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Editorial Response: Antibiotic Resistance Worldwide-A Spanish Task Force
Responds
This issue of Clinical Infectious Diseases contains the highlights of a unique document from a multidisciplinary group in
Spain. This English-language summary of their report addresses the scope and depth of antibiotic resistance in Spain
and includes recommendations to address the problem. The
uniqueness of this document lies in the fact that it reflects
acceptance of partial responsibility for the problem of drug
resistance in countries outside Spain.
While it is true that resistant pneumococcal strains that are
appearing in other countries have been linked to those initially
described in Spain, there has never been a question as to fault.
In fact, selection of drug-resistant bacteria is occurring globally.
However, the Task Force of the General Direction for Health
Planning at the Ministry of Health in Madrid has decided to
confront this question head on. They are to be congratulated
and admired. They argue for improved use of antibiotics, not
only because of the potential beneficial impact on the resistance
problem in Spain, but also because of the impact in other
countries. They have provided facts that are difficult to obtain,
such as the amounts of antibiotics used in Spain in humans
and animals and for agricultural purposes and the frequency of
resistance in a number of important pathogens and in different
environments.
See the article by Baquero on pages 819-23.
Of particular note is the frequency of resistance among bacteria that cause diseases in the various communities of Spain.
Although rates of resistance among hospital-acquired pathogens throughout Europe are high, the frequency of resistance
among common community-acquired agents of infectious diseases in Spain is higher than in other European countries. Why?
The group points to the high country-wide consumption of
antibiotics, 90% of which occurs outside hospitals. A high level
of antibiotic consumption characterized the period 1966-1976
(31 defined daily doses [DDD] per 1,000 persons per dayequivalent to 1 ton per day). Although antibiotic use has now
decreased to 19 DDD per 1,000 persons per day (how this has
occurred is not clear), the authors state that ~90% of the
population in Spain receives at least one prescription for antibiotics each year.
Received 30 May 1996.
Reprints or correspondence: Dr. Stuart B. Levy, Center for Adaptation Genetics and Drug Resistance, Tufts University School of Medicine, Boston,
Massachusetts 02111.
Clinical Infectious Diseases
1996;23:824-6
© 1996 by The University of Chicago. All rights reserved.
1058-4838/96/2304-0026$02.00
The amount of antibiotics reportedly used in animals was also
high. In 1984 (the current estimates are not known), the amount
of antibiotics consumed by animals in Spain was ~ 75% of that
consumed by humans. This total included antibiotics used as
growth promoters, some of which are members of the classes of
antibiotics used in people. The growth promoter avoparcin is a
glycopeptide that resembles vancomycin; its use in Europe has
been associated with the emergence of a large reservoir of vancomycin-resistant enterococci among animals [1]. Virgiuiamycin,
another growth promoter, is a mixture of streptogramins and is
structurally similar to a new pharmaceutical, Synercid (Rh6nePoulenc Rorer, Collegeville, PA; Synercid is a combination of
pristinamycins), which is being reviewed for introduction in the
United States. Use of virginiamycin in the United States and
Europe has also presumably resulted in selection for resistant
bacteria with probable cross-resistance to the human antibacterial.
The juxtaposition in this document of antibiotic consumption in
both animals and humans underscores the effects of using these
drugs in both of these groups, which have a commonly shared
microbial population.
In a single day in 1994, 22% of Spanish doctors reported
diagnosing infectious diseases, but 67% of them prescribed
antibiotics. Why was there a discrepancy between diagnosis
and treatment? The reasons the Spanish authors have given
are not so different from those cited in the United States and
elsewhere. Patients, who are influenced by a misconception
that antibiotics are miracle drugs that cure any kind of infection,
demand and get the antibiotics from their physicians. To avoid
a prolonged explanation or diagnostic testing, the physician
prescribes the drug. It is not easy to refuse an anxious, demanding patient; however, physicians need encouragement and
new weapons to defend their clinical knowledge.
The latter situation is facilitated by clinicians' failure to
appreciate the scope of antibiotic resistance. Again, this is true
in other countries besides Spain. To be of help, infectious
diseases specialists need to share their expertise with general
practitioners and other members of the health care community.
We have to define the consequence of antibiotic resistance
and how patients are affected. Unfortunately, up to now the
antibiotic resistance message has not gotten out to physicians
and patients in the community.
Medical schools need to emphasize the problem in the education of future doctors; these medical students can help deliver
the message to their student peers and to other members of
society. Health maintenance organizations can include the subject in their newsletters to subscribers. In the United States,
the Association of Family Practice Physicians has recently included lectures on antibiotic resistance in its state and national
programs; other health professional groups need to do likewise.
