Resistencia Antibiotica A Nivel Global - Lancet 2022

Articles
Global burden of bacterial antimicrobial resistance in 2019:

a systematic analysis
Antimicrobial Resistance Collaborators*
Summary
Background Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous Published Online
publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for January 20, 2022
https://doi.org/10.1016/
specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most S0140-6736(21)02724-0
comprehensive estimates of AMR burden to date.
See Online/Comment
https://doi.org/10.1016/
Methods We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial S0140-6736(22)00087-3
AMR for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019. We obtained *Collaborators are listed at the
data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering end of the paper
471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to Correspondence to:
Dr Mohsen Naghavi, Institute for
produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be
Health Metrics and Evaluation,
divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths University of Washington,
attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given Seattle, WA 98195, USA
pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or nagham@uw.edu
duration of an infection associated with this resistance. Using these components, we estimated disease burden
based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-
resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an
alternative scenario in which all drug-resistant infections were replaced by no infection). We generated
95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws,
and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the
global and regional level.
Findings On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62–6·57) deaths
associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911–1·71) deaths attributable to bacterial
AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-
Saharan Africa, at 27·3 deaths per 100 000 (20·9–35·3), and lowest in Australasia, at 6·5 deaths (4·3–9·4) per 100 000.
Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making
it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance
(Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter
baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000–1 270 000) deaths attributable to AMR
and 3·57 million (2·62–4·78) deaths associated with AMR in 2019. One pathogen–drug combination, meticillin-
resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused
50 000–100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation
cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistant E coli, carbapenem-
resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae.
Interpretation To our knowledge, this study provides the first comprehensive assessment of the global burden of
AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the
highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen–drug
combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly
about infection prevention and control programmes, access to essential antibiotics, and research and development of
new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to
expand microbiology laboratory capacity and data collection systems to improve our understanding of this important
human health threat.
Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid
funding managed by the Fleming Fund.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY
4.0 license.
www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 1

Articles
Research in context
Evidence before this study disease incidence, prevalence, and mortality from the Global
To identify previous estimates of antimicrobial resistance Burden of Diseases, Injuries, and Risk Factors Study 2019, our
(AMR) burden before this study, we did a systematic review and findings on the burden of bacterial AMR can be compared with
consulted with content experts. We searched the evidence other causes of death, offering crucial context on the
available in PubMed for published works that evaluate exposure magnitude of the burden of this important health issue.
to antimicrobial resistant organisms (bacteria only) and Improvements to the input data and models compared with
evaluated all human-focused publications with more than ten previous publications make our AMR estimates the most robust
cases, all genders, and all age groups. From these findings, we of any to date. Finally, this study is the first to quantify the
extracted study type, pathogen–drug combinations, burden of AMR using two different AMR counterfactual
counterfactuals, locations, methods, outcomes, and scenarios.
population. Extensive literature exists estimating incidence,
Implications of all the available evidence
deaths, hospital length of stay, and health-care costs associated
Our estimates indicate that bacterial AMR is a health problem
with AMR from a small number of drug-resistant infections in
whose magnitude is at least as large as major diseases such as
select locations. There is widespread agreement that AMR poses
HIV and malaria, and potentially much larger. Bacterial AMR is a
a serious potential threat to human health around the world.
problem in all regions; we estimated that, in 2019, the highest
The Review on Antimicrobial Resistance, published in 2016,
rates of AMR burden were in sub-Saharan Africa. Six pathogens
estimated that as many as 10 million people could die annually
accounted for 73·4% (95% uncertainty interval 66·9–78·8) of
from AMR by 2050. Recent estimates of the burden of drug-
deaths attributable to bacterial AMR. Seven pathogen–drug
resistant infections covering several pathogens have also been
combinations each caused more than 50 000 deaths,
published for the USA, Thailand, the EU and European
highlighting the importance of developing policies that
Economic Area, and several other locations, as well as estimates
specifically target the deadliest pathogen–drug combinations,
for several pathogen–drug combinations for a wider range of
particularly through expansion of infection prevention and
locations. To our knowledge, however, there have been no
control programmes, improving access to essential second-line
comprehensive estimates covering all locations and a broad
antibiotics where needed, and through vaccine and antibiotic
range of pathogens and pathogen–drug combinations.
development. Additionally, our comprehensive data collection
Added value of this study effort shows that high-quality data on infectious disease,
This study is the most comprehensive analysis of the burden of pathogens, and AMR are only sparsely available in many
AMR to date, producing estimates for 204 countries and low-income settings. Both preventing bacterial AMR and
territories, 23 bacterial pathogens, and 88 pathogen–drug increasing microbiological laboratory and data collection
combinations, in 2019. This study uses major methodological capacity to improve scientific understanding of this health
innovations to provide important new insights into the AMR threat should be a very high priority for global health policy
burden. Additionally, since this analysis builds on estimates of makers.
Introduction where surveillance is minimal and data are sparse.

Bacterial antimicrobial resistance (AMR)—which occurs Extensive literature exists estimating the effects of AMR
when changes in bacteria cause the drugs used to treat on incidence, deaths, hospital length of stay, and health-
infections to become less effective—has emerged as one care costs for select pathogen–drug combinations in
of the leading public health threats of the 21st century. specific locations,1,2,6,9–12 but, to our knowledge, no
The Review on Antimicrobial Resistance, commissioned comprehensive estimates covering all locations and
by the UK Government, argued that AMR could kill a broad range of pathogens and pathogen–drug
10 million people per year by 2050.1,2 Although these combinations have ever been published. For instance, the
forecasts have been criticised by some,3,4 WHO and US Centers for Disease Control and Prevention (CDC)
numerous other groups and researchers agree that the published a 2019 report on AMR infections and deaths in
spread of AMR is an urgent issue requiring a global, the USA for 18 AMR threats using surveillance data,6
coordinated action plan to address.5–8 Information about while Cassini and colleagues10 estimated the burden of
the current magnitude of the burden of bacterial AMR, eight bacterial pathogens and 16 pathogen–drug
trends in different parts of the world, and the leading combinations in the EU and European Economic Area
pathogen–drug combinations contributing to bacterial for 2007–15. Likewise, Lim and colleagues estimated the
AMR burden is crucial. If left unchecked, the spread of burden of multidrug resistance in six bacterial pathogens
AMR could make many bacterial pathogens much more in Thailand in 2010,11 and Temkin and colleagues
lethal in the future than they are today. estimated the incidence of Escherichia coli and Klebsiella
One major challenge to tackling AMR is understanding pneumoniae resistant to third-generation cephalosporins
the true burden of resistance, particularly in locations and carbapenems in 193 countries in 2014.12
2 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

Articles
Although these publications are important contribu For the first counterfactual scenario—where all drug-
tions to the body of work on AMR, they are insufficient to resistant infections are replaced by susceptible infections—
understand the global burden of AMR and identify and we estimated only deaths and DALYs directly attributable
target the highest priority pathogens in different to resistance. For the second counterfactual scenario—
locations. Additionally, existing studies have generally where all drug-resistant infections are replaced by no
considered only one measure of AMR burden.13 Because infection—we estimated all deaths and DALYs associated
we do not know the extent to which drug-resistant with resistant infection. Estimates of AMR burden based
infections would be replaced by susceptible infections or on each counterfactual are useful in different ways for
by no infection in a scenario in which all drug resistance informing the development of potential intervention
was eliminated, it is important to quantify the burden on strategies to control AMR.13,17,18
the basis of both these counterfactual scenarios.
In this study, we present the first global estimates of Input data
the burden of bacterial AMR covering an extensive set of We used several data collection strategies. Through our
pathogens and pathogen–drug combinations using large collaborator networks, we obtained datasets not
consistent methods for both counterfactual scenarios. previously available for AMR research, including hospital
and laboratory data, as well as datasets published previously
Methods and those outlined in research articles.19 Each component
Overview of the estimation process had different data requirements
We developed an approach for estimating the burden of and, as such, the input data used for each modelling
AMR that makes use of all available data and builds on component differed. The diverse data sought included the
death and incidence estimates for different underlying following sources: pharmaceutical companies that run
conditions from the Global Burden of Diseases, Injuries, surveillance networks, diagnostic laboratories, and clinical
and Risk Factors Study (GBD) 2019, which provides trial data; high-quality data from researchers including
age-specific and sex-specific estimates of disease burden large multisite research collaborations, smaller studies,
for 369 diseases and injuries in 204 countries and clinical trials, and well established research institutes
territories in 1990–2019.14 Our approach can be divided based in low-income and middle-income countries
into ten estimation steps that occur within five broad (LMICs); data from public and private hospitals and public
modelling components (a flowchart of the estimation health institutes providing diagnostic testing; global
steps is given in the appendix p 123). First, we obtained surveillance networks; enhanced surveillance systems; See Online for appendix
data from multiple data sources, including from national surveillance systems; and surveillance systems for
published studies (eg, microbiology data, inpatient data, specific organisms such as Mycobacterium tuberculosis and
data on multiple causes of death, and pharmaceutical Neisseria gonorrhoeae (all sources are listed by data type in
sales data) and directly from collaborators on the Global the appendix pp 8–15).
Research on Antimicrobial Resistance project,15 members Figure 1 shows a summary of the distinct data types
of the GBD Collaborator Network, and other data gathered and for which estimation step each data type
providers. was used. Also shown in figure 1 is the number of unique
We estimated the disease burdens associated with and study-location-years and individual records or isolates
attributable to AMR for 12 major infectious syndromes available for each data type. Location-years of data refer
(lower respiratory infections and all related infections in to unique GBD locations and years for which we have
the thorax; bloodstream infections; peritoneal and intra- records or isolates. In total, 471 million individual records
abdominal infections; meningitis and other bacterial or isolates covering 7585 study-location-years were used
CNS infections; typhoid, paratyphoid, and invasive non- as input data to the estimation process. Table 1 shows the
typhoidal Salmonella spp; urinary tract infections and number of individual records or isolates used and
pyelonephritis; diarrhoea; tuberculosis [not including number of countries covered in each of the five broad
tuberculosis associated with HIV]; bacterial infections of modelling components separately by GBD region. Two of
the skin and subcutaneous systems; endocarditis and five components included data from every GBD region
other cardiac infections; infections of bones, joints, and two of five included data from 19 of 21 GBD regions.
and related organs; and gonorrhoea and chlamydia) and Our models of sepsis and infectious syndrome were the
one residual category, 23 bacterial pathogens, 18 drug most geographically sparse, covering 16 countries from
categories or combinations of drugs for which there ten regions; the input data for these models were highly
is resistance, and 88 pathogen–drug combinations detailed microdata that are only sparsely available.
(appendix pp 45–46). We modelled all-age and age-specific However, our framework for estimating the total
deaths and disability-adjusted life-years (DALYs) for envelope of infectious syndrome mortality used GBD
204 countries and territories, and we present aggregated cause-specific mortality estimates to minimise reliance
estimates for 21 GBD regions, seven GBD super-regions, on these sparse data.
and globally in 2019 (a full list of GBD locations by region All data inputs for the models were empirical data, not
is available in the appendix pp 100–05).16 modelled estimates, except for a custom meta-analysis of

Articles
Source type Number Sample size Sample Estimation step

of size units
study- 1: 2: 3: 4: 5: 6: 7: 8: 9:
location- sepsis infectious case- pathogen antibiotic prevalence resistance relative relative
years syndrome fatality distribution use of profiles risk of length
ratio resistance death of stay
Multiple cause
2980 120 871 372 Deaths
of death
Hospital
391 192 533 415 Discharges
discharge
Microbial or
laboratory data 1102 3 060 802 Isolates
with outcome
Microbial or
laboratory data 2302 145 067 113 Isolates
without
outcome
Cases,
Literature isolates, or
607 701 356
studies pathogen–
drug
susceptibility
tests
Pathogen–
Single drug
drug
resistance 158 8 648 390
susceptibility
profiles
tests
Study-
Pharmaceutical
1536 1536 country-
sales
years
Antibiotic use
among children
Households
younger than 203 151 455
surveyed
5 years with
reported illness
Mortality
surveillance
(minimally
invasive tissue 7 870 Deaths
sampling from
Child Health
and Mortality
Prevention
Surveillance)
Linkage
38 264 010 Deaths
(mortality only)
Grand total 9324 471 300 319
Figure 1: Data inputs by source type

Total sample size for each source type, regardless of specific inclusion criteria for a given estimation step. Individual isolates that were tested multiple times for
resistance to different antibiotics are listed only once here whenever isolates were identified uniquely in the data. For datasets where isolates could not be uniquely
identified across pathogen–drug combinations, such as some antimicrobial resistance surveillance systems, some isolates might be double counted. Yellow boxes
indicate that the source type was used in that estimation step. A full list of data sources included in this study, organised by data type, is included in the appendix
(pp 8–15).
vaccine probe data that we did to estimate the fraction appendix (pp 17–18, 31, 34–35, 44, 54). Data input citations
For the data input citations see of pneumonia caused by Streptococcus pneumoniae are available online.
http://ghdx.healthdata.org/ (appendix pp 37–38). All study-level covariates for
record/ihme-data/global-
models, such as age and sex, were extracted from Estimation steps one and two: deaths in which
bacterial-antimicrobial-
resistance-burden- empirical data. All country-level covariates were modelled infection played a role by infectious syndrome
estimates-2019 estimates that were produced previously for GBD 2019,20,21 First, to define the number of deaths where infection
or those that were modelled by Browne and colleagues.22 plays a role, we used GBD 2019 cause of death estimates14
We describe data inputs for each of ten estimation steps to determine the number of deaths by age, sex, and
in greater detail in the following subsections and in the location for which either the underlying cause of death

