Scientific American (March 1998) for acces to this article!
infections now defy all antibiotics. The resistance problem may
be reversible, but only if society begins to consider how the
drugs affect "good" bacteria as well as "bad"
by Stuart B. Levy
Last year an event doctors
had been fearing finally occurred. In three geographically
separate patients, an often deadly bacterium, Staphylococcus aureus,
responded poorly to a once reliable antidote--the antibiotic vancomycin.
Fortunately, in those patients, the staph microbe remained susceptible
to other drugs and was eradicated. But the appearance of S. aureus
not readily cleared by vancomycin foreshadows trouble.
Worldwide, many strains
of S. aureus are already resistant to all antibiotics except vancomycin.
Emergence of forms lacking sensitivity to vancomycin signifies
that variants untreatable by every known antibiotic are on their
way. S. aureus, a major cause of hospital-acquired infections,
has thus moved one step closer to becoming an unstoppable
The looming threat
of incurable S. aureus is just the latest twist in an international
public health nightmare: increasing bacterial resistance to many
antibiotics that once cured bacterial diseases readily.
Ever since antibiotics became widely available in the 1940s, they
have been hailed as miracle drugs--magic bullets able to eliminate
bacteria without doing much harm to the cells of treated individuals.
Yet with each passing decade, bacteria that defy not only single
but multiple antibiotics--and therefore are extremely difficult
to control--have become increasingly common.
What is more, strains
of at least three bacterial species capable of causing life-threatening
illnesses (Enterococcus faecalis, Mycobacterium tuberculosis and
Pseudomonas aeruginosa) already evade every antibiotic in the
clinician's armamentarium, a stockpile of more than 100 drugs.
In part because of the rise in resistance to antibiotics, the
death rates for some communicable diseases (such as tuberculosis) have started to rise again,
after having declined in the industrial nations.
How did we end up in this
worrisome, and worsening, situation? Several interacting processes
are at fault. Analyses of them point to a number of actions that
could help reverse the trend, if individuals, businesses and governments
around the world can find the will to implement them.
One component of
the solution is recognizing that bacteria are a natural, and needed,
part of life.
Bacteria, which are microscopic, single-cell entities, abound
on inanimate surfaces and on parts of the body that make contact
with the outer world, including the skin, the mucous membranes
and the lining of the intestinal tract. Most live blamelessly. In fact, they often protect us from disease, because they
compete with, and thus limit the proliferation of, pathogenic
bacteria--the minority of species that can multiply aggressively
(into the millions) and damage tissues or otherwise cause illness.
The benign competitors can be important allies in the fight against
People should also
realize that although antibiotics are needed to control bacterial
infections, they can have broad, undesirable effects on microbial
ecology. That is, they can produce long-lasting change in the kinds and
proportions of bacteria--and the mix of antibiotic-resistant and
antibiotic-susceptible types--not only in the treated individual
but also in the environment and society at large. The compounds
should thus be used only when they are truly needed, and they
should not be administered for viral infections, over which they
have no power.
A Bad Combination
Although many factors can
influence whether bacteria in a person or in a community will
become insensitive to an antibiotic, the two main forces
are the prevalence of resistance genes (which give rise to proteins
that shield bacteria from an antibiotic's effects) and the extent
of antibiotic use. If the collective bacterial flora in
a community have no genes conferring resistance to a given antibiotic,
the antibiotic will successfully eliminate infection caused by
any of the bacterial species in the collection. On the other
hand, if the flora possess resistance genes and the community
uses the drug persistently, bacteria able to defy eradication
by the compound will emerge and multiply.
are not more virulent than susceptible ones: the same numbers
of resistant and susceptible bacterial cells are required to produce
disease. But the resistant forms are harder to destroy.
Those that are slightly insensitive to an antibiotic can often
be eliminated by using more of the drug; those that are highly
resistant require other therapies.
To understand how resistance
genes enable bacteria to survive an attack by an antibiotic, it
helps to know exactly what antibiotics are and how they harm bacteria.
Strictly speaking, the compounds are defined as natural substances
(made by living organisms) that inhibit the growth, or proliferation,
of bacteria or kill them directly. In practice, though,
most commercial antibiotics have been chemically altered in the
laboratory to improve their potency or to increase the range of
species they affect. Here I will also use the term to
encompass completely synthetic medicines, such as quinolones and
sulfonamides, which technically fit under the broader rubric of
PICKING UP RESISTANCE GENES
Whatever their monikers,
antibiotics, by inhibiting bacterial growth, give a host's immune
defenses a chance to outflank the bugs that remain. The
drugs typically retard bacterial proliferation by entering the
microbes and interfering with the production of components needed
to form new bacterial cells. For instance, the antibiotic tetracycline
binds to ribosomes (internal structures that make new proteins)
and, in so doing, impairs protein manufacture; penicillin and
vancomycin impede proper synthesis of the bacterial cell wall.
