Oral step-down, optimal drug, and total duration of antibiotic treatment in African children hospitalised with severe community-acquired pneumonia (PediCAP): a factorial randomised controlled trial.

We aimed to investigate the safety of a step-down to different oral antibiotics and the shortest effective duration.

我们旨在研究降低至不同口服抗生素的安全性以及最短有效治疗持续时间。

Methods

PediCAP was an open-label, parallel group, 2 × 5 factorial randomised controlled trialof children aged 2 months to 6 years hospitalised with severe CAP without complicating factors in 13 hospitals across five sub-Saharan African countries.

PediCAP是一项开放标签、平行组、2×5因素的随机对照试验，针对2个月至6岁因重症社区获得性肺炎(CAP)住院且无并发症的儿童，该试验在撒哈拉以南非洲五个国家的13家医院进行。

Children weighing 3-30 kg and with point-of-care C-reactive protein of more than 10 mg/L were randomly assigned (5:5:1) to either a step-down from intravenous antibiotics to oral amoxicillin (250 mg) or amoxicillin-clavulanate (co-amoxiclav; 200 mg amoxicillin to 28·5 mg clavulanate) via dispersible tablets twice daily (superiority comparison) for five total (intravenous plus oral) durations (4-8 days; non-inferiority comparison), or a 5-day, fixed-duration, intravenous-only treatment (non-inferiority comparison).

体重在3-30公斤之间且床旁C反应蛋白超过10 mg/L的儿童，按照5:5:1的比例随机分配到以下三组之一：一组是从静脉抗生素逐步过渡到口服阿莫西林（250毫克）或阿莫西林-克拉维酸（co-amoxiclav；200毫克阿莫西林对28.5毫克克拉维酸）通过分散片每日两次（优势比较），总疗程（静脉加口服）为4-8天（非劣效比较）；另一组是为期5天的固定疗程，仅使用静脉注射治疗（非劣效比较）。

Children were stepped down when clinically improved and able to take oral antibiotics.

患儿在临床症状改善且能够口服抗生素时，可以降级治疗。

Clinicians could change antibiotics if clinically indicated.

如果临床需要，临床医生可以更换抗生素。

The primary outcome was the proportion of readmission or death at day 28 (non-inferiority margin vs intravenous only: +10%).

主要结果是28天内再次入院或死亡的比例（非劣效性边界与仅静脉给药相比：+10%）。

The study was registered with the ISRCTN registry (ISRCTN63115131) and is complete.

该研究已在ISRCTN注册（ISRCTN63115131），研究已完成。

Results

Between Dec 7, 2020, and Aug 14, 2023, 2248 children were screened for eligibility and 1101 were randomly allocated (480 [43·6%] girls and 621 [56·4%] boys).

在2020年12月7日至2023年8月14日期间，共有2248名儿童进行了资格筛查，其中1101名儿童被随机分配（480名[43.6%]女孩和621名[56.4%]男孩）。

The primary outcome was available in 1055 (95·8%) children.

主要结果在1055名（95.8%）儿童中可获得。

For children in the step-down groups, the mean total antibiotic exposure was 6·0 days (SD 3·5) in the 4-day group, 6·8 days (4·2) in the 5-day group, 7·4 (3·6) in the 6-day group, 8·3 days (3·4) in the 7-day group, and 9·2 days (2·9) in the 8-day group (p<0·0001), with 140 (68·6%) of 204, 151 (76·3%) of 198, 167 (85·2%) of 196, 179 (89·5%) of 200, and 186 (91·6%) of 203, respectively, stepping down within their randomised duration (p<0·0001).

在降级治疗组的儿童中，平均总抗生素暴露时间在4天组为6.0天（标准差3.5），5天组为6.8天（4.2），6天组为7.4天（3.6），7天组为8.3天（3.4），8天组为9.2天（2.9）（p<0.0001），分别有140名（68.6%）的204名，151名（76.3%）的198名，167名（85.2%）的196名，179名（89.5%）的200名，以及186名（91.6%）的203名在随机化治疗期间内降级（p<0.0001）。

Primary outcomes occurred in 33 (6·9%) of 475 in the co-amoxiclav group, 27 (5·6%) of 484 in the amoxicillin group, and six (6·3%) of 96 in the intravenous-only group, with both oral step-down strategies non-inferior to the intravenous-only strategy (upper 95% CIs of 6·0 for co-amoxiclav and 5·7 for amoxicillin) and no evidence of superiority for co-amoxiclav over amoxicillin (adjusted risk difference 1·3% [95% CI -1·8 to 4·4]; p=0·40).

在475名接受阿莫西林克拉维酸组的儿童中，主要结果发生在33名（6.9%），在484名接受阿莫西林组的儿童中，主要结果发生在27名（5.6%），在仅静脉组的96名儿童中，主要结果发生在6名（6.3%），两种口服降级策略均不劣于仅静脉策略（阿莫西林克拉维酸的95%置信区间上限为6.0，阿莫西林的95%置信区间上限为5.7），并且没有证据表明阿莫西林克拉维酸优于阿莫西林（调整后的风险差异为1.3% [95%置信区间-1.8至4.4]；p=0.40）。

Primary outcomes occurred in eight (4·1%) of 194 in the 4-day group, ten (5·3%) of 190 in the 5-day group, 16 (8·5%) of 188 in the 6-day group, 16 (8·3%) of 193 in the 7-day group, and ten (5·2%) of 194 in the 8-day group; all durations were non-inferior to the 8-day group (all upper 95% CIs ≤6·0%).

主要结果发生在194名4天组中的8人（4.1%），190名5天组中的10人（5.3%），188名6天组中的16人（8.5%），193名7天组中的16人（8.3%），以及194名8天组中的10人（5.2%）；所有治疗时长均不劣于8天组（所有95%置信区间上限≤6.0%）。

There was no evidence of consistent differences in adverse events for oral antibiotic or duration comparisons.

在口服抗生素或治疗时长的比较中，没有证据表明不良事件存在一致的差异。

For antibiotic-related or serious adverse events, there was one (1·0%) in the intravenous-only group and 12 (2·5%) in the amoxicillin group (adjusted risk difference -2·3% [95% CI -4·2 to -0·3]; p=0·025), and 16 (3·4%) in the co-amoxiclav group (+0·8% [-1·2 to 2·8]; p=0·42); rates increased with randomised duration (slope estimate +0·9% [0·1 to 1·7]; p=0·032).

在抗生素相关或严重不良事件方面，单独静脉给药组有1例（1.0%），阿莫西林组有12例（2.5%）（调整后风险差异-2.3% [95% 置信区间-4.2至-0.3]；p=0.025），而阿莫西林/克拉维酸组有16例（3.4%）（+0.8% [-1.2至2.8]；p=0.42）；随随机化治疗时间延长，发生率增加（斜率估计+0.9% [0.1至1.7]；p=0.032）。

interpretation

For sub-Saharan African children hospitalised with severe CAP without complicating factors, a strategy of stepping down upon clinical improvement to oral amoxicillin after initial intravenous antibiotics, with a total treatment duration of 4-5 days, is non-inferior to WHO-recommended 5-day intravenous treatment.

对于没有并发症的撒哈拉以南非洲住院儿童，严重社区获得性肺炎（CAP）的治疗策略是，在初始静脉注射抗生素后，一旦临床症状改善，改为口服阿莫西林治疗，总治疗时间为4-5天，这种策略与世界卫生组织推荐的5天静脉注射治疗相比，具有非劣效性。

funding

The Second European and Developing Countries Clinical Trials Partnership (EDCTP2).

第二个欧洲与发展中国家临床试验伙伴关系（EDCTP2）。