# What is the impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review

Lison Rambliere, Didier Guillemot, Elisabeth Delarocque-Astagneau,
Bich-Tram Huynh

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What is the impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review

Lison Rambliere, Didier Guillemot,
Elisabeth Delarocque-Astagneau, Bich-Tram Huynh

PII: S0924-8579(21)00113-8

DOI: https://doi.org/10.1016/j.ijantimicag.2021.106364

Reference: ANTAGE 106364

To appear in: *International Journal of Antimicrobial Agents*

Received date: 7 December 2020

Accepted date: 15 May 2021

Please cite this article as: Lison Rambliere, Didier Guillemot, Elisabeth Delarocque-Astagneau, Bich-Tram Huynh, What is the impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review, *International Journal of Antimicrobial Agents* (2021), doi: https://doi.org/10.1016/j.ijantimicag.2021.106364

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1 Highlights:

2 • Mass and systematic antibiotic administration target a large portion of communities

3 • These interventions may increase the level of antibiotic resistance

4 • Particularly after azithromycin and co-trimoxazole administration

5 • More systematic and standardized surveillance of resistance is urgently needed

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# Title page

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**Title** What is the impact of mass and systematic antibiotic administration on antibiotic resistance in low- and middle-income countries? A systematic review

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**Running Title:** AR after mass/systematic antibiotic administration

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## Authors

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Lison Rambliere<sup>1,2</sup>, Didier Guillemot<sup>1,2,3</sup>, Elisabeth Delarocque-Astagneau<sup>1,3</sup>, Bich-Tram Huynh<sup>1,2</sup>

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## Affiliations

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1- Université Paris-Saclay, UVSQ, Inserm, CESP, Anti-infective evasion and pharmacoepidemiology team, F-78180, Montigny-Le-Bretonneux, France

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2- Institut Pasteur, Epidemiology and Modelling of Antibiotic Evasion (EMAE), F-75015, Paris, France

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3- AP-HP. Paris Saclay, Public Health, Medical Information, Clinical research, F-94276, Le Kremlin-Bicêtre

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## Key words

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Antibiotic resistance, prophylaxis, mass drug administration, systematic drug administration, Antibiotic usage, global health, Public health, low- and middle-income countries

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Lison Ramblière (corresponding author)

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Address: 25-28 rue du Dr Roux, 75015 Paris

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Telephone: +33 (0)1 45 68 83 01

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Fax: 01 45 68 82 04

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E-mail: lison.rambliere@pasteur.fr

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Abstract

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Antibiotic consumption is a key driver of antibiotic resistance (AR), particularly in low- and middle-income countries, where risk factors for AR emergence and spread are rife. However, the potential contribution of mass and systematic antibiotic administration (MDA/SDA) to AR spread is unknown. We conducted a systematic review to provide an overview of MDA/SDA in low- and middle-income countries, including indications, antibiotics used and, if investigated, levels of AR over time. This systematic review is reported in accordance with the PRISMA statement. Of 2438 identified articles, 63 were reviewed: indications for MDA/SDA were various, and targeted populations were particularly vulnerable, including pregnant women, children, HIV-infected populations and communities in outbreak settings. Available data suggest MDA/SDA may lead to significant AR increase, especially after azithromycin administration. However, only 40% of studies evaluated AR. Integrative approaches that evaluate AR in addition to clinical outcomes are needed to understand consequences of MDA/SDA implementation, combined with standardized AR surveillance for timely detection of antibiotic resistance emergence.

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51 Units and Abbreviations:

52 AR: Antibiotic Resistance

53 MDA: Mass Drug Administration

54 SDA: Systematic Drug Administration

55 LMICs: Low- and Middle-income countries

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58 Introduction

59 Antibiotic resistance (AR) is one of the greatest threats to global health, particularly in low- and
60 middle-income countries (LMICs) where risk factors for its emergence are widespread. Bacterial
61 infections are already leading causes of death in LMICs, and further dissemination of AR could
62 lead to increased mortality due to treatment failure, particularly in settings with restricted access
63 to second-line drugs [1].

64 Poor infection control, inadequate sanitation and poor living conditions have been identified as
65 key drivers of AR in LMICs. Misuse, over-the-counter availability and low quality of antibiotics
66 are also important contributors to AR in these settings [2]. Though antibiotics are predominantly
67 used for treatment of bacterial infections, they are also used for prophylaxis at both the individual
68 and population levels. Mass prophylactic use of antibiotics can broadly be classified as either
69 mass drug administration (MDA) or systematic drug administration (SDA). MDA describes
70 administration of antibiotics to entire communities to control the spread of particular infectious
71 diseases. For instance, WHO (World Health Organization) recommends azithromycin MDA for
72 trachoma control in high-prevalence settings [3]. Systematic drug administration (SDA) aims to
73 prevent specific health outcomes or complications by prescribing antibiotics to targeted groups.
For example, co-trimoxazole can be given to HIV-infected individuals to prevent opportunistic infections [4]. Both of these repeated individual and/or large population exposures to antibiotics may play a critical role in the emergence and spread of AR [5-7].

To our knowledge no systematic review has been conducted to describe antibiotic MDA/SDA interventions, despite their significance to public health and potentially important consequences for AR. The main objectives of this study were (i) to provide a descriptive overview of MDA/SDA interventions implemented in LMICs, including indications, targeted populations, antibiotics used and modes of administration, and (ii) to investigate their potential impact on AR.

## Methods

We systematically reviewed the literature for studies describing use of MDA/SDA in LMICs. This systematic review is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement (Supplementary Table 1). The full study protocol was registered with PROSPERO, number CRD42020140182.

## Search strategy and selection criteria

PubMed, Web of Science, Scopus and Cochrane Library were searched for articles published between January 2000 and January 2019. Additional searches were conducted monthly until March 2020 to capture recently published literature. Further information was obtained using snowball searching by screening references identified from articles.

