Comparison of in vivo intrinsic activity of cefepime and imipenem in a Pseudomonas aeruginosa rabbit endocarditis model: effect of combination with tobramycin simulating human serum pharmacokinetics.

OBJECTIVES The purpose of this experimental study was first to compare the in vivo intrinsic activity of imipenem and cefepime administered as a continuous infusion and to determine their lowest effective serum steady-state concentration (LESSC). Secondly, we studied the effect of combining therapy with tobramycin. METHODS In a Pseudomonas aeruginosa (ATCC 27853) rabbit endocarditis model, beta-lactam antibiotics were administered by continuous infusion over a 24 h treatment period at different doses until the LESSC was reached, i.e. able to achieve a 2-log drop of cfu/g of vegetations versus untreated animals. The effect of adding tobramycin (3 mg/kg once daily) was then studied. RESULTS The LESSC was between 3 x and 4 x MIC of cefepime for P. aeruginosa and about 0.2 5x MIC of imipenem. Combination of tobramycin with each of the two beta-lactams did not result in any further significant killing. CONCLUSION The optimal Css/MIC ratio might differ from one molecule to another. The LESSC of imipenem is lower than that of cefepime, giving a better intrinsic activity in vivo, despite a higher MIC in vitro.