title: Bactericidal synergism between daptomycin and the phage lysin Cpl-1 in a mouse model of pneumococcal bacteraemia.
abstract: Combination therapy may improve the outcome of Streptococcus pneumoniae-induced bacteraemia. Here we tested the combination of two antipneumococcal agents, daptomycin and Cpl-1 (the pneumococcal Cp-1 bacteriophage lysin), in a mouse model of pneumococcal bacteraemia. Mice were challenged intraperitoneally (i.p.) with 10(6)CFU of the extremely virulent serotype 2 S. pneumoniae D39 isolate. Subtherapeutic doses of daptomycin (0.4mg/kg) and Cpl-1 (0.4mg/kg and 1mg/kg) were administrated i.p. either alone or in combination by a single bolus injection 1h after bacterial challenge. Survival rates of animals were followed over a period of 7 days. Daptomycin (0.4mg/kg) in combination with Cpl-1 (0.4mg/kg) significantly increased the percentage of surviving mice at Day 7 (80%) compared with the untreated control (0%) and daptomycin or Cpl-1 monotherapy (35% and 0%, respectively). Whilst increasing the concentration of Cpl-1 to 1.0mg/kg did not improve survival when injected alone, its combination with 0.4mg/kg daptomycin further increased the survival rate to 95%. Thus, it was found that the combination of daptomycin with Cpl-1 was synergistic and bactericidal against S. pneumoniae in a mouse model of pneumococcal bacteraemia. To our knowledge, this is the first report of synergism between daptomycin and a phage lysin demonstrated in vivo. Such a combination could represent an interesting alternative therapy for the treatment of pneumococcal bacteraemia/sepsis and possibly other severe pneumococcal infections.
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vouillamoz
authors.forename: José M
authors.initials: JM
authors.lastname: Entenza
authors.forename: Marlyse
authors.initials: M
authors.lastname: Giddey
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Fischetti
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreillon
authors.forename: Grégory
authors.initials: G
authors.lastname: Resch
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy*; D017576:Daptomycin / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D009088:Mucoproteins / Q000627:therapeutic use*; D011008:Pneumococcal Infections / Q000188:drug therapy*; D017108:Streptococcus Phages / Q000201:enzymology*; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D009088:Mucoproteins; C010393:lysin, gastropoda; D017576:Daptomycin
keywords: Bacteriophage; Cpl-1; Daptomycin; Enzybiotic; Lysin; Streptococcus pneumoniae