Elkhaïli H, Pompei D, Peter J D, Linger L, Salmon J, Levêque D, Niedergang S, Salmon Y, Thierry R C, Monteil H, Jehl F
Institut de Bactériologie, Laboratoire de Pharmacocinétique, STRASBOURG, France.
Pathol Biol (Paris). 1997 May;45(5):347-56.
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.
纳入了3只雌性尤卡坦小型猪，通过短时间输注（30分钟）给予单剂量阿米卡星（15毫克/千克），并联合单剂量头孢吡肟或头孢匹罗（30毫克/千克/12小时）或美罗培南（7毫克/千克/8小时）。β-内酰胺类药物通过静脉间歇注射或持续输注给药。阿米卡星的平均消除半衰期和清除率分别为1.88小时和2.15毫升/分钟·千克-1。这些药代动力学参数与在人类中获得的参数相似（t1/2 = 2.42小时，Cl = 1.61毫升/分钟·千克-1）。此外，它们不受头孢吡肟、头孢匹罗和美罗培南联合给药的影响。在体外/体内小型猪模型中，产超广谱β-内酰胺酶的肺炎克雷伯菌对头孢吡肟、头孢匹罗和阿米卡星耐药，但对这些头孢菌素与阿米卡星的联合用药敏感。对于本研究中使用的六种给药方案，杀菌活性相似，在药物暴露后6小时导致至少4个对数级的下降。对于阿米卡星推注加头孢吡肟或头孢匹罗持续输注组成的抗菌联合用药，头孢吡肟给药方案的12小时血清杀菌滴度（SBTs）为1:8，头孢匹罗给药方案为1:2。当每种药物间歇给药时，头孢吡肟的12小时SBTs为1:4，头孢匹罗为1:2。含美罗培南与阿米卡星联合给药方案的8小时SBTs在30分钟短时间输注和持续输注后分别为1:4和1:16。总之，我们的研究表明小型猪模型是阿米卡星药代动力学研究的可靠模型。得出的结论是，与阿米卡星联用的受试β-内酰胺类抗生素可采用阿米卡星的标准推荐给药方案联合给药。β-内酰胺类药物持续输注联合阿米卡星单次给药似乎与每种药物间歇注射一样有效或更有效。
