Azithromycin, a macrolide antibiotic, is commonly used in mass drug administration (MDA) programs to control trachoma. The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Resistance (MORDOR) study trial conducted in Niger, Malawi and Tanzania, found a 13 to 5% decrease in overall mortality in children aged from 1 to 5 months after MDA. Based on such findings, the World Health Organization (WHO) recommends MDA for children aged 1 to 11 months in high-mortality settings. However, there is concern about antimicrobial resistance (AMR), particularly in pathogens with a high disease burden, such as Streptococcus pneumoniae. This study, published in Lancet Infectious Diseases, aims to assess the durability and transmission of S. pneumoniae macrolide resistance after a community-randomized MDA trial.
A cross-sectional and population-based pneumococcal transmission study was conducted in Mangochi, Malawi, 3.5 years after the MORDOR trial. Populations had received either a placebo or twice-yearly azithromycin for two years. This study included children aged 4 to 9 years who resided in a placebo- or azithromycin-treated cluster during the MORDOR trial, as well as children aged 1 to 3 years who were born after the trial in the same clusters.
Nasopharyngeal samples were collected and analysed using whole-genome sequencing. Control pneumococcal genomes were sourced from a remote Malawian location without MDA. Ethical approval was obtained from the University College London Research Ethics Committee and the College of Medicine Research Ethics Committee in Malawi.
This study employed a Kruskal-Wallis test for comparing the median MICs of isolates across surveys, a Wilcoxon test for Simpson’s and Shannon’s indices, and a Fisher’s exact test for evaluating differences in pneumococcal serotype. Multiple testing correction was obtained by using the Benjamini–Hochberg false discovery rate of 5%. A p-value below 0.05 was calculated statistically significant.
Nine hundred twenty-four children between 1 and 9 years old were tested from April 8 to May 14, 2021, with 905 included in the final analysis after 19 exclusions. The MORDOR experiment included 453 placebo-treated and 452 azithromycin-treated clusters, spanning baseline and 6-month post-MDA time points.
A total of 426 isolates (236 placebo-treated groups, 190 from azithromycin-treated groups), baseline samples (83 azithromycin-treated groups, 81 placebo-treated groups;164 isolates), and 6 months after MDA (223 isolates;104 placebo-treated groups, 119 azithromycin-treated groups) were evaluated in this study.
Macrolide resistance in azithromycin-treated clusters increased from 21.7% (95% confidence interval [CI] 14.2% to 31.7% in 18 isolates) to baseline 32.1% (25.9% to 39.0% in 61 isolates) after 3.5 years of MDA and 31.9% (24.2% to 40.8% in 38 isolates) at 6 months after MDA. In the placebo treated groups, resistance elevated from 21.0% (13.5% to 31.1% in 17 isolates) at the baseline to 30.9% (25.4% to 37.1% in 73 isolates) after 3.5 years of MDA and 25.0% (17.7% to 34.1% in 26 isolates) in 6 months after MDA.
There were no significant differences observed in the odds ratios between treatment groups across survey time points: 0.97% (95% CI 0.36 to 2.55) at the baseline, 1.46% (0.67 to 3.17) at 6 months after MDA, and 1.12% (0.66 to 1.91) after 3.5 years of MDA. In the control (non-MDA) location, macrolide resistance remained stable: at baseline 16.9% (95% CI 12.8 to 21.8 in 45 isolates), 16.5% (13.3 to 20.3 in 70 isolates) after 6 months, and 16.5% (12.5 to 21.4 in 44 isolates) after 3.5 years.
Among children born in azithromycin-treated clusters following MDA, macrolide resistance was 36.0% (27.7 to 45.1 in 41 children). Multidrug resistance (resistance to more than three antibiotic classes) was significantly higher in both azithromycin- and placebo-treated clusters than in the control group after 3.5 years (p < 0.0001 and p = 0.0015, respectively), and was associated with integrative conjugative elements.
In conclusion, azithromycin MDA is associated with increased microbial resistance, which remains and spreads even to untreated populations. The combination of multidrug resistance and transmissible resistance on the integrative conjugative components in the population is a significant public health concern. This highlights the importance of AMR monitoring in regions that implement MDA.
Reference: Kalizang’oma A, Chan JM, Kalua K, et al. 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. Lancet Infect Dis. 2025. doi:10.1016/s1473-3099(25)00212-9
