What is the recommended empiric antibiotic regimen for community‑acquired pneumonia in an otherwise healthy adult outpatient, in hospitalized non‑ICU patients, and in severe ICU patients, including guidance for β‑lactam allergy, macrolide resistance, MRSA risk, and appropriate treatment duration?

Empiric Antibiotic Regimens for Community-Acquired Pneumonia

Outpatient Treatment – Previously Healthy Adults

Amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line therapy for previously healthy adults without comorbidities, providing superior coverage against Streptococcus pneumoniae including many penicillin-resistant strains. 1

• Doxycycline 100 mg orally twice daily for 5–7 days serves as an acceptable alternative when amoxicillin is contraindicated. 1
• Macrolide monotherapy (azithromycin or clarithromycin) 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, 2

Outpatient Treatment – Adults with Comorbidities

For patients with chronic heart, lung, liver, or renal disease, diabetes, malignancy, or recent antibiotic use within 90 days, combination therapy is required.

• Option 1: Amoxicillin-clavulanate 875/125 mg orally twice daily plus azithromycin (500 mg day 1, then 250 mg daily for days 2–5) or doxycycline 100 mg twice daily. 1
• Option 2: Respiratory fluoroquinolone monotherapy—levofloxacin 750 mg daily or moxifloxacin 400 mg daily for 5–7 days—reserved for β-lactam allergy or when combination therapy is contraindicated due to FDA safety warnings. 1

Hospitalized Non-ICU Patients

Two equally effective regimens exist with strong evidence:

• Preferred regimen: Ceftriaxone 1–2 g IV daily plus azithromycin 500 mg IV or orally daily, providing comprehensive coverage of typical pathogens (S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1, 3, 4
• Alternative regimen: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily), which systematic reviews show has fewer clinical failures compared to β-lactam/macrolide combinations. 1
• For penicillin-allergic patients: Use respiratory fluoroquinolone as the preferred alternative. 1
• Doxycycline alternative: β-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) plus doxycycline 100 mg twice daily is acceptable when macrolides are contraindicated, though this carries lower-quality evidence. 1, 5

Severe CAP Requiring ICU Admission

Combination therapy is mandatory for all ICU patients; β-lactam monotherapy is associated with higher mortality.

• Standard 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, 6
• For penicillin-allergic ICU patients: Aztreonam 2 g IV every 8 hours plus a respiratory fluoroquinolone (levofloxacin 750 mg IV daily). 1

Special Pathogen Coverage (Add Only When Risk Factors Present)

Pseudomonas aeruginosa Coverage

Add antipseudomonal therapy only when the following risk factors exist:

• Structural lung disease (bronchiectasis, cystic fibrosis)
• Recent hospitalization with IV antibiotics within 90 days
• Prior respiratory isolation of P. aeruginosa
• Chronic broad-spectrum antibiotic exposure (≥7 days in past month) 1, 6

Antipseudomonal 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) for dual coverage. 1

MRSA Coverage

Add MRSA therapy only when the following risk factors exist:

• Prior MRSA infection or colonization
• Recent hospitalization with IV antibiotics within 90 days
• Post-influenza pneumonia
• Cavitary infiltrates on imaging 1, 6

MRSA 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 CAP regimen. 1, 6

Duration of Therapy

• Minimum duration: 5 days, continuing until the patient is afebrile for 48–72 hours with no more than one sign of clinical instability. 1
• Typical course for uncomplicated CAP: 5–7 days. 1
• Extended duration (14–21 days): Required only for Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1, 6

Transition from IV to Oral Therapy

Switch to oral antibiotics when all of the following stability criteria are met:

• Temperature ≤37.8°C
• Heart rate ≤100 bpm
• Respiratory rate ≤24 breaths/min
• Systolic blood pressure ≥90 mmHg
• Oxygen saturation ≥90% on room air
• Ability to maintain oral intake
• Normal mental status 1

This transition typically occurs by hospital day 2–3. 1

Critical Timing and Diagnostic Considerations

• Administer the first antibiotic dose immediately in the emergency department; delays beyond 8 hours increase 30-day mortality by 20–30%. 1
• Obtain blood cultures and sputum Gram stain/culture before initiating antibiotics in all hospitalized patients to enable pathogen-directed therapy and safe de-escalation. 1

Common Pitfalls to Avoid

• Never use macrolide monotherapy in hospitalized patients—it provides inadequate coverage for typical pathogens like S. pneumoniae and leads to treatment failure. 1, 7
• Never use macrolide monotherapy in outpatients when local pneumococcal macrolide resistance exceeds 25%—this increases risk of breakthrough bacteremia. 1
• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about serious adverse events (tendon rupture, peripheral neuropathy, aortic dissection) and rising resistance. 1
• Do not add broad-spectrum antipseudomonal or MRSA agents routinely—restrict to patients with documented risk factors to prevent unnecessary resistance and adverse effects. 1
• Never use β-lactam monotherapy in ICU patients—combination therapy is mandatory and reduces mortality. 1, 6, 4