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 β-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., β-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.
