Guidelines 1) Students must write an argumentative philosophi.docx

Guidelines:
1) Students must write an argumentative philosophical essay on
a topic relevant to any of the course themes. It is recommended,
but not required, that you discuss your topic with me via email
or in my office hours (or by appointment) so that I may provide
suggestions and help to narrow down and clarify your topic.
2) Each student must select at least two academic sources
besides the assigned course reading (e.g. peer-reviewed journal
articles, books, or book chapters) to cite in their essay, and
these sources must be approved by me (via email or hard copy)
any time before the due date for the first draft of the essay.
Students may incorporate and cite assigned course readings in
their papers in addition to citing two other academic sources.
Besides academic works, relevant news articles may be cited as
needed, though these do not count as academic sources.
3) Essays must be at least 1200 words (not including
bibliography), double-spaced, in Times New Roman 12-point
font, with one-inch margins. Sources must be cited according to
an official style of the student's choosing (APA, MLA, Chicago,
etc.).
4) Essays must be argumentative. You should identify a position
that you think needs to be challenged or modified in some way.
Present the problem that you are dealing with as fairly and
clearly as possible. Then, advance your own argument. Finally,
raise at least one objection to your own position, and provide a
response to this objection in defense of your view. Avoid
"fluff," or unnecessary statements. Everything you write should
be relevant to your topic.
Basic Essay Structure
I. Introduction
-Describe the problem on which you are focusing. What is the

debate? Briefly summarize your position, the objection you are
considering, and how you intend to respond to the objection.
II. Your Argument
-Present your own argument. You should aim to expand upon,
reject, modify, or otherwise contribute to some aspect of an
ongoing discussion.
III. Objection
-Set up the objection from your "opponent" as clearly and fairly
as possible. Be sure to represent their position accurately (as if
it were your own position). This objection can come from a real
or imagined opposing side. Basically, you should present what
you take to be the strongest and most legitimate objection to
your own view.
IV. Your Response
-Provide a response to the objection in defense of your own
position.
V. Conclusion
-Similar to the introduction; summarize what you've done in the
paper and how you've done it. Don't add anything new in the
conclusion; only refer to points that are already addressed
within the paper.
Vol. 34, N° 2, 2018
ISSN 0120-5552
eISSN 2011-7531
494 Salud Uninorte. Barranquilla (Col.) 2018; 34 (2): 494-505
artículo de revisión/review article
http://dx.doi.org/10.14482/sun.34.1.9720
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Antibiotic Resistance: Origins, evolution
and healthcare-associated infections
Resistencia a antibióticos: Origen, evolución e
infecciones asociadas a la atención en salud
María Inés Torres-Caycedo1, Lisbeth Teresa Castro-Gutiérrez1,
Carlos Fernando Prada-Quiroga1, Diana Paola López-Velandia1

Abstract
The increased incidences of Healthcare-associated Infections
(HAI) caused by multidrug-resistant
bacteria, have led to an enlarged number of morbidity and
mortality cases. Besides, other factors
that are affected are patients, families and institutions providing
health services. Therefore, the
permanent study of the subject is necessary to identify possible
strategies that contribute to the
reduction of the issue. A critical review of the literature based
on the origin of antibiotics, the
evolution of their respective resistance, and the impact on
public health from a historical and
current perspective was developed. The search of the literature
was carried out in the bibliogra-
phic databases: Pubmed, Web of Science, Scopus, SciELO, The
Cochrane Library and Lilacs.
The reviewed literature showed, from the historical viewpoint,
the discovery of antibiotics to
the last-generation antibiotics. The rapid coevolution of genes
for antibiotics resistance and its
subsequent spread to hundreds of species of microorganisms by
Horizontal Transfer gene (HTG)
was also reviewed. It is also discussed how the expansion in
antimicrobial resistance (AMR)
generates a series of factors that increase health-care associated
infections care (HAI) and their
impact on public health. The development of antibiotics from
the discovery to recent changes
in the behavior and response of the microorganisms with the
generation of AMR shortly after,
is one of the most fantastic examples of the evolution that exists
in nature.
Key words: Microbial Drug Resistance, Bacterial Genes,
Infection, Horizontal Gene

Transfer, History.
1 Bacteriology and Clinical Laboratory research group.
Universidad de Boyacá.
Correspondence: Diana López-Velandia University campus. Cra
2 este N 64-169 Tunja, Boyacá; Colombia.
Tel. (8)7450000 - Fax. (8) 7450044. Email: [email protected] -
[email protected]
495Salud Uninorte. Barranquilla (Col.) 2018; 34 (2): 494-505
Antibiotic Resistance: Origins, evolution and healthcare-
associated infections
Resumen
El aumento en la incidencia de infecciones asociadas a la
atención en salud causada por mi-
croorganismos multiresistentes a antibióticos, han incrementado
la morbilidad, mortalidad
y otros factores que afectan a paciente, familias e instituciones
prestadoras de servicios de
salud; por lo que se ha hecho necesario el estudio permanente
del tema, para identificar posibles
estrategias que contribuyan a disminuir la situación. Se realizó
una revisión de la literatura
sobre el origen de los antibióticos, la evolución de su respectiva
resistencia, el impacto en la
salud pública; desde una perspectiva histórica y actual. La
búsqueda de la literatura se realizó
en las bases de datos bibliográficas: Pubmed, Web of Science,
Scopus, SciELO, The Cochra-
ne Library y Lilacs. El análisis de la literatura mostró desde el
punto de vista histórico, el

descubrimiento de los antibióticos hasta los últimos antibióticos
de última generación, y la
rápida coevolución de los genes de resistencia a los antibióticos
y su posterior diseminación
a cientos de especies de microorganismos mediante la
Transferencia Horizontal de Genes
(THG). También es discutido como el incremento de la
resistencia a los antibióticos (RAM)
genera una serie de factores que potencian las infecciones
asocia de las a los cuidados de la
salud (IACS) y su impacto en la salud pública. La historia desde
el descubrimiento, los cam-
bios en el comportamiento de uso de los antibióticos y la
respuesta de los microorganismos
con la generación de la RAM poco tiempo después, es uno de
los ejemplos más fantásticos de
coevolución que existe en la naturaleza.
Keywords: Resistencia microbiana a los medicamentos, genes
bacterianos, infección,
Transferencia horizontal de genes, Historia.
INTRODUCTION
Since the beginning of the antibiotics era, the
resistance to these substances has described,
during several decades; antimicrobial resistance
(AMR) has been an increasing menace for the
effective treatment of a wide range of infections
caused by bacteria, parasites, virus and fungi.
AMR produces a reduced efficacy of antibacte-
rials, antiparasitics, antivirals and antifungals;
turning difficult the treatment of patients who
have got this kind of microorganisms (1). The ori-
gin, evolution and resistance mechanisms have
appeared during the last 60 years; at the begin-
ning, the problem was solved with the synthesis

of new substances which were capable to control
bacteria with AMR, then other medicaments
appeared such as aminoglycosides, macrolides,
glycopeptides, among others (2). During the first
world congress about antibiotics resistance, the
World Health Organization (WHO)) exposed
that the so called “killer bacteria” are a world-
wide menace, with a great ability to mutate;
even avoiding broad-spectrum antibiotics,
in the same way the data of 114 countries
previously analyzed and it was also exposed
that AMR is currently present worldwide
and at every social level (3). The alarming
increase of AMR is, without a doubt, one of
the biggest problems of current public health,
since these compounds are one of the main
tools to control and treat bacterial infections,
in human medicine as well as in veterinary.
Recent studies estimated the economical
effects of ARM, for example; the annual cost
for health system in USA is estimated from
21 to 34 billion dollars, accompanied by
more than 8 million days in hospital (4); in
Europe, it is estimated a cost around €1.600-
6.000 per year in patients with resistance
to third-generation cephalosporines (5); a
study made in 12 European countries (Bel-
gium, France, Germany, Italy, Netherlands,
Yonathan Rueda Paez, Mario Santos Chacon, David Mantilla

