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In VivoSynergism of Ceftobiprole and Vancomycin against Experimental Endocarditis Due to Vancomycin-Intermediate Staphylococcus aureus

Authors :
Entenza, J. M.
Veloso, T. R.
Vouillamoz, J.
Giddey, M.
Majcherczyk, P.
Moreillon, P.
Source :
Antimicrobial Agents and Chemotherapy; June 2011, Vol. 55 Issue: 9 p3977-3984, 8p
Publication Year :
2011

Abstract

ABSTRACTThe efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate Staphylococcus aureus(VISA) strains, PC3 and Mu50, in rats with experimental endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (P< 0.001 versus controls). In comparison, LD-ceftobiprole sterilized 10 of 11 (91%) vegetations infected with PC3 (P< 0.01 versus controls) but only 3 of 12 (25%) vegetations infected with Mu50 (P> 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (P< 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA experimental endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.

Details

Language :
English
ISSN :
00664804 and 10986596
Volume :
55
Issue :
9
Database :
Supplemental Index
Journal :
Antimicrobial Agents and Chemotherapy
Publication Type :
Periodical
Accession number :
ejs57155348
Full Text :
https://doi.org/10.1128/AAC.00402-11