Pre-clinical mechanistic assessment of two bacteriophage cocktails targeting multidrug-resistant Pseudomonas aeruginosa and Escherichia coli for the treatment of ventilator-associated pneumonia – MAPVAP

Nosocomial infections cause high morbidity and mortality rates among hospitalized patients. Ventilator-associated pneumonia (VAP), defined as pneumonia that occurs later than 48 hours following endotracheal intubation, is characterized by high incidence (9-27% of all mechanically ventilated patients) and accounts for ca. 50% of all cases of hospital-acquired pneumonia. Approximately half of all antibiotics used in the intensive care units (ICU) are employed for VAP treatment. VAP caused by multidrug-resistant (MDR) bacterial pathogens is associated with increased mortality. The most relevant MDR bacteria include Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, all of which, when resistant to carbapenem, are listed as critical on the priority pathogens list published by WHO. A well-known drawback of conventional antimicrobial therapy is the disturbance of the host´s microbiota. Exposure to broad-spectrum antibiotics damages the microbiota homeostasis, thereby opening niches for colonizing and subsequently infecting opportunistic MDR bacteria. Given the significance of VAP attributed to MDR bacteria as well as side effects associated with conventional therapy, implementation of strategies overcoming these issues to efficiently treat MDR respiratory infections on the ICU is of high medical value.
Bacteriophage (phage) therapy provides an attractive option to the increasing failure of antibiotics. Lytic phages are viruses that specifically target, infect, replicate and destroy bacteria. In experimental animal studies, phages are effective in treating fatal respiratory bacterial infections induced by either P. aeruginosa or E. coli. In these models, intranasal application of a single dose of phages saved 100% of lives. More recently, the importance of a synergistic action of phages with innate immune cells (immunophage synergy model) for phage therapy success was reported.
However, scientific and translational data addressing the emergence of bacteriophage resistance, the control of biofilm forming bacteria, detailed immuno-safety and immune-efficacy are largely missing. In MAPVAP, we will synergistically combine our extensive and complementary expertise and resources to strengthen phage therapy in France and Germany and significantly improve its transition towards human treatments. Using two established bacteriophage cocktails specific for P. aeruginosa or E. coli originating from German and French teams, respectively, we will join forces to (1) characterize bacteriophage-resistance development during in vivo pre-clinical treatment, (2) decipher the impact of these cocktails on the respiratory and intestinal microbiota as well as on microbiota-dependent immune responses, (3) evaluate the efficacy of the cocktails to penetrate biofilms produced in vitro and ex vivo on explanted human lung tissue, (4) investigate the direct interactions of phages with the immune system and the mechanistic basis for the synergy between innate immune cells and bacteriophages during therapies, and (5) characterize by mathematical modeling the efficacy of these cocktails in humans and propose optimized treatment regimens.
MAPVAP will therefore provide the necessary pre-clinical information on two established cocktails of phages targeting MDR P. aeruginosa and E. coli, regarding biology, efficacy and impact on microbiota and immunity to support a future Phase II clinical trial on severe MDR pneumonia in VAP patients.