Articles
Component Fraction of Component Fraction of Component Fraction of Component Fraction of Component Fraction of
1: sepsis and countries 2: case- countries 3: pathogen countries 4: fraction of countries 5: relative countries
infectious represented in fatality ratio represented in distribution represented in resistance† represented in risk represented in
syndrome component 1 component 2 component 3 component 4 component 5
models*
Andean Latin America 0 0/3 1784 2/3 12 010 2/3 538 644 3/3 4338 2/3
Australasia 320 909 1/2 94 818 1/2 6 294 677 2/2 4 653 832 2/2 5211 2/2
Caribbean 0 0/19 2858 5/19 6225 5/19 68 078 10/19 529 1/19
Central Asia 0 0/9 43 852 2/9 2785 1/9 304 341 9/9 6065 1/9
Central Europe 0 0/13 371 112 10/13 627 844 11/13 3 148 864 13/13 397 885 10/13
Central Latin America 8 130 066 2/9 3 932 601 9/9 11 641 626 8/9 829 686 9/9 20 210 5/9
Central sub-Saharan Africa 0 0/6 0 0/6 770 2/6 40 243 6/6 0 0/6
East Asia 1 189 309 1/3 385 443 2/3 257 522 2/3 2 501 536 3/3 185 980 2/3
Eastern Europe 0 0/7 118 754 4/7 64 212 5/7 968 565 7/7 102 904 4/7
Eastern sub-Saharan 292 3/15 6388 4/15 68 791 9/15 474 280 14/15 3436 2/15
Africa
High-income Asia Pacific 0 0/4 135 907 3/4 99 042 3/4 18 909 332 4/4 7577 3/4
High-income North 84 520 574 2/3 7 184 424 3/3 7 255 147 2/3 32 205 001 3/3 14 071 025 2/3
America
North Africa and Middle 0 0/21 209 479 13/21 53 833 16/21 531 120 21/21 90 079 10/21
East
Oceania 0 0/18 0 0/18 20 1/18 4297 12/18 0 0/18
South Asia 54 1/5 77 811 4/5 51 810 4/5 1 413 840 5/5 97 131 4/5
Southeast Asia 0 0/13 195 087 9/13 91 259 8/13 3 128 014 12/13 172 947 8/13
Southern Latin America 0 0/3 200 665 3/3 73 512 2/3 740 385 3/3 5000 1/3
Southern sub-Saharan 4 696 789 1/6 80 717 2/6 4 699 304 2/6 910 509 6/6 1051 1/6
Africa
Tropical Latin America 17 224 511 1/2 3 988 611 1/2 20 956 932 2/2 286 450 2/2 6443 1/2
Western Europe 10 599 906 2/24 94 506 554 20/24 105 183 184 21/24 18 909 732 21/24 932 016 21/24
Western sub-Saharan 83 2/19 26 985 9/19 21 896 10/19 369 482 18/19 14 880 2/19
Africa
Total sample size and fraction of countries covered for each modelling component by GBD region. The units for sample size are deaths for sepsis and infectious syndrome models; cases for case-fatality ratios; cases,
deaths, or isolates for pathogen distribution; pathogen–drug tests for fraction of resistance; and pathogen–drug tests for relative risk. Sample sizes reflect model-specific selection criteria, resulting in lower totals for
the sepsis, infectious syndrome, case-fatality ratio, and pathogen distribution models in this table than those in figure 1. Totals for fraction of resistance and relative risk are higher in this table than in figure 1 because
of the difference in units for certain source types, such as microbial data (isolates in figure 1, pathogen–drug tests here). Several data sources inform multiple components; therefore, data points should not be
summed across a row as that will lead to duplication. More information on the data types used and the components that they inform is presented in the appendix (pp 8–15). GBD=Global Burden of Diseases, Injuries,
and Risk Factors Study. *The data points listed in the sepsis and infectious syndrome models include only sources used to determine the fraction of sepsis in non-communicable diseases; maternal, neonatal, and
nutritional diseases; and injuries, as well as the distribution of infectious syndromes; final estimates of the number of deaths in each infectious syndrome were generated by multiplying the fractions of sepsis and
infection syndromes on GBD 2019 death estimates; GBD 2019 death estimates include 7417 sources with 28 106 location-years of data for under-5 mortality and 7355 sources with over 7322 location-years of data.
†For sources in the fraction of resistance modelling component, de-duplication across antibiotic resistance tests was not possible, leading to potential double counting, as seen in the high-income Asia Pacific region.
Table 1: Data included in each modelling component by region and the fraction of countries represented in each region
was infectious or—for non-communicable, maternal, logistic regression models to predict the fraction of
neonatal, nutritional, and injury deaths—for which the sepsis occurring in each communicable, maternal,
pathway to death was through sepsis. Sepsis is defined as neonatal, and nutritional underlying cause of death;
a life-threatening organ dysfunction due to a dysregulated non-communicable underlying cause of death; and
host response to infection.23 The methods used to injury underlying cause of death. This approach follows
estimate infectious underlying causes of death and sepsis the methods validated by many researchers in sepsis
deaths have been published previously14,24 and are epidemiology25–28 and used by Rudd and colleagues.24
summarised in the appendix (pp 17–18). We then multiplied the fraction of sepsis predicted
In estimation step one, we used data for multiple from the logistic regression models onto GBD cause-
causes of death covering 121 million deaths, 5·54 million specific mortality estimates to determine the mortality
hospital discharges with discharge status of death, and envelope for our analysis. Our mortality envelope
264 000 records of multiple causes of death linked to consisted of all deaths in which infection played a
hospital records from ten countries and territories, as role, which included all sepsis deaths with non-
well as 870 deaths from Child Health and Mortality infectious underlying causes, plus all deaths with an
Prevention Surveillance (CHAMPS) sites across six infectious underlying cause in GBD 2019 (appendix
countries (appendix pp 17–18), to develop random effects pp 21–23).

Articles
In estimation step two, we used details on the Estimation steps three and four: pathogen distribution
pathways of disease provided in multiple causes of for deaths and incident cases
death and hospital discharge data in a second stage of To estimate the pathogen distribution of each infectious
random effects logistic regression models to further syndrome separately for deaths and incident cases for
subdivide deaths in which infection played a role into each age, sex, and location, we made use of multiple data
12 major infectious syndromes and one residual sources. For estimation step three, we took data that
category. These regressions predicted the proportion of linked pathogen-specific disease incidence to deaths to
sepsis-related deaths that were caused by a given develop models for pathogen-specific CFRs that varied
infectious syndrome separately for each communicable, by age, location, and syndrome. We used the Bayesian
maternal, neonatal, and nutritional underlying cause of meta-regression tool MR-BRT29 to estimate CFRs as a
death; non-communicable underlying cause of death; function of the Healthcare Access and Quality Index and
and injury underlying cause of death. We used this various bias covariates (appendix pp 31–34).21 These
fraction to subdivide sepsis deaths with non-infectious CFRs allowed us to integrate sources that reported
underlying causes into specific infectious syndromes. pathogen distribution only for deaths and those that
For underlying causes of death that are themselves reported only incidence by mapping the reported deaths
infectious, all deaths were assigned to their single by pathogen into implied cases by pathogen. After
corresponding infectious syndrome (eg, the GBD cause mapping, we had 157 million isolates and cases from
“lower respiratory infections” was assigned to the 118 countries and territories to estimate the pathogen
infectious syndrome “lower respiratory infections and distribution of each infectious syndrome (estimation
all related infections in the thorax”; appendix pp 21–23). step four), with each dataset including a unique
Due to the pathogen distributions varying substantially spectrum of pathogens and groups of pathogens. To
for hospital-acquired and community-acquired infections incorporate all these heterogeneous data, we used a new
in two infectious syndromes—lower respiratory and modelling environment, termed multinomial estimation
thorax infections and urinary tract infections—we with partial and composite observations. This modelling
further estimated the subdivision of these syndromes environment allows for the inclusion of covariates in the
into community-acquired and hospital-acquired network analysis29 and for Bayesian prior probability
infections (appendix pp 17–30; table with community- distributions to be incorporated. To model the infectious
acquired and hospital-acquired subdivisions presented syndrome pathogen distribution comprehensively, we
on pp 24–25). estimated, where applicable, the incidence and death
proportions attributable to viral, fungal, parasitic, and
Incidence of infectious syndromes disaggregated by bacterial pathogens; however, AMR burden was
age, sex, and location calculated only for selected bacteria for which resistance
For the nine infectious syndromes in this study that were is clinically relevant and sufficient data are available.
estimated as one or more causes of death and disability More details on this approach are provided in the
in GBD 2019 (lower respiratory and thorax infections; appendix (pp 34–44).
CNS infections; typhoid, paratyphoid, and invasive non-
typhoidal Salmonella spp; urinary tract infections; Estimation steps five to seven: prevalence of resistance
diarrhoea; tuberculosis; bacterial skin infections; cardiac by pathogen
infections; and gonorrhoea and chlamydia), we used We used data from 52·8 million isolates to analyse the
GBD 2019 incidence estimates as a baseline for infectious proportion of phenotypic AMR for each pathogen—the
syndrome incidence (appendix p 16).14 To this baseline, proportion of infections that were drug resistant, hereafter
we added the number of incident cases of each infectious referred to as prevalence of resistance—for 88 pathogen–
syndrome that co-occurred with underlying non- drug combinations. We chose these 88 combinations by
communicable diseases (NCDs); maternal, neonatal, and first creating an exhaustive list of all clinically relevant
nutritional diseases (MNNDs); and injuries, which we combinations for which we had any data and then
calculated by dividing the number of infectious syndrome eliminating combinations that did not meet minimum
deaths that occurred with underlying NCDs, MNNDs, data availability and computational feasibility requirements
and injuries (by age, sex, location, and GBD cause) by for accurate statistical modelling (appendix pp 59–60).
syndrome-specific and pathogen-specific case-fatality For the pathogen–drug combinations in the 2014 WHO
ratios (CFRs; estimation described in the following AMR global report on surveillance,30 as well as
subsection). Bloodstream infections, bone and joint fluoroquinolone and multidrug resistance in Salmonella
infections, and intra-abdominal infections are not enterica serotypes Typhi and Paratyphi, we supplemented
estimated in GBD, so for these infectious syndromes, we microbial datasets from collaborators and surveillance
exclusively used the number of incident cases of each networks with aggregate microbiology data from sys
infectious syndrome that co-occurred with underlying tematic reviews and published surveillance reports. The
NCDs, MNNDs, and injuries to estimate incidence number of positive isolates identified for each pathogen–
(appendix pp 56–60). drug combination is shown in the appendix (pp 90–91).

Articles
Clinical and Laboratory Standard Institute (CLSI) binomial distributions that define the prevalence of
guidelines were used to define minimum inhibitory resistance of every combination of resistance to the
concentration breakpoints when these minimums were antibiotics analysed. Every such distribution was
provided. When only a phenotypic disk interpretation was characterised by a contingency table specifying
available, we used the interpretation as provided. We probabilities of all combinations of resistance and
used two categories of susceptibility: susceptible and susceptibility among the antibiotics analysed. The
non-susceptible. The non-susceptible group includes observed prevalence of each drug overall and Pearson
isolates reported as “non-susceptible”, “intermediate”, and correlations between drugs provided noisy partial
“resistant”. To account for bias in resistance data provided observations of combinations of these entries. We
by tertiary care facilities, we adjusted tertiary rates of optimised over the space of such contingency tables to
resistance by crosswalking them to data from non-tertiary find the nearest feasible distribution given the data,
and mixed facilities using MR-BRT as described in the producing, for each pathogen, a set of resistance
appendix (pp 45–48).31 profiles: the proportions of bacteria with each com
We used a two-stage spatiotemporal modelling bination of resistance and susceptibility among all the
framework to estimate the prevalence of resistance in antibiotics analysed (appendix pp 48–49).
each pathogen–drug combination by location for 2018.
Given the many challenges to data collection and Estimation steps eight and nine: relative risk of death
reporting caused by the COVID-19 pandemic,32,33 as well for drug-resistant infection compared with drug-
as our collaborators’ process of data collation and sensitive infections
cleaning, we were unable to collect more contemporary Using data from 164 sources representing 511 870 patients
data; we assumed no change in prevalence of resistance with known outcome and resistance information, we
for 2019. First, we fitted a stacked ensemble model estimated the relative risk of death for each pathogen–
between the input data and selected covariates from the drug combination for a resistant infection compared
list of plausible and health-related covariates available in with that of a drug-sensitive infection using MR-BRT.
GBD 2019 (appendix pp 48–49, 92–93); the estimates Because of data sparsity, we assumed the relative risk
from the stacked ensemble model were then inputted was the same for every syndrome, location, and age
into a spatiotemporal Gaussian process regression group; the assumptions on location and age group risk
model31 to smooth the estimates in space and time. The are consistent with those in the estimation process
exceptions to this modelling approach were multidrug- previously used by Cassini and colleagues.10 We used a
resistant (MDR) excluding extensively drug-resistant two-stage nested mixed effects meta-regression model to
(XDR) tuberculosis and XDR tuberculosis, for which estimate relative risk of death for each pathogen–drug
published GBD 2019 estimates were already available.14 combination that was adjusted for age, admission
Given the strong relationship between antibiotic diagnosis, hospital-acquired versus community-acquired
consumption levels and the proliferation of resistance, infection, and site of infection (appendix pp 54–56). For
we modelled antibiotic consumption at the national the non-fatal excess risk, we estimated the relative
level to use as a covariate in the stacked ensemble increase in length of stay associated with a resistant
model of prevalence of resistance. We analysed data infection compared with that of a drug-sensitive
from 65 Demographic and Health Surveys and infection, adjusted for length of stay prior to culture
138 Multiple Indicator Cluster Surveys using model- being drawn. Data on length of stay were available from
based geostatistics to quantify antibiotic usage in 59 sources representing 455 906 admissions. We used
LMICs. These LMIC-specific estimates of antibiotic the same modelling framework for excess length of stay
usage were combined with pharmaceutical sales data as we used for relative risk of death. Due to data sparsity
from IQVIA, WHO, and the European Centre for on the excess risk of death associated with drug-resistant
Disease Prevention and Control (ECDC) by use of an N gonorrhoeae, we did not produce a fatal estimate for
ensemble spatiotemporal Gaussian process regression this pathogen.
model to produce a location-year covariate on antibiotic To produce burden estimates of multiple pathogen–
consumption for all 204 countries and territories drug combinations that were mutually exclusive within
included in this study.22 Additional details on our a given pathogen (and thus could be added), we
estimation method for prevalence of resistance are produced a population-attributable fraction (PAF) for
available in the appendix (pp 44–53). each resistance profile with resistance to at least one
To account for multidrug resistance, we used line- drug (appendix pp 56–60). The PAF represents the
level microbiology data that tested multiple antibiotics proportional reduction in deaths or years lived with
for the same isolate to produce Pearson correlation disability (YLDs) that would occur if all infections
coefficients of the co-occurrence of resistance to with the resistance profile of interest were instead
different antibiotics. With these Pearson correlations susceptible to all antibiotics included in the analysis.
and our prevalence of resistance estimates, we used an When two or more antibiotics were resistant in a single
optimisation-based approach to solve for multivariate profile, we used the relative risk for the antibiotic class