The hardest group to reach is still consumers. Of the countries in Europe, the demand for antibiotics in Spain was second
eID 1996;23 (October)
Editorial Response
only to that in France. The rate of compliance (taking the full
course of antibiotics) was found to be only 58% in Spain,
whereas it was found to be 84% in France and the United
Kingdom. Estimates from the United States were no better. In
a recent Gallop poll, compliance was determined to be only
46% [2].
Procurement of antibiotics is controlled by prescription in
many countries, including Spain. However, regulation is not
tight in Spain. The report by the Task Force claims that 7%
of drugs are obtained on an over-the-counter basis; one-third
of these drugs are antibiotics. Some observers who have visited
Spain might put this figure even higher. These over-the-counter
sales are the norm in some countries. Thus, a significant proportion of antibiotic use is uncontrolled-overuse, underuse, and
misuse prevail. This lack of control contributes to selection of
resistant strains that emerge locally and can eventually travel
the globe.
However, even where prescriptions for antibiotics are the
rule, patients can still obtain them through coercion and demand. Once obtained, these antibiotics may be stockpiled by
the patients to be taken at a later date or given to others. The
actual numbers of patients who obtain antibiotics this way are
not known, but a recent report of prior antibiotic use without
prescription among patients treated at a sexually transmitted
diseases clinic in Georgia was estimated at 14% [3]. Therefore,
in practice the same uncontrolled use occurs; once obtained,
antibiotics are taken without the supervision of a physician.
Having stated the problem, the Task Force members layout
approaches to its solution, calling on different segments of the
health care community. They point out that continued collection
of data on use and resistance can be helpful in choosing an
appropriate antibiotic and in developing the means to improve
drug use and curtail resistance. They recommend, as have other
investigators, the evaluation of commensals as well as clinical
strains from animals and humans for determining the frequency
of resistance. Other suggestions include the possible addition of
an evaluation for the emergence of resistance during the clinical
trials of new antibiotics; a more-extensive educational process for
the prescribers (physicians, veterinarians, and other health care
workers), with better communication and more instruction for all
persons involved in the dispensing and/or use of antibiotics; and
support for vaccine development, which will prevent infections
and decrease the need for antibiotics.
The role of pharmacists is also mentioned. In my judgment,
this group could play an exceedingly greater role in effecting
prudent antibiotic use. They are the largest group that serves
as a source of antibiotics and has direct contact with consumers,
and they serve as links between doctors and patients. In the
United States, the Society of Infectious Diseases Pharmacists
is particularly interested in the question of antibiotic use and
resistance; the creation of similar groups in other countries
could be done successfully, as well. In hospitals, pharmacists
protect against potentially harmful drug interactions; they can
also help in curtailing the misuse of antibiotics.
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The Task Force report also outlines recommendations targeted at consumers. Up to now, this constituency has been
reached largely through the news media, with little attention
from the scientific or medical community. More information
should be available to consumers, particularly in doctors' offices. Farmers need to understand the indications for specific
antibiotic therapies and the problems stemming from the misuse
of antibiotics.
The Task Force also called on the pharmaceutical industry
to participate, not only in the needed discovery and development of antibiotics, but also in the prevention of misuse as an
approach to curtailing resistance. Overmarketing of a product
will surely lead to loss of efficacy as a result of the emergence
of resistance. It is in the interests of the pharmaceutical industry, as well as those of society, that this industry become a
partner in assuring the proper use of antibiotics and the control
of resistance.
The report also calls for government support for the pharmaceutical industry. Through legislative action, tax incentives can
be provided to encourage the discovery and development of
new antimicrobial agents. A similar recommendation came
from a U.S. Office of Technology Assessment report published
in 1995 [4].
Furthermore, there is a need to obtain data on how resistance
emerges. How much drug leads to a public health problem? It
would appear that antibiotic usage can be continued as long as
the susceptible strains in the environment that keep the resistant
strains under control can be maintained [5]. It is a "numbers
game. " We can imagine thresholds of antibiotic usage below
which the environmental flora remains unchanged or reversibly
changed. In such an environment, antibiotics can be used successfully [6]. Above this threshold, the susceptible bacterial
strains are suppressed, allowing the overpopulation and spread
of resistant strains and their resistance traits. But what are these
thresholds? Are they the same for each antibiotic? The answers
to these questions would benefit both the medical and the pharmaceutical sectors.
