Are Antibiotics Killing Us? - Very important article

[Guest guest]

http://www.discover.com/issues/nov-05/features/are-antibiotics-killing/

Article in Discover Magazine, November 2005

Are Antibiotics Killing Us?

For every cell in your body, you support 10 bacterial

cells that make vitamins, trigger hormones, and may

even influence how fat you are. Guess what happens to

them when you pop penicillin?.

By Snyder Sachs

Photography by Lutz

DISCOVER Vol. 26 No. 10 | October 2005 | Biology &

A lan Hudson likes to tell a story about a soldier and

his high school sweetheart.

That's what microbiologist Alan Hudson says the

bacterium chlamydia looks like in its inactive, or

persistent, form. The human cell shown above contains

several developmental forms of the bacterium, which

has persisted even after treatment with penicillin.

The bacterium must be studied in cells because it

cannot survive outside of them. Chlamydia trachomatis,

which is sexually transmitted, is a major cause of

infertility in developed countries. A nonsexually

transmitted strain is a leading cause of blindness in

undeveloped regions around the world.

The young man returns from an overseas assignment for

their wedding with a clean bill of health, having

dutifully cleared up an infection of sexually

transmitted chlamydia.

" Three weeks later, the wife has a screaming genital

infection, " Hudson recounts, " and I get a call from

the small-town doctor who's trying to save their

marriage. " The soldier, it seems, has decided his wife

must have been seeing other men, which she denies.

Hudson pauses for effect, stretching back in his seat

and propping his feet on an open file drawer in a

crowded corner of his microbiology laboratory at Wayne

State Medical School in Detroit. " The doctor is

convinced she's telling the truth, " he continues,

folding his hands behind a sweep of white,

collar-length hair. " So I tell him, 'Send me a

specimen from him and a cervical swab from her.' "

This is done after the couple has completed a full

course of antibiotic treatment and tested free of

infection.

" I PCR 'em both, " Hudson says, " and he is red hot. "

PCR stands for polymerase chain reaction—a technique

developed about 20 years ago that allows many copies

of a DNA sequence to be made. It is often used at

crime scenes, where very little DNA may be available.

Hudson's use of the technique allowed him to find

traces of chlamydia DNA in the soldier and his wife

that traditional tests miss because the amount left

after antibiotic treatment is small and asymptomatic.

Nonetheless, if a small number of inactive chlamydia

cells passed from groom to bride, the infection could

have became active in its new host.

Hudson tells the tale to illustrate how microbes that

scientists once thought were easily eliminated by

antibiotics can still thrive in the body. His findings

and those of other researchers raise disturbing

questions about the behavior of microbes in the human

body and how they should be treated.

For example, Hudson has found that quiescent varieties

of chlamydia may play a role in chronic ailments not

traditionally thought to be related to this infectious

agent. In the early 1990s, he found two types of

chlamydia—Chlamydia trachomatis and Chlamydia

pneumonia—in the joint tissue of patients with

inflammatory arthritis. More famously, in 1996, he

began fishing C. pneumonia out of the brain cells of

Alzheimer's victims. Since then, other researchers

have made headlines after reporting the genetic

fingerprints of C. pneumonia, as well as several kinds

of common mouth bacteria, in the arterial plaque of

heart attack patients. Hidden infections are now

thought to be the basis of still other stubbornly

elusive ills like chronic fatigue syndrome, Gulf War

syndrome, multiple sclerosis, lupus, Parkinson's

disease, and types of cancer.

To counteract these killers, some physicians have

turned to lengthy or lifelong courses of antibiotics.

At the same time, other researchers are

counterintuitively finding that bacteria we think are

bad for us also ward off other diseases and keep us

healthy. Using antibiotics to tamper with this

complicated and little-understood population could

irrevocably alter the microbial ecology in an

individual and accelerate the spread of drug-resistant

genes to the public at large.

The two-faced puzzle regarding the role of bacteria

is as old as the study of microbiology itself. Even as

Louis Pasteur became the first to show that bacteria

can cause disease, he assumed that bacteria normally

found in the body are essential to life. Yet his

protégé, Élie Metchnikoff, openly scoffed at the idea.

Metchnikoff blamed indigenous bacteria for senility,

atherosclerosis, and an altogether shortened life

span—going even so far as to predict the day when

surgeons would routinely remove the human colon simply

to rid us of the " chronic poisoning " from its abundant

flora.

Today we know that trillions of bacteria carpet not

only our intestines but also our skin and much of our

respiratory and urinary tracts. The vast majority of

them seem to be innocuous, if not beneficial. And

bacteria are everywhere, in abundance—they outnumber

other cells in the human body by 10 to one.

Relman and his team at Stanford University and the VA

Medical Center in Palo Alto, California, recently

found the genetic fingerprints of several hundred new

bacterial species in the mouths, stomachs, and

intestines of healthy volunteers.

" What I hope, " Relman says, " is that by starting with

specimens from healthy people, the assumption would be

that these microbes have probably been with us for

some time relative to our stay on this planet and may,

in fact, be important to our health. "

Meanwhile, the behavior of even well-known bacterial

inhabitants is challenging the old, straightforward

view of infectious disease. In the 19th century,

Koch laid the foundation for medical

microbiology, postulating: Any microorganism that

causes a disease should be found in every case of the

disease and always cause the disease when introduced

into a new host. That view prevailed until the middle

of this past century. Now we are more confused than

ever. Take Helicobacter pylori. In the 1980s infection

by the bacterium, not stress, was found to be the

cause of most ulcers. Overnight, antibiotics became

the standard treatment. Yet in the undeveloped world

ulcers are rare, and H. pylori is pervasive.

" This stuff drives the old-time microbiologists mad, "

says Hudson, " because Koch's postulates simply don't

apply. " With new technologies like PCR, researchers

are turning up stealth infections everywhere, yet they

cause problems only in some people sometimes, often

many years after the infection.

These mysteries have nonetheless not stopped a free

flow of prescriptions. Many rheumatologists, for

example, now prescribe long-term—even lifelong—courses

of antibiotics for inflammatory arthritis, even

though it isn't known if the antibiotics actually

clear away bacteria or reduce inflammatory arthritis

in some other unknown manner.

Even more far-reaching is the use of antibiotics to

treat heart disease, a trend that began in the early

1990s after studies associated C. pneumonia with the

accumulation of plaque in arteries. In April two

large-scale studies reported that use of antibiotics

does not reduce the incidence of heart attacks or

eliminate C. pneumonia. But researchers left

antibiotic-dosing cardiologists a strange option by

admitting they do not know if stronger, longer courses

of antibiotics or combined therapies would succeed.

Meanwhile, many researchers are alarmed.

Infectious-diseases specialist Curtis Donskey, of Case

Western Reserve University in Cleveland, says:

" Unfortunately, far too many physicians are still

thinking of antibiotics as benign. We're just now

beginning to understand how our normal microflora does

such a good job of preventing our colonization by

disease-causing microbes. And from an ecological point

of view, we're just starting to understand the medical

consequences of disturbing that with antibiotics. "

Donskey has seen the problem firsthand at the

Cleveland VA Medical Center, where he heads infection

control. " Hospital patients get the broadest spectrum,

most powerful antibiotics, " he says, but they are also

" in an environment where they get exposed to some of

the nastiest, most drug-resistant pathogens. " Powerful

antibiotics can be dangerous in such a setting because

they kill off harmless bacteria that create

competition for drug-resistant colonizers, which can

then proliferate. The result: Hospital-acquired

infections have become a leading cause of death in

critical-care units.

" We also see serious problems in the outside

community, " Donskey says, because of inappropriate

antibiotic use.

