International Journal of Infectious Diseases 134 (2023) 142–149

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Review

Global knowledge gaps on antimicrobial resistance in the human

health sector: A scoping review
Raph L. Hamers 1,2,∗, Zlatina Dobreva 3, Alessandro Cassini 3,4,5, Alice Tamara 1,
Gilbert Lazarus 1, Koe Stella Asadinia 1, Stefano Burzo 3, Ioana Diana Olaru 6,7,
Daniele Dona 3,8, Fiona Emdin 9, Kitty Van Weezenbeek 3, Silvia Bertagnolio 3
1
Oxford University Clinical Research Unit Indonesia, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
2
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
3
Antimicrobial Resistance Division, World Health Organization, Geneva, Switzerland
4
Public Health Department, Canton of Vaud, Lausanne, Switzerland
5
Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland
6
Institute of Medical Microbiology, University of Münster, Münster, Germany
7
Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
8
Division of Paediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, Padua, Italy
9
Global Strategy Lab, Toronto, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To identify and summarize existing global knowledge gaps on antimicrobial resistance (AMR)
Received 17 March 2023 in human health, focusing on the World Health Organization (WHO) bacterial priority pathogens, My-
Revised 2 June 2023
cobacterium tuberculosis, and selected fungi.
Accepted 5 June 2023
Methods: We conducted a scoping review of gray and peer-reviewed literature, published in English from
January 2012 through December 2021, that reported on the prevention, diagnosis, treatment, and care of
Keywords: drug-resistant infections. We extracted relevant knowledge gaps and, through an iterative process, con-
Antimicrobial resistance solidated those into thematic research questions.
Scoping review Results: Of 8409 publications screened, 1156 were included, including 225 (19.5%) from low- and middle-
Knowledge gaps
income countries. A total of 2340 knowledge gaps were extracted, in the following areas: antimicrobial
Bacteria
research and development, AMR burden and drivers, resistant tuberculosis, antimicrobial stewardship, di-
Fungi
Tuberculosis agnostics, infection prevention and control, antimicrobial consumption and use data, immunization, sex-
ually transmitted infections, AMR awareness and education, policies and regulations, fungi, water san-
itation and hygiene, and foodborne diseases. The knowledge gaps were consolidated into 177 research
questions, including 78 (44.1%) specifically relevant to low- and middle-income countries and 65 (36.7%)
targeting vulnerable populations.
Conclusion: This scoping review presents the most comprehensive compilation of AMR-related knowledge
gaps to date, informing a priority-setting exercise to develop the WHO Global AMR Research Agenda for
the human health sector.
© 2023 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction be directly responsible for 1.27 million deaths and associated

with 4.95 million deaths in 2019 alone [2]. Globally, there were
The global increase in antimicrobial resistance (AMR) is con- an estimated 450,0 0 0 incident cases of multi-drug-resistant or
sidered one of the greatest public health threats, with a dispro- rifampicin-resistant tuberculosis (MDR/RR-TB), and 191,0 0 0 asso-
portionate burden in low- and middle-income countries (LMICs) ciated deaths in 2021, with increasing trends for several regions
[1]. Antibiotic-resistant bacterial infections were estimated to and high-burden countries [3]. Increasing trends of invasive fun-
gal diseases constitute a growing concern worldwide, particularly
among immunocompromised populations, although data on anti-
∗
Corresponding author: Tel: +62 811180912. fungal resistance patterns are lacking [4,5]. The main drivers of the
E-mail address: [email protected] (R.L. Hamers). emergence of AMR in micro-organisms include antimicrobial expo-

https://doi.org/10.1016/j.ijid.2023.06.004
1201-9712/© 2023 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
R.L. Hamers, Z. Dobreva, A. Cassini et al. International Journal of Infectious Diseases 134 (2023) 142–149