Certain resistance genes
ward off destruction by giving rise to enzymes that degrade antibiotics
or that chemically modify, and so inactivate, the drugs. Alternatively,
some resistance genes cause bacteria to alter or replace molecules
that are normally bound by an antibiotic--changes that essentially
eliminate the drug's targets in bacterial cells. Bacteria
might also eliminate entry ports for the drugs or, more effectively,
may manufacture pumps that export antibiotics before the medicines
have a chance to find their intracellular targets.
My Resistance Is Your Resistance
Bacteria can acquire resistance
genes through a few routes. Many inherit the genes from their
forerunners. Other times, genetic mutations, which occur readily
in bacteria, will spontaneously produce a new resistance trait
or will strengthen an existing one. And frequently, bacteria
will gain a defense against an antibiotic by taking up resistance
genes from other bacterial cells in the vicinity. Indeed, the
exchange of genes is so pervasive that the entire bacterial world
can be thought of as one huge multicellular organism in which
the cells interchange their genes with ease.
Bacteria have evolved several
ways to share their resistance traits with one another [see "Bacterial
Gene Swapping in Nature," by Robert V. Miller; Scientific
American, January]. Resistance genes commonly are carried
on plasmids, tiny loops of DNA that can help bacteria survive
various hazards in the environment. But the genes may also occur
on the bacterial chromosome, the larger DNA molecule that stores
the genes needed for the reproduction and routine maintenance
of a bacterial cell.
Often one bacterium will
pass resistance traits to others by giving them a useful plasmid.
Resistance genes can also be transferred by viruses that occasionally
extract a gene from one bacterial cell and inject it into a different
one. In addition, after a bacterium dies and releases its contents
into the environment, another will occasionally take up a liberated
gene for itself.
In the last two situations,
the gene will survive and provide protection from an antibiotic
only if integrated stably into a plasmid or chromosome. Such integration
occurs frequently, though, because resistance genes are often
embedded in small units of DNA, called transposons, that readily
hop into other DNA molecules. In a regrettable twist of
fate for human beings, many bacteria play host to specialized
transposons, termed integrons, that are like flypaper in their
propensity for capturing new genes. These integrons can consist
of several different resistance genes, which are passed to other
bacteria as whole regiments of antibiotic-defying guerrillas.
Many bacteria possessed
resistance genes even before commercial antibiotics came into
use. Scientists do not know exactly why these genes evolved
and were maintained. A logical argument holds that natural
antibiotics were initially elaborated as the result of chance
genetic mutations. Then the compounds, which turned out to eliminate
competitors, enabled the manufacturers to survive and proliferate--if
they were also lucky enough to possess genes that protected them
from their own chemical weapons. Later, these protective genes
found their way into other species, some of which were pathogenic.
Regardless of how
bacteria acquire resistance genes today, commercial antibiotics
can select for--promote the survival and propagation of--antibiotic-resistant
strains. In other words, by encouraging the growth of resistant
pathogens, an antibiotic can actually contribute to its own undoing.
How Antibiotics Promote Resistance
The selection process is
fairly straightforward. When an antibiotic attacks a group
of bacteria, cells that are highly susceptible to the medicine
will die. But cells that have some resistance from the start,
or that acquire it later (through mutation or gene exchange),
may survive, especially if too little drug is given to overwhelm
the cells that are present. Those cells, facing reduced
competition from susceptible bacteria, will then go on to proliferate.
When confronted with an antibiotic, the most resistant cells in
a group will inevitably outcompete all others.
Promoting resistance in
known pathogens is not the only self-defeating activity of antibiotics.
When the medicines attack disease-causing bacteria, they also
affect benign bacteria -- innocent bystanders -- in their path. They
eliminate drug-susceptible bystanders that could otherwise limit
the expansion of pathogens, and they simultaneously encourage
the growth of resistant bystanders. Propagation of these
resistant, nonpathogenic bacteria increases the reservoir of resistance
traits in the bacterial population as a whole and raises the odds
that such traits will spread to pathogens. In addition,
sometimes the growing populations of bystanders themselves become
agents of disease.
Widespread use of
cephalosporin antibiotics, for example, has promoted the proliferation
of the once benign intestinal bacterium E. faecalis, which is
naturally resistant to those drugs.
