Prevention of bacterial infections in the newborn by pre-delivery administration of azithromycin

Lead Research Organisation: MRC Unit, The Gambia

Abstract

The last decade has witnessed an important reduction of the mortality in children less than 5 years of age. Nevertheless, such reduction occurred mainly in children older than 1 month; no change was observed in newborns (between birth and one month of age). Mortality in this age group contributes half of all deaths occurring in children below 5 years of age. Sixteen out of the 20 countries with the highest neonatal mortality are in sub-Saharan Africa. In 1990, the United Nations established the Millennium Development Goals (MDG) aiming at improving by 2015 living conditions of the poorest populations. The MDG number 4 aims at reducing by two-thirds the under-five mortality, a result attainable only with a substantial reduction in neonatal deaths.

Technical Summary

Millennium Development Goal number 4 (MDG-4) identifies decreasing childhood mortality as a priority area for international development. Despite important reduction in under-five mortality observed in some countries, neonatal mortality has remained stable, with consequent increase in the proportion of neonatal deaths (40%) among all under five fatalities. MDG-4 is unlikely to be achieved without substantial reduction in neonatal mortality.
Sepsis is a leading cause of neonatal deaths in developing countries, mainly in sub-Saharan Africa (SSA). Neonatal sepsis is a consequence of early bacterial infection. These infections are often transmitted by the mother to the newborn, either intrapartum (vaginal canal) or during the first days of life (nasopharyngeal carriage) when the close physical contact between her and the newborn expose the latter to the risk of being infected.
In SSA, additional benefits of mass-campaigns administering one oral dose of azithromycin (AZI) for trachoma control include lower nasopharyngeal bacterial carriage and lower childhood mortality. AZI is a broad spectrum antibiotic that covers a wide range of bacteria and is suitable for being used in SSA. Though AZI is defined by the Food and Drug Administration as a pregnancy category B drug, extensive published data of randomized clinical trials show no harm for both pregnant women and newborns.
The objective of the study is to evaluate the impact of one dose of AZI given during labour on bacterial carriage of the newborn and the mother. The underlying hypothesis is that this intervention can decrease bacterial carriage both in the mother and the newborn and consequently the risk of invasive bacterial disease in the newborn. Our proof-of-concept - Phase III-b randomized clinical trial - will be conducted in a rural health facility in Gambia. If successful, next step will be a larger study evaluating the same intervention given at the lowest level of care on the incidence of neonatal sepsis.

Planned Impact

Our study opens the opportunity to impact on the Millennium Development Goal number 4 of reducing childhood mortality by 2015, a current priority in Global Health. Such an impact on under-five mortality should occur on newborns, the most vulnerable age group, by preventing neonatal bacterial infections and most likely subsequently sepsis. Along with this, the study will expand the worldwide academic knowledge on the prevention of neonatal bacterial infections, subsequent sepsis and associated mortality, using innovate methodologies.

All participants recruited for the study (720 mother/newborn pairs - two groups at very high risk of morbidity and mortality) will benefit from the intervention during birth and the follow-up period (the first month of life) as a healthy effect of the intervention. The impact of such healthy effect is marked in populations where health personnel are scarce. In addition, if our study hypothesis proves correct, children born from treated mothers will have a lower risk of nasopharyngeal bacterial carriage and consequently of sepsis.

This study will offer the opportunity for at least one PhD training fellowship (either a medical doctor to be trained in research methods of infectious diseases and global health or a laboratory-based scientist). Young West-African scientists will be preferentially selected, though the training opportunity will be open to any young researcher with the required expertise and working in an African context.

As any study conducted in a poor-resource setting, capacity building is an important component. Study staff at different levels will receive continuous training on several aspects related to clinical research such as Good Clinical Practices or Ethics. In addition, we will include specific training sessions for the field staff; laboratory technicians will be exposed, as part of the study, to a high-standard microbiological and scientific environment (WHO reference laboratory for microbiology), an almost unique opportunity in the African continent.

