Clinical use of ceftriaxone: a pharmacokinetic-pharmacodynamic perspective on the impact of minimum inhibitory concentration and serum protein binding

Abstract

Ceftriaxone is a third-generation cephalosporin that is used for a variety of infections such as meningitis, gonorrhoea and community-acquired pneumonia. The most important aspects of its pharmacokinetics include a long half-life, excellent tissue penetration and saturable (dose-dependent) serum protein binding of the drug. A pharmacodynamic analysis [total area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC)] was performed in several populations (healthy volunteers, children, the elderly, and patients with renal and hepatic impairment) against various bacterial species (Streptococcus pneumoniae, the Enterobacteriacieae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa). AUC/MIC [area under the inhibitory time curve (AUIC)] was chosen as the pharmacodynamic parameter for this analysis since ceftriaxone is a time-dependent killer and high peak concentrations are not needed. In addition, there is a significant correlation between AUIC, time when concentration exceeds the MIC (t > MIC) and time to eradication. Total and free AUICs (assuming a free fraction = 10%) were calculated since it is highly protein bound. It was postulated that a free AUIC of at least 125 would be required to achieve efficacy. From our analysis of these various populations, we were able to conclude that the free AUIC values support the use of Ig daily in infections where MIC values are below 2 mg/L. In addition, consistent with its reported good activity against CSF organisms with MICs < or =1.0 mg/L and marginal activity against organisms with MICs > or =2.0 mg/L, we also recommend the target free AUIC values of at least 125 for patients with severe infections such as meningitis. Patients with mild infections may recover with values below 125 but they may remain at risk of the development of resistant organisms. Furthermore, it is essential to further validate these findings in patients who have received treatment, calculate AUICs and correlate these parameters with both clinical and microbiological outcomes.