Clarithromycin as an immunomodulator in sepsis: still a (IN)CLASS act,Critical Care

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Clarithromycin as an immunomodulator in sepsis: still a (IN)CLASS act
Critical Care ( IF 15.1 ) Pub Date : 2022-08-05 , DOI: 10.1186/s13054-022-04104-y
Timothy Arthur Chandos Snow ₁ , Antonio Cesar ₁ , Mervyn Singer ₁ , Nishkantha Arulkumaran ₁

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Dear Editor,

We read with great interest the INCLASS study by Karakike et al [1]. We commend the authors on conducting a clinical trial providing mechanistic insights, underpinned by a sound scientific rationale. While the primary objective, 28-day mortality, was unaffected by addition of clarithromycin to a beta-lactam in the management of community-acquired pneumonia, the authors report a significant reduction in sepsis recurrence associated with increased monocyte HLA-DR. The lack of mortality benefit associated with clarithromycin use is consistent with a previous study from the authors in patients with ventilator-associated pneumonia [2].

Persistent downregulation of monocyte HLA-DR expression, and lymphopenia are characteristic of sepsis-induced immunosuppression. The authors suggest a four-day course of clarithromycin may expedite recovery of monocyte HLA-DR expression by day- 10 which may, in turn, be responsible for reduced recurrence of sepsis. It would be intriguing to know if monocyte co-stimulatory molecule CD86 increased in tandem, as reported by the authors in a previous study [3]. Assessment of effector cell receptor expression (e.g., T-lymphocyte CD28 and CTLA4) would provide greater insight.

Transcriptomics were performed from total RNA isolated from whole blood, in which monocytes constitute a small proportion of the leukocyte population. Whether whole blood transcriptomic data reflect changes specifically in monocytes is questionable. This may explain why RNA sequencing data did not reveal differences in pathways regulating monocyte HLA-DR, even though HLA-DR is typically regulated at the transcriptional level via Class II transactivator (CIITA) [4]. Intuitively, a reduction in HLA-DR expression would be expected as clarithromycin inhibits protein translation via bacterial ribosomal inhibition, with human ribosomes affected at higher concentrations [5].

Although clarithromycin use was associated with a significantly lower day- 28 sepsis recurrence (67.9% vs. 30.4%), acute kidney injury was in fact, more common in patients receiving clarithromycin and mortality rates (at both 28 and 90 days) were similar between groups.

Finally, it is worth commenting on antimicrobial resistance issues. Antimicrobial resistance is now endemic in many parts of the world. The SENTRY Antimicrobial Surveillance Program, collected between 2015 and 2017, reported that 32.4% of S. pneumoniae isolates were resistant to azithromycin. The authors report that the pathogens identified in their patient population were already highly resistant (multi-drug resistant 24.4%; extremely drug-resistant 47.4%; pan-drug resistant 7.7%) on study enrollment, but do not provide data on macrolide resistance. Additionally, the emergence of macrolide-resistant organisms following clarithromycin treatment is worthy of reporting.

Whilst this trial may not have achieved its primary clinical outcome, it adds to our understanding of macrolide-induced immunomodulation. Identification of the optimal dose, time, duration and patient cohort to benefit from macrolide-induced immune modulation are yet to be realised.

Not applicable.

Karakike E, Scicluna BP, Roumpoutsou M, Mitrou I, Karampela N, Karageorgos A, et al. Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial. Crit Care. 2022;26(1):183.
Article Google Scholar
Giamarellos-Bourboulis EJ, Pechere JC, Routsi C, Plachouras D, Kollias S, Raftogiannis M, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis. 2008;46(8):1157–64.
CAS Article Google Scholar
Spyridaki A, Raftogiannis M, Antonopoulou A, Tsaganos T, Routsi C, Baziaka F, et al. Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by Gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother. 2012;56(7):3819–25.
CAS Article Google Scholar
Ting JP, Trowsdale J. Genetic control of MHC class II expression. Cell. 2002;109(Suppl):S21-33.
CAS Article Google Scholar
Svetlov MS, Koller TO, Meydan S, Shankar V, Klepacki D, Polacek N, et al. Context-specific action of macrolide antibiotics on the eukaryotic ribosome. Nat Commun. 2021;12(1):2803.
CAS Article Google Scholar

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Authors and Affiliations

Bloomsbury Institute of Intensive Care Medicine, University College London, Gower Street, London, WC1E 6DH, UK
Timothy Arthur Chandos Snow, Antonio Cesar, Mervyn Singer & Nishkantha Arulkumaran

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Timothy Arthur Chandos SnowView author publications
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Antonio CesarView author publications
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Mervyn SingerView author publications
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Nishkantha ArulkumaranView author publications
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NA and MS conceived the manuscript and provided critical review. TACS and AC drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Timothy Arthur Chandos Snow.

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The authors declare that they have no competing interests.