sure; lack of access to clean water, sanitation and hygiene (WASH), by the core team and an experienced WHO librarian (full search
poor infection prevention and control (IPC) in health care facili- terms in Tables S3, S4, S5);
ties; poor access to quality-assured medicines (including new and • A hand search of WHO guidelines and other publications in
existing essential antimicrobials), vaccines and diagnostics; lack of relevant WHO repositories (WHO Institutional Repository for
awareness and knowledge; and lack of enforcement of legislation Data Sharing, Data Platform, The Global Health Observatory,
[6]. and WHO Observatory for Health R&D);
Concerted efforts have been made to develop strategies to mit- • A hand search of the websites of 92 key organizations in the
igate the global impact of AMR. The World Health Organization area of AMR, identified through a stakeholder mapping exercise
(WHO) coordinated the development of a Global Action Plan (GAP) (Table S6), supplemented with a Google search including the
on AMR in 2015 [7]. The GAP identified targeted research as one terms “filetype:pdf” and “antimicrobial resistance”.
of five strategic objectives, highlighting the importance of a solid
evidence base for interventions to measure, prevent, diagnose, and The searches were restricted to the English language and the
manage drug-resistant infections. Despite progress, there is an ur- 10-year period from January 01, 2012, through December 31, 2021.
gent need to expand the evidence on the AMR burden and its The search results were reviewed by the WHO Core Steering Group
drivers, on tools and interventions for AMR prevention, diagno- on AMR, and any additional relevant publications suggested by
sis, and treatment and care, also considering impact, prioritization, its members were also considered. The scoping review involved
cost-effectiveness, financing, and how to deliver them at scale [8– only documents available in the public domain and did not include
11]. any personal information on individuals; therefore, ethical approval
To accelerate a coordinated and effective global effort in line was not required.
with the pressing timeline to attain the 2030 Sustainable Develop- Documents were included if they (1) described one or more
ment Goals (SDGs), WHO has been mandated to develop a Global knowledge gaps on AMR, including priorities, framework, com-
Research Agenda for AMR for the human health sector [12] that ponents, elements, or steps for the description (i.e., epidemiol-
aims to provide an assessment and prioritization of knowledge ogy, burden, and drivers), delivery, development and/or discovery
gaps related to AMR in WHO bacterial priority pathogens [13], My- of tools, products, or interventions for AMR prevention, diagnosis
cobacterium tuberculosis and fungi of critical importance for AMR and/or treatment and care; and (2) had a global or regional ap-
[4]. We conducted a comprehensive scoping review of the global plication and/or relevance for LMICs. Documents were excluded if
gray and peer-reviewed literature that sought to identify existing they (1) only described original research studies or case reports;
knowledge gaps on the burden, drivers, technologies, tools, and in- (2) were not related to bacteria included in the WHO bacterial
terventions for the prevention, diagnosis, treatment, and care of in- priority pathogen list, M. tuberculosis or selected fungi (i.e., Can-
fections with antimicrobial-resistant pathogens, and the best ways dida spp. and Aspergillus spp.); (3) were related to the nonhuman
to deliver these. This scoping review will result in a set of consol- sector; (4) had no identifiable authors, publisher and/or year of
idated, thematic research questions, which will provide a frame- publication. The searches comprised an iterative process involv-
work to inform the subsequent priority-setting exercise. ing searching the literature, reviewing documents by the prede-
fined eligibility criteria, and refining the search strategy as needed.
All steps in the literature search were conducted using Mendeley
Methods
reference manager. Two reviewers (KSA, EE, GL, RLH) separately
screened all titles and abstracts. Full-text articles were indepen-
Study design
dently evaluated by at least two reviewers (AT, GL, KSA, KS, FE,
RT, RLH). We assessed the degree of agreement of document in-
Scoping reviews are often defined as a process of summarizing
clusion between the first and second reviewer (Tables S7, S8, S9).
(“mapping”) a range of evidence to convey the breadth and depth
Any disagreement on document inclusion was resolved by a senior
of a field and are an increasingly popular approach to reviewing
researcher (RLH). Duplicate documents were removed manually as
health research evidence [14]. We adhered to the methods devel-
well as by using automated tools (i.e., Mendeley for gray literature
oped by Arksey and O’Malley [14], Levac et al, [15] and the Joanna
and Bramer method [19] for bibliographic databases). Superseded
Briggs Institute [16], following a six-stage process of defining the
documents were excluded. We did not perform a formal assess-
scope and main question of the scoping review; searching for rel-
ment of the methodological quality of the included documents as
evant documents; document selection; data extraction; collating,
the purpose was to achieve a broad description of existing knowl-
summarizing and reporting results; and consulting stakeholders.
edge gaps.
The scoping review protocol has been previously published [17].
We followed the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Extraction of knowledge gaps
(Supplementary Material) [18]. The scoping review was conducted Data elements were extracted using a data extraction form de-
between November 01, 2021, and September 30, 2022. veloped in Microsoft Excel, which was updated during the itera-
tive extraction process. The content of the included documents was
Search strategy and selection criteria read to identify relevant knowledge gaps within the scope of the
review. A single reviewer (RLH, AT, GL, KSA, KS, FE, RT) extracted
The scope of the review is summarized in Table S1. Given that explicitly stated knowledge gaps, as well as text extracts to formu-
the scoping review aimed to identify and compile knowledge gaps late knowledge gaps, each in question format.
rather than individual research findings, our search strategy mainly Each identified knowledge gap was classified according to a
focused on reports, guidelines, and systematic reviews, and not on predefined “knowledge matrix”, comprising three people-centered
individual original research studies. We searched the following in- themes (prevention, diagnosis, treatment, and care) [20] and four
formation sources of peer-reviewed and gray literature to identify research domains from the Child Health and Nutrition Research
relevant documents in areas relevant to AMR (Table S2): Initiative (CHNRI) (description, delivery, development, and discov-
ery research) [21,22] (Table S10). Each knowledge gap was anno-
• A systematic search of peer-reviewed systematic reviews in tated with relevant attributes, such as research discipline, AMR-
three bibliographic databases (PubMed, Embase, and Web of relevant area, socio-economic context, sub-population, and target
Science). The searches were jointly developed and conducted pathogen. At least two other team members (AT, GL, AC, RLH) of

