What are the first‑generation cephalosporins?

First-Generation Cephalosporins

First-generation cephalosporins are a class of beta-lactam antibiotics with excellent activity against gram-positive cocci (particularly staphylococci and streptococci) and limited gram-negative coverage, primarily used for skin/soft tissue infections, surgical prophylaxis, and susceptible infections in penicillin-allergic patients.

Specific Agents

The first-generation cephalosporins include:

Oral Agents

• Cephalexin (most commonly used oral agent) 1
• Cefadroxil 2, 3
• Cefadroxil 2
• Cefprozil 2

Parenteral Agents

• Cefazolin (most commonly used IV/IM agent) 4, 1, 5

Antimicrobial Spectrum

Good Activity Against:

• Staphylococci (including methicillin-susceptible Staphylococcus aureus/MSSA) 4, 5
• Streptococci (including Streptococcus pyogenes) 4, 6
• Most gram-positive cocci 7

Poor or No Activity Against:

• Pasteurella multocida (important for animal bites) 4
• Eikenella corrodens (important for human bites) 4
• Anaerobes (including Bacteroides fragilis) 4, 7
• Enterococci 7
• Pseudomonas aeruginosa 7
• Borrelia burgdorferi (Lyme disease) - cephalexin is specifically noted as inactive and ineffective 8
• MRSA (methicillin-resistant S. aureus) 4

Clinical Applications

Appropriate Uses:

• Skin and soft tissue infections caused by staphylococci and streptococci 4, 5, 9
• Surgical prophylaxis for clean operations 5, 7
• Alternative for penicillin-allergic patients (except those with anaphylaxis, angioedema, or urticaria to penicillins) 1, 6
• Acute hematogenous osteomyelitis in children (for MSSA) 3
• MSSA bacteremia in hemodialysis patients (cefazolin preferred over vancomycin) 10

Inappropriate Uses:

• Animal or human bite wounds as monotherapy 4
• Lyme disease 8
• Infections requiring anaerobic coverage 4
• Empiric therapy when MRSA is suspected 4, 5

Important Clinical Distinctions

Cefazolin vs. Other First-Generation Agents

Cefazolin has unique properties despite being classified as first-generation: It has a unique R1 side chain with very low cross-reactivity to penicillins (0.7-0.8% in penicillin-allergic patients), making it safer than other first-generation cephalosporins in penicillin allergy 2. This is clinically significant because cefazolin can often be used even when other first-generation agents might be avoided.

Oral Agent Considerations

Cephalexin requires more frequent dosing (3-4 times daily) compared to cefadroxil (twice daily), which may affect adherence 3, 11. However, cephalexin is widely available, generic, and relatively inexpensive 1. Studies show cefadroxil has nearly 100% urinary excretion within 6 hours 12.

Cross-Reactivity with Penicillins

The degree of cross-reactivity is higher between penicillins and first-generation cephalosporins than with later generations 13. Specifically, aminocephalosporins (cephalexin, cefadroxil, cefprozil, cefaclor) share R1 side chains with aminopenicillins, resulting in 16.45% cross-reactivity risk in proven penicillin allergy 2.

Critical caveat: Cephalosporins should NOT be used in patients with history of anaphylaxis, angioedema, or urticaria to penicillins 1.

Resistance Patterns

First-generation cephalosporins show variable activity against viridans group streptococci, with cephalexin being notably less active (96% resistance in one study) compared to later-generation agents 1. This is relevant for endocarditis prophylaxis considerations, though cephalexin remains an acceptable option 1.

Comparative Efficacy

For MSSA bacteremia in hemodialysis patients, cefazolin is superior to vancomycin, with treatment failure rates of 13% vs. 31.2% respectively 10. This represents a critical clinical decision point where first-generation cephalosporins should be strongly preferred over vancomycin when susceptibility allows.