PACUTI: Pivmecillinam With Amoxicillin/Clavulanic Acid for Step Down Oral Therapy in ESBL UTIs

Sponsor

Lund University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05224401

Collaborator

(none)

330

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

To evaluate if the combination of pivmecillinam and clavulanic acid (PAC) is non-inferior to ciprofloxacin or trimethoprim-sulfamethoxazole as step down oral therapy in patients with febrile UTI caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales (EPE).

Condition or Disease	Intervention/Treatment	Phase
Urinary Tract Infections Bacteremia Antibiotic Resistant Infection	Drug: Pivmecillinam and amoxicillin/clavulanic acid Drug: Standard treatment, ciprofloxacin or trimethoprim/sulfamethoxazole depending on susceptibility	Phase 3

Detailed Description

A recent observational cohort study supports the notion that beta-lactams can be used with similar efficacy to fluoroquinolones as step down therapy in bacteremic E. coli UTI's. As such, pivmecillinam clavulanic acid (PAC) constitute an appealing per oral alternative, but the combination's safety and efficacy has not been evaluated in a clinical trial The aim of this trial is to investigate whether the PAC combination is non-inferior to ciprofloxacin or trimethoprim-sulfamethoxazole as step down oral therapy in treating EPE-causing febrile UTI.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

330 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Pivmecillinam With Amoxicillin/Clavulanic Acid for Step Down Oral Therapy in Febrile UTIs Caused by ESBL-producing Enterobacterales (PACUTI)

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2026

Anticipated Study Completion Date :

Sep 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PAC treatment	Drug: Pivmecillinam and amoxicillin/clavulanic acid 1 tablet pivmecillinam 400 mg and 1 tablet Amoxicillin/clavulanic acid 875/125 mg, three times daily. Other Names: Coactin or selexid etc, and Augmentin or Clavulin etc
Active Comparator: Standard treatment	Drug: Standard treatment, ciprofloxacin or trimethoprim/sulfamethoxazole depending on susceptibility Ciprofloxacin 500 mg twice daily or trimethoprim/sulfamethoxazole 800 mg/160 mg twice daily Other Names: Bactrim

Arm

Intervention/Treatment

Experimental: PAC treatment

Drug: Pivmecillinam and amoxicillin/clavulanic acid

1 tablet pivmecillinam 400 mg and 1 tablet Amoxicillin/clavulanic acid 875/125 mg, three times daily.

Other Names:

Coactin or selexid etc, and Augmentin or Clavulin etc

Active Comparator: Standard treatment

Drug: Standard treatment, ciprofloxacin or trimethoprim/sulfamethoxazole depending on susceptibility

Ciprofloxacin 500 mg twice daily or trimethoprim/sulfamethoxazole 800 mg/160 mg twice daily

Other Names:

Bactrim

Outcome Measures

Primary Outcome Measures

Clinical cure [Clinical cure 10 days (+/- 2 days)]
Clinical cure defined as being alive with absence of fever (≥ 38.3 C) and resolution of, or return to non-infected baseline of, urinary tract symptoms (as defined in inclusion criteria) without additional antibiotic treatment (for UTI symptoms) based on fever control and a semi-structured interview at a live return visit to an independent physician (i.e. not previously involved in the care of the study participant) at an infectious disease clinic.

Secondary Outcome Measures

Growth of EPE in urine culture at live return visit [Clinical cure 10 days (+/- 2 days)]
Defined as growth of identical species, with identical susceptibility pattern. Yes or no.
Growth of EPE in faecal culture at live return visit [Clinical cure 10 days (+/- 2 days)]
Yes or no.
Death from all causes within 28 days from hospital admission. [28 days]
Yes or no.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
Urine and/or blood culture positive for EPE.
In-patient who has received 1-5 days of empiric intravenous antibiotics
Fever (≥ 38.3 C) or shaking chills at least once at home or in hospital
Clinical suspicion of UTI based on at least one of the following symptoms:
Dysuria, urinary urgency, difficulty urinating or increased urinary frequency
Positive dipstick analysis including positive nitrite or leucocytes ≥ 1
Percussion/palpation tenderness over kidneys or bladder tenderness
Discontinuing parenteral treatment and starting treatment with per oral antibiotics is considered safe according to treating physician.

Exclusion Criteria:

Known or suspected allergy towards beta-lactams, fluoroquinolones or trimethoprim-sulfamethoxazole
Clinical isolate of EPE is pivmecillinam-resistant, or resistant to both ciprofloxacin and trimethoprim-sulfamethoxazole, or resistant to ciprofloxacin and the patient has eGFR below 20 mL/min (i.e. when trimethoprim-sulfamethoxazole is not recommended).
Known or suspected pregnancy
Aortic aneurysm, myasthenia gravis, long QT-syndrome, severe liver damage, genetic metabolic diseases associated with severe carnitine deficiency, creatinine clearance < 15 ml/min and/or megaloblastic haematopoiesis.
Treatment with Tizanidine (interacts with ciprofloxacin) or dofetilide (interacts with trimethoprim-sulfamethoxazole).
Other reason to which patient is unfit to be included in the study according to treating physician, e.g. cognitive impairment making the patient unable to leave informed consent or missing personal identification number complicating follow-up.