The pharmacodynamics of fosfomycin against Staphylococcus aureus studied in an in vitro model of infection.

OBJECTIVES: The pharmacodynamics of intravenous fosfomycin have not been described for Gram positive pathogens such as Staphylococcus aureus. We describe the dominant pharmacodynamic index for fosfomycin against S.aureus and its size for antibacterial effect. METHODS: A single compartment dilutional in vitro pharmacokinetic model was used to provide fosfomycin exposures against S.aureus, 3 MSSA and 2 MRSA, fosfomycin MICs, 2mg/L (1 strain), 4mg/L (1 strain), 8mg/L (2 strains) and 16mg/L (1 strain). The fosfomycin half-life modelled was 2.5h. Cmax/MICs from 0 to 74.8; AUC/MICs from 0 to 750 and T>MIC 0 to 100% were simulated. The primary end points were changes in bacterial load after 24h (d24) and changes in population profiles after 48h. RESULTS: Log AUC/MIC R(2) 0.55 and log Cmax/MIC R(2) 0.66 were related to S.aureus log reduction in viable count at 24h; T>MIC was poorly related. Cmax/MIC for a 24h static, -1 log drop, -2 log drop were 3.0+/-1.7, 4.6+/-2.4 and 6.6+/-3.8 respectively. AUC/MIC for a 24h static, -1 log drop, -2 log drop were 26.4+/-11.8, 42.8+/-21.8 and 66.6+/-39.1. Emergence of resistance as indicated by >2 log growth on MICx8 recovery media was maximal at AUC/MIC ratios of 10-40 and was suppressed at AUC/MIC ratios of >/=250. CONCLUSIONS: The dominant PDI for fosfomycin against S.aureus are Cmax/MIC in terms of reduction of bacterial load and AUC/MIC in terms of suppressing emergence of resistance. AUC/MIC ratios of 20-75 are associated with a -1 log reduction in bacterial load and AUC/MIC of 10-40 maximally increase emergence of resistance.