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Snow, T.A.C., Cesar, A., Singer, M. et al. Clarithromycin as an immunomodulator in sepsis: still a (IN)CLASS act. Crit Care 26, 238 (2022). https://doi.org/10.1186/s13054-022-04104-y

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Received: 01 July 2022
Accepted: 09 July 2022
Published: 05 August 2022
DOI: https://doi.org/10.1186/s13054-022-04104-y

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中文翻译：

克拉霉素作为败血症的免疫调节剂：仍然是（IN）CLASS 行为

亲爱的编辑，

我们非常感兴趣地阅读了 Karakike 等人的 INCLASS 研究 [1]。我们赞扬作者进行了一项临床试验，提供了机械方面的见解，并以合理的科学原理为基础。虽然主要目标 28 天死亡率不受在社区获得性肺炎治疗中将克拉霉素添加到 β-内酰胺类药物中的影响，但作者报告与单核细胞 HLA-DR 增加相关的脓毒症复发显着减少。与使用克拉霉素相关的死亡率缺乏益处与作者之前对呼吸机相关性肺炎患者的研究一致[2]。

单核细胞 HLA-DR 表达持续下调和淋巴细胞减少是脓毒症诱导的免疫抑制的特征。作者提出，为期四天的克拉霉素疗程可能会在第 10 天加速单核细胞 HLA-DR 表达的恢复，这反过来又可能有助于减少败血症的复发。正如作者在之前的一项研究中所报道的那样，了解单核细胞共刺激分子 CD86 是否同时增加会很有趣 [3]。评估效应细胞受体表达（例如，T 淋巴细胞 CD28 和 CTLA4）将提供更深入的了解。

从全血中分离的总 RNA 进行转录组学，其中单核细胞占白细胞群的一小部分。全血转录组数据是否反映了单核细胞的特异性变化是值得怀疑的。这可以解释为什么 RNA 测序数据没有揭示调节单核细胞 HLA-DR 的途径的差异，尽管 HLA-DR 通常在转录水平通过 II 类反式激活因子 (CIITA) [4] 进行调节。直观地说，预计 HLA-DR 表达会降低，因为克拉霉素通过细菌核糖体抑制来抑制蛋白质翻译，而人类核糖体在较高浓度下会受到影响 [5]。

尽管克拉霉素的使用与第 28 天的脓毒症复发率显着降低相关（67.9% 对 30.4%），但事实上，急性肾损伤在接受克拉霉素的患者中更为常见，死亡率（28 天和 90 天）之间相似团体。

最后，值得对抗菌素耐药性问题发表评论。抗菌素耐药性现在在世界许多地方流行。2015 年至 2017 年间收集的 SENTRY 抗菌药物监测计划报告称，32.4% 的肺炎链球菌分离株对阿奇霉素耐药。作者报告说，在他们的患者群体中发现的病原体在研究入组时已经具有高度耐药性（多重耐药性 24.4%；极度耐药性 47.4%；泛耐药性 7.7%），但没有提供大环内酯类耐药性的数据。此外，克拉霉素治疗后出现大环内酯类耐药微生物值得报道。

虽然该试验可能尚未达到其主要临床结果，但它增加了我们对大环内酯诱导的免疫调节的理解。尚未实现从大环内酯诱导的免疫调节中受益的最佳剂量、时间、持续时间和患者队列的确定。

不适用。

Karakike E、Scicluna BP、Roumpoutsou M、Mitrou I、Karampela N、Karageorgos A 等。静脉注射克拉霉素对脓毒症、呼吸和多器官功能障碍综合征患者的影响：一项随机临床试验。暴击护理。2022;26(1):183。
文章谷歌学术
Giamarellos-Bourboulis EJ、Pechere JC、Routsi C、Plachouras D、Kollias S、Raftogiannis M 等。克拉霉素对脓毒症和呼吸机相关性肺炎患者的影响。临床感染疾病。2008;46(8):1157-64。
CAS 文章谷歌学术
Spyridaki A、Raftogiannis M、Antonopoulou A、Tsaganos T、Routsi C、Baziaka F 等。克拉霉素对革兰氏阴性菌引起的呼吸机相关性肺炎和脓毒症患者炎症标志物的影响：一项随机临床研究的结果。抗菌剂 Chemother。2012;56(7):3819-25。
CAS 文章谷歌学术
Ting JP，Trowsdale J. MHC II 类表达的遗传控制。细胞。2002；109（增刊）：S21-33。
CAS 文章谷歌学术
Svetlov MS、Koller TO、Meydan S、Shankar V、Klepacki D、Polacek N 等。大环内酯类抗生素对真核核糖体的上下文特异性作用。纳康。2021；12（1）：2803。
CAS 文章谷歌学术

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布鲁姆斯伯里重症监护医学研究所，伦敦大学学院，高尔街，伦敦，WC1E 6DH，英国
Timothy Arthur Chandos Snow、Antonio Cesar、Mervyn Singer 和 Nishkantha Arulkumaran

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NA 和 MS 构思了手稿并提供了严格的审查。TACS 和 AC 起草了手稿。所有作者阅读并认可的终稿。

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