Background

Mass drug administration (MDA) is a strategy to improve health at the population level through the widespread delivery of safe and inexpensive medications for the prevention and treatment of disease [1]. Although unusual in high-income settings, MDA remains relevant in resource-limited settings, as it does not require individual diagnosis or treatment decisions [1,2,3,4].

MDA programs have targeted both infectious and non-infectious threats, ranging from programs distributing anti-parasitic agents for decreasing malaria incidence to programs distributing vitamin A supplements for reducing childhood blindness [5]. However, it is in battling the neglected tropical diseases (NTDs), a group of 20 diseases that typically affect the world’s poorest citizens, that MDA has met with the greatest success [1]. MDA has been associated with a substantial reduction in the burden of the infectious diseases targeted by these campaigns, including trachoma, onchocerciasis, lymphatic filariasis, soil-transmitted helminthic infections, and schistosomiasis [6]. In 2017, at least 1.7 billion MDA treatments with antimicrobials were delivered to 1 billion people for the prevention and treatment of NTDs [7]. Recently, MDA programs distributing antibacterials have gained increased attention due to evidence that they may reduce childhood mortality [5, 8, 9]. This use of MDA for reduction of childhood mortality is in contrast to the prior use of antimicrobials in MDA campaigns, when a specific pathogen was targeted.

To date, most MDA programs using an antibacterial agent have distributed oral azithromycin, a macrolide antibacterial that has a long half-life (67 h) and high tissue penetration [10]. Other antibacterials such as intramuscular (IM) benzathine penicillin G and topical tetracycline have also been used in MDA programs, but to a much lesser extent. Benzathine penicillin G is a beta-lactam antibacterial that can be used as a single-dose, IM treatment for yaws, but it is being replaced by oral azithromycin given the ease of delivery associated with the latter [11]. Tetracycline can be used in topical form for the treatment of trachoma, but it is predominantly used in children < 6 months of age in whom the safety of azithromycin is debated, as topical therapy must be administered twice daily for 6 weeks [12].

Since MDA programs distributing antibacterials have largely used oral, single-dose azithromycin, this review will focus on the literature on MDA-azithromycin. We survey the evidence regarding benefits and risks associated with MDA-azithromycin programs and raise questions that are critical in determining the future of these programs, specifically when used to reduce childhood mortality.

Methods

Results

Data for this review were initially identified through a search of PubMed using the search terms “mass drug administration” and “antibiotic.” This search provided an initial set of studies relevant to the topic. References from the initially identified studies were also reviewed and included in this review if relevant. Only articles published in English were included, and articles were not limited based on year of publication. Only peer-reviewed, published studies were considered for this review.

MDA-azithromycin programs: diseases and conditions for which there is probable benefit

Existing evidence and World Health Organization (WHO) recommendations support the use of MDA-azithromycin in treating two NTDs, trachoma and yaws, and in reducing under-five mortality in regions most affected by these conditions [2, 13, 14]. All three conditions are associated with poverty, crowded households, and lack of access to water and sanitation. In addition, children < 10 years of age are the main target of all three MDA programs.

Trachoma

MDA-azithromycin first gained widespread use in the treatment of trachoma, the most common infectious cause of blindness. Approximately 21 million people worldwide have active trachoma and 232 million people live in trachoma-endemic areas worldwide [13]. Trachoma is caused by certain serovars of Chlamydia trachomatis, with repeated episodes of ophthalmic infection and conjunctival inflammation, known as active trachoma, causing scarring of the eyelids and eventually leading to corneal opacification and blindness [15]. Children are the core group for transmission, and in endemic areas, active trachoma may affect up to 60–90% of preschool children [2, 16].

In 1998, the World Health Assembly endorsed the Alliance for the Global Elimination of Trachoma by 2020 (GET2020) and recommended the SAFE strategy for eliminating trachoma (Surgery, Antimicrobial distribution, Facial cleanliness, and Environmental improvements) [17]. Annual, district-wide MDA of azithromycin was recommended as part of this strategy for districts with a prevalence of active trachoma ≥ 10% in children aged 1‒9 years of age [2]. To date, more than 900 million doses of oral azithromycin have been distributed through trachoma control programs [18].

