title: Activity of ceftaroline against extracellular (broth) and intracellular (THP-1 monocytes) forms of methicillin-resistant Staphylococcus aureus: comparison with vancomycin, linezolid and daptomycin.
abstract: BACKGROUND
  Ceftaroline fosamil is approved for treatment of acute bacterial skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We examined the activity of its active metabolite (ceftaroline) against intracellular forms of S. aureus in comparison with vancomycin, daptomycin and linezolid.
  
  
  METHODS
  Two methicillin-susceptible S. aureus (MSSA) and 11 MRSA strains with ceftaroline MICs from 0.125 to 2 mg/L [two strains vancomycin- and one strain linezolid-resistant (EUCAST interpretative criteria); VISA and cfr+] were investigated. The activity was measured in broth and after phagocytosis by THP-1 monocytes in concentration-dependent experiments (24 h of incubation) to determine: (i) relative potencies (EC(50)) and static concentrations (C(s)) (mg/L and × MIC); and (ii) relative activities at human C(max) (E(C)(max)) and maximal relative efficacies (E(max)) (change in log(10) cfu compared with initial inoculum). Ceftaroline stability and cellular accumulation (at 24 h) were measured by mass spectrometry.
  
  
  RESULTS
  Ceftaroline showed similar activities in broth and in monocytes compared with vancomycin, daptomycin and linezolid, with no impact of resistance mechanisms to vancomycin or linezolid. For all four antibiotics, intracellular E(C)(max) and E(max) were considerably lower than in broth (∼0.5 log(10) versus 4-5 log(10) cfu decrease), but the EC(50) and C(s) showed comparatively little change (all values between ∼0.3 and ∼6× MIC). The mean cellular to extracellular ceftaroline concentration ratios (20 mg/L; 24 h) were 0.66 ± 0.05 and 0.90 ± 0.36 in uninfected and infected cells, respectively.
  
  
  CONCLUSIONS
  In vitro, ceftaroline controls the growth of intracellular MRSA to an extent similar to that of vancomycin, linezolid and daptomycin for strains with a ceftaroline MIC ≤ 2 mg/L.
authors.affiliation: Pharmacologie cellulaire et moléculaire,  Louvain Drug Research Institute, Université catholique de Louvain, Brussels,  Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Mélard
authors.forename: Laetitia G
authors.initials: LG
authors.lastname: Garcia
authors.forename: Debaditya
authors.initials: D
authors.lastname: Das
authors.forename: Raoul
authors.initials: R
authors.lastname: Rozenberg
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemaire
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology; D006801:Humans; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000382:microbiology*; D023303:Oxazolidinones / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology; D000097583:Ceftaroline
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D017576:Daptomycin; D000069349:Linezolid; D023303:Oxazolidinones; D014640:Vancomycin; D000097583:Ceftaroline