Articles
that was the largest as the relative risk for calculating infection and the burden associated with bacterial AMR
the PAF: based on the counterfactual of no infection (appendix
pp 56–60). Briefly, to estimate the burden attributable to
RKd(RRKD–1) AMR, we first calculated the deaths attributable to
PAF= resistance by taking the product of deaths for each
1+Σd=1
n
RKd (RR KD –1)
underlying cause, the proportion of these deaths in
which infection played a role, the proportion of infectious
Where R is prevalence of resistance, RR is relative risk, K deaths attributable to each infectious syndrome, the
is a pathogen with d=1, …, n resistance profiles with proportion of infectious syndrome deaths attributable to
resistance to at least one antibiotic class, and D is the each pathogen, and the mortality PAF for each resistance
antibiotic class in profile d with the highest relative risk profile. We used previously described GBD methods14 to
(appendix pp 56–60). convert age-specific deaths into years of life lost (YLLs)
using the standard counterfactual life expectancy at each
Estimation step ten: computing burden attributable to age.34 To calculate attributable YLDs, we took the product
drug resistance and burden associated with drug- of the infectious syndrome incidence, the proportion of
resistant infections infectious syndrome incident cases attributable to each
We computed two counterfactuals to estimate the drug- pathogen, YLDs per incident case, and the non-fatal PAF.
resistant burden: the burden attributable to bacterial For resistance profiles that had resistance to more than
AMR based on the counterfactual of drug-sensitive one antibiotic class, we redistributed burden to the
Associated with resistance Attributable to resistance

Deaths YLLs DALYs YLDs Deaths YLLs DALYs YLDs
Counts, thousands
Global 4950 189 000 192 000 2290 1270 47 600 47 900 275
(3620–6570) (145 000–245 000) (146 000–248 000) (1520–3450) (911–1710) (35 000–63 400) (35 300–63 700) (161–439)
Central Europe, eastern 283 7530 7630 102 73·7 1980 1990 9·95
Europe, and central Asia (190–403) (5240–10 500) (5320–10 600) (69–140) (48·7–105) (1350–2790) (1360–2800) (4·79–16·8)
High income 604 10 100 10 300 123 141 2390 2410 20·2
(434–824) (6960–14 200) (7040–14 400) (79·7–183) (98·6–197) (1620–3400) (1640–3420) (12·7–31·2)
Latin America and Caribbean 338 9550 9640 97·2 84·3 2370 2380 16
(243–453) (6770–12 900) (6830–13 100) (63·2–146) (60·3–117) (1660–3310) (1680–3330) (9·79–24·9)
North Africa and Middle East 256 9970 10 100 116 68·3 2590 2610 20·7
(174–362) (6880–13 900) (6970–14 000) (73·4–176) (45·6–99) (1770–3700) (1790–3720) (12–33·5)
South Asia 1390 58 900 59 900 1000 389 16 000 16 100 111
(1030–1830) (44 800–76 300) (45 700–77 500) (638–1550) (273–538) (11 500–21 600) (11 600–21 700) (58·5–188)
Southeast Asia, east Asia, 1020 27 500 27 900 437 254 6830 6870 45·6
and Oceania (678–1460) (18 700–38 600) (19 100–39 100) (256–776) (167–369) (4620–9840) (4670–9890) (25–80·1)
Sub-Saharan Africa 1070 65 800 66 200 416 255 15 400 15 500 51·1
(847–1340) (51 400–83 600) (51 800–84 000) (270–599) (196–331) (11 700–19 900) (11 800–20 000) (30·2–81·8)
Rates, per 100 000
Global 64·0 2448·1 2477·7 29·6 16·4 615·1 618·7 3·6
(46·8–84·9) (1868·9–3170·3) (1889·9–3199·1) (19·7–44·5) (11·8–22·0) (452·4–819·1) (455·7–823·2) (2·1–5·7)
Central Europe, eastern 67·7 1802·5 1826·9 24·4 17·6 474·3 476·7 2·4
Europe, and central Asia (45·4–96·6) (1253·9–2515·1) (1274·5–2545·4) (16·5–33·6) (11·7–25·3) (323·0–667·3) (325·2–671·0) (1·1–4·0)
High income 55·7 935·3 946·7 11·3 13·0 220·4 222·3 1·9
(40·1–76·0) (641·9–1310·1) (649·8–1327·2) (7·3–16·9) (9·1–18·2) (149·9–314·0) (151·5–315·9) (1·2–2·9)
Latin America and Caribbean 57·9 1633·8 1650·5 16·6 14·4 405·3 408·1 2·7
(41·6–77·6) (1158·7–2215·9) (1169·0–2236·6) (10·8–25·0) (10·3–20·0) (284·8–566·6) (286·9–570·0) (1·7–4·3)
North Africa and Middle East 42·0 1637·5 1656·6 19·1 11·2 425·6 429·0 3·4
(28·7–59·5) (1130·4–2283·2) (1145·2–2300·9) (12·1–28·9) (7·5–16·3) (291·2–608·4) (293·7–611·5) (2·0–5·5)
South Asia 76·8 3262·6 3318·1 55·4 21·5 885·8 892·0 6·2
(57·2–101·2) (2482·4–4228·2) (2532·9–4291·7) (35·4–86·0) (15·1–29·8) (636·3–1194·6) (643·1–1200·2) (3·2–10·4)
Southeast Asia, east Asia, and 47·1 1272·6 1292·8 20·2 11·7 316·1 318·2 2·1
Oceania (31·4–67·7) (866·8–1789·0) (884·7–1811·4) (11·8–35·9) (7·8–17·1) (213·9–455·7) (216·1–458·0) (1·2–3·7)
Sub-Saharan Africa 98·9 6105·3 6143·9 38·6 23·7 1432·0 1436·7 4·7
(78·6–124·2) (4770·2–7749·1) (4802·8–7792·2) (25·1–55·6) (18·2–30·7) (1084·6–1848·1) (1090·0–1853·5) (2·8–7·6)
DALYs=disability-adjusted life-years. GBD=Global Burden of Diseases, Injuries, and Risk Factors Study. YLDs=years lived with disability. YLLs=years of life lost.
Table 2: Deaths, YLLs, YLDs, and DALYs (in counts and all-age rates) associated with and attributable to bacterial antimicrobial resistance, globally and by GBD super-region, 2019

Articles
individual antibiotic classes proportionally on the basis globally in 2019 (including those directly attributable to
of excess risk, providing a mutually exclusive burden for AMR). Table 2 provides estimates of deaths, YLLs, and
each pathogen–drug combination (appendix pp 56–60). DALYs from AMR for each counterfactual.
To calculate DALYs, we took the sum of YLLs and YLDs. We estimated that among the 21 GBD regions,
To estimate the overall AMR burden of the drug-sensitive Australasia had the lowest AMR burden in 2019, with
counterfactual, we added the burden estimates of all the 6·5 deaths per 100 000 (95% UI 4·3–9·4) attributable to
pathogen–drug combinations. AMR and 28·0 deaths per 100 000 (18·8–39·9) associated
The approach for calculating the fatal burden with AMR in 2019 (figure 2). Western sub-Saharan Africa
associated with AMR was identical to that for fatal had the highest burden, with 27·3 deaths per
burden attributable to AMR, except we replaced the 100 000 (20·9–35·3) attributable to AMR and 114·8 deaths
mortality PAF for each resistance profile with the per 100 000 (90·4–145·3) associated with AMR. Five
prevalence of resistance in deaths. For the number of regions had all-age death rates associated with bacterial
incident infections associated with resistance, we took AMR higher than 75 per 100 000: all four regions of
the product of infectious syndrome incidence, the sub-Saharan Africa and south Asia. Although
proportion of infectious incident cases attributable to sub-Saharan Africa had the highest all-age death rate
each pathogen, and the prevalence of resistance in attributable to and associated with AMR, the percentage
incident cases. On the basis of these death and incidence of all infectious deaths attributable to AMR was lowest in
estimates, we then computed YLLs, YLDs, and DALYs this super-region (appendix p 97).
associated with drug-resistant infections. We calculated Three infectious syndromes dominated the global
YLLs using the same methods used to calculate YLLs burdens attributable to and associated with AMR in 2019:
attributable to AMR. We converted incidence into YLDs lower respiratory and thorax infections, bloodstream
using a YLDs per incident case ratio for each infectious infections, and intra-abdominal infections (figure 3).
syndrome based on a proxy GBD cause (a simplified Combined, these three syndromes accounted for 78·8%
YLD calculation compared with the standard sequelae- (95% UI 70·8–85·2) of deaths attributable to AMR
based method; appendix pp 56–60). Finally, we calculated in 2019; lower respiratory infections alone accounted for
DALYs by summing YLLs and YLDs. To estimate the more than 400 000 attributable deaths and 1·5 million
overall AMR burden of this counterfactual, we repeated associated deaths (figure 3).
the described calculations with the prevalence of
resistance to one or more antibiotics estimated and
GBD super-region Resistance
summed across all pathogens. Central Europe, eastern Europe, and central Asia Associated with resistance
150 High income Attributable to resistance
Latin America and Caribbean
Uncertainty analysis and out-of-sample validation North Africa and Middle East
Following previously described GBD methods,14 we South Asia
propagated uncertainty from each step of the analysis into Southeast Asia, east Asia, and Oceania
Sub-Saharan Africa
the final estimates of deaths and infections attributable to
Deaths (rate per 100000 population)
and associated with drug resistance by taking the 25th and 100
975th of 1000 draws from the posterior distribution of each
quantity of interest. Out-of-sample validity estimates are
provided in the appendix for our models of sepsis
(pp 25–30), infectious syndrome distribution (pp 25–30),
pathogen distribution (pp 43–44), prevalence of resistance
(pp 51–53), and relative risk (pp 55–56). 50
Role of the funding source

The funders of the study had no role in study design,
data collection, data analysis, data interpretation, or the
writing of the report. 0
rn -Sa n a
Sa n a
ra rica
ut as uth ca
La Eu a
Am pe
m Oc ica
Ce sia P nia
Tr n L ar ope
l L Am n
So Am ica
as a
co es tra ia
Ce e No rn E sia
l L Am e
Am ca
nd Eas ica
id sia
str st
sia
lE c
ra ifi
he b ara ric
b- ra ric
rn rn si
he ric
ra h op
ica in bea
-in W Cen t As
Au e Ea
So Afri
in eri
tin ro
ala
he te A
m te l A
M tA
er
in er
er
Results
nt ac
e A ea
ut l su ah Af
su ha Af
ha Af
ut e
ur
nt rt ur
op a ib
dl
So tra b-S ran
C
a
We estimated that, in 2019, 1·27 million deaths

t
at
at
Ce rn s Sah
E
-
co
aa
ste ub
a
n u
de
(95% uncertainty interval [UI] 0·911–1·71) were directly

-in
ric
Ea rn s
An
gh
Af
So
te
Hi
rth
attributable to resistance (ie, based on the counterfactual

es
gh
W
No
Hi
scenario that drug-resistant infections were instead drug GBD region

susceptible) in the 88 pathogen–drug combinations
Figure 2: All-age rate of deaths attributable to and associated with bacterial antimicrobial resistance by GBD
evaluated in this study. On the basis of a counterfactual region, 2019
scenario of no infection, we estimated that 4·95 million Estimates were aggregated across drugs, accounting for the co-occurrence of resistance to multiple drugs. Error
deaths (3·62–6·57) were associated with bacterial AMR bars show 95% uncertainty intervals. GBD=Global Burden of Diseases, Injuries, and Risk Factors Study.