The consequences of disrupting the body's bacterial

ecosystem can be minor, such as a yeast infection, or

they can be major, such as the overgrowth of a

relatively common gut bacterium called Clostridium

difficile. A particularly nasty strain of C. difficile

has killed hundreds of hospital patients in Canada

over the past two years. Some had checked in for

simple, routine procedures. The same strain is moving

into hospitals in the United States and the United

Kingdom.

Gordon, a gastroenterologist turned full-time

microbiologist, heads the spanking new Center for

Genomic Studies at Washington University in Saint

Louis. The expansive, sun-streaked laboratory sits

above the university's renowned gene-sequencing

center, which proved a major player in powering the

Human Genome Project. " Now it's time to take a broader

view of the human genome, " says Gordon, " one that

recognizes that the human body probably contains 100

times more microbial genes than human ones. "

Gordon supervises a lab of some 20 graduate students

and postdocs with expertise in disciplines ranging

from ecology to crystallography. Their collaborations

revolve around studies of unusually successful

colonies of genetically engineered germ-free mice and

zebra fish.

Gordon's veteran mouse wranglers, Marie Karlsson and

her husband O'Donnell, manage the rearing of

germ-free animals for comparison with genetically

identical animals that are colonized with one or two

select strains of normal flora. In a cavernous

facility packed with rows of crib-size bubble

chambers, Karlsson and O'Donnell handle their

germ-free charges via bulbous black gloves that serve

as airtight portals into the pressurized isolettes.

They generously supplement sterilized mouse chow with

vitamins and extra calories to replace or complement

what is normally supplied by intestinal bacteria.

" Except for their being on the skinny side, we've got

them to the point where they live near-normal lives, "

says O'Donnell. Yet the animals' intestines remain

thin and underdeveloped in places, bizarrely bloated

in others. They also prove vulnerable to any stray

pathogen that slips into their food, water, or air.

All Gordon's protégés share an interest in following

the molecular cross talk among resident microbes and

their host when they add back a component of an

animal's normal microbiota. One of the most

interesting players is Bacteroides thetaiotaomicron,

or B. theta, the predominant bacterium of the human

colon and a particularly bossy symbiont.

The bacterium is known for its role in breaking down

otherwise indigestible plant matter, providing up to

15 percent of its host's calories. But Gordon's team

has identified a suite of other, more surprising

skills. Three years ago, they sequenced B. theta's

entire genome, which enabled them to work with a gene

chip that detects what proteins are being made at any

given time. By tracking changes in the activity of

these

Meanwhile, Abigail Salyers of the University of

Illinois at Urbana-Champaign (above) is trying to

figure out how anaerobic bacteria transfer antibiotic

resistance genes to other bacteria. The anaerobics are

kept in oxygen-free vials (below) and must be removed

by syringe to avoid exposure to the air.

genes, the team has shown that B. theta helps guide

the normal development and functioning of the

intestines—including the growth of blood vessels, the

proper turnover of epithelial cells, and the

marshaling of components of the immune system needed

to keep less well behaved bacteria at bay. B. theta

also exerts hormonelike, long-range effects that may

help the host weather times when food is scarce and

ensure the bacterium's own survival.

Fredrik Bäckhed, a young postdoc who came to Gordon's

laboratory from the Karolinska Institute in Stockholm,

has caught B. theta sending biochemical messages to

host cells in the abdomen, directing them to store

fat. When he gave germ-free mice an infusion of gut

bacteria from a conventionally raised mouse, they

immediately put on an average of 50 percent more fat

although they were consuming 30 percent less food than

when they were germ-free. " It's as if B. theta is

telling its host, 'save this—we may need it later,' "

Gordon says.

