Benzylpenicillin versus flucloxacillin or cloxacillin for the treatment of penicillin-susceptible Staphylococcus aureus bacteraemia (SNAP): an international, multicentre, open-label, non-inferiority randomised controlled trial.

Although benzylpenicillin might offer advantages in terms of pharmacokinetic and adverse effect profiles, anti-staphylococcal penicillins are recommended for serious infections because of concern over undetected penicillin resistance.

尽管苯唑西林在药代动力学和不良反应特征方面可能具有优势，但由于担心未检测到的青霉素耐药性，因此推荐使用抗葡萄球菌青霉素治疗严重感染。

We aimed to compare benzylpenicillin with anti-staphylococcal penicillins (cloxacillin or flucloxacillin) for the treatment of PSSA bacteraemia in adults.

我们旨在比较苯唑西林与抗葡萄球菌青霉素（氯唑西林或氟氯西林）治疗成人PSSA菌血症的效果。

Methods

This investigator-initiated, international, multicentre, open-label, non-inferiority, randomised controlled trialwas conducted within the PSSA silo of the backbone domain of the ongoing S aureus Network Adaptive Platform (SNAP) trial. We enrolled patients of all ages who were admitted with S aureus bacteraemia at 67 hospitals across Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa.

这项由研究者发起的、国际性的、多中心的、开放标签的、非劣效性、随机对照试验是在正在进行的S aureus网络适应性平台（SNAP）试验的PSSA领域内进行的。我们在澳大利亚、新西兰、加拿大、以色列、荷兰、英国、新加坡和南非的67家医院中招募了所有年龄的患者，他们因S aureus菌血症而入院。

Herein, we report results for adult patients (aged ≥18 years).

在此，我们报告了成年患者（年龄≥18岁）的研究结果。

Participants were randomly allocated 1:1 to receive either benzylpenicillin, or flucloxacillin or cloxacillin.

参与者被随机分配为1:1，分别接受青霉素G、氟氯西林或氯唑西林治疗。

Trial staff, staff caring for participants, and participants were aware of the treatment allocated and received.

试验工作人员、照顾参与者的工作人员以及参与者均知晓分配的治疗和接受的治疗。

Cloxacillin was used only where flucloxacillin was not available (ie, Canada, Israel, Singapore, and South Africa).

仅在氟氯西林不可用的情况下使用克罗沙星（例如，在加拿大、以色列、新加坡和南非）。

Recommended standard dosing for benzylpenicillin was 1·8 g intravenously once every 4 h or 2·4 g once every 6 h; for flucloxacillin 2·0 g intravenously once every 6 h; and for cloxacillin 2·0 g intravenously once every 4 h.

推荐的苯唑西林标准剂量为每4小时静脉注射1.8克或每6小时静脉注射2.4克；氟氯西林为每6小时静脉注射2.0克；而氯唑西林为每4小时静脉注射2.0克。

The primary outcome was all-cause mortality 90 days after platform entry, assessed in the intention-to-treatpopulation, including all patients with available data.

主要结果是平台进入后90天的全因死亡率，在意向治疗人群中进行评估，包括所有有可用数据的患者。

The primary outcome was analysed by use of a hierarchical Bayesian logistic regression model, with non-inferiority of benzylpenicillin defined as an adjusted odds ratio (OR) of less than 1·20.

主要结果通过使用分层贝叶斯逻辑回归模型进行分析，其中青霉素G的非劣效性定义为调整后的比值比（OR）小于1.20。

Analyses occurred after every 500 participants reached 90-day follow-up.

分析在每500名参与者达到90天随访后进行。

The SNAP trial is registered with ClinicalTrials.gov (NCT05137119) and is ongoing.

SNAP试验已在ClinicalTrials.gov注册（NCT05137119），目前正在进行中。

Results

Following the fourth interim analysis, the data and safety monitoring committee recommended ceasing recruitment before prespecified stopping thresholds were reached because of increased acute kidney injury (AKI) in participants receiving flucloxacillin or cloxacillin, and the PSSA silo was closed for recruitment on Aug 7, 2024.

