caa a22 4500 357894642 CHVBK 20170617155249.0 cr unu---uuuuu 160308s2015 xx s 000 0 eng 10.1128/AAC.02139-15 doi (SERVAL)BIB_F4F9C54B7FF2 26525803 pmid 000369154600060 isiid Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus [Elektronische Daten] [A. Del Río, C. García-de-la-Mària, J.M. Entenza, O. Gasch, Y. Armero, D. Soy, C.A. Mestres, J.M. Pericás, C. Falces, S. Ninot, M. Almela, C. Cervera, J.M. Gatell, A. Moreno, P. Moreillon, F. Marco, J.M. Miró] The urgent need of effective therapies for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain the in vitro and in vivo activity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate-resistant S. aureus (GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg; P = 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%]; P = 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg; P &lt; 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%]; P = 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE. Del Río A. aut García-de-la-Mària C. aut Entenza J.M. aut Gasch O. aut Armero Y. aut Soy D. aut Mestres C.A. aut Pericás J.M. aut Falces C. aut Ninot S. aut Almela M. aut Cervera C. aut Gatell J.M. aut Moreno A. aut Moreillon P. aut Marco F. aut Miró J.M. aut Antimicrobial Agents and Chemotherapy 60/1(2015), 478-486 60:1<478-486 2015 60 1 article serval SERVAL 700 1- Del Río A. aut SERVAL 700 1- García-de-la-Mària C. aut SERVAL 700 1- Entenza J.M. aut SERVAL 700 1- Gasch O. aut SERVAL 700 1- Armero Y. aut SERVAL 700 1- Soy D. aut SERVAL 700 1- Mestres C.A. aut SERVAL 700 1- Pericás J.M. aut SERVAL 700 1- Falces C. aut SERVAL 700 1- Ninot S. aut SERVAL 700 1- Almela M. aut SERVAL 700 1- Cervera C. aut SERVAL 700 1- Gatell J.M. aut SERVAL 700 1- Moreno A. aut SERVAL 700 1- Moreillon P. aut SERVAL 700 1- Marco F. aut SERVAL 700 1- Miró J.M. aut SERVAL 773 0- Antimicrobial Agents and Chemotherapy 60/1(2015), 478-486 60:1<478-486 2015 60 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article