Mass treatment with the antibiotic azithromycin may lead to increased drug resistance

Efforts to reduce child mortality in Africa via mass treatment with the antibiotic azithromycin (AZM) may lead to increased drug resistance in bacteria that frequently cause pneumonia and meningitis, highlighting the need for careful monitoring, finds a new study led by UCL.

The study, published in The Lancet Infectious Diseases, is a collaboration with researchers from the Malawi Liverpool Wellcome Programme, the University of Liverpool, the London School of Hygiene & Tropical Medicine, the Wellcome Sanger Institute and Yale University.

It provides the first data on how mass antibiotic drug administration (MDA) for infectious diseases - whereby all eligible members of a vulnerable population are treated with a particular drug to reduce childhood mortality - may shape bacterial populations over time, facilitating the evolution and spread of strains with antimicrobial resistance (AMR).

As a result of their findings, the authors of the study are calling for long-term genomic surveillance, which is used to track changes in the DNA of pathogens, to monitor trends in antibiotic resistance in places where MDA is used. This would allow the risks of AMR to be appropriately weighed against the benefits of MDA, and to make interventions if necessary.

Dr. Akuzike Kalizang'oma, lead researcher on the study from UCL Division of Infection & Immunity and the Malawi Liverpool Wellcome Programme, said: "Our findings highlight the potential trade-offs between MDA to improve childhood survival and increased AMR that makes common infections more difficult to treat. It is important to get the balance right.

"In high mortality regions where this type of programme is being rolled out, mortality surveillance to assess the benefits of intervention is needed, so that the risks of AMR can be appropriately weighed against the benefits of MDA. Careful monitoring using robust genomic approaches to monitor the impact of MDA, and guide the appropriate course of action to prevent resistant strains from rapidly spreading in the community is also essential."

In the study, the researchers compared samples from 452 children living in areas that received repeated rounds of AZM MDA with 453 samples from children living in areas that received a placebo. Both areas were in Mangochi, a largely rural district close to Lake Malawi.

Focusing on bacteria called Streptococcus pneumoniae (the pneumococcus), which are commonly carried at the back of the nose of children but also frequently cause life-threatening pneumonia, meningitis, and sepsis, the team used genome sequencing techniques to read the genetic information of the bacteria, in order to characterise the different pneumococcal types in circulation and identify any AMR traits that they carried.

The researchers found that in areas that had received MDA, resistance to AZM and similar antibiotics rose from 21.7% to 32.1% three and a half years after treatment concluded, and that this resistance also spread to children born in these communities subsequently.

However, resistance also increased in areas that had received a placebo, from 21% to 30.9% three and a half years post-treatment, suggesting that AMR appeared to be spreading across communities.

Additionally, S. pneumoniae strains were identified that had acquired resistance to multiple other antibiotics, including the frontline antibiotic penicillin, which is in widespread use.

The prevailing view for many years has been that resistance to macrolide antibiotics such as AZM goes away once you stop using them. We show that pneumococcal AZM resistance persists and spreads to children not exposed to the antibiotic.

There is also the view that in Africa, because macrolides are not first line treatment for most serious infections, some resistance is not that important. However, macrolides are used for treating pneumonia, and are first line treatment for cholera and drug-resistant typhoid. We show that the emergence of pneumococcal AZM resistance is frequently associated with resistance to other important antibiotics.

Without timely detection of resistant strains and intervention, these trends may become difficult to reverse."

Professor Robert Heyderman, senior author of the study from UCL Division of Infection & Immunity

Following several large clinical trials, in 2020 the World Health Organisation (WHO) published a guideline conditionally recommending MDA consisting of two doses per year of AZM among children aged one to 11 months in areas where there is high childhood mortality.

The authors stress that AZM MDA programmes remain an important tool for improving child survival in populations where mortality is unacceptably high. However, the findings of the study raise questions about the long-term impact of MDA on public health. Without timely detection and intervention, they say these trends have the potential to make common serious infections much more difficult to treat, potentially reversing the benefits of the MDA programme.

Professor Neil French, an author of the study from the University of Liverpool, said: "Antimicrobial resistance is a major global threat but particularly amongst the most vulnerable, the exact same population of children who will benefit from AZM MDA. It is essential to get the balance right between early benefits and long-term harm and ensuring efficient surveillance of these mass drug programmes will be essential."

This research was primarily funded by the Gates Foundation.