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the core team reviewed the extracted knowledge gaps and anno- AMR (201, 8.6%) (Figure S4). Pharmacological and clinical research
tations and ensured data extraction was accurate and consistent (1658, 70.9%) was the predominant research discipline, followed
with the defined scope. The whole exercise resulted in a database by epidemiology (527, 22.5%), behavioral and social science (275,
of annotated knowledge gaps. 11.8%), health economics (181, 7.7%), and legislation and regu-
lation (76, 3.2%) (Figure S5). The knowledge gaps covered the
Consolidation of research questions three people-centered themes of prevention (747, 31.9%), diagnosis
In the first round of review, the knowledge gaps were consol- (283, 12.1%), and treatment and care (1310, 56.0%), across the four
idated into higher-level thematic research questions, by removing CHNRI domains of description (627, 26.8%), delivery (1035, 44.2%),
duplicates, merging overlapping knowledge gaps, and rejecting in- development (349, 14.9%), and discovery (329, 14.1%) research
valid knowledge gaps, where appropriate and feasible. In doing so, (Figure 1).
groups of knowledge gaps were curated and listed under the perti- Antimicrobials (including R&D) (800, 34.2%) were the most
nent research question. Each research question was formulated as frequent AMR area, followed by AMR burden and drivers (526,
a statement in the PI/ECO (population, intervention/exposure, com- 22.5%), resistant tuberculosis (505, 21.6%), antimicrobial steward-
parator, outcome) format, where possible, and annotated with rel- ship (392, 16.8%), diagnostics (266, 11.4%), IPC (254, 10.9%), an-
evant attributes (as above). In the second round of review, core timicrobial consumption and use data (175, 7.5%), immuniza-
team members (ZD, DD, IDO, SB), who had not been involved in tion (79, 3.4%), sexually transmitted infections (75, 3.2%), AMR
the knowledge gap extraction and consolidation process, advised awareness and education (72, 3.1%), policies and regulations (53,
on further merging, rejecting, and/or rephrasing the research ques- 2.3%), fungi (30, 1.3%), water, sanitation and hygiene (WASH) (17,
tions. In the third round of review, experts from the WHO Core 0.7%), and foodborne diseases (13, 0.6%) (Figure 1). In total, 704
Steering Group on AMR reviewed the research questions to im- (30.1%) knowledge gaps specifically targeted WHO bacterial pri-
prove clarity, remove redundant research questions, and propose ority pathogens, 505 (21.6%) targeted resistant tuberculosis, and
new research questions to fill any remaining gaps. 30 (1.3%) targeted fungi. In total, 2246 (96.0%) knowledge gaps
had a global focus, 184 (7.9%) knowledge gaps were specifically
Data collation and analysis relevant to LMICs, and 407 (17.4%) knowledge gaps targeted vul-
We used descriptive analytics to present numerical and the- nerable groups (such as neonates, children, pregnant women, or
matic summaries of the key characteristics of included documents, migrants).
knowledge gaps, and research questions. All analyses and visualiza-
tions were conducted in R version 4.2.1 and GraphPad Prism ver- Characteristics of the thematic research questions after consolidation
sion 7.0a.
Through an iterative review process, we consolidated the 2340
Results knowledge gaps into 177 research questions (Table 1 and Figure
S6). Pharmacological and clinical research (120, 67.8%) was the pre-
Characteristics of included documents dominant discipline, followed by epidemiology (53, 29.9%), behav-
ioral and social science (37, 20.9%), health economics (29, 16.4%),
