Third and Fourth Generation Cephalosporins

Mechanism

💊 Generic and Commercial Names

Third generation: ceftriaxone (Rocephin), ceftazidime (Fortam), cefotaxime (Claforan). Fourth generation: cefepime (Maxipime).

🔬 Pharmacological Group

Beta-lactams. Broad-spectrum systemic cephalosporins with high central nervous system penetration.

Mechanism of Action

They covalently modulate the essential PBPs of the periplasmic space:

• Chemical Stability Against Beta-lactamases in the Third Generation: The addition of an aminothiazolyl group and a methoxymino residue at the side chain position confers to ceftriaxone and cefotaxime excellent stability against hydrolysis by Gram-negative penicillinases and an increase in binding affinity for bacterial PBP2 and PBP3.
• Anti-Pseudomonal Activity of Ceftazidime: Its side chain includes a carboxypropyloxy group that specifically orients its binding affinity toward PBP3. Pseudomonas aeruginosa, facilitating its osmotic lysis, but at the expense of losing almost all activity against Gram-positive cocci.
• Fourth-Generation Cephalosporins (Cefepime): Dipolar ion structure (zwitterion) that allows it to cross the outer membrane of Gram-negatives extraordinarily quickly through porins. Its neutral net charge significantly decreases its binding affinity and vulnerability to hydrolysis by Class C beta-lactamases (AmpC) and inducible chromosomal beta-lactamases.

Pharmacokinetics

Key Pharmacokinetics

Antimicrobial Spectrum

• Ceftriaxone / Cefotaxime: Very high activity against Streptococcus pneumoniae (including strains with intermediate resistance to penicillin), N. meningitidis, N. gonorrhoeaeand common enterobacteria. They lack useful activity againstP. aeruginosa, MRSA, VRE or strict anaerobes.
• Ceftacidime: Directed against Pseudomonas aeruginosa and enterobacteria. No coverage against Gram-positives.
• Cefepime: Very broad spectrum. It combines the excellent Gram-positive activity of the first generation (robust coverage of MSSA and streptococci) with the Gram-negative coverage of the third generation, actively including Pseudomonas aeruginosa and strains producing derepressed AmpC.

Indicators and dose

Dosage and Adjustment

• Ceftriaxone: 1 to 2 g IV every 12 or 24 hours (in severe pneumococcal meningitis it is dosed strictly at 2 g every 12 hours). It does not require dose adjustment in pure renal failure due to its double compensatory biliary clearance.
• Cefepime: 1 to 2 g IV every 8 to 12 hours.
• Adjustment of Cefepime in Renal Failure:
  • Cl_cr 30-50 mL/min: Administer 1 to 2 g every 24 hours.
  • Cl_cr 11-29 mL/min: Administer 500 mg at 1 g every 24 hours.
  • Cl_cr < 10 mL/min: Administer 250 to 500 mg every 24 hours (or reduce according to close monitoring of neurotoxicity).

Security

Contraindications and ADRs

• Contraindications: Allergy to cephalosporins. Ceftriaxone is absolutely contraindicated in premature hyperbilirubinemic neonates because it competitively displaces bilirubin from serum albumin, increasing the risk of storage encephalopathy (kernicterus).
• Adverse Effects (ADR):
  • Cholestasis and Biliary Sludge: Precipitation of ceftriaxone calcium crystals in the gallbladder (pseudolithiasis cholecystitis), reversible after stopping treatment.
  • Cefepime encephalopathy (Dose-dependent): Drowsiness, stupor, myoclonus and non-convulsive status epilepticus. Favored by the systemic accumulation of cefepime in patients with advanced renal failure who did not undergo dose adjustment.

Risk of Precipitation of Ceftriaxone with Calcium Solutions

Simultaneous administration of Ceftriaxone with intravenous solutions containing calcium (such as Lactated Ringer's solution or total parenteral nutrition) may induce rapid formation of insoluble ceftriaxone-calcium precipitates in the dural bloodstream and target organs. This has caused pulmonary microembolism and fatal acute kidney failure, especially in neonates. The co-administration of ceftriaxone and calcium solutions through the same infusion route simultaneously is prohibited.