Empiric Antibiotic Regimens for Community-Acquired Pneumonia in Adults
For outpatient CAP without comorbidities, use amoxicillin 1 g three times daily; for hospitalized non-ICU patients, use ceftriaxone 1–2 g IV daily plus azithromycin 500 mg daily; for ICU patients, use ceftriaxone 2 g IV daily plus azithromycin 500 mg IV daily or a respiratory fluoroquinolone.
Outpatient Treatment
Previously Healthy Adults (No Comorbidities)
- Amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line agent because it retains activity against 90–95% of Streptococcus pneumoniae isolates, including many penicillin-resistant strains, and provides superior pneumococcal coverage compared with oral cephalosporins. 1
- Doxycycline 100 mg orally twice daily is an acceptable alternative, offering coverage of both typical and atypical organisms, though this carries a conditional recommendation with lower-quality 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%; in most U.S. regions resistance is 20–30%, making monotherapy unsafe as first-line. 1
Adults with Comorbidities or Recent Antibiotic Use
- Combination therapy is required: a β-lactam (amoxicillin-clavulanate 875/125 mg twice daily, cefpodoxime, or cefuroxime) plus a macrolide (azithromycin or clarithromycin) or doxycycline 100 mg twice daily. 1
- Respiratory fluoroquinolone alternative: levofloxacin 750 mg daily or moxifloxacin 400 mg daily may be used when β-lactams or macrolides are contraindicated, though fluoroquinolone use should be discouraged in uncomplicated cases due to FDA warnings about serious adverse events and resistance concerns. 1
- Comorbidities include COPD, diabetes, chronic heart/liver/renal disease, malignancy, or antibiotic use within the past 3 months. 1
Inpatient Non-ICU Treatment
Standard Regimen
Two equally effective regimens exist with strong recommendations and high-quality evidence: 1
- β-lactam plus macrolide: ceftriaxone 1–2 g IV daily plus azithromycin 500 mg daily (IV or oral)
- Respiratory fluoroquinolone monotherapy: levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily
The β-lactam plus macrolide combination provides comprehensive coverage for typical pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1
Alternative β-lactams include cefotaxime 1–2 g IV every 8 hours or ampicillin-sulbactam 3 g IV every 6 hours, always combined with a macrolide. 1
For penicillin-allergic patients, respiratory fluoroquinolone is the preferred alternative. 1
ICU Treatment (Severe CAP)
Mandatory Combination Therapy
- Combination therapy is mandatory for all ICU patients; β-lactam monotherapy is linked to higher mortality. 1
- Preferred ICU 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 or a respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily). 1
- 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 and β-lactam plus fluoroquinolone. 1
Special Pathogen Coverage (Only When Risk Factors Present)
Antipseudomonal Coverage
- Add antipseudomonal coverage only when risk factors are present: structural lung disease (bronchiectasis, cystic fibrosis), recent hospitalization with IV antibiotics within 90 days, or 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 an aminoglycoside (gentamicin or tobramycin 5–7 mg/kg IV daily). 1
MRSA Coverage
- Add MRSA coverage only when risk factors are present: prior MRSA infection/colonization, recent hospitalization with IV antibiotics within 90 days, post-influenza pneumonia, or cavitary infiltrates on imaging. 1
- Regimen: vancomycin 15 mg/kg IV every 8–12 hours (target trough 15–20 mg/L) or linezolid 600 mg IV every 12 hours, added to the base regimen. 1
Duration of Therapy
- Minimum duration: treat for at least 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) is required only for infections caused by 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 (SBP ≥90 mmHg, HR ≤100 bpm), clinically improving (afebrile 48–72 hours, RR ≤24 breaths/min), able to take oral medications, and has oxygen saturation ≥90% on room air—typically by hospital day 2–3. 1
- Oral step-down options include amoxicillin 1 g three times daily plus azithromycin 500 mg daily, or continuation of azithromycin alone after 2–3 days of IV therapy. 1
Critical Pitfalls to Avoid
- Never delay antibiotic administration: initiating therapy >8 hours after diagnosis raises 30-day mortality by 20–30%. 1
- Avoid macrolide monotherapy in hospitalized patients because it fails to cover typical pathogens and is associated with treatment failure. 1
- Do not use macrolide monotherapy in outpatients when local pneumococcal macrolide resistance exceeds 25%; this increases risk of breakthrough bacteremia and failure. 1
- Obtain blood and sputum cultures before antibiotics in all hospitalized patients to enable pathogen-directed therapy and safe de-escalation. 1
- Restrict fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about serious adverse events and rising resistance. 1
- Do not add broad-spectrum antipseudomonal or MRSA agents automatically; restrict to patients with documented risk factors to prevent resistance, adverse effects, and unnecessary cost. 1