The Challenge of Antibiotic Resistance Certain bacterial infections now defy all antibiotics

09 Jun The Challenge of Antibiotic Resistance Certain bacterial infections now defy all antibiotics

Question
The Challenge
of Antibiotic Resistance
Certain bacterial 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

trol—have become increasingly common.
What is more, strains of at least three
bacterial species capable of causing lifethreatening 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

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aureus, a major cause of hospital-acquired infections, has thus moved one
step closer to becoming an unstoppable
killer.
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 con-

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L

ast 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.

Staphylococcus aureus

Acinetobacter

Enterococcus faecalis

Neisseria gonorrhoeae

Causes blood poisoning,
wound infections and pneumonia; in some hospitals, more
than 60 percent of strains are
resistant to methicillin; some
are poised for resistance to all
antibiotics (H/C; 1950s)

Causes blood poisoning
in patients with compromised
immunity (H, 1990s)

Causes blood poisoning and
urinary tract and wound
infections in patients with
compromised immunity; some
multidrug-resistant strains are
untreatable (H, 1980s)

Causes gonorrhea;
multidrug resistance now
limits therapy chiefly to
cephalosporins (C; 1970s)

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Scientific American March 1998

Copyright 1998 Scientific American, Inc.

Haemophilus
influenzae
Causes pneumonia, ear
infections and meningitis,
especially in children. Now
largely preventable by
vaccines (C; 1970s)

The Challenge of Antibiotic Resistance

and they should not be administered for
viral infections, over which they have no
power.
A Bad Combination

A

lthough 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.
Antibiotic-resistant pathogens 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.

Mycobacterium
tuberculosis
Causes tuberculosis;
some multidrug-resistant
strains are untreatable
(H/C; 1970s)

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fections mainly in hospitals (H) or mainly in the community (C);
others, in both settings. The decade listed with each entry indicates the period when resistance first became a significant problem for patient care. The bacteria, which are microscopic, are
highly magnified in these false-color images.

Escherichia coli
Causes urinary tract infections,
blood poisoning, diarrhea and
kidney failure; some strains that
cause urinary tract infections
are multidrug-resistant
(H/C; 1960s)

The Challenge of Antibiotic Resistance

Pseudomonas
aeruginosa
Causes blood poisoning and
pneumonia, especially in
people with cystic fibrosis or
compromised immunity; some
multidrug-resistant strains are
untreatable (H/C; 1960s)

Shigella dysenteria
Causes dysentery (bloody
diarrhea); resistant strains have
led to epidemics, and some can
be treated only by expensive
fluoroquinolones, which are
often unavailable in developing
nations (C; 1960s)

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ROGUE’S GALLERY OF BACTERIA features some types having variants resistant to multiple antibiotics; multidrug-resistant
bacteria are difficult and expensive to treat. Certain strains of
the species described in red no longer respond to any antibiotics
and produce incurable infections. Some of the bacteria cause in-

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 antimicrobials.
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

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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 antibiotic-resistant pathogens.
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,

Streptococcus
pneumoniae
Causes blood poisoning,
middle ear infections,
pneumonia and meningitis
(C; 1970s)

Scientific American March 1998

47

ANTIBIOTIC-RESISTANT BACTERIA owe their drug insensitivity to resistance genes. For example, such genes might code for “efflux” pumps that
eject antibiotics from cells (a). Or the genes might give rise to enzymes that
degrade the antibiotics (b) or that chemically alter—and inactivate—the
drugs (c). Resistance genes can reside on the bacterial chromosome or, more
typically, on small rings of DNA called plasmids. Some of the genes are inherited, some emerge through random mutations in bacterial DNA, and
some are imported from other bacteria.

ANTIBIOTICRESISTANCE
GENES
ANTIBIOTICDEGRADING
ENZYME

ANTIBIOTICEFFLUX PUMP

a
b

ANTIBIOTIC

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

B
DAN WAGNER (photograph); LAURIE GRACE (digital manipulation)

acteria 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
c
PLASMID
existing one. And frequently,
bacteria will gain a defense
ANTIBIOTIC
against an antibiotic by taking up resistance genes from
ANTIBIOTICother bacterial cells in the viALTERING
BACTERIAL
cinity. Indeed, the exchange
ANTIBIOTIC
ENZYME
CELL
of genes is so pervasive that
the entire bacterial world can
CHROMOSOME
be thought of as one huge
multicellular organism in
which the cells interchange
their genes with ease.
mids, tiny loops of DNA that can help
Bacteria have evolved several ways to bacteria survive various hazards in the
share their resistance traits with one an- environment. But the genes may also
other [see “Bacterial Gene Swapping in occur on the bacterial chromosome, the
Nature,” by Robert V. Miller; Scien- larger DNA molecule that stores the
tific American, January]. Resistance genes needed for the reproduction and
genes commonly are carried on plas- routine maintenance of a bacterial cell.

