Mentec H, Vallois J M, Bure A, Saleh-Mghir A, Jehl F, Carbon C
Institut National de la Santé et de la Recherche Médicale U13, Hôpital Claude Bernard, Paris, France.
Antimicrob Agents Chemother. 1992 Sep;36(9):1883-9. doi: 10.1128/AAC.36.9.1883.
The efficacy of tazobactam, a beta-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extended-spectrum beta-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 micrograms/ml, MBC = 8 micrograms/ml with 10(7)-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 micrograms/ml). Tazobactam (1 microgram/ml) restored the activity of piperacillin against KpR (MIC = 2 micrograms/ml, MBC = 4 micrograms/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 micrograms/ml for KpS and KpR, respectively). The piperacillin-tazobactam-gentamicin combination was synergistic in vitro. The piperacillin/tazobactam ratio in plasma and in vegetations was always lower than the 4/1 injected dose ratio. In vivo, piperacillin (300 mg/kg of body weight four times a day [QID]) was active against KpS but not against KpR. Tazobactam (75 mg/kg QID) was able to restore the in vivo effect of piperacillin (300 mg/kg QID) against KpR (-3.0 log10 CFU/g of vegetation versus that of controls). Gentamicin (4 mg/kg twice a day [BID]) was active against both strains. Compared with controls, the combination of gentamicin plus piperacillin against KpS (-5.6 log10 CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against KpR (-4.4 log10 CFU/g of vegetation) achieved the greatest decrease in bacterial counts in vegetations and were the only regimens that significantly increased the proportion of sterile vegetations. It is concluded that (i) tazobactam was able to restore the effect of piperacillin against a TEM-3 extended-spectrum Beta-lactamase-producing strain of K. pneumoniae, both in vitro and in a severe experimental infection with high inoculum, when used in a 4/1 piperacillin/tazobactam dose ratio; (ii) gentamicin alone was effective because of the high peak/MBC ratio in plasma; (iii) piperacillin-tazobactam-gentamicin, probably because of the effect of gentamicin in reducing bacterial inoculum in vivo, as stressed by the results obtained by piperacillin-gentamicin against KpS, may be the most effective regimen against KpR.
对一种β-内酰胺酶抑制剂他唑巴坦与哌拉西林联合用药的疗效进行了体外研究，并在兔实验性心内膜炎模型中进行了研究，该模型的病原体为一株产生超广谱β-内酰胺酶TEM-3的肺炎克雷伯菌（KpR）或其不产酶变体（KpS）。体外实验中，哌拉西林对KpS有活性（接种量为10⁷CFU/ml时，MIC = 4μg/ml，MBC = 8μg/ml），但对KpR无活性（MIC = MBC = 256μg/ml）。他唑巴坦（1μg/ml）恢复了哌拉西林对KpR的活性（MIC = 2μg/ml，MBC = 4μg/ml）。庆大霉素对两种菌株均有活性（KpS和KpR的MIC分别为0.25和0.5μg/ml）。哌拉西林-他唑巴坦-庆大霉素联合用药在体外具有协同作用。血浆和赘生物中的哌拉西林/他唑巴坦比值始终低于注射剂量比4/1。体内实验中，哌拉西林（300mg/kg体重，每日4次[QID]）对KpS有活性，但对KpR无活性。他唑巴坦（75mg/kg QID）能够恢复哌拉西林（300mg/kg QID）对KpR的体内疗效（与对照组相比，赘生物中细菌计数减少3.0 log₁₀CFU/g）。庆大霉素（4mg/kg，每日2次[BID]）对两种菌株均有活性。与对照组相比，庆大霉素加哌拉西林治疗KpS（赘生物中细菌计数减少5.6 log₁₀CFU/g）以及庆大霉素-哌拉西林-他唑巴坦联合治疗KpR（赘生物中细菌计数减少4.4 log₁₀CFU/g）使赘生物中的细菌计数下降幅度最大，且是仅有的能显著增加无菌赘生物比例的治疗方案。结论如下：（i）当以4/1的哌拉西林/他唑巴坦剂量比使用时，他唑巴坦能够在体外以及在高接种量的严重实验性感染中恢复哌拉西林对产TEM-3超广谱β-内酰胺酶的肺炎克雷伯菌菌株的疗效；（ii）由于血浆中庆大霉素的高峰浓度/MBC比值较高，庆大霉素单药治疗有效；（iii）哌拉西林-他唑巴坦-庆大霉素联合用药可能是因为庆大霉素在体内降低细菌接种量的作用（如哌拉西林-庆大霉素治疗KpS所显示的结果）而成为针对KpR最有效的治疗方案。
