapenem resistance to preserve its utility.

Siderophore

A small molecule that binds and transports iron in bacteria.

Carbapenem-resistant

Resistant to carbapenem antibiotics, often via β-lactamase production.

Periplasm

The space between the inner and outer membranes of Gram-negative bacteria.