The Antibacterial Fad:
A New Threat

A

ntibiotics are not the only antimicrobial substances being overexploited today. Use of antibacterial agents—
compounds that kill or inhibit bacteria
but are too toxic to be taken internally—
has been skyrocketing as well. These compounds, also known as
disinfectants and antiseptics, are applied to inanimate objects or
to the skin.
Historically, most antibacterials were used in hospitals, where
they were incorporated into soaps and surgical clothes to limit
the spread of infections. More recently, however, those substances (including triclocarbon, triclosan and such quaternary
ammonium compounds as benzalkonium chloride) have been
mixed into soaps, lotions and dishwashing detergents meant for
general consumers. They have also been impregnated into such
items as toys, high chairs, mattress pads and cutting boards.
There is no evidence that the addition of antibacterials to such
household products wards off infection. What is clear, however,
is that the proliferation of products containing them raises public health concerns.
Like antibiotics, antibacterials can alter the mix of bacteria:
they simultaneously kill susceptible bacteria and promote the
growth of resistant strains. These resistant microbes may include
bacteria that were present from the start. But they can also include ones that were unable to gain a foothold previously and
are now able to thrive thanks to the destruction of competing

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Scientific American March 1998

microbes. I worry particularly about that second group—the interlopers—because once they have a chance to proliferate,
some may become new agents of disease.
The potential overuse of antibacterials in the home is troubling on other grounds as well. Bacterial genes that confer resistance to antibacterials are sometimes carried on plasmids (circles of DNA) that also bear antibiotic-resistance genes. Hence, by
promoting the growth of bacteria bearing such plasmids, antibacterials may actually foster double resistance—to antibiotics
as well as antibacterials.
Routine housecleaning is surely necessary. But standard soaps
and detergents (without added antibacterials) decrease the
numbers of potentially troublesome bacteria perfectly well. Similarly, quickly evaporating chemicals—such as the old standbys
of chlorine bleach, alcohol, ammonia and hydrogen peroxide—
can be applied beneficially. They remove potentially diseasecausing bacteria from, say, thermometers or utensils used to prepare raw meat for cooking, but they do not leave long-lasting
residues that will continue to kill benign bacteria and increase
the growth of resistant strains long after target pathogens have
been removed.
If we go overboard and try to establish a sterile environment,
we will find ourselves cohabiting with bacteria that are highly resistant to antibacterials and, possibly, to antibiotics. Then, when
we really need to disinfect our homes and hands—as when a
family member comes home from a hospital and is still vulnerable to infection—we will encounter mainly resistant bacteria. It is
not inconceivable that with our excessive use of antibacterials
and antibiotics, we will make our homes, like our hospitals,
havens of ineradicable disease-producing bacteria.
—S.B.L.

Copyright 1998 Scientific American, Inc.

The Challenge of Antibiotic Resistance

BACTERIA PICK UP RESISTANCE GENES from other bacterial cells in
three main ways. Often they receive whole plasmids bearing one or more
such genes from a donor cell (a). Other times, a virus will pick up a resistance gene from one bacterium and inject it into a different bacterial cell (b).
Alternatively, bacteria sometimes scavenge gene-bearing snippets of DNA
from dead cells in their vicinity (c). Genes obtained through viruses or from
dead cells persist in their new owner if they become incorporated stably into
the recipient’s chromosome or into a plasmid.

