Choosing between the new cephalosporin antibiotics: a pharmacodynamic approach

The use of pharmacodynamic properties when formulating antibacterial administration guidelines can maximise the potential for efficacy while minimising the risk of toxicity. Aminoglycosides and quinolones demonstrate concentration-dependent bactericidal killing, which is maximised when their concentrations appreciably exceed their minimum inhibitory concentration (MIC) for an organism. beta-Lactams demonstrate time-dependent or concentration-independent bactericidal killing, which is maximised when the time that concentrations exceed the MIC is prolonged, regardless of the absolute levels attained. Methods of prolonging the time beta-lactam concentrations exceed the MIC include the following: interfering with excretion (e.g. probenecid); decreasing the dosage interval; increasing the dose; infusing continuously rather than by bolus; and choosing an agent with a prolonged elimination half-life. The optimal duration for exceeding the MIC varies with the infecting organism, site of infection, inoculum effect, and the immunocompetence of the host. Integration of the microbiological activity and pharmacokinetic properties enables estimation of the time that serum concentrations of various cephalosporins will exceed the MIC of a given organism, consequently allowing estimation of the relative potential for clinical success. Cefixime, a third generation oral cephalosporin with a long plasma elimination half-life, allowing once-daily administration, achieves serum concentrations that exceed the MIC of Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, and Group A streptococci for greater than 90% of the dosage interval, and the MIC of Streptococcus pneumoniae for 50 to 90% of the dosage interval.