title: Efficacy of bacteriophage therapy in experimental sepsis and meningitis caused by a clone O25b:H4-ST131 Escherichia coli strain producing CTX-M-15.
abstract: We evaluated phage therapy in experimental infections due to S242, a fatal neonatal meningitis Escherichia coli strain belonging to the worldwide-distributed O25b:H4-ST131 clone that produces extended-spectrum beta-lactamase CTX-M-15. A lytic phage, EC200(PP), active against S242, was isolated from environmental water. After determining in vitro and ex vivo stabilities and pharmacokinetic properties of EC200(PP) in rat pups, we assessed the therapeutic efficacy of a single dose of 10(8) PFU using models of sepsis and meningitis in which fatality was 100%. EC200(PP) was partially neutralized by human serum. In contrast to the high concentration of phage in the spleen and the kidney, low titers in urine and the central nervous system were observed. Nevertheless, in the sepsis model, EC200(PP) administered 7 h or 24 h postinfection resulted in 100% and 50% pup survival, respectively. In the meningitis model, EC200(PP) administered 1 h or 7 h postinfection rescued 100% of the animals. The most delayed treatments were associated with the selection of phage-resistant S242 mutants. However, a representative mutant was highly sensitive to killing serum activity and avirulent in an animal model. EC200(PP) is a potential therapeutic agent for sepsis and meningitis caused by the widespread E. coli O25:H4-ST131 multidrug-resistant clone.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Equipe d'Accueil EA3105, and AP-HP, Hôpital Robert Debré, Paris, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Pouillot
authors.forename: Maryline
authors.initials: M
authors.lastname: Chomton
authors.forename: Hélène
authors.initials: H
authors.lastname: Blois
authors.forename: Celine
authors.initials: C
authors.lastname: Courroux
authors.forename: Julien
authors.initials: J
authors.lastname: Noelig
authors.forename: Philippe
authors.initials: P
authors.lastname: Bidet
authors.forename: Edouard
authors.initials: E
authors.lastname: Bingen
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bonacorsi
mesh_terms: D000818:Animals; D001435:Bacteriophages / Q000502:physiology*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000201:enzymology* / Q000472:pathogenicity / Q000821:virology*; D004927:Escherichia coli Infections / Q000628:therapy*; D005260:Female; D006801:Humans; D008581:Meningitis / Q000382:microbiology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000382:microbiology / Q000628:therapy*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: C473109:beta-lactamase CTX-M-15; D001618:beta-Lactamases