ro13-9904 and Neonatal-Sepsis

The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice, and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin with ceftriaxone as first-line treatment, assessing outcome and adverse events.. This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi, from 2010 to 2013. Infants <60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge.. Three-hundred forty-eight infants were included in analyses. Outcome in the benzylpenicillin and gentamicin and ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae were 14.5% and 11.2%, respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% versus 5%, P = 0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge, 11 more infants had died, and 17 more children were found to have sequelae.. Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long-term follow-up as many poor outcomes occurred after hospital discharge.

Topics: Anti-Bacterial Agents; Bilirubin; Ceftriaxone; Gentamicins; Hearing Loss; Humans; Infant; Infant, Newborn; Malawi; Meningitis, Bacterial; Neonatal Sepsis; Penicillin G; Treatment Outcome

Current pediatric antibiotic therapies often use oral and parenteral routes of administration. Neither are suitable for treating very sick neonates who cannot take oral medication and may be several hours away from hospital in developing countries. Here, we report on the development of rectal forms of ceftriaxone, a third-generation cephalosporin. Rectodispersible tablets and capsules were developed and successfully passed 6-month accelerated stability tests. Rabbit bioavailability showed plasma concentrations above the minimal inhibitory concentrations for 3 formulations of rectodispersible tablets and 2 formulations of hard capsules. Clinical batches are currently being prepared for human evaluation with the prospect of offering therapeutic alternatives for treating critically ill neonates. This proof of concept for efficient rectal delivery of antibiotics could help the development of other rectal antibiotic treatments and increase options for noninvasive drug development for pediatric patients.

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Capsules; Ceftriaxone; Drug Compounding; Humans; Infant; Infant, Newborn; Male; Neonatal Sepsis; Rabbits; Suppositories; Tablets

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. 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 and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Topics: Administration, Rectal; Adult; Animals; Anti-Bacterial Agents; Biological Availability; Ceftriaxone; Chenodeoxycholic Acid; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Healthy Volunteers; Humans; Infant, Newborn; Intestinal Absorption; Male; Neonatal Sepsis; Papio; Rabbits; Triglycerides