ROLE OF PHARMACOKINETICS AND PHARMACODYNAMICS IN THE DESIGN OF DOSAGESCHEDULES FOR 12-H CEFOTAXIME ALONE AND IN COMBINATION WITH OTHER ANTIBIOTICS

Pharmacodynamic principles have provided important tools to evaluate a nd compare antimicrobial agents, and well as to guide dosing. For beta -lactams, time above the minimum inhibitory concentration (MIG) has su rfaced as the most important factor. However, the area under the inhib itory serum concentration time-curve (AUIC) may be superior when appro priate dosing intervals are selected. Although the target time over th e MIC is unclear in humans even when concentrations remain continuousl y above the MIG, a higher AUIC predicts better clinical outcome up to a maximum. This article provides a pharmacodynamic assessment of 1- an d 2-g doses of cefotaxime every 12 h. AUIC(24) values and published MI C values for common pathogens (grouped into four groups based on MIC(9 0)) were used to predict organisms suitable for treatment with every-1 2-h regimens. Cefotaxime was inadequate for group 4 organisms includin g: Pseudomonas aeruginosa, Acienetobacter sp., and Enterococcus sp. Or ganisms such as Enterobacter cloacae, Serratia marcescens, Staphylococ cus aureus, and B. fragilis may be suboptimally treated with cefotaxim e every 12 h. Cefotaxime in doses of 1-2 g every 12 h should be useful in patients with normal renal function infected with organisms having MICs <0.5 mu g/ml. This regimen should obtain AUIC(24) values >125 an d ensure adequate time above the MIG. In patients with impaired renal function, because of a longer half-life and higher area under the curv e, pathogens with MIC values in the 0.5-2 mu g/ml range may be treated with cefotaxime every 12 h while maintaining AUICs >125. Data are als o presented for cefotaxime 2 g every 8 h alone and in combination with ofloxacin. Measured serum inhibitory titers show strengths and weakne ss of cefotaxime and ofloxacin monotherapies, and show that the combin ation often provided greater inhibitory activity than monotherapy with either agent.