What is the best oral antibiotic for an otherwise healthy adult with uncomplicated community‑acquired pneumonia?

Best Oral Antibiotic for Community-Acquired Pneumonia in Healthy Adults

For an otherwise healthy adult with uncomplicated community-acquired pneumonia, amoxicillin 1 gram orally three times daily for 5–7 days is the preferred first-line oral antibiotic. 1, 2

Rationale for Amoxicillin as First-Line

• Amoxicillin provides superior pneumococcal coverage, retaining activity against 90–95% of Streptococcus pneumoniae isolates—the most common bacterial pathogen in CAP—including many penicillin-resistant strains. 1, 2
• Both European respiratory societies and the U.S. CDC endorse amoxicillin as the standard empirical outpatient therapy for previously healthy adults with CAP. 1
• High-dose amoxicillin (3–4 g per day) demonstrates the most effective in-vitro activity against the predominant bacterial pathogen compared with other oral agents. 1

Acceptable Alternative: Doxycycline

• Doxycycline 100 mg orally twice daily for 5–7 days serves as an acceptable alternative when amoxicillin cannot be used, providing broad-spectrum coverage including atypical organisms (Mycoplasma, Chlamydophila, Legionella). 1, 2
• This recommendation carries conditional strength with lower-quality evidence compared with amoxicillin's strong recommendation. 1, 2

When to Avoid Macrolide Monotherapy

• Macrolides (azithromycin or clarithromycin) should only be used when local pneumococcal macrolide resistance is documented to be <25%; in most U.S. regions, resistance ranges from 20–30%, making monotherapy unsafe as first-line. 1, 2
• Macrolide-resistant S. pneumoniae may also exhibit cross-resistance to doxycycline, further limiting empiric options in high-resistance areas. 2
• Despite in-vitro resistance, some studies show clinical efficacy of azithromycin even against macrolide-resistant strains, though this does not justify routine monotherapy in high-resistance settings. 3

Agents to Avoid

• Oral cephalosporins (cefuroxime, cefpodoxime) should not be used as first-line therapy because they demonstrate inferior in-vitro activity compared with high-dose amoxicillin, lack coverage of atypical pathogens, and are more costly without demonstrated clinical superiority. 1
• Fluoroquinolones (levofloxacin, moxifloxacin) should be reserved for patients with comorbidities or when other options cannot be used, due to FDA warnings about serious adverse events (tendinopathy, peripheral neuropathy, aortic dissection) and rising resistance concerns. 1, 2

Treatment Duration

• Treat for a minimum of 5 days and continue until the patient is afebrile for 48–72 hours with no more than one sign of clinical instability. 1, 2
• Standard duration for uncomplicated CAP is 5–7 days; extending beyond 7–8 days in responding patients increases antimicrobial resistance risk without improving outcomes. 1, 2
• Extended courses (14–21 days) are reserved only for infections caused by Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli. 1, 2

Monitoring and Follow-Up

• Mandatory clinical review at 48 hours (or sooner if indicated) to assess symptom resolution, oral intake, and treatment response. 1, 2
• Signs of treatment failure warranting hospital referral include no clinical improvement by day 2–3, development of respiratory distress or hypoxemia, inability to tolerate oral antibiotics, or new complications such as pleural effusion. 1, 2
• If amoxicillin monotherapy fails, add or substitute a macrolide to cover atypical pathogens; if combination therapy fails, switch to a respiratory fluoroquinolone. 1, 2
• Follow-up at 6 weeks for all patients; routine chest radiograph is not required unless symptoms persist, physical signs remain, or the patient is at high risk for underlying malignancy (e.g., smokers >50 years). 1, 2

Critical Pitfalls to Avoid

• Do not use standard-dose amoxicillin (500 mg three times daily) due to insufficient pneumococcal coverage against resistant strains; always use the high-dose regimen (1 g three times daily). 2
• Do not automatically escalate to fluoroquinolones or combination therapy in previously healthy adults without comorbidities, as this promotes resistance without proven benefit. 1, 2
• Do not delay antibiotic initiation while awaiting diagnostic testing; empiric therapy should begin immediately based on clinical and radiographic findings. 1, 2