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.
This is according to a recent study led by University College London, published in The Lancet Infectious Diseases, 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 also follows recommendations by the European Medical Association’s human medicines committee (CHMP) for several changes to how azithromycin is used, including a warning to highlight the risk of antimicrobial resistance. As reported in MedicalBrief, it said the medication should only be initiated after a careful assessment of the benefits and the risks – considering the local prevalence of resistance – and when preferred treatment regimens are not indicated.
The latest study 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 study authors 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), commonly carried at the back of children’s noses but which also frequently cause life-threatening pneumonia, meningitis, and sepsis, the team used genome sequencing techniques to read the genetic information of the bacteria to characterise the different pneumococcal types in circulation and identify any AMR traits they carried.
They 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 commonly used.
“The prevailing view for many years has been that resistance to macrolide antibiotics – such as AZM – goes away once you stop using them,” said Professor Robert Heyderman, senior author of the study from UCL Division of Infection & Immunity
“We show that pneumococcal AZM resistance persists and spreads to children not exposed to the antibiotic.”
He added that there was 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.”
After 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 among 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.”
Study details
Long-term effects of azithromycin mass administration to reduce childhood mortality on Streptococcus pneumoniae antimicrobial resistance: a population-based, cross-sectional, follow-up carriage survey
Akuzike Kalizang'oma, Jia Mun Chan, Khumbo Kalua et al.
Published in The Lancet on 2 June 2025
Summary
Background
Mass drug administration (MDA) programmes with the macrolide antibiotic azithromycin to reduce childhood mortality are expanding in Africa; however, concerns remain about the long-term effects of these programmes on antimicrobial resistance (AMR). We aimed to evaluate the persistence and spread of Streptococcus pneumoniae AMR following a community-randomised MDA trial.
Methods
This population-based, cross-sectional, pneumococcal carriage survey was conducted in Mangochi, Malawi, 3·5 years after the MORDOR trial, in which communities received twice-yearly azithromycin or placebo for 2 years. Eligible participants in this carriage survey were children aged 4–9 years who lived in an azithromycin-treated or placebo-treated cluster during the MORDOR trial, and children aged 1–3 years who were resident in a cluster but born after the MORDOR trial ended. Nasopharyngeal swabs were collected from participants and analysed by whole genome sequencing; pneumococcal genomes obtained from a distant site in Malawi, in which MDA had not been conducted, were used as reference genomes. The primary outcome was the prevalence of S pneumoniae macrolide resistance, comparing placebo-treated and azithromycin-treated clusters at baseline, 6 months post-MDA, and 3·5 years post-MDA.
Findings
Between April 8 and May 14, 2021, 924 children aged 1–9 years were screened, of whom 19 were excluded and 905 were recruited to the follow-up carriage survey: 452 from azithromycin-treated clusters and 453 from placebo-treated clusters of the MORDOR trial. We assessed 426 isolates from these participants (190 from azithromycin-treated clusters and 236 from placebo-treated clusters), as well as samples from the baseline of the MORDOR trial (164 isolates; 83 from azithromycin-treated clusters and 81 from placebo-treated clusters) and from 6 months post-MDA (223 isolates; 119 from azithromycin-treated clusters and 104 from placebo-treated clusters). In azithromycin-treated clusters, macrolide resistance increased from 21·7% (95% CI 14·2–31·7; 18 of 83 isolates) at baseline to 31·9% (24·2–40·8; 38 of 119 isolates) 6 months post-MDA and to 32·1% (25·9–39·0; 61 of 190 isolates) 3·5 years post-MDA. In placebo-treated clusters, resistance increased from 21·0% (13·5–31·1; 17 of 81 isolates) at baseline to 25·0% (17·7–34·1; 26 of 104 isolates) 6 months post-MDA and to 30·9% (25·4–37·1; 73 of 236 isolates) 3·5 years post-MDA. No significant differences were observed in odds ratios between treatment groups across the survey timepoints: 0·97 (95% CI 0·36–2·55) at baseline, 1·46 (0·67–3·17) at 6 months post-MDA, and 1·12 (0·66–1·91) at 3·5 years post-MDA. Macrolide resistance in the non-MDA site remained stable: 16·9% (95% CI 12·8–21·8; 45 of 267 isolates) at baseline, 16·5% (13·3–20·3; 70 of 424 isolates) at 6 months, and 16·5% (12·5–21·4; 44 of 267 isolates) at 2·5 years. Among children born into azithromycin-treated clusters after MDA, macrolide resistance was 36·0% (27·7–45·1; 41 of 114 children). Multidrug resistance to at least three antibiotic classes was significantly higher in azithromycin-treated (p=0·0015) and placebo-treated (p<0·0001) clusters than in the comparator population at 3·5 years post-MDA and was associated with integrative conjugative elements.
Interpretation
Azithromycin MDA is associated with macrolide resistance that persists and potentially spreads to untreated populations. The co-existence of multidrug resistance and transmissible resistance on integrative conjugative elements in these populations is a public health concern. Careful monitoring of AMR is essential in areas where MDA is implemented.
See more from MedicalBrief archives:
New warning and changes to use of antibiotic azithromycin
AMR burden weighs heavily on Africa – global study
Azithromycin in combination may increase risk for cardiac events