Articles
Resistance
Associated with resistance
Attributable to resistance
2000000
1500000
Deaths (count)
1000000
500000
0
LRI+ BSI Intra- UTI Tuberculosis Skin CNS TF–PF–iNTS Diarrhoea Cardiac Bone+
abdominal
Infectious syndrome
Figure 3: Global deaths (counts) attributable to and associated with bacterial antimicrobial resistance by infectious syndrome, 2019
Estimates were aggregated across drugs, accounting for the co-occurrence of resistance to multiple drugs. Error bars show 95% uncertainty intervals. Does not
include gonorrhoea and chlamydia because we did not estimate the fatal burden of this infectious syndrome. Bone+=infections of bones, joints, and related organs.
BSI=bloodstream infections. Cardiac=endocarditis and other cardiac infections. CNS=meningitis and other bacterial CNS infections. Intra-abdominal=peritoneal and
intra-abdominal infections. LRI+=lower respiratory infections and all related infections in the thorax. Skin=bacterial infections of the skin and subcutaneous systems.
TF–PF–iNTS= typhoid fever, paratyphoid fever, and invasive non-typhoidal Salmonella spp. UTI=urinary tract infections and pyelonephritis.
In 2019, six pathogens were each responsible for more leading pathogens were distinct from those of the high-
than 250 000 deaths associated with AMR (figure 4): income super-region, and each represented a smaller
E coli, Staphylococcus aureus, K pneumoniae, S pneumoniae, share of the AMR burden; S pneumoniae contributed to
Acinetobacter baumannii, and Pseudomonas aeruginosa, by 15·9% (11·4–21·0) of the deaths attributable to AMR and
order of number of deaths. Together, these six pathogens 19·0% (17·1–21·1) of the deaths associated with AMR,
were responsible for 929 000 (95% UI 660 000–1 270 000) whereas K pneumoniae contributed to 19·9% (15·1–25·4)
of 1·27 million deaths (0·911–1·71) attributable to AMR of the deaths attributable to AMR and 17·5% (16·3–18·7)
and 3·57 million (2·62–4·78) of 4·95 million deaths of the deaths associated with AMR.
(3·62–6·57) associated with AMR globally in 2019. In 2019, meticillin-resistant S aureus was the one
Six more pathogens were each responsible for between pathogen–drug combination in our analysis with more
100 000 and 250 000 deaths associated with AMR: than 100 000 deaths and 3·5 million DALYs attributable
M tuberculosis, Enterococcus faecium, Enterobacter spp, to resistance (figure 6; appendix pp 121–22, 129). Six
Streptococcus agalactiae (group B Streptococcus), S Typhi, more pathogen–drug combinations each caused
and Enterococcus faecalis. For deaths attributable to AMR, between 50 000 and 100 000 resistance-attributable
E coli was responsible for the most deaths in 2019, deaths in 2019: MDR excluding XDR tuberculosis, third-
followed by K pneumoniae, S aureus, A baumannii, generation cephalosporin-resistant E coli, carbapenem-
S pneumoniae, and M tuberculosis. resistant A baumannii, fluoroquinolone-resistant E coli,
The share of AMR burden caused by each of the carbapenem-resistant K pneumoniae, and third-genera
six leading pathogens differed substantially across GBD tion cephalosporin-resistant K pneumoniae (figure 6).
super-regions. In the high-income super-region, In the next tier of pathogen–drug combinations,
approximately half of the fatal AMR burden was linked to ten combinations each caused between 25 000 and
two pathogens: S aureus (constituting 26·1% [95% UI 50 000 deaths attributable to AMR. Four of these ten
17·4–34·1] of deaths attributable to AMR and 25·4% combinations included fluoroquinolone resistance,
[24·1–27·0] of deaths associated with AMR) and E coli three included carbapenem resistance, and two had
(constituting 23·4% [19·5–28·2] of deaths attributable to trimethoprim-sulfamethoxazole resistance.
AMR and 24·3% [22·9–25·8] of deaths associated with In the appendix, we present the equivalent AMR
AMR; figure 5). By contrast, in sub-Saharan Africa, the findings for DALYs instead of deaths (pp 124–29), as well

Articles
Resistance
Associated with resistance
Attributable to resistance
900000
600000
Deaths (count)
300000
0
pp
pp
pp
p
li
iae
iae
nii
is
us
lis
ci
us
ae
i
ph
ph
reu
co
os
ell
sp
sp
sp
los
oc
ciu
ca
nz
cc
cc
an
rs
ss
rs
on
on
ty
Ty
gin
on
ia
au
oc
tia
lla
lla
co
co
rcu
fae
ue
fae
cte
cte
m
eu
m
ra
ch
alm
to
to
pe
ru
ige
ne
er
rra
infl
au
us
be
eu
eu
ot
Pa
us
ba
ba
eri
us
nt
rep
rep
ae
ga
ty
Sh
cc
rb
Se
Pr
tu
lS
pn
pn
cc
ro
ro
ch
pe
cc
us
re
ro
or
co
as
St
St
co
da
cte
te
Cit
m
co
Es
la
us
hil
ty
M
se
he
on
lo
ro
En
pB
pA
riu
oi
iel
ro
ba
cc
ro
hy
op
ca
Ot
m
te
ph
bs
te
te
co
to
se
ou
ap
ou
em
do
En
eri
En
Kle
ac
to
ty
ine
ca
St
Gr
Gr
eu
nt
Ha
ob
rep
n-
eri
Ac
ae
Ps
yc
No
St
nt
ell
M
ae
on
ell
lm
on
Sa
lm
Sa
Pathogen
Figure 4: Global deaths (counts) attributable to and associated with bacterial antimicrobial resistance by pathogen, 2019
Estimates were aggregated across drugs, accounting for the co-occurrence of resistance to multiple drugs. Error bars show 95% uncertainty intervals.
as the burden attributable to and associated with specific deaths were directly attributable to drug resistance. In
pathogen–drug combinations by age group (neonatal, other words, if all drug-resistant infections were replaced
post-neonatal, age 1–4 years, and age 5 years or older) and by no infection, 4·95 million deaths could have been
super-region (pp 106–18). prevented in 2019, whereas if all drug-resistant infections
Among the seven leading pathogen–drug combinations were replaced by drug-susceptible infections, 1·27 million
for deaths attributable to resistance, the proportion of deaths could have been prevented. Compared with all
isolates estimated to be resistant varied substantially by underlying causes of death in GBD 2019, AMR would
country and territory (figure 7A–G). For meticillin- have been the third leading GBD Level 3 cause of death
resistant S aureus, resistance was generally highest in 2019, on the basis of the counterfactual of no infection;
(60% to less than 80%) in countries in north Africa and only ischaemic heart disease and stroke accounted for
the Middle East (eg, Iraq and Kuwait) and lowest (less more deaths that year.14 Using the counterfactual of
than 5%) in several countries in Europe and sub-Saharan susceptible infection, AMR would have been the 12th
Africa (figure 7A). For isoniazid and rifampicin co- leading GBD Level 3 cause of death globally, ahead of
resistant (MDR excluding XDR) M tuberculosis, isolate both HIV and malaria (more information on GBD causes
resistance was highest (primarily 10% to less than 30%) by level presented in the appendix pp 18, 67–75).14 By any
in eastern Europe and under 5% in many countries metric, bacterial AMR is a leading global health issue.12
around the world (figure 7B). To show where data are Additionally, our analysis showed that AMR all-age death
available and how the modelled estimates differ from the rates were highest in some LMICs, making AMR not
input data, figure 7 also shows the raw, unadjusted only a major health problem globally but a particularly
prevalence of resistance for each of the seven leading serious problem for some of the poorest countries in the
pathogen–drug combinations. world.
All six of the leading pathogens contributing to the
Discussion burden of AMR in 2019 (E coli, S aureus, K pneumoniae,
The global burden associated with drug-resistant S pneumoniae, A baumannii, and P aeruginosa) have
infections assessed across 88 pathogen–drug combina been identified as priority pathogens by WHO34 and
tions in 2019 was an estimated 4·95 million (95% UI AMR has been highlighted in the political arena through
3·62–6·57) deaths, of which 1·27 million (0·911–1·71) the Global Action Plan on AMR,8 the UN Interagency

Articles
A
Pathogen
Acinetobacter baumannii
Pathogen-attributable fraction of AMR deaths attributable to resistance
Escherichia coli
Klebsiella pneumoniae
0·30 Pseudomonas aeruginosa
Staphylococcus aureus
Streptococcus pneumoniae
0·20
0·10
B
Pathogen-attributable fraction of AMR deaths associated with resistance
0·20
0·10
0
Central Europe, High income Latin America North Africa South Asia Southeast Asia, Sub-Saharan Africa
eastern Europe, and and Caribbean and Middle East east Asia, and Oceania
central Asia
Figure 5: Pathogen-attributable fraction of deaths attributable to (A) and associated with (B) bacterial AMR for the six leading pathogens by GBD super-
region, 2019
Error bars show 95% uncertainty intervals. AMR=antimicrobial resistance. GBD=Global Burden of Diseases, Injuries, and Risk Factors Study.
Coordination Group,35 the One Health Global Leaders to date, clearly show that drug resistance in each of these
Group,36 and several others. However, only one of these leading pathogens is a major global health threat that
pathogens has been the focus of a major global health warrants more attention, funding, capacity building,
intervention programme—S pneumoniae, primarily research and development, and pathogen-specific priority
through pneumococcal vaccination.37 Furthermore, the setting from the broader global health community.
first Sustainable Development Goal38 indicator for Resistance to fluoroquinolones and β-lactam antibiotics
antimicrobial resistance was only proposed in 2019, and (ie, carbapenems, cephalosporins, and penicillins)—
this indicator (3.d.2) is very limited in scope.39,40 Our antibiotics often considered first line for empirical
findings, which—to our knowledge—are the most therapy of severe infections41—accounted for more than
comprehensive estimates of the burden of bacterial AMR 70% of deaths attributable to AMR across pathogens.

Articles
Count (thousands)
≥100 75 to <100 50 to <75 25 to <50 10 to <25 5 to <10 <5 NA
Acinetobacter baumannii 132 000 6860 3280 10 400 13 300 811 57 700 40 000
Citrobacter spp 10 600 1840 1340 411 2170 2300 2510
Enterobacter spp 46 100 5320 3070 9950 15 300 7800 4650
Enterococcus faecalis 30 200 26 800 3420
Enterococcus faecium 51 500 37 200 14 300
Other enterococci 14 500 12 200 2220
Escherichia coli 219 000 59 900 11 700 10 500 21 300 29 500 56 000 30 200
Group A Streptococcus 3630 3630
Group B Streptococcus 25 800 11 500 13 500 799
Haemophilus influenzae 6760 2470 4290
Klebsiella pneumoniae 193 000 50 100 26 300 7930 55 700 29 000 23 500
Morganella spp 749 168 154 427
Mycobacterium tuberculosis 84 800 64 600 11 600 3350 5210
Proteus spp 11 500 4730 887 1,330 2970 1620
Pseudomonas aeruginosa 84 600 10 400 4370 3010 10 300 38 100 18 300
S Paratyphi 4110 4040 64
S Typhi 23 700 17 200 6460
Non-typhoidal Salmonella 5620 5620
Serratia spp 10 700 1100 2610 953 2450 1080
Shigella spp 5990 5990
Staphylococcus aureus 178 000 2480 15 900 19 600 121 000 18 700 3120
Streptococcus pneumonia 122 000 3330 2040 41 900 11 200 12 500 12 400 38 700
All pathogens 1 270 000 141 000 17 100 56 800 16 100 38 200 32 100 243 000 306 000 49 300 64 600 6530 121 000 11 600 3350 13 200 117 000 23 100 5210
+
es
llin
al
LI
sis
llin
NH
IF
lin
sis
in
ph
em
ne
lid
o1
3G
4G
SM
on
−B
oR
yc
id
cil
lo
lo
ici
ici
ty
oI
lo
ro
os
om
en
et
cu
cu
m
BL
P-
ni
on
ra
en
et
no
on
ac
lyc
do
Pe
ap
er
er
TM
nc
Pa
nc
M
op
M
ui
M
ub
ub
og
eu
ta
rb
Va
oq
dS
in
sis
Ca
nt
nt
ps
in
Am
or
an
Am
Re
ti−
Ri
Ri
Flu
hi
XD
XD
An
yp
ng
ST
di
in
clu
DR
ex
M
DR
M
Figure 6: Global deaths (counts) attributable to bacterial antimicrobial resistance by pathogen–drug combination, 2019
For this figure, only deaths attributable to resistance, not deaths associated with resistance, are shown due to the very high levels of correlation for resistance patterns between some drugs. 3GC=third-
generation cephalosporins. 4GC=fourth-generation cephalosporins. Anti-pseudomonal=anti-pseudomonal penicillin or beta-lactamase inhibitors. BL-BLI=β-lactam or β-lactamase inhibitors.
MDR=multidrug resistance. Mono INH=isoniazid mono-resistance. Mono RIF=rifampicin mono-resistance. NA=not applicable. Resistance to 1+=resistance to one or more drug. S Paratyphi=Salmonella
enterica serotype Paratyphi. S Typhi=S enterica serotype Typhi. TMP-SMX=trimethoprim-sulfamethoxazole. XDR=extensive drug resistance.
In 2017, WHO published a priority list for developing pathogen–drug combinations can inform future work on
new and effective antibiotic treatments. The list was WHO priority pathogen–drug combinations.
intended to inform research and development priorities Intervention strategies for addressing the challenge of
related to new antibiotics and put the most emphasis on bacterial AMR fall into five main categories. First, the
pathogens with multidrug resistance that cause severe principles of infection prevention and control remain a
and often deadly infections in health-care and nursing foundation for preventing infections broadly and a
home settings. Although the intention of this list was to cornerstone in combating the spread of AMR.44 These
set new antibiotic research and development priorities include both hospital-based infection prevention and
rather than identify the most burdensome pathogen– control programmes focused on preventing health-care-
drug combinations, its utility in dictating priorities has acquired infections, and community-based programmes
still been limited by the absence of a global assessment focused on water, sanitation, and hygiene. Community-
of the burden of bacterial AMR. Only five of the seven based programmes are particularly important in LMICs
pathogen–drug combinations that we estimated to have where the AMR burden is highest and clean water and
caused the most deaths attributable to bacterial AMR sanitation infrastructure is weak; sustained support for
in 2019 are currently on the list; MDR tuberculosis and these programmes is an essential element of combating
fluoroquinolone-resistant E coli are not included.34 AMR.
Additionally, meticillin-resistant S aureus—the leading Second, preventing infections through vaccinations is
pathogen–drug combination in our analysis for paramount for reducing the need for antibiotics. Vaccines
attributable deaths in 2019—is listed as “high” but not are available for only one of the six leading pathogens
“critical” priority.34 WHO has explained that the absence (S pneumoniae), although new vaccine programmes are
of MDR tuberculosis from its priority list is because it underway for S aureus, E coli, and others.45 Vaccination
has already been established globally as a top priority for programmes are an important strategy for preventing
innovative treatments, but this exclusion remains a S pneumoniae,46 and vaccine development is crucial for
source of considerable debate.42,43 Although many factors pathogens that currently have no vaccine. Other vaccines,
were considered in producing the WHO priority list, such as the influenza or rotavirus vaccines, also play a
these new estimates of the global burden of specific role in preventing febrile illness, which can lead to a

