Implementation of mass drug administration of antibiotics in low- and middle- income countries

Implementation of mass drug administration of antibiotics in low- and middle- income countries | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Implementation of mass drug administration of antibiotics in low- and middle- income countries Natasha O’Sullivan, David McCoy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2112557/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Recent years has seen the mass administration of certain antimicrobials, including antibiotics, increasingly promoted as a public health strategy in low- and middle-income countries (LMICs). The WHO currently recommends the mass administrations of azithromycin for three indications: yaws, trachoma, and child mortality. Methods We conducted a desk-based review of secondary data to discuss the clinical, public health and economic evidence underpinning the decision to adopt, and the issues to consider when implementing a mass drug administration (MDA) programme involving azithromycin. Results Before deciding to adopt and implement a policy of MDA of antibiotics, the evidence base should be evaluated, including an economic assessment, and consideration of the distribution of benefits and risks amongst individuals and within communities and populations. Once the decision to adopt has been made, key considerations for successful implementation of a programme include ensuring it does not draw attention and resources away from other health services and finding opportunities for generating efficiencies through integration with existing health interventions. Understanding local attitudes and gaining trust are essential for stakeholder buy-in Furthermore, there must be appropriate attention to the potential harms which include worsening antimicrobial resistance, unintended consequences of public health interventions and reinforcement of a selective primary healthcare paradigm at the expense of a more bottom-up, comprehensive and socially driven pathway to health improvement. Conclusion Although MDA of antibiotics presents an opportunity to prevent mortality and improve health in the short-term, in the case of childhood mortality, MDA of azithromycin can only be a short-term quick fix. Ultimately, long-term, and sustainable child mortality reductions – especially in high mortality settings – will require more comprehensive approaches to health system strengthening and broader-based socio-economic development. Global health Mass drug administration Azithromycin Child mortality Background Population-wide administration of health interventions come in many forms and have a long history. They include water fluoridation, vitamin K injections for newborns, food fortification, vaccinations, Vitamin A supplementation (VAS) and the mass drug administration (MDA) of antimicrobials 1 – 5 . In some instances these interventions are preventative, while in other cases they are designed to treat disease or illness. But a common feature of these interventions is that they are applied to all individuals en masse within a defined population regardless of their risk profile or clinical state. Recent years have seen the mass administration of antimicrobials being increasingly promoted as a public health strategy in low- and middle-income countries (LMICs). Based on a literature review we conducted, we identified 14 different applications of MDA of antimicrobials (see Appendix 1) covering a range of treatments, diseases and indications. Five of these involve the administration of antibiotics of which three have associated World Health Organisation (WHO) guidelines. Two of these guidelines cover the mass administration of azithromycin to treat and prevent yaws and trachoma in endemic countries, while the third involves the non-disease-specific application of MDA of azithromycin designed to reduce overall child mortality in Sub-Saharan Africa (SSA). One rationale for the MDA of antibiotics is that it provides a mechanism to obviate the weak health systems and lack of access to effective diagnostic and curative care that many individuals within LMICs suffer from. However, while mass administration of antibiotics to entire populations may reduce morbidity and mortality in the absence of stronger health systems, there are also risks to consider, particularly in relation to causing or accelerating antibiotic resistance. MDA programmes may also reinforce a selective primary health care (PHC) paradigm mindset and a paradigm that prioritises vertical and technologically mediated reductions in mortality, at the expense of health systems strengthening efforts and more comprehensive and socially-driven pathways to health improvement. This paper examines the three WHO guidelines on the mass administration of azithromycin (Table 1 ) through a critical public health perspective. The aim of the paper is to provide a discussion of the clinical, public health and economic issues that Ministries of Health must consider when deciding to adopt and implement an MDA programme involving azithromycin. [Table 1 : Indications for mass drug administration of azithromycin from WHO Guidelines] Table 1 Indications for mass drug administration of azithromycin from WHO Guidelines Indications Regimen and target population Trachoma WHO and the International Coalition for Trachoma Control recommend MDA of azithromycin for the elimination of blinding trachoma in populations where prevalence of Trachoma Follicular Inflammation is >/10% in children 1–9 years. 6 , 7 Oral azithromycin 20mg/kg to all children > 6months + all adults annually for a minimum of 3 years combined with Tetracycline eye ointment twice daily for 6/52 for infants < 6months. Coverage should not be less than 90%. Yaws WHO recommends MDA of azithromycin for the eradication of yaws in areas where the disease is consistently present, or where there is at least one clinically and serologically confirmed case of yaws. 8 , 9 Single-dose azithromycin 30mg/kg to all children > 6months + all adults, to be followed by active clinical and serological surveillance with treatment of any residual cases and their contacts until there are no new infectious cases. WHO recommends that two or three rounds of total community treatment at 6–12 monthly intervals may be required. Population coverage of > 90% is essential. Child Mortality WHO does not recommend universal MDA of azithromycin for prevention of childhood mortality but states that consideration should be given only in sub-Saharan African settings where: 10 • Infant mortality is > 60 per 1000 live births OR under-five mortality is > 80 per 1000 live births and • child mortality rates, adverse effects and antibiotic resistance are continuously monitored and • Existing child survival interventions, including seasonal malaria chemoprophylaxis where recommended, are already implemented and being strengthened Single-dose azithromycin 20 mg/kg every 6 months to all children aged 1–11 months. The guideline does not state the number of cycles of treatment that are needed but notes the need to update or revise the current guidelines within 2–3 years based on new evidence from large ongoing studies and planned research. Methods This paper present a semi-systematic search and narrative review of the published and grey literature, including the actual WHO guidelines. The paper draws from multiple literatures on various topics: a) MDA programmes; b) public health interventions (PHIs) applied to whole populations; c) unintended consequences of PHIs; and d) antimicrobial resistance (AMR). We identified literature to review by searching Google Scholar and PubMed, as well as the World Bank, Centers for Disease Control and Prevention, and Gates Foundation websites up to May 2022, and selected documents to review on the basis of a qualitative assessment of the titles and abstracts of the search results. Search terms used can be found in Appendix 2. Only documents published in English were included. This review did not limit the included articles based on year of publication. Although non-systematic literatures reviews conducted in this manner are vulnerable to bias, the purpose of this review was not to identify all relevant literature, rather to draw out relevant aspects of different literatures on the four topics mentioned above. We then reviewed and assessed the guidance in available guidelines and discuss the findings in this paper. Results Evidence in support of an MDA programme Treatment and prevention of yaws The evidence for promoting the use of MDA of azithromycin for the eradication of yaws is centred on three separate trials conducted that each observed a significant decrease in the prevalence of active and latent yaws following the administration of a single dose of azithromycin, as described in Table 2 . A trial on a yaws-endemic island in Papua New Guinea saw the prevalence of active infectious yaws reduce from 2.4–0.3% at 12 months ( p > 0.001) and the prevalence of high-titre latent yaws among children reduced from 18.3–6.5% ( p < 0.001) , with no significant side effects and no evidence of mutations conferring resistance to azithromycin in the 90 randomly selected swabs obtained during clinical surveys from all participants with papillomatous or ulcerative lesions 11 . Table 2 Trials providing evidence for MDA of azithromycin for yaws, trachoma, and child mortality Trial Name Time period & Setting Study Population & Sample Size Intervention End points Yaws Mass Treatment for Single-Dose Azithromycin for Yaws 11 April 2013- May 2014 Papua New Guinea All persons > 2 months of age in study villages 28 villages with 400–600 inhabitants each. Estimated population in 2013 was 16,092 according to regularly updated census Single-dose oral azithromycin 30mg/kg, max dose 2g Initial mass treatment followed every 6 months by targeted treatment program, performed that consistent of clinical examination of resident population, with treatment of all persons with active clinical cases and their contacts. Pregnant women and persons with known allergy to macrolides given penicillin G benzathine 50,000 units/kg intramuscularly Overall rate of treatment coverage during mass treatment program was 83.8%, with all study villages having coverage rate > 70.0%. Prevalence of infectious active yaws fell from 2.4% at baseline to 0.3% at 6 months and remained at 0.3% at 12 months (difference from baseline 2.1 percentage points; 95% confidence interval [CI] 1.9 to 2.4; p < 0.001). Prevalence of high-titer latent yaws decreased from 18.3% at baseline to 6.5% at 12 months (difference 11.8 percentage points; 95% CI 8.9 to 14.7; p < 0.001). Proportion of 90 participants ulcers at baseline with PCR-confirmed T.pallidum was 21.1%, H.ducreyi was 46.7% and co-infection with both in 13.3%. Proportion of patients with lesions due to yaws 6 months after treatment did not decrease significantly as compared to baseline, and proportion patients with dual infection increased. At 12 months there was significant reduction in the proportion of ulcers containing either T.pallidum subspecies pertenue alone (risk difference, 10.6 percentage points, 95% CI 0.4 to 20.7; p = 0.04) or coinfection (risk difference, 7.2 percentage points; 95% CI -1.1 to 15.5; p = 0.08), whereas proportion ulcers containing H.ducreyi alone remained similar level to baseline (risk difference 0.1 percentage points; 95% CI -13.6 to 14.0; p = 0.98). No severe adverse events attributable to study drug were reported from passive surveillance. Active surveillance of 316 participants from 60 households yielded 54 participants (17.1%) reporting adverse events (all mild). No evidence of mutations conferring resistance to azithromycin in 90 randomly selected swabs obtained during clinical surveys from all participants with papillomatous or ulcerative lesions at any of the time points Community-based mass treatment with azithromycin for the elimination of yaws in Ghana – Results of a pilot study 12 October 2013 – December 2014 Eastern Region of Ghana All persons > 6 months of age, excluding pregnant women 15,310 people Single-dose oral azithromycin 30mg/kg, max dose 2g Assessment survey at baseline and one-year post-intervention. of school-age children from 10 randomly selected schools. 89% of residents received a single oral dose of azithromycin Prevalence rate of dual seropositivity (non-treponemal and treponemal antibody positivity) in DPP test decreased significantly, from 10.9% (95% CI 6.5–17.5) among children in the pre-TCT survey to 2.2% [(95% CI 1.3–3.7), OR 0.19 (95% CI 0.09–0.37)] in the post-TCT survey. Prevalence of rate of serologically confirmed yaws-like active lesions among schoolchildren was significantly reduced from a pre-TCT rate of 5.7% (95% CI 3.2–9.9) to 0.6% (95% CI 0.2–1.6; OR 0.10, 95% CI 0.25-35) in post-TCT schoolchildren sample. No severe adverse events attributable to study drug and only 0.3% of participants reported mild to moderate adverse events. No evidence of resistance to macrolides against Treponema pallidum subspecies pertenue was seen. Impact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws 13 Mid-2014 Solomon Islands Not described 897 children from 441 householders in 11 communities enrolled for assessment 6 months post-intervention Single dose of azithromycin 20mg/kg, max 1g Single round of community mass treatment reduced prevalence of active and latent yaws from 1.5% and 20.2% respectively to 0.0% and 3.6% 6 months post-treatment (p = 0.002 and < 0.001 respectively). Reduction in mean number of cases of yaws reported per month of 101, relative reduction 57%, p = 0.044 TPPA seroprevalence at 18 months didn’t differ significantly from pre-MDA survey or initial follow-up survey at 6 months (31.4% and 25.0% respectively, p > 0.05 for both comparisons) No treponemal DNA detected in 20 lesion swabs. Trachoma Azithromycin in control of trachoma 16 Pairs of villages in The Gambia, Tanzania and Egypt (matched on trachoma rates in 1-10year old children) All children up to age 15 years, all men, and all women beyond child-bearing age Randomly assigned to: 1. Azithromycin - Adults received 1g oral azithromycin once a week for 3 weeks. Children received 20mg/kg, max dose 1g 2. 1% topical tetracycline once daily for 6 weeks Clinical examinations at baseline, 2-4.5, and 12–14 months Of participants initially LCR positive ( Chlamydia trachomatis identified by ligase chain reaction), 866 (95%) of 924 who received at least one azithromycin dose and 482 (82%) of 587 who received 28 days or more of topical tetracycline, were negative at follow-up. At 1 year, village wide LCR positive rates were substantially lower than at baseline with both treatments, and the decreases were greater with azithromycin than with tetracycline (93% vs. 77% in Egypt, 78% vs 66% in The Gambia, 64% vs 55% in Tanzania). Child Mortality Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children: A Randomized Trial 22 May 2006 - May 2007 Ethiopia Children aged 1–10 years 48 communities randomised into 1 of 3 treatment schedules: 1. Annual treatment all resident (15,902 residents) 2. Biannual treatment of all residents (17,288) 3. Quarterly treatment of children (14,716) Or into control group for which treatment delayed by 1 year (18,498 participants) Single-dose oral azithromycin (adults 1g, children 20mg/kg) Odds ratio for childhood mortality in intervention communities 0.51 (95% CI, 0.29–0.90; p = 0.02) compared to control group. Estimated overall mortality rate during this period for children aged 1 to 9 years in the untreated group was 8.3 per 1000 person-years (95% CI, 5.3–13.1) while it was 4.1 per 1000 person-years for children 1–9 years in the treated communities (95% CI, 3.0-5.7) Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa 23 Malawi, Niger, and Tanzania Children aged 1–59 months weighing at least 3,800 grams 1533 communities (190,238 children) Communities randomised to oral azithromycin (at least 20 mg/kg) or placebo Overall annual mortality rate in placebo-treated communities was 16.5 per 1000 person-years (9.6 per 1000 person-years in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Azithromycin-treated communities had an estimated 13.5% lower mortality overall (95% CI, 6.7%-19.8%, p < 0.001). Mortality was 5.7% lower in Malawi (CI -9.7%-18.9%, p = 0.45), 18.1% lower in Niger (CI 10.0%-25.5%, p = 0.77) and 3.4% lower in Tanzania (CI -21.2%-23.0%, p = 0.77). Greatest reduction in mortality observed in 1–5 month-old children (24.9% lower, CI 10.6%-37.0%, p = 0.001) 20 hospitalisations or life-threatening illnesses occurred; 11 in the treated arm and 9 in the untreated arm. Cause of death was significantly different between country sites (p < 0.001), with relatively more deaths attributed to malaria in Niger and pneumonia in Tanzania. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention 24 2014 to 2017 Burkina Faso and Mali Children aged 3–59 months 1) Distribution of azithromycin and sulfadoxine-pyrimethamine plus amodiquine in four 3-day cycles at monthly intervals for three successive seasons, and 2) a control group receiving a placebo instead of azithromycin with same combination and schedule Addition of azithromycin to antimalarials for chemoprevention did not result in lower incidence of death or hospital admission [Table 2 : Trials providing evidence for MDA of azithromycin for yaws, trachoma and child mortality] A trial in in a yaws-endemic sub-district in Ghana saw the prevalence of latent yaws among children reduce from 10.9–2.2% (Odds ratio [OR] 0.19; 95% confidence interval [CI] 0.09–0.37) one year after the intervention and the prevalence of serologically-confirmed skin lesions decrease from 5.7–0.6% (OR 0.10; 95% CI 0.25–0.35) 12 . Similarly, there were no severe adverse events attributable to azithromycin, with only 0.3% of participants reporting mild and self-limiting side effects, and no evidence of bacterial mutations associated with azithromycin resistance. A trial in the Solomon Islands found no cases of active yaws six months post-treatment and a significant difference in the prevalence of latent yaws between individuals who had and had not been treated (2.8% vs 6.5% p = 0.015) 13 . Not receiving azithromycin was associated with a higher risk of infection (OR 3.9; p = 0.001). A survey 18 months after the intervention also showed that seroprevalence was still significantly lower than it had been pre-MDA 14 . A sample of lesions six months after the intervention found no evidence of living Treponema pallidum pertenue and therefore no evidence of macrolide resistance. Although the WHO guidelines do not discuss the cost effectiveness of MDA of azithromycin to eradicate yaws, a cost-effectiveness analysis of four yaws eradication pilot sites found that the cost for each additional year of life lived without disability or disfigurement due to yaws being eradicated was $ 26 (4.2–78), making the intervention highly cost-effective 15 . Trachoma The MDA of azithromycin as an intervention to eliminate trachoma began in 1998 and was included in a WHO guideline on trachoma control that was produced in 2006 6 . This has subsequently been complemented by a more expansive guideline produced by the International Coalition for Trachoma Control (ICTC) Guideline in 2013 following an extensive literature review, a survey of national trachoma control programme coordinators, and a series case studies in several countries to document ‘what worked, what did not work, and why’ 7 . The evidence underpinning these guidelines mainly comes from a cluster-randomised trial in trachoma-endemic villages in Egypt, The Gambia and Tanzania that compared mass treatment with a topical tetracycline ointment daily for six weeks with the MDA of a single weekly dose of oral azithromycin for three weeks as detailed in Table 3 16 . The trial found lower trachoma positivity rates in the azithromycin group compared to the tetracycline group (93% vs 77% in Egypt, 78% vs 66% in The Gambia, 64% vs 55% in Tanzania). The trial did not report on adverse events nor AMR. As with yaws, cost-effectiveness is not discussed in the trachoma guidelines. However, one study from 2005 that estimated cost-effectiveness of MDA of azithromycin in trachoma-endemic areas in seven world regions found that MDA of azithromycin for trachoma could avert more than 4 million disability-adjusted life years (DALY) per year globally but was not cost-effective, costing between $ 9,000–65,000 per DALY averted 17 . According to the authors, the MDA of azithromycin to control trachoma would only be cost-effective if the drug was donated or made available at a reduced price. A study from 2011 in a remote area of South Sudan found that the average economic cost per person treated with azithromycin was 1.53 USD 18 . The major cost drivers were personnel (41.3%) and travel/transport (29.1%), but this estimate excluded the cost of azithromycin. If the economic cost of the donated antibiotic had been included, the estimated economic cost per person treated would have been 34.2 USD, significantly higher than the frequently quoted 0.5 USD annual per capita cost for simultaneous delivery of multiple drugs during MDA programmes 19 , 20 . A 2010 study that calculated cost-effectiveness using previously published data found targeted treatment to households rather than mass treatment could be significantly more cost-effective than mass treatment when azithromycin was not donated. However, MDA was predicted to be more cost-effective when azithromycin was donated, unless opportunity costs incurred by individuals collecting antibiotics were included or household visits improved treatment uptake 21 . Clearly, there is a need for more recent cost-analysis studies using current azithromycin prices. Child mortality WHO’s guideline on the use of MDA of azithromycin was developed by a Guideline Steering Group (GSG) made up of technical officers from different departments in WHO that had commissioned separate systematic reviews to synthesise the evidence of MDA of azithromycin relating to: (1) efficacy in terms of mortality and morbidity and the factors which might modify the effect of the intervention; (2) AMR and (3) adverse effects, dose strength and regimen, and potential mechanisms of action 10 . Central to the evidence were three randomised controlled trial (RCT) studies in sub-Saharan African malaria-endemic countries with high under-5 mortality rates (U5MR) as described in Table 2 . The first was a four-armed cluster-randomised trial (annual, biannual or quarterly azithromycin, and no treatment) of children aged 1–9 years in Ethiopia 22 . The mortality rate among children in treated communities was half that of untreated communities (OR: 0.51, p = 0.02), although subsequent case-control analysis of the mortality rate among children aged 1–5 years reported a non-significant OR of 0.31 ( p = 0.06). The second was the multi-country MORDOR trial of biannual azithromycin MDA (20 mg/kg) in children aged 1–59 months in Malawi, Niger and Tanzania which reported 14% lower mortality in azithromycin- compared to placebo-treated communities, with a 24.9% lower mortality in children 1–5 months of age 23 . The third study, a cluster-randomised trial of MDA of azithromycin added to seasonal malaria chemoprophylaxis (SMC) on a monthly basis for four months during the peak malaria season over three years in Mali and Burkina Faso, found that MDA of azithromycin did not reduce hospitalisation or mortality compared to SMC alone 24 . Because of the heterogeneity of the interventions, outcome measures and geographical contexts, the results from these trials could not be pooled. The GSG also concluded that the evidence of MDA of azithromycin reducing childhood mortality was ‘low’ and that the evidence of mortality reduction only justified considering MDA of azithromycin in infants below the age of one. However, because of an increased risk of pyloric stenosis in the first month of life after azithromycin, WHO advised exclusion of neonates from the programme 10 . The GSG also noted that there were only sparse data on the potential impact of MDA of azithromycin on AMR, and that it was not possible to determine the longer-term MDA of azithromycin programmes increasing the circulation of resistant strains in the community and what impact this might have on enteric pathogens and clinical outcomes 10 , 25 – 27 . Information provided by WHO about the economic dimensions of MDA of azithromycin for child mortality is centred around two primary economic evaluation studies that found that the estimated cost per dose of MDA ranges from $ 0.37 to $ 0.74, and that the cost per DALY averted ranges from $ 9.98 to $ 14.26, which indicates that the MDA of azithromycin to reduce child mortality would be cost-effective 28 , 29 . Indeed, data from the MORDOR trial in Malawi points to the intervention being highly cost effective as defined by willingness-to-pay thresholds established by WHO 29 , 30 . This would make MDA of azithromycin comparable to other core interventions for reducing child mortality such as integrated management of childhood illness and SMC 31 – 33 . However, Hart et al also note considerable variation in cost-effectiveness by geographical location within Malawi and state that a better understanding of the reasons for this would be desirable before wider implementation of the intervention, alongside a better understanding of the mechanism of action and potential for the development of macrolide resistance 29 . In a more recent review of the cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa, it has been suggested that instead of MDA of azithromycin, targeting high-risk children is an option that could make economic sense while reducing exposure to azithromycin 28 , although the evidence supporting this strategy is currently limited. A trial in neonates receiving biannual azithromycin in sub-Saharan Africa found no evidence to support its’ use for prevention of mortality 34 and a trial targeting children under 5 years after hospital discharge found no significant benefit of a 5-day course of azithromycin to the risk of death of rehospitalization 35 . In the case of yaws and trachoma, cost-effectiveness will change as the incidence and prevalence of disease changes and depending on the timeframe for which the costs and benefits of disease control or elimination are assessed. In the case of child mortality, WHO currently only recommends that this be considered in areas where the infant mortality rate (IMR) is high (over 60 per 1000 live births) 10 . It should be reasonable therefore to expect any MDA of azithromycin to reduce mortality to be short lived as child health and healthcare improves through other services and interventions. Importantly, the WHO guideline states that the implementation of “existing child survival interventions, including SMC where recommended [are] concurrently strengthened’ and that “SMC scale-up should take precedence over MDA of azithromycin implementation” 10 . Implementing an MDA programme Multiple trials and programmes have now generated a significant body of learning about what determines the effective, efficient and equitable mass administration of azithromycin 36 . WHO’s three guidelines 6 , 8 , 10 draw on this experience and provide varying amounts of guidance covering the procurement of drugs (and diagnostic tests if needed) and management of the drug supply chain; the mapping and listing of the target population and measurement of coverage levels; community and stakeholder engagement; personnel training and supervision; the management of transport and other logistical requirements; drug administration and the management of non-compliant individuals; and the collection of data to enable monitoring and evaluation. Integration into the wider healthcare system A plan to deliver an MDA programme is not all that national and local health managers have to develop and implement. MDA programmes should also be designed and implemented in a way that contributes positively to the needs and demands placed on the health system more generally. At the very least, they should avoid inadvertently impacting negatively on the wider health system, especially in settings where health systems are under-resourced and fragmented. In ideal circumstances, any new programme would be carefully added to the panoply of existing services and programmes in a way that would avoid any inadvertent harms, while also finding opportunities for generating efficiencies through economies of scale or for strengthening the health system through positive synergies with other interventions. While the WHO guideline on the MDA of azithromycin to reduce child mortality makes explicit mention of the need to consider other child survival services and interventions 10 , there is no clear guidance as to how local planners and managers should weigh up and choose between prioritising an MDA programme over other critical child health services such as improving skilled birth attendance rates or child vaccination coverage rates. Nor does it explicitly suggest ways in which MDA could be integrated with other community-based public health interventions such as VAS programmes or vaccination campaigns. Interestingly, the WHO guideline for trachoma notes that MDA for trachoma has historically been delivered through stand-alone vertical programmes, and that the overlap and similarities in treatment strategies with other NTD programmes should offer opportunities for synergy 6 . One example given was the combination of mass treatment with azithromycin with fever screening and malaria treatment in Ethiopia. The guidelines for yaws do not however include any discussion about possible opportunities for integration or synergy with other services or needs 8 , 9 . Coordinated and integrated health planning is however challenging in settings where selective and vertical programmes are championed by external donors, or where there is insufficient decentralised capacity and authority capable of integrating centrally-funded and centrally-directed programmes 37 . Thus while MDA programmes could in theory contribute to more integrated healthcare and economic efficiencies, unless there is sufficient commitment to a health systems strengthening agenda, an integrated approach also runs the risk of sub-optimal delivery of an MDA programme. Antimicrobial stewardship Another aspect of the wider health system that should feed into the implementation of an MDA programme are the efforts to strengthen antibiotic stewardship. Preventing widespread AMR is viewed as a major global health priority, with one study estimating 4.95 million deaths (95% uncertainty interval [UI] 3.62–6.57) associated with bacterial AMR occurred in 2019, including 1.27 million deaths attributable to bacterial AMR 38 . Of particular note is that the highest all-age death rate attributable to AMR occurred in western sub-Saharan Africa, at 27.3 deaths per 100,000 (95% UI 20.9–35.3), and in addition serious data gaps existing in many LMICs were highlighted and the need to expand microbiology laboratory capacity and data collection systems emphasised. Investigation of the gut resistome of children after receiving twice-yearly azithromycin for four years in the Niger site of the MORDOR study found determinants of macrolide resistance were 7.5 times as high (95% CI, 3.8 to 23.1) in villages treated with azithromycin as in villages that received a placebo 39 . Of note was that resistance extended beyond macrolides; an additional two rounds of azithromycin MDA caused a notable increase in resistance determinants to several nonmacrolide antibiotics, including 2.1 times (95% CI 1.2-4.0) greater number of beta-lactam resistance determinants. However, the clinical and public health relevance of such resistance is not yet known. A further study that evaluated the impact of MDA of azithromycin in communities within the Malawi site of the MORDOR trial suggests this impact may be limited as it found that the proportion of gastrointestinal bacteria carrying macrolide resistance increased after azithromycin treatment, but that this had limited impact on clinically relevant bacteria and on the diversity and global community structure of the gut 40 . According to one recent systematic review of the literature, only 40% of studies of mass and systematic drug administration (SDA) of antibiotics evaluated the risk of AMR developing. Nonethless, the review gave reason to be concerning by warning that MDA and SDA of antibiotics might lead to a significant increase in AMR, especially following azithromycin administration 41 . Even if MDA of azithromycin is not considered to be a significant risk for producing or worsening bacterial resistance to macrolides, it should not undermine efforts to stop the misuse and over-use of antibiotics. For example, care should be taken to avoid any perception by some people that mass treatment with antibiotics is a sign that antibiotic resistance is unimportant. While the WHO guideline on child mortality advises that AMR be monitored through sentinel surveillance of resistance in nasopharyngeal and gut flora, and in common bacteria causing invasive infections 10 , the guidelines on trachoma and yaws make no reference to AMR monitoring at all 6 – 9 . Furthermore, none of the guidelines call for an AMR awareness and prevention strategy to be included in the design of their respective MDA programmes nor recommend that a basic standard of good antibiotic stewardship is present before implementing an MDA programme. Views and attitudes of stakeholders (acceptability) When thinking about the implementation of MDA programmes, there may also be wider social and cultural factors to consider. For example, the ICTC guideline emphasises the importance of gaining the support and trust of local communities and exploring local attitudes towards medicines and other pharmaceuticals 7 . This may be especially important now given the problems of misinformation on social media and an apparent rise in levels of mistrust towards figures of authority, including healthcare workers and members of the scientific community, as evidenced by growing levels of ‘vaccine hesitancy’ in many parts of the world 38 and increasing levels of resistance to other mass interventions such as the routine intramuscular injection of vitamin K to all newborns 43 – 46 . There is a potential for MDA programmes, especially those that are not targeted at a particular disease, to not just be undermined by mistrust and misinformation, but to amplify these social phenomena, particularly if insufficient efforts are taken to win community support for an MDA programme and if any perception that antibiotics are being forced en masse upon a population emerges. Discussion Clinical and public health evidence suggest that the MDA of azithromycin to eradicate yaws and reduce child mortality in certain settings are cost-effective. But studies from 2005 and 2010 indicate that this would not be the case for the control and treatment of trachoma 17 , 18 , 21 . The proposal to periodically mass administer azithromycin to reduce child mortality is however questionable given that its precise mechanism of action is unclear, and that evidence of efficacy is somewhat mixed. However, the primary purpose of this paper is not to discuss this evidence, but to rather examine the MDA of antibiotics through a wider