High activity of Fosfomycin and Rifampin against methicillin-resistant staphylococcus aureus biofilm in vitro and in an experimental foreign-body infection model

Antimicrob Agents Chemother. 2014 May;58(5):2547-53. doi: 10.1128/AAC.02420-12. Epub 2014 Feb 18.

Abstract

Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 μg/ml; daptomycin, 0.125 μg/ml; vancomycin, 1 μg/ml; rifampin, 0.04 μg/ml; and tigecycline, 0.125 μg/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log10 CFU/ml at 128 × the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log10 CFU/ml with fosfomycin and tigecycline, 1.7 log10 with daptomycin, 2.2 log10 with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log10 with fosfomycin-daptomycin, and >6.0 log10 with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cage-associated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 μg/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cage-associated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Biofilms / drug effects*
  • Fosfomycin / therapeutic use*
  • Guinea Pigs
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / pathogenicity*
  • Microbial Sensitivity Tests
  • Rifampin / therapeutic use*
  • Staphylococcal Infections / drug therapy*

Substances

  • Anti-Bacterial Agents
  • Fosfomycin
  • Rifampin