Ojeda1, Aracely Pinilla Plata1, María Alejandra Díaz Peñuela,
Angélica María Vera Arias, Heider Carreño Garcia, Julio César
Mantilla Hernández, Patricia Escobar Rivero
Poland, Slovakia, Slovenia, Spain, Sweden and
the United Kingdom) evaluated the costs of
medical attention and the resistance to multi-
ple medicines finding that this amounted to €
727.4 135 (£ 589 856) (6); the costs in Singapore
are around USD$ 8638.58 in multiresistant in-
fections (7); in Spain, the average economical
cost per admission of patients who have got
strains resistant to multiple medicines is higher
than the ones with non-resistant strains with
€15.265 compared to €4.933 for the others (8);
in South Africa, the average cost of a successful
tuberculosis treatment in patients resistant to
rifampicin was USD $8359 (9). Therefore, the
objective of this study was to make a critical
review of the literature about the evolution
of AMR, from different perspectives: Histo-
rical, molecular, mechanisms and its impact
in public health.
MeThODOlOgy
A thorough review about the origin and impact
of antibiotics and their endurance regarding
the infections associated with health assistance
worldwide was made with a historical and
current perspective. This review is the result
of the execution of the research project entit-
led: “Molecular typing of resistance genes in
gram-negative bacilli associated to infections
in a health service provider institution in
Boyacá”. For the identification of the studies,

the bibliographic databases consulted were;
Pubmed; Web of Science; Scopus; SciELO;
The Cochrane Library and Lilacs. It was set a
deadline for publications from 2010 to 2017.
They were considered original researches or
review articles, available in English or Spanish.
Key words validated in Descriptors in Health
Sciences were also used, which included mi-
crobial resistance to drugs, bacterial genes,
infection, horizontal gene transfer and history.
ResUlTs
Evolution of AMR
Since the emergence of humankind, the use
of natural resources ha sbeen sought for its
benefit, as an adaptive strategy to different
environments.Several natural products were
used by observation or intuition, in order to
improve their health and welfare, mainly, fa-
cing the presence of pathogenic agents.Once
these resources were considered exhausted
and measured by advances in science, they
resorted to chemical synthesis (10).
AMR has been described since the beginning
of the 30s. After the use of penicillin in World
War I, the first resistant bacteria emerged;
in 1945, Fleming postulated the potential
risks associated to the use of antibiotics; he
showed that the use of a large and prolonged
scale can select resistant bacteria, observing
in his laboratory that bacteria sensitive to pe-
nicillin multiply in the presence of increasing
concentrations of the antibiotic (11). During

the 40s, the first report of penicillin resistan-
ce by strains of Escherichia coli (E. coli) and
Staphylococcus sp was reported (12). In 1947,
resistance to streptomycin among patients
with tuberculosis was detected, where 80%
of them relapsed within three months due
to the formation of resistant bacilli (13). In
the years 1952 and 1957, resistance to tetra-
cycline and chloramphenicol was reported
and in the decade of the 60s, β-lactamases
producing strains, such as TEM and SHV of
wide spectrum (detected in gram-negative
bacilli) were discovered (14) (15).
Extended-spectrum β-lactamases (ESBLs)
are phenotypically resistant to penicillins
and cephalosporins; they were registered for
the first time in E. coli in 1964 (16). Later, in
the 80s, antibiotics such as aminoglycosides
(including vancomycin) were detected from
resistant strains of Enterococcus; a short time
later, it was found resistance to ampicillin in
different species and the list kept growing (17).
At the end of the 70s, bacteria resistant to am-
picillin and cephalosporins were reported (12).
In 1980, it was estimated that between 3-5%
of Streptococcus pneumoniae (S. pneumoniae)
was resistant to penicillin; but in 1998, 34% of

these bacteria increased their resistance to this
antibiotic. In the same decade, resistance to
vancomycin and erythromycin was observed
(13). Subsequently, in 1999 the multiresistance
of gram-negative bacteria was described. For
the period from 2002 to 2009, an increase in
strains of E. coli resistant to broad-spectrum
cephalosporins was observed, which is pre-
sent in most of European countries. In 2008,
a new enzyme called “New Delhi Metallobe-
talactamase” was observed, which confers
resistance to all beta-lactam antibiotics, except
aztreonam; showing a global alert against
AMR to several non-beta-lactam antibiotics
(18), leaving a few therapeutic options for
the treatment of patients infected with these
bacteria. After this report, the presence of
this type of resistance was identified in 2010
in Canada, in 2011 in the United States and
Guatemala; in 2012 in Uruguay, Paraguay
and Colombia (19).
AMR is one of the most spectacular and docu-
mented natural event in microbial evolution,
from the origin and application of antibiotics,
passing through a few years in order to make
that the different phenotypes arise; twelve
years after the origin and application of pe-
nicillin, the first resistance mechanism was
detected (20). This is how it is observed that,
in a few years, bacteria can increase the speed
of AMR generation. For example, in ten years
after having resistant strains to penicillin and
methicillin, resistance to chloramphenicol
emerged, and in four years to streptomycin.

Therefore, AMR is a growing public health
problem, seen barely some years after the
discovery of penicillin (21). That is why, a
question arises from the emergence of AMR:
What is or what are the mechanisms involved
in this fast production of AMR?
Origin of AMR
Throughout the five decades that followed the
synthesis and the indiscriminate use of anti-
biotics in people, animals and agriculture; a
selective process unprecedented in the history
of evolution has been observed, due to the fact
that it has been an unregulated practice that
lacks control and supervision (22); but this
selection, considered by many researchers as
artificial, has many components to consider
in this review; in addition to the selective
effect, the high rate of mutations in bacteria,
the formation of bacterial communities and
the horizontal transfer of genes, are impor-
tant factors in the generation of AMR (23).
There are several examples in the literature
of spontaneous mutations in bacteria; some
researchers consider that the evolution of resis-
tance, through the acquisition of spontaneous
mutations is particularly relevant for certain
drugs, such as quinolones and rifamycins,
for which the high-level resistance can result
from a point mutation (22, 24). For example, in
Salmonella typhimurium (S. typhimuriun), with
a point mutation in the henC gene, the resis-
tance of the bacteria to protamine increases,
but with a cost in the reduction in bacterial
growth (25); similar results were described

in Salmonella enterica, where mutations in
the tRNA-isoleucine gene confer resistance
to mupirocin but with a reduction in growth
(26). Other authors consider that AMR can
evolve through the accumulation of multiple
sequential mutations and not by single point
mutations (27); this mechanism would be
responsible of the high levels of AMR that
currently present many of the microorganism
species, pathogenic species(28). These results,
have shown that microorganisms that have a
strong selective pressure (high concentrations
of antibiotics), have RAM in a short period;
similar to the one presented currently, es-
pecially in treatments against infections in
humans (29).
It is presumed that there exist around 20 thou-
sand resistant genes, predicted through the
analysis of DNA sequences of different bacte-
rial genomes however, they are functionally
expressed in just some of them (28); many of
them are originated by unique or consecutive
punctual mutations, or also by gen duplica-
tions. But, what is the reason for these genes
to be distributed in other strains or bacterial

species presented in different environments?
The answer to this question can be found in
studies of comparative genomics. The iden-
tification of the sequences of bacterial genes
in eukaryotic genomes, as the presence and
genomics of pathogenicity islands presented
in E.coli, found in other animal pathogenic, in
human genome and some plant species; they
confirm the theory of horizontal gene transfer
(30). Horizontal gene transfer (HGT) has been
considered as the mechanism responsible of
the dissemination of antimicrobial resistance
genes through different bacterial species (31).
Actually, the genes that present resistance to
certain antibiotics in non-related phylogene-
tically bacteria, demonstrate to have iden-
tical nucleotide sequences, including Gram
positive and negative bacteria; it emerged at
the beginning of the decade of 1990; it was a
way to explain the phylogenetic incongruence
using different gene trees. This process can also
occur among the domains in all the possible
directions, from bacteria to archaea, bringing
new data about the rise of the genomic era,
which has permitted the comparison of genes
among different species (32). The interchange
of genetic material in HGT among genomes
is carried in different ways, acquiring a great
relevance in the prokaryotic evolution due to
the resistance to antibiotics that contribute to
the inclusion of new mechanisms by bacteria
(33, 34).
HGT is a phenomenon which takes place in
and within the three domains of life (Fig. 1).