public health and health systems lens. In doing so, two broad issues stand out. The first issue concerns the manner in which MDA programmes are funded, conceptualised, organised and implemented, and how they are situated within the context of longstanding tensions between differing approaches to health improvement in LMICs. While vertically managed and dedicated MDA programmes allow for focused, rapid and effective delivery, when they are conceived and constructed as single-focused interventions that are delivered through centralised and vertical structures, there is a risk that they may undermine other health services and more comprehensive and holistic approaches to health and lower the overall efficiency of the health system. For example, they can draw resources and attention away from other health services, and they can add to the fragmentation and duplication of efforts across the health system 47 , 48 , especially if there are other vertical programme, which may be associated with higher total expenditures 49 .. MDA programmes and their focus on antimicrobials may also reinforce a mindset that privileges or exalts the superiority of biomedical interventions over the more messy social, political and economic pathways to health improvement. Although MDA programmes can be a component of a comprehensive and holistic approach to the prevention and treatment of infectious diseases and improved child survival, they may also be used as an excuse or alibi for the lack of progress made in reducing poverty, extending access to clean water and sanitation, improving infant and child nutrition and ensuring universal access to comprehensive maternal and newborn care. Worse still, they could even divert attention and resources from upstream interventions that might produce more sustainable and long-term benefits 50 . Other PHIs that are ‘mass administered’ share similar tensions. For example, while water fluoridation reduces the prevalence and incidence of dental caries 51 and has a disproportionately beneficial impact on children from lower socio-economic groups 52 , it may have shifted dental public health attention away from the underlying causes of dental caries such as excessive sugar consumption and poor dental hygiene 53 . Similarly, VAS may bypass the underlying causes of vitamin A deficiency such as poor hygiene and poor diet 54 . Tensions have long existed between approaches that give differing degrees of emphasis to selectivity as opposed to comprehensiveness, or to biomedicalism as opposed to social medicine, or to centralised and top-down vertical delivery systems as opposed to decentralised, bottom-up and integrated systems. Importantly these tensions cannot be resolved through evidence or science as they partly reflect different philosophical and ideological positions, whilst also adopting different timeframes. However, it is important that those funding, studying and advocating MDA programmes are open to discussing these tensions, and to seeking optimal integration and positive synergy with other interventions and services that may also reduce morbidity and mortality. Importantly, WHO’s current advice that the MDA of azithromycin as a non-specific child survival strategy should only be considered in places where the IMR > 60 automatically means that it will be implemented in conditions where the rights of children to adequate nutrition and healthcare are not being universally met 10 . At present, 13 SSA countries have an IMR > 60: Burkina Faso, CAR, Chad, Ivory Coast, Eswatini, Guinea, Lesotho, Mali, Niger, Nigeria, Sierra Leone, Somalia, South Sudan 55 . However, there will be many sub-national geographies and populations in other countries with an IMR of more than 60. It remains unclear if such areas should be identified and assessed as to whether an MDA programme would be appropriate. It is notable that an increasing number of MDA programmes are now recommended by WHO or researchers. In addition to the three discussed in this paper, WHO guidelines on MDA exist for several non-bacterial diseases: malaria 56 , lymphatic filariasis 57 , onchoceriasis 58 , schistosomiasis 59 , Taenia Solium 60 , soil-transmitted helminths 61 and foodbourne trematodiase 62 . Other MDA applications recommended by researchers include single-dose oral ciprofloxacin in areas prone to meningitis epidemics 63 ; azithromycin to reduce genital chlamydia trachomatis infection 64 ; and albendazole or mebendazole to pregnant women to reduce neonatal mortality 65 . When coupled with the prominence of various vertical and top-down selective health programmes that exist, such as the Global Fund and the Global Alliance for Vaccines and Immunisations, it could be argued that MDA programmes are part of a wider prevailing selective primary health care paradigm that is partly responsible for perpetuating the problems of weak, fragmented and under-resourced health systems 47 . The second issue that stands out when examining MDA programmes through a wider public health lens is that of AMR. One prediction is that by 2050, AMR will result in 10 million additional deaths per year, with a disproportionately high burden in LMICs 66 . Therefore, evidence that the mass administration of antibiotics will do more harm than good is crucial. Meanwhile, progress in improving antibiotic stewardship has been slow and inadequate, especially in LMICs where antibiotic consumption is increasing in the context of poor clinical practice 67 , 68 , inadequate regulation of pharmaceutical markets, and inadequate clinical and laboratory surveillance of AMR prevalence 69 . The contribution that MDA programmes might make to the worsening of AMR is not known. Evidence exists that suggests azithromycin MDA may lead to a degree of macrolide and nonmacrolide resistance, however the clinical and public health relevant of such resistance is currently unknown and clearly warrants further research 39 , 40 , 70 . Despite this, the guidelines discussed above appear to downplay the risk of worsening AMR 6 – 10 . For example, they do not recommend that a situation analysis of current patterns of antibiotic use or of levels of AMR is conducted prior to implementing an MDA programme. The two issues raised here may be described as unintended consequences (UCs) associated with MDA programmes. Importantly, UCs associated with public health interventions (PHIs) tend to be neglected in the academic literature because relative to the UCs of clinical interventions, they are harder to detect and to attribute directly to the effects of PHIs 71 and because many UCs associated with PHIs are second- or third-order consequences that are hard to anticipate 72 , 73 . UCs may also be neglected or ignored by policymakers and researchers because of a general unwillingness to engage with uncertainty or to acknowledge gaps in knowledge 71 . Thus the hard data on the impact that MDA programmes might have on the incidence of disease or the saving of lives will tend to have more sway over the unknown potential (and longer term) harms arising from UCs, even if those harms may be considerably greater than the benefits. Conclusion While the MDA of antibiotics presents an opportunity to prevent mortality and improve health in the short term, particularly amongst some of the poorest and most vulnerable populations, there must also be appropriate attention to the potential harms. The two greatest harms to consider are the risk of worsening AMR and the potential undermining of a holistic and comprehensive health improvement agenda. In the case of child mortality reduction in particular, MDA can only be a short-term quick fix. Ultimately, long-term and sustainable child mortality reductions – especially in high mortality settings – will require more comprehensive approaches to health system strengthening and broader-based socio-economic development. Abbreviations AMR Antimicrobial resistance CI Confidence interval DALY Disability-adjusted life year GSG Guideline Steering Group ICTC International Coalition of Trachoma Control IMR Infant mortality rate LMIC Low- and middle-income country MDA Mass drug administration OR Odds ratio PHI Public health intervention RCT Randomised controlled trial SDA Systematic drug administration SMC Seasonal malaria chemoprophylaxis UC Unintended consequences VAS Vitamin A supplementation WHO World Health Organisation Declarations Ethics approval: Not applicable Competing interests: The authors declare they have no competing interests. Authors contributions : DM provided critical conceptual input. NOS performed the literature search, analysed and interpreted the literature. DM and NOS wrote the manuscript collaboratively. All authors read and approved the final manuscript. Funding. This work was supported under a Greenwall Foundation grant on the “Mass Administration of Antibiotics: Reaching Clinical and Community Equipoise” as part of the Making a Difference in Real-World Bioethics Dilemmas program. The Greenwall Foundation did not have a role in the design of the study, collection, analysis, and interpretation of data or in writing the manuscript. Availability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files]. Acknowledgements : We thank the research team of Dr. Anthony So and Dr. Matthew DeCamp (co-principal investigators on the Greenwall Foundation grant) and of Alex Kong and Ahmed Alasmar for providing helpful comments on earlier drafts, for organizing an expert feedback session on the manuscript, and for supporting its submission. We also thank the following persons for their expert commentary on the initial draft of this manuscript: Martha Gyansa-Lutterodt, Mickey Chopra, and Ayesha DaCosta, and Tom Lietman and Robin Bailey for their informal interviews regarding implementation challenges for MDA programmes. References Fawell J, Bailey J, Chilton E, Dahi E, Fewtrell L, Magara Y. Fluoride in drinking-water. Geneva: World Health Organisation; 2006. World Health Organization. Immunization. 2019 Dec 5. Available from: https://www.who.int/news-room/facts-in-pictures/detail/immunization [accessed 2021 Oct 14]. Guideline. vitamin A supplementation in infants and children 6–59 months of age. Geneva: World Health Organisation; 2011. WHO Recommendations on. newborn health: guidelines approved by the WHO Guidelines Review Committee. Geneva: World Health Organisation; 2017. Webster JP, Molyneux DH, Hotez PJ, Fenwick A. The contribution of mass drug administration to global health: past, present and future. Philos Trans R Soc Lond B Biol Sci. 2014;369(1645):20130434. Trachoma control – a guide for programme managers. Geneva: World Health Organisation; 2006. International Coalition for Trachoma Control (ICTC). Preferred practices for Zithromax mass drug administration. London: International Coalition for Trachoma Control; 2013. Eradication of yaws. a guide for programme managers. Geneva: World Health Organization; 2018. World Health Organisation. Eradication of yaws–the Morges strategy. Wkly Epidemiol Rec, 2012. 87(20): p. 189 – 94. WHO guideline on mass drug administration of. azithromycin to children under five years of age to promote child survival. Geneva: World Health Organization; 2020. Mitjà O, Houinei W, Moses P, Kapa A, Paru R, Hays R, et al. Mass treatment with single-dose azithromycin for yaws. N Engl J Med. 2015 Feb 19;372(8):703 – 10. doi: 10.1056/NEJMoa1408586 . Abdulai AA, Agana-Nsiire P, Biney F, Kwakye-Maclean C, Kyei-Faried S, Amponsa-Achiano K, et al. Community-based mass treatment with azithromycin for the elimination of yaws in Ghana-Results of a pilot study. PLoS Negl Trop Dis. 2018 Mar 22;12(3):e0006303. Marks M, Sokana O, Nachamkin E, et al. Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma [published correction appears in PLoS Negl Trop Dis. 2018 Mar 7;12. Marks M, Vahi V, Sokana O, et al. Impact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws. PLoS Negl Trop Dis. 2015;9(8):e0003988. doi: 10.1371/journal.pntd.0003988 . Published 2015 Aug 4. Fitzpatrick C, Asiedu K, Jannin J. Where the Road Ends, Yaws Begins? The Cost-effectiveness of Eradication versus More Roads. PLoS Negl Trop Dis. 2014;8(9):e3165. https://doi.org/10.1371/journal.pntd.0003165 . Schachter J, West SK, Mabey D, Dawson CR, Bobo L, Bailey R, Vitale S, Quinn TC, Sheta A, Sallam S, Mkocha H, Mabey D, Faal H. Azithromycin in control of trachoma. Lancet. 1999 Aug 21;354(9179):630-5. doi: 10.1016/S0140-6736(98)12387-5 . PMID: 10466664. Baltussen RM, Sylla M, Frick KD, Mariotti SP. Cost-effectiveness of trachoma control in seven world regions. Ophthalmic Epidemiol. 2005 Apr;12(2):91–101. doi: 10.1080/09286580590932761. PMID: 16019692. Kolaczinski JH, Robinson E, Finn TP. The cost of antibiotic mass drug administration for trachoma control in a remote area of South Sudan. PLoS Negl Trop Dis. 2011;5(10):e1362. doi: 10.1371/journal.pntd.0001362 . Molyneux DH, Hotez PJ, Fenwick A. “Rapid-impact interventions”: how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med. 2005;2:e336. [PMC free article] [PubMed] [Google Scholar]. Brady MA, Hooper PJ, Ottesen EA. Projected benefits from integrating NTD programs in sub-Saharan Africa. Trends Parasitol. 2006;22:285–91. [PubMed] [Google Scholar]. Blake IM, Burton MJ, Solomon AW, et al. Targeting antibiotics to households for trachoma control. PLoS Negl Trop Dis. 2010;4(11):e862. doi: 10.1371/journal.pntd.0000862 . Published 2010 Nov 2. Keenan JD, Bailey RL, West SK, et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018;378:1583–92. Chandramohan D, Dicko A, Zongo I, et al. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. N Engl J Med. 2019;380:2197–206. Seidman JC, et al. Increased carriage of macrolide-resistant fecal E. coli following mass distribution of azithromycin for trachoma control. Int J Epidemiol. 2014; 43: 1105–13. Doi: 10.1093/ije/ dyu062 . Seidman JC, et al. Increased carriage of macrolide-resistant fecal E. coli following mass distribution of azithromycin for trachoma control. Int J Epidemiol. 2014; 43: 1105–13. Doi: 10.1093/ije/ dyu062 . Doan T, Arzika AM, Hinterwirth A, Maliki R, Abdou A, et al. Gut and Nasopharyngeal Macrolide Resistance in the MORDOR Study: A Cluster-Randomized Trial in Niger. N Engl J Med. 2019;380(23):2271–3. Keenan JD, Klugman KP, McGee L, et al. Evidence for clonal expansion after antibiotic selection pressure: pneumococcal multilocus sequence types before and after mass azithromycin treatments. J Infect Dis. 2015;211(6):988–94. doi: 10.1093/infdis/jiu552 . Brander RL, Weaver MR, Pavlinac PB, John-Stewart GC, Hawes SE, Walson JL. Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa. Clin Infect Dis. 2020 Jan 6:ciz1220. doi: 10.1093/cid/ciz1220 . Hart JD, Kalua K, Keenan JD, Lietman TM, Bailey RL. Cost-Effectiveness of Mass Treatment with Azithromycin for Reducing Child Mortality in Malawi: Secondary Analysis from the MORDOR Trial. Am J Trop Med Hyg. 2020 Sep;103(3):1283–90. doi: 10.4269/ajtmh.19-0622 . Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bull World Health Organ. 2015;93:118–24. Prinja S, Bahuguna P, Mohan P, Mazumder S, Taneja S, Bhandari N, van den Hombergh H, Kumar R. Cost effectiveness of implementing integrated management of neonatal and childhood illnesses program in district Faridabad, India. PLoS ONE. 2016;11:e0145043. Nonvignon J, Aryeetey GC, Issah S, Ansah P, Malm KL, Ofosu W, Tagoe T, Agyemang SA, Aikins M. Cost-effectiveness of seasonal malaria chemoprevention in upper west region of Ghana. Malar J. 2016;15:367. Horton S, Levin C. Cost-effectiveness of interventions for reproductive, maternal, neonatal, and child health. In: Black R, Temmerman M, Laxminarayan R, Walker N, editors. Disease control priorities. 3rd ed (Vol 2): reproductive, maternal, newborn, and child health. Washington, DC: World Bank; 2016. pp. 319–34. Oldenburg CE, Sié A, Bountogo M, Zakane A, Compaoré G, Ouedraogo T, Koueta F, Lebas E, Brogdon J, Nyatigo F, Doan T, Porco TC, Arnold BF, Lietman TM, NAITRE Study Team. Neonatal azithromycin administration for prevention of infant mortality. NEJM Evid. 2022 Apr;1(4):EVIDoa2100054. doi: 10.1056/EVIDoa2100054 . Pavlinac PB, Singa BO, Tickell KD, Brander RL, McGrath CJ, Amondi M, Otieno J, Akinyi E, Rwigi D, Carreon JD, Tornberg-Belanger SN, Nduati R, Babigumira JB, Meshak L, Bogonko G, Kariuki S, Richardson BA, John-Stewart GC, Walson JL. Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial. Lancet Glob Health. 2021 Nov;9(11):e1569-e1578. doi: 10.1016/S2214-109X(21)00347-8 . Silumbwe A, Zulu JM, Halwindi H, et al. A systematic review of factors that shape implementation of mass drug administration for lymphatic filariasis in sub-Saharan Africa. BMC Public Health. 2017;17::484. Cairncross S, Peries H, Cutts F. Vertical health programmes. Lancet. 1997;349:20–1. doi: 10.1016/S0140-6736(97)90079-9 . Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629–655. doi: 10.1016/S0140-6736(21)02724-0 . Doan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, Zhong L, Chen C, Cook C, Lebas E, O'Brien KS, Oldenburg CE, Chow ED, Porco TC, Lipsitch M, Keenan JD, Lietman TM. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med. 2020 Nov 12;383(20):1941–1950. doi: 10.1056/NEJMoa2002606 . Pickering H, Hart JD, Burr S, Stabler R, Maleta K, Kalua K, Bailey RL, Holland MJ. Impact of azithromycin mass drug administration on the antibiotic-resistant gut microbiome in children: a randomized, controlled trial. Gut Pathog. 2022 Jan 6;14(1):5. doi: 10.1186/s13099-021-00478-6 . Ramblière L, Guillemot D, Delarocque-Astagneau E, Huynh BT. Impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review. Int J Antimicrob Agents. 2021 Jul;58(1):106364. doi: 10.1016/j.ijantimicag.2021.106364 . Kennedy J. Populist politics and vaccine hesitancy in Western Europe: an analysis of national-level data. Eur J Public Health. 