We used comprehensive Boolean search strategies with search terms pertaining to antibiotics, MDA, SDA and corresponding English MeSH headings for each database (Supplementary Text 1).
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Articles included were original research articles describing antibiotic MDA or SDA
interventions, with indication of administration that could potentially targeted a substantial part
of the population in at least one countries defined as LMICs by the World Bank [8] (2019).

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Exclusion criteria were systematic reviews and meta-analyses articles (only used as a source of references in snowball searches), data collection prior to January 1 2000 and studies on MDA for trachoma control, owing to a recently updated systematic review and meta-analysis investigating AR following azithromycin MDA for trachoma control [9]. No language restrictions were applied.

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Three researchers were involved in the review process (LR, BTH and EDA). One reviewer (LR) assessed article titles for relevance. Two of the three investigators (LR and BTH or EDA) independently reviewed all potentially relevant abstracts. The same process was used for full text screening and quality assessment. Disagreements were resolved by consensus among all parties.

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For all eligible studies, we extracted details on objectives, methods and MDA/SDA
characteristics. If AR was evaluated, epidemiological and microbiological methods were
extracted. We stratified studies by target populations and types of antibiotic, and summarized
data on AR when evaluated (resistant pathogen prevalence, measures of association).

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The Critical Appraisal Skills Programme tools based on Cochrane guidelines were used to assess
study quality. To assess data extraction quality, two investigators (LR and BTH or EDA)
reviewed extracted data for selected articles.

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Findings

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Overall, 2438 articles were identified (Figure 1). After duplicate removal, 2131 articles were
eligible for title screening, of which 150 were eligible for abstract screening. Of 86 full-text

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articles assessed, 63 met our inclusion criteria. These 63 articles described 36 different studies across 19 countries. The majority of studies were from Africa (32 studies, 89%), in particular Southern Africa (17 studies, 47%) (Figure 2). Twenty-five studies (69%) were randomized controlled trials and 26 (72%) were implemented in an urban setting. Other study characteristics are available in supplementary Table 2.

## Antibiotics administered

Overall, the most commonly used antibiotic was co-trimoxazole (16 studies, 14 of which among HIV-exposed or -infected individuals), with dosing consistent with international recommendations. Other common antibiotics under study were azithromycin (seven studies) and amoxicillin (six studies), with variable dosing. Details of populations, antibiotic, doses and frequency, and main outcomes investigated are presented in Table 1 and Figure 3.

## Populations Targeted

Fourteen of the 36 studies (39%) assessed MDA/SDA in children [10–40].

MDA was administered to healthy infants in three studies [10–22]. First, ARMCA investigated the impact of amoxicillin, co-trimoxazole or azithromycin MDA on infant weight gain [10–12]. Second, MORDOR assessed the effect of azithromycin MDA on infant morbidity and mortality [13–21]. The last study investigated the effect on infant morbidity and mortality of adding azithromycin to seasonal malaria chemoprophylaxis [22].

Five studies targeted severely malnourished infants under two years old [23–27]. Among them, four investigated the impact of amoxicillin as SDA on nutritional recovery [23–26], of which two further included arms with ceftriaxone [24] or cefdinir [25]. The fifth assessed the impact of co-trimoxazole as SDA on mortality [27].

Six studies targeted HIV-exposed or -infected children [28–40], all in the context of co-trimoxazole as SDA to decrease morbi-mortality.
Eleven studies [41–59] (31%) evaluated efficacy of SDA in pregnant women.

Six studies targeted healthy pregnant women [41–53], of which four evaluated azithromycin to decrease maternal/infant morbidity, preterm birth or low birth weight, or to improve gestational weight gain [42–51]. Two studies evaluated antibiotic SDA to prevent early neonatal sepsis, using either amoxicillin, cephalexin or penicillin [41], or ampicillin in combination or not with metronidazole [53].

Three studies targeted HIV-infected pregnant women [54–57] to prevent morbi-mortality using either co-trimoxazole [57], cefoxitin [56], or metronidazole in combination with erythromycin or ampicillin [54,55].

The remaining two studies targeted women with risk factors at delivery [58,59]. The first administered ampicillin to women with premature rupture of fetal membranes to prevent early onset neonatal sepsis [58]. The other assessed cefazolin administration at cord clamping to prevent maternal infections among women who underwent Caesarian section [59].

Eight studies (22%) investigated co-trimoxazole as SDA in HIV-infected adults [60–68] (or adults and children) and its potential to decrease mortality rates, infections or malaria incidence.

The remaining three studies (8%) described MDA in outbreak settings [69–72] which administered : doxycycline to contacts of cholera patients in Cameroon [69]; ciprofloxacin to members of Nigerien villages with high prevalence of meningitis [70]; and azithromycin to members of villages with high prevalence of yaws in Papua New Guinea [71,72].

## Antibiotic resistance

AR was evaluated post-baseline (after first antibiotic administration) in 39% of studies [11,17,18,32,36,37,39,50,52,60,63,66–72] (14/36): in 36% (5/14) of studies among children
[11,17,18,32,36,37,39], in 18% (2/11) among pregnant women [50,52], in 50% (4/8) among HIV-infected adults [60,63,66–68], and in 100% (3/3) in outbreak settings [69–72]. Of note, two additional studies investigated AR at baseline without post-exposure follow-up and were thus excluded from the following results [23,48]. AR was detected with either phenotypic [17,32,36,37,50,52,60,63,66–70] (11/14) or molecular methods [11,17,18,39,71,72] (4/14) with one study using both methods [17].

Four studies with both intervention and control groups evaluated carriage of resistant bacteria cross-sectionally [11,17,18,36,60] (table 2). Single sampling time points ranged from 6 to 730 days following first antibiotic administration. AR was evaluated longitudinally in ten studies [32,36,37,39,50,52,60,63,66–72] (Figure 4). Follow-up ranged from 30 days to ten years.

## Azithromycin

Of seven studies investigating azithromycin MDA/SDA, four evaluated AR.

