title: Antipseudomonal Bacteriophage Reduces Infective Burden and Inflammatory Response in Murine Lung.
abstract: As antibiotic resistance increases, there is a need for new therapies to treat infection, particularly in cystic fibrosis (CF), where Pseudomonas aeruginosa is a ubiquitous pathogen associated with increased morbidity and mortality. Bacteriophages are an attractive alternative treatment, as they are specific to the target bacteria and have no documented side effects. The efficacy of phage cocktails was established in vitro. Two P. aeruginosa strains were taken forward into an acute murine infection model with bacteriophage administered either prophylactically, simultaneously, or postinfection. The infective burden and inflammation in bronchoalveolar lavage fluid (BALF) were assessed at various times. With low infective doses, both control mice and those undergoing simultaneous phage treatment cleared P. aeruginosa infection at 48 h, but there were fewer neutrophils in BALF of phage-treated mice (median, 73.2 × 10(4)/ml [range, 35.2 to 102.1 × 10(4)/ml] versus 174 × 10(4)/ml [112.1 to 266.8 × 10(4)/ml], P < 0.01 for the clinical strain; median, 122.1 × 10(4)/ml [105.4 to 187.4 × 10(4)/ml] versus 206 × 10(4)/ml [160.1 to 331.6 × 10(4)/ml], P < 0.01 for PAO1). With higher infective doses of PAO1, all phage-treated mice cleared P. aeruginosa infection at 24 h, whereas infection persisted in all control mice (median, 1,305 CFU/ml [range, 190 to 4,700 CFU/ml], P < 0.01). Bacteriophage also reduced CFU/ml in BALF when administered postinfection (24 h) and both CFU/ml and inflammatory cells in BALF when administered prophylactically. A reduction in soluble inflammatory cytokine levels in BALF was also demonstrated under different conditions. Bacteriophages are efficacious in reducing both the bacterial load and inflammation in a murine model of P. aeruginosa lung infection. This study provides proof of concept for future clinical trials in patients with CF.
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Rishi
authors.initials: R
authors.lastname: Pabary
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Charanjit
authors.initials: C
authors.lastname: Singh
authors.affiliation: Special Phage Services, Brookvale, New South Wales, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Morales
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.affiliation: Department of Microbiology, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Khalid
authors.initials: K
authors.lastname: Alshafi
authors.affiliation: Adult Cystic Fibrosis Unit, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Bilton
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
authors.affiliation: Special Phage Services, Brookvale, New South Wales, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Smithyman
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom j.c.davies@imperial.ac.uk.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects*; D001435:Bacteriophages / Q000254:growth & development*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000821:virology*