Background

Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment.

Methods

This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 10⁹/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60–84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329.

Findings

Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52–65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI –1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3–5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections.

Interpretation

Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating.

Funding

The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

中文翻译：

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中性粒细胞减少期间不明原因高危发热患者的碳青霉烯类短期与延长治疗：非劣效性、开放标签、多中心、随机试验

背景

对于化疗引起的中性粒细胞减少期间不明原因发热的血液病患者，提倡早期停用抗生素，但其安全性尚不清楚。我们旨在评估碳青霉烯类的短期治疗是否不劣于延长治疗。

方法

这项非劣效性、开放标签、多中心、随机试验在荷兰的六家医院进行。接受强化化疗或造血干细胞移植 (HSCT) 治疗血液系统恶性肿瘤的成年患者（≥18 岁），在高危中性粒细胞减少症期间出现不明原因发热 (<0·5 × 10 ⁹/L 预计 ≥7 天）符合条件。发热后，患者接受每天 4 次 500 mg 亚胺培南-西司他丁静脉注射或每天 3 次 1000 mg 静脉注射美罗培南。在治疗的 48 小时和 72 小时之间，参与者被随机分配（1:1）通过计算机生成的顺序接受短期（72 小时 [60-84]；短期治疗组）或延长（≥9 天直到无发热5天或中性粒细胞恢复；延长治疗组）碳青霉烯类方案。复合主要终点是治疗失败，定义为在第 4 天和第 9 天之间反复发烧或碳青霉烯敏感感染，以及从第 4 天到中性粒细胞恢复的感染性休克或呼吸衰竭或死亡。该研究旨在评估短期治疗与延长治疗方案相比的非劣效性，10% 的非劣效性边际。主要结局由一个独立结局委员会裁定，该委员会对治疗分配不知情，并在意向治疗人群和符合方案人群中进行了分析。该试验已完成并在 ClinicalTrials.gov 注册，NCT02149329。

发现

2014 年 12 月 1 日至 2019 年 7 月 1 日期间，281 名患者被纳入意向治疗分析：144 名（51%）患者被分配到短期治疗组，137 名（49%）患者被分配到延长治疗组。中位年龄为 59 岁（IQR 52-65）；109 名 (39%) 患者为女性，172 名 (61%) 为男性；205 (73%) 名患者接受了 HSCT。在意向治疗分析中，短期治疗组 144 名患者中有 28 名（19%）与延长治疗组 137 名患者中有 21 名（15%）治疗失败（调整风险差异 [ARD] 4·0% [90% CI –1·7% 至 9·7%]；p=0·25)。在符合方案分析 (n=225) 中，短期治疗组 104 名患者中有 24 名 (23%) 和延长治疗组 121 名患者中有 19 名 (16%) 治疗失败 (ARD 7·3% [0 ·3% 至 14·9%]；p=0·11)。延长治疗组 98 例不良事件中的 28 例 [29%]）、不明原因发热（20 [18%]对16 [16%] 事件）和菌血症（15 [13%]对13 [13%]事件）。短期治疗组（144 名患者中的 23 名 [16%]）的严重不良事件数量高于延长治疗组（137 名患者中的 14 名 [10%]），这是由于再入院率增加（17 [短期治疗组 12%] 的患者与延长治疗组 10 名 [7%] 的患者）。短期治疗组有 5 名 (3%) 参与者在中性粒细胞恢复后 30 天前死亡：2 人死于进行性白血病，2 人死于念珠菌血症，1 人死于粪肠球菌菌血症和药物性肺炎。在延长治疗组中，一名 (1%) 患者因念珠菌血症而死亡。没有一例死亡与碳青霉烯类敏感感染有关。

解释

原因不明的发热性中性粒细胞减少症患者早期停止碳青霉烯类药物治疗不会导致治疗失败率增加。如果患者在碳青霉烯类药物治疗 3 天后无发热，我们的研究支持短期治疗。然而，由于二次分析表明，短期治疗组持续发热的患者更常发生严重不良事件和全因死亡率，因此我们建议对非易感病原体保持警惕，并在病情恶化的患者中尽早恢复经验性治疗。

资金

荷兰卫生研究与发展组织和 Fonds NutsOhra。