High-quality studies support the use of MDA-azithromycin in trachoma control. A recent Cochrane review assessed four cluster randomized trials (RCTs) that compared community-level treatment with MDA-azithromycin and no treatment. Three of four studies showed a reduction of 40‒60% in ocular infection or active trachoma by 12 months. The fourth, lower-quality study did not show a difference in prevalence of active trachoma at 12 months in low-prevalence communities [12].

Yaws

Yaws is a relapsing non-venereal treponemal disease caused by Treponema pallidum subspecies pertenue and affects skin, bone, joints, and cartilage. From 2010 to 2013, 256,343 cases of yaws were reported to the WHO from 13 endemic countries, and there were an estimated 89 million people living in yaws-endemic districts in 2012 [19]. Approximately 75–80% of those affected by yaws are children less than 15 years of age, with peak incidence at 6‒10 years of age [20].

Previously, a single dose of IM, long-acting, benzathine penicillin G was recommended for MDA treatment of yaws. However, treatment with IM penicillin is resource intensive and can be painful. In 2011‒2012, two open-label, randomized controlled trials were conducted in yaws-endemic regions in Ghana and Papua New Guinea to explore the impact of treatment with oral azithromycin compared to IM benzathine penicillin [21, 22]. Both studies consisted of children < 15 years of age who had active yaws lesions. Treatment with a single dose of azithromycin was found to be non-inferior to a single dose of IM penicillin [21, 22]. These two studies set the stage for recommending MDA-azithromycin in the control of yaws.

Childhood mortality

The potential for MDA-azithromycin to decrease childhood mortality has gained a great deal of attention in recent years. MDA-azithromycin has been promoted as a strategy that could help the world meet targets such as Sustainable Development Goal (SDG) 3, which aims to eliminate all preventable deaths in children < 5 years of age and to reduce under-five mortality to at least 25 deaths per 1000 live births by 2030 [23]. In 2019, there were 5.2 million deaths in children under five years of age, with mortality highest in sub-Saharan Africa at 76 deaths per 1000 live births [24]. To date, there are 3 cluster randomized controlled trials (RCTs) that have assessed the impact of community level MDA-azithromycin compared to placebo on childhood mortality, with 2 of 3 showing benefit (Table 1). In addition, one cluster RCT which compared annual versus twice-yearly MDA-azithromycin and a pre-post continuation study of a prior cluster RCT both suggest mortality benefit associated with MDA-azithromycin. However, the underlying mechanism by which childhood mortality is decreased in these studies is unclear.

Table 1 Cluster randomized controlled trials assessing the impact of MDA-azithromycin on childhood mortality
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The five studies were conducted in six countries in which the under-five mortality rate is high: Ethiopia; Malawi, Niger, Tanzania, Mali, and Burkina Faso [8, 9, 16, 25, 26]. All five studies carried out randomization at the community level. Of the three placebo-controlled trials, the first study (TANA) was conducted in Ethiopia from 2005 to 2006, the second was conducted in Mali and Burkina Faso from 2014 to 2016, and the third (MORDOR I) was conducted in Malawi, Niger, and Tanzania from 2014 to 2017. The three studies implemented MDA-azithromycin in children aged 1 year and older and adults, children 3‒60 months of age, and children 1‒59 months of age, respectively. Table 1 details the dosing and schedule of the MDA intervention. All trials studied azithromycin monotherapy in the intervention arm, except for the second study, which included azithromycin superimposed on seasonal malaria chemoprophylaxis (SMC) with sulfadoxine-pyrimethamine and amodiaquine in both study arms. TANA showed an almost 50% reduction in mortality 12 months after the intervention in children 1‒5 years of age. The second study did not show a reduction in mortality in children aged 3‒59 months over a period of 3 years (as per data obtained by the WHO) [2]. MORDOR I showed an almost 15% reduction in mortality 26 months after intervention in children < 5 years of age. Sub-group analysis of MORDOR I showed that the reduction in mortality was significant only in Niger but not in the other two countries. In addition, children between 1 and 5 months of age had the highest overall mortality, but this age group also had the largest difference in mortality rates when comparing those in the treatment and placebo arms with 24.9% lower mortality. However, effect modification by age was not statistically significant [8].

