What is the treatment for Extensively Drug-Resistant (XDR) Pseudomonas (P.) Aeruginosa infections?

Treatment of Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa

For severe XDR P. aeruginosa infections, use ceftolozane-tazobactam or ceftazidime-avibactam as first-line monotherapy if the isolate is susceptible in vitro; if these newer agents are inactive or unavailable, use combination therapy with two active agents, typically a polymyxin (colistin or polymyxin B) plus another active drug such as an aminoglycoside or fosfomycin. 1, 2

First-Line Treatment: Novel Beta-Lactam Agents

The 2022 ESCMID guidelines and Italian consensus strongly recommend novel beta-lactam/beta-lactamase inhibitor combinations as first-line therapy for XDR P. aeruginosa 1, 2:

• Ceftolozane-tazobactam: 3g IV every 8 hours (infused over 3 hours) for pneumonia; 1.5g IV every 8 hours for other infections 1, 2
• Ceftazidime-avibactam: 2.5g IV every 8 hours (infused over 3 hours) 1, 2
• Imipenem-cilastatin-relebactam: 1.25g IV every 6 hours 1, 2
• Cefiderocol: May be considered as an alternative, though evidence is limited 1

These agents demonstrate superior activity against XDR strains compared to traditional antibiotics and have lower toxicity profiles than polymyxins 1, 3. Ceftolozane-tazobactam showed clinical cure in 66.7% of XDR P. aeruginosa cases in observational data 1.

Second-Line Treatment: Polymyxin-Based Therapy

When newer beta-lactams are inactive, unavailable, or for resource-limited settings, polymyxin-based regimens remain viable options 1, 4:

Colistin Dosing

• Loading dose: 9 million units (MU) of colistin methanesulfonate (CMS) IV 5
• Maintenance: 4.5 MU CMS IV every 12 hours, adjusted for renal function 5
• Alternative calculation: 2.5 mg colistin base activity (CBA) per [1.5 × CrCl + 30] IV every 12 hours 2

Polymyxin B Dosing

• 15,000-25,000 units/kg/day IV in divided doses (maximum 25,000 units/kg/day) 6
• Polymyxin B demonstrates lower nephrotoxicity than colistin (adjusted HR 2.27 for colistin vs. polymyxin B) 1

Combination Therapy Strategy

For severe XDR P. aeruginosa infections treated with polymyxins, aminoglycosides, or fosfomycin, combination therapy with two active agents is recommended over monotherapy. 1, 2

The evidence supporting combination therapy includes:

• A retrospective study of 114 patients with XDR P. aeruginosa pneumonia showed colistin combined with another active antibiotic reduced mortality compared to colistin alone or with inactive antibiotics (adjusted OR 6.63,95% CI 1.99-22.05) 1
• In a small subgroup with XDR P. aeruginosa, mortality was 14/15 with monotherapy versus 0/3 with combinations 1
• Fosfomycin-containing combinations are specifically highlighted as reasonable companion agents 1

However, combination therapy should not be routine for newer beta-lactams (ceftolozane-tazobactam, ceftazidime-avibactam) when used as monotherapy, as no benefit was demonstrated (66.7% cure with monotherapy vs. 60% with combinations) 1.

Treatment Duration

• Complicated UTI/intra-abdominal infections: 5-10 days 2
• Hospital-acquired pneumonia/VAP/bloodstream infections: 10-14 days 2
• Individualize based on source control, clinical response, and underlying comorbidities 2

Infection-Specific Considerations

Pneumonia/VAP

• Ceftolozane-tazobactam 3g IV every 8 hours is preferred 2
• Consider adjunctive inhaled colistin (75-150 mg every 12 hours) in addition to IV therapy for pneumonia 1, 2

Bloodstream Infections

• Novel beta-lactams (ceftolozane-tazobactam or ceftazidime-avibactam) are preferred over polymyxins 2
• If polymyxin-based therapy is necessary, use combination therapy 1

Non-Severe or Low-Risk Infections

• Monotherapy with any active agent (including older antibiotics like aminoglycosides for UTI) is acceptable based on susceptibility testing and infection source 1

Critical Monitoring and Safety Considerations

Renal function must be monitored closely during polymyxin therapy due to high nephrotoxicity risk (RIFLE-defined nephrotoxicity occurred with adjusted HR 2.27 for colistin) 1, 5. Dose adjustment is mandatory based on creatinine clearance 5, 6.

Prolonged infusion of beta-lactams (3-4 hours) is recommended for pathogens with high MICs to optimize pharmacokinetic/pharmacodynamic targets 1, 2.

Common Pitfalls to Avoid

• Do not use aminoglycoside monotherapy except for uncomplicated urinary tract infections 2
• Do not use tigecycline monotherapy for P. aeruginosa pneumonia (lacks adequate lung penetration and activity) 1
• Do not assume carbapenem activity in XDR strains; verify susceptibility testing 1
• Avoid empiric use of newer agents (ceftolozane-tazobactam, ceftazidime-avibactam) without considering local resistance patterns and antimicrobial stewardship, as resistance can develop (10.4% and 3.8% respectively in some cohorts) 1

Infectious Disease Consultation

Infectious disease consultation is highly recommended for all XDR P. aeruginosa infections to optimize antibiotic selection, dosing, duration, and monitoring 1, 2.

Emerging Resistance Considerations

XDR P. aeruginosa often exhibits "difficult-to-treat resistance" (DTR), defined as non-susceptibility to all first-line agents including piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, carbapenems, and fluoroquinolones 1, 5. Colistin susceptibility remains highly preserved in most XDR isolates (100% in some institutional series), making it a critical last-line option when newer agents fail 4. However, resistance to ceftolozane-tazobactam and ceftazidime-avibactam is increasingly reported in XDR strains, necessitating careful susceptibility testing before use 4.