In most people, the immune system is able to check the growth
of even multidrug-resistant E. faecalis, so that it does not produce
illness. But in hospitalized patients with compromised immunity,
the enterococcus can spread to the heart valves and other organs
and establish deadly systemic disease.
of vancomycin over the years has turned E. faecalis into a dangerous
reservoir of vancomycin-resistance traits.
Recall that some strains of the pathogen S. aureus are multidrug-resistant
and are responsive only to vancomycin. Because vancomycin-resistant
E. faecalis has become quite common, public health experts fear
that it will soon deliver strong vancomycin resistance to those
S. aureus strains, making them incurable.
The bystander effect
has also enabled multidrug-resistant strains of Acinetobacter
and Xanthomonas to emerge and become agents of potentially fatal
blood-borne infections in hospitalized patients. These formerly
innocuous microbes were virtually unheard of just five years ago.
As I noted earlier, antibiotics
affect the mix of resistant and nonresistant bacteria both in
the individual being treated and in the environment. When resistant
bacteria arise in treated individuals, these microbes, like other
bacteria, spread readily to the surrounds and to new hosts. Investigators
have shown that when one member of a household chronically takes
an antibiotic to treat acne, the concentration of antibiotic-resistant
bacteria on the skin of family members rises. Similarly, heavy
use of antibiotics in such settings as hospitals, day care centers
and farms (where the drugs are often given to livestock for nonmedicinal
purposes) increases the levels of resistant bacteria in people
and other organisms who are not being treated--including in individuals
who live near those epicenters of high consumption
or who pass through the centers.
Given that antibiotics
and other antimicrobials, such as fungicides, affect the kinds
of bacteria in the environment and people around the individual
being treated, I often refer to these substances as societal
drugs -- the only class of therapeutics that can be so designated.
Anticancer drugs, in contrast, affect only the person taking the
On a larger scale, antibiotic
resistance that emerges in one place can often spread far and
wide. The ever increasing volume of international travel
has hastened transfer to the U.S. of multidrug-resistant tuberculosis
from other countries. And investigators have documented the migration
of a strain of multidrug-resistant Streptococcus pneumoniae from
Spain to the U.K., the U.S., South Africa and elsewhere.
This bacterium, also known as the pneumococcus, is a cause of
pneumonia and meningitis, among other diseases.
Antibiotic Use Is Out of Control
For those who understand
that antibiotic delivery selects for resistance, it is not surprising
that the international community currently faces a major
public health crisis. Antibiotic use (and misuse) has soared since
the first commercial versions were introduced and now includes
many nonmedicinal applications. In 1954 two million pounds were
produced in the U.S.; today the figure exceeds 50 million pounds.
Human treatment accounts
for roughly half the antibiotics consumed every year in the U.S.
Perhaps only half that use is appropriate, meant to cure bacterial
infections and administered correctly--in ways that do not strongly
Notably, many physicians
acquiesce to misguided patients who demand antibiotics to treat
colds and other viral infections that cannot be cured by the drugs. Researchers at the Centers for Disease Control and Prevention
have estimated that some 50 million of the 150 million outpatient
prescriptions for antibiotics every year are unneeded. At a seminar
I conducted, more than 80 percent of the physicians present admitted
to having written antibiotic prescriptions on demand
against their better judgment.
In the industrial world,
most antibiotics are available only by prescription, but this
restriction does not ensure proper use. People often fail
to finish the full course of treatment. Patients then stockpile
the leftover doses and medicate themselves, or their family and
friends, in less than therapeutic amounts. In both circumstances,
the improper dosing will fail to eliminate the disease agent completely
and will, furthermore, encourage growth
of the most resistant strains, which may later produce hard-to-treat
disorders. In the developing world, antibiotic use is
even less controlled. Many of the same drugs marketed in the industrial
nations are available over the counter. Unfortunately, when resistance
becomes a clinical problem, those countries, which often do not
have access to expensive drugs, may have no substitutes available.
A PHARMACEUTICAL STRATEGY
The same drugs prescribed
for human therapy are widely exploited in animal husbandry and
agriculture. More than 40 percent of the antibiotics manufactured
in the U.S. are given to animals. Some of that amount goes to
treating or preventing infection, but the lion's share is mixed
into feed to promote growth.
In this last application, amounts too small to combat infection
are delivered for weeks or months at a time. No one is entirely
sure how the drugs support growth. Clearly, though, this
long-term exposure to low doses is the perfect formula for selecting
increasing numbers of resistant bacteria in the treated animals--which
may then pass the microbes to caretakers and, more broadly, to
people who prepare and consume undercooked meat.