Two studies, both among healthy children, investigated gut meta-genomic resistance after MDA. In ARMCA, antibiotic resistance determinants corresponding to each antibiotic class were identified using DNA-seq extracted from rectal swabs [11]. Five days after last MDA, increases in prevalence of macrolide and sulfonamide resistance genes were found (RR=3.6, p<0.001 and RR=16.0, p=0.01) [11]. For resistance genes for other antibiotic classes, such as beta-lactams and fluoroquinolones, prevalence was not different between antibiotic and placebo groups [11]. In MORDOR, antibiotic resistance determinants/genes identified were Ls, ermA, ermB, ermF, ermT, ermX, lnuA, lnuC, Lsa, macB, mefA, MEL, mphA, msrD [18]. Six months after last MDA, determinants of macrolide resistance from metagenomic DNA sequencing were significantly higher in the antibiotic group than in placebo in the intestinal flora (12.3% vs. 2.9%, p= 0.02) and in the nasopharyngeal flora (68.8% vs. 46.7%, p=0.002) [17]. The presence of genetic resistance determinants at the DNA level is not always associated with phenotypic
190 resistance. This requires analysis of gene expression at the RNA level. In MORDOR, the
191 expression of macrolide resistance genes in the gut was also significantly higher in the antibiotic
192 group than in the placebo group (16.7% vs. 2.7%, p=0.001 [18]).

193 Two studies, one in infants (MORDOR) [17] and the other in pregnant women [50], assessed
194 *Streptococcus pneumoniae* resistance. In MORDOR, the proportion of resistance to erythromycin
195 in nasopharyngeal samples was higher in the antibiotic group than controls (12.3% vs. 2.9%,
196 p=0.02) [17]. In pregnant women receiving antibiotics, proportions of *S. pneumoniae* and *S.
197 aureus* resistant to azithromycin were higher compared to the control group in nasopharyngeal,
198 breast milk and vaginal samples at day 28 [50]. While antibiotics were administered only to
199 mothers, infants born to mothers in the antibiotic group had higher rates of *S. aureus* resistant to
200 azithromycin in nasopharyngeal samples taken at one month of age (4.5% vs 16.7%, p<0.001),
201 but rates were similar to controls at 12 months (3.1% vs. 2.6%, p=0.724) [50,52]. Prevalence of
202 resistant *S. pneumoniae* and *S. aureus* to other antibiotic classes (such as erythromycin,
203 chloramphenicol, and clindamycin) was similar between both arms at 28 days and 12 months
204 [52].

205 In a study evaluating *Treponema pallidum* resistance after azithromycin MDA in residents of
206 yaws-endemic villages [71,72], rates of macrolide resistance genes (*A2058G* and *A2059G*) did
207 not change over time and remained below 10% [71] (Supplementary Figure 1).

208 Co-trimoxazole

209 Of the sixteen studies in which co-trimoxazole was used as SDA, nine evaluated AR.

210 AR was assessed using meta-genomic analysis in two studies. Analysis of rectal swabs from
211 healthy infants from ARMCA showed a significant increase in risk of carrying sulfonamide
212 (RR=8.8, p=0.05) and trimethoprim (RR=3.3, p=0.04) resistance gene determinants relative to
213 the placebo group, while no difference was observed for beta-lactam and macrolide resistance
genes [11]. The second study targeted HIV-exposed uninfected infants [39]. In the group treated with co-trimoxazole compared to placebo, the authors showed a decrease of gut microbiome β-diversity (diversity in resistance gene composition), increased AR gene α-diversity (resistance gene richness) (p=0.0045) and increased overall resistance gene prevalence (p=0.007) [39].

S. pneumoniae AR was investigated in three studies [32,36,68]. Based on a national surveillance system, Everett and colleagues reported a high rate of co-trimoxazole resistance (>90%) in S. pneumoniae cultures of cerebrospinal fluid and blood from adults and children admitted to hospital for severe bacterial infection [68]. No resistance to other antibiotics such as tetracycline, chloramphenicol or penicillin was reported [68]. The two remaining studies investigated AR in nasopharyngeal samples of HIV-infected children: high levels of co-trimoxazole resistance were observed at baseline in both antibiotic (85.2% [36] and 58% [32]) and control groups (83.3% [36] and 60% [32]), with an increase in both groups observed in the first months of administration [36]. Over two years, one study showed a higher level of co-trimoxazole resistant S. pneumoniae in the co-trimoxazole arm than in the placebo arm (88%/72% p < 0.0001) [32].

The proportion of Haemophilus influenzae resistant to co-trimoxazole was also higher in the co-trimoxazole arm [32]. The second study found an increase in nasopharyngeal colonization with S. pneumoniae resistant to co-trimoxazole (RR=3.2, p=0.04) and clindamycin (RR=1.6, p=0.04) [36]. However, no increase was detected for resistance to penicillin, erythromycin, tetracycline or chloramphenicol [36].

Four studies investigated phenotypic AR of fecal *Escherichia coli*: all in HIV-infected or - exposed populations.

In adults, proportions of *E. coli* resistant to co-trimoxazole were similar at 24 weeks in both groups. In the co-trimoxazole arm compared to placebo higher proportions of *E. coli* resistant to ampicillin (OR=10.2, p<0.001), chloramphenicol (OR=7.8, p<0.001), ciprofloxacin (OR=17.1,
p=0.006) and nalidixic acid (OR=26.4, p=0.001) were found [60]. In HIV-exposed but uninfected infants, the proportion of *E. coli* resistant to co-trimoxazole was higher in co-trimoxazole recipients compared with placebo (3 months: 94% vs. 51% p<0.0001, 6 months: 84% vs. 57% p=0.01); as well as in *Klebsiella spp.* at 3 months (94% vs. 51% p<0.0001) and 6 months (69% vs. 14% p=0.002)[37]. In HIV-infected patients with CD4-cell counts <350 cell/mm3, the resistant rate of *E. coli* to co-trimoxazole was 54% (29% in the control group) and reached 100% (53%) at 12 months [63]. Resistance rates were also higher when compared to baseline for ampicillin (from 74% to 100%), amoxicillin/clavulanic acid (from 33% to 100%) and ceftriaxone (from 2% to 54%) [63]. In the remaining study, 76% of bacterial isolates (*E. coli*, *Shigella spp.*, *Campylobacter spp.* or *Salmonella spp.*) were classified as resistant before, and 83% after co-trimoxazole use among HIV-infected adults [67]. In their HIV-negative family members with diarrhea, no difference in the proportion of resistance to co-trimoxazole was observed [66].

