Third generation cephalosporins

Definition and Clinical Role

Third-generation cephalosporins are a subclass of β-lactam antibiotics within the cephalosporin family. These agents are semisynthetic derivatives of the core cephalosporin structure and exhibit broad-spectrum bactericidal activity, particularly enhanced efficacy against Gram-negative organisms, while maintaining moderate activity against Gram-positive bacteria. Compared to first- and second-generation cephalosporins, third-generation agents possess improved resistance to β-lactamases, increased penetration into cerebrospinal fluid (CSF), and are suitable for the treatment of severe community- and hospital-acquired infections.

These drugs are frequently used in sepsis, meningitis, pneumonia, complicated urinary tract infections, gonorrhea, and intra-abdominal infections, and they form a key component of empiric therapy in febrile neutropenia and other serious infections.

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Mechanism of Action

• Third-generation cephalosporins inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs).

• This disrupts peptidoglycan cross-linking, leading to weakening of the bacterial cell wall, osmotic lysis, and cell death.

• Their bactericidal activity is time-dependent, with greater efficacy seen when serum concentrations are maintained above the minimum inhibitory concentration (MIC) for an extended period.

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General Features

• Broad spectrum: Strong Gram-negative coverage, moderate Gram-positive.

• Variable activity against Pseudomonas aeruginosa (some agents like ceftazidime are active).

• High resistance to many β-lactamases (especially Enterobacteriaceae enzymes).

• Good tissue penetration, including CSF, especially with ceftriaxone and cefotaxime.

• Many are administered parenterally, though a few oral agents exist.

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Common Third-Generation Cephalosporins

Parenteral Agents

1. Ceftriaxone

   • Brand Names: Rocephin

   • Indications: Meningitis, pneumonia, gonorrhea, pyelonephritis, intra-abdominal infections, Lyme disease, typhoid fever

   • Notable Characteristics:

     • Once-daily dosing (long half-life)

     • Biliary excretion – not suitable in neonates with hyperbilirubinemia

     • Effective against Streptococcus pneumoniae and Neisseria spp.

     • Contraindicated with calcium-containing solutions in neonates

2. Cefotaxime

   • Brand Names: Claforan

   • Indications: Meningitis (pediatric), bacteremia, gynecologic infections, respiratory infections

   • Notable Characteristics:

     • Preferred in neonates over ceftriaxone

     • Shorter half-life than ceftriaxone; requires more frequent dosing

3. Ceftazidime

   • Brand Names: Fortaz, Tazicef

   • Indications: Febrile neutropenia, Pseudomonas infections, hospital-acquired pneumonia, complicated UTI

   • Notable Characteristics:

     • Anti-pseudomonal activity

     • Weaker Gram-positive coverage

     • Often used in combination with aminoglycosides or vancomycin

4. Cefoperazone

   • Brand Names: Cefobid (limited global availability)

   • Indications: Biliary tract infections, respiratory tract infections, intra-abdominal infections

   • Notable Characteristics:

     • High biliary excretion

     • May cause vitamin K–dependent coagulopathy

     • Also has activity against Pseudomonas

5. Ceftizoxime

   • Less commonly used; similar to cefotaxime but with better β-lactamase stability

6. Cefdinir (also classified as oral by some sources)

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Oral Agents

1. Cefixime

   • Brand Names: Suprax

   • Indications: Uncomplicated UTI, otitis media, pharyngitis, gonorrhea (single dose)

   • Notable Characteristics:

     • Moderate bioavailability (~40%)

     • Less active against staphylococci

     • Poor activity against Pseudomonas

2. Cefpodoxime proxetil

   • Brand Names: Vantin

   • Indications: Respiratory tract infections, UTIs, skin infections

   • Notable Characteristics:

     • Prodrug, hydrolyzed in GI tract

     • Good against Streptococcus pneumoniae

3. Ceftibuten

   • Brand Names: Cedax

   • Indications: Otitis media, bronchitis, pharyngitis

   • Notable Characteristics:

     • Long half-life, once-daily dosing possible

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Antibacterial Spectrum

Gram-Positive Activity

• Streptococcus species (including S. pneumoniae)

• Modest activity against MSSA (weaker than first-gen)

• Limited MRSA activity (ineffective)

Gram-Negative Activity

• E. coli, Klebsiella spp., Proteus spp.

