What is the first-line antibiotic treatment for an adult patient with community-acquired pneumonia?

First-Line Antibiotic Treatment for Community-Acquired Pneumonia

For previously healthy adults without comorbidities, amoxicillin 1 gram orally three times daily for 5-7 days is the first-line antibiotic treatment for community-acquired pneumonia. 1, 2

Treatment Algorithm Based on Patient Characteristics

Healthy Adults Without Comorbidities (Outpatient)

Primary recommendation:

• Amoxicillin 1 gram orally three times daily for 5-7 days (strong recommendation, moderate quality evidence) 1, 2
• This targets Streptococcus pneumoniae, the most common pathogen accounting for 48% of identified CAP cases, with activity against 90-95% of pneumococcal strains including many with intermediate penicillin resistance 1, 2

Alternative options:

• Doxycycline 100 mg orally twice daily for 5-7 days (conditional recommendation, low quality evidence) 1, 2
• Macrolides (azithromycin 500 mg day 1, then 250 mg daily for days 2-5, or clarithromycin 500 mg twice daily) ONLY if local pneumococcal macrolide resistance is documented <25% 1, 2

Critical pitfall: Never use macrolide monotherapy in areas where pneumococcal macrolide resistance exceeds 25%, as breakthrough pneumococcal bacteremia occurs significantly more frequently with resistant strains 1, 2

Adults With Comorbidities (Outpatient)

Comorbidities include: chronic heart/lung/liver/renal disease, diabetes mellitus, alcoholism, malignancy, asplenia, immunosuppression, or recent antibiotic use within 90 days 1, 2

Primary recommendation - Combination therapy:

• Amoxicillin-clavulanate 875 mg/125 mg orally twice daily PLUS azithromycin 500 mg day 1, then 250 mg daily for days 2-5 (strong recommendation, moderate quality evidence) 1, 2
• Alternative β-lactams: cefpodoxime or cefuroxime can substitute for amoxicillin-clavulanate 1, 2
• Alternative macrolide: doxycycline 100 mg twice daily can substitute for azithromycin 1, 2

Alternative - Fluoroquinolone monotherapy:

• Levofloxacin 750 mg orally daily for 5-7 days OR moxifloxacin 400 mg orally daily for 5-7 days (strong recommendation, moderate quality evidence) 1, 2
• However, fluoroquinolones should be reserved for patients with contraindications to β-lactams or macrolides due to FDA warnings about tendinopathy, peripheral neuropathy, and CNS effects 1, 2

Critical consideration: If the patient used antibiotics within the past 90 days, select an agent from a different antibiotic class to reduce resistance risk 1, 2

Hospitalized Patients (Non-ICU)

Two equally effective regimens with strong recommendations:

Option 1 - Combination therapy:

• Ceftriaxone 1-2 grams IV once daily PLUS azithromycin 500 mg IV or oral daily (strong recommendation, high quality evidence) 1, 2
• Alternative β-lactams: cefotaxime 1-2 grams IV every 8 hours or ampicillin-sulbactam 3 grams IV every 6 hours 1, 2

Option 2 - Fluoroquinolone monotherapy:

• Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily (strong recommendation, high quality evidence) 1, 2

Critical timing: Administer the first antibiotic dose in the emergency department immediately upon diagnosis, as delayed administration beyond 8 hours increases 30-day mortality by 20-30% 2

Transition to oral therapy: Switch when the patient is hemodynamically stable, clinically improving, afebrile for 48-72 hours, able to take oral medications, and has normal GI function—typically by day 2-3 of hospitalization 1, 2

Severe CAP Requiring ICU Admission

Mandatory combination therapy for all ICU patients:

• Ceftriaxone 2 grams IV once daily (or cefotaxime 1-2 grams IV every 8 hours or ampicillin-sulbactam 3 grams IV every 6 hours) PLUS either azithromycin 500 mg IV daily OR respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) (strong recommendation) 1, 2

Monotherapy is inadequate for severe disease 2

Special Circumstances Requiring Broader Coverage

When to Add Antipseudomonal Coverage:

Add if patient has:

• Structural lung disease (bronchiectasis)
• Recent hospitalization with IV antibiotics within 90 days
• Prior respiratory isolation of Pseudomonas aeruginosa

Regimen: Antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) PLUS ciprofloxacin 400 mg IV every 8 hours OR levofloxacin 750 mg IV daily PLUS aminoglycoside 1, 2

When to Add MRSA Coverage:

Add if patient has:

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

Regimen: Add vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) OR linezolid 600 mg IV every 12 hours to the base regimen 1, 2

Treatment Duration

Standard duration:

• Minimum of 5 days AND until afebrile for 48-72 hours with no more than one sign of clinical instability 1, 2
• Typical duration for uncomplicated CAP: 5-7 days 1, 2, 3
• Meta-analysis of 15 RCTs (2,796 patients) showed short-course regimens (≤7 days) had equivalent clinical cure rates with fewer adverse events compared to extended courses 3

Extended duration (14-21 days) required for:

• Legionella pneumophila
• Staphylococcus aureus
• Gram-negative enteric bacilli 1, 2

Evidence Quality Considerations

The 2019 IDSA/ATS guidelines represent the highest quality evidence, with strong recommendations based on moderate-to-high quality evidence from multiple randomized controlled trials and meta-analyses 1, 2. The European Respiratory Society and British Thoracic Society favor amoxicillin as first-line therapy, consistent with the IDSA/ATS recommendations 1. A 2025 Bayesian network meta-analysis of 40 RCTs involving 12,838 hospitalized adults found that combination β-lactam/macrolide therapy achieved optimal clinical outcomes 4.

Common Pitfalls to Avoid

• Never use macrolide monotherapy in hospitalized patients—it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1, 2
• Never use macrolide monotherapy in areas with ≥25% pneumococcal macrolide resistance 1, 2
• Never delay antibiotic administration beyond 8 hours in hospitalized patients 2
• Never automatically escalate to broad-spectrum antibiotics without documented risk factors for resistant organisms 2
• Always obtain blood and sputum cultures before initiating antibiotics in all hospitalized patients 2