The acquisition of genes by bacteria has got
accelerated by the increase of adaptive and
selective pressure needs, specifically the use
of antibiotics in infections control in medicine,
veterinary, agriculture and animal nutrition
(35); the mark of the transference corresponds
to the existence of a gene or genic sequence in
the phylogenetic tree of the organism and to
the observation of the same genic disposition
in the donor and receptor bacterial population
(31, 36).
With the recent increase of the studies in me-
tagenomics, in which resistance to antibiotics
has been identified in different ecosystems
(37), for example; in human micro biome
which generated complete genome sequences
of several hundreds of human microbes, it has
confirmed this HGT theory. Liu et al, detected
a total of 13.514 genes coming from HGT
identified in 308 human microbes in different
parts of the body (including intestine, mouth,
skin, etc.), with an average of 43,9 HGT per
microbe THG (30). Besides this finding, resear-
chers discuss the possibility of THG among
the micro biome and the cells of our body;
and how this event can be related to human
health due to the fact that the total number of
microbial cells hosted by the human body is
10 times greater than the number of human

cells in the body (100 times the number of
genes in the human genome); The theory of
HGT between the microbiome and the cells
of our body is more than supported, but this
behavior is not exclusive of the human mi-
crobiome (38).
The acquisition of genes by bacteria is accele-
rated, increasing the need of adaptation and
selective pressure, specifically, by the use of
antibiotics to control infections in human
medicine, veterinary medicine and agricul-
ture. Therefore, being in permanent contact
with diverse environments, farm or domestic
animals, plants, insects, among others HGT
could be present even more frequently than
it is commonly thought (31, 39)
Among the most probable mechanisms of
HGT are conjugation, transformation and
transduction; in which mobiñe genetic mole-
cules take part such as plasmids, bacteriopha-
ges, transposons, integrons and gene cassettes
that have genes with functions for their own
transfer and / or bacterial resistance (40). In
chat 1 examples can be found of mobile ge-
netic elements that transfer resistance genes.
One of the most common and known mecha-
nism is the conjugation by means of plasmid
transfer, taking resistance genes; in Gram-
negative bacteria, resistance genes are found
as a part of small mobile genetic elements or
“cassettes”, integrated in greater elements

(integrons) (41). Integrons are structures of
interest because they are found in the bacte-
rial chromosome structure presented in the
cassettes of genes related to resistance; it has
been observed that more than a cassette can
be inserted in the same integron to generate
molds that contribute to the spreading of the
multiple resistance (42). Resistance genes
spreading is higher when these are part of
mobile genetic cassettes, which permit them
to be transferred by several mechanisms (43).
There exists enough scientific evidence of
the high rate of HGT among gram-negative
and positive bacteria, generated mainly by
conjugation.
Cassettes can codify several compounds that
generate resistance for a huge range of anti-
biotics including ß-lactam, aminoglycosides,
trimethroprim, amphenicol, sulfonamide,
tetracyclines, rifampicin, erytromycin and
quinolones (44).Therefore, integrons and cas-
settes that bring multiple ARM are, currently,
the most studied genic elements by researchers
in order to explain the origin of ARM and its
impact in public health.
AMR in health-care associated infections
During more than 60 years, antibiotics have
been considered as the panacea to cure in-
fections, with enormous benefits for human
health. The development of the resistance to
this important class of medicaments, and the
consequent loss of its efficacy as an antimi-

crobial therapy, represents a serious health
menace. Despite the efforts of hospitals to
improve the caring process and health of the
patient, infections still occur with a higher
frequency; it has been complex to determine
the world range exactly; it is estimated that
every year billions of patients get affected
(45). Health-care associated infections (HAI)
are defined as any infectious process, general
or localized, that occurs due to the stay or
attendance to a health center and appears
during or after the discharge more than 48
hours after the entry. They include blood
infections, affected area by a surgery, skin
and soft tissue, pneumonia, and urinary tract
infections which are the most common (46).
Therefore, HAI, besides entailing an adverse
effect for the patient, are also an indicator of
the caring quality. The rise and reemergence of
HAI, caused by ARM microorganisms, has as
a consequence the increase of morbidity and
mortality in hospitals around the world (47,
48). They are associated to economic effects in
institutions, in health systems and therefore
in economical ranges for the countries (49-51).

In the American continent, a prevalence of
HAI is present which varies from 4.5% in
the United States, to 14% in Brazil (52). Other
studies in several countries of America reveal
a wide variation in the incidence of resis-
tance in common bacterial pathogens, as an
example, the resistance to third generation
cephalosporines observed in E. coli, varying
from 0% in the case of Brazil to 50% in Peru;
in comparison with the world reports where
they are found in 26.8% (53).
The increase of the resistance has become one
of the most important aspects in the world
and this is why, the antimicrobial resistance
was declared as a public health problem by
the World Health Organization in 1999; it is
related to the excessive and indiscriminate use
of antibiotics in the community and hospitals,
as a decisive factor in the origin of the rise of
resistant pathogens nowadays (3).Therefore,
it is necessary to promote strategies of control
of AMR through the exact identification of the
microorganism and its resistance phenotype,
besides the opportune information of these
results to the service of infectious disease
treatment in the hospital, in order to avoid
the proliferation of multiresistant strains that
produce new HAI (46).
CONClUsIONs
The history of the discovery and usage of
antibiotics and their corresponding ARM
generation a short time later, is one of the

most fantastic examples of coevolution that
exist in nature. One of the decisive factors in
this case is the indiscriminate use of antibio-
tics at different levels: In human, animal and
environmental medicine. The last mentioned,
can emerge when the antibiotics that were not
consumed are thrown, taking the risk of gene-
rating resistant bacteria in the environment.
On the other hand, the rise of resistance
genes can have several origins: (a) Punctual
mutations, (b) Consecutive mutations of high
frequency and, (c) genic duplications. Besides,
microorganisms are held to strong selective
pressures, due to the indiscriminate use of
antibiotics which cause multiresistant strains.
In the same way, these ARM microorganisms
are able to transfer their resistant genic pool to
other strains or sensitive species to antibiotics
by different HGT mechanisms as transduction,
transformation and conjugation. HGT can
be presented in different auspicious envi-
ronments as health attention centers where
different types of infections are treated and
their different origins increasing the HGT
potential. The increase of HAI is originated for
multiple factors, most of them, avoidable. Un-
fortunately, in many HGT cases, infections are
originated by multiresistant microorganisms,
even to last generation antibiotics, increasing
the morbidity and mortality around the world.
In a consistent way with the alarms of the
WHO, the studies related to ARM must be
increased as well the respective restrictions
of antibiotics usage, mainly in developing

