Effectiveness of vancomycin plus cloxacillin compared with vancomycin, cloxacillin and daptomycin single therapies in the treatment of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a rabbit model of experimental endocarditis.

Abstract

OBJECTIVES:

To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits.

METHODS:

Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400.

RESULTS:

Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains.

CONCLUSIONS:

Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.

• Authors: Ximena Castañeda, Cristina García-De-la-Mària, Oriol Gasch, Juan M Pericàs, Dolors Soy, Maria-Alejandra Cañas-Pacheco, Carlos Falces, Javier García-González, Marta Hernández-Meneses, Bàrbara Vidal, Manel Almela, Eduard Quintana, Jose M Tolosana, David Fuster, Jaume Llopis, Anders Dahl, Asuncion Moreno, Francesc Marco, Jose M Miró, Hospital Clínic Endocarditis Study Group
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 76 Issue 6 Pg. 1539-1546 (05 12 2021) ISSN: 1460-2091 [Electronic] England
• PMID: 33837406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Vancomycin
• Daptomycin
• Cloxacillin
• Methicillin

Topics

• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Cloxacillin
• Daptomycin
• Endocarditis (drug therapy)
• Endocarditis, Bacterial (drug therapy)
• Methicillin (pharmacology)
• Methicillin Resistance
• Methicillin-Resistant Staphylococcus aureus
• Microbial Sensitivity Tests
• Rabbits
• Staphylococcus aureus
• Vancomycin