Azithromycin: MORDOR & beyond, one drug to rule them all?

Peter Doherty Institute – Melbourne Children’s Global Health Forum

The MCGH-Doherty Institute Global Health Seminar Series is a quarterly seminar series co-convened by the Peter Doherty Institute for Infection and Immunity and Melbourne Children’s Global Health. This month, the series covered three different studies on the use of azithromycin, a broad-spectrum antibiotic, to prevent neonatal and maternal infections in low-middle income countries (LMICs), with potentially transformative public health impacts and important considerations around antimicrobial resistance.

This forum featured three speakers, Dr John Hart, Professor Fiona Russell and Professor Stephen Rogerson and was chaired by Professor Andrew Steer.

Mortality Reduction after Oral Azithromycin: The MORDOR trial

Dr John Hart

The MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial was a cluster-randomised trial of the mass drug administration (MDA) of azithromycin to prevent mortality in children aged 1-59 months in Niger, Malawi and Tanzania. Dr Hart, based at the London School of Hygiene and Tropical Medicine, led the trial in Mangochi District, Malawi. MORDOR provides the best evidence to date for a beneficial effect of azithromycin MDA on child mortality, with findings indicating that the effect may be greater in higher mortality areas and in infants.

The study found 14% lower mortality in children aged 1-59 months receiving azithromycin compared to placebo. There was a relatively large effect in Niger (18% reduction in mortality), compared to results in Malawi (6%) and Tanzania (3%). The largest reduction was in the youngest age group (1-5 months). Verbal autopsy in Malawi and Niger suggested lower numbers of deaths due to pneumonia, diarrhoea, HIV, malaria and meningitis in communities where children received azithromycin. Interestingly, MORDOR found a trend towards an increasing effect of azithromycin over the course of the study.

Antimicrobial resistance is an important consideration with MDA of a broad-spectrum antibiotic and MORDOR has shown that macrolide resistance develops following biannual azithromycin MDA in children aged 1-59 months. Further trials are needed to understand the implications of this and to inform guidance on the implementation of azithromycin MDA to reduce child mortality.

Bulabula Mapei – Using azithromycin in labour to prevent maternal and infant infections in Fiji

Professor Fiona Russell

Maternal and infant infections are a significant issue in low-middle income countries (LMICs), where they cause around half of all deaths of children under five. There are around 5 million cases of maternal perinatal infections annually. Skin and soft tissue infections caused by Staphylococcus aureus and Group A Streptococcus are especially common. Impetigo is particularly problematic, affecting more than 160 million children worldwide – with the highest burden in the Pacific.

In Fiji, around 16% of neonatal deaths are due to infectious diseases. Studies have also found high rates of sexually transmitted infections in pregnant women in Fiji. The Bulabula Mapei trial aims to prevent maternal and infant infections by administering oral azithromycin during labour. The trial is a randomised blinded study being conducted with 2,110 mother/infant pairs in Colonial War Memorial Hospital, Suva. The primary outcome is a reduction in infant skin and soft tissue infections (SSTIs) up to 3 months. Secondary outcomes include antimicrobial resistance and microbiome studies. Results are forthcoming and will contribute to evidence for azithromycin alongside a number of other randomised control trials that are underway in LMICs.

Malaria in Pregnancy: Azithromycin as intermittent preventative treatment (IPTp)

Professor Stephen Rogerson

Over 100 million women globally are at risk of malaria during pregnancy each year. Malaria infection during pregnancy can lead to miscarriage, premature delivery, low birth weight (<2,500 grams), congenital infection and perinatal death. Intermittent preventative treatment (IPTp) with sulphadoxine pyrimethamine during antenatal care in some malaria endemic settings is recommended by WHO. However, increasing resistance to SP is fast reducing its effectiveness. Professor Rogerson led a randomised controlled trial of SP and azithromycin in combination as compared to one dose of SP and chloroquine, in 2,792 pregnant women in Papua New Guinea.

The trial found a 27% reduction in low birth weight for babies born to mothers who received SP and azithromycin. A 40% reduction in malaria infection at delivery was also detected, along with a 38% reduction in pre-term delivery. However, malaria prevalence in both groups was low, so it is unclear if these positive effects are due to antimalarial activity or could be attributed to reduction of sexually-transmitted infections, reduction in maternal inflammation (as indicated by alpha 1 acid glycoprotein) or improved gestational weight gain. However, results confirm that azithromycin remains a promising preventative treatment for neonatal and maternal infections in low-middle income countries (LMICs).

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