Antibiotics are the only pharmaceutical with direct societal
and environmental consequences [5]. Use of these drugs affects
not only the individual but also society at large in terms of its
effect on microbial flora. When they are used in small
amounts, the effect remains limited. With large and repeated
amounts, the impact is greater and more sustained, affecting
the environment at large [5]. In using antibiotics, we wreak
havoc with the natural balance between susceptible bacteria
and resistant bacteria-the former are suppressed and taken
over by the latter. The intensity of antibiotic use in various
environments is a critical factor: the numbers of people and
animals involved influence the number of resistant bacteria
propagated. All countries should reexamine all aspects of antibiotic use, since all bacteria (i.e., infectious and commensal)
are subject to the activity of antibiotics. The frequency with
which animate and inanimate surfaces are colonized with resistant organisms represents a barometer of antibiotic use and the
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end result of competition between drug-resistant and susceptible strains.
If we keep the environmental impact of antibiotics in mind
while prescribing them and directing them specifically at infectious organisms, our use of these drugs will be considered
rational with regard to environmental consequences. We can
make use of-and encourage the propagation of-the natural
competitive microbial flora in order to maintain an environment
of susceptible microorganisms. In this way, we would not be
eliminating susceptible strains by a continual onslaught with
antibiotics. With rational use of antibiotics, resistant strains can
be kept in check by the susceptible microbial flora.
The report by this Spanish Task Force is challenging and
courageous and serves as a model for other investigators. It
follows historically a number of other attempts at bringing
reason into the use of antibiotics. In 1981, a group of medical
scientists and microbiologists at a meeting in the Dominican
Republic issued the Antibiotic Misuse Statement [7]. This statement described the problem in a general sense and included a
warning of the impending threat of worldwide antibiotic resistance. At the time, resistance was clearly compromising public
health in developing countries. After the meeting, the Alliance
for the Prudent Use of Antibiotics (APUA) emerged; this organization is dedicated to curtailing antibiotic resistance by advocating and communicating appropriate use of antibiotics.
Today, APUA has chapters in six countries and members in
more than 90 countries around the world.
From 1983 to 1986, the Fogarty International Center of the
National Institutes of Health supported internationally represented task forces that gathered information on six different
aspects of antibiotic use and resistance [8]. Unfortunately, the
impact of this effort was never realized, since political pressures
intervened, and the resistance problem was claimed to be overstated. That was in 1987; let's hope that documents like the
current one from Spain will not be subject to this same fate.
More recently, the American Society for Microbiology released
a Task Force on Antibiotic Resistance report on antibiotic resis-
cm
Levy
1996;23 (October)
tance; this report identified a persistent and intensifying
problem.
The conclusions of the Spanish Task Force must be taken
seriously. However, it is one thing to write a document and
set goals; it is another to see that the recommendations are
implemented. The challenge for the group in Spain is to master
the implementation of their recommendations. This group
should continue to report on how the recommendations are
being accepted and on the resultant problems and achievements. Of course, the resistance problem is global in proportion, but it is local in context. It is hoped that other countries
will take note and form their own groups to describe and
address the problem, because investigations and actions at the
10calleve1 will undoubtedly help in achieving a global solution.
Stuart B. Levy
Center for Adaptation Genetics and Drug Resistance, Tufts University
School of Medicine, Boston, Massachusetts
References
1. Klare I, Heier H, Claus H, Reissbrodt R, Witte w. vanA-mediated high-level
glycopeptide resistance in Enterococcus faecium from animal husbandry.
FEMS Microbiol Lett 1995; 125:165-72.
2. The Gallop Organization. Consumer attitudes toward antibiotic use (conducted for Pfizer Laboratories). New York: American Lung Association,
12 October 1995.
3. Gordon SM, Mosure DJ, Lewis J, Brown S, McNagny SE, Schmid GF.
Prevalence of self-medication with antibiotics among patients attending
a clinic for treatment of sexually transmitted diseases. Clin Infect Dis
1993; 17:462-5.
4. U.S. Office of Technology Assessment. Impacts of antibiotic-resistant bacteria. Report OTA-H-629. Washington, DC: Government Printing Office,
1995.
5. Levy SB. The antibiotic paradox: how miracle drugs are destroying the
miracle. New York: Plenum, 1992.
6. Levy SB. Balancing the drug resistance equation. Trends in Microbiology
1994;2:341-2.
7. Levy SB, Clowes RC, Koenig EL. Molecular biology, pathogenicity, and
ecology of bacterial plasmids. New York: Plenum, 1981, 679-81.
8. Levy SB, Burke JP, Wallace CK, eds. Antibiotic use and antibiotic resistance worldwide. Rev Infect Dis 1987;9(suppI3):S231-316.