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

NCT ID: NCT05224401

Last Updated: 2023-08-28

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

330 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-05-29

Study Completion Date

2027-09-01

Brief Summary

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

Detailed Description

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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, trimethoprim-sulfamethoxazole or ertapenem as step down oral therapy in treating EPE-causing febrile UTI.

Conditions

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Urinary Tract Infections Bacteremia Antibiotic Resistant Infection

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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PAC treatment

Group Type EXPERIMENTAL

Pivmecillinam and amoxicillin/clavulanic acid

Intervention Type DRUG

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

Standard treatment

Group Type ACTIVE_COMPARATOR

Standard treatment, ciprofloxacin, trimethoprim/sulfamethoxazole or ertapenem depending on susceptibility

Intervention Type DRUG

Ciprofloxacin 500 mg twice daily, trimethoprim/sulfamethoxazole 800 mg/160 mg twice daily or ertapenem 1 g once daily.

Interventions

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Pivmecillinam and amoxicillin/clavulanic acid

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

Intervention Type DRUG

Standard treatment, ciprofloxacin, trimethoprim/sulfamethoxazole or ertapenem depending on susceptibility

Ciprofloxacin 500 mg twice daily, trimethoprim/sulfamethoxazole 800 mg/160 mg twice daily or ertapenem 1 g once daily.

Intervention Type DRUG

Other Intervention Names

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Coactin or selexid etc, and Augmentin or Clavulin etc Bactrim

Eligibility Criteria

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Inclusion Criteria

1. Age ≥ 18 years
2. Fever (≥ 38.3 C) or shaking chills at least once at home or in hospital
3. Clinical suspicion of UTI including at least one of the following symptoms:

1. Dysuria, urinary urgency, difficulty urinating, new or worsened urinary incontinence, macroscopic haematuria or increased urinary frequency
2. Low abdominal pain or flank pain with percussion or palpation tenderness over kidneys and/or bladder.
4. Urine (≥ 103 CFU/mL) and/or blood culture positive for EPE\* with susceptibility to pivmecillinam†.
5. In-patient who has received 1-5 days of EPE-active‡ intravenous antibiotics
6. Discontinuing parenteral treatment and starting treatment with oral antibiotics is considered safe according to the treating physician.

* EPE refers to ESBL-producing Enterobacterales. This includes Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, and Citrobacter koseri.

* Susceptibility for pivmecillinam in the study is based on zone diameter breakpoints for pyelonephritis (≥ 20 mm) which was received by personal communication with professor Christian Giske, the chairman of the European Committee of Antimicrobial Susceptibility Testing (EUCAST) (26).

* EPE-active intravenous antibiotics refers to EUCAST susceptibility testing and will most often be piperacillin-tazobactam, meropenem or imipenem-cilastatin in the Swedish setting, and less often aminoglycosides or newer beta-lactamase-inhibitor-containing beta-lactam antibiotics (27). Participants who have only received one dose of EPE-active intravenous antibiotics are also eligible and are considered within the "1-5 days" of antibiotics.

Patients may only be recruited and randomised once in this trial.

Exclusion Criteria

1. Known or suspected pregnancy.
2. Known or suspected life-threatening allergy towards beta-lactam antibiotics.
3. Clinical isolate of EPE is resistant to ciprofloxacin, TMX and ertapenem.
4. Severe renal insufficiency with estimated glomerular filtration rate (eGFR) \<10mL/min or requiring any form of dialysis.
5. Severe decompensated liver failure (i.e., child Pugh class B or C).
6. Genetic metabolic diseases associated with severe carnitine deficiency.
7. Megaloblastic haematopoiesis.
8. Co-treatment with valproate or valproic acid (due to interaction with pivmecillinam and ertapenem respectively)
9. Other reason to which patient is unfit to be included in the study according to treating physician, e.g., cognitive impairment preventing informed consent and follow-up, inability to speak and/or read Swedish, missing national personal identification number or missing telephone number preventing follow-up or planned duration of antibiotics \> 10 days due to complicating factors.
Minimum Eligible Age

18 Years

Maximum Eligible Age

130 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Lund University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Oskar Ljungquist, MD, PhD.

Role: PRINCIPAL_INVESTIGATOR

Lunds universitet

Emeli Månsson, MD, PhD.

Role: STUDY_CHAIR

Västmanland Hospital Västeras

Locations

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Helsingborg hospital

Helsingborg, , Sweden

Site Status RECRUITING

Kristianstad hospital

Kristianstad, , Sweden

Site Status RECRUITING

Skåne University Hospital, Lund

Lund, , Sweden

Site Status RECRUITING

Skåne University Hospital, Malmö

Malmo, , Sweden

Site Status RECRUITING

Västmanland hospital Västerås

Västerås, , Sweden

Site Status RECRUITING

Countries

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Sweden

Central Contacts

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Oskar Ljungquist, M.D, PhD

Role: CONTACT

+46424063182

Jonas Tverring, M.D, PhD

Role: CONTACT

+46424062673

Facility Contacts

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Oskar Ljungquist, PhD

Role: primary

Emil Thiman

Role: primary

Christian Kampmann, PhD

Role: primary

Johan Tham, Ass professor

Role: primary

Emeli Månsson, PhD

Role: primary

References

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Saad S, Mina N, Lee C, Afra K. Oral beta-lactam step down in bacteremic E. coli urinary tract infections. BMC Infect Dis. 2020 Oct 21;20(1):785. doi: 10.1186/s12879-020-05498-2.

Reference Type BACKGROUND
PMID: 33087051 (View on PubMed)

Tverring J, Mansson E, Andrews V, Ljungquist O. Pivmecillinam with Amoxicillin/Clavulanic acid as step down oral therapy in febrile Urinary Tract Infections caused by ESBL-producing Enterobacterales (PACUTI). Trials. 2023 Sep 2;24(1):568. doi: 10.1186/s13063-023-07542-3.

Reference Type DERIVED
PMID: 37660037 (View on PubMed)

Other Identifiers

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2021-PACUTI

Identifier Type: -

Identifier Source: org_study_id

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