Drug of Choice for Community-Acquired Pneumonia in Previously Healthy Adults
For previously healthy adults with community-acquired pneumonia treated as outpatients, amoxicillin 1 gram orally three times daily for 5-7 days is the preferred first-line therapy. 1
Outpatient Treatment Algorithm
First-Line Therapy for Healthy Adults Without Comorbidities
Amoxicillin 1 g orally three times daily is the drug of choice, providing excellent coverage against Streptococcus pneumoniae (the most common bacterial pathogen), Haemophilus influenzae, and Moraxella catarrhalis with strong recommendation and moderate-quality evidence 1, 2
Doxycycline 100 mg orally twice daily serves as an acceptable alternative for patients who cannot tolerate amoxicillin, though this carries lower quality evidence 1
Avoid macrolide monotherapy (azithromycin or clarithromycin) unless local pneumococcal macrolide resistance is documented to be <25%, as resistance rates now exceed this threshold in most U.S. regions 1, 3
Treatment for Adults With Comorbidities
If the patient has COPD, diabetes, chronic heart/liver/renal disease, malignancy, or recent antibiotic use within 3 months, escalate to 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 1
Alternative: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily) 1, 4, 5
Inpatient Treatment for Hospitalized Non-ICU Patients
Two equally effective regimens exist with strong recommendations and high-quality evidence:
β-lactam plus macrolide combination: Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily 1, 2
Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily 1, 6
Research demonstrates that levofloxacin monotherapy achieves 94.1% clinical success rates compared to 92.3% with azithromycin/ceftriaxone combination therapy, with comparable tolerability 6
ICU-Level Severe CAP
Combination therapy is mandatory for all ICU patients—monotherapy is inadequate for severe disease:
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, 2
Alternative: β-lactam PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 1
Duration of Therapy
Treat for a minimum of 5 days AND until the patient is afebrile for 48-72 hours with no more than one sign of clinical instability 1, 2
Typical duration for uncomplicated CAP is 5-7 days 1
Extend to 14-21 days only for Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli 1
Transition to Oral Therapy
- Switch from IV to oral antibiotics when the patient is hemodynamically stable, clinically improving, able to take oral medications, and has normal gastrointestinal function—typically by day 2-3 of hospitalization 1, 2
Special Pathogen Coverage
Add Antipseudomonal Coverage ONLY When:
- Structural lung disease (bronchiectasis, cystic fibrosis)
- 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
Add MRSA Coverage ONLY When:
- 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 OR linezolid 600 mg IV every 12 hours to the base regimen 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, 7
Never use macrolide monotherapy for hospitalized patients, as it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1
Obtain blood cultures and sputum Gram stain/culture 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 FDA warnings about serious adverse events and resistance concerns 1
Do not automatically add broad-spectrum coverage for Pseudomonas or MRSA without documented risk factors, as this promotes resistance without improving outcomes 1