Objectives: Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic-pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections.
Methods: Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data.
Results: Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects.
Conclusions: Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients.