PcrV antibody prophylaxis in combination with antibiotic therapy reduces lung injury and improves survival in Pseudomonas aeruginosa infected mice

The type III secretion system (TTSS) of Pseudomonas aeruginosa facilitates direct injection of cytotoxins into host cell cytoplasm. PcrV, located at the tip of the needle-like injectosome, is an essential component of this virulence system. Mab166, a murine monoclonal antibody against PcrV has demonstrated efficacy against P. aeruginosa infection resulting in increased survival and reduced lung injury in a variety of mouse models of infection. We hypothesized that administration of Mab166 prophylactically in combination with conventional antibiotics (administered subsequent to infection) could further improve survival of P. aeruginosa infected mice. Three antibiotics (ciprofloxacin, tobramycin and ceftazidime), commonly prescribed for P. aeruginosa infections were used for this study. Consistently, compared to other treatment groups, the combination of Mab166 administered with an antibiotic significantly improved survival of mice infected with three times the lethal dose (LD90) of the highly cytotoxic ExoU-secreting strain, PA103. The underlying mechanism of the anti-PcrV-tobramycin combination appears to involve a synergistic protection against lung injury and bactericidal effect in the airways, ultimately preventing bacterial dissemination to other organs. We conclude that a combination of prophylactic Mab166 with subsequent antibiotic administration provides a new strategy against P. aeruginosa airway infection, even heavy burden of highly virulent strains are present and may represent a viable prophylactic approach for patients at high risk for P. aeruginosa infection.