New Alternative to Injectable Antibiotics May be Key to Treating Neonatal Sepsis

Neonatal sepsis is a serious threat to newborn infants in developing countries, but a new study shows that rectal rather than injectable delivery of antibiotics may be far more effective at saving babies with sepsis.

According to the World Health Organization (WHO), neonatal sepsis kills about 1 million newborn infants worldwide each year. These life-threatening blood infections affect infants younger than 90 days old and are caused by bacteria such as Escherichia coli (E.coli), Listeria, and some strains of Streptococcus, as well as viruses such as herpes simplex. Mothers can pass these pathogens on to their babies before or during birth, and infants are at greater risk of developing sepsis if their mothers have Group B Streptococcus colonization if they are born preterm, and if a mother’s water breaks early in a prolonged labor. In a hospital, a baby can also become infected during extended hospitalization or from a catheter. Symptoms of sepsis in new infants include body temperature changes, breathing problems, rising or falling heart rate, swelling in the abdomen, and vomiting. Tissue damage, organ failure, and death can occur if sepsis is not properly treated.

Intravenous antibiotics are typically given to treat neonatal sepsis cases for up to 3 weeks if bacteria are found in the blood or spinal fluid. In a new paper published on October 22, 2018 in the journal Antimicrobial Agents and Chemotherapy, a team of investigators lead by scientists from the University of Bordeaux in France point out that non-injectable formulations of antibiotics are needed in the developing countries hardest hit by neonatal sepsis, noting that the lack of sterile hospital facilities leads to delays in injectable treatment. The new paper details investigators’ collaboration with pharmaceutical maker Hoffman-La Roche on the development of the first bioavailable rectal formulation of the antibiotic ceftriaxone, a broad-spectrum cephalosporin that exhibits potent activity against gram-positive and gram-negative bacteria.

"Rectal delivery of drugs for severely ill patients has been shown to be lifesaving for malaria and could achieve the same objective with neonatal sepsis, a treatable infection," the paper’s corresponding author Tina Kauss, PhD, PharmD, said in a recent statement. "A rectal antibiotic could reduce mortality by shortening lethal delays in treating critically ill newborns.”

Given alone, rectal ceftriaxone has proven to have low bioavailability, therefore not delivering enough of the antibiotic to effectively target infection. Key to the development of a highly-bioavailable rectal suppository of ceftriaxone has been finding the formulation with the right absorption enhancer. In the recent collaboration, university scientists built upon research from Hoffman La-Roche dating back to the 1980s on different absorption enhancing agents for an effective rectal form of the drug. This was made possible after Hoffman La-Roche made its unpublished reports on rectal ceftriaxone available to the WHO under confidentiality agreements.

After testing 30 absorption enhancers in rabbit models, the investigators found that a bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125 mg dose together with a 500 mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone with good tolerance in human subjects.

Now, in an interview with Contagion^®, Dr. Kauss noted that further human assessment of the formulation will begin soon, with phase I adult bioavailability studies on clinical batches planned for early 2019, followed by further neonate clinical studies. “Our experience is that a community-based trial will eventually be required in high burden countries, in order to change WHO Treatment Guidelines, national guidelines, and practice,” she said. Dr. Kauss added that the aim of getting the formulation available on the market is within 4 years.

“The target price is less than $1 per dose,” she added. “We are working with a pharmaceutical company that has these very principles in mind— high-value drugs produced at low cost and packaged in a way that makes feasible use possible in resource-poor countries.”