在第四次中期分析后，数据和安全监测委员会建议在达到预定的停止阈值之前停止招募，原因是接受氟氯西林或氯唑西林治疗的参与者中急性肾损伤（AKI）的病例增加，因此PSSA招募通道已于2024年8月7日停止接受新参与者。

Between Feb 18, 2022, and June 21, 2024, of 493 adults with PSSA bacteraemia, 125 were randomly assigned to the flucloxacillin or cloxacillin group and 156 to the benzylpenicillin group.

在2022年2月18日至2024年6月21日期间，493名患有PSSA菌血症的成年人中，125人被随机分配到氟氯西林或氯唑西林组，156人被分配到苯唑西林组。

The median age was 67 years (IQR 56-77), 87 (31%) were female, and 194 (69%) were male. 21 (14%) of 152 in the benzylpenicillin group and 26 (22%) of 121 in the flucloxacillin or cloxacillin group met the primary outcome of death at 90 days (adjusted OR 0·67, 95% credible interval [CrI] 0·35-1·28), with a posterior probability of benzylpenicillin non-inferiority of 96·1% and of benzylpenicillin superiority of 88·9%.

中位年龄为67岁（四分位数间距56-77），女性87人（31%），男性194人（69%）。在苯唑西林组的152人中有21人（14%），在氟氯西林或氯唑西林组的121人中有26人（22%）在90天内达到了主要结局——死亡（调整后的OR为0.67，95%可信区间[CrI]为0.35-1.28），苯唑西林的非劣效性后验概率为96.1%，苯唑西林的优越性后验概率为88.9%。

AKI occurred in 17 (11%) of 153 patients in the benzylpenicillin group and 27 (22%) of 124 patients in the flucloxacillin or cloxacillin group (adjusted OR 0·50, 95% CrI 0·26-0·94), corresponding to a posterior probability of non-inferiority of benzylpenicillin of 99·8% and superiority of benzylpenicillin of 98·4%.

在153名接受苯唑西林治疗的患者中，有17名（11%）发生了急性肾损伤（AKI），而在124名接受氟氯西林或氯唑西林治疗的患者中，有27名（22%）发生了AKI（调整后的优势比为0.50，95%可信区间为0.26-0.94），这表明苯唑西林的非劣效性后验概率为99.8%，苯唑西林的优势后验概率为98.4%。

Seven total serious adverse reactions were reported from six (4%) of 156 participants in the benzylpenicillin group and ten were reported from nine (7%) of 125 participants in the flucloxacillin or cloxacillin group.

在156名接受苯唑西林治疗的参与者中，有6名（4%）报告了7例严重不良反应，而在125名接受氟氯西林或氯唑西林治疗的参与者中，有9名（7%）报告了10例严重不良反应。

interpretation

Although the prespecified non-inferiority criterion for benzylpenicillin was not met, the probability of benzylpenicillin being non-inferior for mortality, along with a reduction in risk of AKI, indicates that benzylpenicillin should be preferred over flucloxacillin or cloxacillin for treatment of PSSA bacteraemia in adults.

尽管青霉素B的预设非劣效标准未达到，但青霉素B在死亡率上具有非劣效的可能性，以及降低急性肾损伤（AKI）风险，表明对于成人PSSA菌血症的治疗，青霉素B应优于氟氯西林或氯唑西林。

funding

National Health and Medical Research Council, Medical Research Future Fund, Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, UMC Utrecht, ZonMW Good Use of Medicines programme, Health Research Council of New Zealand, Starship Foundation, National Healthcare Group Fund, National Medical Research Council, National Institute for Health and Care Research, Medical Research Council, and Paterson Family Foundation.

国家卫生与医学研究委员会、医学研究未来基金、加拿大健康研究院、加速临床试验联盟、乌特勒支大学医学中心、ZonMW合理用药计划、新西兰健康研究委员会、Starship基金会、国家医疗集团基金、国家医学研究委员会、国家健康与护理研究所、医学研究委员会以及Paterson家族基金会。