Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
24
12
2019
accepted:
16
07
2020
pubmed:
28
8
2020
medline:
25
6
2021
entrez:
28
8
2020
Statut:
ppublish
Résumé
In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE). Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h). At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC. The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.
Sections du résumé
BACKGROUND
In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE).
METHODS
Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h).
RESULTS
At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC.
CONCLUSIONS
The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.
Identifiants
pubmed: 32853336
pii: 5897680
doi: 10.1093/jac/dkaa354
doi:
Substances chimiques
Anti-Bacterial Agents
0
Gentamicins
0
Fosfomycin
2N81MY12TE
Daptomycin
NWQ5N31VKK
Cloxacillin
O6X5QGC2VB
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3586-3592Investigateurs
Jose M Juan Miró
(JMJ)
Adrian Ambrosioni
(A)
Juan M Téllez
(JM)
Anders Pericàs
(A)
Asuncion Dahl
(A)
Cristina García Moreno
(CG)
Yolanda de la Mària
(Y)
Javier Armero
(J)
Maria-Alejandra García-González
(MA)
Manel Cañas-Pacheco
(M)
Climent Almela
(C)
Francisco-Javier Casals
(FJ)
Francesc Morales
(F)
Jordi Marco
(J)
Eduard Vila
(E)
Elena Quintana
(E)
Juan C Sandoval
(JC)
Carlos Paré
(C)
Daniel Falces
(D)
Ramon Pereda
(R)
Salvador Cartañá
(S)
Manel Ninot
(M)
Marta Azqueta
(M)
Barbara Sitges
(B)
José L Vidal
(JL)
Manuel Pomar
(M)
José M Castella
(JM)
José Tolosana
(J)
Guillermina Ortiz
(G)
Irene Fita
(I)
David Rovira
(D)
Jose Fuster
(J)
Mercè Ramírez
(M)
Dolors Brunet
(D)
Pedro Soy
(P)
Jaume Castro
(J)
Jaume Llopis
(J)
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.