Articles
A Meticillin-resistant Staphylococcus aureus

Raw data
Percentage of isolates with resistance

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Caribbean and central America Persian Gulf Balkan Peninsula Southeast Asia West Africa Mediterranean
Northern Europe
Modelled estimates
Eastern
Northern Europe
(Figure 7 continues on next page)

Articles
B Isoniazid and rifampicin co-resistant (excluding XDR) Mycobacterium tuberculosis

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
C Third-generation cephalosporin-resistant Escherichia coli

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
D Carbapenem-resistant Acinetobacter baumannii

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
E Fluoroquinolone-resistant Escherichia coli

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
F Carbapenem-resistant Klebsiella pneumoniae

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
G Third-generation cephalosporin-resistant Klebsiella pneumoniae

Raw data

<5% 40 to <50%
5 to <10% 50 to <60%
10 to <20% 60 to <70%
20 to <30% 70 to <80%
30 to <40% ≥80%
Eastern
Northern Europe
Modelled estimates
Eastern
Northern Europe

Articles
reduction in antibiotic prescribing and can reduce AMR The higher burden in low-resource health systems
emergence even for pathogens without vaccines.45 highlights the importance—both for the management of
Third, reducing exposure to antibiotics unrelated to individual patients and for the surveillance of AMR—of
treating human disease is an important potential way to well developed national action plans and laboratory
reduce risk. Increased use of antibiotics in farming has infrastructure in all regions and countries. The pattern of
been identified as a potential contributor to AMR in AMR varies geographically, with different pathogens and
humans,2,47–49 although the direct causal link remains pathogen–drug combinations dominating in different
controversial.50,51 locations. Our regional estimates could prove useful for
Fourth, minimising the use of antibiotics when they tailoring local responses as a one size fits all approach
are not necessary to improve human health—such as might be inappropriate. Although antibiotic stewardship
treating viral infections—should be prioritised. To this is a foundational aspect for preventing the spread of
end, building infrastructure that allows clinicians to AMR, limiting access to antibiotics is not a suitable
diagnose infection accurately and rapidly is crucial so response to AMR in all settings. In fact, it could be argued
that antimicrobial use can be narrowed or stopped when that an increase in access to antibiotics would decrease
appropriate.52 The notion of antibiotic stewardship the AMR burden in some locations where second-line
remains a core strategy in most national and international antibiotics are unavailable and would be lifesaving; this
AMR management plans, although barriers to might well be the case in western sub-Saharan Africa. By
implementing stewardship programmes in LMICs contrast, limiting access to antibiotics in south Asia
should be addressed.53,54 through stewardship programmes might be the
Fifth, maintaining investment in the development appropriate response for that region because antibiotic
pipeline for new antibiotics—and access to second-line overuse or misuse is believed to be a major driver of AMR
antibiotics in locations without widespread access—is there.58 AMR is a global problem and one that requires
essential. In the past few decades, investments have both global action and nationally tailored responses.
been small compared with those in other public health This study evaluated both the burden of bacterial
issues with similar or less impact.55 Given the global infections associated with drug resistance and the burden
importance of bacterial AMR, more assessment of directly attributable to drug resistance.13 At the global level,
which policies have worked, and where, is urgently the difference is nearly four-times that attributable to
needed. AMR. We estimated both measures of burden because
Many might expect that with higher antibiotic there is insufficient evidence to determine the extent to
consumption in high-resource settings, the burden of which drug-resistant infections would be replaced by no
bacterial AMR would be correspondingly higher in those infection or susceptible infection if drug resistance was
settings. We found, however, that the highest rates of eliminated. Some evidence from the spread of meticillin-
death were in sub-Saharan Africa and south Asia. High resistant S aureus and meticillin-susceptible S aureus
bacterial AMR burdens are a function of both the suggests that drug-resistant infections do not simply
prevalence of resistance and the underlying frequency of replace drug-susceptible infections,63,64 but this finding
critical infections such as lower respiratory infections, might not generalise to all other pathogens and other
bloodstream infections, and intra-abdominal infections, mechanisms of resistance.
which are higher in these regions.14 Other drivers of the Both measures are informative in different ways. For
observed higher burden in LMICs include the scarcity of instance, when considering the specific burden of each
laboratory infrastructure making microbiological testing pathogen–drug combination, we believe that the burden
unavailable to inform treatment to stop or narrow attributable to resistance is more appropriate because
antibiotics,56 the inappropriate use of antibiotics driven very high levels of co-resistance among some drugs lead
by insufficient regulations and ease of acquisition,57 to many deaths being duplicated across drugs when
inadequate access to second-line and third-line considering burden associated with resistance. When
antibiotics, counterfeit or substandard antibiotics that thinking about the role of vaccination to combat AMR,
can drive resistance,52,58,59 and poor sanitation and the no-infection counterfactual is more appropriate
hygiene.60–62 because infections would be eliminated, whereas
interventions based on antimicrobial stewardship might
be better informed by the susceptible infection
counterfactual because some resistant bacteria might be
Figure 7: Raw data and modelled estimates for the percentage of pathogen
replaced by susceptible bacteria.22 In either case, the
isolates that are resistant by country and territory, 2019
Meticillin-resistant Staphylococcus aureus (A), isoniazid and rifampicin co-resistant magnitude of the global bacterial AMR problem is very
(excluding XDR) Mycobacterium tuberculosis (B), third-generation cephalosporin- large and likely bounded by the two measures.
resistant Escherichia coli (C), carbapenem-resistant Acinetobacter baumannii (D), Our ability to compare our estimates with previous
fluoroquinolone-resistant E coli (E), carbapenem-resistant Klebsiella pneumoniae
estimates is somewhat limited. The only global burden
(F), and third-generation cephalosporin-resistant K pneumoniae (G). Locations
with no data or modelled estimates are presented in white. XDR=extensively drug estimates for AMR are from the Review on Antimicrobial
resistant. Resistance,1 which did not provide death estimates by

Articles
pathogen–drug combination, making direct comparison cephalosporin-resistant E coli to exceed that of

challenging. The Review on Antimicrobial Resistance carbapenem-resistant A baumannii in high-income
estimated 700 000 deaths in 2014 attributable to resistance settings, whereas the inverse pattern was found in south
to six pathogens: HIV, tuberculosis, malaria, S aureus, Asia, where a higher relative burden of carbapenem-
E coli, and K pneumoniae. We produced estimates for four resistant A baumannii than that in high-income regions
of those pathogens—tuberculosis, S aureus, E coli, and has been documented.11 Our global burden was strongly
K pneumoniae—and estimated 670 000 deaths attributable influenced by this higher relative burden of carbapenem-
to resistance to those pathogens in 2019. resistant A baumannii in south Asia and other LMICs.
Cassini and colleagues10 produced an estimate for the Our estimate for the burden of resistance is confined to
EU of 16 pathogen–antibiotic combinations in 2015. We the 88 pathogen–drug combinations we analysed.
produced estimates for 11 of these 16 combinations; we Expanding our resistance analysis to more pathogen–
did not estimate colistin resistance in E coli, P aeruginosa, drug combinations—particularly adding viruses,
or A baumannii because of the paucity of data on colistin parasites, and fungi—would increase our estimate of the
resistance in LMICs, or multidrug resistance in burden and could alter some of the results reported,
P aeruginosa or A baumannii because of our approach to depending on the correlation structure of resistance
MDR infections. For the 11 pathogen–drug combinations between the newly added and original 88 pathogen–drug
that overlap, Cassini and colleagues estimated approx combinations. It would provide a more thorough account
imately 30 000 deaths and 796 000 DALYs caused by of the threat of AMR and improve the accuracy of our
resistance in the EU in 2015. For these same 11 pathogen– estimates for the combinations reported here that share a
For the pathogen–drug drug combinations, we estimated 23 100 deaths (95% UI high degree of co-resistance with combinations not yet
combinations estimates see 14 600–34 600) and 393 000 DALYs (246 000–595 000) analysed.
http://ghdx.healthdata.org/
record/ihme-data/global-
attributable to bacterial AMR for western and central This study has several limitations, the most important
bacterial-antimicrobial- Europe combined. Cassini and colleagues used a mix of being the sparsity of data from many LMICs on the
resistance-burden- both counterfactuals to inform their estimates, so it is distribution of pathogens by infectious syndrome, the
estimates-2019 expected that their EU estimate is somewhat higher than prevalence of resistance for key pathogen–drug
ours for the susceptible counterfactual. This comparison combinations, and the number of deaths involving
is not perfect because there is not complete overlap in the infection; and the severe scarcity of data linking laboratory
locations included in western and central Europe and EU results to outcomes such as death. 19 of 204 countries and
member countries (ie, Switzerland is included in our territories had no data available for any of our modelling
estimate and not in the EU designation, whereas Estonia components. Limited availability of data in some parts of
is in the EU but is part of our eastern Europe region; the world was particularly consequential for the
appendix pp 100–05), but it offers some idea of how our prevalence of resistance and relative risk modelling
estimates compare with those of previous publications. components; we assumed that the relative risk for each
Some of our estimates might be unexpected and pathogen–drug combination, as well as the correlation
deserve special attention, particularly the high burden in structure of resistance between drugs, was the same in
sub-Saharan Africa and the burden of carbapenem- every location, age, and infectious syndrome. This might
resistant A baumannii. Although we estimated underestimate the AMR burden for LMICs, since the
sub-Saharan Africa to be the super-region with the lowest relative risk might be higher in locations where fewer
percentage of infectious deaths attributable to AMR second-line and third-line antibiotics are available.
(appendix p 97), the rate of deaths in which infection Assuming a single relative risk for all infectious
plays a role was so much greater in sub-Saharan Africa syndromes is a potentially strong assumption; it is not
than in other super-regions that it overcame a relatively immediately clear what direction this biases results, but it
low prevalence of resistance and was the super-region might lead to overestimation. Another substantial
with the highest estimated AMR burden in 2019. assumption we made due to insufficient linked data was
Regarding carbapenem-resistant A baumannii, we that the relative risk of death or length of stay for infection
estimated that it was the fourth leading pathogen–drug from an MDR organism was assumed to be equal to the
combination globally for 2019, responsible for slightly highest individual relative risk among the drugs assessed.
fewer deaths than third-generation cephalosporin- This mostly likely underestimates the relative risk of
resistant E coli. At first glance, this finding seems to MDR infections because fewer effective antibiotic options
contrast with other estimates such as those from Cassini remain as resistance accumulates. In light of data sparsity,
and colleagues or the CDC, who have estimated the we made several additional methodological assumptions
burden of carbapenem-resistant A baumannii to be (appendix pp 17–60). Despite scarcity, our estimates are
substantially lower than that of third-generation informed by data from all regions (figure 7, table 1). These
cephalosporin-resistant E coli.6,10 When assessed by super- figures, and the appendix (pp 26–30, 43–44, 52–53, and
region, however, our results are much more consistent 56, which provides out-of-sample model validation),
with the published literature: similar to the CDC and suggest that our modelled estimates fit the data, where
ECDC, we found the burden of third-generation available.

