What are the antibiotics of choice for treating community-acquired pneumonia (CAP) in adults with or without underlying health conditions?

Antibiotic Selection for Community-Acquired Pneumonia

For outpatient treatment of previously healthy adults without comorbidities, amoxicillin 1 g orally three times daily for 5-7 days is the preferred first-line therapy, with doxycycline 100 mg twice daily as an acceptable alternative. 1

Outpatient Treatment Algorithm

Previously Healthy Adults (No Comorbidities)

• Amoxicillin 1 g orally three times daily is the preferred first-line agent based on strong recommendation and moderate-quality evidence, providing excellent coverage against Streptococcus pneumoniae including drug-resistant strains 1
• Doxycycline 100 mg orally twice daily serves as an acceptable alternative, though this carries a conditional recommendation with lower quality evidence 1
• Macrolides should be avoided unless local pneumococcal macrolide resistance is documented to be <25%, as resistance rates now exceed this threshold in most regions 1

Adults with Comorbidities (COPD, Diabetes, Heart/Liver/Renal Disease, Recent Antibiotic Use)

• Combination therapy is mandatory: β-lactam (amoxicillin-clavulanate 875 mg/125 mg twice daily, cefpodoxime, or cefuroxime) PLUS macrolide (azithromycin 500 mg day 1, then 250 mg daily) or doxycycline 100 mg twice daily 1
• Alternative monotherapy: Respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily) 1, 2
• Fluoroquinolone use should be discouraged in uncomplicated cases due to FDA warnings about serious adverse events and resistance concerns 1

Hospitalized Non-ICU Patients

Two equally effective regimens exist with strong recommendations and high-quality evidence:

• β-lactam plus macrolide: Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily, providing coverage for both typical bacterial pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella) 1
• Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily 1, 2
• For penicillin-allergic patients, respiratory fluoroquinolone is the preferred alternative 1

Severe CAP Requiring ICU Admission

Combination therapy is mandatory for all ICU patients—monotherapy is inadequate and associated with higher mortality:

• Preferred regimen: Ceftriaxone 2 g IV daily (or cefotaxime 1-2 g IV every 8 hours or ampicillin-sulbactam 3 g IV every 6 hours) PLUS azithromycin 500 mg IV daily 1
• Alternative: β-lactam PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 1, 2
• A 2025 network meta-analysis of 8,142 patients demonstrated that β-lactam plus macrolide was the most effective regimen, significantly reducing overall mortality compared to β-lactam monotherapy 1

Special Pathogen Coverage

When to Add Antipseudomonal Coverage

Add only when specific risk factors are present:

• Structural lung disease (bronchiectasis, cystic fibrosis) 1
• Recent hospitalization with IV antibiotics within 90 days 1
• Prior respiratory isolation of P. aeruginosa 1

Regimen: Antipseudomonal β-lactam (piperacillin-tazobactam 4.5 g IV every 6 hours, cefepime 2 g IV every 8 hours, imipenem, or meropenem) PLUS ciprofloxacin 400 mg IV every 8 hours OR levofloxacin 750 mg IV daily PLUS aminoglycoside (gentamicin or tobramycin 5-7 mg/kg IV daily) 1, 3

When to Add MRSA Coverage

Add only when specific risk factors are present:

• Prior MRSA infection or colonization 1
• Recent hospitalization with IV antibiotics within 90 days 1
• Post-influenza pneumonia 1
• Cavitary infiltrates on imaging 1

Regimen: Vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) OR linezolid 600 mg IV every 12 hours 1

Duration of Therapy

• Minimum 5 days AND until afebrile for 48-72 hours with no more than one sign of clinical instability 1
• Typical duration: 5-7 days for uncomplicated CAP 1
• Extended duration (14-21 days) required for Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli 1

Transition to Oral Therapy

• Switch from IV to oral antibiotics when hemodynamically stable, clinically improving, able to take oral medications, and has normal GI function 1
• Typically achievable by day 2-3 of hospitalization 1

Critical Pitfalls to Avoid

• Never delay antibiotic administration beyond 8 hours in hospitalized patients—this increases 30-day mortality by 20-30% 1
• Never use macrolide monotherapy in areas where pneumococcal macrolide resistance exceeds 25%, as this leads to treatment failure 1
• Never use macrolide monotherapy in hospitalized patients, as it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1
• Obtain blood and sputum cultures before initiating antibiotics in ALL hospitalized patients to allow pathogen-directed therapy and de-escalation 1
• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to resistance concerns and serious adverse events 1
• Do not add antipseudomonal or MRSA coverage without documented risk factors, as this contributes to antimicrobial resistance without improving outcomes 1