What are the recommended initial empiric antibiotic regimens for community‑acquired pneumonia in an otherwise healthy adult outpatient, an outpatient with comorbidities or recent antibiotic use, a hospitalized non‑ICU patient, an ICU patient, and in patients allergic to β‑lactams?

Treatment for Community-Acquired Pneumonia

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

Outpatient Management

Previously Healthy Adults (No Comorbidities)

• Amoxicillin 1 g orally three times daily for 5–7 days is the preferred first-line regimen 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, 2

• Doxycycline 100 mg orally twice daily for 5–7 days serves as an acceptable alternative, offering coverage of both typical bacterial pathogens and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1, 2

• Macrolide monotherapy (azithromycin 500 mg day 1, then 250 mg daily for days 2–5; 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 macrolide monotherapy unsafe as first-line therapy. 1, 2

Adults with Comorbidities or Recent Antibiotic Use

• Combination therapy is required for patients with chronic heart, lung, liver, or renal disease, diabetes, malignancy, immunosuppression, or antibiotic use within the past 90 days. 1

• Preferred combination regimen: amoxicillin-clavulanate 875 mg/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, providing comprehensive coverage of typical and atypical pathogens. 1

• Alternative monotherapy: levofloxacin 750 mg orally once daily or moxifloxacin 400 mg orally once daily for 5–7 days may be used when β-lactams or macrolides are contraindicated, though fluoroquinolones should be reserved due to FDA warnings about serious adverse events (tendon rupture, peripheral neuropathy, aortic dissection). 1

Hospitalized Non-ICU Patients

• Two equally effective regimens with strong, high-quality evidence:

  1. β-lactam plus macrolide: ceftriaxone 1–2 g IV once daily plus azithromycin 500 mg IV or orally daily
  2. Respiratory fluoroquinolone monotherapy: levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily 1, 2

• 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

• For penicillin-allergic patients, respiratory fluoroquinolone is the preferred alternative. 1

• Administer the first antibiotic dose 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, 2

• 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, 2

• For penicillin-allergic ICU patients, use aztreonam 2 g IV every 8 hours plus a respiratory fluoroquinolone. 1

Special Pathogen Coverage (Risk-Based)

Pseudomonas aeruginosa Coverage

• Add antipseudomonal therapy only when specific risk factors are present: structural lung disease (bronchiectasis, cystic fibrosis), recent hospitalization with IV antibiotics within 90 days, prior respiratory isolation of P. aeruginosa, or chronic broad-spectrum antibiotic exposure (≥7 days in the past month). 1

• 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 antipseudomonal coverage. 1

MRSA Coverage

• Add MRSA therapy only when specific risk factors are present: prior MRSA infection/colonization, recent hospitalization with IV antibiotics, post-influenza pneumonia, or cavitary infiltrates on imaging. 1

• 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

Duration of Therapy and Transition to Oral Antibiotics

• Minimum treatment duration is 5 days, continuing 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, SpO₂ ≥90% on room air, able to maintain oral intake, normal mental status). 1, 2

• Typical duration for uncomplicated CAP is 5–7 days. 1, 2

• Extended courses of 14–21 days are required only for infections caused by Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1

• Switch from IV to oral therapy when the patient is hemodynamically stable, clinically improving, afebrile for 48–72 hours, able to take oral medications, and has normal GI function—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 use macrolide monotherapy in hospitalized patients because it fails to cover typical pathogens such as 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 use fluoroquinolone monotherapy in ICU patients; combination therapy with a β-lactam is mandatory and reduces mortality. 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

• Do not add broad-spectrum antipseudomonal or MRSA agents routinely; restrict their use to patients with documented risk factors to avoid unnecessary resistance and adverse effects. 1

• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about serious adverse events and rising resistance. 1

Diagnostic Testing and Monitoring

• For hospitalized patients, monitor temperature, respiratory rate, pulse, blood pressure, mental status, and oxygen saturation at least twice daily to detect early deterioration. 1

• If no clinical improvement by day 2–3, obtain a repeat chest radiograph, inflammatory markers (CRP, white blood cell count), and additional microbiologic specimens to evaluate for complications such as pleural effusion, empyema, or resistant organisms. 1

• For outpatients, arrange a clinical review at 48 hours (or sooner if symptoms worsen) to assess response, oral intake, and adherence. 1

• Schedule a routine follow-up visit at 6 weeks for all patients; obtain a chest radiograph only if symptoms persist, physical findings remain abnormal, or the patient has high risk for underlying malignancy (e.g., smokers >50 years). 1

Prevention

• Offer pneumococcal polysaccharide vaccine to all adults ≥65 years and those with high-risk conditions (chronic heart, lung, liver, or renal disease, diabetes, immunosuppression). 1

• Recommend annual influenza vaccination for all patients, especially those with chronic medical illnesses. 1

• Provide smoking-cessation counseling to all current smokers. 1