[In vivo pharmacokinetic of amikacin and its pharmacodynamic in combination with cefepime, cefpirome and meropenem in an in vitro/ex vivo micropig model].
Three female Yucatan micropigs were included and received a single dose of amikacin (15 mg/kg) by short infusion (30 min) combined either with a single dose of cefepime or cefpirome (30 mg/kg/12 h) or meropenem (7 mg/kg/8 h). The beta-lactams were administered either by intravenous intermittent injection or by continuous infusion. The mean elimination half-life and clearance value of amikacin were 1.88 h and 2.15 ml/min.kg-1 respectively. These pharmacokinetic parameters were similar to those obtained in man (t1/2 = 2,42 h et Cl = 1,61 ml/min kg-1). Furthermore, they were not affected by coadministration of cefepime, cefpirome and to meropenem. While resistant to cefepime, cefpirome and amikacin, Klebsiella pneumoniae producing ESBL was susceptible to combination of these cephalosporins with amikacin in an in vitro/ex vivo micropig model. For the six dosage regimens used in this study, the killing activities were similar and resulted in at least 4 log decrease at 6 h after drug exposure. For antimicrobial combination consisting of bolus dosing of amikacin plus continuous infusion of cefepime or cefpirome, the 12 h serum bactericidal titers (SBTs) were 1:8 for cefepime and 1:2 for cefpirome dosage regimen. When each drug administered intermittently, the 12 h SBTs were 1:4 for cefepime and 1:2 for cefpirome. The 8 h SBTs for dosing schedule containing meropenem combined with amikacin were 1:4 and 1:16 after 30 min short infusion and continuous infusion respectively. In conclusion, our study showed that the micropig model is a reliable model for pharmacokinetic investigation of amikacin. It was concluded that beta-lactam antibiotics tested with amikacin may be coadministered by using the standard recommended dosing regimen of amikacin. Continuous infusion of beta-lactams combined with once dosing of amikacin seems to be as or more effective than intermittent injection of each drug.
Elkhaïli
H
H
Institut de Bactériologie, Laboratoire de Pharmacocinétique, STRASBOURG, France.
Pompei
D
D
Peter
J D
JD
Linger
L
L
Salmon
J
J
Levêque
D
D
Niedergang
S
S
Salmon
Y
Y
Thierry
R C
RC
Monteil
H
H
Jehl
F
F
D000583:Amikacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D000077731:Meropenem; D010477:Perfusion; D015610:Serum Bactericidal Test; D013552:Swine; D013845:Thienamycins / Q000008:administration & dosage*; D000097572:Cefpirome
D000583:Amikacin; D000900:Anti-Bacterial Agents; D000077723:Cefepime; D002511:Cephalosporins; D000077731:Meropenem; D013845:Thienamycins; D000097572:Cefpirome