## Amoxicillin

Of the five studies using amoxicillin as MDA, AR was evaluated in only one study [11]. While prevalence of beta-lactam, macrolide and trimethoprim resistance genes were not significantly different, prevalence of sulfonamide resistance was higher in the amoxicillin arms compared to control (RR=15.3, p=0.01) [11].

## Ciprofloxacin

Fecal carriage of extended-spectrum beta-lactamase producing *Enterobacteriaceae* was evaluated in a cluster-randomized trial evaluating administration of a single oral dose of ciprofloxacin to prevent meningococcal meningitis [70]. Carriage of ciprofloxacin-resistant *Enterobacteriaceae* was higher than 90% at baseline and at 28 days post-intervention without significant change observed (Supplementary Figure 1) [70].

## Doxycycline
Doxycycline was administered to contacts of cholera patients and *Vibrio cholerae* resistance was tested in stool samples of cholera patients during the eight months of outbreak [69]. The authors reported stable susceptibility patterns, including high rates of resistance for co-trimoxazole and colistin, and low rates for amoxicillin, clavulanic acid, cefotaxime, doxycycline, and perfloxacin [69].

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## Discussion

MDA/SDA interventions can reduce the burden of infectious diseases and improve population health [73–75]. Yet MDA/SDA may also contribute to the mounting global health crisis posed by AR [5–7]. We conducted an exhaustive review of published MDA/SDA studies conducted in LMICs since 2000 and, when evaluated, their impacts on AR.

We found that MDA/SDA interventions targeted a diverse range of particularly vulnerable populations, including severely malnourished infants, pregnant women, young children, HIV-exposed and -infected individuals, and communities in outbreak settings. These populations are over-represented in many LMICs [76–79] and sometimes overlap, such that the same individuals may be targeted by more than one MDA/SDA. Three main families of antibiotics were administered for three main purposes: amoxicillin and azithromycin administration for weight gain, ampicillin to prevent neonatal sepsis, and co-trimoxazole to decrease mortality and morbidity. Despite potentially important consequences for AR, only 14 of 36 included studies (40%) evaluated AR following MDA/SDA. However limited, our findings are consistent with the expectation that MDA/SDA interventions lead to greater AR prevalence, especially after co-trimoxazole and azithromycin administration. Co-trimoxazole resistance was high at baseline in *E. coli* [37, 60, 63, 66, 67] (>50%) and *S. pneumoniae* [36, 68] (>75%), yet increased further in
several populations receiving co-trimoxazole MDA/SDA. In some included studies, co-trimoxazole prophylaxis was followed by increased resistance to other antibiotic classes such as aminopenicillins, chloramphenicols and quinolones [60]. It is possible that co-trimoxazole induces cross-resistance, although there is currently no scientific consensus [80]. One alternative explanation is that co-trimoxazole resistance genes can be found alongside other resistance genes, for example on the same plasmid [80]. Another explanation for co-trimoxazole favouring resistance to unrelated antibiotics, such as clindamycin, is co-selection of related antibiotic resistance genes [80].

Azithromycin MDA/SDA was associated with increased macrolide resistance in *S. pneumoniae*, *S. aureus* [50,52,81], and increased resistance genes among microbiota [11,17,18]. These results are concordant with those reported by O'Brien *et al*. that found a transient or persistent increase in the proportion of *S. pneumoniae*, *E. coli* and *S. aureus* resistant to macrolides after MDA for trachoma control [9].

MDA/SDA is currently recommended by WHO for various indications, so potentially large numbers of people are eligible recipients. For example, following recent updates to treatment guidelines, WHO now recommends SDA for children with uncomplicated severe acute malnutrition, both in hospital and community settings, without practical guideline such as antibiotic class, dose or duration [82].

Since 2014, in settings with high infectious disease prevalence, WHO also recommends co-trimoxazole for all HIV-infected persons, irrespective of their CD4 count, as well as HIV-exposed neonates until 6 weeks of age [4]. With HIV prevalence above 20% in some LMICs [78], significant proportions of the population may be eligible for SDA under these guidelines.

Guidelines for other uses of MDA/SDA will likely evolve as more evidence from current and future studies becomes available. This has potential to further expand populations targeted by
these interventions. For instance, a research priority identified by WHO is evaluation of SDA for all women during the second or third trimesters of pregnancy to prevent infectious morbidity [83]. Several randomized controlled trials investigating azithromycin MDA are currently ongoing, targeting diverse populations including children after discharge from hospital, children with non-severe diarrhoea and malnourished children [84–86]. Moreover, in several low-income countries the official guidelines for treatment of Covid-19 patients at the primary care level recommend azithromycin for mild symptomatic Covid-19 patients, asymptomatic contacts or for prophylaxis [87].

The vast majority of included studies were set in Africa, thus limiting information regarding the indications and populations targeted by MDA/SDA and their potential impact on AR in others continents.

Epidemiological methods were heterogeneous without systematic evaluation of AR over time. AR can be transient [88–90] or may remain elevated for long periods because of low fitness costs of resistance [91] and/or continued selection pressure from other sources of antibiotic consumption. Temporal dynamics of AR were often poorly described or difficult to interpret, largely owing to variability in study design and duration of follow-up, which varied from five days to ten years.

Most studies investigated AR only in the treatment group, and evaluated AR only to the focal antibiotic and among few bacterial species. In addition, AR was evaluated only in bacteria specifically targeted by MDA/SDA, yet antibiotic exposure broadly selects for resistance across human microflora, particularly in the digestive tract [7,92]. In addition to the focal pathogen, assessment of resistance across non-focal species and across multiple antibiotic classes will be necessary to assess the overall impact of broad-spectrum antibiotic use on pathogenic bacterial species. AR is a concern not only for individuals targeted by MDA/SDA, but also their contacts
and environments, raising concerns about propagation of multidrug-resistant bacteria both within
individuals and throughout communities. For example, among pregnant women receiving
azithromycin MDA, rise of AR in S. aureus was also observed in their untreated neonates [50].

