What is the best antibiotic for community-acquired pneumonia (CAP)?

Best Antibiotic for Community-Acquired Pneumonia

For previously healthy outpatients without comorbidities, amoxicillin 1 gram three times daily is the first-line antibiotic of choice, with doxycycline 100 mg twice daily as the preferred alternative. 1, 2

Outpatient Treatment Algorithm

For Patients WITHOUT Comorbidities

First-line options:

• Amoxicillin 1 gram every 8 hours (strong recommendation, moderate quality evidence) 1, 2
• Doxycycline 100 mg twice daily (conditional recommendation, low quality evidence) 1, 2

The recommendation for amoxicillin is based on its proven efficacy against Streptococcus pneumoniae (the most common pathogen, accounting for 48% of identified cases), excellent safety profile, and activity against 90-95% of pneumococcal strains at this high dose. 1, 3 Doxycycline provides broad-spectrum coverage including atypical organisms and has demonstrated comparable efficacy to fluoroquinolones in hospitalized patients at significantly lower cost. 1, 4

Macrolide monotherapy (azithromycin 500 mg day 1, then 250 mg daily OR clarithromycin 500 mg twice daily) should ONLY be used if local pneumococcal macrolide resistance is documented to be <25%. 1, 2 This is a critical caveat because breakthrough pneumococcal bacteremia with macrolide-resistant strains is more common than with beta-lactams or fluoroquinolones. 1

For Patients WITH Comorbidities (COPD, diabetes, heart/liver/renal disease, malignancy, recent antibiotic use)

Combination therapy (strong recommendation, moderate quality evidence):

• Beta-lactam (amoxicillin-clavulanate 2000 mg twice daily OR cephalosporin) PLUS macrolide (azithromycin OR clarithromycin) 1, 2

OR Monotherapy:

• Respiratory fluoroquinolone: levofloxacin 750 mg daily, moxifloxacin 400 mg daily, OR gemifloxacin 320 mg daily (strong recommendation, moderate quality evidence) 1, 2

The fluoroquinolones are active against >98% of S. pneumoniae strains including penicillin-resistant isolates, and meta-analyses have shown significantly better outcomes compared to beta-lactams or macrolides alone. 1, 5 However, the American Thoracic Society advises caution due to potential adverse effects including tendinopathy, peripheral neuropathy, and CNS effects. 2

Inpatient (Non-ICU) Treatment

Standard regimen:

• Beta-lactam (ampicillin-sulbactam, ceftriaxone, cefotaxime, OR ceftaroline) PLUS macrolide (azithromycin OR clarithromycin) 1, 2, 3

OR

• Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily OR moxifloxacin 400 mg daily) 1, 2

Comparative trials demonstrate that combination beta-lactam/macrolide therapy achieves 91.5% favorable clinical outcomes versus 89.3% with fluoroquinolone monotherapy, with superior eradication rates for S. pneumoniae (100% vs 44%). 6 Full-course oral levofloxacin has been shown to be as effective as IV-to-oral sequential therapy in hospitalized patients, with resolution rates of 91.1%. 7

Severe CAP (ICU Patients)

Mandatory combination therapy:

• Beta-lactam PLUS either macrolide OR respiratory fluoroquinolone 2, 3

When Pseudomonas aeruginosa is suspected (prior respiratory isolation, recent hospitalization with parenteral antibiotics in last 90 days):

• Antipseudomonal beta-lactam PLUS either ciprofloxacin OR aminoglycoside PLUS macrolide 2, 3

When MRSA is suspected (prior MRSA infection):

• Add vancomycin OR clindamycin to standard regimen 2, 3

Critical Treatment Considerations

Antibiotic class switching: Patients with recent antibiotic exposure (within 90 days) should receive treatment from a different antibiotic class due to increased risk of bacterial resistance. 1, 2, 3

Treatment duration: Standard duration is 5-7 days for most antibiotics. 2 Extended treatment (14-21 days) is required ONLY for suspected Legionella pneumophila, Staphylococcus aureus, or gram-negative enteric bacilli. 2

High-dose short-course option: Levofloxacin 750 mg daily for 5 days is FDA-approved and achieves 90.9% clinical success rates, equivalent to 500 mg daily for 10 days, though 7 of 151 patients (4.6%) experienced recurrent pneumonia versus 2 of 147 (1.4%) with the longer course. 8, 9

Common Pitfalls to Avoid

Do not use macrolide monotherapy in areas with >25% pneumococcal macrolide resistance or in patients with comorbidities, as breakthrough bacteremia is significantly more common. 1, 2

Do not reserve fluoroquinolones unnecessarily for patients with comorbidities requiring hospitalization—the panel concluded that fluoroquinolone therapy is justified despite adverse event concerns, given their superior performance in numerous clinical trials. 1

Do not obtain routine sputum cultures in outpatients, as they do not improve individual patient outcomes and have poor yield. 3 Reserve blood and sputum cultures for suspected multidrug-resistant pathogens (MRSA, Pseudomonas). 3

Do not continue broad-spectrum coverage when cultures are negative and the patient is improving—narrow therapy within 48 hours. 3