In agriculture, antibiotics
are applied as aerosols to acres of fruit trees, for controlling
or preventing bacterial infections.
High concentrations may kill all the bacteria on the trees at
the time of spraying, but lingering antibiotic residues can encourage
the growth of resistant bacteria that later colonize the fruit
during processing and shipping. The aerosols also hit more
than the targeted trees. They can be carried considerable distances
to other trees and food plants, where they are too dilute to eliminate
full-blown infections but are still capable of killing off sensitive
bacteria and thus giving the edge to resistant versions. Here,
again, resistant bacteria can make their way into people through
the food chain, finding a home in the intestinal tract after the
produce is eaten.
The amount of resistant
bacteria people acquire from food apparently is not trivial. Denis
E. Corpet of the National Institute for Agricultural Research
in Toulouse, France, showed that when human volunteers went on
a diet consisting only of bacteria-free foods, the number of resistant
bacteria in their feces decreased 1,000-fold. This finding
suggests that we deliver a supply of resistant strains to our
intestinal tract whenever we eat raw or undercooked items. These
bacteria usually are not harmful, but they could be if by chance
a disease-causing type contaminated the food.
The extensive worldwide
exploitation of antibiotics in medicine, animal care and agriculture
constantly selects for strains of bacteria that are resistant
to the drugs. Must all antibiotic use be halted to stem the rise
of intractable bacteria? Certainly not. But if the drugs are to
retain their power over pathogens, they have to be used more responsibly. Society can accept some increase in the fraction of resistant
bacteria when a disease needs to be treated; the rise is unacceptable
when antibiotic use is not essential.
A number of corrective
measures can be taken right now. As a start, farmers should be
helped to find inexpensive alternatives for encouraging animal
growth and protecting fruit trees.
Improved hygiene, for instance, could go a long way to enhancing
The public can wash
raw fruit and vegetables thoroughly
to clear off both resistant bacteria and possible antibiotic residues.
When they receive prescriptions for antibiotics, they should
complete the full course of therapy (to ensure that all
the pathogenic bacteria die) and should not "save"
any pills for later use. Consumers also should refrain
from demanding antibiotics for colds and other viral infections
and might consider seeking nonantibiotic therapies for minor conditions,
such as certain cases of acne. They can continue to put antibiotic
ointments on small cuts, but they should think twice about routinely
using hand lotions and a proliferation of other products now imbued
with antibacterial agents. New laboratory findings indicate
that certain of the bacteria-fighting chemicals being incorporated
into consumer products can select for bacteria resistant both
to the antibacterial preparations and to antibiotic drugs.
Physicians, for their part, can take some immediate steps to minimize any
resistance ensuing from required uses of antibiotics. When possible,
they should try to identify the causative pathogen before
beginning therapy, so they can prescribe an antibiotic targeted
specifically to that microbe instead of having to choose a broad-spectrum
product. Washing hands after seeing each patient is a major and
obvious, but too often overlooked, precaution.
To avoid spreading multidrug-resistant
infections between hospitalized patients, hospitals place
the affected patients in separate rooms, where they are seen by
gloved and gowned health workers and visitors. This practice should
Having new antibiotics
could provide more options for treatment.
In the 1980s pharmaceutical manufacturers, thinking infectious
diseases were essentially conquered, cut back severely on searching
for additional antibiotics. At the time, if one drug failed, another
in the arsenal would usually work (at least in the industrial
nations, where supplies are plentiful). Now that this happy state
of affairs is coming to an end, researchers are searching for
novel antibiotics again. Regrettably, though, few drugs are likely
to pass soon all technical and regulatory hurdles needed to reach
the market. Furthermore, those that are close to being ready are
structurally similar to existing antibiotics; they could easily
encounter bacteria that already have defenses against them.
With such concerns
in mind, scientists are also working on strategies that will give
new life to existing antibiotics. Many bacteria evade penicillin
and its relatives by switching on an enzyme, penicillinase, that
degrades those compounds. An antidote already on pharmacy shelves
contains an inhibitor of penicillinase; it prevents the breakdown
of penicillin and so frees the antibiotic to work normally. In
one of the strategies under study, my laboratory at Tufts University is developing a compound to jam a microbial pump that ejects tetracycline from bacteria;
with the pump inactivated, tetracycline can penetrate bacterial
Considering the Environmental Impact
As exciting as the pharmaceutical
research is, overall reversal of the bacterial resistance problem
will require public health officials, physicians, farmers and
others to think about the effects of antibiotics in new ways.
Each time an antibiotic is delivered, the fraction of resistant
bacteria in the treated individual and, potentially, in others,
increases. These resistant strains endure for some time -- often
for weeks -- after the drug is removed.
