1. J Antimicrob Chemother. 2013 Mar;68(3):648-58. doi: 10.1093/jac/dks442. Epub 2012
Nov 27.

Activity of ceftaroline against extracellular (broth) and intracellular (THP-1
monocytes) forms of methicillin-resistant Staphylococcus aureus: comparison with 
vancomycin, linezolid and daptomycin.

Mélard A, Garcia LG, Das D, Rozenberg R, Tulkens PM, Van Bambeke F, Lemaire S.

Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.

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 x 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 (approx. 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 approx. 0.3 and approx. 6 x 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.
CONCLUSION: 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 < or = 2 mg/L.

PMID: 23188792  [PubMed - in process]