In addition to these 3 cluster RCTs, there was one cluster RCT (PRET) conducted in Niger from 2010 to 2013 that compared annual treatment for all individuals in the community over 6 months of age with twice-yearly treatment in persons 6 months‒12 years [16, 27]. PRET showed a reduction in mortality of 20% in twice-yearly treatment compared to annual treatment. Another longitudinal study (MORDOR II, continuation of MORDOR I) conducted in Niger from 2017 to 2018 compared two additional twice-yearly doses of azithromycin in groups that had previously received placebo. MORDOR II showed a mortality reduction of 13.3% compared to prior to the intervention, and also showed that the mortality reduction in the group that originally received azithromycin-MDA was sustained [9]. Finally, more recently, a multi-site RCT in Kenya among children aged 1‒59 months who were randomized to receive a five day course of azithromycin or placebo after discharge from hospital admission showed no statistical difference in death or rehospitalization in the six months following hospital discharge [28]. However, this study was not an MDA-azithromycin study.

Following the publication of results from MORDOR I, the WHO released guidelines in 2020 regarding the use of MDA-azithromycin to reduce childhood mortality. They recommended against universal implementation of MDA-azithromycin for prevention of childhood mortality, and that MDA-azithromycin be considered in children 1‒11 months of age for prevention of childhood mortality in sub-Saharan settings where (1) infant mortality is > 60 per 1000 live births or under-five mortality is > 80 per 1000 live births; (2) infant and under-five mortality rates, adverse effects, and antibiotic resistance are continuously monitored; and (3) existing child survival interventions, such as SMC where recommended, is concurrently strengthened. The recommended dose of azithromycin was 20 mg/kg every 6 months. The committee stated that the guideline would be applicable for 2‒3 years, at which time new data were expected [2].

Since the release of the WHO guidelines, a secondary analysis from MORDOR-Malawi has shown that MDA-azithromycin has the potential to be very cost effective, but that wide geographic variation in effectiveness exists [29]. Another study has projected that a targeted strategy, in which high-risk children are selected for receipt of azithromycin, has higher cost effectiveness compared to MDA-azithromycin and would minimize azithromycin exposure in the community [30]. Further studies regarding the effectiveness and cost effectiveness of MDA-azithromycin in reducing childhood mortality have not been published.

What are the potential mechanisms by which MDA-azithromycin may reduce mortality?

Despite apparent success in reducing childhood mortality, the mechanism by which MDA-azithromycin reduces childhood mortality has not yet been elucidated. Understanding how MDA azithromycin reduces childhood mortality may help determine which settings and populations should be targeted for implementation. It has been hypothesized that MDA-azithromycin may reduce deaths from respiratory infection, diarrheal infection, and/or malaria in treated children and their close contacts, since these illnesses are major causes of childhood mortality in low- or middle-income countries (LMICs) [6]. Impact on inflammation or chronic disease is also possible, since macrolides are rare among antibacterials as they may be used to combat chronic lung disease [31]. MORDOR I suggested that the greatest mortality benefit was in children < 1 year of age, thus conditions affecting children in this age group may particularly shed light. Table 2 details infections for which azithromycin is commonly used in the clinical setting. Treatment of these infections may contribute to the reduction in childhood mortality.

Table 2 Common infectious syndromes or pathogens that may be treated with azithromycin in the clinical setting
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Verbal autopsies were conducted in the MDA-azithromycin childhood mortality studies to determine causes of death and may shed light on the mechanism by which MDA-azithromycin reduces mortality. Table 3 summarizes these verbal autopsy data. However, even these data to date are conflicting, and sub-studies have been under-powered to answer the question accurately. Some studies show that common illnesses such as respiratory illnesses, diarrheal illnesses, and malaria were less common in the MDA-azithromycin groups, while others do not show such differences. In the Niger arm of MORDOR I, which was the definitive study showing mortality benefit with MDA-azithromycin in children, the proportions for individual types of infections did not vary significantly between treatment and control arms [32]. If reduction in one type of infection were driving the change in mortality, we would expect the proportion of deaths due to this infection to be decreased in the treatment compared to placebo arms.