Better understanding of mechanisms of AR across species could help to better target particular
bacteria while minimizing bystander selection [75]. Microbiological assessment of AR was also
highly heterogeneous, and included phenotypic, molecular or metagenomic testing methods.

Phenotypic methods can identify resistance of specific organisms to specific antibiotics, and are
commonly used to characterize AR among both gram-positive and gram-negative bacteria.

Metagenomic methods can detect resistance determinants in several types of organisms at the
same time, but cannot determine whether this affects pathogenic or non-pathogenic bacteria.

These complementary methods should be considered simultaneously for future cross-
assessments. Moreover, the microbiome can be affected in terms of bacterial abundance, richness
and diversity [5]. It may take long periods for microbiota to recover and return to a species
composition similar to baseline, particularly in the context of repeated administration during
vulnerable time periods, such as childhood [5,7]. Disruption of the microbiome can further select
for emergence of resistant pathogens responsible for acute disease and increase risk of intestinal
infection [5]. More studies are needed to better understand potentially far-reaching consequences
of MDA/SDA on the microbiome.

To our knowledge, this review is the first to provide a global overview of MDA/SDA
administration and its potential impact on AR. Our findings suggest that MDA/SDA with
antibiotics such as azithromycin and co-trimoxazole may lead to significant increases in AR
levels across bacterial species. Guidelines for AR evaluation in the context of MDA/SDA are
sorely needed, including integrative approaches that incorporate standardized methodologies for
AR evaluation.
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**Acknowledgments**

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We thank the scientific information resources center (CERIS) of the Pasteur Institut for assisting
in the search strategy and David RM Smith for his critical review of the article and proofreading
in English.

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**Declarations**

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**Funding:** The work was supported directly by internal resources from University Paris-Sud.

**Competing Interests:** The corresponding author had full access to all data in the study and takes final responsibility for the decision to submit for publication. All authors declare no conflicts of interest.

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**Ethical Approval:** Not required

