What are the recommended antibiotic regimens for community‑acquired pneumonia in outpatients (healthy versus with comorbidities), inpatients (non‑ICU versus ICU), and in patients with penicillin allergy?

Community-Acquired Pneumonia: Antibiotic Regimens by Clinical Setting

For outpatient healthy adults without comorbidities, prescribe amoxicillin 1 g orally three times daily for 5–7 days as first-line therapy; for hospitalized non-ICU patients, use 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

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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 for 5–7 days serves as an acceptable alternative, offering coverage of both typical bacterial pathogens and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1

• Macrolides (azithromycin 500 mg day 1, then 250 mg daily; 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

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 for 5–7 days. 1

• Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily or moxifloxacin 400 mg daily for 5–7 days) is an alternative when β-lactams or macrolides are contraindicated, though fluoroquinolones should be reserved for patients with comorbidities due to FDA warnings about serious adverse events (tendon rupture, peripheral neuropathy, aortic dissection). 1

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Inpatient Non-ICU Treatment

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

  1. β-lactam plus macrolide: ceftriaxone 1–2 g IV 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

• The β-lactam + macrolide combination provides comprehensive coverage for typical pathogens (S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1

• For penicillin-allergic patients, respiratory fluoroquinolone is the preferred alternative. 1, 2

• 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

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ICU Treatment (Severe CAP)

• 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 (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily). 1, 2

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Special Pathogen Coverage (Add Only When Risk Factors Present)

Pseudomonas aeruginosa

• Add antipseudomonal coverage only when specific risk factors exist: structural lung disease (bronchiectasis, cystic fibrosis), recent hospitalization with IV antibiotics within 90 days, or prior respiratory isolation of P. aeruginosa. 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 coverage. 1

Methicillin-Resistant Staphylococcus aureus (MRSA)

• Add MRSA coverage only when 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

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Duration of Therapy

• Minimum duration: at least 5 days, continuing until the patient is afebrile for 48–72 hours and has 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

• Typical course 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

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Transition from IV to Oral Therapy

• Switch from IV to oral antibiotics when all clinical stability criteria are met (hemodynamically stable, clinically improving, afebrile 48–72 hours, able to take oral medications, 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 azithromycin alone after 2–3 days of IV therapy). 1

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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% in hospitalized patients. 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

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Common 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% (the situation in most U.S. areas); this increases risk of breakthrough bacteremia and treatment failure. 1

• Do not add broad-spectrum antipseudomonal or MRSA agents routinely; restrict their use to patients with documented risk factors to prevent 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 concerns. 1

• Do not use oral cephalosporins (cefuroxime, cefpodoxime) as first-line agents because they have inferior in-vitro activity against S. pneumoniae compared with high-dose amoxicillin, lack atypical coverage, and are more costly without demonstrated clinical superiority. 1

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Follow-Up and Monitoring

• Outpatient review at 48 hours (or sooner if symptoms worsen) to assess symptom resolution, oral intake, and treatment response. 1

• Routine follow-up at 6 weeks for all patients; chest radiograph only for those with persistent symptoms, abnormal physical findings, or high risk for underlying malignancy (e.g., smokers >50 years). 1

• For hospitalized patients, monitor vital signs (temperature, respiratory rate, pulse, blood pressure, oxygen saturation) at least twice daily to detect early deterioration. 1

• If no clinical improvement by day 2–3, obtain 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