title: PcrV antibody-antibiotic combination improves survival in Pseudomonas aeruginosa-infected mice.
abstract: The type III secretion system (TTSS) of Pseudomonas aeruginosa, associated with acute infection, facilitates the direct injection of cytotoxins into the host cell cytoplasm. Mab166, a murine monoclonal antibody against PcrV, a protein located at the tip of the injectisome, has demonstrated efficacy against P. aeruginosa infection, resulting in reduced lung injury and increased survival in murine models of infection. We hypothesised that the administration of Mab166 in combination with an antibiotic would further improve the survival of P. aeruginosa-infected mice. A murine model of P. aeruginosa acute infection, three clinically relevant antibiotics (ciprofloxacin, tobramycin and ceftazidime) and the Mab166 antibody were used for this study. Consistently, compared to other treatment groups (antibiotic or antibody administered in isolation), the combination of Mab166 and antibiotic significantly improved the survival of mice infected with three times the lethal dose (LD(90)) of the highly cytotoxic ExoU-secreting strain, PA103. This synergistic effect was primarily due to enhanced bactericidal effect and protection against lung injury, which prevented bacterial dissemination to other organs. Hence, the combination of Mab166 with antibiotic administration provides a new, more effective strategy against P. aeruginosa airway infection, especially when large numbers of highly virulent strains are present.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. song.yuanlin@zs-hospital.sh.cn
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.forename: M
authors.initials: M
authors.lastname: Baer
authors.forename: R
authors.initials: R
authors.lastname: Srinivasan
authors.forename: J
authors.initials: J
authors.lastname: Lima
authors.forename: G
authors.initials: G
authors.lastname: Yarranton
authors.forename: C
authors.initials: C
authors.lastname: Bebbington
authors.forename: S V
authors.initials: SV
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D000907:Antibodies, Bacterial / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000942:Antigens, Bacterial / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D052899:Pore Forming Cytotoxic Proteins; C118546:antigen V, Pseudomonas