The search gave 13,786 hits from peer-reviewed (12,897) and and legislation and regulation (11, 6.2%) (Figure S5). The research
gray literature (889), of which after duplicate removal 8409 (7585 questions covered the three people-centered themes of preven-
and 824, respectively) remained. After title and abstract screening, tion (63, 35.6%), diagnosis (24, 13.6%), and treatment and care (90,
3169 documents remained (Figure S1). After full-text screening, 50.8%), across the four CHNRI domains of description (52, 29.4%),
1156 documents were included, comprising 979 from bibliographic delivery (65, 36.7%), development (24, 13.6%), and discovery (36,
databases; 108 through the websites of 92 key organizations; 20.3%) research (Figure 1).
29 WHO guidelines and other publications; and 40 documents Antimicrobial stewardship (33, 18.6%) was the most frequent
additionally suggested by the WHO Core Steering Group on AMR. AMR area, followed by antimicrobials (including R&D) (30, 16.9%),
Document characteristics are summarized in Table S11. Included AMR burden and drivers (29, 16.4%), resistant tuberculosis (26,
publications originated from 68 different countries and included 14.7%), diagnosis/diagnostics (24, 13.6%), antimicrobial consump-
225 (19.5%) publications originating from LMICs (Table S11 and tion and use data (22, 12.4%), IPC (19, 10.7%), policies and regu-
Figure S2). Most documents were systematic reviews or meta- lations (12, 6.8%), fungi (11, 6.2%), immunization (9, 5.1%), sexually
analyses (749, 64.8%), followed by narrative reviews or editorials transmitted infections (7, 4.0%), AMR awareness and education (4,
(294, 25.4%), reports (61, 5.3%), 39 (3.4%) guidelines or guidance 2.3%), foodborne diseases (2, 1.1%), and WASH (1, 0.6%) (Figure 1).
documents, and other (13, 1.1%). Most documents were authored In total, 29 (16.4%) research questions targeted one or more WHO
by a research organization (1030, 89.1%), followed by international bacterial priority pathogens, 26 (14.7%) targeted resistant tubercu-
technical agencies (56, 4.8%), governmental agencies (29, 2.5%), losis, and 11 (6.2%) targeted fungi. All 177 research questions had
professional associations (17, 1.5%), nongovernmental organiza- a global scope, 78 (44.1%) research questions were specifically rel-
tions (14, 1.2%), funding agencies (6, 0.5%), and private for-profit evant to LMICs, and 65 (36.7%) targeted vulnerable groups (such as
organizations (4, 0.3%). In total, 1069 (92.5%) documents had a neonates, children, pregnant women, and migrants).
global scope, while 41 (3.5%) and 46 (4.0%) had a regional or The full list of annotated knowledge gaps and research ques-
national scope, respectively. The number of annual publications tions and their distribution by micro-organism group, socio-
showed an increasing trend over time (2012-2021), particularly on economic context, and sub-populations are included in Figures S7,
WHO bacterial priority pathogens, selected fungi, and from LMICs S8, S9, and GitHub link.
(Figure S3).
Discussion
Characteristics of extracted knowledge gaps
This scoping review presents the most comprehensive and
We extracted a total of 2340 knowledge gaps (Table 1) novel compilation of AMR-related knowledge gaps in the pub-
from documents identified through bibliographic databases (1229, lic domain to date, published in the ten-year period from 2012
52.5%), key organizational websites (578, 24.7%), WHO publica- through 2021, covering the prevention, diagnosis, and treatment of
tions (332, 14.2%), and from the WHO Core Steering Group on infections caused by resistant WHO bacterial priority pathogens,

