Best Antibiotic for Community-Acquired Pneumonia
For healthy outpatients without comorbidities, amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line therapy, providing superior pneumococcal coverage compared to all other oral agents. 1
Outpatient Treatment – Healthy Adults (No Comorbidities)
Amoxicillin 1 g orally three times daily is the gold standard because it retains activity against 90–95% of Streptococcus pneumoniae isolates, including many penicillin-resistant strains, and demonstrates superior in-vitro activity compared to oral cephalosporins. 1
Doxycycline 100 mg orally twice daily serves as an acceptable alternative when amoxicillin is contraindicated, providing coverage of both typical and atypical pathogens. 1
Macrolide monotherapy (azithromycin 500 mg day 1, then 250 mg daily; or clarithromycin 500 mg twice daily) should only be used when local pneumococcal macrolide resistance is documented to be <25%—in most U.S. regions, resistance is 20–30%, making macrolides unsafe as first-line agents. 1
Treat for a minimum of 5 days and continue until afebrile for 48–72 hours with no more than one sign of clinical instability; typical duration is 5–7 days. 1
Outpatient Treatment – Adults with Comorbidities
Patients with COPD, diabetes, chronic heart/liver/renal disease, malignancy, or recent antibiotic use within 90 days require combination therapy or respiratory fluoroquinolone monotherapy. 1
Option 1: Combination Therapy
Amoxicillin-clavulanate 875/125 mg orally twice daily PLUS azithromycin 500 mg day 1, then 250 mg daily (or doxycycline 100 mg twice daily as macrolide substitute). 1
Alternative β-lactams include cefpodoxime or cefuroxime, though these have inferior in-vitro activity compared to high-dose amoxicillin. 1
Option 2: Respiratory Fluoroquinolone Monotherapy
Levofloxacin 750 mg orally once daily OR moxifloxacin 400 mg orally once daily for 5–7 days. 1
Fluoroquinolones should be reserved for patients with β-lactam allergies or macrolide contraindications due to FDA warnings about tendon rupture, peripheral neuropathy, and aortic dissection. 1
Hospitalized Patients (Non-ICU)
Two equally effective regimens exist with strong recommendations and high-quality evidence: 1
Preferred Regimen: β-Lactam + Macrolide
Ceftriaxone 1–2 g IV once daily PLUS azithromycin 500 mg IV or orally 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 azithromycin. 1
This combination provides comprehensive coverage for typical pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1
Alternative Regimen: Respiratory Fluoroquinolone Monotherapy
Levofloxacin 750 mg IV once daily OR moxifloxacin 400 mg IV once daily. 1
Reserved for penicillin-allergic patients or when macrolides are contraindicated. 1
A 2024 network meta-analysis demonstrated that levofloxacin had the highest probability of achieving clinical response and lower mortality in outpatient CAP, though confidence intervals were broad. 2
Critical Timing
Administer the first antibiotic dose in the emergency department immediately upon diagnosis—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 enable pathogen-directed therapy. 1
Transition to Oral Therapy
Switch from IV to oral when the patient is hemodynamically stable (SBP ≥90 mmHg, HR ≤100 bpm), clinically improving, afebrile for 48–72 hours, respiratory rate ≤24 breaths/min, oxygen saturation ≥90% on room air, and able to take oral medications—typically by hospital day 2–3. 1
Oral step-down options: amoxicillin 1 g three times daily PLUS azithromycin 500 mg daily. 1
ICU Patients (Severe CAP)
Combination therapy is mandatory for all ICU patients—β-lactam monotherapy is associated with significantly higher mortality. 1
Standard ICU Regimen
Ceftriaxone 2 g IV once 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 OR a respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily). 1
A 2021 network meta-analysis of 27 RCTs found that ceftriaxone 2 g once daily plus levofloxacin 500 mg twice daily had the highest probability of reducing mortality in hospitalized CAP patients. 3
A 2025 network meta-analysis of 8,142 ICU patients demonstrated that β-lactam plus macrolide was the most effective regimen, significantly reducing overall mortality compared to β-lactam monotherapy and β-lactam plus fluoroquinolone. 1
For Penicillin-Allergic ICU Patients
- Aztreonam 2 g IV every 8 hours PLUS levofloxacin 750 mg IV daily (or azithromycin 500 mg IV daily). 1
Special Pathogen Coverage (Only When Risk Factors Present)
Antipseudomonal Coverage
Add only when the patient has structural lung disease (bronchiectasis, cystic fibrosis), recent hospitalization with IV antibiotics within 90 days, or prior respiratory isolation of Pseudomonas aeruginosa. 1
Regimen: Piperacillin-tazobactam 4.5 g IV every 6 hours (or cefepime 2 g IV every 8 hours) PLUS ciprofloxacin 400 mg IV every 8 hours OR levofloxacin 750 mg IV daily PLUS an aminoglycoside (gentamicin or tobramycin 5–7 mg/kg IV daily). 1
Dual antipseudomonal therapy is required for severe infections when Pseudomonas risk is present. 1
MRSA Coverage
Add only when the patient has prior MRSA infection/colonization, recent hospitalization with IV antibiotics, post-influenza pneumonia, or cavitary infiltrates on imaging. 1
- Regimen: Vancomycin 15 mg/kg IV every 8–12 hours (target trough 15–20 µg/mL) OR linezolid 600 mg IV every 12 hours, added to the base regimen. 1
Duration of Therapy
Minimum of 5 days and continue 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) is required only for infections caused by Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1
Critical Pitfalls to Avoid
Never use macrolide monotherapy in hospitalized patients—it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae and is associated with treatment failure. 1
Never use macrolide monotherapy in outpatients when local pneumococcal macrolide resistance exceeds 25%—this increases the risk of breakthrough bacteremia and treatment failure. 1
Never delay antibiotic administration beyond 8 hours in hospitalized patients—this increases 30-day mortality by 20–30%. 1
Do not add antipseudomonal or MRSA coverage automatically—restrict to patients with documented risk factors to prevent unnecessary broad-spectrum exposure, resistance, and adverse effects. 1
Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP—reserve for patients with comorbidities or β-lactam allergies due to FDA warnings about serious adverse events. 1
Do not use oral cephalosporins (cefuroxime, cefpodoxime) as first-line outpatient therapy—they have inferior in-vitro activity compared to high-dose amoxicillin and lack atypical pathogen coverage. 1