CLINICAL PHARMACOKINETICS OF NEWER CEPHALOSPORINS

Several new cephalosporins have been developed in recent years. These agents include several oral and parenteral agents with extended activity against Gramnegative pathogens. The pharmacokinetic literature for these agents is quite extensive; therefore, we have summarised this information and presented it in tabular form for critical comparison, With a few exceptions, the newer cephalosporins share similar pharmacokinetic properties. Cefixime, cefetamet pivoxil and ceftibuten differ from the others in that they exhibit nonlinear pharmacokinetic properties. The nonlinear nature of these agents is reflected by decreasing maximal concentrations with escalating doses of cefixime and cefetamet pivoxil, decreasing area under the serum concentration-time curve with increasing doses for cefixime, and a reduced bioavailability with large doses of ceftibuten. Attention to such characteristics aid the clinician in selecting appropriate dosage regimens that will optimise drug absorption. The majority of agents are primarily renally eliminated; however, renal elimination accounts for only 20% of cefixime elimination. The pharmacokinetic parameters noted for the newer cephalosporins are not influenced by multiple-dose administration, suggesting lack of drug accumulation over time. The pharmacodynamics of antimicrobials should be considered when extrapolating pharmacokinetic information into the clinical arena. In the case of the p-lactams, the time which drug concentrations remain above some critical threshold, such as the minimal inhibitory concentration, appears to have the greatest influence on bactericidal activity. Therefore, it is important to select dosage regimens that will optimise the time serum concentrations remain above this threshold. We present an evaluation of these agents with respect to their activity against a variety of pathogens in an effort to demonstrate a pharmacokinetically-based process of antimicrobial selection.