Background

Use of third-generation cephalosporins, such as cefotaxime, is associated with an increased risk of selection for antimicrobial resistance, so alternative antibiotics need to be considered. The aim of the present study was to evaluate intestinal colonisation with third-generation cephalosporin-resistant pathogens following use of temocillin—an alternative antibiotic to cefotaxime that is potentially less prone to disturbing the intestinal microbiota—in empirical treatment of febrile urinary tract infection (UTI).

Methods

We did a randomised, multicentre, superiority, open-label phase 4 trial in patients who had been admitted to inpatient care in 12 Swedish hospitals with suspected or diagnosed febrile UTI (complicated or uncomplicated). To meet inclusion criteria, a patient was required to have at least one sign or symptom of pyelonephritis (ie, flank pain; costovertebral angle tenderness; and changes to urinary frequency or urgency or dysuria), a fever of 38·0°C or higher, and a positive urine dipstick (for nitrites, white blood cells, or both). Participants were also required to have an indication for intravenous antibiotic treatment. Participants were randomly assigned (1:1) to receive either 2 g temocillin or 1–2 g cefotaxime, by local investigators opening consecutive sealed randomisation envelopes that were generated centrally in advance. Both drugs were administered intravenously every 8 h. The trial was open label for investigators and patients, but those doing the microbiological analyses were masked to the groups. Participants were treated with antibiotics for 7–10 days (or up to 14 days if they had bacteraemia), at least 3 days of which were on the study drug; at day 4 and later, participants who were showing improvement could be given an oral antibiotic (ciprofloxacin, ceftibuten, cefixime, or co-trimoxazole). Patients not showing improvement were regarded as having treatment failures. Rectal swabs were collected at three timepoints: at baseline (before the first dose), after the last dose of study drug, and 7–10 days after treatment stopped. The composite primary outcome was colonisation with Enterobacterales with reduced susceptibility to third-generation cephalosporins, or colonisation with toxin-producing Clostridioides difficile, or both, to evaluate disturbance of the intestinal microbiota. The study is registered in the EU Clinical Trials Register (EudraCT 2015-003898-15).

Findings

Between May 20, 2016, and July 31, 2019, 207 patients were screened for eligibility, of whom 55 patients were excluded. 152 participants were randomly assigned to groups: 77 (51%) patients received temocillin, 75 (49%) patients received cefotaxime. The composite primary endpoint was met by 18 (26%) of 68 participants receiving temocillin versus 30 (48%) of 62 patients receiving cefotaxime (risk difference −22% [95% CI −42% to −3%]), showing superiority of temocillin versus cefotaxime (ie, less disturbance of the intestinal microbiota). 43 adverse events were reported in 40 (52%) of 77 patients in the temocillin group, versus 46 adverse events in 34 (45%) of 75 patients in the cefotaxime group. Most events were of mild to moderate severity. 21 (27%) patients in the temocillin and 17 (23%) patients in the cefotaxime group had an adverse event that was considered to be associated with the study drug.

Interpretation

Temocillin was found to be less selective than cefotaxime of Enterobacterales with reduced susceptibility to third-generation cephalosporins, and it could therefore be a favourable alternative in the empirical treatment of febrile UTI. Use of this antibiotic could reduce hospital transmission and health-care-associated infections by these pathogens.

Funding

Public Health Agency of Sweden.

中文翻译：

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替莫西林与头孢噻肟对成人发热性尿路感染的临床和微生物学疗效及其对肠道微生物群的影响：瑞典的一项随机多中心临床试验

背景

使用第三代头孢菌素，如头孢噻肟，会增加选择抗生素耐药性的风险，因此需要考虑替代抗生素。本研究的目的是评估使用替莫西林（一种可能不太容易干扰肠道微生物群的头孢噻肟的替代抗生素）在发热性尿路感染（UTI）的经验性治疗中对第三代头孢菌素耐药病原体的肠道定植）。

方法

我们对 12 家瑞典医院的疑似或诊断为发热性尿路感染（复杂或不复杂）的住院患者进行了一项随机、多中心、优效性、开放标签的 4 期试验。为满足纳入标准，要求患者至少有一种肾盂肾炎的体征或症状（即，腰痛；肋椎角压痛；尿频或尿急或排尿困难的变化），发烧 38·0°C 或更高和阳性尿液试纸（用于亚硝酸盐、白细胞或两者）。参与者还需要有静脉抗生素治疗的适应症。参与者被随机分配 (1:1) 接受 2 g 替莫西林或 1-2 g 头孢噻肟，当地研究人员打开预先集中生成的连续密封随机信封。两种药物每 8 小时静脉注射一次。该试验对研究人员和患者开放，但进行微生物分析的人员对这些组不知情。参与者接受了 7-10 天的抗生素治疗（如果他们患有菌血症，则最多 14 天），其中至少 3 天服用研究药物；在第 4 天及之后，表现出改善的参与者可以口服抗生素（环丙沙星、头孢替布、头孢克肟或复方新诺明）。没有表现出改善的患者被视为治疗失败。在三个时间点收集直肠拭子：基线（第一次给药前）、最后一剂研究药物后和治疗停止后 7-10 天。复合主要结果是肠杆菌定植，对第三代头孢菌素的敏感性降低，艰难梭菌，或两者兼而有之，以评估肠道微生物群的紊乱。该研究已在欧盟临床试验注册 (EudraCT 2015-003898-15) 中注册。

发现

2016 年 5 月 20 日至 2019 年 7 月 31 日期间，筛选了 207 名患者的资格，其中 55 名患者被排除在外。152 名参与者被随机分组​​：77 名（51%）患者接受替莫西林治疗，75 名（49%）患者接受头孢噻肟治疗。接受替莫西林治疗的 68 名参与者中有 18 人（26%）达到了复合主要终点，而接受头孢噻肟治疗的 62 名患者中有 30 人（48%）达到了复合主要终点（风险差异 -22% [95% CI -42% 至 -3%]），显示出优势替莫西林与头孢噻肟比较（即对肠道微生物群的干扰较小）。替莫西林组 77 名患者中有 40 名（52%）报告了 43 次不良事件，而头孢噻肟组 75 名患者中有 34 名（45%）报告了 46 次不良事件。大多数事件的严重程度为轻度至中度。

解释

发现替莫西林比肠杆菌的头孢噻肟选择性低，对第三代头孢菌素的敏感性降低，因此它可能是发热性尿路感染经验性治疗的有利替代品。使用这种抗生素可以减少这些病原体的医院传播和与医疗保健相关的感染。

资金

瑞典公共卫生署。