Bruna Kochhann Menezes1, Izabel Almeida Alves2, Keli Jaqueline Staudt3, Betina Montanari Beltrame4, Letícia Venz4, Lessandra Michelin4, Bibiana Verlindo Araujo5, Leandro Tasso6. 1. Health Sciences Graduate Program, University of Caxias do Sul, Caxias do Sul, Brazil. 2. Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 3. Medical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 4. College of Pharmacy, University of Caxias do Sul, Caxias do Sul, Brazil. 5. College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 6. Health Sciences Graduate Program, University of Caxias do Sul, Caxias do Sul, Brazil. ltasso@ucs.br.
Abstract
OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against vancomycin-resistant Enterococcus faecium bacteraemia using computer modelling. METHODS: Data obtained in vitro from time-kill curves were evaluated by PK/PD modelling and Monte Carlo simulations to determine the logarithmic reduction in the number of colony-forming units (CFU)/mL over 18 days of daptomycin treatment at 6, 8, and 10 mg/kg doses every 24 or 48 h and with variations in creatinine clearance (CLCR) of 15-29, 30-49, and 50-100 mL/min/1.73 m2. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) for an area under the unbound drug concentration-time curve/minimum inhibitory concentration (fAUC/MIC) > 36 at the same doses and CLCR. RESULTS: Static time-kill model was employed to investigate the antibacterial efficacy of constant daptomycin concentrations. The time-kill curve analysis was performed using mathematical modelling based on a Hill coefficient factor. There was an expressive reduction (> 2 Log CFU/mL) over 18 days of daptomycin treatment in 75th percentile of individuals with CLCR of 15-100 mL/min/1.73 m2) with daptomycin 6-10 mg/kg/day, except for daptomycin every 48 h. Using fAUC/MIC > 36, PTA was > 90% at MICs ≤ 2 μg/mL. CONCLUSIONS: Higher daptomycin doses were associated with higher mortality in time-kill curves. The simulations indicated that independent of the CLCR the therapeutic responses of VRE occur with doses of daptomycin ≥ 6 mg/kg/day and daptomycin every 48 h is insufficient to treat enterococcal bacteraemia.
OBJECTIVES: The aim of this study was to investigate the effect of daptomycin against vancomycin-resistant Enterococcus faeciumbacteraemia using computer modelling. METHODS: Data obtained in vitro from time-kill curves were evaluated by PK/PD modelling and Monte Carlo simulations to determine the logarithmic reduction in the number of colony-forming units (CFU)/mL over 18 days of daptomycin treatment at 6, 8, and 10 mg/kg doses every 24 or 48 h and with variations in creatinine clearance (CLCR) of 15-29, 30-49, and 50-100 mL/min/1.73 m2. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) for an area under the unbound drug concentration-time curve/minimum inhibitory concentration (fAUC/MIC) > 36 at the same doses and CLCR. RESULTS: Static time-kill model was employed to investigate the antibacterial efficacy of constant daptomycin concentrations. The time-kill curve analysis was performed using mathematical modelling based on a Hill coefficient factor. There was an expressive reduction (> 2 Log CFU/mL) over 18 days of daptomycin treatment in 75th percentile of individuals with CLCR of 15-100 mL/min/1.73 m2) with daptomycin 6-10 mg/kg/day, except for daptomycin every 48 h. Using fAUC/MIC > 36, PTA was > 90% at MICs ≤ 2 μg/mL. CONCLUSIONS: Higher daptomycin doses were associated with higher mortality in time-kill curves. The simulations indicated that independent of the CLCR the therapeutic responses of VRE occur with doses of daptomycin ≥ 6 mg/kg/day and daptomycin every 48 h is insufficient to treat enterococcal bacteraemia.
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