The clinical and microbiological effect of temocillin versus cefotaxime in adults with febrile urinary tract infection, and its effects on the intestinal microbiota: a randomized multicenter clinical study in Sweden
The use of third-generation cephalosporins, such as cefotaxime, is associated with an increased risk of selection for antimicrobial resistance, so alternative antibiotics must be considered. The purpose of this study was to evaluate bowel colonization with third-generation cephalosporin-resistant pathogens after using temocillin – an alternative antibiotic to cefotaxime that is potentially less likely to interfere with intestinal microbiota – in empirical treatment of febrile urinary tract infection (UTI).
We conducted a randomized, multicenter, superior, open phase 4 study in patients who had been admitted to inpatient care at 12 Swedish hospitals with suspected or diagnosed febrile UTI (complicated or uncomplicated). To meet the inclusion criteria, a patient was required to have at least one sign or symptom of pyelonephritis (ie, flank pain, tenderness angle, and changes in urinary frequency or urgency or dysuria), 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 who opened consecutive sealed randomization envelopes generated centrally in advance. Both drugs were administered intravenously every 8 hours. The study was open to investigators and patients, but those who performed the microbiological analyzes were masked for the groups. Participants were treated with antibiotics for 7-10 days (or up to 14 days if they had bacteremia), of which at least 3 days on the study drug; at day 4 and later, participants who showed improvement could be given an oral antibiotic (ciprofloxacin, ceftibuten, cefixime or co-trimoxazole). Patients who did not show improvement were considered to have failed treatment. Rectal swabs were collected at three time points: at baseline (before the first dose), after the last dose of the study medicine, and 7–10 days after the end of treatment. The composite primary outcome was colonization with Enterobacterales with reduced susceptibility to third generation cephalosporins, or colonization with toxin-producing Clostridioides difficult, or both, to evaluate disturbance of the intestinal microbiota. The study is registered in the EU Clinical Trials Register (EudraCT 2015-003898-15).
Between 20 May 2016 and 31 July 2019, 207 patients were screened for qualification, of which 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 compared with 30 (48%) of 62 patients receiving cefotaxime (difference in risk −22% [95% CI
−42% to −3%]), which shows superiority of temocillin compared to cefotaxime (ie less disturbance of the intestinal microbiota). 43 adverse reactions were reported in 40 (52%) of 77 patients in the temocillin group, compared with 46 adverse reactions in 34 (45%) of 75 patients in the cefotaxime group. Most events were of mild to moderate severity. 21 (27%) patients on temocillin and 17 (23%) patients in the cefotaxime group had a side effect that was considered to be associated with the study drug.
Temocillin was found to be less selective than cefotaxime from Enterobacterales with reduced sensitivity to third-generation cephalosporins, and could therefore be a favorable alternative in the empirical treatment of febrile UTIs. Use of this antibiotic may reduce hospitalization and healthcare-associated infections of these pathogens.
The Swedish Public Health Agency.