title: Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus.
abstract: 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 < 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.
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: A
authors.initials: A
authors.lastname: del Río
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: C
authors.initials: C
authors.lastname: García-de-la-Mària
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: J M
authors.initials: JM
authors.lastname: Entenza
authors.affiliation: Corporació Sanitària Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Gasch
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Armero
authors.affiliation: Pharmacy Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Soy
authors.affiliation: Cardiovascular Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: C A
authors.initials: CA
authors.lastname: Mestres
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Pericás
authors.affiliation: Cardiovascular Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Falces
authors.affiliation: Cardiovascular Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ninot
authors.affiliation: Microbiology Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Almela
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cervera
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Gatell
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moreno
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
authors.affiliation: Microbiology Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Marco
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain jmmiro@ub.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Miró
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001021:Aortic Valve / Q000382:microbiology / Q000473:pathology; D019540:Area Under Curve; D002443:Ceftriaxone / Q000493:pharmacokinetics / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D015870:Gene Expression; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology*; D007260:Infusion Pumps; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D014640:Vancomycin / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D046915:Penicillin-Binding Proteins; D020033:Protein Isoforms; D005578:Fosfomycin; D014640:Vancomycin; D015378:Imipenem; D002443:Ceftriaxone