School of Medicine, University of Notre Dame Australia, Sydney, NSW, Australia.
Department of Clinical Microbiology, St Vincent's Hospital, Sydney, NSW, Australia.
J Antimicrob Chemother. 2017 Oct 1;72(10):2891-2897. doi: 10.1093/jac/dkx209.
To determine the existence of concentration-toxicity relationships for common β-lactam antibiotic adverse effects and define thresholds above which toxicity is more likely.
Retrospective review of consecutive patients treated with piperacillin, meropenem or flucloxacillin who underwent therapeutic drug monitoring (TDM) at St Vincent's Hospital (Sydney, Australia) between January 2013 and December 2015. Adverse events investigated included neurotoxicity, nephrotoxicity, hepatotoxicity and opportunistic Clostridium difficile infection. Toxicity was measured using observational grading criteria, clinical assessment and relevant serum biomarkers. These findings were correlated with trough TDM measurements at the time of toxicity presentation.
TDM results from 378 patients (piperacillin = 223, meropenem = 94 and flucloxacillin = 61) were investigated. There was no difference in baseline patient characteristics across antibiotic groups. A statistically significant elevation in mean serum trough concentrations (Cmin) was found in patients diagnosed with neurotoxicity (piperacillin, P < 0.01; meropenem, P = 0.04; flucloxacillin, P = 0.01) and those who developed nephrotoxicity whilst being treated with piperacillin (P < 0.01) or meropenem (P < 0.01). Incidence of hepatotoxicity and C. difficile was not related to Cmin. Threshold concentrations for which there is 50% risk of developing a neurotoxicity event (piperacillin, Cmin >361.4 mg/L; meropenem, Cmin >64.2 mg/L; flucloxacillin, Cmin >125.1 mg/L) or nephrotoxicity (piperacillin, Cmin >452.65 mg/L; meropenem, Cmin >44.45 mg/L) varied across antibiotics.
Our data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.
确定常见β-内酰胺类抗生素不良反应的浓度-毒性关系是否存在，并确定毒性更有可能发生的阈值。
对 2013 年 1 月至 2015 年 12 月期间在澳大利亚悉尼圣文森特医院接受哌拉西林、美罗培南或氟氯西林治疗并进行治疗药物监测（TDM）的连续患者进行回顾性分析。调查的不良事件包括神经毒性、肾毒性、肝毒性和机会性艰难梭菌感染。毒性使用观察性分级标准、临床评估和相关血清生物标志物进行测量。这些发现与毒性发生时的 TDM 测量结果相关。
对 378 名患者（哌拉西林 223 名，美罗培南 94 名，氟氯西林 61 名）的 TDM 结果进行了研究。在抗生素组之间，患者的基线特征没有差异。在诊断为神经毒性的患者中（哌拉西林，P<0.01；美罗培南，P=0.04；氟氯西林，P=0.01）和接受哌拉西林或美罗培南治疗时发生肾毒性的患者中（哌拉西林，P<0.01；美罗培南，P<0.01），发现平均血清谷浓度（Cmin）显著升高。肝毒性和艰难梭菌的发生率与 Cmin 无关。发生神经毒性事件（哌拉西林，Cmin>361.4mg/L；美罗培南，Cmin>64.2mg/L；氟氯西林，Cmin>125.1mg/L）或肾毒性（哌拉西林，Cmin>452.65mg/L；美罗培南，Cmin>44.45mg/L）的毒性浓度阈值因抗生素而异。
我们的数据显示，一些β-内酰胺类药物的毒性浓度与神经毒性/肾毒性之间存在关联。我们已经确定了这些毒性更有可能发生的阈值浓度。当考虑强化治疗时，临床医生应在关注治疗效果和潜在毒性之间取得平衡。
