Antimicrobial resistance (AMR) is a global public health threat. Researchers have estimated that AMR was associated with nearly 5 million deaths in 2019, including over 1 million deaths associated with resistant bacterial infections. ¹ If nothing is done to abate this, by 2050, it is estimated that AMR will lead to 10 million deaths and cost approximately $100 trillion (USD). ²

Mass drug administration (MDA) of azithromycin (MDA-AZM) for the prevention and treatment of ocular chlamydia trachomatis (trachoma), and more recently, for the reduction of child mortality in high-mortality settings, are public health strategies that are feared to contribute to the development of azithromycin resistance in treated communities, as well as possible resistance to macrolide antibiotics more broadly and potentially to the transfer of resistance to other organisms. ³ Several studies have examined the effects of MDA-AZM on the development of bacterial resistance to the drug over the past decade, and results from these studies have been mixed. Some studies have found evidence of transient resistance in some bacteria, while others have found no evidence of bacterial resistance following MDAs. A few studies have demonstrated that post-MDA resistance may be determined by pre-MDA levels of resistant bacteria in MDA targeted communities. ^{4 – 19}

Two relatively recent (2015 and 2019) systematic literature reviews have summarized the evidence provided by this body of research. Ho et al. (2015) evaluated eight studies that examined the effects of MDA-AZM on the carriage and subsequent development of resistance to the drug in Streptococcus pneumoniae (S. pneumoniae). ¹⁸ According to the authors, five of the eight studies found low levels of baseline resistance to azithromycin in communities targeted for MDA; in three of these five studies, resistance increased shortly after drug distribution but dropped considerably over time, returning to near baseline by 12 months after the MDAs. Two studies revealed high baseline resistance levels that were sustained at six months after the MDAs; however, in both studies, MDAs were carried out at greater frequencies than in other research settings (biannually or quarterly). The authors concluded that communities with low levels of baseline resistance to azithromycin experienced only transient increases in resistance; however, communities with higher levels of resistance, which were also correlated with more frequent MDA events, were more likely to experience sustained higher levels of resistance.

O’Brien et al. updated the Ho review in 2019 and expanded it to include studies that examined resistance to other pathogens in addition to S. pneumoniae. The authors identified 18 published studies and one unpublished dataset that examined the effect of MDA-AZM on the development of resistance in communities for the following organisms: S. Pneumoniae (n = 12), Staphylococcus Aureus (n = 3), Chlamydia trachomatis (n = 3), Escherichia coli (n = 3), and Plasmodium falciparum (n = 1). MDA frequency varied across studies from annual distribution to multiple times per year; follow-up periods also varied considerably from 2 weeks to 4 years. Six studies included pre-MDA baseline assessments and five others included control communities for comparison. Of the studies that examined resistance in S. pneumoniae, findings were consistent with the previous review: resistance increased transiently after MDAs and returned to near baseline after some time. Among the three studies that examined E. coli, all three found increased levels of resistance immediately after, and six months post MDA. For the two studies that examined resistance in S. aureus, neither study had a control group or baseline assessment; however, both studies revealed that resistance in this organism increased over time following MDAs. Lastly, no studies have found evidence of the development of resistance in either C. trachomatis or P. falciparum following MDA of azithromycin.

More recently, analyses of data from the MORDOR ( Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trials have been reported. ²⁰ One study noted that after two years of bi-annual MDA-AZM for children, the prevalence of resistant strains of S. pneumoniae to both erythromycin and clindamycin was significantly greater in azithromycin-treated communities than in untreated control communities, as was macrolide resistance among gut bacteria from rectal swabs; however, there were no differences between the two groups in resistance to other classes of antibiotics. ¹¹ A second study on the effect of MDA-AZM on gut biomes in preschool children in Niger demonstrated that prolonged MDA-AZM was associated with reductions in certain gut bacteria, including pathogens, as well as increases in both macrolide and non-macrolide resistance in treated communities as compared to non-treated control communities. ¹²

A total of 606 eligible children from 41 clusters in 2022 and 692 eligible children from 44 clusters in 2023 were included in the study analyses. ²⁵ Parent characteristics did not differ significantly across time points ( Table 1). Coverage from MDA-AZM was lower than anticipated (targeted 90% coverage) at both time points but did not differ significantly between the two surveys.

The prevalence of S. pneumoniae carriage was 28.8% (95% CI:22.4, 35.3) in 2022 and 30.8% (95% CI:25.0, 36.7) in 2023 and did not differ significantly across time points (p = 0.6506) ( Table 2). Resistance to erythromycin was tested as a proxy for azithromycin at both time points, although azithromycin itself was added to the resistance testing panel in 2023. Approximately 32.8% (95% CI:25.3, 40.2) of specimens in 2022 and 26.2% (95% CI:19.8, 32.6) in 2023 were resistant to erythromycin, although the difference between the two timepoints was not statistically significant (p = 0.0537).

The resistance of S. pneumoniae isolates to clindamycin was slightly lower, at 23.7% [14.1, 33.4] in 2022 and 11.8% [6.9, 16.7] in 2023 ( Table 2).

Phenotypic test results for the first survey showed that among the S. pneumoniae isolates examined, 42 (23%) had a constitutive MLSb resistance phenotype and five isolates (2.7%) had an inductive MLSb resistance phenotype. During survey 2, the constitutive MLSb resistance phenotype was present in 24 isolates (12.4%), and 1 isolate (0.5%) had an inductive MLSb resistance phenotype ( Table 3).

