Empiric Antibiotic Therapy for Community-Acquired Pneumonia in Healthy Adults
For an otherwise healthy adult with suspected typical community-acquired bacterial pneumonia, prescribe amoxicillin 1 g orally three times daily for 5–7 days as first-line therapy. 1
Outpatient Regimen for Healthy Adults Without Comorbidities
Amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line agent because it retains activity against approximately 90–95% of Streptococcus pneumoniae isolates, including many penicillin-resistant strains, and provides superior pneumococcal coverage compared with oral cephalosporins or macrolides. 1
Doxycycline 100 mg orally twice daily for 5–7 days serves as an acceptable alternative when amoxicillin is contraindicated, offering coverage of both typical bacterial pathogens and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1
Macrolide monotherapy (azithromycin 500 mg on day 1, then 250 mg daily; or clarithromycin 500 mg twice daily) should be avoided in most U.S. regions because pneumococcal macrolide resistance ranges from 20–30%, exceeding the 25% threshold at which macrolides become unsafe as first-line agents. 1
Outpatient Regimen for Adults With Comorbidities or Recent Antibiotic Use
Patients with comorbidities (COPD, diabetes, chronic heart/liver/renal disease, malignancy) or antibiotic use within the past 90 days require broader coverage:
Option 1 – Combination therapy: Amoxicillin-clavulanate 875/125 mg orally twice daily plus azithromycin 500 mg on day 1, then 250 mg daily for days 2–5 (or doxycycline 100 mg twice daily as an alternative to azithromycin). 1
Option 2 – Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg orally once daily or moxifloxacin 400 mg orally once daily for 5–7 days. 1, 2, 3
Rationale: Both strategies provide coverage of typical pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1
Fluoroquinolone caution: Reserve fluoroquinolones for patients with documented β-lactam or macrolide contraindications due to FDA warnings about serious adverse events (tendon rupture, peripheral neuropathy, aortic dissection) and rising resistance. 1
Penicillin Allergy Alternatives
For patients with documented penicillin allergy:
Outpatient (no comorbidities): Doxycycline 100 mg orally twice daily for 5–7 days. 1
Outpatient (with comorbidities) or inpatient (non-ICU): Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg IV or orally daily, or moxifloxacin 400 mg IV or orally daily). 1, 2, 3
ICU patients with penicillin allergy: Aztreonam 2 g IV every 8 hours plus azithromycin 500 mg IV daily or a respiratory fluoroquinolone. 1
Hospitalized Patients (Non-ICU)
Two equally effective regimens with strong guideline support:
β-lactam plus macrolide combination: Ceftriaxone 1–2 g IV once daily plus azithromycin 500 mg IV or orally daily. 1
Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily. 1, 2, 3
- Rationale: The β-lactam + macrolide regimen provides comprehensive coverage for typical bacterial pathogens and atypical organisms; fluoroquinolone monotherapy achieves equivalent efficacy but should be reserved for penicillin-allergic patients. 1
Severe CAP Requiring ICU Admission
Combination therapy is mandatory for all ICU patients; monotherapy is associated with higher mortality:
- Preferred 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
Duration of Therapy
Minimum duration: Treat for at least 5 days and continue until the patient is afebrile for 48–72 hours with no more than one sign of clinical instability (temperature ≤37.8°C, heart rate ≤100 bpm, respiratory rate ≤24 breaths/min, systolic BP ≥90 mmHg, oxygen saturation ≥90% on room air, ability to maintain oral intake, normal mental status). 1
Typical course for uncomplicated CAP: 5–7 days. 1
Extended courses (14–21 days): Required only for infections caused by Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1
Transition from IV to Oral Therapy
Switch criteria: Transition to oral antibiotics 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, able to take oral medications, and has normal gastrointestinal function—typically by hospital day 2–3. 1
Oral step-down options: Amoxicillin 1 g three times daily plus azithromycin 500 mg daily (or azithromycin alone after 2–3 days of IV therapy). 1
Special Pathogen Coverage (Only When Risk Factors Present)
Antipseudomonal Coverage
Add only if the patient has:
- 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 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
MRSA Coverage
Add only if the patient has:
- Prior MRSA infection/colonization
- Recent hospitalization with IV antibiotics
- Post-influenza pneumonia
- Cavitary infiltrates on imaging
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
Critical Pitfalls to Avoid
Never delay the first antibiotic dose: Administration beyond 8 hours after diagnosis increases 30-day mortality by 20–30% in hospitalized patients. 1
Avoid macrolide monotherapy in hospitalized patients: It fails to cover typical pathogens such as S. pneumoniae and leads to treatment failure. 1
Do not use macrolide monotherapy in outpatients when local pneumococcal macrolide resistance exceeds 25%: This increases the risk of breakthrough bacteremia and treatment failure. 1
Obtain blood and sputum cultures before starting antibiotics in all hospitalized patients to enable pathogen-directed therapy and safe de-escalation. 1
Do not add broad-spectrum antipseudomonal or MRSA agents routinely: Restrict their use to patients with documented risk factors to prevent unnecessary resistance, adverse effects, and cost. 1
Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP: Reserve for patients with comorbidities or documented treatment failure due to FDA warnings about serious adverse events and rising resistance. 1