title: Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium.
abstract: Daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium (VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (∼2 log10 CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-l-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycin-susceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy.
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Warren
authors.initials: W
authors.lastname: Rose
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.forename: Romney
authors.initials: R
authors.lastname: Humphries
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D004357:Drug Synergism; D016984:Enterococcus faecium / Q000187:drug effects*; D066298:In Vitro Techniques; D008560:Membrane Fluidity / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D020713:Vancomycin Resistance / Q000187:drug effects*; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017576:Daptomycin; D000097583:Ceftaroline