Background

Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms.

Methods

NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was −10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996).

Findings

Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference −7% [95% CI −15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group).

Interpretation

In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants.

Funding

EU Seventh Framework Programme for research, technological development and demonstration.

中文翻译：

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革兰氏阳性败血症婴儿万古霉素优化剂量与标准剂量 (NeoVanc)：一项多中心、随机、开放标签、2b 期非劣效性试验

背景

万古霉素是治疗新生儿革兰氏阳性败血症最广泛使用的抗生素，但给药策略的临床结果数据很少。NeoVanc 项目包括广泛的临床前研究，为评估优化万古霉素剂量的随机对照试验提供信息。我们将优化方案与标准方案对患有已知或怀疑由革兰氏阳性微生物引起的迟发性败血症的婴儿的疗效进行了比较。

方法

NeoVanc 是一项开放标签、多中心、2b 期、平行组、随机、非劣效性试验，比较万古霉素优化方案与标准方案在 90 天或更小的婴儿中的疗效和毒性。希腊、意大利、爱沙尼亚、西班牙和英国的 22 个新生儿重症监护病房招募了至少符合 3 项临床或实验室脓毒症标准或确诊为革兰氏阳性脓毒症且至少符合 1 项临床或实验室标准的婴儿。婴儿被随机分配 (1:1) 至优化方案（25 mg/kg 负荷剂量，然后根据经后年龄每 12 小时或 8 小时 15 mg/kg，持续 5 ± 1 天）或标准方案（无负荷剂量；每 24 小时、12 小时或 8 小时 15 mg/kg（取决于月经后年龄，持续 10 ± 2 天）。通过 60 分钟输注，静脉内给予万古霉素。小组分配并未向当地调查人员或家长隐瞒。主要终点是在符合方案人群中治愈访视测试（实际万古霉素治疗结束后 10 ± 1 天）的成功，其中成功定义为参与者在治愈访视测试中存活，并获得成功实际万古霉素治疗结束时的结果，并且在实际万古霉素治疗结束后 10 天内没有出现临床或微生物学显着的复发或需要抗葡萄球菌抗生素超过 24 小时的新感染。非劣效率为-10%。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 上注册 (NCT02790996)。主要终点是在符合方案人群中治愈访视测试（实际万古霉素治疗结束后 10 ± 1 天）的成功，其中成功定义为参与者在治愈访视测试中存活，并获得成功实际万古霉素治疗结束时的结果，并且在实际万古霉素治疗结束后 10 天内没有出现临床或微生物学显着的复发或需要抗葡萄球菌抗生素超过 24 小时的新感染。非劣效率为-10%。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 上注册 (NCT02790996)。主要终点是在符合方案人群中治愈访视测试（实际万古霉素治疗结束后 10 ± 1 天）的成功，其中成功定义为参与者在治愈访视测试中存活，并获得成功实际万古霉素治疗结束时的结果，并且在实际万古霉素治疗结束后 10 天内没有出现临床或微生物学显着的复发或需要抗葡萄球菌抗生素超过 24 小时的新感染。非劣效率为-10%。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 上注册 (NCT02790996)。在实际万古霉素治疗结束时具有成功的结果，并且在实际万古霉素治疗结束后 10 天内没有出现临床或微生物学显着的复发或需要抗葡萄球菌抗生素的新感染超过 24 小时。非劣效率为-10%。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 上注册 (NCT02790996)。在实际万古霉素治疗结束时具有成功的结果，并且在实际万古霉素治疗结束后 10 天内没有出现临床或微生物学显着的复发或需要抗葡萄球菌抗生素的新感染超过 24 小时。非劣效率为-10%。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 上注册 (NCT02790996)。

发现

2017年3月3日至2019年7月29日期间，242名婴儿被随机分配到标准方案组（n=122）或优化方案组（n=120）。优化组中的 90 名婴儿和标准组中的 92 名婴儿可获得符合方案人群的主要结果数据。优化组 90 名婴儿中有 64 名（71%）和标准组 92 名婴儿中有 73 名（79%）在治愈访视测试中取得成功；未确认非劣效性（调整后的风险差异-7% [95% CI -15 至 2]）。万古霉素治疗 5 ± 1 天后临床或实验室症状不完全消退是优化组临床失败的主要因素。优化组 84 名婴儿中有 25 名（30%）听力测试结果异常，标准组 79 名婴儿中有 12 名（15%）听力测试结果异常（调整后风险比 1·96 [95% CI 1·07 至 3·59] ，p=0·030)。优化组出现 6 例万古霉素相关不良事件（1 例严重不良事件），标准组有 4 例（2 例严重不良事件）。意向治疗人群中有 11 名婴儿死亡（优化组 102 名婴儿中有 6 名[6%]死亡，标准组 98 名婴儿中有 5 名[5%]死亡）。

解释

在迄今为止进行的最大规模的新生儿万古霉素疗效试验中，没有证明负荷剂量治疗较短持续时间的明显临床影响。不建议使用优化方案，因为已发现潜在的听力安全信号；长期随访正在进行中。这些结果强调了对婴儿新型抗生素给药方案进行强有力的临床安全性评估的重要性。

资金

欧盟第七个研究、技术开发和示范框架计划。