What empiric antibiotics are recommended for a patient with community-acquired pneumonia (CAP)?

Empiric Antibiotics for Community-Acquired Pneumonia

Outpatient Treatment Without Comorbidities

Amoxicillin 1 g orally three times daily for 5-7 days is the preferred first-line therapy for previously healthy adults with CAP. 1, 2 This regimen provides excellent coverage against Streptococcus pneumoniae including most drug-resistant strains, with activity against 90-95% of pneumococcal isolates at this high dosage. 3

• Doxycycline 100 mg orally twice daily serves as an acceptable alternative if amoxicillin cannot be tolerated, though this carries lower quality evidence. 3, 1

• Macrolides (azithromycin, clarithromycin) should only be used when local pneumococcal macrolide resistance is documented <25%, as resistance rates now exceed this threshold in most U.S. regions. 3, 1, 2

Outpatient Treatment With Comorbidities

For patients with COPD, diabetes, chronic heart/liver/renal disease, malignancy, or recent antibiotic use within 3 months, combination therapy is required. 3, 1, 2

• Preferred regimen: Amoxicillin-clavulanate 875/125 mg orally twice daily PLUS azithromycin 500 mg day 1, then 250 mg daily for days 2-5. 1, 2 High-dose amoxicillin-clavulanate targets ≥93% of S. pneumoniae including drug-resistant strains while providing coverage for β-lactamase-producing organisms. 3

• Alternative: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily OR moxifloxacin 400 mg daily), though fluoroquinolone use should be discouraged in uncomplicated cases due to resistance concerns and FDA warnings about serious adverse events. 3, 1, 2

Hospitalized Non-ICU Patients

Two equally effective regimens exist with strong recommendations: β-lactam plus macrolide combination OR respiratory fluoroquinolone monotherapy. 3, 1, 2

• Preferred combination: Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily (IV or oral). 3, 1, 2 This provides coverage for both typical bacterial pathogens (S. pneumoniae, H. influenzae, M. catarrhalis) and atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1

• Alternative β-lactams: Cefotaxime 1-2 g IV every 8 hours OR ampicillin-sulbactam 3 g IV every 6 hours, always combined with azithromycin. 3, 1

• Fluoroquinolone monotherapy: Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily. 3, 1, 2 Systematic reviews demonstrate fewer clinical failures with fluoroquinolones compared to β-lactam/macrolide combinations. 1

• For penicillin-allergic patients: Respiratory fluoroquinolone is the preferred alternative. 3, 1, 2

Severe CAP Requiring ICU Admission

Combination therapy is mandatory for all ICU patients—monotherapy is never adequate for ICU-level severity. 1, 2

• Preferred 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. 3, 1, 2

• Alternative: β-lactam PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily). 3, 1, 2

• For penicillin-allergic ICU patients: Aztreonam 2 g IV every 8 hours PLUS levofloxacin 750 mg IV daily. 1, 2

Risk Factors for Pseudomonas aeruginosa

Add antipseudomonal coverage only when specific risk factors are present: structural lung disease (bronchiectasis), recent hospitalization with IV antibiotics within 90 days, or prior respiratory isolation of P. aeruginosa. 1, 2

• Antipseudomonal regimen: Piperacillin-tazobactam 4.5 g IV every 6 hours (OR cefepime 2 g IV every 8 hours OR imipenem 500 mg IV every 6 hours OR meropenem 1 g IV every 8 hours) PLUS ciprofloxacin 400 mg IV every 8 hours OR levofloxacin 750 mg IV daily PLUS aminoglycoside (gentamicin OR tobramycin 5-7 mg/kg IV daily) PLUS azithromycin 500 mg IV daily. 1, 2

Risk Factors for MRSA

Add MRSA coverage 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, 2

• MRSA regimen: Add vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) OR linezolid 600 mg IV every 12 hours to the base regimen. 1, 2

Duration of Therapy

Treat for a minimum of 5 days and until the patient is afebrile for 48-72 hours with no more than one sign of clinical instability. 1, 2, 4 Clinical stability criteria include: temperature ≤37.8°C, heart rate ≤100 beats/min, respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mmHg, oxygen saturation ≥90% on room air, ability to maintain oral intake, and normal mental status. 1, 2

• Typical duration for uncomplicated CAP is 5-7 days total. 1, 2, 4

• Extended duration (14-21 days) is required for specific pathogens: Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1, 2

• Recent evidence supports 3-day treatment for non-severe CAP stabilized at day 3, particularly in younger patients with few comorbidities. 4

Transition to Oral Therapy

Switch from IV to oral antibiotics when the patient is hemodynamically stable, clinically improving, able to take oral medications, and has normal GI function—typically by day 2-3 of hospitalization. 1, 2

• Oral step-down options: Amoxicillin 1 g three times daily PLUS azithromycin 500 mg daily, OR amoxicillin-clavulanate 875/125 mg twice daily PLUS azithromycin, OR levofloxacin 750 mg daily. 1, 2

Critical Timing Considerations

Administer the first antibiotic dose immediately upon diagnosis, ideally while still in the emergency department. 1, 2 Delayed administration beyond 8 hours increases 30-day mortality by 20-30% in hospitalized patients. 1

Diagnostic Testing for Hospitalized Patients

Obtain blood cultures and sputum Gram stain/culture before initiating antibiotics in all hospitalized patients. 1, 2 This allows pathogen-directed therapy and de-escalation when appropriate. 1

• Consider urinary antigen testing for Legionella pneumophila serogroup 1 in severe CAP or ICU patients. 1

Common Pitfalls to Avoid

• Never use macrolide monotherapy for hospitalized patients, as it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae. 1, 2 Breakthrough pneumococcal bacteremia occurs significantly more frequently with macrolide-resistant strains. 3

• Never use macrolide monotherapy in areas where pneumococcal macrolide resistance exceeds 25%, as this leads to treatment failure. 3, 1, 2

• Do not add antipseudomonal coverage routinely—only when specific risk factors are present (structural lung disease, recent hospitalization with IV antibiotics, prior P. aeruginosa isolation). 1, 2

• Do not add MRSA coverage routinely—only when specific risk factors are present (prior MRSA infection, recent hospitalization with IV antibiotics, post-influenza pneumonia, cavitary infiltrates). 1, 2

• Do not extend therapy beyond 7 days in responding patients without specific indications (atypical pathogens, S. aureus, Gram-negative bacilli), as this increases antimicrobial resistance risk without improving outcomes. 1, 2

• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about serious adverse events (tendon rupture, peripheral neuropathy, aortic dissection) and resistance concerns. 1, 2