Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response—the new regulatory endpoint for community-acquired pneumonia—and explored the possible contribution of modulation of the inflammatory host response to that outcome. The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and (). Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7–40·3]; odds ratio [OR] 3·40 [95% CI 2·06–5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI –2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

中文翻译：

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克拉霉素治疗希腊社区获得性肺炎的早期抗炎反应（ACCESS）：一项随机、双盲、安慰剂对照试验

在β-内酰胺抗生素中添加大环内酯类抗生素来治疗住院社区获得性肺炎患者是基于观察性研究和荟萃分析的结果，而不是随机临床试验的结果。我们研究了在该人群中使用 β-内酰胺抗生素治疗时添加大环内酯克拉霉素是否可以改善早期临床反应（社区获得性肺炎的新监管终点），并探讨了调节炎症宿主反应对该结果的可能贡献。 ACCESS 试验是一项 3 期前瞻性、双盲、随机对照试验，受试者为患有社区获得性肺炎、患有全身炎症反应综合征、序贯器官衰竭评估 (SOFA) 评分为 2 分或以上、降钙素原为 0 分的住院成人。 ·希腊公立医院的 18 个内科部门登记了 25 ng/mL 或以上。通过计算机生成的分组随机化将患者随机分配 (1:1) 至标准护理药物（包括静脉注射第三代头孢菌素或静脉注射 β-内酰胺加 β-内酰胺酶抑制剂组合）加口服安慰剂或口服克拉霉素 500 mg，每日两次，持续 7 天。研究人员、工作人员和患者对分组分配情况不知情。主要复合终点要求患者在 72 小时（即治疗第 4 天）后满足以下两个条件：(1) 呼吸道症状严重程度评分降低 50% 或更多，作为早期临床反应的指标；(2) SOFA 评分下降至少 30% 或有利的降钙素原动力学（定义为较基线下降 ≥80% 或降钙素原 <0·25 ng/mL），或两者兼而有之，作为早期炎症反应的指标。随机分配并接受分配治疗的参与者被纳入主要分析人群。该试验已完成并已在欧盟临床试验注册处注册 (2020-004452-15) 和 ()。患者于 2021 年 1 月 25 日至 2023 年 4 月 11 日期间入组，278 名患者被随机分配接受标准护理联合克拉霉素 (n=139) 或安慰剂 (n=139)。主要终点分析包括克拉霉素组 134 名患者（5 名撤回同意）和安慰剂组 133 名患者（6 名撤回同意）。克拉霉素组有 91 名 (68%) 患者达到主要终点，安慰剂组有 51 名 (38%) 患者达到主要终点（差异 29·6% [95% CI 17·7–40·3]；比值比 [OR ] 3·40 [95% CI 2·06–5·63]；p<0·0001）。克拉霉素组有 58 名患者 (43%) 发生严重治疗相关不良事件 (TEAE)，安慰剂组有 70 名患者 (53%)（差异 9·4% [95% CI –2·6 至 20·9] ]；OR 0·67 [95% CI 0·42 至 1·11]；p=0·14)。没有任何严重的 TEAE 被判定与治疗分配相关。在标准护理中添加克拉霉素可增强早期临床反应并减轻社区获得性肺炎的炎症负担。获益机制与免疫反应的变化有关。这些发现表明，在β-内酰胺类药物中添加克拉霉素对于治疗社区获得性肺炎住院患者以实现早期临床反应和早期减轻炎症负担具有重要意义。希腊脓毒症研究所和雅培产品运营。