Table 3 Verbal autopsy data on infections in MDA of azithromycin to reduce childhood mortality studies
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Studies have also evaluated if the effect of MDA-azithromycin on childhood mortality may be related to anemia or nutritional status. A study conducted in parallel with MORDOR I was performed in 30 communities in Tanzania between 2015 and 2017. Children between the age of 1–59 months at baseline were eligible for inclusion and treated with twice-yearly azithromycin for 24 months. The outcome of interest for this study was mild moderate or severe anemia. Twice-yearly azithromycin treatment to preschool children did not significantly impact anemia prevalence in this study [33]. MDA-azithromycin did not impact growth or nutritional status in separate studies conducted in Niger, Ethiopia, the Gambia, Burkina Faso, and Mali [34,35,36,37].

Can MDA-azithromycin offer ancillary benefit for conditions that are not explicitly targeted by MDA programs?

Macrolides are used commonly in the treatment of many community-acquired infections. The mass distribution of azithromycin has the potential to positively impact the burden of these infections. In Table 2, we summarized the data on the impact MDA-azithromycin may have on these common infections. These infections include skin and soft tissue infections/impetigo, rheumatic heart disease, acute respiratory infection, diarrheal illness, malaria, syphilis, and chlamydia. To date, studies assessing the impact of MDA-azithromcyin on these common infections have either not been conducted or have yielded mixed results. However, the potential for MDA-azithromycin to reduce the burden of these infections exists.

What are the potential direct health risks associated with MDA-azithromycin?

Prior to the implementation of MDA-azithromycin campaigns on a large scale, it is important to understand the health risks that MDA-azithromycin may pose to the individual and the community, as well as which individuals may carry the greatest risk. The main direct health risks associated with azithromycin include gastrointestinal side effects, infantile hypertrophic pyloric stenosis (IHPS), cardiovascular side effects, and microbiome modulation which may contribute to the development of chronic diseases. In general, due to its broad antibacterial spectrum and safety profile, azithromycin is one of the most commonly prescribed antibacterials in children. In the last two decades, over 700 million doses of MDA-azithromycin have been delivered to children [38]. However, the safety of azithromycin use in infants is debated. There is a paucity of data regarding the safety of azithromycin in children < 6 months of age, and the WHO does not recommend use of azithromycin in this age group for the treatment of trachoma, although it does recommend azithromycin for use in children < 1 year for reducing childhood mortality [2]. Data regarding risks associated with azithromycin when administered in MDA programs are sparse.

Gastrointestinal side effects

Gastrointestinal side effects are among the most common adverse effects seen after the use of any antibacterial. In a study of almost 17,000 people in Ethiopia who received MDA-azithromycin, side effects were solicited three weeks after MDA. The prevalence of self-reported side effects was 9.6% among all age groups and 4.7% among children aged 1–9 years in the MDA-azithromycin arm. The most commonly reported side effects were abdominal pain (53.1%), nausea (21.7%), vomiting (12.8%), and diarrhea (12.5%). However, the prevalence of side effects in the placebo group was not reported [38, 39]. In a systematic review of neonates (< 28 days) who received at least one dose of azithromycin, data from 4 RCTs indicated that gastrointestinal side effects were seen in 19.6% of patients [40].

IHPS

IHPS is caused by thickening of the pylorus muscle in the stomach, with eventual gastric outlet obstruction that can cause vomiting and dehydration. It affects about 1.9 of every 1000 live births and is the most common indication for surgery in the first six months of life [41]. The risk of IHPS may be increased in infants taking oral erythromycin or azithromycin, especially during the first two weeks of life, due to the macrolides’ potent stimulation of gastrointestinal motility. In a retrospective cohort study from 2001 to 2012 of children in a US military database, exposure to azithromycin or erythromycin in the first 2 weeks of life was associated with 8 or 13 times greater odds of IHPS, respectively. There was no association between either antibacterial exposure and IHPS after 6 weeks of life through 12 weeks [42]. A meta-analysis found that infants exposed to erythromycin had an odds ratio of 2.45 for developing IHPS, and a 12-fold increase if they were given erythromycin in the first two weeks of life [41]. In a case series in Nigeria of 26 infants with IHPS, presentation for care and diagnosis was generally late, although many infants had symptoms that started in the neonatal period with a mean age at diagnosis of 7 weeks. Most infants received open pylorotomyotomy and 15% had post-operative complications. Three of the patients in this case series died, with two during resuscitation attempts prior to surgery and one during surgery [43].

