What antibiotics cover drug-resistant pneumococcus?

Antibiotics for Drug-Resistant Streptococcus pneumoniae (DRSP)

For drug-resistant pneumococcus with penicillin MIC ≤2 mg/L, use high-dose amoxicillin (3g/day), amoxicillin-clavulanate, ceftriaxone, cefotaxime, or a respiratory fluoroquinolone (levofloxacin 750mg, moxifloxacin, gemifloxacin); for high-level resistance (MIC ≥4 mg/L), use a respiratory fluoroquinolone, vancomycin, or linezolid. 1, 2

Stratified Treatment Approach by Resistance Level

Moderate Resistance (Penicillin MIC ≤2 mg/L)

Oral options:

• High-dose amoxicillin 1g every 8 hours (total 3g/day) 1
• Amoxicillin-clavulanate 875mg twice daily 1
• Cefuroxime, cefpodoxime, or cefprozil 1
• Respiratory fluoroquinolones: levofloxacin 750mg daily, moxifloxacin 400mg daily, or gemifloxacin 1, 2

Intravenous options:

• Ceftriaxone 1-2g every 12-24 hours 1
• Cefotaxime 1-2g every 6-8 hours 1
• Ampicillin-sulbactam 1.5-3g every 6 hours 1

High-Level Resistance (Penicillin MIC ≥4 mg/L)

First-line agents:

• Respiratory fluoroquinolones (levofloxacin 750mg daily, moxifloxacin 400mg daily, gemifloxacin) 1, 2
• Vancomycin 15-20 mg/kg every 8-12 hours 1
• Linezolid 600mg every 12 hours 1
• Clindamycin 600mg every 8 hours (if susceptible) 1

Clinical Context-Specific Recommendations

Outpatient Management (No Comorbidities)

For previously healthy patients without DRSP risk factors, macrolide monotherapy (azithromycin or clarithromycin) or doxycycline 100mg twice daily remains acceptable 1, 2. However, if DRSP is suspected based on recent antibiotic use (within 3 months), age >65 years, or comorbidities, escalate to respiratory fluoroquinolone monotherapy or high-dose amoxicillin plus macrolide combination 1, 2.

Hospitalized Non-ICU Patients

Use either respiratory fluoroquinolone monotherapy OR beta-lactam (ceftriaxone 1-2g daily or cefotaxime 1-2g every 8 hours) plus macrolide (azithromycin 500mg daily or clarithromycin 500mg twice daily) 1, 2. The combination approach provides dual coverage for both typical and atypical pathogens 1.

ICU/Severe Pneumonia

Mandatory combination therapy: Beta-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) PLUS either azithromycin or respiratory fluoroquinolone 1, 2. This dual approach reduces mortality in severe cases and ensures coverage of both DRSP and atypical pathogens including Legionella 1.

Critical Agents to AVOID

Never use these for DRSP:

• First-generation cephalosporins (cefazolin, cephalexin) 1, 2
• Cefaclor or loracarbef 1, 2
• Trimethoprim-sulfamethoxazole 1, 2
• Ciprofloxacin - has inadequate pneumococcal activity and documented treatment failures 1, 3, 2

The evidence is unequivocal: ciprofloxacin should never be used for community-acquired pneumonia due to poor pneumococcal coverage, even for susceptible strains 3, 4. Levofloxacin has 4-8 times greater activity against S. pneumoniae compared to ciprofloxacin 2.

Fluoroquinolone Selection Hierarchy

When choosing a fluoroquinolone, prioritize based on pneumococcal activity (lowest MIC values) 1:

1. Gemifloxacin - most active, FDA-approved specifically for multidrug-resistant S. pneumoniae 1
2. Moxifloxacin 400mg daily 1
3. Levofloxacin 750mg daily (higher dose overcomes resistance mechanisms) 1, 5
4. Avoid: Ciprofloxacin and ofloxacin (inadequate activity) 1, 3

Emerging Resistance Concerns

Critical warning: Fluoroquinolone resistance in pneumococcus is increasing, particularly in patients from long-term care facilities and those with prior fluoroquinolone exposure 1, 2. Clinical failures with levofloxacin have been documented when pneumococcal MIC values are elevated, especially with double mutations in parC and gyrA genes 1, 4. The IDSA guidelines committee expressed concern that continued misuse could render fluoroquinolones ineffective within 5-10 years 1, 2.

Macrolide Considerations

Although macrolide resistance rates can reach 35-61% in areas with high penicillin resistance 1, 6, clinical failures remain relatively uncommon when MIC ≤2 mg/L 1. This paradox likely reflects high tissue penetration and the efflux mechanism (rather than ribosomal) predominating in North America 1. However, documented bacteriological failures occur at macrolide MIC ≥4 mg/mL 4, 6. Therefore, use macrolides only in combination with active beta-lactams when DRSP is suspected, never as monotherapy 1.

Vancomycin: Limited Role

Vancomycin should be reserved for patients failing other therapies or those with suspected meningitis, not used empirically 1, 2. The multiple alternative agents with excellent DRSP activity make routine vancomycin use unnecessary and contribute to resistance pressure 1.

Newer Agents

Ceftaroline (600mg every 12 hours) - fifth-generation cephalosporin with superior activity against DRSP and MRSA, demonstrated superiority over ceftriaxone in severe pneumonia (OR 1.66,95% CI 1.34-2.06) 1. Linezolid (600mg every 12 hours) - available IV and orally with excellent DRSP efficacy 1. Omadacycline and lefamulin - recently approved alternatives showing non-inferiority to moxifloxacin in clinical trials 1.

Treatment Duration

• Minimum 5 days for uncomplicated cases 2
• 7-10 days for standard pneumococcal pneumonia 1, 2
• Continue until afebrile for 72 hours with clinical improvement 2
• Levofloxacin 750mg regimen: 5 days demonstrated equivalent efficacy to 10-day courses 5

Special Populations

Penicillin allergy: Use respiratory fluoroquinolones or doxycycline 2. Suspected meningitis: Ceftriaxone or cefotaxime PLUS vancomycin until susceptibilities known 2. Recent antibiotic exposure (within 3 months): Avoid the same antibiotic class; if recent fluoroquinolone use, select beta-lactam-based regimen and vice versa 1, 2.

Pharmacodynamic Principles

Beta-lactam success requires drug concentration exceeding MIC for 40-50% of the dosing interval 4. High-dose amoxicillin (3g/day) and IV penicillin, ceftriaxone, or cefotaxime achieve this for strains with MIC ≤4 mg/mL 1, 4. There is no evidence of bacteriological failure when appropriate high-dose beta-lactams are used for resistant strains within this MIC range 4, 7.