First-Generation Cephalosporins for Bacterial Infections
The two primary first-generation cephalosporins recommended for treating bacterial infections are cefazolin (intravenous) and cephalexin (oral), both providing excellent coverage against methicillin-susceptible Staphylococcus aureus and streptococci. 1
Primary First-Generation Agents
Cefazolin (Intravenous)
Cefazolin is the preferred parenteral first-generation cephalosporin for serious infections requiring IV therapy, including:
Standard dosing: 1 gram IV every 8 hours 1
Cephalexin (Oral)
Cephalexin is the preferred oral first-generation cephalosporin for outpatient treatment of:
Standard dosing: 500 mg PO every 6 hours 1
FDA-approved indications include respiratory tract infections, otitis media, skin/soft tissue infections, bone infections, and genitourinary tract infections 2
Other First-Generation Cephalosporins
Less Commonly Used Agents
- Cephradine: 500 mg PO every 6 hours 1
- Cefadroxil: 500 mg PO every 12 hours (longer dosing interval may improve compliance) 1
Microbiologic Spectrum
Excellent Activity Against:
- Gram-positive cocci: Methicillin-susceptible S. aureus, Streptococcus pyogenes, S. pneumoniae 3, 4, 5
- First-generation cephalosporins maintain the best activity against gram-positive bacteria among all cephalosporin generations 4
Moderate Activity Against:
- Selected gram-negative bacilli: E. coli, Proteus mirabilis, Klebsiella pneumoniae 2, 5
- Activity against gram-negative organisms is limited compared to later-generation cephalosporins 3, 4
No Activity Against:
- Enterococcus species (critical gap in coverage) 5
- Methicillin-resistant S. aureus (MRSA) 1
- Pseudomonas aeruginosa 5
- Anaerobic bacteria (including Bacteroides fragilis) 5
- Atypical organisms (Mycoplasma, Chlamydia) 6
Clinical Advantages
Why First-Generation Cephalosporins Remain Valuable:
- Most active against gram-positive bacteria compared to later-generation agents 4, 5
- Excellent bioavailability and resistance to gastric acid degradation (cephalexin) 7
- Low incidence of adverse reactions 3
- Cost-effective for susceptible organisms 7, 5
- Proven efficacy with cure rates of 90% or higher for streptococcal and staphylococcal skin infections 7
Common Pitfalls and Caveats
Critical Limitations to Avoid:
- Never use for MRSA infections—switch to vancomycin, linezolid, or daptomycin 1
- Never use for enterococcal infections—these organisms are inherently resistant 5
- Never use alone for infections involving anaerobes (e.g., intra-abdominal infections, diabetic foot infections with deep tissue involvement)—add metronidazole or use a different regimen 6, 5
- Never use for Pseudomonas infections—requires antipseudomonal agents like ceftazidime, cefepime, or piperacillin-tazobactam 1, 5
Important Clinical Considerations:
- Penicillin remains the drug of choice for streptococcal infections when susceptibility is confirmed; first-generation cephalosporins are alternatives for penicillin-allergic patients 2, 7
- Culture and susceptibility testing should guide therapy—initiate cultures before starting antibiotics when possible 2
- Use first-generation agents for susceptible organisms rather than automatically escalating to broader-spectrum cephalosporins, which helps prevent resistance and reduces costs 5
- Approximately 10% cross-reactivity exists with penicillin allergies, though true IgE-mediated reactions are less common 1
When to Choose Cefazolin vs. Cephalexin:
- Use cefazolin (IV) for: severe infections, hospitalized patients, inability to tolerate oral medications, or when higher tissue concentrations are needed 1
- Use cephalexin (oral) for: mild-to-moderate outpatient infections, step-down therapy after IV treatment, or when oral administration is feasible 1, 2