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Rational design of a hospital-specific phage cocktail to treat Enterobacter cloacae complex infections
Dinesh Subedi1,2,3, Fernando Gordillo Altamirano4,5,6, Rylee Deehan4,7
1School of Biological Sciences, Monash University, Clayton, Victoria, Australia. dinesh.subedi@monash.edu.
Abstract:
The Alfred Hospital in Melbourne, Australia, has reported an ongoing outbreak of infections caused by multidrug-resistant Enterobacter cloacae complex (ECC). Phage therapy is a promising strategy to treat antimicrobial-resistant infections. Utilizing the hospital's isolate collection, built over the past decade, we established an initial 3-phage cocktail with 54% ECC coverage. We then iteratively improved this product by enhancing phage killing efficiency using phage adaptation and expanded host range through targeted phage isolation against low-coverage ECC isolates. This optimization yielded Entelli-02, containing five well-characterized virulent phages that target clinical ECC isolates via distinct bacterial cell surface receptors. Entelli-02 exhibits 88% host coverage against The Alfred Hospital's ECC isolate collection (n = 206), confirmed by plaque formation and reduced bacterial load in septicaemic mice by >99%. We produced this cocktail as a therapeutic-grade product, ready for clinical use. Entelli-02 represents a hospital-specific phage cocktail with frontline efficacy and on-demand availability.
Insights
A new phage therapy, Entelli-02, effectively targets multidrug-resistant Enterobacter cloacae complex (ECC) infections. This hospital-specific cocktail shows high efficacy and is ready for clinical use.
Area of Science:
- Microbiology
- Infectious Diseases
- Bacteriophage Therapy
Background:
- An ongoing outbreak of multidrug-resistant Enterobacter cloacae complex (ECC) infections at The Alfred Hospital necessitates novel treatment strategies.
- Antimicrobial resistance is a growing global health threat, driving the need for alternative therapies like phage therapy.
Purpose of the Study:
- To develop a targeted phage therapy cocktail effective against clinical isolates of multidrug-resistant ECC.
- To optimize phage efficacy and host range for a hospital-specific therapeutic product.
Main Methods:
- An initial 3-phage cocktail was created using the hospital's ECC isolate collection.
- Phage adaptation and targeted isolation were employed to enhance killing efficiency and broaden host coverage.
- The optimized cocktail, Entelli-02, was characterized for its efficacy against clinical ECC isolates and in a murine sepsis model.
Main Results:
- The optimized Entelli-02 cocktail contains five virulent phages with 88% host coverage against 206 clinical ECC isolates from The Alfred Hospital.
- Entelli-02 demonstrated significant reduction (>99%) in bacterial load in a murine model of sepsis.
- The phage cocktail was produced as a therapeutic-grade product, indicating readiness for clinical application.
Conclusions:
- Entelli-02 is a potent, hospital-specific phage cocktail demonstrating frontline efficacy against multidrug-resistant ECC infections.
- Phage therapy offers a viable and readily available solution for combating challenging bacterial infections in a clinical setting.
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