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688

689

690

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691 Table

692

<table><caption>Table 1: Mass or systematic administration of antibiotics among 63 included articles: target populations, antibiotics used, antibiotic dosing and frequency, and main outcomes investigated.</caption><thead><tr><th>Target population</th><th>MDA/SDA<sup>a</sup></th><th>Dose (mg)</th><th>Frequency</th><th>Main outcomes investigated</th></tr></thead><tbody><tr><td colspan="5"><strong>Amoxicillin</strong></td></tr><tr><td>1-59m healthy [10–12]</td><td>MDA</td><td>25/kg</td><td>2/d<sup>b</sup> x 5d</td><td>Weight gain</td></tr><tr><td>1-59m malnourished [23]</td><td>SDA</td><td>80/kg</td><td>2/d x7d</td><td>Nutritional recovery</td></tr><tr><td>1-59m malnourished [24]</td><td>SDA</td><td>12.5</td><td>1/d x5d</td><td>Weight gain</td></tr><tr><td>1-59m malnourished [25]</td><td>SDA</td><td>80/kg</td><td>2/d x2w<sup>c</sup></td><td>Mortality and nutritional recovery</td></tr><tr><td>6-59m malnourished [26]</td><td>SDA</td><td>60/kg</td><td>1/d x7d</td><td>Nutritional recovery</td></tr><tr><td>Healthy [41]</td><td>SDA</td><td>500</td><td>1 at delivery</td><td>Early-onset neonatal sepsis</td></tr><tr><td colspan="5"><strong>Ampicillin</strong></td></tr><tr><td>Vaginal delivery [53]</td><td>SDA</td><td>1000</td><td>1/6h before delivery</td><td>Early-onset neonatal sepsis</td></tr><tr><td>HIV-infected [54,55]</td><td>SDA</td><td>500 + 250</td><td>3/d x7d</td><td>Mortality and morbidity<sup>d</sup></td></tr><tr><td>Pre-labor SROM<sup>e</sup> [58]</td><td>SDA</td><td>1500</td><td>1 at delivery</td><td>Early-onset neonatal sepsis</td></tr><tr><td colspan="5"><strong>Azithromycin</strong></td></tr><tr><td>1-59m healthy[13–21]</td><td>MDA</td><td>20/kg</td><td>2/y<sup>f</sup> x3y</td><td>Mortality, morbidity and resistance gene abundance</td></tr><tr><td>1-59m healthy [10–12]</td><td>MDA</td><td>5/kg</td><td>1/d x5d</td><td>Mortality, hospital admission</td></tr><tr><td>3-59m healthy [22]</td><td>MDA</td><td>100 or 200</td><td>1/d x3d</td><td>Weight gain</td></tr><tr><td>Healthy [42]</td><td>SDA</td><td>1000</td><td>1 at 2<sup>nd</sup> and 3<sup>rd</sup> trimester</td><td>Preterm-birth</td></tr><tr><td>Healthy [43–45]</td><td>SDA</td><td>500</td><td>2 at 3<sup>rd</sup> trimester</td><td>Preterm deliveries, fetal and neonatal weight</td></tr><tr><td>Healthy [29–33]</td><td>SDA</td><td>500</td><td>2/d x2d up to 3 times</td><td>Gestational weight gain, birth weight</td></tr><tr><td>Healthy [49–52]</td><td>SDA</td><td>2000</td><td>1 at delivery</td><td>Mortality and morbidity**, infant weight gain</td></tr><tr><td>Yaws outbreak [71,72]</td><td>MDA</td><td>30/kg</td><td>1 dose</td><td>Prevalence of yaws</td></tr><tr><td colspan="5"><strong>Cefazolin</strong></td></tr><tr><td>C-section [59]</td><td>SDA</td><td>2000</td><td>1 at cord clamping</td><td>Maternal infections</td></tr></tbody></table>
<table><thead><tr><th>Target population</th><th>MDA/SDA<sup>a</sup></th><th>Dose (mg)</th><th>Frequency</th><th>Main outcomes investigated</th></tr></thead><tbody><tr><td><strong>Cefdinir</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♂ 1-59m malnourished [25]</td><td>MDA</td><td>14/kg</td><td>2/d x2w</td><td>Mortality and nutritional recovery</td></tr><tr><td><strong>Cefoxitin</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♀ HIV-infected, vaginal delivery [56]</td><td>SDA</td><td>2000</td><td>1 at delivery</td><td>Maternal infections</td></tr><tr><td><strong>Ceftriaxone</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♂ 1-59m malnourished [24]</td><td>SDA</td><td>50/kg</td><td>1/d x5d</td><td>Weight gain</td></tr><tr><td><strong>Cephalexin</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♂ Healthy [41]</td><td>SDA</td><td>500</td><td>1 at delivery</td><td>Early-onset neonatal sepsis</td></tr><tr><td><strong>Ciprofloxacin</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♂♂ Previous meningitis outbreak [70]</td><td>MDA</td><td>250 or 500</td><td>1 dose</td><td>Meningitis attack rate</td></tr><tr><td><strong>Co-trimoxazole</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>♂ 1-59m healthy [10-12]</td><td>MDA</td><td>240</td><td>2/d x5d</td><td>Weight gain</td></tr><tr><td>♂ 2-59m malnourished [27]</td><td>SDA</td><td>120 or 240</td><td>1/d x1y</td><td>Mortality</td></tr><tr><td>♂ 3-17y HIV-infected [28,40]</td><td>SDA</td><td>480 or 960</td><td>1/d x96w or x200w</td><td>Mortality, hospital admission, skin infection</td></tr><tr><td>♂ 3-14y HIV-infected [29-33]</td><td>SDA</td><td>240 or 480</td><td>1/d x4y</td><td>Mortality, hospital admission, antibiotic consumption and pneumococcal colonization</td></tr><tr><td>♂ 2-5y HIV-infected [34,35]</td><td>SDA</td><td>60/kg</td><td>1/d x4y</td><td>Malaria incidence</td></tr><tr><td>♂ 0-1y HIV-exposed [36]</td><td>SDA</td><td>60/kg</td><td>1/d x1y</td><td>Pneumococcal colonization</td></tr><tr><td>♂ 0-15m HIV-exposed [37]</td><td>SDA</td><td>120 or 240</td><td>1/d x15m<sup>g</sup></td><td>Colonization of resistant Enterobacteriaceae</td></tr><tr><td>♂ 0-1y HIV-exposed [38,39]</td><td>SDA</td><td>120 or 240</td><td>1/d</td><td>Morbidity and resistance gene abundance</td></tr><tr><td>♂ HIV-infected [57]</td><td>SDA</td><td>480</td><td>2/d x16d</td><td>Mortality and hospital admission</td></tr><tr><td>♀ HIV-infected [60]</td><td>SDA</td><td>960</td><td>2/d</td><td>Colonization of resistant E. coli</td></tr><tr><td>♀ HIV-infected [61]</td><td>SDA</td><td>960</td><td>1/d</td><td>Mortality</td></tr><tr><td>♀ HIV-infected [62]</td><td>SDA</td><td>960</td><td>1/d</td><td>Mortality and malaria incidence</td></tr><tr><td>♀ HIV-infected [63]</td><td>SDA</td><td>960</td><td>1/d</td><td>Colonization of resistant E. coli</td></tr><tr><td>♀ HIV-infected with immune recovery [64]</td><td>SDA</td><td>960</td><td>1/d</td><td>Mortality and morbidity</td></tr><tr><td>♀ HIV-infected with immune recovery [64]</td><td>SDA</td><td>960</td><td>1/d</td><td>Incidence of co-trimoxazole-preventable events or death</td></tr></tbody></table>
<table><thead><tr><th>Target population</th><th>MDA/SDA<sup>a</sup></th><th>Dose (mg)</th><th>Frequency</th><th>Main outcomes investigated</th></tr></thead><tbody><tr><td>And children HIV-infected [66,67]</td><td>SDA</td><td>960</td><td>1/d</td><td>Mortality and morbidity</td></tr><tr><td>>15y HIV-infected [68]</td><td>SDA</td><td>960</td><td>1/d</td><td>Pneumococcal colonization</td></tr><tr><td colspan="5"><strong>Doxycycline</strong></td></tr><tr><td> contacts of infected Cholera patients [69]</td><td>MDA</td><td>5/kg</td><td>1 dose</td><td>Cholera incidence and rate of V. cholerae resistance</td></tr><tr><td colspan="5"><strong>Erythromycin</strong></td></tr><tr><td>HIV-infected [54,55]</td><td>SDA</td><td>500 + 250</td><td>3/d x7d</td><td>Mortality and morbidity (pregnant women and neonates)</td></tr><tr><td colspan="5"><strong>Penicillin</strong></td></tr><tr><td>Healthy [41]</td><td>SDA</td><td>500</td><td>1 at delivery</td><td>Early-onset neonatal sepsis</td></tr></tbody></table>

695

696 **Legends**

697 ♀ Infants and children d- day

698 ♀ Pregnant women w- week

699 ♂ HIV-infected individuals m- month

700 ♀ Communities y- year

701

702 a- MDA/SDA: Mass or systematic drug administration

703 b- d: day

704 c- w: week

705 d- of pregnant women and their neonate

706 e- SROM: Spontaneous Rupture of Membranes

707 f- y: year

708 g- m: month

709

710

711 [10–12] – 3 arms: co-trimoxazole, azithromycin, amoxicillin

712 [41] – 3 arms: amoxicillin, cephalexin, penicillin

713 [24] – 2 arms: amoxicillin, ceftriaxone

714 [25] – 2 arms: amoxicillin, cefdinir

715 [54,55] – 3 arms: ampicillin + metronidazole or erythromycin + metronidazole

716 [53] – 2 arms: ampicillin or ampicillin + metronidazole

717
718 Table 2: Single time-point evaluation of antibiotic resistance following antibiotic administration

