Laboratory of Veterinary Internal Medicine, Tottori University, Tottori, Japan.
Joint Graduate School of Veterinary Sciences, Tottori University, Tottori, Japan.
J Vet Med Sci. 2024 Aug 2;86(8):841-846. doi: 10.1292/jvms.24-0197. Epub 2024 Jun 18.
One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). This study applied a pharmacokinetic/pharmacodynamic (PK/PD) strategy in validating optimal latamoxef (LMX) therapeutic regimens against canine ESBL-E infections. Five dogs were administered a bolus dose of 40 mg/kg LMX intravenously to measure serum drug concentrations and determine PK indices using the noncompartmental model. The highest minimum inhibitory concentration (MIC) with a probability of target attainment ≥90% was used to compute the PK/PD cutoff values for bacteriostatic (time for which the unbound drug concentration was above the MIC [fTAM] ≥ 40%) and bactericidal (fTAM ≥ 70%) effects when administered at 20, 30, 50, and 60 mg/kg, in addition to 40 mg/kg. The cumulative fraction of response (CFR) was determined using the MIC distribution of wild-type ESBL-E in companion animals. The PK/PD cutoff values can be increased by reducing the dosing interval rather than increasing the dose per time. Based on the calculated CFRs for ESBL-producing Escherichia coli and Klebsiella pneumoniae, all LMX regimens in this study and those administered at 30-60 mg/kg every 8 and 6 hr were found to be optimal (CFR ≥ 90%) for exerting bacteriostatic and bactericidal effects, respectively. However, the regimens of 50 and 60 mg/kg every 6 hr may merely exert bacteriostatic effects on ESBL-producing Enterobacter cloacae. Further clinical trials are required to confirm the clinical efficacy of LMX.
兽医医学中最重要的研究领域之一是寻找碳青霉烯类抗生素的替代品,以治疗产生超广谱β-内酰胺酶(ESBL)的肠杆菌科(ESBL-E)。本研究应用药代动力学/药效学(PK/PD)策略来验证拉莫头孢(LMX)治疗犬 ESBL-E 感染的最佳治疗方案。给 5 只狗静脉注射 40mg/kg 的 LMX 负荷剂量,以测量血清药物浓度,并使用非房室模型确定 PK 指数。使用最高最小抑菌浓度(MIC)和目标达成概率≥90%,计算出 20、30、50 和 60mg/kg 以及 40mg/kg 时的 PK/PD 杀菌和抑菌(fTAM≥70%)切点值,其中 fTAM 是指未结合药物浓度高于 MIC 的时间(fTAM≥40%)。使用伴侣动物野生型 ESBL-E 的 MIC 分布来确定累积反应分数(CFR)。通过减少给药间隔而不是增加每次剂量,可以增加 PK/PD 切点值。根据计算出的产 ESBL 大肠埃希菌和肺炎克雷伯菌的 CFR,本研究中的所有 LMX 方案以及每 8 小时和 6 小时给予 30-60mg/kg 的方案都被发现对发挥抑菌和杀菌作用是最佳的(CFR≥90%)。然而,每 6 小时给予 50 和 60mg/kg 的方案可能仅对产 ESBL 的阴沟肠杆菌产生抑菌作用。需要进一步的临床试验来确认 LMX 的临床疗效。