The final aim of our trial is to transform the proposed intervention into policy to be implemented at any level of antenatal care in Africa, including delivering women assisted by traditional birth attendants, a common practice in rural Africa where health centres are not easily accessible for a substantial proportion of the population. The potential of a major impact on early neonatal mortality with a relatively simple intervention is high. Assuming favourable results, the intervention could save hundreds of thousands of lives.

Publications

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Usuf E (2018) Maternal pneumococcal nasopharyngeal carriage and risk factors for neonatal carriage after the introduction of pneumococcal conjugate vaccines in The Gambia. in Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

 
Description International Symposium on Streptoccocus agalacatiae Disease
Amount £4,000 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2018 
End 02/2018
 
Description MRCG at LSHTM PhD Scholarship "Effect of 2g of azithromycin given to women during labour on antibiotic resistance and mechanism of gram- negative bacteria"
Amount £64,868 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2018 
End 11/2022
 
Description PhD Funding: Abdoulie Bojang
Amount £36,247 (GBP)
Organisation University of Melbourne 
Sector Academic/University
Country Australia
Start 08/2017 
End 03/2018
 
Description Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase III double-blind randomized
Amount £2,180,000 (GBP)
Funding ID MR/N022149/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 12/2020
 
Description Azithromycin measurement 
Organisation University of Western Australia
Country Australia 
Sector Academic/University 
PI Contribution We have provided the study hypotheses, study design, clinical information and samples
Collaborator Contribution This laboratory is measuring concentration of azithromycin in the breast milk samples of 40 participants of the trial
Impact The work is ongoing
Start Year 2013
 
Description Low birth weigth and bacterial infection in the vaginal tract 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Faculty of Infectious and Tropical Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution Add an additional research question to the study which is to assess maternal vaginal bacterial carriage as a risk factor for low birth weigth in the gambia
Collaborator Contribution Laboratory analysis
Impact The analysis needs yet to start.
Start Year 2016
 
Description Molecular analysis 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution Provide samples and epidemiological expertise
Collaborator Contribution Molecular analysis and resistance mechanisms
Impact PhD ongoing
Start Year 2014
 
Description Statistical Expertise and Analysis 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Department Tropical Epidemiology Group
Country United Kingdom 
Sector Academic/University 
PI Contribution Study question; design and implementation; participants recruitment and sample collection; laboratory analysis
Collaborator Contribution Statistical Expertise and Analytical plan
Impact Ongoing
Start Year 2012
 
Description Community sensitisation events 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact The community sensitisation events are regularly conducted to inform past, present and future participants in our research on the results of previous studies and upcoming new research studies and clinical trials. They serve as a link to the community decision makers and are well supported by community members and MRC researchers.

Increased participation in clincial trials and ongoign research
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description INMIS media interveiw 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact as part of the International Symposium for neonatal and maternal immunisations hick I organised in The Gambia I gave a television interview to the national media which was broadcasted on the same day
Year(s) Of Engagement Activity 2015
 
Description MRCG Annual report 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact MRC Unit The Gambia annual report shows the results of the PregnAnZI trial and the future steps
Year(s) Of Engagement Activity 2015
 
Description TAMA - Unit The Gambia journal 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Description of the trial that the Unit was going to undertake and the importance of a trial targeting new-borns who concentrate a high burden of mortality in Africa

NA
Year(s) Of Engagement Activity 2012,2014
 
Description WellCome Trust Meeting: Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation describing the results from PregnAnZI 1 and the on-going work with PregnAnZI-2.
Year(s) Of Engagement Activity 2019
 
Description Women In Science - Medical Research Council the Gambia Unit at LSHTM 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Five schools were invited to join an Open Day held at MRCG where female scientists and professionals discussed their work and career paths with groups of high school students. Additionally, a round table event was held for all MRCG staff members to discuss the obstacles for women in science.
Year(s) Of Engagement Activity 2018