title: Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections.
abstract: Monte Carlo simulation is often used to predict the cumulative fraction of response (CFR) for antibiotics, but the relevance of these predictions to outcomes in humans has not been well studied. We compared the CFR for meropenem 500 mg every 8h against pathogens causing complicated skin and skin structure infections from a randomised, multicentre clinical trial with clinical response (CR) and microbiological response (MR). A population pharmacokinetic model was utilised to estimate pharmacokinetic parameters for 96 clinically evaluable patients with pathogen and minimum inhibitory concentration (MIC) data available. A 1000-subject Monte Carlo simulation was performed to estimate bacteriostatic (20% of time serum concentration above the MIC (T>MIC)) and bactericidal (40% T>MIC) exposures for comparison. Only the bactericidal CFR versus the CR was not statistically different (92% CR versus 91.9% CFR; 95% confidence interval of the difference, -7.7% to 4.2%), whilst bacteriostatic CFRs overestimated actual CR and MR. This study demonstrates that the use of Monte Carlo simulation to predict the CR of meropenem in complicated skin and skin structures is accurate.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.forename: Christine
authors.initials: C
authors.lastname: Ong
authors.forename: Mathew
authors.initials: M
authors.lastname: Lo
authors.forename: David
authors.initials: D
authors.lastname: Melnick
authors.forename: Norberto
authors.initials: N
authors.lastname: Soto
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D017063:Outcome Assessment, Health Care; D012871:Skin Diseases / Q000188:drug therapy*; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000890:Anti-Infective Agents; D013845:Thienamycins; D000077731:Meropenem