2019;29:512–6. 10.1093/eurpub/ckz004 . d oi:. Coffey PS, Gerth-Guyette E. Current perspectives and practices of newborn vitamin K administration in low and middle income countries. Res Rep Neonatol. 2018;8:45–51. doi: 10.2147/RRN.S154652 . Hamrick HJ, Gable EK, Freeman EH, Dunn LL, Zimmerman SP, Rusin MM, Linthavong OR, Wright ME, Moss LA, Skinner AC. Reasons for Refusal of Newborn Vitamin K Prophylaxis: Implications for Management and Education. Hosp Pediatr. 2016 Jan;6(1):15–21. doi: 10.1542/hpeds.2015-0095 . Sahni V, Lai FY, MacDonald SE. Neonatal vitamin K refusal and nonimmunization. Pediatrics. 2014 Sep;134(3):497–503. doi: 10.1542/peds.2014-1092 . Loyal J, Taylor J, Phillipi C, Dhepyasuwan N, Shapiro E, Colson E, et al. Refusal of Vitamin K by Parents of Newborns: A Survey of the Better Outcomes Through Research for Newborns Network. Acad Pediatr. 2017;17(4):368–73. Spicer N, Agyepong I, Ottersen T, et al. ‘It’s far too complicated’: why fragmentation persists in global health. Global Health. 2020;16:60. doi.org/10.1186/s12992-020-00592-1 . World Health Organization Maximizing Positive Synergies Collaborative Group. Samb B, Evans T, Dybul M, Atun R, Moatti JP, Nishtar S, Wright A, Celletti F, Hsu J, Kim JY, Brugha R, Russell A, Etienne C. An assessment of interactions between global health initiatives and country health systems. Lancet. 2009 Jun 20;373(9681):2137-69. doi: 10.1016/S0140-6736(09)60919-3 . Robinson JC, Miller K. Total Expenditures per Patient in Hospital-Owned and Physician-Owned Physician Organizations in California. JAMA. 2014;312(16):1663–9. doi: 10.1001/jama.2014.14072 . Lassi ZS, Mallick D, Das JK, Mal L, Salam RA, Bhutta ZA. Essential interventions for child health. Reprod Health. 2014;11(Suppl 1):4. doi: 10.1186/1742-4755-11-S1-S4 . Suppl 1 ) . O'Mullane DM, Baez RJ, Jones S, Lennon MA, Petersen PE, Rugg-Gunn AJ, Whelton H, Whitford GM. Fluoride and Oral Health. Community Dent Health. 2016 Jun;33(2):69–99. Social factors and. oral health in children. London: Office for National Statistics; 2004. Selwitz RH, Ismail AI, Pitts NB. Dental caries. Lancet. 2007 Jan 6;368(9555):51 – 9. Doi: 10.1016/S0140-6736(07)60031-2 . Stevens GA, Bennett JE, Hennocq Q, Lu Y, De-Regil LM, Rogers L, Danaei G, Li G, White RA, Flaxman SR, Oehrle SP, Finucane MM, Guerrero R, Bhutta ZA, Then-Paulino A, Fawzi W, Black RE, Ezzati M. Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: a pooled analysis of population-based surveys. Lancet Glob Health. 2015 Sep;3(9):e528-36. doi: 10.1016/S2214-109X(15)00039-X . The World Bank. Mortality rate, infant (per 1,000 live births) [online]. 2022. Available at: Mortality rate, infant (per 1,000 live births) | Data (worldbank.org) [accessed 2022 June 9]. Mass drug administration. for falciparum malaria: a practical field manual. Geneva: World Health Organisation; 2017. Guideline. Alternative mass drug administration regimens to eliminate lymphatic filariasis. Geneva: World Health Organisation; 2017. Onchocerciasis. and its control: report of a WHO expert committee on onchocerciasis control. Geneva: World Health Organisation; 1995. Helminth control in. school-age children: a guide for managers of control programmes. Geneva: World Health Organisation; 2017. Guideline for preventative chemotherapy for the control of taenia solium taeniasis. Washington, D.C: Pan American Health Organisation; 2021. Guideline. preventative chemotherapy to control soil-transmitted helminth infections in at-risk population groups. Geneva; World Health Organisation; 2017. World Health Organisation. Foodbourne trematode infections. 2021. Available from: Foodborne trematode infections (who.int) [accessed 14 October 2021]. Coldiron ME, Assao B, Page AL, Hitchings MDT, Alcoba G, Ciglenecki I, Langendorf C, Mambula C, Adehossi E, Sidikou F, Tassiou EI, De Lastours V, Grais RF. Single-dose oral ciprofloxacin prophylaxis as a response to a meningococcal meningitis epidemic in the African meningitis belt: A 3-arm, open-label, cluster-randomized trial. PLoS Med. 2018 Jun;26(6):e1002593. doi: 10.1371/journal.pmed.1002593 . 15 ) . Marks M, Bottomley C, Tome H, et al. Mass drug administration of azithromycin for trachoma reduces the prevalence of genital Chlamydia trachomatis infection in the Solomon Islands. Sexually Transmitted Infections. 2016 Jun;92(4):261–5. DOI: 10.1136/sextrans-2015-052439 . Walia B, Kmush BL, Lane SD, Endy T, Montresor A, Larsen DA. Routine deworming during antenatal care decreases risk of neonatal mortality and low birthweight: A retrospective cohort of survey data. PLoS Negl Trop Dis. 2021 Apr 29;15(4):e0009282. doi: 10.1371/journal.pntd.0009282 . O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. Review on antimicrobial resistance. Wellcome Trust and HM Government; 2016. Sulis G, Adam P, Nafade V, Gore G, Daniels B, Daftary A, et al. Antibiotic prescription practices in primary care in low- and middle-income countries: A systematic review and meta-analysis. PLoS Med. 2020;17(6):e1003139. Torres NF, Chibi B, Kuupiel D, et al. The use of non-prescribed antibiotics; prevalence estimates in low-and-middle-income countries. A systematic review and meta-analysis. Arch Public Health. 2021. 79(2). Tadesse BT, Ashley EA, Ongarello S, Havumaki J, Wijegoonewardena M, González IJ, Dittrich S. Antimicrobial resistance in Africa: a systematic review. BMC Infect Dis. 2017 Sep 11;17(1):616. doi: 10.1186/s12879-017-2713-1 . Gough EK. The impact of mass drug administration of antibiotics on the gut microbiota of target populations. Infect Dis Poverty. 2022. 11(76). doi: 10.1186/s40249-022-00999-5 . Oliver K, Lorenc T, Tinkler J, et al. Understanding the unintended consequences of public health policies: the views of policymakers and evaluators. BMC Public Health. 2019 : 19; 1057. doi: 10.1186/s12889-019-7389-6 . Eisenberg L. The human nature of human nature. Science. 1972;176:123–8. Mittelmark M. Unintended effects in settings-based health promotion. Scand J Public Health. 2014;42(Suppl 15):17–24. Additional Declarations No competing interests reported. Supplementary Files Appendix.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2112557","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":142017701,"identity":"7b640e91-55e5-4c01-ac9e-b6f6e92f80b0","order_by":0,"name":"Natasha O’Sullivan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYLACxgYIdeCBAZBib2AjoJ4ZroXhQAJIC88BiBYe4rSASIkE/FrM2c8f/Phzhx0DP/8ZgwMJBYflzSXfHnv4g+GOnD0OLZY9yczSvGeSGSRn5AC1GBw23Dk7L92Yh+GZMS5bDA4kM0gztjEzGNzgAWlJY9xwO8dMmoHhcGIPLi3nHzP//NlWD2ScAWux33DzjJnkD4bD9Ti13Ehmk+BtOwy0Duwwm8QNN3jMJHgYDifgdNiNx2bWvG3HeSRnpBWAtCRvOAN0GA/QUz0HcDks8fHNn23Vcvz8hzc++PBHwnbDcZDDKg7LszfgsAYK0F1hgF/5KBgFo2AUjAL8AACEn1rAzA1VEQAAAABJRU5ErkJggg==","orcid":"","institution":"Wolfson Institute of Population Health, Queen Mary University London","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Natasha","middleName":"","lastName":"O’Sullivan","suffix":""},{"id":142017704,"identity":"a4f8a217-c795-489b-915f-534e77c5c0a9","order_by":1,"name":"David McCoy","email":"","orcid":"","institution":"United Nations University-International Institute for Global Health","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"McCoy","suffix":""}],"badges":[],"createdAt":"2022-09-28 11:44:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2112557/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2112557/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62354576,"identity":"8e60da86-772c-488c-b9e5-7b2957877273","added_by":"auto","created_at":"2024-08-13 08:55:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":708989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2112557/v1/e83854a6-86db-4a65-921b-6fe19e1ad436.pdf"},{"id":27576452,"identity":"2bd327b6-f25b-4649-83ab-d21c8bc8980a","added_by":"auto","created_at":"2022-10-10 19:12:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23542,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-2112557/v1/1241b6341b81fd3b6cb804dd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Implementation of mass drug administration of antibiotics in low- and middle- income countries","fulltext":[{"header":"Background","content":"\u003cp\u003ePopulation-wide administration of health interventions come in many forms and have a long history. They include water fluoridation, vitamin K injections for newborns, food fortification, vaccinations, Vitamin A supplementation (VAS) and the mass drug administration (MDA) of antimicrobials\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In some instances these interventions are preventative, while in other cases they are designed to treat disease or illness. But a common feature of these interventions is that they are applied to all individuals \u003cem\u003een masse\u003c/em\u003e within a defined population regardless of their risk profile or clinical state.\u003c/p\u003e \u003cp\u003eRecent years have seen the mass administration of antimicrobials being increasingly promoted as a public health strategy in low- and middle-income countries (LMICs). Based on a literature review we conducted, we identified 14 different applications of MDA of antimicrobials (see Appendix 1) covering a range of treatments, diseases and indications. Five of these involve the administration of antibiotics of which three have associated World Health Organisation (WHO) guidelines. Two of these guidelines cover the mass administration of azithromycin to treat and prevent yaws and trachoma in endemic countries, while the third involves the non-disease-specific application of MDA of azithromycin designed to reduce overall child mortality in Sub-Saharan Africa (SSA).\u003c/p\u003e \u003cp\u003eOne rationale for the MDA of antibiotics is that it provides a mechanism to obviate the weak health systems and lack of access to effective diagnostic and curative care that many individuals within LMICs suffer from. However, while mass administration of antibiotics to entire populations may reduce morbidity and mortality in the absence of stronger health systems, there are also risks to consider, particularly in relation to causing or accelerating antibiotic resistance. MDA programmes may also reinforce a selective primary health care (PHC) paradigm mindset and a paradigm that prioritises vertical and technologically mediated reductions in mortality, at the expense of health systems strengthening efforts and more comprehensive and socially-driven pathways to health improvement.\u003c/p\u003e \u003cp\u003eThis paper examines the three WHO guidelines on the mass administration of azithromycin (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) through a critical public health perspective. The aim of the paper is to provide a discussion of the clinical, public health and economic issues that Ministries of Health must consider when deciding to adopt and implement an MDA programme involving azithromycin. [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: Indications for mass drug administration of azithromycin from WHO Guidelines]\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndications for mass drug administration of azithromycin from WHO Guidelines\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIndications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRegimen and target population\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTrachoma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWHO and the International Coalition for Trachoma Control recommend MDA of azithromycin for the elimination of blinding trachoma in populations where prevalence of Trachoma Follicular Inflammation is \u0026gt;/10% in children 1\u0026ndash;9 years.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOral azithromycin 20mg/kg to all children\u0026thinsp;\u0026gt;\u0026thinsp;6months\u0026thinsp;+\u0026thinsp;all adults annually for a minimum of 3 years \u003cem\u003ecombined with\u003c/em\u003e\u003c/p\u003e \u003cp\u003eTetracycline eye ointment twice daily for 6/52 for infants\u0026thinsp;\u0026lt;\u0026thinsp;6months. Coverage should not be less than 90%.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYaws\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWHO recommends MDA of azithromycin for the eradication of yaws in areas where the disease is consistently present, or where there is at least one clinically and serologically confirmed case of yaws.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-dose azithromycin 30mg/kg to all children\u0026thinsp;\u0026gt;\u0026thinsp;6months\u0026thinsp;+\u0026thinsp;all adults, to be followed by active clinical and serological surveillance with treatment of any residual cases and their contacts until there are no new infectious cases. WHO recommends that two or three rounds of total community treatment at 6\u0026ndash;12 monthly intervals may be required. Population coverage of \u0026gt;\u0026thinsp;90% is essential.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChild Mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWHO does not recommend universal MDA of azithromycin for prevention of childhood mortality but states that \u003cem\u003econsideration\u003c/em\u003e should be given only in sub-Saharan African settings where:\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Infant mortality is \u0026gt;\u0026thinsp;60 per 1000 live births OR under-five mortality is \u0026gt;\u0026thinsp;80 per 1000 live births \u003cem\u003eand\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; child mortality rates, adverse effects and antibiotic resistance are continuously monitored \u003cem\u003eand\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Existing child survival interventions, including seasonal malaria chemoprophylaxis where recommended, are already implemented and being strengthened\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-dose azithromycin 20 mg/kg every 6 months to all children aged 1\u0026ndash;11 months.\u003c/p\u003e \u003cp\u003eThe guideline does not state the number of cycles of treatment that are needed but notes the need to update or revise the current guidelines within 2\u0026ndash;3 years based on new evidence from large ongoing studies and planned research.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis paper present a semi-systematic search and narrative review of the published and grey literature, including the actual WHO guidelines. The paper draws from multiple literatures on various topics: a) MDA programmes; b) public health interventions (PHIs) applied to whole populations; c) unintended consequences of PHIs; and d) antimicrobial resistance (AMR). We identified literature to review by searching Google Scholar and PubMed, as well as the World Bank, Centers for Disease Control and Prevention, and Gates Foundation websites up to May 2022, and selected documents to review on the basis of a qualitative assessment of the titles and abstracts of the search results. Search terms used can be found in Appendix 2. Only documents published in English were included. This review did not limit the included articles based on year of publication. Although non-systematic literatures reviews conducted in this manner are vulnerable to bias, the purpose of this review was not to identify all relevant literature, rather to draw out relevant aspects of different literatures on the four topics mentioned above. We then reviewed and assessed the guidance in available guidelines and discuss the findings in this paper.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvidence in support of an MDA programme\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eTreatment and prevention of yaws\u003c/h2\u003e \u003cp\u003eThe evidence for promoting the use of MDA of azithromycin for the eradication of yaws is centred on three separate trials conducted that each observed a significant decrease in the prevalence of active and latent yaws following the administration of a single dose of azithromycin, as described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A trial on a yaws-endemic island in Papua New Guinea saw the prevalence of active infectious yaws reduce from 2.4\u0026ndash;0.3% at 12 months (\u003cem\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.001)\u003c/em\u003e and the prevalence of high-titre latent yaws among children reduced from 18.3\u0026ndash;6.5% (\u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003c/em\u003e, with no significant side effects and no evidence of mutations conferring resistance to azithromycin in the 90 randomly selected swabs obtained during clinical surveys from all participants with papillomatous or ulcerative lesions\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTrials providing evidence for MDA of azithromycin for yaws, trachoma, and child mortality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrial Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime period \u0026amp; Setting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy Population \u0026amp; Sample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEnd points\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYaws\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMass Treatment for Single-Dose Azithromycin for Yaws\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eApril 2013- May 2014\u003c/p\u003e \u003cp\u003ePapua New Guinea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll persons\u0026thinsp;\u0026gt;\u0026thinsp;2 months of age in study villages\u003c/p\u003e \u003cp\u003e28 villages with 400\u0026ndash;600 inhabitants each. Estimated population in 2013 was 16,092 according to regularly updated census\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-dose oral azithromycin 30mg/kg, max dose 2g\u003c/p\u003e \u003cp\u003eInitial mass treatment followed every 6 months by targeted treatment program, performed that consistent of clinical examination of resident population, with treatment of all persons with active clinical cases and their contacts.