Aminoglycoside Therapeutic Drug Monitoring: On Paper vs in Practice.
Aminoglycoside Therapeutic Drug Monitoring: On Paper vs in Practice.
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氨基糖苷类治疗药物监测：纸面上与实践。
DOI：
10.1093/cid/ciad446
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lewis2nd,JamesS
中科院分区：
文献类型：
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作者：
Narayanan,Navaneeth;Lewis2nd,JamesS
更新的2023年美国传染病学会（IDSA）耐药革兰氏阴性感染治疗指南（AMR指南）现在包含了氨基糖苷类（特别是庆大霉素、托布霉素和阿米卡星）治疗药物监测（TDM）建议的补充。TDM可提高抗微生物药物的有效性、安全性或两者兼有，但患者药代动力学（PK）存在差异，暴露-反应关系明确，治疗指数较窄。AMR指南恰当地推荐氨糖苷类药物（单一疗法）作为复杂尿路感染（cUTIs）和急性肾盂肾炎（AP）的一种选择。然而，要使用该选项，需要TDM，建议目标24小时曲线下面积(AUC0-24)/最小抑制浓度（MIC）比为80-100。我们愿就这项建议提出几点供审议。首先，表明氨基糖苷单药治疗cUTI/AP的有效性需要TDM的证据非常有限。从pk药效学（PK-PD）的角度来看，氨基糖苷在尿和肾组织中的浓度远远超过血浆浓度。这有助于解释为什么当血浆药物暴露覆盖野生型肠杆菌群只达到与净细菌停滞（即，对全身感染的次优抗菌活性）相关的PK-PD靶点时，这类药物对uti[3]仍然有效。从临床角度来看，在一项当代试验中，plazomicin在治疗cUTI/AP方面表现出与美罗培南相比的非劣效性，并且在不使用TDM的情况下具有相当的安全性（每组中只有2%的患者因不良事件而停止治疗）。Elbaz等人观察到，使用氨基糖苷类药物治疗住院肾盂肾炎患者的安全性和有效性类似或更好，同样不使用TDM。使用标准剂量（庆大霉素每天5mg /kg，阿米卡星每天15mg /kg），监测仅包括低谷水平以确保安全。其次，AUC0-24 /MIC作为cUTI/AP中TDM有效性度量的效用值得进一步考虑。有证据表明，AUC/MIC是与细菌杀灭（即抗菌效果）相关的最可靠的PK-PD指数。临床前模型表明，AUC/MIC比值为80-100与1-log10细菌杀灭有关，比值为30-50与净细菌停滞有关。然而，支持AUC/MIC作为预测临床结果和最佳靶点阈值的人类数据总体上有限，并且缺乏治疗cUTI/AP bbb的数据。使用任何TDM措施都需要临床证据来支持其实践实施。通常，作为一个概念框架，对于高负担疾病（如医院性肺炎），需要与≥1-log10细菌杀伤相关的PK-PD靶点，而对于uti（即非危重疾病/较低细菌负担）等适应症，则需要细菌停滞靶点[4,7,8]。正如目前临床和实验室标准研究所氨基糖苷的断点所反映的那样，每天一次的血清药物暴露为7mg /kg（庆大霉素/妥布霉素）或每天15mg /kg（阿米卡星），可以可靠地达到野生型肠杆菌细菌停滞的PK-PD目标
TO THE EDITOR—The updated 2023 Infectious Diseases Society of America (IDSA) Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections (AMR Guidance) now contains a supplement with therapeutic drug monitoring (TDM) recommendations for aminoglycosides (specifically, gentamicin, tobramycin, and amikacin)[1]. TDM enhances effectiveness, safety, or both for antimicrobials with variability in pharmacokinetics (PK) across patients, a defined exposure–response relationship, and a narrow therapeutic index. The AMR Guidance aptly recommends a full course of aminoglycosides (monotherapy) as an option for complicated urinary tract infections (cUTIs) and acute pyelonephritis (AP). However, to use this option, TDM is required with a suggested target 24-h area under the curve (AUC0–24)/minimum inhibitory concentration (MIC) ratio of 80–100. We wish to address several points for consideration regarding this recommendation. First, the evidence suggesting that TDM is required for effectiveness of aminoglycoside monotherapy for treatment of cUTI/AP is extremely limited. From a PK–pharmacodynamic (PK–PD) perspective, aminoglycosides reach concentrations in the urine and renal tissue that far exceed plasma concentrations [2]. This helps explain why this drug class remains effective for UTIs [3] when the plasma drug exposure necessary to cover a wild-type population of Enterobacterales only achieves a PK–PD target associated with net bacterial stasis (ie, suboptimal antibacterial activity for systemic infections)[4]. From a clinical perspective, in a contemporary trial, plazomicin demonstrated noninferiority to meropenem for treatment of cUTI/AP and comparable safety (only 2% in each group discontinuing treatment due to adverse events) without the use of TDM [5]. Elbaz et al [6] observed similar or superior outcomes for safety and effectiveness with an institutional program using aminoglycosides to treat hospitalized patients with pyelonephritis, also without the use of TDM for efficacy. Standard dosing was used (gentamicin 5 mg/kg daily and amikacin 15 mg/kg daily), and monitoring only included trough levels to ensure safety.Second, the utility of AUC0–24/MIC as the TDM measure for effectiveness in cUTI/AP warrants further consideration. Evidence suggests that AUC/MIC is the most robust PK–PD index associated with bacterial kill (ie, antibacterial efficacy). Preclinical models demonstrate that an AUC/MIC ratio of 80–100 is associated with a 1-log10 bacterial kill and that a ratio of 30–50 is associated with net bacterial stasis. However, data in humans supporting AUC/MIC as a measure to predict clinical outcomes and the optimal thresholds to target are limited overall and absent for treating cUTI/AP [7]. Use of any measure for TDM requires clinical evidence to support its practice implementation. Generally, as a conceptual framework, a PK–PD target associated with≥ 1-log10 bacterial kill is desired for high-burden diseases (eg, nosocomial pneumonia), while a bacterial stasis target is required for indications such as UTIs (ie, noncritically ill/lower bacterial burden)[4, 7, 8]. As reflected in current Clinical and Laboratory Standards Institute breakpoints for aminoglycosides, serum drug exposures achieved with 7 mg/kg once daily (gentamicin/tobramycin) or 15 mg/kg daily (amikacin) reliably attain PK–PD targets for bacterial stasis across a wild-type Enterobacterales