countries as the ones of South-America.
Las HSPs tienen 4 regiones funcionales conservadas. En Azul
claro dominio N-terminal (llamado dominio J), En azul
la región flexible rica en glicina/fenilalanina, en verde la región
M de unión al sustrato y en rojo la región N-terminal.
Fuente: Realizada por los autores de la revisión.
Figure 1. Evolution of antibiotics synthesis
Chart 1. Examples of mobile genic elements that transfer
resistance genes
Donor bacterium
Receptive
bacterium
Vector (genetic element) /
genes
Resistance phenotype
Klebsiella pneumoniae,
Eschericha coli,
Enteroacter cloacae
Eschericha coli
Plasmids R6K, RP4, R1 y

pUA21 / BLEEs tipo SHV-2 y
SHV-5 (54, 55).
Cephalosporins
Escherichia coli MKD13
Klebsiella
pneumoniae
Plasmids pNU147 / blaTEN-1
(56).
ß-lactam, gentamicin, kanamycin,
tetraciclyne and chloranphenicol
Ancestral
Pseudomonas
aeruginosa
Integron In0 - plasmid pVS1 /
sul 1 (57).
Sulfonamide
Ancestral
Acinetobacter
baumannii biotype
9
intI1 - intl2 (Tn7, Tn21)/ sul1
(50).
ß-lactam, sulfonamides,
trimethoprim, tetraciclyne,

chloranphenicol, and
aminoglycosides
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12. Ahmed OB, Omar AO, Asghar AH, Elhassan
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2016;18(1):190-202.
Conflict of interests: The authors have de-
clared that there are no conflict of interests.
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incentives to stimulate research and development of new
antibiotics • summer 2018 81
The Journal of Law, Medicine & Ethics, 46 S1 (2018): 81-94. ©
2018 The Author(s)
DOI: 10.1177/1073110518782919
Introduction
Access to Effective Antibiotics
Resistance to antibiotics is increasing in a wide range
of pathogenic bacteria, threatening the availability
of effective antibiotics.1 Increasing rates of antimi-
crobial resistance (AMR) are reported in all regions
of the globe.2 This threat is partly attributed to the
excessive use of antibiotics, since consumption has-
tens the selective pressure on bacteria which results in
the survival of resistant, and multi-resistant, strains.3

Moreover, antibiotic consumption is increasing glob-
ally, with high levels of antibiotics prescribed unneces-
sarily.4 Thus, making sure that existing antibiotics are
used appropriately is fundamental.
Notwithstanding, access to life-saving antibiotics is
inadequate in many parts of the world, especially in
low- and middle-income countries.5 An estimated 5.7
million people die from treatable infectious diseases
every year, surpassing the estimated 700,000 annual
deaths due to AMR (which includes not only antibi-
otic resistance but also antifungal, antiparasitic, and
antiviral resistance).6 Therefore, measures to increase
access should be linked with proper control measures
to ensure appropriate use. This has led to calls for anti-
biotics, especially novel and specific last-resort antibi-
otics, to be treated as a type of controlled medicines
similar to the controlled drug regimen for narcotics
with the intent being that these precious antibiotics
can be safeguarded.7
The Current Drug Control System
Three United Nations (UN) Conventions make up
the current drug control regimen. The first conven-
tion that was devised is the 1961 Single Convention
on Narcotic Drugs, as amended by the 1972 Protocol,
often referred to as the Single Convention. One hun-
dred and eighty-six nations have officially ratified the
Single Convention, making it one of the most widely
adopted international legal instruments.8 The aim of
the Single Convention is to achieve a “balanced policy”
— in other words to prevent abuse as well as to ensure
adequate access for sound medical practice (especially
access to opioids for pain management). Provisions
of the Single Convention are designed to fulfill these

objectives, and include measures related to control-
ling the production, manufacture, export, import,
distribution, trade, cultivation, and possession of con-
trolled medicines.
The Single Convention created a foundation for
strict control over the consumption of narcotic drugs
where all governments must provide annual estimates
of their drug requirements and statistical returns on
actual activities involving narcotics to the International
Narcotics Control Board (INCB). All governments are
obligated to comply with this system, including coun-
tries that have not ratified the Single Convention. If
countries require more than their annual estimates,
they must request adjustments to their estimates. If
Should Antibiotics Be Controlled
Medicines? Lessons from the
Controlled Drug Regimen
Live Storehagen, Friha Aftab, Christine Årdal, Miloje Savic,
and John-Arne Røttingen
Live Storehagen, M.Pharm., M.Phil., is an advisor on
global health and antimicrobial resistance for the Norwegian
Institute of Public Health (NIPH) in Oslo, Norway. Friha
Aftab, M.D., is working at the Oslo University Hospital, Nor-
way. She wrote her dr.med. thesis on controlled medicines and
antibiotic stewardship. Christine Årdal, Ph.D., is a senior
advisor on global health and antimicrobial resistance for the
Norwegian Institute of Public Health (NIPH) in Oslo, Nor-
way. Miloje Savic, Ph.D., is a senior advisor on global health
and antimicrobial resistance for the Norwegian Institute of
Public Health (NIPH) in Oslo, Norway. John-Arne Røttin-
gen, M.D., Ph.D., M.Sc., M.P.A., is the Chief Executive of
the Research Council of Norway and Adjunct Professor at the
Department of Global Health and Population, Harvard T.H.

Chan School of Public Health.
http://crossmark.crossref.org/dialog/?doi=10.1177%2F10731105
18782919&domain=pdf&date_stamp=2018-07-17
82 journal of law, medicine & ethics
J L M E S U P P L E M E N T
2018 The Author(s)
the annual estimates are exceeded and not adjusted,
these are deducted from the estimates for the follow-
ing year. Exporting countries are obliged to limit sales
to the quantities remaining with the annual national
estimates.9 The Single Convention also introduced a
drug classification system where narcotic drugs are
classified in four schedules according to dependence
potential, abuse liability and therapeutic usefulness
(Table 1). The different schedules are subject to differ-
ent “degrees of control”. It ranges from most restrictive
to least restrictive in this order: Schedule IV, Sched-
ule I, Schedule II, and Schedule III. The INCB pub-
lishes annually a list of narcotic drugs under interna-
tional control, which contains more than one hundred
substances.10
A decade after the introduction of the Single Con-
vention, the 1971 Convention on Psychotropic Sub-
stances was developed. This Convention expanded
the range of drugs to include synthetic drugs, but
imposed a weaker control system compared to nar-
cotics. In 1988, in response to the rapidly growth of
the illicit drug trafficking market, the Convention

against Illicit Traffic in Narcotic Drugs and Psycho-
tropic Substances was adopted.11 Yet, despite the exis-
tence of these widely adopted conventions, abuse of
narcotics continue to be a major problems, with the
United States (US) recently declaring it a “public
health emergency.”
Methods
The aim of this qualitative study was to evaluate the
applicability of the current controlled drug regimen
for ensuring appropriate use of antibiotics. The study
was guided by the following research questions:
1. What are the measures embedded in the Single
Convention, and which could be applicable in the
area of ensuring appropriate use of antibiotics?
2. How successful in general have these measures
(identified in the first research question) been to
control opioid use and to ensure access for medi-
cal purposes?
3. What can be learned from the measures and
interventions implemented in different coun-
tries’ regulatory systems as a result of the Single
Convention?
A content analysis of the Single Convention was con-
ducted in order to identify all the measures embed-
ded in it designed to prevent abuse or ensure avail-
ability (research question 1). The identified measures
were then classified into different categories. Next
we decided on the categories of measures relevant to
include in our analysis for their applicability to antibi-
otics. For the measures assessed as “possibly relevant,”
we identified similar measures already in existence for

