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

Phase 3

Recruiting

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

• Registration Number: NCT05224401
• Lead Sponsor: Lund University

Brief Summary

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

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 Timeline

• Study First Submitted: 2021-12-14
• Study First Submitted QC: 2022-01-25
• Study First Posted: 2022-02-04
• Study Start: 2023-05-29
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-25
• Last Update Posted: 2023-08-28
• Primary Completion: 2027-09-01
• Study Completion: 2027-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 330

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PAC treatment	Pivmecillinam and amoxicillin/clavulanic acid	-
Standard treatment	Standard treatment, ciprofloxacin, trimethoprim/sulfamethoxazole or ertapenem depending on susceptibility	-

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (5)

Helsingborg hospital; 🇸🇪 Helsingborg, Sweden

Kristianstad hospital; 🇸🇪 Kristianstad, Sweden

Skåne University Hospital, Lund; 🇸🇪 Lund, Sweden

Västmanland hospital Västerås; 🇸🇪 Västerås, Sweden

Skåne University Hospital, Malmö; 🇸🇪 Malmö, Sweden