MICA: Developing a rectal formulation of ceftriaxone for community-based management of neonatal sepsis in low- and middle-income countries

Neonatal sepsis (life-threatening infection in infants aged below 28 days of age) is the single greatest cause of preventable death in children living in tropical countries, being responsible for more than half a million of the estimated 2.4 million deaths that occur each year. Most deaths occur at or near home. Prompt administration of effective antibiotics by injection is life saving, but is usually not possible in the rural tropics where health centres are frequently several hours' journey away from home. Alternative strategies are needed to deliver effective treatment at the community level.
Since 2012 we have worked on the pharmaceutical development of a suppository formulation of ceftriaxone. Ceftriaxone is an antibiotic used to treat severe infections, including meningitis, which has the advantage of being dosed just once day because it is a long-acting medicine. Our goal is to make effective community-based neonatal sepsis treatment feasible at low cost, and therefore used early and widely enough to prevent a substantial proportion of neonatal deaths from sepsis in high-burden low- and middle-income countries. We have developed several prototype suppositories already and we are ready to move testing into humans. We have an industrial partner (Orofino Pharmaceuticals) who has evaluated our candidate formulations for feasibility for industrial production and has lowered the cost of producing the absorption enhancer that will be combined with the antibiotic in the formulation. In this research project we plan to manufacture two different suppositories and assess how well they are absorbed in healthy adults in Thailand first. Based on absorption and safety results from this study we will then select the leading formulation to be tested in babies. We plan to give 60 babies who are in hospital under treatment for an infection one dose of the suppository in addition to their usual treatment and evaluate the absorption of antibiotic in the suppository. If ceftriaxone is absorbed adequately by this route and is well-tolerated, we will assess this formulation in large trials to measure impact on mortality, with the longer term goal of including the treatment in global treatment guidelines. This would pave the way for widespread uptake in high burden low- and middle-income countries.

Neonatal sepsis is the single greatest cause of preventable death in children living in tropical countries, being responsible for more than half a million of the estimated 2.4 million deaths that occur each year. Most deaths occur at or near home. Prompt administration of effective antibiotics by injection is life saving, but is usually not possible in the rural tropics where health centres are frequently several hours' journey away. Alternative strategies are needed to deliver effective treatment at the community level.
Since 2012 we have worked on the pharmaceutical development of a rectal formulation of ceftriaxone, a broad spectrum, slowly eliminated, and widely-used antibiotic. The objective is to make effective community-based neonatal sepsis treatment feasible at low cost, and therefore used early and widely enough to prevent a substantial proportion of neonatal deaths from sepsis in high-burden low- and middle-income countries (LMICs). Roche gave us access to data from prior studies of intra-rectal ceftriaxone in animals and man showing bioavailability sufficient for treatment of serious infections. We developed several prototypes, and tested pre-clinical bioavailability, confirming earlier results. Our industrial partner (Orofino), has evaluated our candidate formulations for feasibility for industrial production and has lowered the cost of producing the absorption enhancer. The next steps are to i) manufacture GMP clinical batches, ii) evaluate bioavailability and tolerability of two formulations in healthy adults and iii) assess absorption and tolerability of the leading formulation in sick neonates. If rectal ceftriaxone is absorbed adequately and is well-tolerated, we will assess this formulation in field trials to measure impact on mortality, with the goal of including rectal formulations of ceftriaxone in World Health Organization Treatment Guidelines. This would pave the way for widespread uptake in high burden LMICs.