Tebipenem Trial in Children With Shigellosis

• Status: Not yet recruiting
• Trial end date: 2024-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Background (brief):

Shigellosis is the second leading cause of death due to diarrheal diseases worldwide (>200,000 deaths/year). Though the mortality rate associated with Shigellosis has decreased, the fact that the bacteria have acquired resistance to multiple antibiotics, is a cause for major concern. Oral azithromycin and intravenous ceftriaxone are the recommend first and second line therapies, respectively in Bangladesh. Approximately 20% of Shigella isolates are resistant to azithromycin suggesting that a substantial number of children will require second-line therapy. While resistance to ceftriaxone in shigellosis is low in Bangladesh at 5%, the potential for rapid emergence of antibiotic resistance to this third-generation cephalosporin and ceftriaxone's resource-intensive delivery method, underscore the need for evidence-based alternative antibiotic regimens for multidrug resistant Shigella infections

Hypothesis:

Children treated with tebipenem-pivoxil will have no worse clinical and microbiologic failure rates compared to ceftriaxone.

Objectives:

Primary objective:

The proposed study involves aims to determine whether tebipenem-pivoxil is non-inferior to the currently WHO-recommended second line Shigella therapy (ceftriaxone).

Secondary objectives:

To describe the number of adverse events, between children with shigellosis treated with oral tebipenem-pivoxil or IV ceftriaxone.

To compare the prevalence of ceftriaxone and tebipenem-pivoxil resistance, as well as ESBL- and carbapenemase-producing E. coli, in children treated with tebipenem-pivoxil or ceftriaxone 4- and 30-days after initiation of second-line therapy.

Methods:

We propose a phase IIb randomized controlled trial (RCT) to determine the efficacy and safety of oral tebipenem-pivoxil, compared to IV ceftriaxone, for children with Shigella infections unresponsive to first-line antibiotic therapy. Bangladeshi children aged 24 to 59 months with suspected Shigella infections and no clinical improvement within 48 hours of first-line therapy will be randomized to a 3-day course of oral tebipenem-pivoxil (4 mg/kg 3x daily) or 3-days of IV ceftriaxone (50 mg/kg 1x daily). The children will be evaluated for key clinical, microbiologic, and safety outcomes during the subsequent 30-day period. Additionally, we propose a lead in study of 15 patients to confirm the safety profile and pharmacokinetics and efficacy of tebipenem in the study population. During this pharmacokinetic study period we will compare 15 children with oral Tebipenem randomizing with 15 children with oral Azithromycin arm. We will also check invitro susceptibility of Tebipenem-pivoxil in 200 shigella isolates prior to the clinical trial in collaboration with Infectious Diseases Division, icddr,b.

Outcome measures/variables:

• Clinical and microbiologic success as defined by the absence of both clinical and microbiologic failure at Day 7

• Clinical failure of test drugs as defined by the presence of fever (axillary temperature ≥38°C), diarrhoea (3 or more abnormally loose or watery stools in the last 24 hours), or blood in stool, at Day 7 of follow-up or a death prior to Day 7

• Microbiological failure as defined by the presence of Shigella in culture or Shigella DNA at quantities equal to or higher than enrolment values or Shigella isolated by microbiologic culture at Day 7.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: International Centre for Diarrhoeal Disease Research, Bangladesh
• Collaborators: GlaxoSmithKline; University of Washington
• Treatments: Azithromycin; Ceftriaxone

Criteria

Inclusion Criteria:

-Children aged 24-59 months with suspected Shigella infection (clinical features of fever, mucus and/or blood in stools, tenesmus, and RBC and leucocytes >10 per hpf)

Exclusion Criteria:

• Child received another antibiotic prior to presentation (as confirmed by bottle or prescription)

• Severe acute malnutrition (SAM), defined as weight-for-height z-score less than -3 or mid upper arm circumference less than 115mm

• Patients with other infectious foci who are potentially unresponsive to treatment with orally administered medication

• Patients in whom the efficacy and safety of the study drug is difficult to determine because of a progressive, complicated, or severe underlying disease believed to critically influence the onset of the infection, its clinical course, and therapeutic efficacy

• Patients with convulsive disorders, such as epilepsy, as an underlying disease

• Patients with a known lipid metabolism disorder or congenital carnitine deficiency

• Patients with severe hepatic or renal dysfunction

• Patients with a history of allergy to β-lactam antibiotics (e.g., carbapenems, penicillin, and cephems)

• Patients who have received other antibiotics for the illness and exhibited improvements

• Clinically improved after first-line therapy

• Unable to provide a stool sample at enrolment