antibiotics.
Classification
of Narcotics Definition
Examples (Cited from the 56th Edition
of the INCB’s “Yellow List” – List of
Narcotic Drugs under International
Control)
Schedule I Substances that are highly addictive and liable to
abuse, or are convertible into drugs that are similarly
addictive and liable to abuse.
Methadone, morphine and other strong opioids.
Schedule II Substances that are less addictive and liable to
lesser
abuse than Schedule I.
Codeine.
Schedule III Preparations containing narcotic drugs intended for
medical use and are unlikely to be abused. These
are exempt from certain provisions, e.g. trade
authorizations, estimates of need and statistical
returns to the Board.
Preparations of codeine and ethyl morphine (when
containing not more than 100 milligrams per dosage
unit and with a concentration of not more than 2.5
per cent in undivided preparations).
Schedule IV Selected substances in Schedule I that are
particularly
harmful in terms of addictive properties and abuse

potential, and are rarely used in medical practice. All
Schedule IV drugs must also be in Schedule I, and
countries can choose to prohibit these substances.
Heroin and cannabis.
Table 1
Classification of Narcotics, Adapted from the INCB’s Training
Material for the International Control
System for Narcotic Drugs
Storehagen et al.
2018 The Author(s)
To answer research questions 2, we did a literature
review using the PubMed database. We searched for
articles published between 2007 and July 2017 using
the search terms “opioids,” “drug and narcotic control,”
“opioid-related disorders,” and “access” or “availabil-
ity”. Only articles published in English were included.
References were checked for additional materials.
Then, eight semi-structured interviews were con-
ducted to provide examples of the challenges and best
practices for ensuring appropriate access to opioids
within different countries (research question 3). We
interviewed government officials or private sector
representatives from Brazil, Finland, India, Mexico,
Norway, Singapore, and Uganda — selected to rep-
resent different country income groups and different
consumption levels of opioids. We also interviewed an

international drug control expert. Findings from the
literature review were also used to support the results
from the interviews. Finally, we combined the findings
from all of the three research questions to derive on
our recommendation regarding which measures could
be applicable to ensure appropriate use of antibiotics.
Results and Discussion
Has the Single Convention Ensured a Balance between
Access and Control?
The international drug control system has been criti-
cized for having had negative effects on public health.
WHO estimates that 5.5 billion people have low to non-
existent access to treatment for moderate to severe
pain despite the growing burden of cancer.12 In our lit-
erature review we found several research articles high-
lighting that access to opioids for pain management
is inadequate in most parts of the world, especially in
Africa and Southeast Asia. In sub-Saharan Africa, it
is estimated that 88% of cancer deaths are untreated
for cancer pain.13 In India only 0.4% of more than a
million people who need opioids for pain relief have
access.14 However, the global opioid consumption for
pain treatment has more than doubled between 2001-
03 and 2011-13, but this increase is concentrated in a
few high-income countries. North America (the US,
Canada and Mexico), Australia, and some western and
central European countries account for 95.7% of the
world’s opioid consumption, but represent only 15%
of the world’s population.15
The reasons for low access to opioids are multifacto-
rial. First, many governments have not focused on the
“access” aim of the Single Convention. Regulations to
reduce abuse have obstructed actions to ensure avail-
ability for medical purposes. Several national laws lack

provisions to ensure adequate access for medical and
scientific purposes. In addition, the UN model laws
that are used by governments to draft national legisla-
tion have not included an obligation for governments
to ensure availability of narcotics for medical use, but
rather focused exclusively on the abuse potential.16
Other factors, such as the international trade controls,
fears of addiction, lack of training for medical profes-
sionals and public awareness, and excessive regulatory
measures related to the prescribing and dispensing of
opioids are causing the low access to pain treatment.17
These factors were also highlighted in our interviews,
and are discussed in the following sections.
Despite the stringent control measures introduced
by the Single Convention, overuse of controlled drugs
has reached alarming levels in some high-income
countries. It is estimated that there are 15.5 mil-
lion opioid-dependent people globally.18 The US has
recently experienced significant increases in morbid-
ity and mortality associated with the overuse of opi-
oids,19 and the non-medical use of prescription opioids
has reached epidemic proportions.20
It is apparent that governments around the world
have struggled at achieving a balanced policy that
prevents drug abuse while at the same time ensures
availability for medical purposes. Moreover, the con-
trol system put in place by the Single Convention is
blamed for causing additional detrimental effects on
public health, such as contributing to the spread of
communicable diseases like HIV and exacerbating the
overdose problem.21
Measures in the Single Convention and Their

Applicability to Antibiotics
For the purposes of this study, we further examined
the specific components of the Single Convention and
assessed the evidence of their effectiveness. In our
content analysis of the Single Convention we identi-
fied thirty-five measures that we categorized into eight
categories:
• Drug classification system
• Prescribing and dispensing
• Consumption control and monitoring
• Licenses
• Drug control organs
• Government obligations and rights
• Illicit activities and abuse
• Measures specific to opium, cannabis and coca
leaf
The detailed categories and underlying measures are
listed in Supplementary Table 1. From these categories
we excluded the last four in the above mentioned list
because the measures were related to providing the
legal framework for countries to organize the imple-
mentation of the Single Convention at the national
2018 The Author(s)
level, thus not directly specific to the drug control

regimen (“drug control organs” and “government obli-
gations and rights”) or the measures were of less rel-
evance for antibiotics (“illicit activities and abuse” and
“measures specific to opium, cannabis and coca leaf ”).
This is not to say that illicit activities and abuse are
not at all relevant for antibiotics, but it is within the
larger context of counterfeiting which is not antibiotic
specific. We then assessed how successful underly-
ing measures have been to control opioid use and to
ensure access for medical purposes. In Table 2 we list
them, comment on their applicability to antibiotics,
and summarize the main findings from the interviews
and literature review. The following sections describe
our findings in greater detail, and include examples
and lessons learned related to how these measures are
implemented in different countries’ national systems.
We also discuss how each of the previously mentioned
categories of control measures may, or may not, apply
to antibiotics.
Drug Classification System
The classification system in the Single Convention
serves as a model for national scheduling systems.
This means that drugs included in different national
control legislations do not necessarily exactly match
the scheduling of drugs according to the Single Con-
vention. Accepting the treaty means that the country
has to implement the treaty as a domestic law, which
can be stricter than the treaty.22 As a consequence,
some countries incorporate control measures required
only for Schedule I drugs over narcotics in Schedule
II, prohibit certain narcotics, or implement additional
regulatory measures not required by the Single Con-
vention. Moreover, the Single Convention leaves some
room for interpretation when formulating domestic
laws. For example, national laws on the possession of

cannabis vary between countries. It is illegal in most
countries, but in some countries medical cannabis is
available and recreational use is accepted, such as in
the Netherlands. In the US, cannabis is illegal for both
medical and recreational purposes by the federal law,
but not necessarily by state laws. The US government
simply has chosen not to prosecute federal law viola-
tions related to cannabis, as long as they comply with
the local law.
Overuse of narcotics is a global concern due to the
abuse potential, whereas overuse of antibiotics is a
global concern due to the emergence of resistance.
A classification system for antibiotics, similar to the
one embedded in the Single Convention, therefore
appears as a useful mechanism for identifying those
critical antibiotics that should be used sparingly. It
might facilitate conservation efforts that could be
harmonized across multiple countries, if not globally.
This may include limiting which physician specialities
are allowed to prescribe selected antibiotics, in what
settings they are used, how use is monitored, require-
ments for strict infection control measures, restricting
manufacturers’ ability to promote certain antibiotics,
and AMR surveillance requirements. However, the
WHO has already introduced a classification system
for antibiotics. In 2015, the WHO introduced the list
of Critically Important Antimicrobials (CIA). This list
ranks antimicrobials according to their importance to
human medicine: critically important, highly impor-
tant, and important. The purpose of the CIA list is
to reduce the use of antimicrobials in food animals,
particularly those antimicrobials that are critically
important for human medicine.23 Moreover, the latest

edition of the WHO essential medicines list includes a
classification system where antimicrobials are placed
in three different tiers: access, watch and reserve.24
The “access” group includes antibiotics, like amoxi-
cillin, that should be readily available for common
infections. The “watch” group contains antibiotics
that should be used sparingly for a small number of
infections. This group contains first- or second-choice
drugs like ciprofloxacin. Lastly, the “reserve” group
contains the “last resort” antibiotics that should be
used only for specific patients and settings or to treat
life-threatening infections due to multidrug-resistant
bacteria like, colistin and new-generation cephalo-
Overuse of narcotics is a global concern due to the abuse
potential, whereas
overuse of antibiotics is a global concern due to the emergence
of resistance.
A classification system for antibiotics, similar to the one
embedded in the Single
Convention, therefore appears as a useful mechanism for
identifying those
critical antibiotics that should be used sparingly. It might
facilitate conservation
efforts that could be harmonized across multiple countries, if
not globally.
Storehagen et al.

