In vivo synergism of ceftobiprole and vancomycin against experimental endocarditis due to vancomycin-intermediate Staphylococcus aureus.

Abstract

The 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.

• Authors: J M Entenza, T R Veloso, J Vouillamoz, M Giddey, P Majcherczyk, P Moreillon
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 55 Issue 9 Pg. 3977-84 (Sep 2011) ISSN: 1098-6596 [Electronic] United States
• PMID: 21730114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Cephalosporins
• ceftobiprole
• Vancomycin

Topics

• Animals
• Anti-Bacterial Agents (therapeutic use)
• Cephalosporins (therapeutic use)
• Drug Synergism
• Endocarditis (drug therapy, microbiology)
• Female
• Microbial Sensitivity Tests
• Rats
• Rats, Wistar
• Staphylococcus aureus (drug effects, pathogenicity)
• Vancomycin (therapeutic use)