脉冲式高剂量 L-AmB 作为高危腹腔念珠菌病患者的预防性治疗的耐受性：一项 2 期研究（LAMBDA 研究）。

Tolerability of pulsed high-dose L-AmB as pre-emptive therapy in patients at high risk for intra-abdominal candidiasis: A phase 2 study (LAMBDA study).

机构信息

Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

出版信息

Int J Antimicrob Agents. 2023 Dec;62(6):106998. doi: 10.1016/j.ijantimicag.2023.106998. Epub 2023 Oct 12.

DOI:10.1016/j.ijantimicag.2023.106998

PMID:37838147

Abstract

BACKGROUND

Intra-abdominal candidiasis (IAC) has a high mortality rate. However, the correct management of a critically ill patient with suspected IAC remains unclear. The aim of this study was to evaluate the safety of pulsed high-dose liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a beta-D-glucan (BDG)-guided strategy.

METHODS

This phase 2 prospective study enrolled adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5 mg/kg on day 1. On day 3, L-AmB was discontinued in patients with a negative basal BDG result, and continued (3 mg/kg/daily) in patients with a positive basal BDG result or microbiologically confirmed IAC. The primary endpoint was the occurrence of adverse events, defined using the Common Toxicity Criteria classification.

RESULTS

In total, 40 patients were enrolled from January 2019 to August 2022. Fifteen (37.5%) patients were male, and the median age was 65 [interquartile range (IQR) 49-76] years. Thirty-one (77.5%) patients underwent urgent surgery, and the principal indication was secondary/tertiary peritonitis (n=22, 55%); half of the patients had undergone a previous surgical operation within the preceding 30 days. Five (12.5%) patients met the criteria for septic shock at enrolment. The median APACHE II score on admission to the intensive care unit was 12 (IQR 10-15). IAC was excluded in 33 (85%) patients, but IAC was probable and proven in five (12.5%) and two (5%) patients, respectively. The single dose of L-AmB 5 mg/kg was well tolerated in all patients, and no early or late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. The all-cause 30-day mortality rate was 15%, and no deaths were related to L-AmB administration or uncontrolled IAC. The mortality rates for patients with and without proven IAC were 0% and 15.8%, respectively (P=0.99).

CONCLUSIONS

The rate of proven IAC among critically ill high-risk patients was low (5%). A single dose of L-AmB 5 mg/kg, with prompt withdrawal in the case of a basal negative BDG result, seems to be a safe and effective approach in this population.

摘要

背景

腹腔内念珠菌病（IAC）死亡率很高。然而，对于疑似 IAC 的危重症患者，正确的处理方法仍不明确。本研究旨在评估在β-D-葡聚糖（BDG）指导策略下，接受脉冲高剂量脂质体两性霉素 B（L-AmB）治疗的疑似 IAC 患者的安全性。

方法

本项 2 期前瞻性研究纳入了手术后合并腹腔内脓毒症的成年患者。患者在第 1 天接受单次 5mg/kg L-AmB 治疗。第 3 天，如果基础 BDG 结果为阴性，则停止使用 L-AmB，如果基础 BDG 结果为阳性或微生物学证实 IAC，则继续使用 L-AmB（3mg/kg/天）。主要终点是根据通用毒性标准分类评估不良事件的发生情况。

结果

2019 年 1 月至 2022 年 8 月，共纳入 40 例患者。15 例（37.5%）患者为男性，中位年龄为 65 岁[四分位距（IQR）：49-76]。31 例（77.5%）患者接受了紧急手术，主要指征为继发性/三级腹膜炎（n=22，55%）；一半的患者在过去 30 天内接受过手术。入组时，5 例（12.5%）患者符合感染性休克标准。入住重症监护病房时，急性生理学与慢性健康状况评分系统 II 评分的中位数为 12（IQR：10-15）。33 例（85%）患者排除了 IAC，而 5 例（12.5%）和 2 例（5%）患者 IAC 可能性大，证实 IAC。所有患者均能耐受单次 5mg/kg L-AmB 治疗，未报告与药物相关的早期或晚期严重不良事件。65%的患者在基础 BDG 结果阴性后停止使用 L-AmB。全因病死率为 15%，无死亡与 L-AmB 给药或未控制的 IAC 相关。证实 IAC 患者和未证实 IAC 患者的 30 天病死率分别为 0%和 15.8%（P=0.99）。