• Third Generation Cephalosporins

Third Generation Cephalosporins: Audio Overview

 

• Third Generation Cephalosporin Overview

  • Mechanism of Action and Resistance

    • The third-generation cephalosporins are bactericidal beta-lactam antibiotics.

      • The primary mechanism involves the inhibition of bacterial cell wall synthesis.²

    • Target Binding 

      • These agents bind to and inhibit specific Penicillin-Binding Proteins (PBPs) which are enzymes like transpeptidases that catalyze the cross-linking of the peptidoglycan polymer.³

    • Cell Lysis

      • By preventing the formation of a stable cell wall, the bacteria become subject to osmotic instability.

        • The binding to PBPs often triggers the release of bacterial autolysins, leading to programmed cell lysis.³  

  • Mechanisms of Resistance

    • Resistance typically arises through three primary pathways.

      • (1)  Beta-lactamase Production

        •  While third-generation agents are highly resistant to many classic penicillinases, they remain vulnerable to Extended-Spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases.⁴

      • (2) PBP Alteration

        •  Modifications in the target PBPs (e.g., PBP2a in MRSA) render these drugs ineffective.

      • (3) Permeability and Efflux

        •  Mutations in porin channels or the upregulation of efflux pumps in organisms like Pseudomonas aeruginosa can limit drug entry.⁵

  • Pharmacological Properties and Pharmacokinetics

    • Cefotaxime (Parenteral)

      • Overview and Pharmacological Properties

        • Cefotaxime is a broad-spectrum parenteral beta-lactam that serves as a cornerstone of hospital-based therapy.

          • One of its most distinctive features is its hepatic metabolism into desacetylcefotaxime.

            • This metabolite is microbiologically active and acts synergistically with the parent drug, particularly against Haemophilus influenzae.⁶

        • With a relatively short half-life of approximately 1 hour, it typically requires dosing every 6 to 8 hours for systemic infections.

          • Cefotaxime is primarily excreted through the kidneys via glomerular filtration and tubular secretion.⁷

      • Mechanism of Action

        • Cefotaxime exerts its bactericidal effect by binding to and inactivating Penicillin-Binding Proteins (PBPs), the transpeptidases, located on the inner bacterial cell membrane.

          • This binding inhibits the final transpeptidation step of peptidoglycan synthesis, causing the cell wall to lose structural integrity.

            • Resulting osmotic instability, combined with the activation of bacterial autolysins, leads to rapid cell lysis.

              • Synergy between the parent drug and its desacetyl metabolite is an important pharmacological advantage.⁸

      • Clinical Uses

        • Neonatal Sepsis

          • Neonatal sepsis is a systemic, life-threatening infection in infants less than 28 days old, often caused by E. coli or Group B Streptococcus.

            • Cefotaxime is a recommended agent because it provides robust Gram-negative coverage without displacing bilirubin from albumin.⁹

        • Bacterial Meningitis

          • Bacterial meningitis is a life-threatening inflammation of the protective membranes (meninges) covering the brain and spinal cord.

            • Cefotaxime is effective in achieving therapeutic concentrations in the cerebrospinal fluid (CSF) during active inflammation.¹⁰

        • Intra-abdominal Infections

          • These infections, such as peritonitis, typically follow a breach in the gastrointestinal tract.

            • Cefotaxime targets the aerobic Gram-negative bacilli involved, often paired with metronidazole to provide anaerobic coverage.

      • Adverse Effects

        • Common side effects include hypersensitivity reactions like rashes and local injection site reactions.

          • Because of its renal clearance, high doses in patients with renal failure can lead to neurotoxicity, including seizures.

      • Case Study: The Febrile Neonate

        • Presentation

          •  A 10-day-old infant is brought to the emergency department with poor feeding, lethargy, and a temperature of 39.1°C (102.4°F).

        • Discussion

          • The clinical priority is empiric coverage for neonatal sepsis.

            • The chosen regimen is ampicillin plus cefotaxime.

              • This selection is important because, unlike ceftriaxone, cefotaxime does not compete for bilirubin binding sites on albumin.

              • In a neonate with an immature blood-brain barrier, using cefotaxime avoids the very serious risk of bilirubin-induced encephalopathy (kernicterus).¹³

      • Practice Question

        • Question

          • What is the primary pharmacological reason cefotaxime is used instead of ceftriaxone in a 2-week-old infant?

        • Answer

          • Cefotaxime does not displace bilirubin from albumin, reducing the risk of kernicterus.¹⁴

    • Ceftriaxone (Parenteral)

      • Overview and Pharmacological Properties

        • Ceftriaxone is characterized by a long elimination half-life of 6 to 9 hours.

          • The long half-life allows for convenient once-daily dosing in most clinical settings.

            • Ceftriaxone utilizes a dual elimination pathway, with approximately 60% excreted renally and 40% through the biliary system.¹⁵

      • Mechanism of Action

        • Ceftriaxone acts by binding to PBPs to inhibit bacterial cell wall synthesis.

          • Resistance in organisms like Pseudomonas aeruginosa is often driven by OprD porin loss (restricting drug entry) and MexAB-OprM efflux upregulation (active outward translocation of the drug).⁵

      • Clinical Uses

        • Gonorrhea

          • A sexually transmitted infection caused by Neisseria gonorrhoeae that can lead to pelvic inflammatory disease.

          • A single intramuscular dose of ceftriaxone is the primary treatment of choice.¹⁶

        • Infective Endocarditis¹⁷

          • This condition represents a serious infection of the heart valves.

            • Ceftriaxone is often used for stable patients finishing a course of IV antibiotics at home (OPAT) because its once-daily dosing improves compliance.

        • Lyme Disease

          • Ceftriaxone is the preferred treatment for advanced stages, such as Lyme meningitis or carditis, due to its excellent tissue penetration.¹⁸

      • Adverse Effects

        • Biliary Sludging

          •  High biliary concentrations can lead to the formation of calcium-ceftriaxone precipitates in the gallbladder, manifesting as "pseudolithiasis."¹⁹

        • Contraindications

          • Ceftriaxone is strictly contraindicated in neonates and with calcium-containing IV fluids.²⁰

    • Cefixime (Oral)

      • Overview and Pharmacological Properties

        • Cefixime provides a critical oral option within the third generation.

          • Cefixime has an oral bioavailability of roughly 40% to 50% and a half-life of 3 to 4 hours. and is cleared by both renal and biliary mechanisms.²¹

      • Mechanism of Action

        • Like the parenteral agents, cefixime inhibits cell wall synthesis by binding to PBPs.

          • However, cefixime has a significantly lower affinity for the PBPs of Staphylococcus aureus, making it an inappropriate choice for staphylococcal infections.²²

      • Clinical Uses²³

        • Uncomplicated Urinary Tract Infections (UTIs)

          •  A UTI is an infection of the bladder (cystitis) or kidneys (pyelonephritis).

            • Cefixime is an excellent oral choice for UTIs caused by E. coli or Proteus mirabilis.

        • Acute Exacerbation of Chronic Bronchitis

          • This condition involves a sudden worsening of airway inflammation in patients with chronic lung disease.

February, 2026