Principal Investigator (PI)
The Foundation is providing £502,500 in support.
NA
GSK contributes with their clinical, statistical, and analytical expertise. GSK clinicians and statisticians work with study team members (clinicians and statisticians at icddr,b) and offer advisement on methods for protocol design and outcomes analysis.
Statistical support from GSK will continue at the end of the study.
Background
Shigella is the second leading cause of diarrheal deaths worldwide (>200,000 deaths/year). Among children under 5 years, 60,000 deaths and 74,000,000 cases of diarrhea were attributed to Shigella in 2016, approximately 20% of which occurred in South Asia. In its severe form, Shigella invades the intestinal tissue resulting in the clinical manifestation of dysentery, blood or mucoid stool. The World Health Organization (WHO) recommends antibiotic therapy for children with Shigella dysentery based on evidence from randomized trials demonstrating clinical and microbiologic benefit of antibiotics for dysentery (>60% of which is caused by Shigella infections.) Oral ciprofloxacin and intravenous (IV) or intramuscular (IM) ceftriaxone are the recommend first and second line therapies, respectively. In Bangladesh, based on the prevalence of Shigella isolates with resistance to ciprofloxacin (~70%), the macrolide antibiotic azithromycin is used as a first line therapy with ceftriaxone (second-line) reserved for the most severe cases. Approximately 20% of Shigella isolates are resistant to azithromycin suggesting a substantial number of children will require second-line therapy (Dhaka hospital, data unpublished). While resistance to ceftriaxone 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. Based on rigorous pre-clinical studies establishing tebipenem-pivoxil as an efficacious therapeutic for the treatment of Shigella infection and its established safety record in pediatrics treating respiratory tract infections, we believe tebipenem-pivoxil will provide a therapeutic option for children with shigellosis that have failed first-line treatment options.
Project vision
A phase IIb randomized controlled trial (RCT) is underway (ClinicalTrials.gov ID NCT05121974 ) 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 will monitor the acquisition of antibiotic resistance, including ESBL- and carbapenemase-producing E. coli, among enrolled children to determine the clinical and public health risk of using carbapenem antibiotics in this context. Furthermore, a lead in study of 15 patients to confirm the safety profile and pharmacokinetics of tebipenem in the study population has completed. Our collaborative research team has over two decades of pediatric clinical research experience in Bangladesh and Kenya, including studies of pediatric diarrheal disease, antimicrobial resistance, and RCTs of antibiotic efficacy.
Scientific rationale
Tebipenem-pivoxil has demonstrated in vivo efficacy against multi-drug resistant Gram-negative infections in children. Our comprehensive pre-clinical in vitro and in vivo studieshave established that tebipenem-pivoxil may provide a much-needed treatment option for shigellosis in children. Based on tebipenem-pivoxil's well characterized safety and pharmacokinetic profiles in pediatrics, our team of clinicians, statisticians, epidemiologists, and drug development experts have designed a clinical trial to evaluate tebipenem-pivoxil as a treatment option in the patient population that needs it the most.