What is the best antibiotic for an otherwise healthy adult with community-acquired pneumonia?

Best Antibiotic for Community-Acquired Pneumonia in Healthy Adults

For otherwise healthy adults with community-acquired pneumonia, amoxicillin 1 gram orally three times daily for 5-7 days is the preferred first-line treatment, with doxycycline 100 mg twice daily as the best alternative. 1, 2

Outpatient Treatment Algorithm

For Previously Healthy Adults WITHOUT Comorbidities

First-line choice: Amoxicillin 1 g orally three times daily for 5-7 days 1, 2

• Provides excellent coverage against Streptococcus pneumoniae (the most common pathogen, accounting for 48% of identified CAP cases), with activity against 90-95% of pneumococcal strains including many with intermediate penicillin resistance 1
• Strong recommendation with moderate-quality evidence 1, 2

Preferred alternative: Doxycycline 100 mg orally twice daily for 5-7 days 1, 2

• Provides broad-spectrum coverage including atypical organisms (Mycoplasma, Chlamydophila, Legionella) 1
• Conditional recommendation with low-quality evidence 1, 2

Macrolides (azithromycin or clarithromycin): Use ONLY if local pneumococcal macrolide resistance is documented <25% 1, 2

• Azithromycin dosing: 500 mg on day 1, then 250 mg daily on days 2-5 1, 3
• Clarithromycin dosing: 500 mg twice daily 1, 2
• Conditional recommendation with moderate-quality evidence 1, 2

For Adults WITH Comorbidities

Comorbidities requiring enhanced therapy include: chronic heart/lung/liver/renal disease, diabetes mellitus, alcoholism, malignancies, asplenia, immunosuppression, or antibiotic use within the past 90 days 1

Preferred regimen: Combination therapy with β-lactam PLUS macrolide 1, 2

• Amoxicillin-clavulanate 875 mg/125 mg orally twice daily PLUS azithromycin 500 mg day 1, then 250 mg daily for days 2-5 1, 2
• Total duration: 5-7 days 1, 2
• Strong recommendation with moderate-quality evidence 1, 2

Alternative monotherapy: Respiratory fluoroquinolone 1, 2

• Levofloxacin 750 mg orally once daily for 5 days 1, 2
• Moxifloxacin 400 mg orally once daily for 5 days 1, 2
• Strong recommendation with moderate-quality evidence 1, 2
• Caution: Reserve fluoroquinolones for patients with contraindications to β-lactam/macrolide combinations due to FDA warnings about serious adverse events including tendinopathy, peripheral neuropathy, and CNS effects 1

Hospitalized Patients (Non-ICU)

Two equally effective regimens with strong evidence: 1, 2

Option 1: β-lactam PLUS macrolide combination 1, 2

• Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg IV or oral daily 1, 2
• Achieves 91.5% favorable clinical outcomes 1

Option 2: Respiratory fluoroquinolone monotherapy 1, 2

• Levofloxacin 750 mg IV daily 1, 2
• Moxifloxacin 400 mg IV daily 1, 2
• Systematic reviews show fewer clinical failures compared to β-lactam/macrolide combinations 2

Transition to oral therapy when: 1, 2

• Hemodynamically stable (systolic BP ≥90 mmHg, heart rate <100 bpm) 2
• Clinically improving with afebrile status for 48-72 hours 1, 2
• Able to take oral medications with normal GI function 1, 2
• Typically by day 2-3 of hospitalization 1, 2

Severe CAP Requiring ICU Admission

Mandatory combination therapy for ALL ICU patients—monotherapy is inadequate 1, 2

Preferred regimen: 1, 2

• Ceftriaxone 2 g IV daily (or cefotaxime 1-2 g IV every 8 hours) PLUS azithromycin 500 mg IV daily 1, 2
• Alternative: β-lactam PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 1, 2

Add antipseudomonal coverage ONLY when risk factors present: 1, 2

• Risk factors: structural lung disease (bronchiectasis), recent hospitalization with IV antibiotics within 90 days, prior P. aeruginosa isolation 1, 2
• Regimen: Antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) PLUS ciprofloxacin or levofloxacin PLUS aminoglycoside (gentamicin 5-7 mg/kg IV daily) 1, 2

Add MRSA coverage ONLY when risk factors present: 1, 2

• Risk factors: prior MRSA infection/colonization, recent hospitalization with IV antibiotics, post-influenza pneumonia, cavitary infiltrates on imaging 1, 2
• 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 1, 2

Treatment Duration

Standard duration: Minimum 5 days AND until afebrile for 48-72 hours with no more than one sign of clinical instability 1, 2

• Typical duration for uncomplicated CAP: 5-7 days 1, 2
• Clinical stability criteria: temperature ≤37.8°C, heart rate ≤100 bpm, respiratory rate ≤24 breaths/min, systolic BP ≥90 mmHg, oxygen saturation ≥90% on room air, ability to maintain oral intake, normal mental status 2

Extended duration (14-21 days) ONLY for specific pathogens: 1, 2

• Legionella pneumophila 1, 2
• Staphylococcus aureus 1, 2
• Gram-negative enteric bacilli 1, 2

Critical Pitfalls to Avoid

Never use macrolide monotherapy in areas where pneumococcal macrolide resistance exceeds 25%—this leads to treatment failure and breakthrough bacteremia with resistant strains 1, 2

Never use macrolide monotherapy in hospitalized patients—provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1, 2

Never delay antibiotic administration beyond 8 hours in hospitalized patients—increases 30-day mortality by 20-30% 1, 2

Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP—reserve for patients with comorbidities or contraindications to first-line agents due to resistance concerns and serious adverse events 1, 2

If patient used antibiotics within past 90 days, select an agent from a different antibiotic class to reduce resistance risk 1, 2

Obtain blood and sputum cultures before initiating antibiotics in ALL hospitalized patients to allow pathogen-directed therapy and de-escalation 2

Special Populations

Penicillin-allergic patients: 1, 2

• Outpatient: Doxycycline 100 mg twice daily or respiratory fluoroquinolone 1, 2
• Inpatient: Respiratory fluoroquinolone monotherapy 1, 2
• ICU: Aztreonam 2 g IV every 8 hours PLUS respiratory fluoroquinolone 2

Elderly or debilitated patients: 1

• Lower threshold for hospitalization using PSI or CURB-65 scores 1
• Classify as having comorbidities requiring combination therapy 1

Renal impairment: 3

• Azithromycin: No dose adjustment needed for GFR ≥10 mL/min; caution with severe impairment (GFR <10 mL/min) 3
• Ceftriaxone: No dose adjustment required 1
• Levofloxacin: Reduce to 750 mg loading dose, then 500 mg every 48 hours if CrCl 20-49 mL/min 2

Evidence Quality

The 2019 IDSA/ATS guidelines represent the highest quality evidence, with strong recommendations based on moderate-to-high quality evidence from multiple randomized controlled trials and meta-analyses 1, 2. European and British guidelines favor amoxicillin as first-line therapy, consistent with these recommendations 1.