\u003c/p\u003e \u003cp\u003ePregnant women and persons with known allergy to macrolides given penicillin G benzathine 50,000 units/kg intramuscularly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOverall rate of treatment coverage during mass treatment program was 83.8%, with all study villages having coverage rate\u0026thinsp;\u0026gt;\u0026thinsp;70.0%.\u003c/p\u003e \u003cp\u003ePrevalence of infectious active yaws fell from 2.4% at baseline to 0.3% at 6 months and remained at 0.3% at 12 months (difference from baseline 2.1 percentage points; 95% confidence interval [CI] 1.9 to 2.4; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003ePrevalence of high-titer latent yaws decreased from 18.3% at baseline to 6.5% at 12 months (difference 11.8 percentage points; 95% CI 8.9 to 14.7; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eProportion of 90 participants ulcers at baseline with PCR-confirmed \u003cem\u003eT.pallidum\u003c/em\u003e was 21.1%, \u003cem\u003eH.ducreyi\u003c/em\u003e was 46.7% and co-infection with both in 13.3%. Proportion of patients with lesions due to yaws 6 months after treatment did not decrease significantly as compared to baseline, and proportion patients with dual infection increased. At 12 months there was significant reduction in the proportion of ulcers containing either \u003cem\u003eT.pallidum\u003c/em\u003e subspecies \u003cem\u003epertenue\u003c/em\u003e alone (risk difference, 10.6 percentage points, 95% CI 0.4 to 20.7; p\u0026thinsp;=\u0026thinsp;0.04) or coinfection (risk difference, 7.2 percentage points; 95% CI -1.1 to 15.5; p\u0026thinsp;=\u0026thinsp;0.08), whereas proportion ulcers containing \u003cem\u003eH.ducreyi\u003c/em\u003e alone remained similar level to baseline (risk difference 0.1 percentage points; 95% CI -13.6 to 14.0; p\u0026thinsp;=\u0026thinsp;0.98).\u003c/p\u003e \u003cp\u003eNo severe adverse events attributable to study drug were reported from passive surveillance. Active surveillance of 316 participants from 60 households yielded 54 participants (17.1%) reporting adverse events (all mild).\u003c/p\u003e \u003cp\u003eNo evidence of mutations conferring resistance to azithromycin in 90 randomly selected swabs obtained during clinical surveys from all participants with papillomatous or ulcerative lesions at any of the time points\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCommunity-based mass treatment with azithromycin for the elimination of yaws in Ghana \u0026ndash; Results of a pilot study\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOctober 2013 \u0026ndash; December 2014\u003c/p\u003e \u003cp\u003eEastern Region of Ghana\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll persons\u0026thinsp;\u0026gt;\u0026thinsp;6 months of age, excluding pregnant women\u003c/p\u003e \u003cp\u003e15,310 people\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-dose oral azithromycin 30mg/kg, max dose 2g\u003c/p\u003e \u003cp\u003eAssessment survey at baseline and one-year post-intervention.\u003c/p\u003e \u003cp\u003eof school-age children from 10 randomly selected schools.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e89% of residents received a single oral dose of azithromycin\u003c/p\u003e \u003cp\u003ePrevalence rate of dual seropositivity (non-treponemal and treponemal antibody positivity) in DPP test decreased significantly, from 10.9% (95% CI 6.5\u0026ndash;17.5) among children in the pre-TCT survey to 2.2% [(95% CI 1.3\u0026ndash;3.7), OR 0.19 (95% CI 0.09\u0026ndash;0.37)] in the post-TCT survey. Prevalence of rate of serologically confirmed yaws-like active lesions among schoolchildren was significantly reduced from a pre-TCT rate of 5.7% (95% CI 3.2\u0026ndash;9.9) to 0.6% (95% CI 0.2\u0026ndash;1.6; OR 0.10, 95% CI 0.25-35) in post-TCT schoolchildren sample.\u003c/p\u003e \u003cp\u003eNo severe adverse events attributable to study drug and only 0.3% of participants reported mild to moderate adverse events.\u003c/p\u003e \u003cp\u003eNo evidence of resistance to macrolides against \u003cem\u003eTreponema pallidum\u003c/em\u003e subspecies \u003cem\u003epertenue\u003c/em\u003e was seen.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMid-2014\u003c/p\u003e \u003cp\u003eSolomon Islands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot described\u003c/p\u003e \u003cp\u003e897 children from 441 householders in 11 communities enrolled for assessment 6 months post-intervention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle dose of azithromycin 20mg/kg, max 1g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSingle round of community mass treatment reduced prevalence of active and latent yaws from 1.5% and 20.2% respectively to 0.0% and 3.6% 6 months post-treatment (p\u0026thinsp;=\u0026thinsp;0.002 and \u0026lt;\u0026thinsp;0.001 respectively).\u003c/p\u003e \u003cp\u003eReduction in mean number of cases of yaws reported per month of 101, relative reduction 57%, p\u0026thinsp;=\u0026thinsp;0.044\u003c/p\u003e \u003cp\u003eTPPA seroprevalence at 18 months didn\u0026rsquo;t differ significantly from pre-MDA survey or initial follow-up survey at 6 months (31.4% and 25.0% respectively, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for both comparisons)\u003c/p\u003e \u003cp\u003eNo treponemal DNA detected in 20 lesion swabs.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTrachoma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzithromycin in control of trachoma\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePairs of villages in The Gambia, Tanzania and Egypt (matched on trachoma rates in 1-10year old children)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll children up to age 15 years, all men, and all women beyond child-bearing age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRandomly assigned to:\u003c/p\u003e \u003cp\u003e1. Azithromycin - Adults received 1g oral azithromycin once a week for 3 weeks. Children received 20mg/kg, max dose 1g\u003c/p\u003e \u003cp\u003e2. 1% topical tetracycline once daily for 6 weeks\u003c/p\u003e \u003cp\u003eClinical examinations at baseline, 2-4.5, and 12\u0026ndash;14 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOf participants initially LCR positive (\u003cem\u003eChlamydia trachomatis\u003c/em\u003e identified by ligase chain reaction), 866 (95%) of 924 who received at least one azithromycin dose and 482 (82%) of 587 who received 28 days or more of topical tetracycline, were negative at follow-up.\u003c/p\u003e \u003cp\u003eAt 1 year, village wide LCR positive rates were substantially lower than at baseline with both treatments, and the decreases were greater with azithromycin than with tetracycline (93% vs. 77% in Egypt, 78% vs 66% in The Gambia, 64% vs 55% in Tanzania).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChild Mortality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEffect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children: A Randomized Trial\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMay 2006 - May 2007\u003c/p\u003e \u003cp\u003eEthiopia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChildren aged 1\u0026ndash;10 years\u003c/p\u003e \u003cp\u003e48 communities randomised into 1 of 3 treatment schedules:\u003c/p\u003e \u003cp\u003e1. Annual treatment all resident (15,902 residents)\u003c/p\u003e \u003cp\u003e2. Biannual treatment of all residents (17,288)\u003c/p\u003e \u003cp\u003e3. Quarterly treatment of children (14,716)\u003c/p\u003e \u003cp\u003eOr into control group for which treatment delayed by 1 year (18,498 participants)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSingle-dose oral azithromycin (adults 1g, children 20mg/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOdds ratio for childhood mortality in intervention communities 0.51 (95% CI, 0.29\u0026ndash;0.90; p\u0026thinsp;=\u0026thinsp;0.02) compared to control group.\u003c/p\u003e \u003cp\u003eEstimated overall mortality rate during this period for children aged 1 to 9 years in the untreated group was 8.3 per 1000 person-years (95% CI, 5.3\u0026ndash;13.1) while it was 4.1 per 1000 person-years for children 1\u0026ndash;9 years in the treated communities (95% CI, 3.0-5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzithromycin to Reduce Childhood Mortality in Sub-Saharan Africa\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMalawi, Niger, and Tanzania\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChildren aged 1\u0026ndash;59 months weighing at least 3,800 grams\u003c/p\u003e \u003cp\u003e1533 communities (190,238 children)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCommunities randomised to oral azithromycin (at least 20 mg/kg) or placebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOverall annual mortality rate in placebo-treated communities was 16.5 per 1000 person-years (9.6 per 1000 person-years in Malawi, 27.5 in Niger, and 5.5 in Tanzania).\u003c/p\u003e \u003cp\u003eAzithromycin-treated communities had an estimated 13.5% lower mortality overall (95% CI, 6.7%-19.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Mortality was 5.7% lower in Malawi (CI -9.7%-18.9%, p\u0026thinsp;=\u0026thinsp;0.45), 18.1% lower in Niger (CI 10.0%-25.5%, p\u0026thinsp;=\u0026thinsp;0.77) and 3.4% lower in Tanzania (CI -21.2%-23.0%, p\u0026thinsp;=\u0026thinsp;0.77).\u003c/p\u003e \u003cp\u003eGreatest reduction in mortality observed in 1\u0026ndash;5 month-old children (24.9% lower, CI 10.6%-37.0%, p\u0026thinsp;=\u0026thinsp;0.001)\u003c/p\u003e \u003cp\u003e20 hospitalisations or life-threatening illnesses occurred; 11 in the treated arm and 9 in the untreated arm. Cause of death was significantly different between country sites (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with relatively more deaths attributed to malaria in Niger and pneumonia in Tanzania.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEffect of Adding Azithromycin to Seasonal Malaria Chemoprevention\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2014 to 2017\u003c/p\u003e \u003cp\u003eBurkina Faso and Mali\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChildren aged 3\u0026ndash;59 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1) Distribution of azithromycin and sulfadoxine-pyrimethamine plus amodiquine in four 3-day cycles at monthly intervals for three successive seasons, and\u003c/p\u003e \u003cp\u003e2) a control group receiving a placebo instead of azithromycin with same combination and schedule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAddition of azithromycin to antimalarials for chemoprevention did not result in lower incidence of death or hospital admission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: Trials providing evidence for MDA of azithromycin for yaws, trachoma and child mortality]\u003c/p\u003e \u003cp\u003eA trial in in a yaws-endemic sub-district in Ghana saw the prevalence of latent yaws among children reduce from 10.9\u0026ndash;2.2% (Odds ratio [OR] 0.19; 95% confidence interval [CI] 0.09\u0026ndash;0.37) one year after the intervention and the prevalence of serologically-confirmed skin lesions decrease from 5.7\u0026ndash;0.6% (OR 0.10; 95% CI 0.25\u0026ndash;0.35)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Similarly, there were no severe adverse events attributable to azithromycin, with only 0.3% of participants reporting mild and self-limiting side effects, and no evidence of bacterial mutations associated with azithromycin resistance.\u003c/p\u003e \u003cp\u003eA trial in the Solomon Islands found no cases of active yaws six months post-treatment and a significant difference in the prevalence of latent yaws between individuals who had and had not been treated (2.8% vs 6.5% \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015)\u003csup\u003e13\u003c/sup\u003e. Not receiving azithromycin was associated with a higher risk of infection (OR 3.9; \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.001).\u003c/em\u003e A survey 18 months after the intervention also showed that seroprevalence was still significantly lower than it had been pre-MDA\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. A sample of lesions six months after the intervention found no evidence of living \u003cem\u003eTreponema pallidum pertenue\u003c/em\u003e and therefore no evidence of macrolide resistance.\u003c/p\u003e \u003cp\u003eAlthough the WHO guidelines do not discuss the cost effectiveness of MDA of azithromycin to eradicate yaws, a cost-effectiveness analysis of four yaws eradication pilot sites found that the cost for each additional year of life lived without disability or disfigurement due to yaws being eradicated was \u003cspan\u003e$\u003c/span\u003e26 (4.2\u0026ndash;78), making the intervention highly cost-effective\u003csup\u003e \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e \u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eTrachoma\u003c/h2\u003e \u003cp\u003eThe MDA of azithromycin as an intervention to eliminate trachoma began in 1998 and was included in a WHO guideline on trachoma control that was produced in 2006\u003csup\u003e6\u003c/sup\u003e. This has subsequently been complemented by a more expansive guideline produced by the International Coalition for Trachoma Control (ICTC) Guideline in 2013 following an extensive literature review, a survey of national trachoma control programme coordinators, and a series case studies in several countries to document \u0026lsquo;what worked, what did not work, and why\u0026rsquo;\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe evidence underpinning these guidelines mainly comes from a cluster-randomised trial in trachoma-endemic villages in Egypt, The Gambia and Tanzania that compared mass treatment with a topical tetracycline ointment daily for six weeks with the MDA of a single weekly dose of oral azithromycin for three weeks as detailed in Table\u0026nbsp;3\u003csup\u003e16\u003c/sup\u003e. The trial found lower trachoma positivity rates in the azithromycin group compared to the tetracycline group (93% vs 77% in Egypt, 78% vs 66% in The Gambia, 64% vs 55% in Tanzania). The trial did not report on adverse events nor AMR.\u003c/p\u003e \u003cp\u003eAs with yaws, cost-effectiveness is not discussed in the trachoma guidelines. However, one study from 2005 that estimated cost-effectiveness of MDA of azithromycin in trachoma-endemic areas in seven world regions found that MDA of azithromycin for trachoma could avert more than 4\u0026nbsp;million disability-adjusted life years (DALY) per year globally \u003cem\u003ebut\u003c/em\u003e was not cost-effective, costing between \u003cspan\u003e$\u003c/span\u003e9,000\u0026ndash;65,000 per DALY averted\u003csup\u003e \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e \u003c/sup\u003e. According to the authors, the MDA of azithromycin to control trachoma would only be cost-effective if the drug was donated or made available at a reduced price. A study from 2011 in a remote area of South Sudan found that the average economic cost per person treated with azithromycin was 1.53 USD\u003csup\u003e \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e \u003c/sup\u003e. The major cost drivers were personnel (41.3%) and travel/transport (29.1%), but this estimate excluded the cost of azithromycin. If the economic cost of the donated antibiotic had been included, the estimated economic cost per person treated would have been 34.2 USD, significantly higher than the frequently quoted 0.5 USD annual per capita cost for simultaneous delivery of multiple drugs during MDA programmes\u003csup\u003e \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e \u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA 2010 study that calculated cost-effectiveness using previously published data found targeted treatment to households rather than mass treatment could be significantly more cost-effective than mass treatment when azithromycin was not donated. However, MDA was predicted to be more cost-effective when azithromycin was donated, unless opportunity costs incurred by individuals collecting antibiotics were included or household visits improved treatment uptake\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Clearly, there is a need for more recent cost-analysis studies using current azithromycin prices.