What are the recommended antibiotics for antipseudomonal (Pseudomonas aeruginosa) coverage?

Antipseudomonal Antibiotic Coverage

First-Line Agents for Susceptible Pseudomonas aeruginosa

For empiric or definitive treatment of Pseudomonas aeruginosa infections, use piperacillin-tazobactam 3.375-4.5g IV every 6 hours as the preferred first-line agent, with ceftazidime, cefepime, or meropenem as equally effective alternatives. 1, 2

Primary Antipseudomonal β-Lactams

• Piperacillin-tazobactam: 3.375-4.5g IV every 6 hours (increase to 4.5g every 6 hours for nosocomial pneumonia) 2, 3
• Cefepime: 2g IV every 8-12 hours 1, 2
• Ceftazidime: 2g IV every 8 hours 1, 2
• Meropenem: 1g IV every 8 hours (can escalate to 2g every 8 hours for severe infections) 2, 4
• Imipenem/cilastatin: 1g IV every 8 hours (maximum 4g daily; avoid due to higher allergic reaction rates) 2, 4
• Aztreonam: 2g IV every 8 hours (reserved for severe β-lactam allergies) 2, 4

Fluoroquinolone Options

• Ciprofloxacin: 400mg IV every 8 hours or 750mg PO twice daily (only fluoroquinolone with reliable antipseudomonal activity) 2, 4, 5
• Levofloxacin: 750mg IV/PO daily (less potent than ciprofloxacin against Pseudomonas) 2, 5

Aminoglycosides

• Tobramycin: 5-7 mg/kg IV daily (preferred over gentamicin due to lower nephrotoxicity) 2, 4
• Amikacin: 15-20 mg/kg IV daily 2, 4
• All aminoglycosides require therapeutic drug monitoring for peak levels (tobramycin target: 25-35 mg/mL) and renal/auditory function monitoring 2, 4

When to Use Combination Therapy

Add a second antipseudomonal agent (aminoglycoside or fluoroquinolone) to the β-lactam backbone in these specific situations: 2, 4

• Critically ill patients or septic shock 2
• Ventilator-associated or nosocomial pneumonia (FDA-mandated for P. aeruginosa pneumonia) 2, 3, 5
• ICU admission 2
• Prior IV antibiotic use within 90 days 2, 4
• Structural lung disease (bronchiectasis, cystic fibrosis) 2, 4
• Local resistance rates exceeding 10-20% 2
• Documented Pseudomonas on Gram stain before susceptibility results 4

Recommended Combinations

• Antipseudomonal β-lactam + tobramycin (preferred combination) 2, 4
• Antipseudomonal β-lactam + ciprofloxacin 2, 4
• Never use aminoglycoside monotherapy for bacteremia or empiric coverage due to rapid resistance emergence 2

Difficult-to-Treat Resistant Pseudomonas (DTR-PA)

For multidrug-resistant strains, use ceftolozane/tazobactam 1.5-3g IV every 8 hours or ceftazidime/avibactam 2.5g IV every 8 hours as first-line options. 2

Alternative Agents for Resistant Strains

• Imipenem/cilastatin/relebactam: 1.25g IV every 6 hours 2
• Cefiderocol: For metallo-β-lactamase producers 4
• Colistin: 5mg CBA/kg IV loading dose, then 2.5mg CBA maintenance (reserved for extensively resistant strains) 2

Risk Factors for Multidrug Resistance

• Prior IV antibiotic use within 90 days 2
• Prolonged hospitalization 2
• Acute respiratory distress syndrome 2
• Septic shock 2
• Acute renal replacement therapy 2

Treatment Duration

• Standard infections: 7-10 days 2
• Pneumonia or bloodstream infections: 10-14 days 2, 3
• Bronchiectasis exacerbations: Exactly 14 days (never extend oral ciprofloxacin monotherapy beyond this) 4

Critical Pitfalls to Avoid

These antibiotics have NO activity against Pseudomonas despite being broad-spectrum: 4

• Ceftriaxone 2, 4
• Cefazolin 4
• Ampicillin/sulbactam 4
• Ertapenem 2, 4
• Vancomycin (Gram-positive only) 2

Common Errors

• Underdosing: Use maximum recommended doses for severe infections to prevent treatment failure and resistance 4
• Carbapenem overuse: Carbapenems show higher rates of subsequent resistant Pseudomonas (17.5%) versus piperacillin-tazobactam (8.4%) or ceftazidime (12.4%) 6
• Fluoroquinolone monotherapy: Rapid resistance emergence, particularly problematic compared to combination therapy 2
• Ceftazidime monotherapy: No longer reliable for empiric use due to poor Gram-positive coverage and increasing resistance 2

De-escalation Strategy

Once susceptibility results confirm susceptibility and the patient is clinically improving, narrow to monotherapy with the most active single agent. 2, 4

• Discontinue the second agent (aminoglycoside or fluoroquinolone) after 3-5 days if cultures show susceptible organism 2
• Switch from IV to oral ciprofloxacin by day 3 if clinically stable (bioavailability matches IV levels) 2
• Always base final antibiotic selection on susceptibility testing, especially in cystic fibrosis patients with higher resistance rates 4

Comparative Effectiveness

Recent meta-analysis of 76 RCTs with 1,681 patients found no mortality difference between antipseudomonal β-lactams, but carbapenems showed higher clinical failure rates for pneumonia (RR 2.55) and higher microbiological failure rates (RR 1.24) versus piperacillin-tazobactam. 7 A multinational study of 767 patients with P. aeruginosa bacteremia demonstrated equivalent 30-day mortality between ceftazidime (17.4%), carbapenems (20%), and piperacillin-tazobactam (16%), but carbapenems resulted in significantly more resistant isolates. 6