2018 The Author(s)
Table 2
Control Measures in the Single Convention: Assessment of
Applicability, Measures Already in Existence
for Antibiotics and Main Findings from Interviews and
Literature Review
Measure
Applicable to
Antibiotics?
Measures for
Antibiotics to Achieve
the Same Intent
Main Findings from
Interviews and
Literature Review
Drug Classification System
Controlled substances are placed in different
schedules (Schedule I-IV) according to their
abuse potential and are under different degree
of control. Schedule I drugs are subject to all
applicable measures.
Possibly WHO’s Essential Medicines
List (EML revision
May 2017 classified
essential antibiotics into
3 categories). WHO’s
Critically Important
Antimicrobials.

- Flexibility exists when
developing national
legislations.
- Many countries have
implemented regulatory
measures not required by
the Convention or made
domestic law stricter.
The Commission on Narcotic Drugs (CND),
based on recommendation by the WHO, may
amend the drug classification list. A state may
propose amendments to the lists.
Possibly
Prescribing and Dispensing
A medical prescription is required for the
supply or dispensation of drugs to individuals
for Schedule I drugs.
Possibly National regulations.
AMR action plans. WHO
guidance.
- Additional regulatory
control measures
implemented by several
countries (e.g. limited
prescription rights and
limited validity of the
prescription).
- Education and training is
essential for adequate pain
management.

- Fear of prescribing and
stigma have contributed to
low access to opioids.
- Some countries use
special prescription forms/
systems.
If deemed necessary, countries may require
that prescriptions for Schedule I drugs are
written on official forms to be issued in the
form of counterfoil books by the government
or authorized professional associations, and be
kept for a period of not less than two years.
Possibly
Governments may choose to regulate the
packaging of medicines (a clearly visible double
red band on the inner package containing a
drug or wrapping thereof).
Possibly
International Consumption Control and Monitoring
Governments must provide annual estimates
to the International Narcotics Control Board
(INCB) of the quantities of controlled drugs
needed for medical and scientific purposes,
quantities needed for manufacturing and
quantities needed for special stocks.
Possibly Currently forecasting of
expected consumption of
antibiotics is performed by
some procurement systems,

but not as a function of the
optimal societal use.
- Governments use different
methods for providing
estimates.
- Not all governments
provide estimates of
their annual need and the
statistical returns on actual
consumption as required.
- Some governments lack
the expertise and resources
to make accurate estimates
and instead make slight
adjustments to the previous
year’s numbers.
- Many countries provide
too low estimates.
- Border control of import/
export works well (not
many countries exceed
their limits).
The INCB shall examine the government
estimates and supplementary estimates and
as expeditiously as possible confirm these
estimates. In cases of disagreements, the INCB
has the right to create its own estimates. If
any government fails to provide estimates, the
INCB will establish the estimates, preferably in
co-operation with the government concerned.
Possibly
Continued on p. 82

2018 The Author(s)
Measure
Applicable to
Antibiotics?
Measures for
the Same Intent
Main Findings from
Interviews and
Literature Review
International Consumption Control and Monitoring Continued
If the annual requirements for consumption
change, the government may submit
supplementary estimates to the INCB.
No, this may
delay access
to life-saving
medicines
Governments must on an annual basis report
to the INCB on the amounts consumed
and amounts used for the production or

manufacture of drugs. Governments must
every quarter report on the amounts of drugs
imported and exported.
Possibly WHO programme on
surveillance of antimicrobial
consumption. The European
Surveillance of Antimicrobial
Consumption programme
(ESAC). National
surveillance systems for
antibiotic resistance. Yet, no
surveillance on antibiotic
manufacturing to our
knowledge.
Governments must report on seizures and
stocks as of 31 December.
Possibly
The INCB shall examine the statistical
returns with a view to determining whether
governments comply with the provisions
of the Single Convention, and may require
further information if considered necessary.
Possibly Does not exist today to our
knowledge.
The total quantities of each drug
manufactured and imported must be
within the limit of the country’s estimated
requirements.
No, this may

delay access
to life-saving
medicines
If the quantity manufactured and imported in
any one year exceeds the country’s estimated
requirements, this shall be deducted from the
required estimates in the following year.
No, this may
delay access
to life-saving
medicines
If the quantity exported to any country
exceed the total of the estimates for that
country, further exports authorizations shall
not be authorized to that country (except
under certain circumstances).
No, this may
delay access
to life-saving
medicines
Records of manufacture, acquisition and
disposal for each individual drug are to
be kept by governmental authorities,
manufacturers, traders, scientific institutions
and hospitals. Such records shall be preserved
for a period of not less than two years.
Possibly Does not exist today to
our knowledge. However,
some countries have good
electronic systems for sales

data at the retail level.
Table 2 (continued)
Literature Review
See previous page.
Storehagen et al.
2018 The Author(s)
sporins. This is the group of antibiotics where a legal
classification system could be useful in the sense that
it would put strict regulations on access, use and
monitoring. So the question is: how could the accep-
tance and adherence to this classification system be
improved through a set of binding measures? We first
examine the potential through controls on prescribing
and dispensing.
Prescribing and Dispensing
The only mandatory control measure in the Single
Convention related to the dispensing of narcotics is to
require a medical prescription for Schedule I narcotics
when dispensing to individuals. In addition, the Single
Convention suggests some additional measures gov-
ernments can implement if deemed necessary (Table
2). However, despite the fact that the Single Convention

does not dictate strict control related to the prescribing
and dispensing of narcotic drugs, governments around
the world have implemented stricter procedures in
their national policies and legislations, attributed as
a consequence of the actual or perceived increase of
misuse and dependence upon opioids.25 There are
several examples of such additional regulatory mea-
sures. For example, many countries have restricted the
prescribing privileges to limited physician specialties,
have complicated reporting or administrative require-
ments when prescribing opioids, require special pre-
scription forms and/or operate with a limited validity
for opioid prescriptions.26 Furthermore, pharmacists
usually have limited authority to correct minor errors
on opioid prescriptions and prescribing for emergency
use via phone or fax is usually not possible or at least
restricted.27
These extra regulatory measures have been blamed
for contributing to the low access rates to opioids for
pain relief observed in many parts of the world. For
example, India has had severely low opioid consump-
tion for decades, with little increase in consumption
even though the country has developed both economi-
cally and in terms of health care.28 India implemented
complex and strict regulations over the prescribing
Table 2 (continued)
Literature Review
Measure
Applicable to

