Mavridou Eleftheria, Melchers Ria J B, van Mil Anita C H A M, Mangin E, Motyl Mary R, Mouton Johan W
Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
Antimicrob Agents Chemother. 2015 Feb;59(2):790-5. doi: 10.1128/AAC.03706-14. Epub 2014 Nov 17.
MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producing Pseudomonas aeruginosa and Klebsiella pneumoniae strains to determine its effect in vitro and in vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5×10(6) CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits for T>MIC and area under the concentration-time curve (AUC)/MIC were comparable (R2 of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activity in vivo and results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans.
MK7655是一种新开发的A类和C类碳青霉烯酶β-内酰胺酶抑制剂。测定了亚胺培南-西司他丁（IMP/C）和MK7655在腹腔注射剂量为4mg/kg至128mg/kg体重时的药代动力学（PK）。对几种产β-内酰胺酶的铜绿假单胞菌和肺炎克雷伯菌菌株进行了MK7655的最低抑菌浓度（MIC）和药效学（PD）研究，以确定其体外和体内效果。在用约5×10⁶CFU的接种物治疗前2小时，对中性粒细胞减少的小鼠每条大腿进行感染。它们单独用IMP/C（每2小时[q2h]，不同剂量）或在剂量分割研究中与MK7655联合使用，或q2h给药24小时，然后处死以进行CFU测定。IMP/MK7655降低了关于IMP MIC的MIC值。在研究的给药范围内，IMP/C和MK7655的PK曲线呈线性，分布容积（V）分别为0.434和0.544升/千克，半衰期（t1/2）分别为0.24和0.25小时。MK7655的蛋白结合率为20%。将一个S形最大效应（Emax）模型拟合到PK/PD指数反应。抑制剂的效果与血清中药物的最大浓度（Cmax）/MIC无关，T>MIC和浓度-时间曲线下面积（AUC）/MIC的模型拟合相当（R²分别为0.7和0.75），但似乎效果与给药频率没有显著关系。递增剂量的MK7655和IMP/C表明，产生静态效应所需的MK7655的AUC取决于IMP/C的剂量和菌株的MIC，药物游离、未结合部分的浓度-时间曲线下平均面积（fAUC）为26.0mg·小时/升。MK7655在体内显示出显著活性，并使IMP/C在其他耐药菌株中产生疗效。所发现的暴露-反应关系可为确定人类给药方案提供依据。
