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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Bacteremia; Urinary Tract Infections; Antibiotic Resistant Infection
• Intervention / Treatment: Drug: Pivmecillinam and amoxicillin/clavulanic acid; Drug: Standard treatment, ciprofloxacin, trimethoprim/sulfamethoxazole or ertapenem depending on susceptibility

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

• Study Type: Interventional
• Enrollment (Estimated): 330
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Oskar Ljungquist, M.D, PhD; Phone Number: +46424063182; Email: oskar.ljungquist@med.lu.se
• Study Contact Backup: Name: Jonas Tverring, M.D, PhD; Phone Number: +46424062673; Email: jonas.tverring@med.lu.se

Study Locations

• Sweden
  • Helsingborg, Sweden
    • Recruiting
    • Helsingborg Hospital
    • Contact: Oskar Ljungquist, PhD
  • Kristianstad, Sweden
    • Recruiting
    • Kristianstad Hospital
    • Contact: Emil Thiman
  • Lund, Sweden
    • Recruiting
    • Skåne University Hospital, Lund
    • Contact: Christian Kampmann, PhD
  • Malmö, Sweden
    • Recruiting
    • Skåne University Hospital, Malmö
    • Contact: Johan Tham, Ass professor
  • Västerås, Sweden
    • Recruiting
    • Västmanland hospital Västerås
    • Contact: Emeli Månsson, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (any of the following)

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard treatment	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.; Other Names: Bactrim
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure	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.	Clinical cure 10 days (+/- 2 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the recurrence prevalence of EPE (phenotypically same species) in urine cultures 10 +/- 2 days after antibiotic treatment between groups (i.e., microbiological cure).	Yes or no.	Up to 28 days
To compare the prevalence of EPE or carbapenemase-producing bacteria in faecal cultures 10 +/- 2 days after antibiotic treatment between groups.	Yes or no.	Up to 28 days
To compare participants' perception of treatment tolerability	Tolerability is measured on a 1-10 scale.	10 days
To compare the incidence of early study drug discontinuation between groups.	Yes or no.	10 days
To compare the incidence of additional antibiotic subscriptions (for UTI) within 28 days between groups.	Yes or no.	28 days
To compare re-admission to hospital (due to UTI-related symptoms) within 28 days between groups.	Yes or no.	28 days
To compare the incidence of drug-related serious adverse events (SAE) within 28 days between groups.	Yes or no.	28 days
To compare the all-cause mortality within 28 days between groups.	Yes or no.	28 days

Collaborators and Investigators

• Sponsor: Lund University
• Investigators: Principal Investigator: Oskar Ljungquist, MD, PhD., Lunds Universitet; Study Chair: Emeli Månsson, MD, PhD., Västmanland hospital Västerås

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2023
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: December 14, 2021
• First Submitted That Met QC Criteria: January 25, 2022
• First Posted (Actual): February 4, 2022

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Infections; Communicable Diseases; Bacteremia; Urinary Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Cytochrome P-450 CYP2C8 Inhibitors; Ciprofloxacin; Amoxicillin; Ertapenem; Trimethoprim; Sulfamethoxazole; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Amdinocillin Pivoxil
• Other Study ID Numbers: 2021-PACUTI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Yes.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes