Empiric Treatment for Community-Acquired Pneumonia
Outpatient Treatment Without Comorbidities
For healthy adults without comorbidities, amoxicillin 1 g orally three times daily for 5-7 days is the preferred first-line therapy. 1
- Doxycycline 100 mg orally twice daily serves as an acceptable alternative, though with lower quality supporting evidence 1
- Macrolides (azithromycin 500 mg day 1, then 250 mg daily; or clarithromycin 500 mg twice daily) should only be used in areas where pneumococcal macrolide resistance is documented to be <25% 1
- Avoid macrolide monotherapy in regions with high resistance rates, as this leads to treatment failure 1
Outpatient Treatment With Comorbidities
Patients with comorbidities (COPD, diabetes, chronic heart/liver/renal disease, malignancy, or recent antibiotic use within 3 months) require combination therapy rather than monotherapy. 1, 2
Preferred regimen: 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 combinations:
- Cefpodoxime or cefuroxime PLUS azithromycin or clarithromycin 1
- High-dose amoxicillin 1 g three times daily PLUS doxycycline 100 mg twice daily 1
Alternative monotherapy: Respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily), though fluoroquinolone use should be discouraged in uncomplicated cases due to resistance concerns and serious adverse events 1
Hospitalized Non-ICU Patients
Two equally effective regimens exist with strong recommendations and high-quality evidence: 1
Regimen 1 (Preferred): Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily 1
- Alternative β-lactams: cefotaxime 1-2 g IV every 8 hours or ampicillin-sulbactam 3 g IV every 6 hours, always combined with a macrolide 1
- Clarithromycin 500 mg twice daily can substitute for azithromycin 1
Regimen 2: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 1, 3
- Systematic reviews demonstrate fewer clinical failures with fluoroquinolone monotherapy compared to β-lactam/macrolide combinations 1
For penicillin-allergic patients: Respiratory fluoroquinolone is the preferred alternative 1
Critical timing: Administer the first antibiotic dose immediately upon diagnosis, ideally while still in the emergency department—delayed administration beyond 8 hours increases 30-day mortality by 20-30% 1
Severe CAP Requiring ICU Admission
Combination therapy is mandatory for all ICU patients—monotherapy is inadequate for severe disease. 1, 4
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
Evidence supporting combination therapy: A 2025 network meta-analysis of 8,142 patients with severe CAP found β-lactam plus macrolides ranked as the most effective treatment (SUCRA 92.0%), significantly reducing overall mortality compared to β-lactam monotherapy (RR 0.79; 95% CI 0.64-0.96) and β-lactam plus fluoroquinolones (RR 0.67; 95% CI 0.64-0.82) 4
Special Pathogen Coverage
Add antipseudomonal coverage when specific risk factors are present: 1
- Structural lung disease (bronchiectasis)
- Recent hospitalization with IV antibiotics within 90 days
- Prior respiratory isolation of Pseudomonas aeruginosa
Antipseudomonal 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 (gentamicin or tobramycin 5-7 mg/kg IV daily) PLUS azithromycin 1
Add MRSA coverage when risk factors are present: 1
- Prior MRSA infection or colonization
- Recent hospitalization with IV antibiotics
- Post-influenza pneumonia
- Cavitary infiltrates on imaging
MRSA 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
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
- Typical duration for uncomplicated CAP: 5-7 days 1
- Extended duration (14-21 days) required for specific pathogens: Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli 1
- Do not extend therapy beyond 7-8 days in responding patients without specific indications, as longer courses increase antimicrobial resistance risk without improving outcomes 1
Transition to Oral Therapy
Switch from IV to oral antibiotics when the patient meets ALL of the following criteria: 1
- Hemodynamically stable
- Clinically improving
- Afebrile for 48-72 hours
- Able to take oral medications
- Normal gastrointestinal function
- Typically by day 2-3 of hospitalization
Oral step-down options: 1
- Amoxicillin 1 g orally three times daily (preferred oral β-lactam)
- Amoxicillin-clavulanate 875 mg/125 mg orally twice daily PLUS azithromycin
- Continue doxycycline 100 mg twice daily if started IV
- Levofloxacin 750 mg orally once daily
Critical Pitfalls to Avoid
Never use macrolide monotherapy in hospitalized patients—it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1
Never use macrolide monotherapy in areas where pneumococcal macrolide resistance exceeds 25%—this leads to treatment failure 1
Never delay antibiotic administration in hospitalized patients—delays beyond 8 hours increase 30-day mortality by 20-30% 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 FDA warnings about serious adverse events (tendon rupture, aortic aneurysm, peripheral neuropathy) and resistance concerns 1
Do not automatically escalate to broad-spectrum antibiotics (antipseudomonal or anti-MRSA coverage) without documented risk factors 1