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The clinical and microbiological efficacy of temocillin versus cefotaxime in adults with febrile urinary tract infection, and its effects on the intestinal microbiota: a randomised multicentre clinical trial in Sweden - 24/02/22

Doi : 10.1016/S1473-3099(21)00407-2 
Charlotta Edlund, ProfDDS a, Anders Ternhag, MD a, b, Gunilla Skoog Ståhlgren, MSciPharm a, Petra Edquist, PhD a, Åse Östholm Balkhed, MD d, Simon Athlin, MD e, Emeli Månsson, MD f, Maria Tempé, MD g, Jakob Bergström, MSciStat a, Christian G Giske, ProfMD c, h, Håkan Hanberger, ProfMD d,
on behalf of the

Temocillin Study Group

  Collaborator list provided at the end of the Article
Charlotta Edlund, Anders Ternhag, Gunilla Skoog Ståhlgren, Petra Edquist, Åse Östholm Balkhed, Simon Athlin, Emeli Månsson, Maria Tempé, Jakob Bergström, Christian G Giske, Daniel Holmström, Anna-Karin Lindgren, Gisela Otto, Maria Furberg, Johan Fält, Elin Hedman, Håkan Hanberger

a The Public Health Agency of Sweden, Solna, Sweden 
b Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Solna, Sweden 
c Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Solna, Sweden 
d Division of Infectious Diseases, Department of Biomedical and Clinical Sciences, Faculty of Medicine, Linköping University, Linköping, Sweden 
e Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden 
f Department of Infectious Diseases and Centre of Clinical Research, Västmanland Hospital, Västerås, Sweden 
g Sundsvall Härnösand Regional Hospital, Sundsvall, Sweden 
h Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden 

* Correspondence to: Prof Håkan Hanberger, Division of Infectious Diseases, Department of Biomedical and Clinical Sciences, Faculty of Medicine, Linköping University, 581 85 Linköping, Sweden Division of Infectious Diseases Department of Biomedical and Clinical Sciences Faculty of Medicine Linköping University Linköping 581 85 Sweden

Summary

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.

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