Fifth Generation Cephalosporins and Siderophores

Mechanism

💊 Generic and Commercial Names

Ceftaroline Fosamil (Teflaro), Ceftobiprole Medocaril (Zevtera), Cefiderocol (Fetcroja).

🔬 Pharmacological Group

Fifth generation cephalosporins (anti-MRSA) and latest generation siderophore cephalosporins.

Mechanism of Action

They radically modify the traditional enzyme affinity or exploit iron metabolism:

• Affinity for Ceftaroline PBP2a: Designed with a lateral 1,3-thiazole residue that allows it to bind specifically to the allosteric site of PBP2a (mutated in MRSA). By binding to this allosteric site, it induces a dural conformational change in the enzyme that opens its catalytic active site, allowing a second ceftaroline molecule to covalently block transpeptidation.
• The Molecular Trojan Horse of Cefiderocol: Cefiderocol is a siderophore cephalosporin that incorporates a side chain with a catechol group. This catechol group actively captures free iron cations (Fe³⁺) in the extracellular space of the host. The bacterium, requiring iron for its metabolic subsistence, actively transports the cefiderocol-iron complex into the periplasmic space through its own active iron transporters (tonB-dependent), avoiding the loss of porins and the overexpression of active efflux pumps. Once inside, it binds lethally to PBP3.

Pharmacokinetics

Key Pharmacokinetics

Antimicrobial Spectrum

• Ceftaroline / Ceftobiprole: Single coverage for multidrug-resistant Gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumoniae and ampicillin-sensitive Enterococcus faecalis. Gram-negative activity equivalent to that of ceftriaxone (vulnerable to ESBL and AmpC).
• Cefiderocol: Ultra-limited Gram-negative spectrum but with maximum nosocomial potency. Uniquely active against multi-resistant and pan-resistant Gram-negative bacilli (including producers of ESBL, AmpC, Class A, B [MBL] and D [OXA] carbapenemases), with outstanding coverage of Acinetobacter baumannii, Pseudomonas aeruginosa and Difficult to control Stenotrophomonas. It lacks activity against Gram-positive or anaerobes.

Indicators and dose

Indication of Critical Reserve of Cefiderocol

Cefiderocol represents a last-line therapeutic tool for extreme nosocomial infections. Its use should be strictly restricted by antimicrobial optimization committees (PROA) to documented infections by Gram-negatives multiresistant to carbapenems that have metallo-beta-lactamases (Class B) or in cases of pan-resistance, avoiding its empirical use so as not to induce accelerated mutations in bacterial iron uptake systems.

Dosage and Adjustment

• Ceftaroline Fosamil: 600 mg every 12 hours by IV route (can be increased to every 8 hours in endocarditis or severe pneumonia due to MRSA).
• Cefiderocol: 2 g every 8 hours as a prolonged infusion of 3 hours by IV route.
• Adjustment of Cefiderocol in Renal Failure:
  • Cl_cr 30-59 mL/min: Reduce to 1.5 g every 8 hours.
  • Cl_cr 15-29 mL/min: Reduce to 1.0 g every 8 hours.
  • Cl_cr < 15 mL/min or hemodialysis: Reduce to 750 mg every 12 hours.

Security

Contraindications and ADRs

• Contraindications: Demonstrated hypersensitivity to cephalosporins.
• Adverse Effects (ADR): Generally safe and well tolerated. Ceftaroline can induce mild transient neutropenia in treatments longer than 21 days. Cefiderocol has rarely been associated with a transient elevation of liver enzymes and risk of seizures in patients with a history of active cortical epilepsy.