What are the differences between the generations of cephalosporins (antibiotics)?

Cephalosporin Generations: A Practical Overview

Cephalosporins are categorized into four generations based on their spectrum of antimicrobial activity, with each successive generation generally offering broader gram-negative coverage while trading off some gram-positive activity. 1, 2

First-Generation Cephalosporins

First-generation agents (e.g., cephalexin, cefazolin, cefadroxil) maintain excellent activity against streptococci and staphylococci but have poor coverage for Haemophilus influenzae and are therefore inappropriate for many respiratory infections. 3, 1

• These agents are most active against gram-positive organisms, particularly Streptococcus and Staphylococcus species 2, 4
• They are more susceptible to beta-lactamases produced by gram-negative bacteria 4
• They have shorter serum half-lives compared to later generations 4
• First-generation cephalosporins are the drugs of choice for surgical prophylaxis (e.g., cesarean section, hysterectomy) due to their efficacy and significantly lower cost 5
• They are recommended for mild skin and soft tissue infections without complicating features 3

Second-Generation Cephalosporins

Second-generation agents (e.g., cefuroxime, cefprozil, cefoxitin) provide enhanced gram-negative coverage through increased resistance to beta-lactamases, with twice-daily dosing and significantly improved activity against beta-lactamase-producing H. influenzae, Moraxella catarrhalis, and S. aureus. 3, 1

• These agents have expanded spectrum due to enhanced beta-lactamase stability 4
• They possess longer serum half-lives than first-generation agents 4
• Cefuroxime and cefprozil are suitable for respiratory tract infections, including acute exacerbations of chronic bronchitis 3
• Cefoxitin and cefotetan have excellent activity against Bacteroides fragilis and are useful for postoperative infections and pelvic inflammatory disease 5
• Cefaclor should be avoided due to inadequate activity against beta-lactamase-producing organisms and high prevalence of serum sickness-like reactions 3

Third-Generation Cephalosporins

Third-generation cephalosporins (e.g., ceftriaxone, cefotaxime, ceftazidime, cefpodoxime, cefdinir) are most active against Enterobacteriaceae with superior beta-lactamase stability, extended plasma half-lives permitting once or twice daily dosing, but are the most expensive. 1, 4

• These agents have expanded gram-negative coverage while maintaining reasonable gram-positive activity 1, 2
• Ceftazidime and cefoperazone are specifically active against Pseudomonas aeruginosa 1
• Ceftizoxime has become the workhorse third-generation cephalosporin for general use 1
• Critical distinction: Cefixime and ceftibuten have poor activity against S. pneumoniae, especially penicillin-resistant strains, and should NOT be used for acute bacterial sinusitis or suspected pneumococcal infections 3, 6
• Cefpodoxime and cefdinir are suitable agents for respiratory infections 3
• The majority of third-generation agents should be reserved for treatment of meningitis and resistant nosocomial infections 5
• They are recommended for moderate to severe diabetic foot infections and community-acquired pneumonia 3

Fourth-Generation Cephalosporins

Fourth-generation agents (e.g., cefepime) provide excellent activity against both gram-positive and gram-negative pathogens, including antibiotic-resistant Enterobacteriaceae, offering an alternative for infections caused by drug-resistant microorganisms. 1, 7

• Cefepime maintains the gram-positive coverage of earlier generations while extending gram-negative activity 1
• It is effective against resistant nosocomial pathogens 7
• Cefepime is recommended for severe infections including Pseudomonas aeruginosa pneumonia and diabetic foot infections 3

Key Clinical Principles

No single cephalosporin satisfies all clinical needs; selection must be based on the specific pathogen, infection site, local resistance patterns, and cost considerations. 1

• Common pitfall: Using first-generation cephalosporins for respiratory infections where H. influenzae is likely—this will result in treatment failure 3
• Bacterial resistance has affected all generations through beta-lactamase production, altered penicillin-binding proteins, and cell wall modifications 2, 4
• As a group, cephalosporins have a favorable toxicity profile compared to other antimicrobial agents 2, 7
• Cost increases significantly with each generation, making first-generation agents preferred when clinically appropriate 5, 4