As a follow up study to MORDOR, 30 communities that participated in the Niger arm were followed two weeks after treatment rounds to evaluate for adverse events. With each round of azithromycin, caregivers of infants aged 1‒5 months of age were surveyed regarding adverse events since treatment. There were no differences in the rates of adverse events between azithromycin and placebo, and notably no reported cases of IHPS in either arm [44]. Excluding infants less than one month of age in MDA azithromycin campaigns may decrease the risks of IHPS in infants.

Cardiovascular side effects

Several macrolides, including azithromycin, have been found to be proarrhythmic, with reports of QT prolongation, torsades de pointes, and ventricular tachycardia in the absence of QT prolongation. In the previously mentioned systematic review of adverse drug reactions to azithromycin in children, six prospective studies (five RCTs, one cohort study) reported 79 cardiac adverse events. QT prolongation was reported in three studies, irregular heart rates were reported in two studies, and no cardiac events were reported in two studies [38]. In general, MDA programs have not systematically monitored for cardiovascular adverse effects. With the popular off-label use of azithromycin combined with hydroxychloroquine early in the coronavirus disease 2019 (COVID-19) pandemic, there is evidence that this combination of drugs can lead to prolongation of QTc [45,46,47]. However, these studies frequently had a high proportion of adult participants with cardiac disease who were receiving other QT-prolonging agents. In several small observational studies, no QT prolongation was noted in hospitalized pediatric patients on hydroxychloroquine and azithromycin [48]. There remains a lack of evidence on the combined effect of hydroxychloroquine or chloroquine with azithromycin on the QT interval in non-hospitalized children. As malaria, HIV, and other conditions treated with QT-prolonging agents are present in many areas where MDA-azithromycin programs may be implemented, additive prolongation of the QT interval is a potential risk.

Chronic diseases

Antibacterial consumption has been linked to chronic diseases such as obesity, asthma, and inflammatory bowel disease through mechanisms that are thought to be related to alteration of the gut microbiome [49]. Among the antibacterials, macrolides in particular have been linked to the development of chronic disease in children. Among Finnish school children aged 2‒7 years who had used macrolides compared to those who had not used macrolides for > 2 years, there was a reduction in Actinobacteria composition and increase in Bacteroidetes and Proteobacteria, with reduction in microbial diversity that did not return to the level of control samples even 12‒24 months after the antibiotic course. In the group who used macrolides, there was a > 6 times odds of asthma compared to the non-exposed group. Similarly, those who received > 2 courses during the first 2 years were more likely to be overweight compared to the non-exposed group [49]. In retrospective birth cohorts in Canada, antibacterial exposure during the first year of life was associated with greater risk of asthma at 2‒9 years of age. Children who used macrolides (compared to other antibacterials) and those who used more courses of antibacterials, especially > 4 courses, had the highest risk of asthma [50]. An ecological study in the US and Europe showed that population-level consumption of macrolides was associated with higher risk of obesity [51].

What are the antibacterial resistance risks associated with MDA-azithromycin?

The development of antibacterial resistance (ABR) in both targeted and commensal organisms is one of the greatest risks associated with MDA-azithromycin [6]. Unlike with helminths, where there is no evidence for sustained anti-helminthic drug resistance despite hundreds of millions of treatment courses with anti-parasitics, resistance in bacterial organisms is common [6]. In the 1960s, global attempts to eradicate malaria resulted in the emergence of drug resistance because of over-reliance on a single medication [1]. MDA programs for malaria are now only recommended in limited scenarios such as when elimination is near or in emergency outbreak settings, given both transient benefit and potential for drug resistance [52]. Similarly, there are many reports of rapid global dissemination of bacterial resistance, for example with the colistin resistance gene (mcr-1) and New Delhi metallo-beta-lactamase-1 gene (NDM-1), which render some of our broadest-spectrum antibacterials ineffective. Bacteria reproduce much more rapidly than parasites and can share resistance genes horizontally. Co-resistance, or resistance to more than one class of antibacterials that is often transmitted on mobile elements such as plasmids, and cross-resistance, in which a target used by multiple antibacterials is altered, can both result in resistance to multiple types of antibacterials [53]. With MDA-azithromycin, it is possible that the benefits may only be seen over a short period before ABR reaches levels that undermine any benefits of such programs [6] In addition, when macrolide resistance prevalence rises, macrolides can no longer be used reliably as empiric therapy for common infections such as pneumonia and diarrhea. In Table 4, we list the existing evidence on ABR following MDA-azithromycin, and we briefly summarize these findings below. The evidence suggests that the prevalence and duration of ABR following MDA-azithromycin varies depending on factors such as type of organism and number of rounds of MDA. Studies are increasingly moving from phenotypic to genotypic methods to identify macrolide resistance, which may also make comparisons between studies difficult.

