What is the best antibiotic for pneumonia?

Best Antibiotic for Pneumonia

For previously healthy outpatients with community-acquired pneumonia, amoxicillin 1 g orally three times daily for 5-7 days is the preferred first-line therapy, providing superior coverage against Streptococcus pneumoniae including drug-resistant strains compared to other oral agents. 1

Outpatient Treatment Algorithm

Previously Healthy Adults Without Comorbidities

• Amoxicillin 1 g orally three times daily is the preferred first-line agent, achieving activity against 90-95% of S. pneumoniae strains including penicillin-resistant isolates when dosed at 3-4 g/day 2, 1
• Doxycycline 100 mg orally twice daily serves as an acceptable alternative, though this carries lower quality evidence 1
• Macrolides (azithromycin 500 mg day 1, then 250 mg daily; or clarithromycin 500 mg twice daily) should only be used in areas where pneumococcal macrolide resistance is documented <25%, as resistance rates of 20-30% are common in many U.S. regions 2, 1

Adults With Comorbidities (COPD, Diabetes, Heart/Liver/Renal Disease)

• Combination therapy is required: amoxicillin-clavulanate 875/125 mg orally twice daily PLUS azithromycin (500 mg day 1, then 250 mg daily for days 2-5) 1
• Alternative combination: oral cephalosporin (cefpodoxime or cefuroxime) plus macrolide or doxycycline 2, 1
• Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg daily, moxifloxacin 400 mg daily, or gemifloxacin 320 mg daily) is equally effective but should be reserved for penicillin-allergic patients or when combination therapy is contraindicated due to FDA warnings about serious adverse events 1, 3

Hospitalized Non-ICU Patients

Two equally effective regimens exist with strong evidence:

Preferred Regimen: β-lactam Plus Macrolide

• Ceftriaxone 1-2 g IV daily PLUS azithromycin 500 mg daily provides coverage for both typical bacterial pathogens (S. pneumoniae, H. influenzae) 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 1
• This combination reduces mortality compared to β-lactam monotherapy or fluoroquinolone-based regimens in hospitalized patients 1, 4

Alternative: Respiratory Fluoroquinolone Monotherapy

• Levofloxacin 750 mg IV daily OR moxifloxacin 400 mg IV daily 1
• Reserve for penicillin-allergic patients, as systematic reviews show fewer clinical failures with this approach compared to β-lactam/macrolide combinations 1

Severe CAP Requiring ICU Admission

Combination therapy is mandatory for all ICU patients—monotherapy is inadequate and associated with higher mortality:

• Ceftriaxone 2 g IV daily PLUS azithromycin 500 mg IV daily 1
• Alternative: ceftriaxone 2 g IV daily PLUS respiratory fluoroquinolone (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 1
• Alternative β-lactams: cefotaxime 1-2 g IV every 8 hours OR ampicillin-sulbactam 3 g IV every 6 hours 1

Special Pathogen Coverage (Only When Risk Factors Present)

Pseudomonas aeruginosa Coverage

Add antipseudomonal therapy ONLY if:

• Structural lung disease (bronchiectasis, cystic fibrosis) 1
• Recent hospitalization with IV antibiotics within 90 days 1
• Prior respiratory isolation of P. aeruginosa 1

Regimen: Antipseudomonal β-lactam (piperacillin-tazobactam 4.5 g IV every 6 hours OR cefepime 2 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) 1

MRSA Coverage

Add MRSA therapy ONLY if:

• Prior MRSA infection or colonization 1
• Recent hospitalization with IV antibiotics 1
• Post-influenza pneumonia 1
• Cavitary infiltrates on imaging 1

Regimen: Vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) OR linezolid 600 mg IV every 12 hours, added to base regimen 1

Duration of Therapy

• Minimum 5 days AND until afebrile for 48-72 hours with no more than one sign of clinical instability 1
• Typical duration for uncomplicated CAP: 5-7 days 1
• Extended duration (14-21 days) required for: Legionella pneumophila, Staphylococcus aureus, or Gram-negative enteric bacilli 1

Transition to Oral Therapy

Switch from IV to oral when:

• Hemodynamically stable (systolic BP ≥90 mmHg, heart rate ≤100 bpm) 1
• Clinically improving (afebrile 48-72 hours, respiratory rate ≤24 breaths/min) 1
• Able to take oral medications 1
• Oxygen saturation ≥90% on room air 1
• Normal gastrointestinal function 1
• Typically achievable by hospital day 2-3 1

Critical Pitfalls to Avoid

• Never delay antibiotic administration beyond 8 hours in hospitalized patients—each hour of delay increases 30-day mortality by 20-30% 1
• Never use macrolide monotherapy in hospitalized patients—provides inadequate coverage for typical bacterial pathogens like S. pneumoniae 1
• Never use macrolides in areas where pneumococcal resistance exceeds 25%—leads to treatment failure with breakthrough bacteremia 2, 1
• Obtain blood and sputum cultures before initiating antibiotics in ALL hospitalized patients to enable pathogen-directed therapy and de-escalation 1
• Avoid indiscriminate fluoroquinolone use in uncomplicated outpatient CAP due to FDA warnings about tendon rupture, peripheral neuropathy, and aortic dissection in elderly patients 1
• Do not automatically add broad-spectrum antipseudomonal or MRSA coverage—restrict to patients with documented risk factors to prevent resistance and unnecessary adverse effects 1
• Avoid oral cephalosporins (cefuroxime, cefpodoxime) as first-line outpatient therapy—they show inferior in-vitro activity compared to high-dose amoxicillin and lack atypical coverage 2, 1