719 CI-Confidence Interval, MG – metagenomics, PDD - Phenotype disk diffusion, PE- Phenotype ellipsometry

720 1 – Time between first antibiotic administration and sampling, 2 – Control versus intervention, 3- Risk of non-

721 susceptibility when co-trimoxazole non-susceptible

<table><thead><tr><th rowspan="2">Outcome evaluated</th><th rowspan="2">Study name</th><th rowspan="2">Sample</th><th rowspan="2">Method</th><th rowspan="2">Class or antibiotic evaluated</th><th rowspan="2">Time<sup>1</sup> (days)</th><th colspan="2">Prevalence</th><th rowspan="2">pvalue</th></tr><tr><th>exposed / unexposed</th><th>Association measure<sup>2</sup></th></tr></thead><tbody><tr><td rowspan="4">Amoxicillin</td><td>ARMCA [11]</td><td>Rectal</td><td>MG</td><td>Beta-lactam</td><td>10</td><td>3.1</td><td>[0.7; 13.3]</td><td>NS</td></tr><tr><td>ARMCA [11]</td><td>Rectal</td><td>MG</td><td>Macrolide</td><td>10</td><td>1.24</td><td>[0.6; 4.4]</td><td>NS</td></tr><tr><td>ARMCA [11]</td><td>Rectal</td><td>MG</td><td>Sulfonamide</td><td>10</td><td>15.3</td><td>[1.8; 129.1]</td><td>0.01</td></tr><tr><td>ARMCA [11]</td><td>Rectal</td><td>MG</td><td>Trimethoprim</td><td>10</td><td>1.4</td><td>[0.5; 4.0]</td><td>NS</td></tr><tr><td rowspan="10">Azithromycin</td><td>MORDOR [18]</td><td>Rectal</td><td>MG</td><td>Aminoglycosides</td><td>730</td><td>1.3 / 2.7</td><td></td><td>NS</td></tr><tr><td>MORDOR [17]</td><td>Rectal</td><td>MG</td><td>Aminoglycosides</td><td>730</td><td>38.0 / 31.3</td><td></td><td>NS</td></tr><tr><td>ARMCA [11]</td><td>Rectal</td><td>MG</td><td>Beta-lactam</td><td>10</td><td>1.9</td><td>[0.5; 6.6]</td><td>NS</td></tr><tr><td>MORDOR [18]</td><td>Rectal</td><td>MG</td><td>Beta-lactam</td><td>730</td><td>36.0 / 34.0</td><td></td><td>NS</td></tr><tr><td>MORDOR [17]</td><td>Rectal</td><td>MG</td><td>Beta-lactam</td><td>730</td><td>68.0 / 63.3</td><td></td><td>NS</td></tr><tr><td>MORDOR [18]</td><td>Rectal</td><td>MG</td><td>Fluoroquinolones</td><td>730</td><td>4.7 / 2.0</td><td></td><td>NS</td></tr><tr><td>MORDOR [17]</td><td>Rectal</td><td>MG</td><td>Fluoroquinolones</td><td>730</td><td>27.3 / 28.7</td><td></td><td>NS</td></tr><tr><td>MORDOR [17]</td><td>Rectal</td><td>MG</td><td>Glycopeptides</td><td>730</td><td>1.3 / 1.3</td><td></td><td>NS</td></tr><tr><td>ARMCA [17]</td><td>Rectal</td><td>MG</td><td>Macrolides</td><td>10</td><td>2.6</td><td>[1.5; 4.4]</td><td>&lt;0.001</td></tr></tbody></table>
<table><tbody><tr><td>MORDOR</td><td>Rectal MG</td><td>Macrolides</td><td>730</td><td>16.7 / 2.7</td><td>[9.3 ; 24.7] / [1.0 ; 5.0]</td><td>0.001</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Macrolides</td><td>730</td><td>68.0 / 46.7</td><td>[61.3 ; 74.0] / [36.0 ; 54.0]</td><td>0.002</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Metronidazole</td><td>730</td><td>30.0 / 23.3</td><td>[18.7 ; 39.3] / [16.0 ; 30.7]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Metronidazole</td><td>730</td><td>31.3 / 23.3</td><td>[20.7 ; 42.0] / [16.0 ; 29.3]</td><td>NS</td></tr><tr><td>ARMCA</td><td>Rectal MG</td><td>Sulfonamides</td><td>10</td><td>16.0</td><td>[1.9 ; 133.5]</td><td>0.01</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Sulfonamides</td><td>730</td><td>0.7 / 2.0</td><td>[0.0 ; 2.0] / [0.0 ; 4.0]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Sulfonamides</td><td>730</td><td>16.7 / 22.7</td><td>[9.3 ; 24.0] / [17.3 ; 29.6]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Tetracyclines</td><td>730</td><td>75.3 / 74.0</td><td>[66.3 ; 80.0] / [68.7 ; 78.7]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Tetracyclines</td><td>730</td><td>27.3 / 30.7</td><td>[20.7 ; 34.7] / [22.7 ; 39.3]</td><td>NS</td></tr><tr><td>ARMCA</td><td>Rectal MG</td><td>Trimethoprim</td><td>10</td><td>1.8</td><td>[0.7 ; 5.1]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Trimethoprim</td><td>730</td><td>51.3 / 48.7</td><td>[44.0 ; 58.0] / [38.7 ; 57.3]</td><td>NS</td></tr><tr><td>MORDOR</td><td>Rectal MG</td><td>Trimethoprim</td><td>730</td><td>2.0 / 2.0</td><td>[0.0 ; 4.0] / [0.0 ; 4.0]</td><td>NS</td></tr><tr><td>Streptococcus</td><td>MORDOR</td><td>PDD</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>[17]</td><td>Nasal</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Co-trimoxazole</td><td>730</td><td>84.7 / 77.1</td><td>[76.4 ; 92.4] / [65.4 ; 88.1]</td><td>NS</td></tr><tr><td>pneumoniae</td><td>MORDOR</td><td>PDD</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td>[17]</td><td>Nasal</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>Clindamycin</td><td>730</td><td>9.0 / 1.7</td><td>[4.3 ; 14.1] / [0.0 ; 4.3]</td><td>NS</td></tr><tr><td></td><td></td><td>Doxycycline</td><td>730</td><td>60.1 / 50.1</td><td>[50.8 ; 70.5] / [33.7 ; 66.0]</td><td>NS</td></tr><tr><td></td><td></td><td>Erythromycin</td><td>730</td><td>12.3 / 2.9</td><td>[5.7 ; 20.0] / [0.0 ; 6.1]</td><td>0.02</td></tr><tr><td></td><td></td><td>Penicillin</td><td>730</td><td>18.7 / 22.3</td><td>[8.2 ; 30.6] / [10.2 ; 37.6]</td><td>NS</td></tr></tbody></table>
<table><tbody><tr><td rowspan="4">Co-trimoxazole<br>Resistome</td><td>ARMCA<br>[11]</td><td>Rectal</td><td>MG</td><td>Beta-lactam</td><td>10</td><td>1.8 [0.5; 6.4]</td><td>NS</td></tr><tr><td>ARMCA<br>[11]</td><td>Rectal</td><td>MG</td><td>Macrolides</td><td>10</td><td>8.9 [0.9; 3.0]</td><td>NS</td></tr><tr><td>ARMCA<br>[11]</td><td>Rectal</td><td>MG</td><td>Sulfonamides</td><td>10</td><td>8.8 [1; 77.0]</td><td>0.05</td></tr><tr><td>ARMCA<br>[11]</td><td>Rectal</td><td>MG</td><td>Trimethoprim</td><td>10</td><td>3.3 [1.1; 10.0]</td><td>0.04</td></tr><tr><td rowspan="4">Escherichia coli</td><td>[60]</td><td>Rectal</td><td>PDD</td><td>Ampicillin</td><td>7 to<br>168</td><td>10.2<sup>3</sup> [5.9; 17.8]</td><td>&lt;0.001</td></tr><tr><td>[60]</td><td>Rectal</td><td>PDD</td><td>Azithromycin</td><td>7 to<br>168</td><td>1.2<sup>3</sup> [0.71; 1.9]</td><td>NS</td></tr><tr><td>[60]</td><td>Rectal</td><td>PDD</td><td>Chloramphenicol</td><td>7 to<br>168</td><td>7.8<sup>3</sup> [3.0; 20.2]</td><td>&lt;0.001</td></tr><tr><td>[60]</td><td>Rectal</td><td>PDD</td><td>Ciprofloxacin</td><td>7 to<br>168</td><td>17.1<sup>3</sup> [2.3; 127.7]</td><td>0.006</td></tr><tr><td rowspan="4">Streptococcus pneumoniae</td><td>TZI project<br>[36]</td><td>Nasal</td><td>PE</td><td>Chloramphenicol</td><td>42</td><td>0.8 [0.3; 2.3]</td><td>NS</td></tr><tr><td>TZI project<br>[36]</td><td>Nasal</td><td>PE</td><td>Clindamycin</td><td>42</td><td>1.6 [1.0; 2.6]</td><td>0.04</td></tr><tr><td>TZI project<br>[36]</td><td>Nasal</td><td>PE</td><td>Erythromycin</td><td>42</td><td>1.0 [0.6; 1.7]</td><td>NS</td></tr><tr><td>TZI project<br>[36]</td><td>Nasal</td><td>PE</td><td>Penicillin</td><td>42</td><td>1.1 [0.7; 1.7]</td><td>NS</td></tr><tr><td></td><td>TZI project<br>[36]</td><td>Nasal</td><td>PE</td><td>Tetracycline</td><td>42</td><td>0.9 [0.6; 1.5]</td><td>NS</td></tr></tbody></table>
723 Figures

