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
Details
Lead Sponsor:
International Centre for Diarrhoeal Disease Research, Bangladesh