Clinical trial NCT05224401: Pivmecillinam With Amoxicillin/Clavulanic Acid for Step Down Oral Therapy in ESBL UTIs
Official title: Pivmecillinam With Amoxicillin/Clavulanic Acid for Step Down Oral Therapy in Febrile UTIs Caused by ESBL-producing Enterobacterales (PACUTI)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Urinary Tract Infections
Bacteremia
Antibiotic Resistant Infection
Lead sponsor: Lund University
Sponsor class: OTHER
First posted: 2022-02-04
Enrollment: 330
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Clinical cure
timeFrame: Clinical cure 10 days (+/- 2 days)
Secondary outcomes:
measure: 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).
timeFrame: Up to 28 days
measure: To compare the prevalence of EPE or carbapenemase-producing bacteria in faecal cultures 10 +/- 2 days after antibiotic treatment between groups.
timeFrame: Up to 28 days
measure: To compare participants' perception of treatment tolerability
timeFrame: 10 days
measure: To compare the incidence of early study drug discontinuation between groups.
timeFrame: 10 days
measure: To compare the incidence of additional antibiotic subscriptions (for UTI) within 28 days between groups.
timeFrame: 28 days
measure: To compare re-admission to hospital (due to UTI-related symptoms) within 28 days between groups.
timeFrame: 28 days
measure: To compare the incidence of drug-related serious adverse events (SAE) within 28 days between groups.
timeFrame: 28 days
measure: To compare the all-cause mortality within 28 days between groups.
timeFrame: 28 days
Other outcomes:
Locations:
city: Helsingborg
country: Sweden
facility: Helsingborg hospital
city: Kristianstad
country: Sweden
facility: Kristianstad hospital
city: Lund
country: Sweden
facility: Skåne University Hospital, Lund
city: Malmö
country: Sweden
facility: Skåne University Hospital, Malmö
city: Västerås
country: Sweden
facility: Västmanland hospital Västerås
Study officials:
affiliation: Lunds universitet
name: Oskar Ljungquist, MD, PhD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Västmanland Hospital Västeras
name: Emeli Månsson, MD, PhD.
role: STUDY_CHAIR
References:
citation: 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.