724 Figure 1: PRISMA flow diagram

725

<figure><img src="image_5.png" /></figure>

726
<figure><img src="image_6.png" /><figcaption>727 Figure 2: Geographic distribution of the 63 included articles (36 studies)</figcaption></figure>

728

729
730
<table><caption>731 Figure 3: Main populations, antibiotics used and indications for MDA/SDA in LMICs</caption><thead><tr><th></th><th>Populations</th><th>Antibiotic most commonly used</th><th>Intended outcome</th></tr></thead><tbody><tr><td rowspan="2">Childhood</td><td>Healthy infants</td><td>azithromycin</td><td>▲ mortality</td></tr><tr><td>Malnourished infants</td><td>amoxicillin</td><td>▲ weight</td></tr><tr><td rowspan="5">Pregnancy</td><td>Healthy pregnant women</td><td>azithromycin</td><td>▲ premature delivery<br>▲ neonatal sepsis<br>▲ maternal/neonatal mortality<br>▲ birth weight</td></tr><tr><td>Premature rupture of membranes</td><td>ampicillin</td><td>▲ Early-onset neonatal sepsis</td></tr><tr><td>C-section</td><td>cefazolin</td><td>▲ Morbidity</td></tr><tr><td>Infected or exposed pregnant women, infants, children and adults</td><td>Co-trimoxazole</td><td>▲ morbidity<br>▲ mortality</td></tr><tr><td>HIV</td><td></td><td></td></tr><tr><td rowspan="3">Outbreak</td><td>Meningitis</td><td>Ciprofloxacin</td><td>▲ meningitis</td></tr><tr><td>Cholera</td><td>Doxycycline</td><td>▲ cholera</td></tr><tr><td>Yaws</td><td>Azithromycin</td><td>▲ yaws</td></tr></tbody></table>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>
733 **Figure 4: Longitudinal evaluation of antibiotic resistance with repeated measures**

734 **Legend**

735

736 **4A – Resistance over time after azitromycin administration, 4B-Resistance over time after co-trimocazole administra**

737

738

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

739