What antibiotics are effective against Haemophilus (H.) influenzae?

Antibiotics Effective Against Haemophilus influenzae

For H. influenzae infections, amoxicillin-clavulanate is the preferred first-line antibiotic because 18-42% of strains produce β-lactamase, rendering plain amoxicillin or ampicillin ineffective. 1, 2, 3

Beta-Lactamase Status Determines Antibiotic Choice

The critical decision point is whether the H. influenzae strain produces β-lactamase:

For β-lactamase-negative strains:

• Amoxicillin 500 mg-1 g PO every 8 hours 1
• Ampicillin 500 mg IV every 6 hours 1

For β-lactamase-positive strains (or unknown status):

• Amoxicillin-clavulanate 625 mg PO three times daily or 1.2 g IV every 8-12 hours 1, 2
• Cefuroxime 750 mg-1.5 g IV every 8 hours 1
• Ceftriaxone 1-2 g IV once daily 1
• Cefotaxime 1-2 g IV every 6-8 hours 1

Fluoroquinolone Alternatives

When β-lactams cannot be used:

• Levofloxacin 750 mg IV/PO once daily 1, 4
• Moxifloxacin 400 mg IV/PO once daily 1
• Ciprofloxacin 400 mg IV every 12 hours 1

Macrolide Considerations

Clarithromycin 500 mg twice daily is the preferred macrolide when a macrolide is needed, as it demonstrates superior activity against H. influenzae compared to azithromycin. 2, 5 However, macrolides are generally less reliable due to efflux mechanisms, and azithromycin should be avoided as first-line empiric therapy when H. influenzae is suspected. 2, 6

Tetracycline Option

• Doxycycline 100 mg IV/PO every 12 hours is an equally preferred alternative to amoxicillin-clavulanate for non-severe infections 1, 2

Severe Infections and CNS Involvement

For meningitis or severe systemic infections:

• Ceftriaxone 2 g IV once daily (or 100 mg/kg initial dose, then 80 mg/kg once daily in children) 7, 8, 9
• Cefotaxime 2 g IV every 6-8 hours 1
• Treatment duration: 10-14 days for severe infections 3

Ceftriaxone has been successfully used as a short 2-day course for epiglottitis with excellent outcomes. 8

Critical Pitfalls to Avoid

• Never use plain ampicillin or amoxicillin empirically without susceptibility testing, as β-lactamase production rates range from 18-42% 1, 2, 3
• Do not assume all macrolides are equivalent—clarithromycin has clinically significant superior activity over azithromycin 2, 5
• Avoid first-generation cephalosporins (e.g., cefazolin) as they lack adequate H. influenzae coverage 6
• Do not use erythromycin or azithromycin as first-line agents due to macrolide efflux mechanisms rendering them unreliable 6

Treatment Duration

• Non-severe infections: 7 days 2, 3
• Severe pneumonia or systemic infections: 10-14 days 3
• Meningitis: Full course per CNS infection protocols 7, 9

Penicillin Allergy Algorithm

If penicillin allergy is present:

1. First choice: Doxycycline 100 mg twice daily 2, 3
2. If tetracycline contraindicated: Clarithromycin 500 mg twice daily 2, 3
3. For severe infections: Ceftriaxone or cefotaxime (if no history of anaphylaxis to penicillin) 1
4. Alternative: Fluoroquinolone (levofloxacin or moxifloxacin) 1