What is the treatment regimen for difficult-to-treat Pseudomonas (Pseudomonas aeruginosa) infections?

Treatment of Difficult-to-Treat Pseudomonas aeruginosa Infections

For invasive infections caused by difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA), ceftolozane/tazobactam and ceftazidime/avibactam are the first-line treatment options when the organism is susceptible to these agents. 1

Understanding DTR-PA Definition

Difficult-to-treat resistance in P. aeruginosa is defined as non-susceptibility to ALL of the following first-line agents: ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, imipenem/cilastatin, meropenem, levofloxacin, and ciprofloxacin. 1 This definition is more clinically relevant than traditional MDR/XDR classifications because it identifies strains that have lost susceptibility to high-efficacy, low-toxicity agents. 1

First-Line Treatment Algorithm

Primary Options (When Susceptible)

• Ceftolozane/tazobactam: Preferred for pneumonia, including hospital-acquired and ventilator-associated pneumonia (dose: 3 g IV every 8 hours for pneumonia; 1.5 g IV every 8 hours for other infections). 1, 2

• Ceftazidime/avibactam: Equally effective for non-pulmonary infections (dose: 2.5 g IV every 8 hours). 1, 2

Rationale: These novel β-lactam/β-lactamase inhibitor combinations demonstrate >90% activity against MDR/XDR P. aeruginosa collections in vitro and have favorable safety profiles consistent with the β-lactam class, avoiding the nephrotoxicity and narrow therapeutic window of polymyxins. 1

Alternative Options

• Imipenem/cilastatin/relebactam (1.25 g IV every 6 hours): May retain activity when ceftolozane/tazobactam and ceftazidime/avibactam resistance is present, particularly when metallo-β-lactamases (MBLs) are absent. 1, 2

• Cefiderocol: Preferred agent when MBLs are present; alternative when other novel agents show resistance. 1, 2

• Colistin-based therapy: Last-resort option (loading dose: 5 mg colistin base activity/kg IV, then 2.5 mg CBA × [1.5 × CrCl + 30] IV every 12 hours). 1

Combination Therapy Considerations

Combination therapy should NOT be routine practice but may be considered on a case-by-case basis, particularly after infectious diseases consultation. 1

When to Consider Combination Therapy

• Severe infections with limited susceptibility options: When DTR-PA is susceptible only to polymyxins, aminoglycosides, tigecycline, or fosfomycin, treat with two in vitro active drugs. 1

• Fosfomycin as companion agent: Combination regimens including fosfomycin show promise, particularly with meropenem demonstrating synergy in preclinical models. 1, 3

• MBL-producing strains: Consider aztreonam plus ceftazidime/avibactam combination when MBLs are present and cefiderocol is unavailable or unsuitable. 1, 2

Important caveat: Despite in vitro synergy and animal model data, clinical evidence supporting combination therapy over monotherapy for DTR-PA infections remains limited. 2, 4 The primary proven benefit of combination therapy is improving the likelihood of adequate empiric coverage in critically ill patients. 4

Site-Specific Considerations

Pneumonia (Hospital-Acquired/Ventilator-Associated)

• Duration: 10-14 days. 1
• Preferred agent: Ceftolozane/tazobactam 3 g IV every 8 hours over ceftazidime/avibactam. 2
• Adjunctive inhaled therapy: Consider adjunctive colistin inhalation (1.25-15 MIU/day in 2-3 divided doses) when using systemic colistin. 1

Bloodstream Infections

• Duration: 10-14 days. 1
• Either ceftolozane/tazobactam or ceftazidime/avibactam acceptable when susceptible. 2

Complicated Urinary Tract Infections

• Duration: 5-10 days. 1
• Aminoglycoside monotherapy acceptable ONLY for urinary tract infections when susceptible. 1

Complicated Intra-Abdominal Infections

• Duration: 5-10 days. 1

Critical Pitfalls to Avoid

1. Do not use older agents empirically: Piperacillin/tazobactam, ceftazidime, cefepime, and carbapenems are by definition ineffective against DTR-PA. 1

2. Avoid carbapenem-based combinations for DTR-PA: Unless meropenem MIC is ≤8 mg/L and extended infusion (>3 hours) is used, carbapenems should not be part of combination therapy. 1

3. Colistin dosing errors: Use proper loading dose (5 mg CBA/kg) followed by maintenance dosing adjusted for renal function to avoid subtherapeutic levels. 1

4. Resistance emergence with monotherapy: Ceftazidime/avibactam monotherapy showed increased recurrence rates in some studies, suggesting potential for resistance development during therapy. 1

5. Cefiderocol for CRAB: Do not use cefiderocol for carbapenem-resistant Acinetobacter baumannii infections (conditional recommendation against). 1

Tailoring Therapy After Susceptibility Results

Once culture and susceptibility results are available, therapy MUST be tailored. 1 In the absence of compelling indications for combination therapy, monotherapy with a highly active antipseudomonal β-lactam is preferred. 1 The newer β-lactam/β-lactamase inhibitor combinations have emerged as the first reliable alternative to polymyxin-based therapy for DTR-PA. 1