Third and Fourth Generation Cephalosporins: Complete List
Third Generation Cephalosporins
Third-generation cephalosporins are broad-spectrum agents with enhanced gram-negative coverage compared to earlier generations, though they vary significantly in their specific activity profiles. 1
Standard Third Generation Agents
- Cefotaxime - Excellent gram-positive coverage among third-generation agents 1
- Ceftizoxime - The "workhorse" third-generation cephalosporin with balanced coverage 2
- Ceftriaxone - Long half-life allowing once-daily dosing, excellent for outpatient therapy 1
- Cefpodoxime axetil - Oral third-generation agent suitable for outpatient use 3
- Cefdinir - Oral third-generation agent with appropriate activity 3
Antipseudomonal Third Generation Agents
- Ceftazidime - One of only two third-generation cephalosporins active against Pseudomonas aeruginosa 1, 4
- Cefoperazone - The other third-generation agent with antipseudomonal coverage 1, 4
Agents to Avoid
- Cefixime - Poor activity against S. pneumoniae and penicillin-resistant strains; should NOT be used for acute bacterial sinusitis 3
- Ceftibuten - Poor activity against S. pneumoniae and penicillin-resistant strains; should NOT be used for acute bacterial sinusitis 3
Fourth Generation Cephalosporins
Fourth-generation cephalosporins provide enhanced gram-positive activity, excellent gram-negative coverage, and greater stability against beta-lactamases compared to third-generation agents. 5
Available Fourth Generation Agents
- Cefepime - The primary fourth-generation cephalosporin recommended by the Infectious Diseases Society of America for severe community-acquired infections 6, 7
- Cefpirome - Active against both gram-positive and gram-negative organisms, including Pseudomonas aeruginosa 8
Key Clinical Distinctions
Third Generation Advantages
- Cerebrospinal fluid penetration is excellent for cefotaxime, ceftazidime, ceftriaxone, and ceftizoxime, making them appropriate for bacterial meningitis (except cefoperazone) 1, 4
- Once-daily dosing with ceftriaxone makes it ideal for outpatient parenteral antibiotic therapy 1
Fourth Generation Advantages
- Activity against AmpC-producing organisms distinguishes fourth-generation from third-generation cephalosporins 6
- Enhanced activity against antibiotic-resistant Enterobacteriaceae, including strains of Enterobacter and Pseudomonas resistant to third-generation agents 2, 8
- Lower likelihood of inducing resistance due to lower beta-lactamase hydrolysis rates and rapid cell permeation 8
Critical Limitations Across Both Generations
Universal Coverage Gaps
- No anaerobic coverage - Must be combined with metronidazole for infections involving anaerobes 3, 6, 9
- No reliable enterococcal activity (exception: cefpirome has some in vitro activity against enterococci) 9, 8
- No MRSA coverage - Only methicillin-susceptible staphylococci are covered 7, 8
- No atypical organism coverage - Ineffective against Mycoplasma, Ureaplasma, and Chlamydia 9
Common Clinical Pitfalls
- Never use ceftriaxone alone for infections distal to the stomach - Anaerobic coverage with metronidazole is essential 9
- Reserve fourth-generation agents for serious infections to minimize resistance development 6
- For intra-abdominal infections, cefepime must be combined with metronidazole due to lack of anti-anaerobic activity 6, 7
- Consider local resistance patterns - Third-generation cephalosporins may be inadequate in areas with high ESBL-producing Enterobacteriaceae prevalence 3, 9