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Table 1
Characteristics of knowledge gaps and research questions.

Characteristics Knowledge gaps Research questions

N = 2340 % N = 177 %

Research discipline
Pharmacological and clinical 1658 70.9 120 67.8
Epidemiology 527 22.5 53 29.9
Behavioral and social science 275 11.8 37 20.9
Health economics 181 7.7 29 16.4
Legislation and regulation 76 3.2 11 6.2
Antimicrobial resistance area
Antimicrobials (including research and development) 800 34.2 30 16.9
AMR burden and drivers 526 22.5 29 16.4
Tuberculosis 505 21.6 26 14.7
Antimicrobial stewardship 392 16.8 33 18.6
Diagnosis/diagnostics 266 11.4 24 13.6
Infection prevention and control 254 10.9 19 10.7
Antimicrobial consumption and use data 175 7.5 22 12.4
Immunization 79 3.4 9 5.1
Sexually transmitted infections 75 3.2 7 4.0
Antimicrobial resistance awareness and education 72 3.1 4 2.3
Policies and regulations 53 2.3 12 6.8
Fungi 30 1.3 11 6.2
Water, sanitation, hygiene (WASH) 17 0.7 1 0.6
Food-borne diseases 13 0.6 2 1.1
Geographical scope/focus
Global 2246 96.0 177 100.0
Regionala 105 4.5 7 4.0
Africa 41 1.8 0 0.0
Southeast Asia 29 1.2 0 0.0
Western Pacific 23 1.0 0 0.0
Americas 8 0.3 0 0.0
Eastern Mediterranean 6 0.3 0 0.0
Europe 5 0.2 0 0.0
National 99 4.2 11 6.2
Subnational/local 13 0.6 1 0.6
Socio-economic context
General/Unspecified 2171 92.8 163 92.1
Low- and middle-income countries 184 7.9 78 44.1
Sub-populations
General/Unspecified 2092 89.4 171 96.6
Children 201 8.6 21 11.9
Immunocompromised 96 4.1 21 11.9
Neonates 49 2.1 7 4.0
Pregnant women 33 1.4 13 7.3
Older persons 20 0.9 2 1.1
Migrants and displaced populations 8 0.3 1 0.6
Setting
General/Unspecified 1774 75.8 21 11.9
Health care system 490 20.9 141 79.7
Acute-care hospitals 140 6.0 22 12.4
Intensive care unit 90 3.8 6 3.4
Primary care 56 2.4 8 4.5
Long-term care facilities 36 1.5 6 3.4
Community 109 4.7 65 36.7
Micro-organism
General/Unspecified 1107 47.3 113 63.8
World Health Organization bacterial priority pathogens 704 30.1 29 16.4
Enterobacterales – carbapenem-resistant, ESBL-producingb 244 10.4 3 1.7
Staphylococcus aureus – methicillin, vancomycin-resistant 178 7.6 7 4.0
Pseudomonas aeruginosa – carbapenem-resistant 147 6.3 3 1.7
Acinetobacter baumanii – carbapenem-resistant 140 6.0 2 1.1
Neisseria gonorrhoeae - 3rd generation 78 3.3 7 4.0
cephalosporin-resistant
Helicobacter pylori – clarithromycin-resistant 42 1.8 2 1.1
Enterococcus faecium – vancomycin-resistant 27 1.2 2 1.1
Streptococcus pneumonia – penicillin-resistant 20 0.9 1 0.6
Salmonella spp. - fluoroquinolone-resistant 9 0.4 1 0.6
Campylobacter spp. – fluoroquinolone-resistant 4 0.2 0 0.0
Shigella spp. – fluoroquinolone-resistant 4 0.2 1 0.6
Haemophilus influenzae – ampicillin-resistant 3 0.1 0 0.0
Mycobacterium tuberculosis 505 21.6 26 14.7
Multidrug-resistant (MDR-TB) 460 19.7 26 14.7
Extensively drug-resistant (XDR-TB) 291 12.4 23 13.0
Rifampicin-resistant (RR-TB) 278 11.9 15 8.5
Isoniazid-resistant (Hr-TB) 267 11.4 15 8.5
Pre-extensively drug-resistant (Pre-XDR-TB) 240 10.3 15 8.5
(continued on next page)

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Table 1 (continued)

Characteristics Knowledge gaps Research questions

N = 2340 % N = 177 %

Fungi 30 1.3 11 6.2

Candida spp. 16 0.7 8 4.5
Aspergillus spp. 6 0.3 4 2.3

TB, tuberculosis.
Numbers in table represent number of knowledge gaps or research questions (percentage of column total). Numbers per category may not add up to the total N knowledge
gaps or research questions, because they could be assigned to more than one category.
a
World Health Organization regions.
b
Includes Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.