PLASMID

RESISTANCE
GENE

c
TRANSFER
OF FREE
DNA

RESISTANCE
GENE

a

PLASMID
TRANSFER
Gene goes
to plasmid
or to
chromosome

which turned out to eliminate competitors, enabled
the manufacturers to survive
b
DEAD
TRANSFER
and proliferate—if they were
BACTERIUM
BY VIRAL
also lucky enough to possess
DELIVERY
genes that protected them
from their own chemical
BACTERIUM
RESISTANCE
weapons. Later, these protecRECEIVING
GENE
RESISTANCE
tive genes found their way
GENES
BACTERIUM
into other species, some of
INFECTED
which were pathogenic.
BY A VIRUS
Regardless of how bacteria acquire resistance genes
Often one bacterium will pass resis- today, commercial antibiotics can select
tance traits to others by giving them a for—promote the survival and propagauseful plasmid. Resistance genes can tion of—antibiotic-resistant strains. In
also be transferred by viruses that occa- other words, by encouraging the growth
sionally extract a gene from one bacte- of resistant pathogens, an antibiotic can
rial cell and inject it into a different one. actually contribute to its own undoing.
In addition, after a bacterium dies and
How Antibiotics Promote Resistance
releases its contents into the environment, another will occasionally take up
he selection process is fairly straighta liberated gene for itself.
forward. When an antibiotic atIn the last two situations, the gene will
survive and provide protection from an tacks a group of bacteria, cells that are
antibiotic only if integrated stably into highly susceptible to the medicine will
a plasmid or chromosome. Such inte- die. But cells that have some resistance
gration occurs frequently, though, be- from the start, or that acquire it later
cause resistance genes are often embed- (through mutation or gene exchange),
ded in small units of DNA, called trans- may survive, especially if too little drug
posons, that readily hop into other DNA is given to overwhelm the cells that are
molecules. In a regrettable twist of fate present. Those cells, facing reduced
for human beings, many bacteria play competition from sushost to specialized transposons, termed ceptible bacteria, will
integrons, that are like flypaper in their then go on to prolifpropensity for capturing new genes. erate. When confrontThese integrons can consist of several ed with an antibiotic,
different resistance genes, which are the most resistant cells
passed to other bacteria as whole regi- in a group will inevitably outcompete all
ments of antibiotic-defying guerrillas.
Many bacteria possessed resistance others.
Promoting resisgenes even before commercial antibiotics came into use. Scientists do not know tance in known pathexactly why these genes evolved and ogens is not the only
were maintained. A logical argument self-defeating activity
holds that natural antibiotics were ini- of antibiotics. When
tially elaborated as the result of chance the medicines attack
genetic mutations. Then the compounds, disease-causing bacILLUSTRATIONS BY TOMO NARASHIMA

VIRUS

T

teria, 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 multidrugresistant 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.
Moreover, administration 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
LAURIE GRACE; SOURCE: CHRISTOPHER G. DOWSON, TRACEY J. COFFEY AND BRIAN G. SPRATT University of Sussex

PLASMID DONOR

SPREAD OF RESISTANT BACTERIA, which occurs readily, can
extend quite far. In one example, investigators traced a strain of multidrug-resistant Streptococcus pneumoniae from Spain to Portugal,
France, Poland, the U.K., South Africa, the U.S. and Mexico.
The Challenge of Antibiotic Resistance

Copyright 1998 Scientific American, Inc.

Scientific American March 1998

49

TOMO NARASHIMA

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 bloodborne infections in hospitalized patients.
These formerly innocuous microbes were
virtually unheard of just five years ago.
As I noted earlier, antibiotics affect

ANTIBIOTIC

a
BACTERIUM
SUSCEPTIBLE
TO ANTIBIOTICS

SOMEWHAT
INSENSITIVE
BACTERIUM

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 medicines.
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 multidrugresistant 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
b

SURVIVING
BACTERIUM

c

bacterium, also known as the pneumococcus, is a cause of pneumonia and
meningitis, among other diseases.
Antibiotic Use Is Out of Control

F

or 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 encourage resistance.
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,

d
e
DEAD
BACTERIA

BACTERIUM
WITH INCREASED
RESISTANCE

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Scientific American March 1998

Copyright 1998 Scientific American, Inc.

The Challenge of Antibiotic Resistance

A

f

g

HIGHLY
RESISTANT
POPULATION

ANTIBIOTIC USE SELECTS—promotes the evolution and growth of—bacteria that
are insensitive to that drug. When bacteria are exposed to an antibiotic (a), bacterial
cells that are susceptible to the drug will die (b), but those with some insensitivity may
survive and grow (c) if the amount of drug delivered is too low to eliminate every last
cell. As treatment continues, some of the survivors are likely to acquire even stronger
resistance (d)—either through a genetic mutation that generates a new resistance trait
or through gene exchange with newly arriving bacteria. These resistant cells will then
evade the drug most successfully (e) and will come to predominate ( f and g ).
Copyright 1998 Scientific American, Inc.

Scientific American March 1998

51

TOMO NARASHIMA

encourage growth of the
SUSCEPTIBLE BACTERIA IN VICINITY
most resistant strains, which
may later produce hard-toa
b
c
d
treat disorders.
In the deve…