title: Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.
abstract: OBJECTIVE
  Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin.
  
  
  METHODS
  All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed.
  
  
  RESULTS
  Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model.
  
  
  CONCLUSIONS
  Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California. Electronic address: gsakoulas@ucsd.edu.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Moise
authors.affiliation: Eugene Applebaum College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Casapao
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California.
authors.forename: Cheryl Y M
authors.initials: CY
authors.lastname: Okumura
authors.affiliation: Eugene Applebaum College of Pharmacy and Health Sciences, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
authors.affiliation: Oregon State University/Oregon Health & Science University, Portland, Oregon.
authors.forename: Ravina
authors.initials: R
authors.lastname: Kullar
authors.affiliation: New York Medical College, Valhalla, New York.
authors.forename: Abhay
authors.initials: A
authors.lastname: Dhand
authors.affiliation: University of Wisconsin Madison School of Pharmacy, Madison, Wisconsin.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Rose
authors.affiliation: The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Goff
authors.affiliation: Dekalb Medical Center, Decatur, Georgia.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Bressler
authors.affiliation: Maimonides Medical Center, Brooklyn, New York.
authors.forename: Yuman
authors.initials: Y
authors.lastname: Lee
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: VA San Diego Healthcare System, San Diego, California.
authors.forename: Scott
authors.initials: S
authors.lastname: Johns
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: John R
authors.initials: JR
authors.lastname: Ebright
authors.affiliation: University of California San Diego School of Medicine, La Jolla, California.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D016470:Bacteremia / Q000188:drug therapy*; D002511:Cephalosporins / Q000494:pharmacology / Q000627:therapeutic use*; D017576:Daptomycin / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D016879:Salvage Therapy; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013210:Staphylococcus / Q000187:drug effects / Q000254:growth & development; D054804:Cathelicidins; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002511:Cephalosporins; D017576:Daptomycin; D054804:Cathelicidins; D000097583:Ceftaroline
keywords: MRSA; MRSE bacteremia; MSSA; VISA; ceftaroline; daptomycin