Figure 1. Distribution of the extracted knowledge gaps (a) and thematic research questions (b) across the “knowledge matrix” as well as across all AMR-related areas (c).
Heatmaps showing the distribution of (a) extracted knowledge gaps (n = 2340) and (b) thematic research questions (n = 177) based on the “knowledge framework” by
people-centered themes (prevention, diagnosis, care, and treatment) and Child Health and Nutrition Research Initiative-domains (descriptive, delivery, development, and
discovery research). (c) Tornado plot showing the distribution of the 2340 knowledge gaps and 177 thematic research questions across the 14 areas related to AMR. Numbers
(%) per category may not add up to the total N (100%) knowledge gaps and research questions, because each knowledge gap and research question could be assigned to
more than one category.
Abbreviations: AMR, antimicrobial resistance; WASH, water, sanitation, and hygiene.

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M. tuberculosis and selected fungi (i.e., Aspergillus spp. and Can- come Trust [24], this Agenda is expected to catalyze investment
dida spp.), across all areas relevant to AMR, geographic regions, and scientific interest among the global scientific community, fun-
socio-economic contexts, and sub-populations. Overall, the increas- ders, and governments to address high-priority knowledge gaps to
ing number of AMR-related publications during recent years seems inform effective global, regional and national policies on AMR, par-
to reflect the increasing AMR burden as well as a growing recog- ticularly in LMICs, by 2030 [12]. Novel approaches that integrate
nition of AMR in the global health agenda. Although still lagging the WHO bacterial and fungal priority pathogens and resistant tu-
behind high-income settings, the number of publications address- berculosis are expected to stimulate shared political momentum,
ing AMR-related issues specifically relevant to LMICs has increased advocacy, funding frameworks, and cross-disciplinary research and
over time, especially those related to the WHO bacterial priority innovation.
pathogens and the selected fungi. The publication of the GAP on Several previous initiatives have attempted to list research gaps
AMR in 2015 [7] and the WHO bacterial priority pathogen list in related to AMR. In February 1999, the first WHO consultation iden-
2017 [13] may have provided an impetus to producing an improved tified research needs across the areas of prescriber behavior, pa-
evidence base as well as highlighting remaining research gaps, al- tient/public behavior, laws and regulations, pharmaceutical indus-
though their direct influence on the scale of research funding, as try (including promotional activities and R&D), pharmacological
well as the scope and impacts of ongoing and planned research and clinical issues, microbial genetics and ecology, detection and
programs, is difficult to ascertain. surveillance of AMR, and nonhuman use of antimicrobials [25]. The
The identified knowledge gaps on WHO bacterial priority GAP on AMR (2015) listed important knowledge gaps, including
pathogens and selected fungi mainly relate to the treatment and the epidemiology, development, and spread of AMR; the ability to
care and prevention of infections with drug-resistant pathogens, rapidly characterize and elucidate mechanisms of newly emerged
whereas significantly fewer knowledge gaps highlighted the need AMR; effective antimicrobial stewardship programs; optimal treat-
for further research on diagnostic tests and other tools for ments and prevention of common bacterial infections, especially
pathogen identification, AMR testing, and clinical decision-support in LMICs; development of new treatments, diagnostic tools, vac-
tools. This finding reflects the neglected importance of quality- cines, and other interventions; and the cost of AMR [7]. A recent
assured laboratory capacity and related innovations, especially in scoping review of the literature from 2015-2019, although some-
LMICs, where the lack of accessible, robust diagnostic processes what limited in its scope and methodology (e.g., did not include
results in poor patient outcomes, irrational antimicrobial use, and gray literature, tuberculosis, or fungi), highlighted the need for a
further emergence and spread of AMR. By contrast, we identified better understanding of the magnitude and transmission of AMR
a substantial number of knowledge gaps related to diagnostic tests across human, environmental, and agricultural reservoirs, interven-
and related tools for resistant tuberculosis, which can be explained tions to mitigate drug-resistant infections, particularly in LMICs,
by decades of significant financial support for tuberculosis pro- and research investigating awareness and behavior related to AMR
grams in LMICs (e.g., Global Fund). [26]. Further previous initiatives have focused on specific areas