Antibiotics?
Measures for
the Same Intent
Main Findings from
Interviews and
Literature Review
Licenses
Import and export licenses are required for
each international transaction.
Possibly Most governments already
require that activities
related to pharmaceuticals
are conducted under
licenses, but do not require
licenses for each import/
export.
- Multiple agencies
involved in import/export
authorizations.
- Limited number of
pharmacies have license to
dispense opioids.
- Limited number of
manufacturers with licence
to manufacture opioids.
All persons and enterprises involved in the
manufacture, trade, distribution, import or
export of drugs must be controlled under

government license (except when carried out
by a state enterprise).
Possibly
All persons who obtain government licenses
must have adequate qualifications for effective
and faithful execution of laws and regulations
enacted to implement the Single Convention.
Possibly
Governments shall require that the drug labels
show the exact drug content by weight and
percentage for Schedule I drugs (not required
when dispensed to an individual on medical
prescription).
No, this measure
is primarily
intended to
facilitate trade
control function
of custom
officials, thus of
less relevance for
antibiotics.
2018 The Author(s)

and sale of opioids under the introduction of the 1985
Narcotic Drugs and Psychotropic Substances (NDPS)
Act, designed to fulfil India´s obligation under the
Single Convention. The strict regulations led to stigma
and negative attitudes, resulting in a fear of both
stocking and prescribing opioids.29 The Act was last
amended in 2014 to simplify opioid regulations, but
there are concerns related to unintended effects.30
A number of control mechanisms have also been
implemented in Brazil, including special color-coded
prescription forms for different medicines. Physicians
receive a set number of these prescription forms, with
a lesser amount of the form designated for controlled
medicines. Brazil has also implemented an electronic
system where physicians’ prescribing habits can be
monitored. According to our stakeholder interviews,
this system has reportedly reduced the number of pre-
scriptions for controlled medicines.
Even though some of these extra control measures
have unintentionally served as a barrier for legitimate
access for medical purposes, some of these measures
could have merit in a stewardship framework for anti-
biotics. We suggest examples in Table 3. Norway has
recently implemented a warning in the clinicians’ pre-
scriptions system that gives an alert when the clini-
cian prescribes a broad-spectrum antibiotic. Norway
is also looking at implementing other interventions,
such as a limited prescription validity for antibiot-
ics.31 Yet, these measures are dependent upon not only
effective healthcare systems, but also the universal use
of information technology. Therefore, the ability to
implement these controls will vary greatly by country
and within countries.

The dispensing of antibiotics without a prescription
is a widespread practice.32 This is especially true in low-
and middle-income countries where laws restricting
this practice may be in place, but enforcement mea-
sures are lacking and access to qualified healthcare
personnel is insufficient.33 In addition, internet ven-
dors provide worldwide access to antibiotics, also for
the population in countries with strict regulations.34
Could a binding agreement like the Single Convention
reduce non-prescription use of “watch” and/or “last
resort” antibiotics?
As we see from our analysis of the Single Conven-
tion, it does not ensure that the right patients are
receiving appropriate palliative care. The Single Con-
vention provides a crude limit on the total national
consumption of a specified narcotic, but does not
include measures that facilitate appropriate use for
the patients in need. Antibiotic stewardship aims to
ensure that the right patient receives the right anti-
biotic in the right dose at the right time. To achieve
this, stewardship needs to be built into community
and hospital-based routines. This is being increasingly
implemented through AMR National Action Plans,
with more and more WHO Member States publish-
ing their plans.35 There is also some evidence that
these stewardship efforts are succeeding in reducing
antibiotic prescribing, including prominently broad-
spectrum antibiotics.36
International Consumption Control and
Monitoring
According to the INCB’s annual report from 2015
excess imports or exports of narcotics occurred in only

four countries. However, not all governments pro-
vide estimates of their annual need and the statistical
returns on actual consumption as required. 70% sub-
Table 3
Control Measures Identified in Countries Regulatory Systems
Related to the Prescribing of Narcotics
That May Have Merit for Regulating the Prescribing of
Antibiotics
Control Measure Identified for
Narcotics Implementation for Antibiotics Desired Outcome(s)
Limited prescription validity. Antibiotics prescribed to patients
for
self-treatment of common infectious
diseases.
Avoid self-medication for future
conditions and avoid misuse.
Limited prescribing rights (e.g. to
selective medical doctors and/or
infectious disease specialities).
Broad spectrum intravenous antibiotics
and/or last resort antibiotics.
Avoid unnecessary use of medically
important antibiotics.
Ensure access to effective antibiotics for
multi-resistant infections.
Implementing special prescription forms
for antibiotics.

All antibiotics. Monitor use. Warning signal for the
prescriber and the patient.
Storehagen et al.
2018 The Author(s)
mitted their requirements for 2016, while 63% pro-
vided the Board with annual statistical reports.37
However, being able to identify the actual require-
ments is a challenging task for many governments as
they lack the expertise and resources needed to make
accurate estimates.38 For example, several countries in
Sub-Saharan Africa provide annual opioid estimates
sufficient to treat only a handful of cancer patients.39
From our interviews, we understand that countries
use different methods and data sources to make
their estimates, and that oftentimes the estimates are
merely slight adjustments to the previous year’s num-
ber. In recent years, INCB and WHO have published
guidelines to help governments to provide adequate
estimates,40 but the impact is yet unclear.
Notwithstanding, the surveillance data provided by
the Single Convention are enviable. Such data within
an antibiotic context would be very beneficial for
understanding the spread of antimicrobial resistance.
Yet, surveillance data regarding antibiotic consump-
tion and resistance levels are improving through sig-
nificant national and multi-national efforts. WHO has

recently launched a program on surveillance on anti-
biotic consumption, as a result of the adoption of the
Global Action Plan (GAP), to assist countries to inte-
grate surveillance of antimicrobial use into national
programs. It provides a common methodology for the
measurement of antimicrobial consumption that will
allow for the monitoring of trends and comparison
between countries at the global level.41 Europe has
already implemented a program for sharing and com-
paring information about antimicrobial consumption,
the European Surveillance of Antimicrobial Con-
sumption (ESAC). The network is coordinated by the
European Centre for Disease Prevention (ECDC), and
collects data from both the hospital and the commu-
nity sector.42 The Fleming Fund is investing GBP 195
million in improving antibacterial surveillance capac-
ity in low- and middle-income countries.43
Requesting countries to estimate antibiotic needs
and reflect upon appropriate consumptions levels
would be a useful exercise for countries to explore areas
where responsible use policies could be improved.
Unfortunately, as mentioned previously, the estimates
are often simple adjustments to the previous year’s
number, thus lacking credibility.
Licenses
The Single Convention requires a license for each
international transaction (i.e. import and export)
involving narcotics (Table 2). Again, some countries
go beyond the Single Convention requirement. For
example, India implemented a complex system for
import/export following the 1985 Act, where a licence
was required for each import/export also between

states and with multiple agencies involved in the
licensing process. The rules have been changed under
the new law with the hope that opioids will be more
available for medical purposes. Singapore limits the
number of licenses for manufacturing opioids to a few
companies. This way the government can better exer-
cise control over the opioid market.
Licenses may also regulate where opioids can be dis-
pensed. In several countries in Asia and Africa opioids
can only be dispensed at hospital pharmacies.44 Simi-
lar restrictions exist also in parts of Eastern Europe.
The utmost example is probably from Georgia where
opioids can only be dispensed through special phar-
macies placed in police stations.45
Controlling the international transactions of anti-
biotics by requiring a license for each import/export,
like the Single Convention, appears excessive. We
cannot see how such trade-related restrictions will
support the responsible use of antibiotics. Moreover,
considering that adequate access to antibiotics is still
a major problem in low- and middle-income coun-
tries, imposing such control mechanisms could result
in an increase of preventable deaths. Yet, there may
be other areas related to the trade of antibiotics where
the inclusion of international binding requirements
could be applicable: (1) the issue of environmental
pollution through pharmaceutical waste manage-
Whereas there may be specific AMR provisions that may be
appropriate
for a convention (e.g., ban on use of antibiotics for livestock
growth