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eChild mortality\u003c/h2\u003e \u003cp\u003eWHO\u0026rsquo;s guideline on the use of MDA of azithromycin was developed by a Guideline Steering Group (GSG) made up of technical officers from different departments in WHO that had commissioned separate systematic reviews to synthesise the evidence of MDA of azithromycin relating to: (1) efficacy in terms of mortality and morbidity and the factors which might modify the effect of the intervention; (2) AMR and (3) adverse effects, dose strength and regimen, and potential mechanisms of action\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCentral to the evidence were three randomised controlled trial (RCT) studies in sub-Saharan African malaria-endemic countries with high under-5 mortality rates (U5MR) as described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The first was a four-armed cluster-randomised trial (annual, biannual or quarterly azithromycin, and no treatment) of children aged 1\u0026ndash;9 years in Ethiopia\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The mortality rate among children in treated communities was half that of untreated communities (OR: 0.51, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.02), although subsequent case-control analysis of the mortality rate among children aged 1\u0026ndash;5 years reported a non-significant OR of 0.31 (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.06). The second was the multi-country MORDOR trial of biannual azithromycin MDA (20 mg/kg) in children aged 1\u0026ndash;59 months in Malawi, Niger and Tanzania which reported 14% lower mortality in azithromycin- compared to placebo-treated communities, with a 24.9% lower mortality in children 1\u0026ndash;5 months of age\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The third study, a cluster-randomised trial of MDA of azithromycin added to seasonal malaria chemoprophylaxis (SMC) on a monthly basis for four months during the peak malaria season over three years in Mali and Burkina Faso, found that MDA of azithromycin \u003cem\u003edid not\u003c/em\u003e reduce hospitalisation or mortality compared to SMC alone\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBecause of the heterogeneity of the interventions, outcome measures and geographical contexts, the results from these trials could not be pooled. The GSG also concluded that the evidence of MDA of azithromycin reducing childhood mortality was \u0026lsquo;low\u0026rsquo; and that the evidence of mortality reduction only justified \u003cem\u003econsidering\u003c/em\u003e MDA of azithromycin in infants below the age of one. However, because of an increased risk of pyloric stenosis in the first month of life after azithromycin, WHO advised exclusion of neonates from the programme\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe GSG also noted that there were only sparse data on the potential impact of MDA of azithromycin on AMR, and that it was not possible to determine the longer-term MDA of azithromycin programmes increasing the circulation of resistant strains in the community and what impact this might have on enteric pathogens and clinical outcomes \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eInformation provided by WHO about the economic dimensions of MDA of azithromycin for child mortality is centred around two primary economic evaluation studies that found that the estimated cost per dose of MDA ranges from \u003cspan\u003e$\u003c/span\u003e0.37 to \u003cspan\u003e$\u003c/span\u003e0.74, and that the cost per DALY averted ranges from \u003cspan\u003e$\u003c/span\u003e9.98 to \u003cspan\u003e$\u003c/span\u003e14.26, which indicates that the MDA of azithromycin to reduce child mortality would be cost-effective\u003csup\u003e \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e \u003c/sup\u003e. Indeed, data from the MORDOR trial in Malawi points to the intervention being \u003cem\u003ehighly\u003c/em\u003e cost effective as defined by willingness-to-pay thresholds established by WHO\u003csup\u003e \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e \u003c/sup\u003e. This would make MDA of azithromycin comparable to other core interventions for reducing child mortality such as integrated management of childhood illness and SMC\u003csup\u003e \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e \u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, Hart et al also note considerable variation in cost-effectiveness by geographical location within Malawi and state that a better understanding of the reasons for this would be desirable before wider implementation of the intervention, alongside a better understanding of the mechanism of action and potential for the development of macrolide resistance\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn a more recent review of the cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa, it has been suggested that instead of MDA of azithromycin, targeting high-risk children is an option that could make economic sense while reducing exposure to azithromycin\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, although the evidence supporting this strategy is currently limited. A trial in neonates receiving biannual azithromycin in sub-Saharan Africa found no evidence to support its\u0026rsquo; use for prevention of mortality\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and a trial targeting children under 5 years after hospital discharge found no significant benefit of a 5-day course of azithromycin to the risk of death of rehospitalization\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the case of yaws and trachoma, cost-effectiveness will change as the incidence and prevalence of disease changes and depending on the timeframe for which the costs and benefits of disease control or elimination are assessed. In the case of child mortality, WHO currently only recommends that this be considered in areas where the infant mortality rate (IMR) is high (over 60 per 1000 live births)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. It should be reasonable therefore to expect any MDA of azithromycin to reduce mortality to be short lived as child health and healthcare improves through other services and interventions. Importantly, the WHO guideline states that the implementation of \u0026ldquo;existing child survival interventions, including SMC where recommended [are] concurrently strengthened\u0026rsquo; and that \u0026ldquo;SMC scale-up should take precedence over MDA of azithromycin implementation\u0026rdquo;\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eImplementing an MDA programme\u003c/h2\u003e \u003cp\u003eMultiple trials and programmes have now generated a significant body of learning about what determines the effective, efficient and equitable mass administration of azithromycin\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. WHO\u0026rsquo;s three guidelines\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e draw on this experience and provide varying amounts of guidance covering the procurement of drugs (and diagnostic tests if needed) and management of the drug supply chain; the mapping and listing of the target population and measurement of coverage levels; community and stakeholder engagement; personnel training and supervision; the management of transport and other logistical requirements; drug administration and the management of non-compliant individuals; and the collection of data to enable monitoring and evaluation.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eIntegration into the wider healthcare system\u003c/h2\u003e \u003cp\u003eA plan to deliver an MDA programme is not all that national and local health managers have to develop and implement. MDA programmes should also be designed and implemented in a way that contributes positively to the needs and demands placed on the health system more generally. At the very least, they should avoid inadvertently impacting negatively on the wider health system, especially in settings where health systems are under-resourced and fragmented.\u003c/p\u003e \u003cp\u003eIn ideal circumstances, any new programme would be carefully added to the panoply of existing services and programmes in a way that would avoid any inadvertent harms, while also finding opportunities for generating efficiencies through economies of scale or for strengthening the health system through positive synergies with other interventions.\u003c/p\u003e \u003cp\u003eWhile the WHO guideline on the MDA of azithromycin to reduce child mortality makes explicit mention of the need to consider other child survival services and interventions\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, there is no clear guidance as to how local planners and managers should weigh up and choose between prioritising an MDA programme over other critical child health services such as improving skilled birth attendance rates or child vaccination coverage rates. Nor does it explicitly suggest ways in which MDA could be integrated with other community-based public health interventions such as VAS programmes or vaccination campaigns.\u003c/p\u003e \u003cp\u003eInterestingly, the WHO guideline for trachoma notes that MDA for trachoma has historically been delivered through stand-alone vertical programmes, and that the overlap and similarities in treatment strategies with other NTD programmes should offer opportunities for synergy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. One example given was the combination of mass treatment with azithromycin with fever screening and malaria treatment in Ethiopia. The guidelines for yaws do not however include any discussion about possible opportunities for integration or synergy with other services or needs\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCoordinated and integrated health planning is however challenging in settings where selective and vertical programmes are championed by external donors, or where there is insufficient decentralised capacity and authority capable of integrating centrally-funded and centrally-directed programmes\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Thus while MDA programmes could in theory contribute to more integrated healthcare and economic efficiencies, unless there is sufficient commitment to a health systems strengthening agenda, an integrated approach also runs the risk of sub-optimal delivery of an MDA programme.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eAntimicrobial stewardship\u003c/h2\u003e \u003cp\u003eAnother aspect of the wider health system that should feed into the implementation of an MDA programme are the efforts to strengthen antibiotic stewardship. Preventing widespread AMR is viewed as a major global health priority, with one study estimating 4.95\u0026nbsp;million deaths (95% uncertainty interval [UI] 3.62\u0026ndash;6.57) associated with bacterial AMR occurred in 2019, including 1.27\u0026nbsp;million deaths attributable to bacterial AMR\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Of particular note is that the highest all-age death rate attributable to AMR occurred in western sub-Saharan Africa, at 27.3 deaths per 100,000 (95% UI 20.9\u0026ndash;35.3), and in addition serious data gaps existing in many LMICs were highlighted and the need to expand microbiology laboratory capacity and data collection systems emphasised.\u003c/p\u003e \u003cp\u003eInvestigation of the gut resistome of children after receiving twice-yearly azithromycin for four years in the Niger site of the MORDOR study found determinants of macrolide resistance were 7.5 times as high (95% CI, 3.8 to 23.1) in villages treated with azithromycin as in villages that received a placebo\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Of note was that resistance extended beyond macrolides; an additional two rounds of azithromycin MDA caused a notable increase in resistance determinants to several nonmacrolide antibiotics, including 2.1 times (95% CI 1.2-4.0) greater number of beta-lactam resistance determinants. However, the clinical and public health relevance of such resistance is not yet known. A further study that evaluated the impact of MDA of azithromycin in communities within the Malawi site of the MORDOR trial suggests this impact may be limited as it found that the proportion of gastrointestinal bacteria carrying macrolide resistance increased after azithromycin treatment, but that this had limited impact on clinically relevant bacteria and on the diversity and global community structure of the gut\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccording to one recent systematic review of the literature, only 40% of studies of mass and systematic drug administration (SDA) of antibiotics evaluated the risk of AMR developing. Nonethless, the review gave reason to be concerning by warning that MDA and SDA of antibiotics might lead to a significant increase in AMR, especially following azithromycin administration\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEven if MDA of azithromycin is not considered to be a significant risk for producing or worsening bacterial resistance to macrolides, it should not undermine efforts to stop the misuse and over-use of antibiotics. For example, care should be taken to avoid any perception by some people that mass treatment with antibiotics is a sign that antibiotic resistance is unimportant.\u003c/p\u003e \u003cp\u003eWhile the WHO guideline on child mortality advises that AMR be monitored through sentinel surveillance of resistance in nasopharyngeal and gut flora, and in common bacteria causing invasive infections\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, the guidelines on trachoma and yaws make no reference to AMR monitoring at all\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Furthermore, none of the guidelines call for an AMR awareness and prevention strategy to be included in the design of their respective MDA programmes nor recommend that a basic standard of good antibiotic stewardship is present before implementing an MDA programme.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eViews and attitudes of stakeholders (acceptability)\u003c/h2\u003e \u003cp\u003eWhen thinking about the implementation of MDA programmes, there may also be wider social and cultural factors to consider. For example, the ICTC guideline emphasises the importance of gaining the support and trust of local communities and exploring local attitudes towards medicines and other pharmaceuticals\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. This may be especially important now given the problems of misinformation on social media and an apparent rise in levels of mistrust towards figures of authority, including healthcare workers and members of the scientific community, as evidenced by growing levels of \u0026lsquo;vaccine hesitancy\u0026rsquo; in many parts of the world\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e and increasing levels of resistance to other mass interventions such as the routine intramuscular injection of vitamin K to all newborns\u003csup\u003e\u003cspan additionalcitationids=\"CR44 CR45\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere is a potential for MDA programmes, especially those that are not targeted at a particular disease, to not just be undermined by mistrust and misinformation, but to amplify these social phenomena, particularly if insufficient efforts are taken to win community support for an MDA programme and if any perception that antibiotics are being forced en masse upon a population emerges.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eClinical and public health evidence suggest that the MDA of azithromycin to eradicate yaws and reduce child mortality in certain settings are cost-effective. But studies from 2005 and 2010 indicate that this would not be the case for the control and treatment of trachoma\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The proposal to periodically mass administer azithromycin to reduce child mortality is however questionable given that its precise mechanism of action is unclear, and that evidence of efficacy is somewhat mixed. However, the primary purpose of this paper is not to discuss this evidence, but to rather examine the MDA of antibiotics through a wider public health and health systems lens. In doing so, two broad issues stand out.\u003c/p\u003e \u003cp\u003eThe first issue concerns the manner in which MDA programmes are funded, conceptualised, organised and implemented, and how they are situated within the context of longstanding tensions between differing \u003cem\u003eapproaches\u003c/em\u003e to health improvement in LMICs. While vertically managed and dedicated MDA programmes allow for focused, rapid and effective delivery, when they are conceived and constructed as single-focused interventions that are delivered through centralised and vertical structures, there is a risk that they may undermine other health services and more comprehensive and holistic approaches to health and lower the overall efficiency of the health system. For example, they can draw resources and attention away from other health services, and they can add to the fragmentation and duplication of efforts across the health system\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, especially if there are other vertical programme, which may be associated with higher total expenditures\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e.. MDA programmes and their focus on antimicrobials may also reinforce a mindset that privileges or exalts the superiority of biomedical interventions over the more messy social, political and economic pathways to health improvement.