What are the indications and preferred uses for cefuroxime, cefixime, co-amoxiclav (amoxicillin-clavulanate), and cefalexin?

Comparative Indications and Preferred Uses of Oral Cephalosporins and Co-Amoxiclav

For most community-acquired infections requiring oral antibiotics, co-amoxiclav (amoxicillin-clavulanate) is the preferred first-line agent due to its superior activity against Streptococcus pneumoniae, including penicillin-resistant strains, and broad coverage of common respiratory and skin pathogens. 1

Co-Amoxiclav (Amoxicillin-Clavulanate): First-Line for Most Infections

Co-amoxiclav is the drug of choice for:

• Mild to moderate skin and soft tissue infections - Listed as first-choice by WHO for empiric treatment 1
• Community-acquired pneumonia - Preferred oral therapy for influenza-related pneumonia and non-severe pneumonia 1
• Acute bacterial rhinosinusitis - High-dose formulations (80-90 mg/kg/day amoxicillin component) provide 95-97% coverage against S. pneumoniae based on pharmacokinetic/pharmacodynamic breakpoints 1
• Acute exacerbations of chronic bronchitis - Recommended as preferred oral therapy 1
• Necrotizing fasciitis - Recommended in combination regimens for severe skin infections 1
• Head and neck cancer surgery prophylaxis - Identified as best option alongside clindamycin-gentamicin 1

The clavulanate component preserves amoxicillin activity against β-lactamase-producing organisms (H. influenzae, M. catarrhalis, S. aureus) while maintaining excellent intrinsic activity against pneumococci 1. Co-amoxiclav demonstrates the most potent activity against S. pneumoniae, including penicillin-nonsusceptible strains, compared to all oral cephalosporins 2.

Cefuroxime: Second-Generation Cephalosporin for Specific Situations

Cefuroxime is the drug of choice for:

• Early Lyme disease - Cefuroxime axetil 500 mg twice daily for 14-21 days is a first-line alternative to doxycycline for erythema migrans 1
• Severe influenza-related pneumonia (parenteral) - IV cefuroxime is recommended when oral therapy is contraindicated, offering adequate MSSA coverage 1
• Surgical prophylaxis - Parenteral cefuroxime provides appropriate coverage for many surgical procedures 3

FDA-approved indications include: Lower respiratory tract infections, UTIs, skin/soft tissue infections, septicemia, meningitis, gonorrhea, and bone/joint infections 3. However, cefuroxime has important limitations: it provides only 70-90% coverage against S. pneumoniae and 70-85% coverage against H. influenzae based on PK/PD breakpoints, making it inferior to co-amoxiclav for respiratory infections 1. Cefuroxime axetil demonstrated superior clinical cure rates (97%) compared to cephalexin (89%) in skin infections 4 and comparable efficacy to co-amoxiclav in community-acquired pneumonia 5.

Cefalexin (Cephalexin): First-Generation for Simple Gram-Positive Infections

Cefalexin is the drug of choice for:

• Mild skin and soft tissue infections caused by gram-positive cocci - Listed as first-choice by WHO alongside cloxacillin for simple cellulitis 1
• Diabetic foot infections (mild) - Recommended for gram-positive coverage in mild infections 6
• Impetigo - Acceptable oral option for uncomplicated cases 6

FDA-approved indications include: Respiratory tract infections (though penicillin preferred for streptococcal infections), otitis media, skin/soft tissue infections, bone infections, and genitourinary tract infections 7.

Critical limitation: Cefalexin is among the least potent oral cephalosporins with the narrowest spectrum 2. It provides only 20% coverage against S. pneumoniae and 70-85% coverage against H. influenzae based on PK/PD breakpoints 1. The WHO Expert Committee specifically excluded cefalexin from respiratory infection recommendations due to inadequate pneumococcal coverage 1. Cefalexin should never be used for Lyme disease as first-generation cephalosporins are ineffective 1.

Cefixime: Third-Generation with Limited Role

Cefixime has very limited preferred indications:

• Uncomplicated gonorrhea - FDA-approved for cervical/urethral gonorrhea 8
• Uncomplicated urinary tract infections - FDA-approved indication 8

FDA-approved indications also include: Otitis media, pharyngitis/tonsillitis, and acute exacerbations of chronic bronchitis 8. However, cefixime should be avoided for most respiratory infections due to poor pneumococcal coverage. The American Academy of Allergy, Asthma, and Immunology specifically recommends against using cefixime for acute bacterial sinusitis 9. The IDSA advises against cefixime for suspected pneumococcal infections including sinusitis, otitis media, or pneumonia 9.

Cefixime provides only 40-70% coverage against S. pneumoniae and 63-75% coverage based on PK/PD breakpoints 1. While it has excellent activity against H. influenzae (95-100% coverage) and M. catarrhalis (100% coverage) 1, this does not compensate for inadequate pneumococcal coverage in respiratory infections where S. pneumoniae remains the predominant pathogen.

Key Clinical Decision Algorithm

For respiratory tract infections (pneumonia, sinusitis, bronchitis):

• First choice: High-dose co-amoxiclav (80-90 mg/kg/day amoxicillin component) 1
• Second choice: Cefuroxime axetil (if penicillin-intolerant but not severely allergic) 1
• Avoid: Cefalexin and cefixime due to inadequate pneumococcal coverage 1, 9

For skin and soft tissue infections:

• Mild infections: Co-amoxiclav, cefalexin, or cloxacillin 1
• Moderate infections: Co-amoxiclav preferred 1
• Avoid: Cefixime (not indicated) 8

For urinary tract infections:

• Uncomplicated: Cefixime or co-amoxiclav acceptable 8
• Complicated: Co-amoxiclav preferred for broader coverage 3

For Lyme disease:

• Cefuroxime axetil 500 mg twice daily is equivalent to doxycycline and amoxicillin 1
• Never use cefalexin - first-generation cephalosporins are ineffective 1

Common Pitfalls to Avoid

Cross-reactivity concerns: Patients with penicillin allergy have 2-4.8% risk of cross-reactivity with cephalosporins 6. Amoxicillin and cefalexin share identical R1 side chains, increasing cross-reactivity risk between these specific agents 6. Cefuroxime and cefixime have different side chains and may be safer alternatives in penicillin-allergic patients.

Resistance patterns: When selecting empiric therapy, co-amoxiclav maintains activity against 95-97% of S. pneumoniae isolates including penicillin-intermediate strains, while cefuroxime covers only 70-90% and cefixime covers 40-70% 1. This difference directly impacts clinical outcomes in respiratory infections where pneumococcus predominates.

Gastrointestinal tolerability: Cefixime causes significantly more diarrhea (15%) compared to cefuroxime axetil (5%) 10. Co-amoxiclav also has higher GI adverse event rates, but this is acceptable given superior efficacy 1.