Table 4 Evidence for antibacterial resistance (ABR) following MDA-azithromycin
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Macrolide resistance in trachoma and yaws

While the development of ABR in organisms seems inevitable, no macrolide-resistant C. trachomatis serovars that cause trachoma have been documented to date in trachoma programs [5, 16]. Whether this finding is due to lack of resistance or lack of detection is unclear, as testing for antibacterial resistance in C. trachomatis is not widespread. Similarly, for many years, macrolide resistance in T. pallidum pertenue was not detected following MDA-azithromycin. However, a more recent study from Papua New Guinea described macrolide-resistant isolates T. pallidum pertenue in communities where MDA-azithromycin had been used for many years [54].

Macrolide resistance in gram-positive bacteria: Streptococcus pneumoniae, S. aureus, and S. pyogenes

Many studies have explored the development of macrolide resistance in S. pneumoniae following MDA-azithromycin. Based on data from observational and interventional studies, it appears that in general, risk of macrolide resistance in S. pneumoniae (1) increases with increased rounds of MDA, (2) is greater when there is higher baseline burden of macrolide-resistant S. pneumoniae, (3) decreases with the cessation of MDA-azithromycin, but may not return to baseline levels, and (4) does not appear to be related to S. pneumoniae serotype [55] However, the overall body of data regarding S. pneumoniae macrolide resistance with MDA-azithromycin are conflicting.

Data regarding macrolide resistance in S. aureus indicate that resistance increases following MDA-azithromycin, and then decreases following cessation of MDA-azithromycin. However, studies are limited [2, 56]. No macrolide resistance has been detected in S. pyogenes following MDA-azithromycin, although studies again are limited [57].

Macrolide resistance in enteric organisms and gut microbiota

Available data indicate that MDA-azithromycin is associated with an increase in antibacterial resistance in enteric organisms. Two studies using phenotypic testing for resistance from Tanzania showed increased macrolide-resistant E. coli which persisted for the six months of observation in one study and over at least 12 months in the other [58, 59]. In the Niger arm of MORDOR I, where genotypic testing was conducted, determinants of macrolide resistance in intestinal flora were elevated at six months in one study and persisted through 48 months in another [60, 61]. Such increases are concerning, although not surprising, since gram-negative organisms can develop antibacterial resistance rapidly and are able to easily spread resistance elements via horizontal gene transfer of mobile elements.

Macrolide cross-resistance with other antibiotics

Both cross-resistance and co-resistance with other antibacterials could pose problems when considering MDA-azithromycin implementation. Azithromycin could be a potent driver of cross-resistance because of its long half-life, high intracellular tissue concentration, and large volume of distribution. However, studies to date are limited and provide conflicting evidence regarding cross-resistance with other classes of antibacterials, with the exception of the lincosamide clindamycin, to which cross-resistance is common. The erm genes are responsible for the most widespread form of macrolide resistance (known as the MLSB phenotype), which results in cross-resistance between macrolides, lincosamides like clindamycin, and streptogramin B [62].

The Niger arm of MORDOR I showed a significant difference in clindamycin-resistant S. pneumoniae in MDA-azithromycin versus placebo groups [2, 63] However, the proportion of S. pneumoniae with resistance to penicillin was similar in the MDA and placebo groups at 24 months, and there were no significant differences in non-macrolide resistance determinants in either nasopharyngeal or rectal swabs between the two groups [60, 63] Interestingly, at 36 months while twice-yearly mass administration was still occurring, MDA-azithromycin selected for non-macrolide resistance determinants, including to beta-lactam antibacterials (2.13 factor difference), tetracyclines (1.68), trimethoprim (2.22), and aminoglycosides (2.32 factor difference). However, only the macrolide, beta lactam, and tetracycline resistance determinants stayed elevated at 48 months [61] The authors note that all but tetracycline belong to the WHO Access group of antibiotics that are typically used against a wide range of community-acquired infections, raising concern if these antibiotics become ineffective.

