Treatment of infections with ESBL-producing organisms: pharmacokinetic and pharmacodynamic considerations

Susceptibility surveillance investigations have demonstrated an increased incidence of ESBL-producing Gram-negative bacilli. Case cohort studies have suggested clinical relevance associated with ESBL-producing Enterobacteriaciae infection. Yet, current laboratory reporting guidelines classify a large percentage of these organisms in the susceptible category. The regulatory agencies Clinical Laboratory Standards Institute (formly NCCLS) and EUCAST, which oversee these guidelines are in the process of re-evaluating the appropriateness of the current classification system. Pharmacokinetic and pharmacodynamic studies examine the relationship between drug exposure (pharmacokinetics), antibiotic potency (MIC), and treatment efficacy. PK/PD studies and analyses have been useful in demonstrating the relevance of increasingly less susceptible pathogens and specific emerging resistance mechanisms. Recent investigations have examined the impact of ESBL-producing Gram-negative bacilli relative to advanced generation cephalosporin pharmacokinetics. Animal model studies suggest that the pharmacodynamic target associated with efficacy in treatment of ESBL-producing organisms is the same as that in therapy against non-ESBL-producing bacteria (50% T > MIC). Simulation of human pharmacokinetics can predict the likelihood of achieving this PD target with specific cephalosporin dosing regimens. In general, the exposure from usual regimens of the advanced generation cephalosporins would not be anticipated to achieve the PD target for many of the organisms currently classified as susceptible. PK/PD analyses should be useful in re-evaluating current susceptibility breakpoints for ESBL-producing organisms and for optimising drug and regimen choice in treatment of these infections.