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. Copyright © 2012, American Society for Microbiology. All Rights Reserved.