title: Pharmacodynamic modeling of imipenem-cilastatin, meropenem, and piperacillin-tazobactam for empiric therapy of skin and soft tissue infections: a report from the OPTAMA Program.
abstract: BACKGROUND
  The bactericidal exposures necessary for positive clinical outcomes among skin and soft tissue infections are largely dependent on interpatient pharmacokinetic variability and pathogen drug susceptibility. By simulating the probability of achieving target bactericidal exposures, the pharmacodynamics of three beta-lactam agents were compared against a range of pathogens implicated commonly in complicated skin and soft tissue infections.
  
  
  METHODS
  Using Monte Carlo simulation, pharmacodynamic target attainment expressed as the percentage of the time interval during which the antibiotic concentration exceeded the minimal inhibitory concentration (%T > MIC) in serum and blister fluid was calculated for 5,000 simulated patients receiving imipenem-cilastatin 0.5 g q8h, meropenem 0.5 g q8h, piperacillin-tazobactam 3.375 g q6h, and piperacillin-tazobactam 4.5 g q8h. The pharmacokinetics for each antibiotic were derived from previously published healthy volunteer studies. The MICs for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Enterobacter sp., Klebsiella sp., coagulase-negative staphylococci, Proteus sp., beta-hemolytic streptococci, and Serratia sp. were taken from the MYSTIC 2003 surveillance study and weighted by the prevalence of each pathogen among 1,404 isolates collected from skin and soft tissue infections during the 2000 SENTRY study. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was added into the model at increasing resistance rates.
  
  
  RESULTS
  Imipenem-cilastatin, meropenem, and piperacillin-tazobactam 3.375 g q6h achieved greater than 90% likelihood of achieving bactericidal exposure in serum and blister fluid until the prevalence of MRSA increased beyond 10%. Piperacillin-tazobactam 4.5 g q8h achieved a lower probability of achieving bactericidal exposure than the other regimens (88.7%, p < 0.001).
  
  
  CONCLUSIONS
  When the incidence of MRSA is low, imipenem-cilastatin, meropenem and piperacillin-tazobactam 3.375 g q6h would be optimal choices for the empiric treatment of complicated skin and soft tissue infections among the regimens studied. When MRSA is suspected, a drug that retains activity against this pathogen should be considered.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Ong
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kuti
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D015377:Cilastatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077728:Cilastatin, Imipenem Drug Combination; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077725:Piperacillin, Tazobactam Drug Combination; D011159:Population Surveillance; D015995:Prevalence; D018461:Soft Tissue Infections / Q000188:drug therapy* / Q000382:microbiology*; D013845:Thienamycins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D013845:Thienamycins; D015377:Cilastatin; D000077725:Piperacillin, Tazobactam Drug Combination; D015378:Imipenem; D010397:Penicillanic Acid; D000077728:Cilastatin, Imipenem Drug Combination; D000077731:Meropenem; D010878:Piperacillin