Treatment of extended-spectrum Beta-lactamase enterobacteriaceae with cefepime: the dose matters, too.
Treatment of extended-spectrum Beta-lactamase enterobacteriaceae with cefepime: the dose matters, too.
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用头孢吡肟治疗超广谱 β-内酰胺酶肠杆菌：剂量也很重要。
DOI：
10.1093/cid/cit383
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Arias,CesarA
中科院分区：
文献类型：
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作者：
Altshuler,Jerry;Aitken,SamuelL;Guervil,David;Esaian,Diana;Papadopoulos,John;Arias,CesarA
临床感染性疾病重点研究[b]。在这项回顾性队列研究中，Lee等人发现，与碳青霉烯类药物相比，使用头孢吡肟治疗产生广谱β-内酰胺酶（ESBL）的肠杆菌科患者，17例倾向评分匹配的患者死亡率增加。这一发现仅与最低抑制浓度（mic）在2-8µg/mL范围内的生物体相关。基于他们的结果，作者得出结论，当MIC≤1 μ g/mL时，头孢吡肟治疗可能仅适用于产生esbl的生物体。尽管我们同意有有限的数据支持头孢吡肟用于产生esbl的生物体的临床应用，但基于这些结果，我们不能完全否认头孢吡肟对mic升高但易感的病原体的疗效。随着临床和实验室标准研究所最近的建议改变，即简单报告mic而不是对ESBL的产生进行确认性表型检测，假设生物体的β内酰胺酶基因是无关的，只要最常用的药物剂量bbb仍然可以达到药效学目标。事实上，安第斯和克雷格已经证明，在中性粒细胞减少小鼠模型中，无论基因型[3]如何，在70%的给药间隔内保持高于MIC的游离头孢菌素浓度都与非esbl和产生esbl的生物体的最佳微生物杀灭有关。正如Lee等人所指出的，几位作者描述了头孢吡肟在较高（2-8µg/mL） MIC范围内与生物体实现有意义的目标达到药效学概率（PTA）的困难。正如Roos等人进行的蒙特卡罗模拟所示，每12小时2 g的剂量导致危重患者群体中4 - 8 μ g/mL的病原体mic的PTA不足，而每8小时2 g能够达到有意义的PTA bb0。这些数据与Bhat等人的研究结果一致，Bhat等人表明，每12小时用1-2 g头孢吡肟治疗微生物mic为8 μ g/mL的菌血症患者死亡率高于mic较低的菌血症患者。由于本研究仅纳入了11例MIC在2-8µg/mL范围内的患者（其中5例在30天内死亡），因此很难得出头孢吡肟无效的结论，特别是没有明确MIC分布和使用的给药方案。例如，对于MIC为8 μ g/mL的生物体，是否每8小时用1 g处理5次失败？鉴于最近碳青霉烯酶产生生物的流行率增加，尽可能减少碳青霉烯类药物的使用是必不可少的。有数据表明，传统剂量的头孢吡肟（每8小时1 g或每12小时2 g）可能不足以治疗头孢吡肟mic升高（≥4 μ g/mL）的肠杆菌科感染，包括产生esbl的微生物；然而，我们不知道有任何试验评估积极的头孢吡肟剂量（每8小时2g，每6小时1g，或延长输注策略），以优化实现PTA的机会，并以较高的头孢吡肟mic治疗肠杆菌科感染。尽管碳青霉烯类药物仍然是产生esbls的生物的首选药物，但应该进行进一步的临床研究，以评估头孢吡肟的药效学优化剂量。
Clinical Infectious Diseases with great interest [1]. In this retrospective cohort, Lee et al showed that 17 propensityscore-matched patients had increased mortality when treated with cefepime, as compared to carbapenems, as definitive therapy for extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae. This finding was only relevant to organisms with minimum inhibitory concentrations (MICs) in the 2–8 µg/mL range. Based on their results, the authors conclude that cefepime therapy may only be appropriate to treat ESBL-producing organisms when the MIC is≤ 1 µg/mL. Although we agree that there are limited data supporting the clinical use of cefepime for ESBL-producing organisms, we cannot entirely dismiss the efficacy of cefepime for pathogens with elevated but susceptible MICs based on these results. With the recent change in the Clinical and Laboratory Standards Institute recommendations to simply report MICs instead of performing confirmatory phenotypic testing for ESBL production, the assumption is that the organism’s βlactamase gene is irrelevant as long as pharmacodynamic targets remain attainable with the most commonly utilized dose of the drug [2]. Indeed, Andes and Craig have shown that maintaining a free cephalosporin concentration above the MIC for 70% of the dosing interval is associated with optimal microbial killing in both non-ESBL-and ESBL-producing organisms in the neutropenic mouse model, irrespective of genotype [3]. As Lee et al point out, several authors have described the difficulty in achieving meaningful pharmacodynamic probability of target attainment (PTA) for cefepime with organisms in the higher (2–8 µg/mL) MIC ranges. As shown in the Monte Carlo simulation performed by Roos et al, a dose of 2 g every 12 hours resulted in insufficient PTA for pathogen MICs of 4–8 µg/mL in the critically ill population, whereas 2 g every 8 hours was able to achieve meaningful PTA [4]. These data are in concordance with the findings of Bhat et al, who showed that a group of bacteremic patients with organism MICs of 8 µg/mL treated with cefepime 1–2 g every 12 hours had higher mortality compared to those with lower MICs [5]. As the present study only included 11 patients (5 of whom had died at 30 days) with MICs in the 2–8 µg/mL range [1], it is difficult to conclude that cefepime is ineffective, especially without specification of the MIC distribution and dosing regimens utilized. For instance, were all 5 failures treated with 1 g every 8 hours for organisms with an MIC of 8 µg/mL? Given the recent increase in prevalence of carbapenemase-producing organisms, it is essential to minimize the use of carbapenems whenever possible. There are data suggesting that traditional doses of cefepime (1 g every 8 hours or 2 g every 12 hours) may be inadequate to treat infections due to Enterobacteriaceae with elevated cefepime MICs (≥ 4 µg/mL), including ESBL-producing organisms; however, we are not aware of any trials evaluating aggressive cefepime doses (2 g every 8 hours, 1 g every 6 hours, or extended infusion strategies) to optimize the chances of achieving PTA and treat infections due to Enterobacteriaceae with higher cefepime MICs. Although carbapenems remain the drug of choice for ESBL-producing organisms, further clinical research evaluating cefepime dosing with pharmacodynamic optimization should be performed.