• H. influenzae, M. catarrhalis

• Neisseria gonorrhoeae and N. meningitidis

• Salmonella, Shigella, Yersinia

• Pseudomonas aeruginosa (ceftazidime, cefoperazone only)

Anaerobes

• Limited; less effective than second-generation cephalosporins like cefoxitin or cefotetan

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Clinical Indications

Clinical Condition	Commonly Used Third-Gen Cephalosporins
Meningitis	Ceftriaxone, Cefotaxime
Community-acquired pneumonia	Ceftriaxone, Cefotaxime
Hospital-acquired pneumonia	Ceftazidime, Cefoperazone (with anti-pseudomonal coverage)
Gonorrhea	Ceftriaxone (first-line, IM single dose)
Pyelonephritis	Ceftriaxone, Cefotaxime
Typhoid fever	Ceftriaxone, Cefixime
Spontaneous bacterial peritonitis	Cefotaxime
Febrile neutropenia	Ceftazidime
Biliary tract infections	Cefoperazone
Pharyngitis, sinusitis (oral forms)	Cefixime, Cefpodoxime, Ceftibuten

Pharmacokinetics

• Absorption: Parenteral agents – 100% bioavailability; oral agents have variable absorption

• Distribution: Excellent tissue and fluid penetration; CSF penetration in inflamed meninges (especially ceftriaxone and cefotaxime)

• Metabolism/Elimination:

  • Ceftriaxone and cefoperazone: Partially excreted in bile

  • Others: Primarily renal excretion

• Half-life:

  • Ceftriaxone: 6–9 hours

  • Cefotaxime: 1 hour

  • Ceftazidime: 1.5–2 hours

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Adverse Effects

• Gastrointestinal: Diarrhea, nausea, vomiting, pseudomembranous colitis (C. difficile)

• Hematologic: Eosinophilia, leukopenia, thrombocytopenia

• Hypersensitivity: Rash, urticaria, anaphylaxis (cross-sensitivity with penicillin ~5–10%)

• Hepatic: Biliary sludging (ceftriaxone), especially in neonates

• Renal: Interstitial nephritis (rare)

• Bleeding: Cefoperazone may cause hypoprothrombinemia due to vitamin K inhibition

• Local: Pain at injection site, phlebitis

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Drug Interactions

• Anticoagulants (warfarin): Potentiation of bleeding risk

• Calcium-containing IV solutions: Contraindicated with ceftriaxone (risk of precipitation in lungs and kidneys in neonates)

• Loop diuretics: Increased nephrotoxicity (especially with aminoglycosides)

• Probenecid: Decreases renal excretion of cephalosporins, increasing plasma levels

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Resistance Considerations

• Resistance mechanisms include:

  • Extended-Spectrum β-Lactamases (ESBLs): Inactivate third-generation cephalosporins; ESBL-producing organisms require carbapenem therapy.

  • AmpC β-lactamases: Common in Enterobacter, Citrobacter; may develop during therapy.

  • Porin mutations and efflux pumps in Gram-negative bacteria

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Clinical Notes and Considerations

• Third-generation cephalosporins are not effective against MRSA or Enterococcus spp.

• Use judiciously to prevent selection for resistant organisms (e.g., ESBLs).

• Ceftriaxone is the drug of choice for gonorrhea, bacterial meningitis, and empiric therapy of severe infections in hospitalized patients.

• Ceftazidime is one of the few cephalosporins active against P. aeruginosa but has poor Gram-positive activity.

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Summary of Selected Agents

Generic Name	Route	Brand Names	Unique Features
Ceftriaxone	IV/IM	Rocephin	Long half-life, CNS penetration, biliary excretion
Cefotaxime	IV/IM	Claforan	Used in neonatal meningitis
Ceftazidime	IV	Fortaz	Anti-pseudomonal activity
Cefixime	Oral	Suprax	Used in gonorrhea, UTI
Cefpodoxime	Oral	Vantin	Prodrug, good Streptococcal coverage
Ceftibuten	Oral	Cedax	Once-daily dosing, otitis media