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)

Overview

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.

Interventions

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

Primary outcome measures

• Clinical cure [Time frame: Clinical cure 10 days (+/- 2 days)]

Secondary outcome measures (8)

• 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). [Time frame: 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. [Time frame: Up to 28 days]
• To compare participants' perception of treatment tolerability [Time frame: 10 days]
• To compare the incidence of early study drug discontinuation between groups. [Time frame: 10 days]
• To compare the incidence of additional antibiotic subscriptions (for UTI) within 28 days between groups. [Time frame: 28 days]
• To compare re-admission to hospital (due to UTI-related symptoms) within 28 days between groups. [Time frame: 28 days]
• To compare the incidence of drug-related serious adverse events (SAE) within 28 days between groups. [Time frame: 28 days]
• To compare the all-cause mortality within 28 days between groups. [Time frame: 28 days]

Eligibility criteria

Inclusion criteria

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

• Dysuria, urinary urgency, difficulty urinating, new or worsened urinary incontinence, macroscopic haematuria or increased urinary frequency
• Low abdominal pain or flank pain with percussion or palpation tenderness over kidneys and/or bladder.
• Urine (≥ 103 CFU/mL) and/or blood culture positive for EPE\* with susceptibility to pivmecillinam†.
• In-patient who has received 1-5 days of EPE-active‡ intravenous antibiotics
• 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)

• Known or suspected pregnancy.
• Known or suspected life-threatening allergy towards beta-lactam antibiotics.
• Clinical isolate of EPE is resistant to ciprofloxacin, TMX and ertapenem.
• Severe renal insufficiency with estimated glomerular filtration rate (eGFR) <10mL/min or requiring any form of dialysis.
• Severe decompensated liver failure (i.e., child Pugh class B or C).
• Genetic metabolic diseases associated with severe carnitine deficiency.
• Megaloblastic haematopoiesis.
• Co-treatment with valproate or valproic acid (due to interaction with pivmecillinam and ertapenem respectively)
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Sweden · 5 centers

• Helsingborg hospital — Helsingborg
• Kristianstad hospital — Kristianstad
• Skåne University Hospital, Lund — Lund
• Skåne University Hospital, Malmö — Malmö
• Västmanland hospital Västerås — Västerås

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. PMID 33087051
• 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. PMID 37660037

Identifiers

NCT: NCT05224401 · 2021-PACUTI

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