Articles
Our analysis echoes that of another paper in limitations specific to each modelling component can be
highlighting critical AMR data gaps in several regions.65 found in the appendix (pp 119–20).
There are many well described barriers to good-quality Despite these limitations, this study is the most
clinical bacteriology in LMICs, and proper quality comprehensive analysis of bacterial AMR burden to date,
assurance and quality-control measures are crucial for reflecting the best and widest range of available data and
quality care and accurate laboratory-based surveillance.66 the use of models that have been tested and iterated over
Many lab-based surveillance systems are not linked to years of GBD analysis to incorporate disparate data
patient diagnoses or outcomes, limiting the inferences sources. Individually, these sources do not fully address
that are possible to obtain from such data. Selection bias the burden of AMR but, when used collectively, they
in how samples get incorporated into surveillance provide a more complete estimate with robust
systems; scarcity of laboratory facilities to test for AMR geographical coverage. To our knowledge, our study is
and other challenges in identifying AMR;17 insufficient the first to report burden both attributable to and
data linking prevalence of resistance to infectious associated with AMR for an extensive list of pathogens
syndrome, underlying cause, and outcome; barriers to and pathogen–drug combinations, with global and
sharing data that have been collected; and other data- regional findings based on estimates for 204 countries
linking and data optimisation issues continue to and territories. In the future, these estimates could be
complicate the assessment and interpretation of the used to better inform treatment guidelines. The
results in many cases. dominant bacterial pathogens for a given infectious
A second limitation of our study was the several syndrome and the antibiotics that would offer effective
potential sources of bias we noted when combining and treatment could be identified using the data for this
standardising data from a wide variety of providers. Our study, which, along with estimates of pathogen–drug
estimates of the proportion of infections that were burden, could be used to inform empirical syndromic
community acquired versus hospital acquired for lower treatment guidelines tailored to a specific location.
respiratory and thorax infections and urinary tract Our analysis clearly shows that bacterial AMR is a
infections were based on the coding of data from multiple major global health problem. It poses the largest threat to
causes of death and hospital discharge data. This human health in sub-Saharan Africa and south Asia, but
approach could lead to misclassification, since the it is important in all regions. A diverse set of pathogens
criteria used in this coding are not strictly related to are involved, and resistance is high for multiple classes
community versus hospital acquisition. In future of essential agents, including beta-lactams and fluoro
iterations of the project, we hope to improve on the quinolones. Efforts to build laboratory infrastructure are
identification of community-acquired and hospital- paramount to addressing the large and universal burden
acquired infections. of AMR, by improving the management of individual
Additionally, no universal laboratory standard exists to patients and the quality of data in local and global AMR
demarcate resistance versus susceptibility, and we often surveillance and bolstering national AMR plans of action.
had to defer to laboratory interpretation to classify the Enhanced infrastructure would also expand AMR
isolates in our data, resulting in heterogeneous research in the future to evaluate the indirect effects of
classification. Whenever possible, we classified resistance AMR, such as the effect of AMR on perioperative
using the most recent CLSI guidelines based on the prophylaxis or prophylaxis of infections in transplant
minimum inhibitory concentrations provided in the recipients, the effects of AMR on transmission, the
data; however, CLSI breakpoints have changed over time, impact and prevalence of specific variants evaluated
and many datasets did not provide sufficient detail to through genotypic epidemiology, and more. Identifying
allow for retrospective reanalysis of the data.67 strategies that can work to reduce the burden of bacterial
Finally, there is a possibility of selection bias in passive AMR—either across a wide range of settings or those
microbial surveillance data, particularly if cultures are that are specifically tailored to the resources available and
not routinely drawn. It might be that, in certain locations, leading pathogen–drug combinations in a particular
cultures are drawn only if a patient does not respond to setting—is an urgent priority.
initial antibiotic therapy, which might lead to an Antimicrobial Resistance Collaborators
overestimate of the prevalence of resistance. Christopher J L Murray, Kevin Shunji Ikuta, Fablina Sharara,
Furthermore, in LMICs, hospital microbial data might Lucien Swetschinski, Gisela Robles Aguilar, Authia Gray, Chieh Han,
Catherine Bisignano, Puja Rao, Eve Wool, Sarah C Johnson,
skew towards more urban populations or more severe Annie J Browne, Michael Give Chipeta, Frederick Fell, Sean Hackett,
disease, which might not be representative of the broader Georgina Haines-Woodhouse, Bahar H Kashef Hamadani,
population. We also received various data from tertiary Emmanuelle A P Kumaran, Barney McManigal, Ramesh Agarwal,
care facilities; although we adjusted for bias in the Samuel Akech, Samuel Albertson, John Amuasi, Jason Andrews,
Aleskandr Aravkin, Elizabeth Ashley, Freddie Bailey, Stephen Baker,
prevalence of resistance data collected from these Buddha Basnyat, Adrie Bekker, Rose Bender, Adhisivam Bethou,
sources, much of our data came from mixed-classification Julia Bielicki, Suppawat Boonkasidecha, James Bukosia,
or unclassifiable facilities, so it is possible that we did not Cristina Carvalheiro, Carlos Castañeda-Orjuela, Vilada Chansamouth,
fully adjust for all potential tertiary bias. Further Suman Chaurasia, Sara Chiurchiù, Fazle Chowdhury, Aislinn J Cook,

Articles
Ben Cooper, Tim R Cressey, Elia Criollo-Mora, Matthew Cunningham, Kathmandu, Nepal; Department of Paediatrics and Child Health
Saffiatou Darboe, Nicholas P J Day, Maia De Luca, Klara Dokova, (A Bekker PhD, A Dramowski PhD), Stellenbosch University,
Angela Dramowski, Susanna J Dunachie, Tim Eckmanns, Cape Town, South Africa; Department of Neonatology (A Bethou PhD,
Daniel Eibach, Amir Emami, Nicholas Feasey, Natasha Fisher-Pearson, N Plakkal MD), Jawaharlal Institute of Postgraduate Medical Education
Karen Forrest, Denise Garrett, Petra Gastmeier, Ababi Zergaw Giref, & Research, Puducherry, India; Paediatric Infectious Disease
Rachel Claire Greer, Vikas Gupta, Sebastian Haller, Andrea Haselbeck, Department (J Bielicki PhD), University of Basel Children’s Hospital,
Simon I Hay, Marianne Holm, Susan Hopkins, Kenneth C Iregbu, Basel, Switzerland; Paediatric Infectious Diseases Research Group
Jan Jacobs, Daniel Jarovsky, Fatemeh Javanmardi, Meera Khorana, (J Bielicki, A J Cook MSc, A Riddell PhD, N Russell MBBS), Institute for
Niranjan Kissoon, Elsa Kobeissi, Tomislav Kostyanev, Fiorella Krapp, Infection and Immunity (T Munera-Huertas PhD), St George’s
Ralf Krumkamp, Ajay Kumar, Hmwe H Kyu, Cherry Lim, University of London, London, UK; Department of Pediatrics
Direk Limmathurotsakul, Michael James Loftus, Miles Lunn, (S Boonkasidecha MD, M Khorana MD), Queen Sirikit National
Jianing Ma, Neema Mturi, Tatiana Munera-Huertas, Patrick Musicha, Institute of Child Health, Bangkok, Thailand; Department of Pediatrics
Marisa Marcia Mussi-Pinhata, Tomoka Nakamura, Ruchi Nanavati, (C Carvalheiro PhD), University of Sao Paulo, Ribeirao Preto, Brazil;
Sushma Nangia, Paul Newton, Chanpheaktra Ngoun, Amanda Novotney, Colombian National Health Observatory (C Castañeda-Orjuela MD),
Davis Nwakanma, Christina W Obiero, Antonio Olivas-Martinez, Instituto Nacional de Salud, Bogota, Colombia; Epidemiology and Public
Piero Olliaro, Ednah Ooko, Edgar Ortiz-Brizuela, Anton Yariv Peleg, Health Evaluation Group (C Castañeda-Orjuela), Universidad Nacional
Carlo Perrone, Nishad Plakkal, Alfredo Ponce-de-Leon, Mathieu Raad, de Colombia, Bogota, Colombia; Department of Neonatology
Tanusha Ramdin, Amy Riddell, Tamalee Roberts, Julie Victoria (S Chaurasia PhD), All India Institute of Medical Sciences, Rishikesh,
Robotham, Anna Roca, Kristina E Rudd, Neal Russell, Jesse Schnall, India; Immunology and Infectious Disease Unit Academic Department
John Anthony Gerard Scott, Madhusudhan Shivamallappa, of Pediatrics (S Chiurchiù MD), Academic Hospital Pediatric
Jose Sifuentes-Osornio, Nicolas Steenkeste, Andrew James Stewardson, Department (M De Luca MD), Bambino Gesù Children’s Hospital,
Temenuga Stoeva, Nidanuch Tasak, Areerat Thaiprakong, Guy Thwaites, Rome, Italy; Internal Medicine (F Chowdhury PhD), Bangabandhu
Claudia Turner, Paul Turner, H Rogier van Doorn, Sithembiso Velaphi, Sheikh Mujib Medical University, Dhaka, Bangladesh; Mahidol-Oxford
Avina Vongpradith, Huong Vu, Timothy Walsh, Seymour Waner, Tropical Medicine Research Unit (F Chowdhury, Prof C Dolecek),
Tri Wangrangsimakul, Teresa Wozniak, Peng Zheng, Benn Sartorius, Faculty of Tropical Medicine (N P J Day, C Perrone), Mahidol University,
Alan D Lopez, Andy Stergachis, Catrin Moore*, Christiane Dolecek*, Bangkok, Thailand; Nuffield Department of Medicine (B Cooper PhD),
Mohsen Naghavi. University of Oxford, Oxford, UK; PHPT-AMS Research Unit
*Contributed equally. (T R Cressey PhD), Chiang Mai University, Chiang Mai, Thailand;
Department of Molecular & Clinical Pharmacology (T R Cressey),
Affiliations
University of Liverpool, Liverpool, UK; Department of Pharmacy
Institute for Health Metrics and Evaluation (Prof C J L Murray DPhil,
(E Criollo-Mora BSc), Department of Medicine (A Olivas-Martinez MD,
K S Ikuta MD, F Sharara MS, L Swetschinski MSc, A Gray BS,
E Ortiz-Brizuela MSc), Department of Infectious Diseases
C Han BA, C Bisignano MPH, P Rao MPH, E Wool MPH,
(A Ponce-de-Leon MD), Instituto Nacional de Ciencias Medicas y
S C Johnson MSc, S Albertson BS, A Aravkin PhD, R Bender BS,
Nutricion Salvador Zubiran, Mexico City, Mexico; Disease Control and
M Cunningham MSc, Prof S I Hay FMedSci, H H Kyu PhD, J Ma MS,
Elimination Department (S Darboe MSc, A Roca PhD), Clinical Services
A Novotney MPH, A Vongpradith BA, P Zheng PhD, A Stergachis PhD),
Department (K Forrest FRCP), Laboratory Services Department
Department of Health Metrics Sciences, School of Medicine
(D Nwakanma PhD), Medical Research Council Unit The Gambia at the
(Prof C J L Murray, A Aravkin, Prof S I Hay, B Sartorius PhD,
London School of Hygiene & Tropical Medicine, Banjul, The Gambia;
Prof M Naghavi PhD), Department of Applied Mathematics (A Aravkin),
Department of Social Medicine and Health Care Organization
Department of Global Health (A Stergachis, Prof M Naghavi),
(K Dokova PhD), Department of Microbiology and Virology
Department of Pharmacy, School of Pharmacy (A Stergachis), University
(T Stoeva PhD), Medical University of Varna, Varna, Bulgaria; Infectious
of Washington, Seattle, WA, USA; Department of Infectious Diseases
Disease Epidemiology (T Eckmanns PhD, S Haller MPH), Robert Koch
(K S Ikuta), Veterans Affairs Greater Los Angeles Healthcare System,
Institute, Berlin, Germany; Infectious Disease Epidemiology
Los Angeles, CA, USA; Department of Infectious Diseases (K S Ikuta),
(D Eibach MD, R Krumkamp DrPH), Bernhard Nocht Institute for
University of California, Los Angeles, Los Angeles, CA, USA; Nuffield
Tropical Medicine, Hamburg, Germany; Microbiology Department
Department of Medicine, Big Data Institute (F Bailey MBChB,
(A Emami PhD), Shiraz University of Medical Sciences, Shiraz, Iran;
A Browne MPH, M Chipeta PhD, F Fell MSc, N Fisher-Pearson BA,
Clinical Sciences (N Feasey PhD), Liverpool School of Tropical Medicine,
S Hackett PhD, G Haines-Woodhouse MRes, E Kobeissi MPH,
Liverpool, UK; Malawi Liverpool Wellcome Trust Clinical Research
E Kumaran MSc, M Lunn BSc, B McManigal PhD, C E Moore DPhil,
Programme, Blantyre, Malawi (N Feasey); Applied Epidemiology
P Olliaro PhD, G Robles Aguilar DPhil), Nuffield Department of
Programs (D Garrett MD), Sabin Vaccine Institute, Washington, DC,
Medicine, Centre for Tropical Medicine and Global Health
USA; Institute of Hygiene (Prof P Gastmeier MD), Charité University
(E Ashley FRCPath, V Chansamouth MSc, B Cooper PhD,
Medicine Berlin, Berlin, Germany; Department of Health Policy and
Prof C Dolecek FRCP, S Dunachie PhD, B Kashef Hamadani MPH,
Management (A Z Giref PhD), Addis Ababa University, Addis Ababa,
C Lim MSc, Prof D Limmathurotsakul PhD, P Newton FRCP,
Ethiopia; National Data Management Center (A Z Giref), Ethiopian
C Perrone MD, G Thwaites FMedSci, P Turner FRCPath,
Public Health Institute, Addis Ababa, Ethiopia; Chiangrai Clinical
B Sartorius PhD, N Day DM, R Greer MRCGP, H van Doorn PhD,
Research Unit (R C Greer, T Wangrangsimakul), Department of
T Wangrangsimakul FRCPath), Ineos Oxford Institute of Antimicrobial
Microbiology (S Dunachie, C Lim, Prof D Limmathurotsakul,
Research (Prof T Walsh DSc), University of Oxford, Oxford, UK;
N Tasak BNS, A Thaiprakong BS), Mahidol-Oxford Tropical Medicine
Department of Pediatrics (R Agarwal DM), All India Institute of Medical
Research Unit, Bangkok, Thailand; MMS Medical Affairs
Sciences, New Delhi, India; Health Services Research Unit
(V Gupta PharmD), Becton, Dickinson and Company, Franklin Lakes,
(S Akech PhD), Nairobi Programme (J Bukosia MSc), Kenya Medical
NJ, USA; Epidemiology & Public Health Research Department
Research Institute (KEMRI)—Wellcome Trust Research Programme,
(A Haselbeck Dr rer medic, M Holm PhD), International Vaccine
Nairobi, Kenya; Department of Global Health (J Amuasi PhD), Kwame
Institute, Seoul, South Korea; National Infection Service
Nkrumah University of Science and Technology, Kumasi, Ghana; Global
(S Hopkins FRCP), Antimicrobrial Resistance Division
Health and Infectious Diseases (J Amuasi), Kumasi Centre for
(J V Robotham PhD), Public Health England, London, UK; Department
Collaborative Research in Tropical Medicine, Kumasi, Ghana;
of Medical Microbiology (K C Iregbu MD), National Hospital, Abuja,
Department of Medicine (J Andrews MD), Stanford University, Stanford,
Nigeria; Department of Medical Microbiology (K C Iregbu), University of
CA, USA; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit
Abuja, Abuja, Nigeria; Department of Clinical Sciences
(E Ashley, V Chansamouth, P Newton, T Roberts PhD), Mahosot
(Prof J Jacobs PhD), Institute of Tropical Medicine, Antwerp, Belgium;
Hospital, Vientiane, Laos; Department of Medicine (S Baker PhD),
Department of Microbiology, Immunology, and Transplantation
University of Cambridge, Cambridge, UK; Oxford University Clinical
(Prof J Jacobs), KU Leuven, Leuven, Belgium; Pediatric Infectious
Research Unit-Nepal (B Basnyat FRCPE), Oxford University,

