The indirect impacts of routine azithromycin prophylaxis during labour on antimicrobial resistance in low-income and middle-income countries: a population-level modelling analysis

Synopsis We aimed to determine the potential population-level impact on antibiotic resistance of a universally adopted policy of azithromycin prophylaxis for pregnant women in labour planning a vaginal birth. We developed three mathematical models with increasing levels of complexity to represent the population processes through which increased use of antibiotics resulting from the policy affects antibiotic resistance. We used each of these models to explore possible impacts of the policy on antibiotic resistance in three important bacterial pathogens: Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus. All three models considered the impacts of the policy on the asymptomatic carriage of macrolide-resistant variants of these three pathogens. We assumed that antibiotic resistance in clinically important infections changes in line with changes in resistance in asymptomatic carriage. The simplest model (model 1) has previously been shown to be able to explain the relationship between antibiotic consumption and antibiotic resistance in E. coli and S. pneumoniae in European countries, with significant improvements over previously described models for these pathogens. The second model (model 2) extended model 1 to consider interactions between a hospital maternity unit (where azithromycin prophylaxis is delivered) and the wider community. The third model (model 3) extended model 2 by dividing the population into three age groups: infants, children aged 1-12 years, and those aged 13 years and over. All three models found that increased azithromycin usage from adopting the prophylaxis policy would be expected to lead to increased macrolide resistance at a population level in the three pathogens studied, with larger effects found in countries with higher per capita birth rates. Increasing the complexity and realism of the model consistently led to smaller estimates of the impact on resistance. For example, using model 3, it was estimated that the policy would increase macrolide resistance in S. aureus and S. pneumoniae in Bangladesh by between 8 and 15%. In contrast, increases of 16% to 25% were seen when using model 1. To put these numbers into context, it has been estimated that globally, in 2021, 22,000 deaths were attributable to macrolide resistance in S. aureus and 20,000 deaths were attributable to macrolide resistance in S. pneumoniae. A 10% increase in macrolide resistance in these pathogens would therefore be expected to lead to an additional 4,200 annual attributable deaths. As with any modelling study there are many caveats: there are many large uncertainties relating to both model structures and parameter values as well as current levels of macrolide use and macrolide resistance. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was funded by The World Health Organization Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Formatting issues in tables 4 and 5 have been addressed. Issues with inconsistent font sizes have been addressed. A couple of minor typos have been fixed. Data Availability All data produced in the present work are contained in the manuscript