What are the recommended antibiotic regimens for community-acquired pneumonia?

Community-Acquired Pneumonia Antibiotic Treatment

For Healthy Outpatients WITHOUT Comorbidities

Amoxicillin 1 gram three times daily is the first-line antibiotic for previously healthy adults with community-acquired pneumonia. 1, 2

• Amoxicillin 1g three times daily is the preferred initial therapy (strong recommendation, moderate quality evidence) 1
• Doxycycline 100mg twice daily is an acceptable alternative (conditional recommendation, low quality evidence) 1, 2
• Macrolides (azithromycin 500mg day 1, then 250mg daily for 4 days OR clarithromycin 500mg twice daily) should ONLY be used if local pneumococcal macrolide resistance is documented to be <25% (conditional recommendation, moderate quality evidence) 1, 2

Rationale for Amoxicillin Priority

The American Thoracic Society prioritizes amoxicillin because it demonstrates efficacy against Streptococcus pneumoniae (the most common pathogen) even without atypical coverage, has an excellent safety profile, and reduces selection pressure for antibiotic resistance compared to broader-spectrum agents 1, 2. Studies of high-dose oral amoxicillin showed effectiveness even in hospitalized CAP patients, supporting its use in lower-risk outpatients 1.

Critical Pitfall: Macrolide Resistance

Do NOT use macrolide monotherapy if local resistance rates are ≥25% or unknown, as 20-30% of S. pneumoniae isolates show macrolide resistance, leading to clinical failures requiring hospitalization 3. If you lack local resistance data, assume resistance is ≥25% and choose amoxicillin or doxycycline instead 2, 3.

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For Outpatients WITH Comorbidities

Patients with chronic heart/lung/liver/renal disease, diabetes, alcoholism, malignancy, asplenia, age >65, or recent antibiotic use within 3 months require either combination therapy OR respiratory fluoroquinolone monotherapy. 1, 2

Option 1: Combination Therapy (Strong Recommendation)

• Beta-lactam: Amoxicillin-clavulanate 875mg/125mg twice daily OR 2000mg/125mg twice daily, OR cefpodoxime 200mg twice daily, OR cefuroxime 500mg twice daily 1
• PLUS one of the following:
  • Azithromycin 500mg day 1, then 250mg daily (strong recommendation, moderate quality evidence) 1
  • Clarithromycin 500mg twice daily OR extended-release 1000mg daily (strong recommendation, moderate quality evidence) 1
  • Doxycycline 100mg twice daily (conditional recommendation, low quality evidence) 1

Option 2: Fluoroquinolone Monotherapy (Strong Recommendation)

• Levofloxacin 750mg daily OR moxifloxacin 400mg daily OR gemifloxacin 320mg daily (strong recommendation, moderate quality evidence) 1, 2, 4

Fluoroquinolone Safety Warning

Exercise caution with fluoroquinolones due to FDA warnings regarding tendinopathy, peripheral neuropathy, CNS effects, aortic dissection/rupture (especially in patients with vascular disease), and QTc prolongation. 2 Reserve fluoroquinolones for patients with true penicillin allergy or when combination therapy cannot be used 1, 2.

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For Hospitalized Patients (Non-ICU)

All hospitalized patients require combination therapy with a beta-lactam PLUS either a macrolide or respiratory fluoroquinolone. 2

• Beta-lactam: Ampicillin-sulbactam, ceftriaxone, cefotaxime, or ceftaroline 2
• PLUS:
  • Azithromycin 500mg daily (preferred) 2, 3
  • OR respiratory fluoroquinolone (levofloxacin 750mg daily or moxifloxacin 400mg daily) 2

Never use azithromycin monotherapy in hospitalized patients—combination therapy is mandatory. 3

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For Severe CAP (ICU Patients)

ICU patients require beta-lactam PLUS either macrolide or respiratory fluoroquinolone, with anti-pseudomonal coverage if risk factors present. 2

Standard Severe CAP Regimen:

• Beta-lactam (ampicillin-sulbactam, ceftriaxone, cefotaxime, or ceftaroline) PLUS azithromycin OR PLUS respiratory fluoroquinolone 2

When Pseudomonas Risk Factors Present:

(Structural lung disease, recent hospitalization, recent broad-spectrum antibiotics)

• Anti-pseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) PLUS ciprofloxacin OR aminoglycoside PLUS macrolide 2

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Treatment Duration

Treat for a minimum of 5 days, and discontinue only after the patient has been afebrile for 48-72 hours with no more than one CAP-associated sign of clinical instability. 2, 5

• 3 days is sufficient for non-severe/moderate CAP if clinically stable at day 3 5
• 5 days is the standard minimum duration for most cases 2, 5, 6
• 7 days for uncomplicated CAP without early stability 2, 5
• 14-21 days ONLY for Legionella pneumophila, Staphylococcus aureus, or gram-negative enteric bacilli 2

Recent meta-analyses confirm non-inferiority of short-course (≤7 days) versus extended-course (>7 days) regimens for clinical cure, mortality, and bacteriologic eradication 6. Do not automatically extend therapy beyond 5-7 days unless specific pathogens or complications warrant it. 5, 6

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Special Considerations

Recent Antibiotic Exposure (Within 3 Months)

Choose a different antibiotic class than recently used to minimize resistance selection. 2, 3 If the patient received a macrolide in the past 3 months, do NOT use azithromycin—select amoxicillin-clavulanate plus doxycycline or a fluoroquinolone instead 2, 3.

Penicillin Allergy

• Type I hypersensitivity (anaphylaxis): Use respiratory fluoroquinolone monotherapy OR doxycycline 1, 2
• Non-severe allergy: Consider cephalosporin (cefpodoxime, cefuroxime) plus macrolide 1

Aspiration Pneumonia

Use amoxicillin-clavulanate or clindamycin for anaerobic coverage. 2

Monitoring Response

Fever should resolve within 2-3 days of initiating antibiotics. 2 If no clinical improvement by day 2-3 (inpatients) or day 5-7 (outpatients), reassess for complications, resistant organisms, or alternative diagnoses rather than reflexively extending duration 2, 5.