Articles
Disease Department (D Jarovsky MD), Santa Casa de São Paulo, Institute for Health Research (NIHR), outside of the submitted work; and
São Paulo, Brazil; Microbiology Department (F Javanmardi PhDc), consulting fees from Shionogi and Sandoz and speaking fees from Pfizer
Shiraz University of Medical sciences, Shiraz, Iran; Department of and Sandoz, outside the submitted work. C Carvalheiro reports financial
Pediatrics (N Kissoon MBBS), University of British Columbia, support for the present manuscript from the Global Antibiotic Research
Vancouver, BC, Canada; Laboratory of Medical Microbiology and Development Partnership, who provided payments to Fundação de
(T Kostyanev MD), University of Antwerp, Antwerp, Belgium; Instituto Apoio ao Ensino, Pesquisa e Assistência of the Clinical Hospital of the
de Medicina Tropical Alexander von Humboldt (F Krapp MSc), Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Universidad Peruana Cayetano Heredia, Lima, Peru; Department of S Dunachie reports financial support for the present manuscript from
Neonatology (A Kumar MD, S Nangia MD), Lady Hardinge Medical UL Flemming Fund at the Department of Health and Social Care, the Bill
College & Kalawati Saran’s Children’s Hospital, New Delhi, India; & Melinda Gates Foundation, and the Wellcome Trust; a paid
Department of Infectious Diseases (M J Loftus MBBS, A Y Peleg PhD, membership role for the Wellcome Trust Vaccines Advisory Selection
A J Stewardson PhD), Monash University, Melbourne, VIC, Australia; Panel Vaccines and AMR in November, 2019; and an unpaid role as an
Clinical Research Department (N Mturi MRCPCH, C W Obiero MPH), expert adviser to WHO’s Global Antimicrobrial Resistance Surveillance
KEMRI—Wellcome Trust Research Programme, Kilifi, Kenya System, from November, 2018 onwards, outside the submitted work. A
(E Ooko PhD); Parasites and Microbes Programme (P Musicha PhD), Haselbeck reports support for the present manuscript from the Bill &
Wellcome Sanger Institute, Cambridge, UK; Deparment of Pediatrics Melinda Gates Foundation (OPP1205877). C Lim was supported by the
(M M Mussi-Pinhata MD), University of São Paulo, Ribeirão Preto, Wellcome Trust Training Fellowship between September, 2017 and March
Brazil; Department of Immunization, Vaccines, and Biologicals 2020 (206736/Z/17/Z), outside the submitted work. M Mussi-Pinhata
(T Nakamura MSPH), World Health Organization, Geneva, Switzerland; reports support for the present manuscript from research from grant
Department of Infectious Disease Epidemiology (T Nakamura), London funding from Fondazione PENTA—Onlus and the Clinical Trial Manager
School of Hygiene and Tropical Medicine, London, UK; Department of Global Antibiotic R&D Partnership (GARDP). P Newton reports support
Neonatology (R Nanavati MD), Seth GSMC & KEM Hospital, Mumbai, for the present manuscript from research grant funding from the
India; Medical Department (C Ngoun MD), Executive Office Wellcome Trust. J Robotham is a member of the UK Government
(C Turner FRCPCH), Cambodia Oxford Medical Research Unit Advisory Committee on Antimicrobial Prescribing Resistance and
(P Turner), Angkor Hospital for Children, Siem Reap, Cambodia; Healthcare Associated Infections, outside the submitted work. J Scott
Department of Global Health (C W Obiero), University of Amsterdam, reports that the London School of Hygiene & Tropical Medicine
Amsterdam, Netherlands; Infectious Disease Department (A Y Peleg, (LSHTM) received financial support from Emory University to support
A J Stewardson), The Alfred Hospital, Melbourne, VIC, Australia; CHAMPS projects in Ethiopia for the present manuscript; reports a paid
Department of Medicine (A Ponce-de-Leon), Universidad Panamericana, fellowship from the Wellcome Trust, research grants from Gavi, the
Mexico City, Mexico; International Operations Department Vaccine Alliance, and NIHR paid to LSHTM, and an African research
(M Raad MD), International Operations Direction (N Steenkeste PhD), leader fellowship paid to LSHTM by the Medical Research Council,
Fondation Mérieux, Lyon, France; Department of Paediatric and Child outside the submitted work; and reports being a member of the data
Health (T Ramdin MBBCh), University of Witwatersrand, Parktown, safety and monitoring board for PATH Vaccines Solutions for SII PCV10
South Africa; Department of Critical Care Medicine (K E Rudd MD), in The Gambia. J Sifuentes-Osornio reports financial support from
University of Pittsburgh, Pittsburgh, PA, USA; Doctors in Training Oxford University for the present manuscript; research grants from
(J Schnall MBBS), Austin Health, Heidelberg, VIC, Australia; Oxford, CONACYT, Sanofi, and Novartis, outside of the study; consulting
Department of Infectious Disease Epidemiology fees from Senosiain and speaker fees from Merck, outside of the study;
(Prof J A G Scott FMedSci), London School of Hygiene & Tropical and membership of the Sanofi advisory board of COVID-19 Vaccine
Medicine, London, UK; Department of Epidemiology & Demography Development, which is currently in progress, outside of the study.
(Prof J A G Scott), KEMRI—Wellcome Trust Research Programme, A J Stewardson reports grants or contracts from Merck, Sharp, & Dohme
Kilifi, Kenya; Department of Neonatology (M Shivamallappa DM), paid to Monash University, Melbourne, outside of the study. P Turner
King Edward Memorial Hospital Mumbai, Mumbai, India; Department reports grants, consulting fees, and support for attending meetings or
of Medicine (J Sifuentes-Osornio MD), Instituto Nactional de Ciencias travel from Wellcome Trust, outside the study. H van Doorn reports
Medicas, Mexico City, Mexico; Microbiology Laboratory (T Stoeva), Varna grants or contracts from the University of Oxford and is the principal
University Hospital, Varna, Bulgaria; Oxford University Clinical investigator for the Fleming Fund pilot grant; and he is a board member
Research Unit Viet Nam (G Thwaites, H Vu PhD), University of Oxford, of Wellcome Trust’s Surveillance and Epidemiology of Drug Resistant
Ho Chi Minh City, Vietnam; Cambodia Oxford Medical Research Unit, Infections. T Walsh reports financial support from the Bill & Melinda
Siem Reap, Cambodia (C Turner); Oxford University Clinical Research Gates Foundation for the BARNARDS (neonatal sepsis and mortality)
Unit, Hanoi, Vietnam (H R van Doorn); School of Clinical Medicine, study for the present manuscript. All other authors declare no competing
Faculty of Health Sciences (S Velaphi PhD), University of the interests.
Witwatersrand, Johannesburg, South Africa; Department of Paediatrics
Data sharing
(S Velaphi), Chris Hani Baragwanath Academic Hospital, Johannesburg,
Citations for the data used in the study can be accessed from the Global
South Africa; Department of Microbiology (S Waner MMed), Lancet
Health Data Exchange AMR website. Access to the data are also provided
Laboratories, Johannesburg, South Africa; Department of Global
as data use agreements permit.
Tropical Health (T Wozniak PhD), Menzies School of Health Research,
Brisbane, QLD, Australia. Acknowledgments
Funding was provided by the Bill & Melinda Gates Foundation
Contributors
(OPP1176062), the Wellcome Trust (A126042), and the UK Department
Detailed information about individual author contributions to the
of Health and Social Care using UK aid funding managed by the
research are available in the appendix (pp 65–66). Members of the core
Fleming Fund (R52354 CN001). E Ashley acknowledges that Lao-Oxford-
research team for this topic area had full access to the underlying data
Mahosot Hospital–Wellcome Trust Research Unit receives core funding
used to generate estimates presented in this paper. All other authors had
from Wellcome (20211/Z/20/Z). N Feasey acknowledges that the Malawi
access to, and reviewed, estimates as part of the research evaluation
Liverpool Wellcome Trust Clinical Research Programme diagnostic
process, which includes additional stages of formal review.
microbiology service is funded by a Wellcome Asia and Africa
Declaration of interests Programme grant. S Dunachie acknowledges funding from NIHR
E Ashley reports that Lao-Oxford-Mahosot Hospital—Wellcome Trust Global Research Professorship (NIHR300791). F Krapp was supported
Research Unit received financial support from the Global Research on by Framework Agreement Belgian Directorate of Development
Antimicrobial Resistance Project (GRAM) to extract and prepare data for Cooperation-Institute of Tropical Medicine in Antwerp. M Khorana and
the present manuscript. J Bielicki reports grants from the European and S Boonkasidecha would like to acknowledge GARDP. A Peleg
Developing Countries Clinical Trials Partnership, Horizon 2020, and acknowledges the support from an Australian National Health and
Swiss National Science Foundation, and a contract from the National Medical Research Council Practitioner Fellowship. A Stewardson is

Articles
supported by an Australian National Health and Medical Research 6 US Centers for Disease Control and Prevention. Antibiotic
Council Early Career Fellowship (GNT1141398). P Turner acknowledges resistance threats in the United States, 2019. Atlanta, GA:
that the Cambodia Oxford Medical Research Unit is part of the Mahidol- US Department of Health and Human Services, 2019.
Oxford Tropical Medicine Research Unit Tropical Health Network and is 7 Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global
core funded by Wellcome (220211/Z/20/Z). T Wangrangsimakul multifaceted phenomenon. Pathog Glob Health 2015; 109: 309–18.
acknowledges funding from the Wellcome Trust, as part of the MORU 8 WHO. Global action plan on antimicrobial resistance. Geneva:
Tropical Health Network institutional funding support. The Medical World Health Organization, 2015.
Research Council Unit—The Gambia at the LSHTM acknowledges all 9 Naylor NR, Atun R, Zhu N, et al. Estimating the burden of
the staff in the microbiology clinical laboratory for their support. antimicrobial resistance: a systematic literature review.
We acknowledge The Australian Group for Antimicrobial Resistance, Antimicrob Resist Infect Control 2018; 7: 58.
and The Australian Commission on Safety and Quality in Healthcare, 10 Cassini A, Högberg LD, Plachouras D, et al. Attributable deaths and
Sydney, Australia. We acknowledge John Murray, Becton, Dickinson and disability-adjusted life-years caused by infections with antibiotic-
Company. We give thanks to the late Rattanaphone Phetsouvanh, the Lao resistant bacteria in the EU and the European Economic Area in
2015: a population-level modelling analysis. Lancet Infect Dis 2019;
Ministry of Health, and the Directorate of Mahosot Hospital who
19: 56–66.
enabled the collection and sharing of Lao data, Vientiane, Lao People’s
11 Lim C, Takahashi E, Hongsuwan M, et al. Epidemiology and
Democratic Republic. We thank Sabrina Bacci, Liselotte Diaz Högberg,
burden of multidrug-resistant bacterial infection in a developing
Marlena Kaczmarek, Maria Keramarou, Favelle Lamb, country. eLife 2016; 5: e18082.
Dominique L Monnet, Gianfranco Spiteri, Carl Suetens,
12 Temkin E, Fallach N, Almagor J, Gladstone BP, Tacconelli E,
Therese Westrell and Klaus Weist at the ECDC, Solna, Sweden, for Carmeli Y. Estimating the number of infections caused by
providing information on databases and discussions on data antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014:
interpretation. We acknowledge Jennifer R Verani and team, CDC, a modelling study. Lancet Glob Health 2018; 6: e969–79.
Nairobi, Kenya; Allan Audi and team, Centre for Global Health Research, 13 de Kraker MEA, Lipsitch M. Burden of antimicrobial resistance:
KEMRI, Kisumu, Kenya. We acknowledge Jephté Kaleb and compared to what? Epidemiol Rev 2021; published online March 12.
Giscard Wilfried Koyaweda, National Laboratory of Clinical Biology and https://doi.org/10.1093/epirev/mxab001.
Public Health, Bangui, Central African Republic. We acknowledge 14 Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and
Tien Viet Dung Vu and Nguyen Minh Trang Nghiem, Oxford University injuries in 204 countries and territories, 1990-2019: a systematic
Clinical Research Unit, Wellcome Africa Asia Programme, National analysis for the Global Burden of Disease Study 2019. Lancet 2020;
Hospital for Tropical Diseases, Hanoi, Vietnam; and the VINARES 396: 1204–22.
Consortium. We acknowledge the Department of Pathology and 15 Hay SI, Rao PC, Dolecek C, et al. Measuring and mapping the
Laboratory Medicine, and Department of Paediatrics and Child Health, global burden of antimicrobial resistance. BMC Med 2018; 16: 78.
Aga Khan University, Karachi, Pakistan. We acknowledge Samuel Akech, 16 Murray CJ, Ezzati M, Flaxman AD, et al. GBD 2010: design,
Ednah Ooko, James Bukosia, Neema Mturi, J Anthony G Scott, definitions, and metrics. Lancet 2012; 380: 2063–66.
Philip Bejon, Lynette Isabella Oyier, Salim Mwarumba, 17 Dunachie SJ, Day NP, Dolecek C. The challenges of estimating the
Esther Muthumbi, Christina Obiero, Robert Musyimi, human global burden of disease of antimicrobial resistant bacteria.
Shebe Mohammed, Caroline Ogwang, Christopher Maronga, Curr Opin Microbiol 2020; 57: 95–101.
Ambrose Agweyu, KEMRI Wellcome Trust Research Programme, Kilifi, 18 Limmathurotsakul D, Dunachie S, Fukuda K, et al. Improving the
Kenya. We acknowledge scientific contributions to this work from the estimation of the global burden of antimicrobial resistant
Pan American Health Organization. We would like to acknowledge the infections. Lancet Infect Dis 2019; 19: e392–98.
scientific contributions made from the GRAM advisory committee, 19 Ashley EA, Recht J, Chua A, et al. An inventory of supranational
specifically Neil Ferguson and Sharon Peacock. We would like to antimicrobial resistance surveillance networks involving low- and
middle-income countries since 2000. J Antimicrob Chemother 2018;
acknowledge Tomislav Mestrovic for his significant contributions to this
73: 1737–49.
manuscript and the overall research enterprise. We thank the Kenya
20 Institute for Health Metrics and Evaluation. Global Burden of Disease
Medical Research Institute, United States Army Medical Research
Study 2019 (GBD 2019) data input sources tool. 2021. http://ghdx.
Directorate-Africa, Kenya, Nairobi, Kenya; we acknowledge the
healthdata.org/gbd-2019/data-input-sources (accessed June 4, 2021).
International Nosocomial Infection Control Consortium, Buenos Aires,
21 Fullman N, Yearwood J, Abay SM, et al. Measuring performance on
Argentina; we would like to thank the CHILDS Trust Medical Research
the Healthcare Access and Quality Index for 195 countries and
Foundation, Chennai, India; we acknowledge the Childhood Acute territories and selected subnational locations: a systematic analysis
Illness & Nutrition Network investigators; we thank Institut Pasteur and from the Global Burden of Disease Study 2016. Lancet 2018;
Laboratoire National de Biologie Clinique et de Santé Publique in 391: 2236–71.
Bangui, Central African Republic; we would like to acknowledge the 22 Browne A, Chipeta M, Haines-Woodhouse G, et al. Global antibiotic
Global Tuberculosis Programme of WHO, Geneva, Switzerland; consumption in humans, 2000 to 2018: a spatial modelling study.
we thank the SENTRY Antimicrobial Surveillance Program, JMI Lancet Planet Health 2021; published online Nov 11. https://doi.org/
Laboratories, North Liberty, Iowa, USA; we acknowledge the Sihanouk 10.1016/S2542-5196(21)00280-1.
Hospital Center of Hope, Phnom Penh, Cambodia. 23 Singer M, Deutschman CS, Seymour CW, et al. The third
international consensus definitions for sepsis and septic shock
Editorial note: the Lancet Group takes a neutral position with respect to (sepsis-3). JAMA 2016; 315: 801–10.
territorial claims in published maps and institutional affiliations. 24 Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and
References national sepsis incidence and mortality, 1990-2017: analysis for the
1 O’Neill J. Tackling drug-resistant infections globally: final report Global Burden of Disease Study. Lancet 2020; 395: 200–11.
and recommendations. London: Review on Antimicrobial 25 WHO. Global report on the epidemiology and burden of sepsis:
Resistance, 2016. current evidence, identifying gaps and future directions. Geneva:
2 O’Neill J. Antimicrobial resistance: tackling a crisis for the health and World Health Organization, 2020.
wealth of nations. London: Review on Antimicrobial Resistance, 2014. 26 Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J,
3 de Kraker MEA, Stewardson AJ, Harbarth S. Will 10 million people Pinsky MR. Epidemiology of severe sepsis in the United States:
die a year due to antimicrobial resistance by 2050? PLoS Med 2016; analysis of incidence, outcome, and associated costs of care.
13: e1002184. Crit Care Med 2001; 29: 1303–10.
4 National Office for Animal Health. NOAH response to final 27 Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of
O’Neill AMR review report July 2016. Middlesex: National Office for sepsis in the United States from 1979 through 2000. N Engl J Med
Animal Health, 2016. 2003; 348: 1546–54.
5 WHO. Antimicrobial resistance. 2021. https://www.who.int/news- 28 Rhee C, Dantes R, Epstein L, et al. Incidence and trends of sepsis in
room/fact-sheets/detail/antimicrobial-resistance (accessed US hospitals using clinical vs claims data, 2009–2014. JAMA 2017;
Feb 23, 2021). 318: 1241–49.