In 2022, 35 S. pneumoniae isolates with resistance phenotypes were tested using PCR. The ermB resistance gene was detected in 13 isolates (37.1%). In 2023, out of the 41 S. pneumoniae isolates on which PCR was performed, seven (17.1%) isolates contained ermB genes. No mef gene was detected.

The REACH project in Côte d’Ivoire carried out two rounds of community-based surveillance studies over the course of the three-year project in an effort to contribute to monitoring the potential adverse effects of the MDA-AZM intervention in targeted communities. The findings from this study are consistent with the results of other studies that examined AMR among children in MDA-azithromycin trials. Other studies have reported rates of S pneumoniae carriage as low as 10-20% and as high as 89-90% in different settings and resistance levels of approximately 10-50% of isolates. ^{5 , 8 , 11 , 12 , 15 , 17 , 19}

The aim of this surveillance was not to examine a direct association between MDA exposure and AMR, but rather to document macrolide resistance rates in communities targeted by the MDA-AZM intervention so that changes over time could be monitored as part of routine surveillance for this intervention. Such community-based surveillance can provide important insights into the prevalence of drug-resistant bacteria in these communities. Further sequential routine assessments will permit the analysis of trends in prevalence over time, which will be useful to decision makers as they weigh the potential benefits and risks of the intervention strategy.

Two main mechanisms of macrolide resistance have been described in S. pneumoniae: methylation of the 23S ribosomal subunit, which gives rise to the MLSb phenotype (high-level resistance to macrolides, lincosamides, and synergistin B); and an active efflux system, which gives rise to the M phenotype. This is due to the expression of the erm(B) and mef(A) genes, which may be chromosomal or plasmid-mediated.

The expression of erm can be inducible or constitutive. The constitutive phenotype is a permanent expression that makes bacteria resistant to MLSBs and ketolides from the outset. An inducible phenotype requires the presence of an inducing antibiotic to be expressed. The inducers were macrolides with 14, 15, and 16 carbon atoms, lincosamides, and streptogramin B.

The majority of macrolide resistance phenotypes in both surveys were constitutive MLSb carried by erm(B)-type genes. Our results, in line with previous studies that have shown that erm(B) is the most common genotype worldwide and the most common mechanism of resistance to erythromycin, indicate that there may be a higher risk of resistance dissemination if these genes are also plasmid-mediated. ^{26 – 28}

Although azithromycin is not widely used outside MDAs in Côte d’Ivoire, ²⁹ it is an important drug for a few common, severe infections, such as community-acquired bacterial pneumonia, some sexually transmitted infections, and enteric fever. ³⁰ Azithromycin is an important treatment option for shigellosis. ³¹ Resistance to erythromycin and azithromycin may also lead to the development of resistance to other antibiotics. ¹⁹ Decision makers need to reflect on the relevance of AMR surveillance trends and consider a threshold for deciding whether and when to discontinue MDAs if increases in AMR are observed over time.

Despite only having data from two time points, it is initially encouraging that AMR in our S. pneumoniae did not increase significantly between the two survey time points; in fact, the absolute values decreased slightly, indicating no preliminary evidence of an upward trend. Exposure to MDA prior to each survey was lower than anticipated.

Community-level surveillance of carriage for specific bacteria and the resistance of these bacteria to various antibiotics in an asymptomatic population can serve as an early warning system in the context of routine mass drug administration programs that distribute antibiotics to community members. It is important that surveillance and routine results review continue to inform actions. Guidance will be needed from stakeholders and AMR experts to define thresholds that would prompt further investigations such as confirmatory sampling, expanded molecular characterization/typing where feasible, and assessment of plausible drivers. Programmatic actions can then be determined in consultation with national guidelines and stakeholders, consistent with the descriptive surveillance purpose of this study.

Given the transient nature of resistance identified in some studies following MDA azithromycin, the long-term clinical relevance of community AMR will also be important. Therefore, establishing or strengthening routine facility-based AMR surveillance to examine trends in infections caused by resistant organisms is also necessary. In Côte d’Ivoire, efforts have been made to add azithromycin to drug sensitivity testing through their regional laboratory network; however, the current passive facility-based AMR surveillance system relies on patients paying for testing when needed. ³² As a result, the number of specimens received for AMR testing are very low across the country. For example, in 2022, 3,849 specimens were received by the National Reference Laboratory for AMR testing, 96% (3,712) of which originated from one facility, the University Hospital of Cocody, where IPCI is headquartered in Abidjan. ³¹ Developing strategies and identifying resources to leverage the existing regional network could provide important insights into trends in clinical infections associated with resistant organisms. This information could further help guide decision-makers in monitoring AMR in MDA azithromycin-targeted areas.

MDA-azithromycin is a promising intervention that may help improve child survival. However, we are still learning about the potential long-term consequences of the ongoing mass distribution of this important antibiotic. As countries weigh the benefits and costs of implementing MDA-AZM, the capacity and resources necessary to adequately monitor AMR must be included in these decisions. The availability of necessary laboratory resources and expertise is paramount.

More is needed to interpret the relevance of AMR changes observed in these settings – at what point do changes in antibiotic resistance warrant considering discontinuing the intervention? Therefore, understanding the potential clinical and environmental outcomes associated with mass antibiotic distribution is critical.