Summary and considerations when implementing MDA-azithromycin programs

Over the past decade, MDA-azithromycin programs have gained increasing attention due to positive impacts beyond their original intent. Available evidence suggests that MDA-azithromycin is beneficial in reducing mortality in children < 5 years of age, combatting the NTDs trachoma and yaws, and possibly reducing the burden of common infectious diseases such as diarrheal illness and impetigo. Interventions that target multiple diseases simultaneously tend to be more cost-effective, and MDA-azithromycin has the potential to affect multiple conditions (NTDs, high child mortality) that occur in the same region [64].

Many questions remain regarding the appropriate use of MDA-azithromycin. The regions and populations in which MDA-azithromycin may provide most benefit must be better understood. It would be prudent for policymakers considering MDA-azithromycin to map out geographical areas in which the highest burden of under-five mortality, targeted NTDs, and illnesses such as ARI, diarrheal illness, and malaria exist. The optimal age group to be targeted must also be determined. The WHO recommends MDA-azithromycin in children < 1 year of age for reducing under-five mortality, since the greatest reduction in mortality occurred in this age group. However, studies suggest that limiting the intervention to those 1‒5 months old or 1‒11 months old would reduce the number of deaths averted by 2.5 to sixfold, given the larger population size in the older age groups, and may decrease the potential positive impact of MDA-azithromycin [65].

The optimal dose, frequency, and number of intervention cycles of MDA-azithromycin has also not been determined yet, and further studies are needed to answer these questions. Local acceptability and preferences must ultimately be given greatest consideration when deciding whether to implement MDA-azithromycin. Local populations may consider the short-term benefits of reduced child mortality to far outweigh longer-term, theoretical risks such as ABR. However, with antimicrobial resistance forecasted to cause millions of deaths and dollars lost in economic productivity by 2050, the benefits and risks associated with MDA-azithromycin programs must be balanced carefully [66]. The lack of a clear rationale by which MDA-azithromycin programs decrease under-five mortality may give policymakers some pause. Evidence to date has not supported a decrease in infectious disease burden as driving the reduction in under-five mortality, although this mechanism is considered most likely. Changes such as modulation of inflammation or increases in weight are interesting hypotheses that need to be explored in future studies.

When implementing MDA-azithromycin programs, attention needs to be given to systematically monitoring adverse effects and antibacterial resistance. Historically, MDA-azithromycin programs have not conducted thorough assessments of mild adverse reactions such as gastrointestinal side effects or even more severe adverse reactions such as IHPS. In MORDOR I, parents were instructed to monitor for adverse effects and report them to a village representative, and such a strategy could be utilized in the future. The impact of MDA-azithromycin on childhood chronic diseases, such as asthma and obesity, has also not been assessed to date. Monitoring these diseases is critical, as LMICs could subsequently face a greater dual burden of communicable and non-communicable diseases [67]. The WHO launched the Global Antimicrobial Resistance Surveillance System (GLASS) in 2015 to support global surveillance to strengthen the evidence base on antimicrobial resistance [68]. GLASS could be leveraged for improving ABR surveillance following MDA-azithromycin. As genomic approaches become more routine and less expensive, combining phenotypic and genotypic approaches to monitor AMR may help generate a larger volume of useful data [61]. Given the growing threat of ABR on health, ABR assessments should include baseline resistance testing followed by multiple cross-sectional assessments, with household contacts also being investigated to generate a broader understanding of ABR risk [69]. Many of the communities that stand to benefit the most from MDA-azithromycin do not have the infrastructure in place to conduct surveillance for adverse effects and ABR, prerequisites recommended by the WHO prior to implementing MDA-azithromycin. Communities where MDA-azithromycin should and can practicably be implemented need to be identified.

Conclusions

MDA-azithromycin programs have shown significant clinical benefits as well as potential risks that should be weighed carefully when deciding how, when, and where to best implement such programs. Impact at the individual, community, and global levels in both the near and long terms should be considered when making policy decisions regarding MDA-azithromycin implementation.