Alan Noel1, Marie Attwood1, Karen Bowker1, Alasdair MacGowan2. 1. Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol, UK. 2. Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol, UK. Electronic address: alasdair.macgowan@nbt.nhs.uk.
Abstract
OBJECTIVES: The pharmacodynamics of intravenous fosfomycin have not been described for Gram-positive pathogens such as Staphylococcus aureus (S. aureus). This paper described 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, three methicillin-susceptible S. aureus (MSSA), two methicillin-resistant S. aureus (MRSA); fosfomycin MICs were 2 mg/L (one strain), 4 mg/L (one strain), 8 mg/L (two strains) and 16 mg/L (one strain). For all simulations, a fosfomycin half-life of 2.5 hours was modelled. Cmax/MICs from 0-74.8, AUC/MICs from 0-750 and T>MIC 0-100% were simulated. The primary end-points were changes in bacterial load after 24 hours and changes in population profiles after 48 hours. RESULTS: Log AUC/MIC R2 = 0.55 and log Cmax/MIC R2 = 0.66 were related to S. aureus log reduction in viable count at 24 hours; T>MIC was poorly related. Cmax/MIC for a 24 hour static, -1 log drop and -2 log drop were 3.0 ± 1.7, 4.6 ± 2.4 and 6.6 ± 3.8, respectively. AUC/MIC for a 24 hour static, -1 log drop and -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 pharmacodynamic index for fosfomycin against S. aureus was 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 were associated with a -1 log reduction in bacterial load and AUC/MIC of 10-40 maximally increased emergence of resistance.
OBJECTIVES: The pharmacodynamics of intravenous fosfomycin have not been described for Gram-positive pathogens such as Staphylococcus aureus (S. aureus). This paper described 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, three methicillin-susceptible S. aureus (MSSA), two methicillin-resistant S. aureus (MRSA); fosfomycin MICs were 2 mg/L (one strain), 4 mg/L (one strain), 8 mg/L (two strains) and 16 mg/L (one strain). For all simulations, a fosfomycin half-life of 2.5 hours was modelled. Cmax/MICs from 0-74.8, AUC/MICs from 0-750 and T>MIC 0-100% were simulated. The primary end-points were changes in bacterial load after 24 hours and changes in population profiles after 48 hours. RESULTS: Log AUC/MIC R2 = 0.55 and log Cmax/MIC R2 = 0.66 were related to S. aureus log reduction in viable count at 24 hours; T>MIC was poorly related. Cmax/MIC for a 24 hour static, -1 log drop and -2 log drop were 3.0 ± 1.7, 4.6 ± 2.4 and 6.6 ± 3.8, respectively. AUC/MIC for a 24 hour static, -1 log drop and -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 pharmacodynamic index for fosfomycin against S. aureus was 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 were associated with a -1 log reduction in bacterial load and AUC/MIC of 10-40 maximally increased emergence of resistance.