Overall, the most frequently reported knowledge gaps con- in AMR, for example, interventions to reduce antibiotic prescrib-
cerned antimicrobial research and development, AMR burden and ing in LMICs [27]; prevention of AMR healthcare-associated infec-
drivers, resistant tuberculosis, and antimicrobial stewardship fol- tions [28]; government policy interventions to reduce human an-
lowed by diagnostics, IPC, antimicrobial consumption and use timicrobial use [29]; and the programmatic management of re-
data, immunization, sexually transmitted infections, AMR aware- sistant tuberculosis [30]. Our scoping review has considered all
ness and education. However, the following areas were found to be abovementioned publications in the knowledge gap identification
markedly less represented in the scoping results: WASH, foodborne process.
diseases, fungi, and policies and regulations. The paucity of knowl- Scoping reviews are an increasingly important method of
edge gaps on WASH and foodborne diseases could be explained by knowledge synthesis and were deemed the most suitable design
the fact that these areas lay at the interface of environmental, an- for our purpose. In doing so, we expanded the standard CHNRI ap-
imal, plant, and human sectors (“One Health”), which was outside proach, which is typically based on research ideas submitted by
the scope of this review (and will be covered by the complemen- invited experts [21,22]. Nonetheless, there are some study limi-
tary WHO One Health Priority Research Agenda for AMR [12]). Fun- tations. First, we cannot rule out the possibility that we missed
gal diseases remain a neglected topic by public health authorities any relevant knowledge gaps, and further expert consultations will
and research funders, despite the increasing incidence of fungal ensure that any omissions are identified and supplemented. Sec-
diseases in both LMICs and high-income countries [4,5]. To ensure ond, although the consolidation of extracted knowledge gaps into
that these underrepresented areas receive sufficient consideration thematic research questions was conducted through several itera-
at the prioritization stage, we deliberately augmented policies and tions with the core study team and WHO Core Steering Group on
regulations and fungi among the consolidated 177 higher-level the- AMR, there is a possibility that personal views and knowledge of
matic research questions. The consolidation process also ensured the investigators may have influenced the selection and phrasing
that delivery and development questions are also being considered, of the research questions. Lastly, this scoping review was restricted
which are particularly important to address current policy-practice to English language documents, which could have biased the
gaps and inform specific interventions to mitigate the impact of overall result to be more representative of high-income, English-
AMR. speaking countries. We have made a deliberate effort to account
Although our scoping review captured a significant breadth and for this bias by formulating research questions that targeted AMR
scope of knowledge gaps related to AMR, it is important to note issues specifically relevant to LMICs (representing 44% of the
that the frequency or “popularity” of certain knowledge gaps as total).
reported in the global literature was not necessarily a proxy for ar- In conclusion, our study is the most comprehensive compila-
eas of greatest research priority or impact. The current set of 177 tion of existing knowledge gaps and research questions related to
research questions will be scored and prioritized by a group of in- AMR in the human health sector to date. The results of this review
dependent experts in the field of AMR to develop the WHO Global will provide a framework to inform a priority-setting exercise, to-
Research Agenda for AMR in the human health sector in 2023. ward the development of a WHO Global AMR Research Agenda for
Supplementing existing research agendas from several key actors the human health sector, to catalyze evidence-based interventions
and funders in the area of AMR, for example, the European Com- and research investments with the highest impact to mitigate the
mission Joint Programming Initiative on AMR [23] and the Well- global burden of AMR by 2030.

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R.L. Hamers, Z. Dobreva, A. Cassini et al. International Journal of Infectious Diseases 134 (2023) 142–149

Funding Supplementary materials

This work is part of the project entitled “Global Research Supplementary material associated with this article can be
Agenda for Antimicrobial Resistance in the Human Health Sector” found, in the online version, at doi:10.1016/j.ijid.2023.06.004.
initiated and funded by the World Health Organization (WHO) An-
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