Role of pharmacokinetics and pharmacodynamics in the design of dosage schedules for 12-h cefotaxime alone and in combination with other antibiotics

Pharmacodynamic principles have provided important tools to evaluate and compare antimicrobial agents, and well as to guide dosing. For β-lactams, time above the minimum inhibitory concentration (MIC) has surfaced as the most important factor. However, the area under the inhibitory serum concentration time-curve (AUIC) may be superior when appropriate dosing intervals are selected. Although the target time over the MIC is unclear in humans even when concentrations remain continuously above the MIC, a higher AUIC predicts better clinical outcome up to a maximum. This article provides a pharmacodynamic assessment of 1- and 2-g doses of cefotaxime every 12 h. AUIC₂₄ values and published MIC values for common pathogens (grouped into four groups based on MIC₉₀) were used to predict organisms suitable for treatment with every-12-h regimens. Cefotaxime was inadequate for group 4 organisms including: Pseudomonas aeruginosa, Acienetobacter sp., and Enterococcus sp. Organisms such as Enterobacter cloacae, Serratia marcescens, Staphylococcus aureus, and B. fragilis may be suboptimally treated with cefotaxime 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 μg/ml This regimen should obtain AUIC₂₄ values > 125 and ensure adequate time above the MIC. In patients with impaired renal function, because of a longer half-life and higher area under the curve, pathogens with MIC values in the 0.5-2 μg/ml range may be treated with cefotaxime every 12 h while maintaining AUICs >125. Data are also presented for cefotaxime 2 g every 8 h alone and in combination with ofloxacin. Measured serum inhibitory titers show strengths and weakness of cefotaxime and ofloxacin monotherapies, and show that the combination often provided greater inhibitory activity than monotherapy with either agent.