\u003c/p\u003e \u003cp\u003eAlthough MDA programmes can be a component of a comprehensive and holistic approach to the prevention and treatment of infectious diseases and improved child survival, they may also be used as an excuse or alibi for the lack of progress made in reducing poverty, extending access to clean water and sanitation, improving infant and child nutrition and ensuring universal access to comprehensive maternal and newborn care. Worse still, they could even divert attention and resources from upstream interventions that might produce more sustainable and long-term benefits\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOther PHIs that are \u0026lsquo;mass administered\u0026rsquo; share similar tensions. For example, while water fluoridation reduces the prevalence and incidence of dental caries\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e and has a disproportionately beneficial impact on children from lower socio-economic groups\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, it may have shifted dental public health attention away from the underlying causes of dental caries such as excessive sugar consumption and poor dental hygiene\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Similarly, VAS may bypass the underlying causes of vitamin A deficiency such as poor hygiene and poor diet\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTensions have long existed between approaches that give differing degrees of emphasis to selectivity as opposed to comprehensiveness, or to biomedicalism as opposed to social medicine, or to centralised and top-down vertical delivery systems as opposed to decentralised, bottom-up and integrated systems. Importantly these tensions cannot be resolved through evidence or science as they partly reflect different philosophical and ideological positions, whilst also adopting different timeframes. However, it is important that those funding, studying and advocating MDA programmes are open to discussing these tensions, and to seeking optimal integration and positive synergy with other interventions and services that may also reduce morbidity and mortality.\u003c/p\u003e \u003cp\u003eImportantly, WHO\u0026rsquo;s current advice that the MDA of azithromycin as a non-specific child survival strategy should only be considered in places where the IMR\u0026thinsp;\u0026gt;\u0026thinsp;60 automatically means that it will be implemented in conditions where the rights of children to adequate nutrition and healthcare are not being universally met\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. At present, 13 SSA countries have an IMR\u0026thinsp;\u0026gt;\u0026thinsp;60: Burkina Faso, CAR, Chad, Ivory Coast, Eswatini, Guinea, Lesotho, Mali, Niger, Nigeria, Sierra Leone, Somalia, South Sudan\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. However, there will be many sub-national geographies and populations in other countries with an IMR of more than 60. It remains unclear if such areas should be identified and assessed as to whether an MDA programme would be appropriate.\u003c/p\u003e \u003cp\u003eIt is notable that an increasing number of MDA programmes are now recommended by WHO or researchers. In addition to the three discussed in this paper, WHO guidelines on MDA exist for several non-bacterial diseases: malaria\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e, lymphatic filariasis\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e, onchoceriasis\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e, schistosomiasis\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e, \u003cem\u003eTaenia Solium\u003c/em\u003e\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, soil-transmitted helminths\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e and foodbourne trematodiase\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. Other MDA applications recommended by researchers include single-dose oral ciprofloxacin in areas prone to meningitis epidemics\u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e; azithromycin to reduce genital chlamydia trachomatis infection\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e; and albendazole or mebendazole to pregnant women to reduce neonatal mortality\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e. When coupled with the prominence of various vertical and top-down selective health programmes that exist, such as the Global Fund and the Global Alliance for Vaccines and Immunisations, it could be argued that MDA programmes are part of a wider prevailing selective primary health care paradigm that is partly responsible for perpetuating the problems of weak, fragmented and under-resourced health systems\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe second issue that stands out when examining MDA programmes through a wider public health lens is that of AMR. One prediction is that by 2050, AMR will result in 10\u0026nbsp;million additional deaths per year, with a disproportionately high burden in LMICs\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e. Therefore, evidence that the mass administration of antibiotics will do more harm than good is crucial. Meanwhile, progress in improving antibiotic stewardship has been slow and inadequate, especially in LMICs where antibiotic consumption is increasing in the context of poor clinical practice\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e, inadequate regulation of pharmaceutical markets, and inadequate clinical and laboratory surveillance of AMR prevalence\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe contribution that MDA programmes might make to the worsening of AMR is not known. Evidence exists that suggests azithromycin MDA may lead to a degree of macrolide and nonmacrolide resistance, however the clinical and public health relevant of such resistance is currently unknown and clearly warrants further research\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e. Despite this, the guidelines discussed above appear to downplay the risk of worsening AMR\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. For example, they do not recommend that a situation analysis of current patterns of antibiotic use or of levels of AMR is conducted prior to implementing an MDA programme.\u003c/p\u003e \u003cp\u003eThe two issues raised here may be described as unintended consequences (UCs) associated with MDA programmes. Importantly, UCs associated with public health interventions (PHIs) tend to be neglected in the academic literature because relative to the UCs of clinical interventions, they are harder to detect and to attribute directly to the effects of PHIs\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e and because many UCs associated with PHIs are second- or third-order consequences that are hard to anticipate\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e. UCs may also be neglected or ignored by policymakers and researchers because of a general unwillingness to engage with uncertainty or to acknowledge gaps in knowledge\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e. Thus the hard data on the impact that MDA programmes might have on the incidence of disease or the saving of lives will tend to have more sway over the unknown potential (and longer term) harms arising from UCs, even if those harms may be considerably greater than the benefits.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhile the MDA of antibiotics presents an opportunity to prevent mortality and improve health in the short term, particularly amongst some of the poorest and most vulnerable populations, there must also be appropriate attention to the potential harms. The two greatest harms to consider are the risk of worsening AMR and the potential undermining of a holistic and comprehensive health improvement agenda. In the case of child mortality reduction in particular, MDA can only be a short-term quick fix. Ultimately, long-term and sustainable child mortality reductions \u0026ndash; especially in high mortality settings \u0026ndash; will require more comprehensive approaches to health system strengthening and broader-based socio-economic development.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAMR\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Antimicrobial resistance\u003c/p\u003e\n\u003cp\u003eCI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Confidence interval\u003c/p\u003e\n\u003cp\u003eDALY\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Disability-adjusted life year\u003c/p\u003e\n\u003cp\u003eGSG\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Guideline Steering Group\u003c/p\u003e\n\u003cp\u003eICTC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;International Coalition of Trachoma Control\u003c/p\u003e\n\u003cp\u003eIMR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Infant mortality rate\u003c/p\u003e\n\u003cp\u003eLMIC\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Low- and middle-income country\u003c/p\u003e\n\u003cp\u003eMDA \u0026nbsp; \u0026nbsp; \u0026nbsp;Mass drug administration\u003c/p\u003e\n\u003cp\u003eOR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Odds ratio\u003c/p\u003e\n\u003cp\u003ePHI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Public health intervention\u003c/p\u003e\n\u003cp\u003eRCT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Randomised controlled trial\u003c/p\u003e\n\u003cp\u003eSDA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Systematic drug administration\u003c/p\u003e\n\u003cp\u003eSMC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Seasonal malaria chemoprophylaxis\u003c/p\u003e\n\u003cp\u003eUC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Unintended consequences\u003c/p\u003e\n\u003cp\u003eVAS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Vitamin A supplementation\u003c/p\u003e\n\u003cp\u003eWHO \u0026nbsp; \u0026nbsp; World Health Organisation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e: DM provided critical conceptual input. NOS performed the literature search, analysed and interpreted the literature. DM and NOS wrote the manuscript collaboratively. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding.\u0026nbsp;\u003c/strong\u003eThis work was supported under a Greenwall Foundation grant on the \u0026ldquo;Mass Administration of Antibiotics: Reaching Clinical and Community Equipoise\u0026rdquo; as part of the Making a Difference in Real-World Bioethics Dilemmas program. The Greenwall Foundation did not have a role in the design of the study, collection, analysis, and interpretation of data or in writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We thank the research team of Dr. Anthony So and Dr. Matthew DeCamp (co-principal investigators on the Greenwall Foundation grant) and of Alex Kong and Ahmed Alasmar for providing helpful comments on earlier drafts, for organizing an expert feedback session on the manuscript, and for supporting its submission. We also thank the following persons for their expert commentary on the initial draft of this manuscript: Martha Gyansa-Lutterodt, Mickey Chopra, and Ayesha DaCosta, and Tom Lietman and Robin Bailey for their informal interviews regarding implementation challenges for MDA programmes.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFawell J, Bailey J, Chilton E, Dahi E, Fewtrell L, Magara Y. Fluoride in drinking-water. Geneva: World Health Organisation; 2006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Immunization. 2019 Dec 5. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/news-room/facts-in-pictures/detail/immunization\u003c/span\u003e\u003cspan address=\"https://www.who.int/news-room/facts-in-pictures/detail/immunization\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [accessed 2021 Oct 14].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuideline. vitamin A supplementation in infants and children 6\u0026ndash;59 months of age. Geneva: World Health Organisation; 2011.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO Recommendations on. newborn health: guidelines approved by the WHO Guidelines Review Committee. Geneva: World Health Organisation; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWebster JP, Molyneux DH, Hotez PJ, Fenwick A. The contribution of mass drug administration to global health: past, present and future. Philos Trans R Soc Lond B Biol Sci. 2014;369(1645):20130434.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrachoma control \u0026ndash; a guide for programme managers. Geneva: World Health Organisation; 2006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Coalition for Trachoma Control (ICTC). Preferred practices for Zithromax mass drug administration. London: International Coalition for Trachoma Control; 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEradication of yaws. a guide for programme managers. Geneva: World Health Organization; 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organisation. Eradication of yaws\u0026ndash;the Morges strategy. Wkly Epidemiol Rec, 2012. 87(20): p. 189 \u0026ndash; 94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO guideline on mass drug administration of. azithromycin to children under five years of age to promote child survival. Geneva: World Health Organization; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitj\u0026agrave; O, Houinei W, Moses P, Kapa A, Paru R, Hays R, et al. Mass treatment with single-dose azithromycin for yaws. N Engl J Med. 2015 Feb 19;372(8):703 \u0026ndash; 10. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1408586\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1408586\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdulai AA, Agana-Nsiire P, Biney F, Kwakye-Maclean C, Kyei-Faried S, Amponsa-Achiano K, et al. Community-based mass treatment with azithromycin for the elimination of yaws in Ghana-Results of a pilot study. PLoS Negl Trop Dis. 2018 Mar 22;12(3):e0006303.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarks M, Sokana O, Nachamkin E, et al. Prevalence of Active and Latent Yaws in the Solomon Islands 18 Months after Azithromycin Mass Drug Administration for Trachoma [published correction appears in PLoS Negl Trop Dis. 2018 Mar 7;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarks M, Vahi V, Sokana O, et al. Impact of Community Mass Treatment with Azithromycin for Trachoma Elimination on the Prevalence of Yaws. PLoS Negl Trop Dis. 2015;9(8):e0003988. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pntd.0003988\u003c/span\u003e\u003cspan address=\"10.1371/journal.pntd.0003988\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2015 Aug 4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitzpatrick C, Asiedu K, Jannin J. Where the Road Ends, Yaws Begins? The Cost-effectiveness of Eradication versus More Roads. PLoS Negl Trop Dis. 2014;8(9):e3165. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pntd.0003165\u003c/span\u003e\u003cspan address=\"10.1371/journal.pntd.0003165\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchachter J, West SK, Mabey D, Dawson CR, Bobo L, Bailey R, Vitale S, Quinn TC, Sheta A, Sallam S, Mkocha H, Mabey D, Faal H. Azithromycin in control of trachoma. Lancet. 1999 Aug 21;354(9179):630-5. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(98)12387-5\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(98)12387-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 10466664.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaltussen RM, Sylla M, Frick KD, Mariotti SP. Cost-effectiveness of trachoma control in seven world regions. Ophthalmic Epidemiol. 2005 Apr;12(2):91\u0026ndash;101. doi: 10.1080/09286580590932761. PMID: 16019692.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolaczinski JH, Robinson E, Finn TP. The cost of antibiotic mass drug administration for trachoma control in a remote area of South Sudan. PLoS Negl Trop Dis. 2011;5(10):e1362. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pntd.0001362\u003c/span\u003e\u003cspan address=\"10.1371/journal.pntd.0001362\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMolyneux DH, Hotez PJ, Fenwick A. \u0026ldquo;Rapid-impact interventions\u0026rdquo;: how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med. 2005;2:e336. [PMC free article] [PubMed] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrady MA, Hooper PJ, Ottesen EA. Projected benefits from integrating NTD programs in sub-Saharan Africa. Trends Parasitol. 2006;22:285\u0026ndash;91. [PubMed] [Google Scholar].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlake IM, Burton MJ, Solomon AW, et al. Targeting antibiotics to households for trachoma control. PLoS Negl Trop Dis. 2010;4(11):e862. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pntd.0000862\u003c/span\u003e\u003cspan address=\"10.1371/journal.pntd.0000862\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2010 Nov 2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeenan JD, Bailey RL, West SK, et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018;378:1583\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChandramohan D, Dicko A, Zongo I, et al. Effect of Adding Azithromycin to Seasonal Malaria Chemoprevention. N Engl J Med. 2019;380:2197\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeidman JC, et al. Increased carriage of macrolide-resistant fecal E. coli following mass distribution of azithromycin for trachoma control. Int J Epidemiol. 2014; 43: 1105\u0026ndash;13. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ije/ dyu062\u003c/span\u003e\u003cspan address=\"10.1093/ije/ dyu062\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeidman JC, et al. Increased carriage of macrolide-resistant fecal E. coli following mass distribution of azithromycin for trachoma control. Int J Epidemiol. 2014; 43: 1105\u0026ndash;13. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ije/ dyu062\u003c/span\u003e\u003cspan address=\"10.1093/ije/ dyu062\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoan T, Arzika AM, Hinterwirth A, Maliki R, Abdou A, et al. Gut and Nasopharyngeal Macrolide Resistance in the MORDOR Study: A Cluster-Randomized Trial in Niger. N Engl J Med. 2019;380(23):2271\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeenan JD, Klugman KP, McGee L, et al. Evidence for clonal expansion after antibiotic selection pressure: pneumococcal multilocus sequence types before and after mass azithromycin treatments. J Infect Dis. 2015;211(6):988\u0026ndash;94. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/infdis/jiu552\u003c/span\u003e\u003cspan address=\"10.1093/infdis/jiu552\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrander RL, Weaver MR, Pavlinac PB, John-Stewart GC, Hawes SE, Walson JL. Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa. Clin Infect Dis. 2020 Jan 6:ciz1220. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciz1220\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciz1220\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHart JD, Kalua K, Keenan JD, Lietman TM, Bailey RL. Cost-Effectiveness of Mass Treatment with Azithromycin for Reducing Child Mortality in Malawi: Secondary Analysis from the MORDOR Trial. Am J Trop Med Hyg. 2020 Sep;103(3):1283\u0026ndash;90. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4269/ajtmh.19-0622\u003c/span\u003e\u003cspan address=\"10.4269/ajtmh.19-0622\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost\u0026ndash;effectiveness of interventions: alternative approaches. Bull World Health Organ. 2015;93:118\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrinja S, Bahuguna P, Mohan P, Mazumder S, Taneja S, Bhandari N, van den Hombergh H, Kumar R. Cost effectiveness of implementing integrated management of neonatal and childhood illnesses program in district Faridabad, India. PLoS ONE. 2016;11:e0145043.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNonvignon J, Aryeetey GC, Issah S, Ansah P, Malm KL, Ofosu W, Tagoe T, Agyemang SA, Aikins M. Cost-effectiveness of seasonal malaria chemoprevention in upper west region of Ghana. Malar J. 2016;15:367.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorton S, Levin C. Cost-effectiveness of interventions for reproductive, maternal, neonatal, and child health. In: Black R, Temmerman M, Laxminarayan R, Walker N, editors. Disease control priorities. 3rd ed (Vol 2): reproductive, maternal, newborn, and child health. Washington, DC: World Bank; 2016. pp.\u0026nbsp;319\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOldenburg CE, Si\u0026eacute; A, Bountogo M, Zakane A, Compaor\u0026eacute; G, Ouedraogo T, Koueta F, Lebas E, Brogdon J, Nyatigo F, Doan T, Porco TC, Arnold BF, Lietman TM, NAITRE Study Team. Neonatal azithromycin administration for prevention of infant mortality. NEJM Evid. 2022 Apr;1(4):EVIDoa2100054. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/EVIDoa2100054\u003c/span\u003e\u003cspan address=\"10.1056/EVIDoa2100054\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePavlinac PB, Singa BO, Tickell KD, Brander RL, McGrath CJ, Amondi M, Otieno J, Akinyi E, Rwigi D, Carreon JD, Tornberg-Belanger SN, Nduati R, Babigumira JB, Meshak L, Bogonko G, Kariuki S, Richardson BA, John-Stewart GC, Walson JL. Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial. Lancet Glob Health. 2021 Nov;9(11):e1569-e1578. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2214-109X(21)00347-8\u003c/span\u003e\u003cspan address=\"10.1016/S2214-109X(21)00347-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilumbwe A, Zulu JM, Halwindi H, et al. A systematic review of factors that shape implementation of mass drug administration for lymphatic filariasis in sub-Saharan Africa. BMC Public Health. 2017;17\u0026lt;bvertical-align:super;\u0026gt;:\u0026lt;/bvertical-align:super;\u0026gt;\u0026lt;bvertical-align:super;\u0026gt;:\u0026lt;/bvertical-align:super;\u0026gt;484.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCairncross S, Peries H, Cutts F. Vertical health programmes. Lancet. 1997;349:20\u0026ndash;1. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(97)90079-9\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(97)90079-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629\u0026ndash;655. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(21)02724-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(21)02724-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoan T, Worden L, Hinterwirth A, Arzika AM, Maliki R, Abdou A, Zhong L, Chen C, Cook C, Lebas E, O'Brien KS, Oldenburg CE, Chow ED, Porco TC, Lipsitch M, Keenan JD, Lietman TM. Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. N Engl J Med. 2020 Nov 12;383(20):1941\u0026ndash;1950. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2002606\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2002606\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePickering H, Hart JD, Burr S, Stabler R, Maleta K, Kalua K, Bailey RL, Holland MJ. Impact of azithromycin mass drug administration on the antibiotic-resistant gut microbiome in children: a randomized, controlled trial. Gut Pathog. 2022 Jan 6;14(1):5. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13099-021-00478-6\u003c/span\u003e\u003cspan address=\"10.1186/s13099-021-00478-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRambli\u0026egrave;re L, Guillemot D, Delarocque-Astagneau E, Huynh BT. Impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review. Int J Antimicrob Agents. 2021 Jul;58(1):106364. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijantimicag.2021.106364\u003c/span\u003e\u003cspan address=\"10.1016/j.ijantimicag.2021.106364\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKennedy J. Populist politics and vaccine hesitancy in Western Europe: an analysis of national-level data. Eur J Public Health. 2019;29:512\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurpub/ckz004\u003c/span\u003e\u003cspan address=\"10.1093/eurpub/ckz004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. d oi:.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoffey PS, Gerth-Guyette E. Current perspectives and practices of newborn vitamin K administration in low and middle income countries. Res Rep Neonatol. 2018;8:45\u0026ndash;51. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/RRN.S154652\u003c/span\u003e\u003cspan address=\"10.2147/RRN.S154652\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamrick HJ, Gable EK, Freeman EH, Dunn LL, Zimmerman SP, Rusin MM, Linthavong OR, Wright ME, Moss LA, Skinner AC. Reasons for Refusal of Newborn Vitamin K Prophylaxis: Implications for Management and Education. Hosp Pediatr. 2016 Jan;6(1):15\u0026ndash;21. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/hpeds.2015-0095\u003c/span\u003e\u003cspan address=\"10.1542/hpeds.2015-0095\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahni V, Lai FY, MacDonald SE. Neonatal vitamin K refusal and nonimmunization. Pediatrics. 2014 Sep;134(3):497\u0026ndash;503. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/peds.2014-1092\u003c/span\u003e\u003cspan address=\"10.1542/peds.2014-1092\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoyal J, Taylor J, Phillipi C, Dhepyasuwan N, Shapiro E, Colson E, et al. Refusal of Vitamin K by Parents of Newborns: A Survey of the Better Outcomes Through Research for Newborns Network. Acad Pediatr. 2017;17(4):368\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpicer N, Agyepong I, Ottersen T, et al. \u0026lsquo;It\u0026rsquo;s far too complicated\u0026rsquo;: why fragmentation persists in global health. Global Health. 2020;16:60. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003edoi.org/10.1186/s12992-020-00592-1\u003c/span\u003e\u003cspan address=\"10.1186/s12992-020-00592-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization Maximizing Positive Synergies Collaborative Group. Samb B, Evans T, Dybul M, Atun R, Moatti JP, Nishtar S, Wright A, Celletti F, Hsu J, Kim JY, Brugha R, Russell A, Etienne C. An assessment of interactions between global health initiatives and country health systems. Lancet. 2009 Jun 20;373(9681):2137-69. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(09)60919-3\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(09)60919-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobinson JC, Miller K. Total Expenditures per Patient in Hospital-Owned and Physician-Owned Physician Organizations in California. JAMA. 2014;312(16):1663\u0026ndash;9. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2014.14072\u003c/span\u003e\u003cspan address=\"10.1001/jama.2014.14072\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLassi ZS, Mallick D, Das JK, Mal L, Salam RA, Bhutta ZA. Essential interventions for child health. Reprod Health. 2014;11(Suppl 1):4. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1742-4755-11-S1-S4\u003c/span\u003e\u003cspan address=\"10.1186/1742-4755-11-S1-S4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Suppl 1 ) .\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Mullane DM, Baez RJ, Jones S, Lennon MA, Petersen PE, Rugg-Gunn AJ, Whelton H, Whitford GM. Fluoride and Oral Health. Community Dent Health. 2016 Jun;33(2):69\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSocial factors and. oral health in children. London: Office for National Statistics; 2004.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSelwitz RH, Ismail AI, Pitts NB. Dental caries. Lancet. 2007 Jan 6;368(9555):51 \u0026ndash; 9. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(07)60031-2\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(07)60031-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStevens GA, Bennett JE, Hennocq Q, Lu Y, De-Regil LM, Rogers L, Danaei G, Li G, White RA, Flaxman SR, Oehrle SP, Finucane MM, Guerrero R, Bhutta ZA, Then-Paulino A, Fawzi W, Black RE, Ezzati M. Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: a pooled analysis of population-based surveys. Lancet Glob Health. 2015 Sep;3(9):e528-36. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2214-109X(15)00039-X\u003c/span\u003e\u003cspan address=\"10.1016/S2214-109X(15)00039-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe World Bank. Mortality rate, infant (per 1,000 live births) [online]. 2022. Available at: Mortality rate, infant (per 1,000 live births) | Data (worldbank.org) [accessed 2022 June 9].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMass drug administration. for falciparum malaria: a practical field manual. Geneva: World Health Organisation; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuideline. Alternative mass drug administration regimens to eliminate lymphatic filariasis. Geneva: World Health Organisation; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnchocerciasis. and its control: report of a WHO expert committee on onchocerciasis control. Geneva: World Health Organisation; 1995.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHelminth control in. school-age children: a guide for managers of control programmes. Geneva: World Health Organisation; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuideline for preventative chemotherapy for the control of taenia solium taeniasis. Washington, D.C: Pan American Health Organisation; 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuideline. preventative chemotherapy to control soil-transmitted helminth infections in at-risk population groups. Geneva; World Health Organisation; 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organisation. Foodbourne trematode infections. 2021. Available from: Foodborne trematode infections (who.int) [accessed 14 October 2021].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColdiron ME, Assao B, Page AL, Hitchings MDT, Alcoba G, Ciglenecki I, Langendorf C, Mambula C, Adehossi E, Sidikou F, Tassiou EI, De Lastours V, Grais RF. Single-dose oral ciprofloxacin prophylaxis as a response to a meningococcal meningitis epidemic in the African meningitis belt: A 3-arm, open-label, cluster-randomized trial. PLoS Med. 2018 Jun;26(6):e1002593. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pmed.1002593\u003c/span\u003e\u003cspan address=\"10.1371/journal.pmed.1002593\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 15 ) .\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarks M, Bottomley C, Tome H, et al. Mass drug administration of azithromycin for trachoma reduces the prevalence of genital Chlamydia trachomatis infection in the Solomon Islands. Sexually Transmitted Infections. 2016 Jun;92(4):261\u0026ndash;5. DOI:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/sextrans-2015-052439\u003c/span\u003e\u003cspan address=\"10.1136/sextrans-2015-052439\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalia B, Kmush BL, Lane SD, Endy T, Montresor A, Larsen DA. Routine deworming during antenatal care decreases risk of neonatal mortality and low birthweight: A retrospective cohort of survey data. PLoS Negl Trop Dis. 2021 Apr 29;15(4):e0009282. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pntd.0009282\u003c/span\u003e\u003cspan address=\"10.1371/journal.pntd.0009282\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Neill J. Tackling drug-resistant infections globally: final report and recommendations. Review on antimicrobial resistance. Wellcome Trust and HM Government; 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSulis G, Adam P, Nafade V, Gore G, Daniels B, Daftary A, et al. Antibiotic prescription practices in primary care in low- and middle-income countries: A systematic review and meta-analysis. PLoS Med. 2020;17(6):e1003139.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorres NF, Chibi B, Kuupiel D, et al. The use of non-prescribed antibiotics; prevalence estimates in low-and-middle-income countries. A systematic review and meta-analysis. Arch Public Health. 2021. 79(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTadesse BT, Ashley EA, Ongarello S, Havumaki J, Wijegoonewardena M, Gonz\u0026aacute;lez IJ, Dittrich S. Antimicrobial resistance in Africa: a systematic review. BMC Infect Dis. 2017 Sep 11;17(1):616. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12879-017-2713-1\u003c/span\u003e\u003cspan address=\"10.1186/s12879-017-2713-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGough EK. The impact of mass drug administration of antibiotics on the gut microbiota of target populations. Infect Dis Poverty. 2022. 11(76). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40249-022-00999-5\u003c/span\u003e\u003cspan address=\"10.1186/s40249-022-00999-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliver K, Lorenc T, Tinkler J, et al. Understanding the unintended consequences of public health policies: the views of policymakers and evaluators. \u003cem\u003eBMC Public Health. 2019\u003c/em\u003e: 19;\u0026lt;bvertical-align:super;\u0026gt; \u0026lt;/bvertical-align:super;\u0026gt;1057. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12889-019-7389-6\u003c/span\u003e\u003cspan address=\"10.1186/s12889-019-7389-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenberg L. The human nature of human nature. Science. 1972;176:123\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMittelmark M. Unintended effects in settings-based health promotion. Scand J Public Health. 2014;42(Suppl 15):17\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Global health, Mass drug administration, Azithromycin, Child mortality","lastPublishedDoi":"10.21203/rs.3.rs-2112557/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2112557/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRecent years has seen the mass administration of certain antimicrobials, including antibiotics, increasingly promoted as a public health strategy in low- and middle-income countries (LMICs). The WHO currently recommends the mass administrations of azithromycin for three indications: yaws, trachoma, and child mortality.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a desk-based review of secondary data to discuss the clinical, public health and economic evidence underpinning the decision to adopt, and the issues to consider when implementing a mass drug administration (MDA) programme involving azithromycin.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBefore deciding to adopt and implement a policy of MDA of antibiotics, the evidence base should be evaluated, including an economic assessment, and consideration of the distribution of benefits and risks amongst individuals and within communities and populations. Once the decision to adopt has been made, key considerations for successful implementation of a programme include ensuring it does not draw attention and resources away from other health services and finding opportunities for generating efficiencies through integration with existing health interventions. Understanding local attitudes and gaining trust are essential for stakeholder buy-in Furthermore, there must be appropriate attention to the potential harms which include worsening antimicrobial resistance, unintended consequences of public health interventions and reinforcement of a selective primary healthcare paradigm at the expense of a more bottom-up, comprehensive and socially driven pathway to health improvement.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAlthough MDA of antibiotics presents an opportunity to prevent mortality and improve health in the short-term, in the case of childhood mortality, MDA of azithromycin can only be a short-term quick fix. Ultimately, long-term, and sustainable child mortality reductions \u0026ndash; especially in high mortality settings \u0026ndash; will require more comprehensive approaches to health system strengthening and broader-based socio-economic development.\u003c/p\u003e","manuscriptTitle":"Implementation of mass drug administration of antibiotics in low- and middle- income countries","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-10 19:12:33","doi":"10.21203/rs.3.rs-2112557/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a4d8283-8e33-4724-9fe0-26d6a7efdaf6","owner":[],"postedDate":"October 10th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-13T08:47:52+00:00","versionOfRecord":[],"versionCreatedAt":"2022-10-10 19:12:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2112557","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2112557","identity":"rs-2112557","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}