What are the first and second line treatments for community-acquired pneumonia?

First and Second Line Treatments for Community-Acquired Pneumonia

Outpatient Treatment (First Line)

For previously healthy adults without comorbidities, amoxicillin 1 g orally three times daily for 5-7 days is the preferred first-line therapy. 1

• Doxycycline 100 mg orally twice daily serves as an acceptable alternative for patients who cannot tolerate amoxicillin 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% 2, 1

Outpatients with Comorbidities (First Line)

For patients with comorbidities (COPD, diabetes, chronic heart/liver/renal disease, malignancy, or recent antibiotic use), combination therapy is required. 1

• Preferred regimen: Amoxicillin-clavulanate 875 mg/125 mg orally twice daily PLUS azithromycin 500 mg day 1, then 250 mg daily for days 2-5 1
• Alternative β-lactams: Cefpodoxime 200 mg twice daily OR cefuroxime 500 mg twice daily, always combined with a macrolide or doxycycline 2
• Alternative monotherapy: Respiratory fluoroquinolone (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily), though this should be reserved for specific situations due to FDA warnings about serious adverse events 1

Hospitalized Non-ICU Patients (First Line)

For hospitalized patients not requiring ICU admission, two equally effective regimens exist: β-lactam plus macrolide combination OR respiratory fluoroquinolone monotherapy. 1, 3

• Preferred combination: Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily 1, 3
• Alternative β-lactams: Cefotaxime 1-2 g IV every 8 hours OR ampicillin-sulbactam 3 g IV every 6 hours, always combined with azithromycin 1
• Alternative monotherapy: Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily 1, 4
• For penicillin-allergic patients: Respiratory fluoroquinolone is the preferred alternative 1

Evidence Supporting First-Line Choices

• Respiratory fluoroquinolone monotherapy demonstrated significantly higher clinical cure rates (86.5% vs. 81.5%) and microbiological eradication rates (86.0% vs. 81.0%) compared to β-lactam plus macrolide combination therapy in meta-analysis of 18 randomized controlled trials 4
• However, both regimens have equivalent mortality rates (7.2% vs. 7.7%) and similar adverse event profiles 4
• Critical timing: Administer the first antibiotic dose immediately in the emergency department, as delayed administration beyond 8 hours increases 30-day mortality by 20-30% 1

Severe CAP Requiring ICU Admission (First Line)

For ICU patients with severe CAP, combination therapy is mandatory—monotherapy is inadequate for severe disease. 1

• 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 1
• Alternative: β-lactam PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily) 1
• For penicillin-allergic ICU patients: Aztreonam 2 g IV every 8 hours PLUS respiratory fluoroquinolone 1

Second Line Treatment (Treatment Failure or Special Circumstances)

When to Consider Second-Line Therapy

If no clinical improvement by day 2-3, obtain repeat chest radiograph, CRP, white cell count, and additional microbiological specimens. 1

Second-Line Options for Non-Severe CAP

• For outpatients initially on amoxicillin monotherapy: Add or substitute a macrolide (azithromycin or clarithromycin) 1
• For outpatients on combination therapy: Switch to a respiratory fluoroquinolone 1

Second-Line Options for Severe CAP

• For severe pneumonia not responding to combination therapy: Consider adding rifampicin 1

Special Pathogen Coverage (Second Line)

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

• Antipseudomonal regimen: Antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) 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 1

Add MRSA coverage when risk factors are present: prior MRSA infection/colonization, recent hospitalization with IV antibiotics, post-influenza pneumonia, or cavitary infiltrates 1

• 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

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, 3

• Typical duration for uncomplicated CAP is 5-7 days 1
• Extended duration (14-21 days) is required for specific pathogens: Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli 1

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

• Oral step-down options: Amoxicillin 1 g orally three times daily PLUS azithromycin 500 mg orally daily 1
• Alternative: Continue doxycycline 100 mg orally twice daily if used initially 1

Critical Pitfalls to Avoid

• Never delay antibiotic administration beyond 8 hours in hospitalized patients, as this significantly increases mortality 1
• Never use macrolide monotherapy in hospitalized patients, as this provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1
• Never use macrolides in areas where pneumococcal macrolide resistance exceeds 25%, as this leads to treatment failure 1
• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about serious adverse events and resistance concerns 1
• Obtain blood and sputum cultures before initiating antibiotics in all hospitalized patients to allow pathogen-directed therapy 1