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
Bibliographic record
Abstract
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. FUNDING: The Gates Foundation, the National Institute for Health and Care Research, and the Wellcome Trust.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.007 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".