Disturbance of the Intestinal Microbiota by Temocillin vs Cefotaxime in Treatment of Febrile Urinary Tract Infections

Phase 4

Completed

Brief Summary: This study will evaluate the ecological impact on the intestinal microbiota and compare the safety and efficacy of temocillin compared to cefotaxime, in empiric treatment of febrile UTI. Half of participants will receive temocillin and the other half will receive cefotaxime.

Detailed Description: Temocillin is a narrow spectrum antibiotic with activity against gram negative bacteria inclusive many ESBL producing bacteria. Temocillin is approved and marketed in a few European countries since the 1980´s but not in Sweden.

The aim of the study is to find an ecological favorable alternative to cephalosporins in the treatment of this common indication.

The hypothesis is that treatment with temocillin causes less disturbances on the intestinal microbiota while at least comparable efficacy.

The study will be performed as an open prospective multicentre study with two parallel groups comparing 2 g temocillin three times daily with 1-2 g cefotaxim three times daily for 7-10 days in male and female adult patients with febrile urinary tract infection.

Recruitment & Eligibility

Inclusion Criteria

Males and females ≥ 18 years of age with suspected or confirmed febrile UTI, fulfilling at least one of the following signs and symptoms:
- Flank pain or suprapubic pain, Tenderness over the kidney on physical examination, Urinary symptoms such as dysuria, urinary frequency or urinary urgency
Fever ≥ 38.0°C (highest temperature recorded at home or at the hospital)
Positive urinalysis tests (U-Nitrit and/or U-LPK)
Have a pre-treatment baseline urinary culture obtained
Require iv antibacterial treatment of the presumed infection
Fertile women: Agree to practice highly effective anti-contraceptive methods from study-start to TOC
Signed informed consent

Exclusion Criteria

Have a documented history of hypersensitivity or allergic reaction to any beta-lactam
Pregnant or nursing women
Receipt of any prior potentially therapeutic antibacterial agent within 1 month before randomisation and sampling for urine and faecal cultures. Exceptions will prior treatment with pivmecillinam or nitrofurantoin.
Known chronic renal insufficiency (creatinine clearance < 10 mL/min at screening as estimated by Cockcroft-Gault), or receiving intermittent haemodialysis or peritoneal dialysis
Known colonization with ESBL
Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of study data.

Arm && Interventions

Group	Intervention	Description
Temocillin	Temocillin	Temocillin powder for solution för injection/infusion, per day 6 g (2 g three times per day). Treatment length 7-10 days of which at least 3 days administration with the study drug.
Cefotaxime	Cefotaxime	Cefotaxime powder for solution för injection/infusion, per day 3-6 g (1-2 g three times per day). Treatment length 7-10 days of which at least 3 days administration with the study drug.

Primary Outcome Measures

Name	Time	Method
Number of patients with emergence of any of the two following events: Colonisation or infection with C. difficile and/or with Enterobacteriaceae resistant to 3rd generation cephalosporins. Measured in cultures from faecal samples.	Within 12 hours after the last dose of study drug.	Superiority analysis.

Secondary Outcome Measures

Name	Time	Method
Bacteriological cure per patient and per pathogen measured as negative urine Culture <1000 CFU/ml.	7-10 days after discontinuation of antibiotic treatment (parenteral and oral).	Non-inferiority analysis.
Number of patients with early clinical response.	Within 12 hours after the 9th dose of study drug.	Non-inferiority analysis.
Early bacteriological response measured as negative urine Culture <1000 CFU/ml.	Within 12 hours after the 9th dose of study drug.	Non-inferiority analysis.
Number of patients with clinical cure in each treatment group.	7-10 days after discontinuation of antibiotic treatment (parenteral and oral).	Clinical cure defined as patient totally recovered with no remaining symptoms of UTI or no recurrence with symptoms or no need of further treatment against the current infection. Non-inferiority analysis.
Rate of patients with diarrhea (≥ 3 loose stools per day)	From the first dose of study drug until 7-10 days after discontinuation of antibiotic treatment (parenteral and oral).

Locations (12): Centralsjukhuset Kristianstad
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Kristianstad, Sweden
Västmanlands sjukhus i Västerås
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Västerås, Sweden
Karolinska University Hospital
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Solna, Stockholm, Sweden
Vrinnevisjukhuset i Norrköping
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Norrköping, Sweden
Örebro University Hospital
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Örebro, Sweden
Helsingborg Hospital
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Helsingborg, Sweden
Skåne University Hospital
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Lund, Sweden
Sundsvall Hospital
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Sundsvall, Sweden
University Hospital of Umeå
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Umeå, Sweden
Linköping University Hospital
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Linköping, Sweden
Capio S:t Görans hospital
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Stockholm, Sweden
Östersund Hospital
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Östersund, Sweden