Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline

Clin Ther. 2014 Oct 1;36(10):1317-33. doi: 10.1016/j.clinthera.2014.05.061. Epub 2014 Jul 10.

Abstract

Purpose: 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.

Findings: 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.

Implications: 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.

Keywords: MRSA; MRSE bacteremia; MSSA; VISA; ceftaroline; daptomycin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Antimicrobial Cationic Peptides / metabolism
  • Bacteremia / drug therapy*
  • Cephalosporins / pharmacology
  • Cephalosporins / therapeutic use*
  • Daptomycin / pharmacology
  • Daptomycin / therapeutic use*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Salvage Therapy
  • Staphylococcal Infections / drug therapy*
  • Staphylococcus / drug effects
  • Staphylococcus / growth & development

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Cephalosporins
  • T 91825
  • CAP18 lipopolysaccharide-binding protein
  • Daptomycin