promotion), we do not see the Single Convention as a suitable
model for
the reasons stately previously. Rather it would be more
effective to identify
the specific gaps in control and oversight and determine if there
is general
agreement and that no other tool can effectively remedy these
gaps.
2018 The Author(s)
ment of antibiotics, and (2) the use of antibiotics in
agriculture.46
Can a Convention Regarding AMR Help to
Enforce Global Norms?
Tackling the global challenge of AMR has already
become an urgent priority. The World Health Orga-
nization (WHO) developed the Global Action Plan
(GAP) on AMR in 2015.47 In 2016, the General Assem-
bly of the UN adopted a political declaration on AMR
reaffirming the need for coordinated action across
sectors and launched the Interagency Coordination
Group on AMR.48 Following this, the G20 Health
Ministers made a declaration for enhanced response
on antimicrobial resistance (the Berlin Declaration).49
The G20 has launched a multi-national AMR R&D
Collaboration Hub. Twenty-six countries have joined

forces in the Joint Programming Initiative on AMR.
A convention is one of the most stringent multilat-
eral instruments for policymaking. Adopting a con-
vention requires near-global consensus regarding
important and unvarying norms. To be successful,
effective enforcement mechanisms must be built in.
Whereas there may be specific AMR provisions that
may be appropriate for a convention (e.g., ban on use
of antibiotics for livestock growth promotion), we do
not see the Single Convention as a suitable model for
the reasons stately previously. Rather it would be more
effective to identify the specific gaps in control and
oversight and determine if there is general agreement
and that no other tool can effectively remedy these
gaps.
Conclusion
A globally agreed system for controlling antibiotic
consumption, similar to the current drug control regi-
men for narcotics, would allow for stringent controls
on sale and consumption. This has been put forth as
a possible mechanism to ensure tighter controls over
critical antibiotics. We have identified components
of the controlled drug regime that may be useful to
consider also for antibiotics. However, we believe a
similar system would detrimentally inhibit access, be
costly and challenging to implement, and end up no
more effective than introducing national stewardship
measures already included in many countries’ national
AMR plans. The challenge, though, is to find mecha-
nisms for accountability. Based upon countries’ abil-
ity to effectively implement their national AMR plans,
new accountability mechanisms may be needed.
Note

The research leading to these results has received support from
the Innovative Medicines Initiative Joint Undertaking under
grant
agreement n°115618 [Driving re-investment in R&D and
responsi-
ble antibiotic use — DRIVE-AB — www.drive-ab.eu ],
resources of
which are composed of financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies’ in-kind contribution. This work does not
necessarily represent the view of all DRIVE-AB partners. This
work
was also supported by the Research Council of Norway through
the
Global Health and Vaccination Programme (GLOBVAC),
project
number 234608.
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from the Global Opioid Policy Initiative (GOPI),” Annals of
Oncology 24, no. 11 Supp (2013): xi24-xi32.
45. See Cherny et al., supra note 27.
46. The Review on Antimicrobial Resistance, Chaired by Jim
O’Neill, Antimicrobials in Agriculture and the Environment:
Reducing Unnecessary Use and Waste (December 2015),
available at <https://amr-review.org/sites/default/files/Anti-
microbials%20in%20agriculture%20and%20the%20envi-
ronment%20-%20Reducing%20unnecessary%20use%20
and%20waste.pdf> (last visited April 2, 2018).
47. See World Health Organization, supra note 35.
48. United Nations, Political Declaration of the High-Level
Meet-
ing of the General Assembly on Antimicrobial Resistance
(2016), available at <http://www.un.org/pga/71/wp-content/
uploads/sites/40/2016/09/DGACM_GAEAD_ESCAB-AMR-
Draft-Political-Declaration-1616108E.pdf> (last visited April
2, 2018).
49. G20 Germany 2017, Berlin Declaration of the G20 Health
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Declaration_engl.pdf> (last visited April 2, 2018).

2018 The Author(s)
Supplementary Table 1
Identified Control Measures in the Single Convention
Measure
Reference to the
Single Convention
Drug classification system
Controlled substances are placed in different schedules
(Schedule I-IV) according to their abuse poten-
tial and are under different degrees of control. Schedule I drugs
are subject to all applicable measures.
Annexed to the Single
Convention, Article 2
The Commission on Narcotic Drugs (CND), based on
recommendation by the WHO, may amend the
drug classification list. A state may propose amendments to the
lists.
Article 3 and 47
Prescribing and dispensing
A medical prescription is required for the supply or
dispensation of drugs to individuals for Schedule I
drugs.
Article 30
If deemed necessary, countries may require that prescriptions

for Schedule I drugs are written on of-
ficial forms to be issued in the form of counterfoil books by the
government or authorized professional
associations, and be kept for a period of not less than two years.
Article 30 and 34
Governments may choose to regulate the packaging of
medicines (a clearly visible double red band on
the inner package containing a drug or wrapping thereof).
Article 30
Consumption control and monitoring
Governments must provide annual estimates to the International
Narcotics Control Board (INCB) of
the quantities of controlled drugs needed for medical and
scientific purposes, quantities needed for
manufacturing and quantities needed for special stocks.
Article 19
The INCB shall examine the government estimates and
supplementary estimates and as expeditiously
as possible confirm these estimates. In cases of disagreements,
the INCB has the right to create its own
estimates. If any government fails to provide estimates, the
INCB will establish the estimates, preferably
in co-operation with the government concerned.
Article 12
If the annual requirements for consumption change, the
government may submit supplementary esti-
mates to the INCB.

Article 19
Governments must on an annual basis report to the INCB on the
amounts consumed and amounts
used for the production or manufacture of drugs. Governments
must every quarter report on the
amounts of drugs imported and exported.
Article 20
Governments must report on seizures and stocks as of 31
December. Article 19
The INCB shall examine the statistical returns with a view to
determining whether governments com-
ply with the provisions of the Single Convention, and may
require further information if considered
necessary.
Article 13
The total quantities of each drug manufactured and imported
must be within the limit of the country’s
estimated requirements.
Article 21
If the quantity manufactured and imported in any one year
exceeds the country’s estimated require-
ments, this shall be deducted from the required estimates in the
following year.
Article 21
If the quantity exported to any country exceeds the total of the

estimates for that country, further ex-
ports authorizations shall not be authorized to that country
(except under certain circumstances).
Article 21
Records of manufacture, acquisition and disposal for each
individual drug are to be kept by governmen-
tal authorities, manufacturers, traders, scientific institutions and
hospitals. Such records shall be pre-
served for a period of not less than two years.
Article 34
Storehagen et al.
2018 The Author(s)
Measure
Reference to the
Single Convention
Licenses
All persons and enterprises involved in the manufacture, trade,
distribution, import or export of drugs
must be controlled under government license (except when
carried out by a State enterprise).
Articles 29, 30, 31

Import and export licenses are required for each international
transaction. Article 31
All persons who obtain licenses must have adequate
qualifications for effective and faithful execution of
laws and regulations enacted to implement the Single
Convention.
Article 34
Governments shall require that the drug labels show the exact
drug content by weight and percentage
for Schedule I drugs (not required when dispensed to an
individual on medical prescription).
Article 30
Drug control organs
The international control organs consists of a Board (the
International Narcotics Control Board) and a
Commission (the Commission on Narcotic Drugs). The United
Nations (UN) covers the expenses, and
non-UN members shall contribute based on decisions made by
the UN General Assembly. The WHO
has an advisory role.
Article 5, 6 and 3
The Commission on Narcotic Drugs (CND) deals with all drug-
related matters. CND decides, on the
basis of recommendations by the WHO, to place narcotic drugs
under international control. CNC also
advices the Board on any relevant matters pertaining to the
control of narcotics, and supervise the
implementation of the aims and provisions of the Single

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