What are the recommended antibiotics for community-acquired pneumonia (CAP)?

Antibiotic Treatment for Community-Acquired Pneumonia

For outpatient CAP without comorbidities, amoxicillin 1 gram three times daily is the preferred first-line therapy, while hospitalized patients should receive combination therapy with a β-lactam (ceftriaxone or cefotaxime) plus a macrolide (azithromycin) for a minimum of 3 days. 1, 2

Outpatient Treatment Algorithm

Healthy Adults Without Comorbidities

First-line options (in order of preference):

• Amoxicillin 1 gram three times daily (strong recommendation, moderate quality evidence) 1
• Doxycycline 100 mg twice daily (conditional recommendation, low quality evidence) 1
• Macrolide monotherapy (azithromycin 500 mg day 1, then 250 mg daily OR clarithromycin 500 mg twice daily) ONLY if local pneumococcal macrolide resistance is <25% (conditional recommendation, moderate quality evidence) 1, 3

The 2019 ATS/IDSA guidelines prioritize amoxicillin as the strongest recommendation based on its effectiveness against Streptococcus pneumoniae, the most common cause of lethal CAP. 1 Macrolide monotherapy should be avoided in most areas due to rising resistance rates exceeding 25% in many regions. 1, 3

Adults With Comorbidities

Comorbidities include: chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancy; or asplenia. 1

Combination therapy (preferred):

• Amoxicillin/clavulanate (500/125 mg three times daily OR 875/125 mg twice daily OR 2000/125 mg twice daily) OR cephalosporin (cefpodoxime 200 mg twice daily OR cefuroxime 500 mg twice daily) PLUS
• Macrolide (azithromycin 500 mg day 1, then 250 mg daily OR clarithromycin 500 mg twice daily) (strong recommendation, moderate quality evidence) 1, 3
• OR doxycycline 100 mg twice daily instead of macrolide (conditional recommendation, low quality evidence) 1

Monotherapy alternative:

• Respiratory fluoroquinolone (levofloxacin 750 mg daily OR moxifloxacin 400 mg daily OR gemifloxacin 320 mg daily) (strong recommendation, moderate quality evidence) 1, 3, 4

Fluoroquinolones demonstrate >90% clinical success rates against S. pneumoniae including multidrug-resistant strains, with excellent lung penetration. 5 However, they carry higher rates of documented adverse events compared to macrolides (adjusted OR 1.23), though with lower retreatment rates (adjusted OR 0.9). 6

Inpatient Non-ICU Treatment

Preferred regimens:

• β-lactam plus macrolide combination: Ceftriaxone (1-2 grams daily) OR cefotaxime OR ampicillin-sulbactam PLUS azithromycin (500 mg daily) (strong recommendation, high quality evidence) 1, 3, 2
• Respiratory fluoroquinolone monotherapy: Levofloxacin (750 mg daily) OR moxifloxacin (400 mg daily) (strong recommendation, high quality evidence) 1, 3, 4
• β-lactam plus doxycycline (conditional recommendation, low quality evidence) 1, 3

The combination of ceftriaxone plus azithromycin is recommended as first-line for hospitalized patients based on coverage of both typical and atypical pathogens. 2 Recent evidence shows no mortality benefit from adding macrolides (OR 1.12,95% CI 0.93-1.34), but guidelines continue to recommend combination therapy based on pathogen coverage considerations. 7

Hospitalized patients receiving IV macrolide/β-lactam combinations have significantly longer hospital stays (4.71 vs 4.38 days) and higher costs ($3,535 more per stay) compared to IV fluoroquinolone monotherapy. 6

ICU Treatment for Severe CAP

Recommended regimens:

• β-lactam (ceftriaxone OR cefotaxime OR ampicillin-sulbactam OR piperacillin-tazobactam) PLUS either azithromycin OR respiratory fluoroquinolone (strong recommendation) 1, 3

For penicillin-allergic ICU patients: Respiratory fluoroquinolone plus aztreonam 3

The 2007 IDSA/ATS severe CAP criteria should guide ICU admission decisions, as patients transferred to ICU after initial ward admission experience higher mortality than those directly admitted. 1

Special Pathogen Considerations

Pseudomonas aeruginosa Risk Factors

When risk factors present (structural lung disease, recent hospitalization with parenteral antibiotics, prior P. aeruginosa isolation, recent broad-spectrum antibiotic use):

• Antipseudomonal β-lactam (piperacillin-tazobactam) PLUS ciprofloxacin/levofloxacin OR aminoglycoside plus azithromycin 1, 3

MRSA Risk Factors

When risk factors present (prior MRSA infection/colonization, recent hospitalization with parenteral antibiotics, cavitary infiltrates, concurrent influenza):

• Add vancomycin OR linezolid to the regimen 1, 3

Multidrug-Resistant S. pneumoniae (MDRSP)

MDRSP isolates are resistant to ≥2 of: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, macrolides, tetracyclines, trimethoprim/sulfamethoxazole. 1, 4

• β-lactams (amoxicillin, cefotaxime, ceftriaxone) remain drugs of choice, though pneumonia from resistant strains (MIC >2 mcg/mL) may not respond as readily 1
• Respiratory fluoroquinolones maintain activity against penicillin-resistant strains with 95% clinical and bacteriologic success rates 4, 5
• Vancomycin, linezolid, quinupristin/dalfopristin have predictable activity against all strains 1

Treatment Duration and Transition

Duration:

• Standard duration: 5-7 days for uncomplicated CAP once clinical stability achieved 1, 3
• Minimum 3 days for hospitalized patients 2
• Longer courses may be required for severe infections or specific pathogens 3

IV to oral transition criteria:

• Clinical improvement evident 1, 8
• Hemodynamically stable 1, 3, 8
• Able to ingest medications 1, 3
• Normal GI function 3
• Typically by day 2-3 of hospitalization 3

Most patients show clinical response within 3-5 days; chest radiograph changes lag behind clinical response and repeat imaging is not indicated for responding patients. 1

Critical Pitfalls to Avoid

Avoid macrolide monotherapy in areas with ≥25% pneumococcal macrolide resistance to prevent treatment failure. 1, 3 This threshold is exceeded in many US regions. 1

Administer first antibiotic dose in the emergency department for hospitalized patients, as delayed administration increases mortality risk. 3

Do not automatically escalate to broad-spectrum antibiotics based solely on comorbidities or immunosuppression without documented risk factors for resistant organisms. 3

Obtain blood and sputum cultures before initiating antibiotics in all hospitalized patients to allow targeted de-escalation when results become available. 1, 3

Do not extend therapy beyond 7 days in responding patients without specific indications, as this increases antimicrobial resistance risk. 3

Recognize that β-lactams other than ceftriaxone, cefotaxime, ampicillin-sulbactam, and piperacillin-tazobactam are not recommended for hospitalized CAP patients. 1

Consider recent antibiotic exposure when selecting therapy, as this increases risk of resistant organisms and may necessitate alternative antibiotic classes. 3