Articles
29 Zheng P, Barber R, Sorensen RJD, Murray CJL, Aravkin AY. 48 Van Boeckel TP, Pires J, Silvester R, et al. Global trends in
Trimmed constrained mixed effects models: formulations and antimicrobial resistance in animals in low- and middle-income
algorithms. J Comput Graph Stat 2021; 0: 1–13. countries. Science 2019; 365: eaaw1944.
30 WHO. Antimicrobial resistance global report on surveillance 2014. 49 Ter Kuile BH, Kraupner N, Brul S. The risk of low concentrations of
Geneva: World Health Organization, 2014. antibiotics in agriculture for resistance in human health care.
31 Murray CJL, Aravkin AY, Zheng P, et al. Global burden of 87 risk FEMS Microbiol Lett 2016; 363: fnw210.
factors in 204 countries and territories, 1990-2019: a systematic 50 Wu G, Day MJ, Mafura MT, et al. Comparative analysis of ESBL-
analysis for the Global Burden of Disease Study 2019. Lancet 2020; positive Escherichia coli isolates from animals and humans from the
396: 1223–49. UK, the Netherlands and Germany. PLoS One 2013; 8: e75392.
32 New York Department of Health. Hospital associated infection 51 Mather AE, Reid SWJ, Maskell DJ, et al. Distinguishable epidemics
reporting persuant to Public Health Law section 2819. 2020. of multidrug-resistant Salmonella Typhimurium DT104 in different
https://www.gnyha.org/wp-content/uploads/2020/06/FINAL- hosts. Science 2013; 341: 1514–17.
DAL-20-10-PHL-2819-HAI-Reporting-6_11_20.pdf (accessed 52 Holmes AH, Moore LSP, Sundsfjord A, et al. Understanding the
May 19, 2021). mechanisms and drivers of antimicrobial resistance. Lancet 2016;
33 Centers for Medicare and Medicaid Services. COVID-19 emergency 387: 176–87.
declaration blanket waivers for health care providers. Baltimore, 53 Cox JA, Vlieghe E, Mendelson M, et al. Antibiotic stewardship in
MD: Centers for Medicare and Medicaid Services, 2021. low- and middle-income countries: the same but different?
34 WHO. Global priority list of antibiotic-resistant bacteria to guide Clin Microbiol Infect 2017; 23: 812–18.
research, discovery, and development of new antibiotics. 2017. 54 Rolfe R Jr, Kwobah C, Muro F, et al. Barriers to implementing
https://www.who.int/medicines/publications/WHO-PPL-Short_ antimicrobial stewardship programs in three low- and middle-
Summary_25Feb-ET_NM_WHO.pdf?ua=1 (accessed April 23, 2021). income country tertiary care settings: findings from a multi-site
35 UN. Interagency Coordination Group on Antimicrobial Resistance. qualitative study. Antimicrob Resist Infect Control 2021; 10: 60.
United Nations. 2017. https://www.un.org/sg/en/content/sg/ 55 WHO. 2019 antibacterial agents in clinical development: an analysis
personnel-appointments/2017-03-17/interagency-coordination- of the antibacterial clinical development pipeline. Geneva: World
group-antimicrobial-resistance (accessed April 29, 2021). Health Organization, 2019.
36 WHO. Global Leaders Group on antimicrobial resistance. 2021. 56 WHO. WHO sepsis technical expert meeting—meeting report.
https://www.who.int/groups/one-health-global-leaders-group-on- Geneva: World Health Organization, 2018.
antimicrobial-resistance (accessed April 29, 2021). 57 Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN,
37 WHO. Pneumococcal conjugate vaccines in infants and children Weisenberg S. Non-prescription antimicrobial use worldwide:
under 5 years of age: WHO position paper—February 2019. Geneva: a systematic review. Lancet Infect Dis 2011; 11: 692–701.
World Health Organization, 2019. 58 Laxminarayan R, Duse A, Wattal C, et al. Antibiotic resistance—
38 UN. SDG Indicators—global indicator framework for the the need for global solutions. Lancet Infect Dis 2013; 13: 1057–98.
Sustainable Development Goals and targets of the 2030 Agenda for 59 Kelesidis T, Falagas ME. Substandard/counterfeit antimicrobial
Sustainable Development. https://unstats.un.org/sdgs/indicators/ drugs. Clin Microbiol Rev 2015; 28: 443–64.
indicators-list/ (accessed Jan 27, 2020).
60 Collignon P, Beggs JJ, Walsh TR, Gandra S, Laxminarayan R.
39 WHO. Indicator 3.d.2: percentage of bloodstream infections due to Anthropological and socioeconomic factors contributing to global
selected antimicrobial-resistant organisms. Geneva: World Health antimicrobial resistance: a univariate and multivariable analysis.
Organization, 2020. Lancet Planet Health 2018; 2: e398–405.
40 UN. Report of the Inter-Agency and Expert Group on Sustainable 61 Ramay BM, Caudell MA, Cordón-Rosales C, et al. Antibiotic use
Development Goal indicators. New York, NY: United Nations and hygiene interact to influence the distribution of antimicrobial-
Economic and Social Council, 2020. resistant bacteria in low-income communities in Guatemala.
41 WHO. The selection and use of essential medicines: report of the Sci Rep 2020; 10: 13767.
WHO Expert Committee, 2017 (including the 20th WHO Model List 62 Hendriksen RS, Munk P, Njage P, et al. Global monitoring of
of Essential Medicines and the 6th WHO Model List of Essential antimicrobial resistance based on metagenomics analyses of urban
Medicines for Children). Geneva: World Health Organization, 2017. sewage. Nat Commun 2019; 10: 1124.
42 Burki TK. Tuberculosis missing from WHO bacteria list. 63 Mera RM, Suaya JA, Amrine-Madsen H, et al. Increasing role of
Lancet Respir Med 2017; 5: 252. Staphylococcus aureus and community-acquired methicillin-
43 Castro J. The WHO made a big mistake on tuberculosis. It must fix resistant Staphylococcus aureus infections in the United States:
it. STAT. 2017. https://www.statnews.com/2017/03/13/tuberculosis- a 10-year trend of replacement and expansion. Microb Drug Resist
who-antibiotic-resistance/ (accessed April 23, 2021). 2011; 17: 321–28.
44 Organisation for Economic Co-operation and Development, 64 Delorme T, Garcia A, Nasr P. A longitudinal analysis of methicillin-
European Centre for Disease Prevention and Control. Antimicrobial resistant and sensitive Staphylococcus aureus incidence in respect to
resistance: tackling the burden in the European Union. Briefing specimen source, patient location, and temperature variation.
note for EU/EEA countries. Paris: OECD Publications, 2019. Int J Infect Dis 2017; 54: 50–57.
45 Jansen KU, Knirsch C, Anderson AS. The role of vaccines in 65 Oldenkamp R, Schultsz C, Mancini E, Cappuccio A. Filling the gaps
preventing bacterial antimicrobial resistance. Nat Med 2018; 24: 10–19. in the global prevalence map of clinical antimicrobial resistance.
46 Klugman KP, Black S. Impact of existing vaccines in reducing Proc Natl Acad Sci USA 2021; 118: e2013515118.
antibiotic resistance: primary and secondary effects. 66 Ombelet S, Ronat J-B, Walsh T, et al. Clinical bacteriology in
Proc Natl Acad Sci USA 2018; 115: 12896–901. low-resource settings: today’s solutions. Lancet Infect Dis 2018;
47 Tang KL, Caffrey NP, Nóbrega DB, et al. Restricting the use of 18: e248–58.
antibiotics in food-producing animals and its associations with 67 Humphries RM, Abbott AN, Hindler JA. Understanding and
antibiotic resistance in food-producing animals and human beings: addressing CLSI breakpoint revisions: a primer for clinical
a systematic review and meta-analysis. Lancet Planet Health 2017; laboratories. J Clin Microbiol 2019; 57: e00203–19.
1: e316–27.

Resistencia Antibiotica A Nivel Global - Lancet 2022

Uploaded by

Copyright:

Available Formats

Resistencia Antibiotica A Nivel Global - Lancet 2022

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Resistencia Antibiotica A Nivel Global - Lancet 2022

Uploaded by

Copyright:

Available Formats

Articles

Global burden of bacterial antimicrobial resistance in 2019:

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 1

Introduction where surveillance is minimal and data are sparse.

2 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 3

Source type Number Sample size Sample Estimation step

Grand total 9324 471 300 319

Figure 1: Data inputs by source type

4 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 5

6 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 7

Associated with resistance Attributable to resistance

8 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

Role of the funding source

We estimated that, in 2019, 1·27 million deaths

(95% uncertainty interval [UI] 0·911–1·71) were directly

attributable to resistance (ie, based on the counterfactual

scenario that drug-resistant infections were instead drug GBD region

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 9

10 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 11

12 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 13

A Meticillin-resistant Staphylococcus aureus

Percentage of isolates with resistance

(Figure 7 continues on next page)

14 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

B Isoniazid and rifampicin co-resistant (excluding XDR) Mycobacterium tuberculosis

Percentage of isolates with resistance

(Figure 7 continues on next page)

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 15

C Third-generation cephalosporin-resistant Escherichia coli

Percentage of isolates with resistance

(Figure 7 continues on next page)

16 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

D Carbapenem-resistant Acinetobacter baumannii

Percentage of isolates with resistance

(Figure 7 continues on next page)

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 17

E Fluoroquinolone-resistant Escherichia coli

Percentage of isolates with resistance

(Figure 7 continues on next page)

18 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

F Carbapenem-resistant Klebsiella pneumoniae

Percentage of isolates with resistance

(Figure 7 continues on next page)

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 19

G Third-generation cephalosporin-resistant Klebsiella pneumoniae

Percentage of isolates with resistance

20 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 21

pathogen–drug combination, making direct comparison cephalosporin-resistant E coli to exceed that of

22 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 23

24 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0

www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0 25

26 www.thelancet.com Published online January 20, 2022 https://doi.org/10.1016/S0140-6736(21)02724-0