Is a single daily dose the correct way to administer ceftriaxone in intensive care patients?

Introduction

The bactericidal activity of β-lactam antibiotics on gram-negative bacilli is related to the time that concentrations of antibiotic in tissues and plasma exceed a certain threshold. The effect is maximal and constant at relatively low concentrations (four times the MIC of the organism). The dosing regime should maintain these serum levels for the entire dosing interval, as there is no significant post-antibiotic effect. Pharmacokinetic data from healthy patients may not be adequate in the critically ill.

Objectives

To determine if the current recommended regimen for ceftriaxone maintains adequate serum concentrations for antibacterial efficacy in critically ill patients.

Methods

We administered ceftriaxone in the maximum recommended dose (2 g daily IV) to 10 intensive care patients without renal or hepatic failure. Plasma samples were taken at timed intervals over 24 h with a further trough sample taken on day 4. Ceftriaxone concentrations were measured by high performance liquid chromatography and analysis performed with Kinetica^™ (Simed SA, Creteil, France).

Results

The pharmacokinetics were different to reported data in healthy subjects. Vd (20.51 vs 11.11) and CI were increased (2.4 l/h vs 1.24 l/h), resulting in a similar, but slightly prolonged T_1/2 (7.2 h vs 6.1 h). However, there was large inter-patient variability in drug concentrations (Fig. 1). and four patients had plasma ceftriaxone concentrations less than the desired four times MIC (8 μg/ml) of common gram-negative organisms found in ICUs. On day 4, trough ceftriaxone concentrations were <8 μg/ml in four patients. There was no clinical predictor of which patients would have low plasma concentrations.

Conclusion

Because of large inter-patient variability in critically ill patients, the recommended dosing regimen for ceftriaxone may result in sub-optimal tissue concentrations and loss of bactericidal efficacy in some patients. This may be overcome by more frequent boluses or possibly by continuous infusion.

Figure 1

Plasma ceftriaxone concentration time curves. Hatched line at 8 μg/ml. Note three patients with sub-optimal levels for 20-40% of the dosing interval.