Cefiderocol in Treating Carbapenem-Resistant Infections

Role of Cefiderocol in Treating Carbapenem-Resistant Infections

• Cefiderocol is a promising drug for treating hospital-acquired and ventilator-acquired pneumonia due to its pharmacokinetics and pharmacodynamics, which include good penetration into epithelial lining fluid and high plasma and tissue concentrations.
• It has bactericidal characteristics and a broad antibacterial spectrum, making it effective against CR gram-negative bacteria, CRE, and CR-AB treatment.
• Cefiderocol is a siderophore cephalosporin that binds with iron, avoiding decomposition by the efflux pump and leading to bacterial cell death.

Mechanism of Action of Cefiderocol

• Siderophores are small molecules secreted by bacteria to chelate ferric iron from the environment, forming a stable and soluble complex to supply bacteria with a necessary nutrient for survival and proliferation.
• Cefiderocol is a catechol-conjugated siderophore cephalosporin that binds ferric iron in three places, enhancing its stability and allowing it to bypass multidrug efflux pumps and use iron transport mechanisms to pass the outer bacterial membrane.
• It can penetrate the outer membrane of gram-negative bacteria and the periplasmic space, overcoming one of the defense mechanisms used by gram-negative bacteria to resist beta-lactams and other antibiotics.

Epidemiology of Carbapenem-Resistant Infections

• Carbapenems are a major class of antibiotics used for treating invasive infections, mainly those caused by multidrug-resistant (MDR) bacteria.
• Carbapenem-resistant pathogen infections are associated with higher morbidity and mortality rates, longer hospital stays, and higher healthcare costs.
• The rise of carbapenem-resistant bacteria isolates is profound in developing countries, which is parallel to the excessive sales and easy access of antibiotics without prescription in these countries.

Clinical Efficacy of Cefiderocol in Carbapenem-Resistant Infections

• Cefiderocol appears to be particularly useful in treating infections caused by gram-negative bacteria, as well as both cUTI and non-CR-HABP, which complements the limited options currently available.
• It failed to achieve the predefined ESD (early standard of care [SOC] de-escalation or no de-escalation ±30%) in one study, but the defined post hoc ESD definition of cUTI appears to be better with cefiderocol than carbapenem therapy.

Safety Profile and Adverse Effects of Cefiderocol

• Cefiderocol shows a good safety profile, with the most frequently reported adverse effects being diarrhea, infusion-site phlebitis, and constipation.
• It may cause hypersensitivity reactions, liver toxic effects, acute kidney function impairment, or Clostridium difficile-associated diarrhea, although these are rare.
• The drug may also cause nephrotoxicity and drug-drug interactions, especially in patients with pre-existing renal disorders and those receiving concomitant drugs.

Future Directions and Research Opportunities

• Post-marketing surveillance, registries, and large cohort studies are needed to consume cefiderocol with judicious stewardship.
• Special studies are required to optimize cefiderocol doses in subpopulations, such as patients with renal impairment.
• Cefiderocol has potential for β-lactam combination therapy for further study of antimicrobial activity and strategy for other life-threatening infections, particularly difficult-to-treat infections caused by MDR, XDR Klebsiella pneumoniae.