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Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to

A del Río1, C García-de-la-Mària1, J M Entenza2

  • 1Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain.

Antimicrobial Agents and Chemotherapy
|November 4, 2015
PubMed

Insights

Fosfomycin combined with imipenem or ceftriaxone shows promise for treating methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate-resistant S. aureus (GISA) infective endocarditis (IE). These combinations were more effective than vancomycin in reducing bacterial load and sterilizing vegetations in animal models.

Area of Science:

  • Infectious Diseases
  • Pharmacology
  • Microbiology

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate-resistant S. aureus (GISA) pose significant therapeutic challenges, particularly in infective endocarditis (IE).
  • There is an urgent need for effective treatment options against these resistant strains.

Purpose of the Study:

  • To evaluate the in vitro and in vivo efficacy of fosfomycin combined with beta-lactam antibiotics against MRSA and GISA.
  • To compare the effectiveness of fosfomycin combinations with vancomycin in a preclinical model of IE.

Main Methods:

  • In vitro time-kill tests were conducted using fosfomycin combined with imipenem (FOF+IPM) against 10 MRSA/GISA isolates.
  • An aortic valve IE rabbit model was used to compare intravenous regimens: FOF+IPM, fosfomycin plus ceftriaxone (FOF+CRO), standard-dose vancomycin (VAN-SD), and high-dose vancomycin (VAN-HD).
  • Bacterial load in vegetations and the number of sterilized vegetations were assessed. Molecular studies investigated the effect on penicillin-binding protein (PBP) synthesis.

Main Results:

  • FOF+IPM demonstrated the highest in vitro activity.
  • In vivo, FOF+IPM significantly reduced MRSA-277H bacterial load in vegetations compared to VAN-SD and sterilized more vegetations (73% vs. 31%).
  • Both FOF+IPM and FOF+CRO significantly reduced GISA-ATCC 700788 load compared to VAN-SD. FOF+CRO sterilized more vegetations (53%) than vancomycin regimens (20%). FOF+IPM treatment decreased PBP1, PBP2, and PBP3 synthesis.

Conclusions:

  • Fosfomycin in combination with imipenem or ceftriaxone is a promising therapeutic strategy for MRSA and GISA IE.
  • These combinations show superior efficacy over vancomycin in preclinical models, potentially by affecting PBP synthesis.
  • Clinicians may consider FOF+IPM or FOF+CRO for treating IE caused by MRSA or GISA.

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