In vitro and intracellular activities of fosfomycin against clinical strains of Listeria monocytogenes

Abstract This study was designed to evaluate the potential role of fosfomycin as a therapeutic agent in human listeriosis. The in vitro activity of fosfomycin against 154 Listeria monocytogenes clinical isolates under conditions that mimic the induction of prf A expression was determined and was correlated with fosfomycin intracellular antimicrobial activity. In vitro, partial induction of prf A expression is achieved through bacterial growth in brain–heart infusion agar supplemented with activated charcoal (BHIC). A fosfomycin pharmacokinetic/pharmacodynamic breakpoint of ≤64mg/L was estimated using a Monte Carlo simulation to assess the success of an intravenous fosfomycin dose of 300mg/kg/day over 5000 individuals. Eighty strains (51.9%) were susceptible to fosfomycin in BHIC, with minimum inhibitory concentrations (MICs) of ≤64mg/L; 13 strains (8.4%) had the epidemic clone (EC) marker. In addition, 27 strains (17.5%) had a three doubling dilutions reduction in the MIC from ≥1024mg/L to 128mg/L (96–128mg/L by Etest). The fosfomycin modal MIC is lower under prf A expression. However, this effect is smaller in terms of clinical categorisation of isolates and can be influenced by the serotype and clonal type. In A549 cells, the reductions in bacterial inocula of the two susceptible isolates studied after 1h and 24h of incubation with fosfomycin at 0.5× the human maximum serum concentration ( C max ) were 45.8% and 46.6%, and 93.8% and 99.1%, respectively. Slightly higher reductions were found with fosfomycin at 1× C max . The resistant strain tested showed significantly lower reductions in all assays.