What is the recommended empiric antibiotic regimen for community‑acquired pneumonia in an otherwise healthy adult outpatient, and how should it be adjusted for patients with comorbidities, recent beta‑lactam use, hospitalization, ICU admission, or risk of MRSA?

Community-Acquired Pneumonia Treatment

For healthy outpatients without comorbidities, prescribe amoxicillin 1 g orally three times daily for 5–7 days as first-line therapy; hospitalized non-ICU patients require ceftriaxone 1–2 g IV daily plus azithromycin 500 mg daily; and ICU patients mandate ceftriaxone 2 g IV daily plus azithromycin 500 mg IV daily or a respiratory fluoroquinolone. 1

Outpatient Management

Previously Healthy Adults (No Comorbidities)

• Amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line regimen, providing superior pneumococcal coverage against 90–95% of Streptococcus pneumoniae isolates, including many penicillin-resistant strains. 1
• Doxycycline 100 mg orally twice daily serves as an acceptable alternative when amoxicillin is contraindicated, offering coverage of both typical and atypical pathogens. 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 ranges from 20–30%, making macrolides unsafe as first-line agents. 1

Patients with Comorbidities or Recent Antibiotic Use

• Combination therapy is required for patients with COPD, diabetes, chronic heart/liver/renal disease, malignancy, or antibiotic use within 90 days. 1
• Option 1: 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
• Option 2: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily or moxifloxacin 400 mg daily), though this should be reserved for patients with contraindications to β-lactams or macrolides due to FDA warnings about serious adverse events. 1
• If the patient received antibiotics within the previous 90 days, select an agent from a different class to minimize resistance risk. 1

Hospitalized Non-ICU Patients

• 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 (or clarithromycin 500 mg twice daily). 1
  • Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily. 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
• The first antibiotic dose must be administered in the emergency department immediately upon diagnosis; delays beyond 8 hours increase 30-day mortality by 20–30%. 1

Severe CAP Requiring ICU Admission

• Combination therapy is mandatory for all ICU patients; β-lactam monotherapy is associated with higher mortality in critically ill patients with bacteremic pneumococcal pneumonia. 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
• For penicillin-allergic ICU patients, use aztreonam 2 g IV every 8 hours plus a respiratory fluoroquinolone. 1

Special Pathogen Coverage (Risk Factor–Based)

Pseudomonas aeruginosa Coverage

• Add antipseudomonal therapy only when specific risk factors are present: 1
  • 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 the past month)
• 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 MRSA therapy only when specific risk factors are present: 1
  • Prior MRSA infection or colonization
  • Recent hospitalization with IV antibiotics within 90 days
  • 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

Duration of Therapy

• Treat for a 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 is 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 from IV to Oral Therapy

• Switch from IV to oral antibiotics when the patient is hemodynamically stable (systolic BP ≥90 mmHg, heart rate ≤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 include amoxicillin 1 g three times daily plus azithromycin 500 mg daily (or azithromycin alone after 2–3 days of IV therapy). 1

Diagnostic Testing

• 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
• Urinary antigen testing for Legionella pneumophila serogroup 1 should be considered in severe CAP or ICU patients. 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
• Avoid macrolide monotherapy in outpatients when local pneumococcal macrolide resistance exceeds 25%, as this increases the risk of breakthrough bacteremia and treatment failure. 1
• Do not add broad-spectrum antipseudomonal or MRSA agents automatically; restrict their use to patients with documented risk factors to prevent resistance, adverse effects, and unnecessary cost. 1
• Do not delay antibiotic administration beyond 8 hours in hospitalized patients, as this significantly increases mortality. 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

Follow-Up and Monitoring

• Outpatients should have clinical review at 48 hours (or sooner if symptoms worsen) to assess symptom resolution, oral intake, and treatment response. 1
• Schedule clinical review at 6 weeks for all hospitalized patients; chest radiograph is reserved for those with persistent symptoms, physical signs, or high risk for underlying malignancy (smokers, age >50 years). 1
• If no clinical improvement by day 2–3, obtain repeat chest radiograph, inflammatory markers (CRP), complete blood count, and additional microbiologic specimens to assess for complications. 1

Prevention

• Offer pneumococcal polysaccharide vaccine to all adults ≥65 years and those with high-risk conditions. 1
• Recommend annual influenza vaccination for all patients, especially those with chronic medical illnesses. 1
• Provide smoking-cessation counseling to all current smokers hospitalized with CAP. 1