Does phage therapy have a role in treating carbapenem-resistant Pseudomonas infections in critically ill patients?

Phage Therapy for Carbapenem-Resistant Pseudomonas Infections in Critically Ill Patients

Phage therapy should be considered as adjunctive treatment to antibiotics for carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections in critically ill patients when conventional antibiotic options are limited or failing, but it cannot be recommended as monotherapy or first-line treatment given the absence of guideline support and limited clinical evidence.

Current Guideline-Based Standard of Care

The 2022 ESCMID guidelines provide the framework for treating CRPA in critically ill patients, but notably do not mention phage therapy as a treatment option 1:

• For severe CRPA infections, ceftolozane-tazobactam is suggested as first-line therapy if active in vitro (conditional recommendation, very low evidence) 1
• When treating severe CRPA infections with polymyxins, aminoglycosides, or fosfomycin, combination therapy with two in vitro active drugs is suggested, though no specific combinations are recommended 1
• There is no recommendation for or against combination therapy with newer beta-lactam/beta-lactamase inhibitors (ceftazidime-avibactam, ceftolozane-tazobactam) or cefiderocol for CRPA 1

Where Phage Therapy May Fit: Salvage and Adjunctive Use

Evidence for Adjunctive Phage Therapy

The most compelling recent evidence comes from a 2025 murine VAP model showing that combining phages with meropenem resulted in faster clinical improvement and prevented lung epithelial damage compared to either treatment alone 2. This study demonstrated that:

• Adjunctive phage therapy reduced the minimum effective concentration of meropenem 2
• The combination prevented resistance development against both treatments 2
• These synergistic effects suggest phages enhance antibiotic effectiveness while reducing adverse effects 2

Clinical Case Evidence

Real-world clinical experience, though limited, shows promise:

• A 2024 burn patient with extensively drug-resistant P. aeruginosa VAP and bacteremia was successfully treated with personalized nebulized and IV phage therapy combined with imipenem-relebactam 3
• A 2022 case of DTR-P. aeruginosa cranial osteomyelitis showed sustained improvement only after phage was added to cefiderocol, with the patient remaining infection-free >12 months post-therapy 4
• A 2017 murine model demonstrated phage therapy effectiveness against chronic P. aeruginosa lung infections and biofilm-associated infections in cystic fibrosis-like environments 5

Practical Algorithm for Considering Phage Therapy

Step 1: Exhaust Guideline-Recommended Options First

• Attempt ceftolozane-tazobactam if susceptible 1
• Try combination therapy with two active agents (polymyxins, aminoglycosides, fosfomycin) 1
• Consider newer agents (imipenem-relebactam, cefiderocol, ceftazidime-avibactam) based on susceptibility 1

Step 2: Identify Candidates for Phage Therapy

Consider phage therapy when:

• All conventional antibiotics have failed or are showing limited response 3, 4
• The patient has extensively drug-resistant or difficult-to-treat P. aeruginosa with limited susceptibility options 3, 4
• Biofilm-associated infections (VAP, chronic lung infections, device-related infections) are present 5
• The infection is life-threatening and no other options remain 3

Step 3: Use Phage Therapy as Adjunctive Treatment

• Never use phage monotherapy—always combine with the most active available antibiotic 2, 3, 4
• Consider both nebulized (for respiratory infections) and IV routes depending on infection site 3
• Personalized phage selection based on the specific bacterial isolate is critical 3

Critical Caveats and Pitfalls

Major Limitations

• No guideline support: Neither ESCMID 2022 1 nor other major guidelines 1 mention phage therapy, reflecting insufficient evidence for routine recommendation
• Limited human clinical trial data: Most evidence comes from case reports and animal models 2, 3, 4, 5
• Regulatory barriers: Phage therapy is not FDA-approved and typically requires compassionate use authorization 3, 4
• Availability issues: Personalized phage therapy requires specialized centers with phage libraries and expertise 3

Practical Considerations

• Phage resistance can develop, though combination with antibiotics may mitigate this risk 2
• Phage selection must be individualized to the patient's specific bacterial isolate 3
• No standardized dosing regimens exist; protocols vary by case 3, 4
• Immunostimulation (interferon-γ) may be needed in severely immunocompromised patients 3

When NOT to Consider Phage Therapy

• When conventional guideline-recommended antibiotics remain effective 1
• As first-line or monotherapy 2, 3, 4
• When adequate source control has not been achieved 1
• In non-severe infections where older antibiotics remain active 1

Bottom Line for Clinical Practice

Phage therapy represents a promising experimental adjunct for salvage treatment of carbapenem-resistant P. aeruginosa in critically ill patients when conventional options are exhausted, based on emerging 2025 preclinical data 2 and successful case reports 3, 4. However, it should only be pursued through compassionate use protocols at specialized centers, always in combination with antibiotics, and never as a substitute for guideline-recommended first-line therapies 1. The absence of phage therapy from major guidelines 1 reflects the current insufficient evidence base for routine clinical recommendation, despite mechanistically sound rationale and encouraging preliminary results 2, 5.