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Adjunctive phage therapy improves antibiotic treatment of ventilator-associated-pneumonia with Pseudomonas aeruginosa
Chantal Weissfuss1, Jingjing Li2, Ulrike Behrendt2
1Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. chantal.weissfuss@charite.de.
Abstract:
Bacterial multidrug resistance poses an urgent challenge for the treatment of critically ill patients developing ventilator-associated pneumonia (VAP). Phage therapy, a potential alternative when conventional antibiotics fail, has been unsuccessful in first clinical trials when used alone. Whether combining antibiotics with phages may enhance effectiveness remains to be tested in experimental models. Here, we use a murine model of Pseudomonas-induced VAP to compare the efficacy of adjunctive phage cocktail for antibiotic therapy to either meropenem or phages alone. Combined treatment in murine VAP results in faster clinical improvement and prevents lung epithelial cell damage. Using human primary epithelial cells to dissect these synergistic effects, we find that adjunctive phage therapy reduces the minimum effective concentration of meropenem and prevents resistance development against both treatments. These findings suggest adjunctive phage therapy represents a promising treatment for MDR-induced VAP, enhancing the effectiveness of both antibiotics and phages while reducing adverse effects.
Insights
Combining bacteriophages with antibiotics offers a promising strategy to combat multidrug-resistant bacterial infections like ventilator-associated pneumonia (VAP), improving patient outcomes and preventing resistance.
Area of Science:
- Bacteriology and Infectious Diseases
- Therapeutic Strategies for Respiratory Infections
- Antimicrobial Resistance Research
Background:
- Bacterial multidrug resistance (MDR) presents a critical threat to treating severe infections, particularly ventilator-associated pneumonia (VAP).
- Phage therapy, using viruses to kill bacteria, shows potential but has had limited success as a standalone treatment in clinical trials.
- The synergistic potential of combining phage therapy with conventional antibiotics for VAP remains largely unexplored in experimental settings.
Purpose of the Study:
- To evaluate the efficacy of a phage cocktail combined with meropenem compared to monotherapy with either agent in a murine model of Pseudomonas-induced VAP.
- To investigate the synergistic mechanisms of adjunctive phage therapy on antibiotic effectiveness and resistance development using human primary epithelial cells.
Main Methods:
- A murine model was established to simulate Pseudomonas-induced VAP.
- Experimental groups included meropenem monotherapy, phage cocktail monotherapy, and combination therapy.
- Human primary epithelial cells were used to analyze the effects of combination therapy on antibiotic minimum effective concentration and resistance emergence.
Main Results:
- Combined antibiotic-phage therapy significantly accelerated clinical improvement in the VAP model compared to monotherapies.
- The combination treatment effectively prevented lung epithelial cell damage.
- Adjunctive phage therapy reduced the required meropenem concentration and inhibited the development of resistance to both phages and antibiotics.
Conclusions:
- Adjunctive phage therapy is a promising strategy for treating multidrug-resistant VAP, enhancing the efficacy of both antibiotics and phages.
- Combination therapy offers a potential approach to reduce antibiotic dosage and mitigate the emergence of antimicrobial resistance.
- This study highlights the potential of phage-antibiotic synergy to improve outcomes for critically ill patients with VAP.
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