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.
OBJECTIVE
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.


CONCLUSIONS
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.
Navas
Dominique
D
Laboratoire d'Antibiologie (UPRES EA-1156), UER de Médecine, 1 rue Gaston Veil, 44035 Nantes Cedex 01, France.
Caillon
Jocelyne
J
Gras-Le Guen
Christele
C
Jacqueline
Cédric
C
Kergueris
Marie-France
MF
Bugnon
Denis
D
Potel
Gilles
G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use*; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011817:Rabbits; D014031:Tobramycin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D015378:Imipenem; D000077723:Cefepime; D014031:Tobramycin