What antibiotics are effective against resistant Streptococcus pneumoniae?

Antibiotics for Resistant Streptococcus pneumoniae

For drug-resistant S. pneumoniae with moderate resistance (penicillin MIC ≤2 mg/L), use high-dose amoxicillin (3g/day in divided doses), amoxicillin-clavulanate (2g twice daily), or third-generation cephalosporins (ceftriaxone 1-2g every 12-24 hours or cefotaxime 1-2g every 6-8 hours); for high-level resistance (MIC ≥4 mg/L), switch to a respiratory fluoroquinolone (levofloxacin 750mg, moxifloxacin, or gemifloxacin), vancomycin, or linezolid. 1

Stratified Approach by Resistance Level

Moderate Resistance (Penicillin MIC ≤2 mg/L)

Oral options:

• High-dose amoxicillin: 1g every 8 hours (total 3g/day) 2, 1
• Amoxicillin-clavulanate: 2g twice daily or 875mg twice daily 2
• Cefuroxime, cefpodoxime (alternative oral cephalosporins) 2

Intravenous options:

• Ceftriaxone: 1-2g every 12-24 hours 2, 1
• Cefotaxime: 1-2g every 6-8 hours 2, 1
• Ampicillin-sulbactam 2

The rationale for high-dose beta-lactams is that serum and pulmonary drug levels achieved are several times higher than the MIC of moderately resistant strains, making them clinically effective despite in vitro resistance. 2, 3

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

First-line agents:

• Respiratory fluoroquinolones (preferred): 2, 1
  • Moxifloxacin (most active against pneumococcus) 2, 1
  • Gemifloxacin (most active in vitro) 2, 1
  • Levofloxacin 750mg daily 2, 1, 4
• Vancomycin 2, 1, 5
• Linezolid 2, 1

Newer alternatives:

• Ceftaroline, omadacycline, lefamulin 1

Clinical Context-Specific Recommendations

Outpatient Management (No Comorbidities)

• Doxycycline 100mg twice daily as monotherapy (if no DRSP risk factors) 6
• High-dose amoxicillin 1g every 8 hours 1
• Respiratory fluoroquinolone monotherapy if recent antibiotic use or DRSP risk factors 1, 7

Outpatient with Comorbidities or DRSP Risk Factors

• High-dose amoxicillin PLUS doxycycline 100mg twice daily 6
• Respiratory fluoroquinolone monotherapy (alternative) 1, 7

Hospitalized Non-ICU Patients

• Respiratory fluoroquinolone monotherapy (preferred) 1, 7
• IV beta-lactam (ceftriaxone, cefotaxime, or ampicillin) PLUS macrolide (alternative) 1, 7
• IV beta-lactam PLUS doxycycline 100mg IV/PO twice daily (alternative) 6

ICU Patients

• Beta-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) PLUS either azithromycin OR fluoroquinolone (mandatory combination therapy) 7

Critical Agents to AVOID

Do not use the following for DRSP:

• First-generation cephalosporins 1
• Cefaclor, loracarbef 1
• Trimethoprim-sulfamethoxazole (50% resistance rate) 2, 1
• Ciprofloxacin (inadequate pneumococcal activity) 1
• Macrolide monotherapy in regions with >25% resistance rates 7

The high prevalence of macrolide-resistant S. pneumoniae in the United States (>40%) makes macrolides unreliable as monotherapy, though clinical failures remain relatively uncommon when combined with beta-lactams. 2, 1

Penicillin-Allergic Patients

For non-type I hypersensitivity:

• Doxycycline 100mg twice daily 2, 1, 6
• Respiratory fluoroquinolone (levofloxacin or moxifloxacin) 2, 1

For type I hypersensitivity:

• Respiratory fluoroquinolone (preferred) 1
• Clindamycin PLUS third-generation oral cephalosporin (cefixime or cefpodoxime) 2

Important Caveats and Pitfalls

Geographic and patient-specific risk factors for DRSP include: 2

• Geographic regions with >10% invasive penicillin-nonsusceptible S. pneumoniae
• Age >65 years
• Recent hospitalization
• Antibiotic use within past month
• Immunocompromised status
• Severe infection (temperature ≥39°C/102°F)

Fluoroquinolone resistance is emerging, particularly in patients from long-term care facilities and those with prior fluoroquinolone exposure, making it critical to reserve these agents appropriately. 1

Vancomycin should be reserved for patients failing other therapies or those with suspected meningitis, not used empirically for pneumonia alone. 1 For suspected meningitis, use ceftriaxone or cefotaxime PLUS vancomycin until susceptibilities are known. 1

Treatment Duration

• Minimum 5 days for uncomplicated cases 1
• 7-10 days for standard pneumococcal pneumonia 1, 7
• Continue until afebrile for 72 hours with clinical improvement 1
• Shorter courses (5-7 days) acceptable for patients showing rapid clinical improvement 7

FDA-Approved Evidence for Levofloxacin

Levofloxacin demonstrated 95% clinical success for multi-drug resistant S. pneumoniae (MDRSP) in clinical trials, with MDRSP defined as isolates resistant to two or more of the following: penicillin (MIC ≥2 mcg/mL), second-generation cephalosporins, macrolides, tetracyclines, and trimethoprim/sulfamethoxazole. 4 The 750mg once-daily regimen for 5 days showed equivalent efficacy to 500mg for 10 days in community-acquired pneumonia. 4