The main way resistant
strains disappear is by squaring off with susceptible versions
that persist in--or enter--a treated person after antibiotic use
has stopped. In the absence of antibiotics, susceptible strains
have a slight survival advantage, because the resistant bacteria
have to divert some of their valuable energy from reproduction
to maintaining antibiotic-fighting traits. Ultimately, the susceptible
microbes will win out, if they are available in the first place
and are not hit by more of the drug before they can prevail.
Correcting a resistance
problem, then, requires both improved management of antibiotic
use and restoration of the environmental bacteria susceptible
to these drugs. If all reservoirs of susceptible bacteria were
eliminated, resistant forms would face no competition for survival
and would persist indefinitely.
In the ideal world, public health officials
would know the extent of antibiotic resistance in both the infectious
and benign bacteria in a community. To treat a specific pathogen,
physicians would favor an antibiotic most likely to encounter
little resistance from any bacteria in the community. And they
would deliver enough antibiotic to clear the infection completely
but would not prolong therapy so much as to destroy all susceptible
bystanders in the body.
Prescribers would also
take into account the number of other individuals in the setting
who are being treated with the same antibiotic. If many patients
in a hospital ward were being given a particular antibiotic, this
high density of use would strongly select for bacterial strains
unsubmissive to that drug and would eliminate susceptible strains.
The ecological effect on the ward would be broader than if the
total amount of the antibiotic were divided among just a few people.
If physicians considered the effects beyond their individual patients,
they might decide to prescribe different antibiotics for different
patients, or in different wards, thereby minimizing the selective
force for resistance to a single medication.
Put another way,
prescribers and public health officials might envision an "antibiotic
threshold": a level of antibiotic usage able to correct the
infections within a hospital or community but still falling below
a threshold level that would strongly encourage propagation of
resistant strains or would eliminate large numbers of competing,
Keeping treatment levels below the threshold would ensure that
the original microbial flora in a person or a community could
be restored rapidly by susceptible bacteria in the vicinity after
The problem, of course,
is that no one yet knows how to determine where that threshold
lies, and most hospitals and communities lack detailed data on
the nature of their microbial populations. Yet with some dedicated
work, researchers should be able to obtain both kinds of information.
Control of antibiotic resistance
on a wider, international scale will require cooperation among
countries around the globe and concerted efforts to educate the
world's populations about drug resistance and the impact of improper
antibiotic use. As a step in this direction, various groups are
now attempting to track the emergence of resistant bacterial strains.
For example, an international organization, the Alliance for the
Prudent Use of Antibiotics (P.O. Box 1372, Boston, MA 02117),
has been monitoring the worldwide emergence of such strains since
1981. The group shares information with members in more than 90
countries. It also produces educational brochures for the public
and for health professionals.
The time has come for global
society to accept bacteria as normal, generally beneficial components
of the world and not try to eliminate them -- except when they give
rise to disease. Reversal of resistance requires a new awareness
of the broad consequences of antibiotic
use -- a perspective that concerns itself not only with curing bacterial
disease at the moment but also with preserving microbial communities
in the long run, so that bacteria susceptible to antibiotics will
always be there to outcompete resistant strains. Similar enlightenment
should influence the use of drugs to combat parasites, fungi and
viruses. Now that consumption of those medicines has begun to
rise dramatically, troubling resistance to these other microorganisms
has begun to climb as well.
THE ANTIBIOTIC PARADOX:
HOW MIRACLE DRUGS ARE DESTROYING THE MIRACLE. S. B. Levy. Plenum
DRUG RESISTANCE: THE
NEW APOCALYPSE. Special issue of Trends in Microbiology, Vol.
2, No. 10, pages 341-425; October 1, 1994.
ORIGINS, EVOLUTION, SELECTION AND SPREAD. Edited by D. J. Chadwick
and J. Goode. John Wiley & Sons, 1997.
STUART B. LEVY is professor
of molecular biology and microbiology, professor of medcine and
director of the Center for Adaptation Genetics and Drug Resistance
at the Tufts University School of Medicine. He is also president
of the Alliance for the Prudent Use of Antibiotics and president-elect
of the American Society for Microbiology.
Contact : Washington State Department
of Health/ Romesh Gautom, Public Health Laboratory, 206/361-2885
Matt Ashworth, Communication Office, 360/753-3237
Invitational EU Conference
"The Microbial Threat"
Health of the Population : Strategies
to prevent and control the emergence and spread of antimicrobial-resistant
Copenhagen, 9-10 September 1998.
(Workshops, 7-8 September 1998).
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