Sonnenburg, another postdoctoral fellow, has

documented that B. theta turns to the host's body for

food when the animal stops eating. He has found that

when a lab mouse misses its daily ration, B. theta

consumes the globs of sugary mucus made every day by

some cells in the intestinal lining. The bacteria

graze on these platforms, which the laboratory has

dubbed Whovilles (after the dust-speck metropolis of

Dr. Seuss's Horton Hears a Who!). When the host

resumes eating, B. theta returns to feeding on the

incoming material.

Gordon's team is also looking at the ecological

dynamics that take place when combinations of normal

intestinal bacteria are introduced into germ-free

animals. And he plans to study the dynamics in people

by analyzing bacteria in fecal samples.

Among the questions driving him: Can we begin to use

our microbiota as a marker of health and disease? Does

this " bacterial nation " shift in makeup when we become

obese, try to lose weight, experience prolonged

stress, or simply age? Do people in Asia or Siberia

harbor the same organisms in the same proportions as

those in North America or the Andes?

" We know that our environment affects our health to an

enormous degree, " Gordon says. " And our microbiota are

our most intimate environment by far. "

A couple hundred miles northeast of Gordon's

laboratory, microbiologist Abigail Salyers at the

University of Illinois at Urbana-Champaign has been

exploring a more sinister feature of our bacteria and

their role in antibiotic resistance. At the center of

her research stands a room-size, walk-in artificial

" gut " with the thermostat set at the human intestinal

temperature of 100.2 degrees Fahrenheit. Racks of

bacteria-laced test tubes line three walls, the sealed

vials purged of oxygen to simulate the anaerobic

conditions inside a colon. Her study results are

alarming.

Salyers says her research shows that decades of

antibiotic use have bred a frightening

degree of drug resistance into our intestinal flora.

The resistance is harmless as long as the bacteria

remain confined to their normal habitat. But it can

prove deadly when those bacteria contaminate an open

wound or cause an infection after surgery.

" Having a highly antibiotic-resistant bacterial

population makes a person a ticking time bomb, " says

Salyers, who studies the genus Bacteroides, a group

that includes not only B. theta but also about a

quarter of the bacteria in the human gut. She has

tracked dramatic increases in the prevalence of

several genes and suites of genes coding for drug

resistance. She's particularly interested in tetQ, a

DNA sequence that conveys resistance to tetracycline

drugs.

When her team tested fecal samples taken in the 1970s,

they found that less than 25 percent of human-based

Bacteroides carried tetQ. By the 1990s, that rate had

passed the 85 percent mark, even among strains

isolated from healthy people who hadn't used

antibiotics in years. The dramatic uptick quashed

hopes of reducing widespread antibiotic resistance by

simply withdrawing or reducing the use of a given

drug. Salyers's team also documented the spread of

several Bacteroides genes conveying resistance to

other antibiotics such as macrolides, which are widely

used to treat skin, respiratory, genital, and blood

infections.

As drug-resistant genes become common in bacteria in

the gut, they are more likely to pass on their

information to truly dangerous bugs that only move

periodically through our bodies, says Salyers. Even

distantly related bacteria can swap genes with one

another using a variety of techniques, from direct

cell-to-cell transfer, called conjugation, to

transformation, in which a bacterium releases snippets

of DNA that other bacteria pick up and use.

" Viewed in this way, the human colon is the bacterial

equivalent of eBay, " says Salyers. " Instead of

creating a new gene the hard way—through mutation and

natural selection—you can just stop by and obtain a

resistance gene that has been created by some other

bacterium. "

Salyers has shown that Bacteroides probably picked up

erythromycin-resistant genes from distantly related

species of staphylococcus and streptococcus. Although

n neither bug colonizes the intestine, they are

routinely inhaled and swallowed, providing a window of

24 to 48 hours in which they can commingle with

intestinal flora before exiting. " That's more than

long enough to pick up something interesting in the

swinging singles bar of the human colon, " she quips.

Most disturbing is Salyers's discovery that

antibiotics like tetracycline actually stimulate

Bacteroides to begin swapping its resistance genes.

" If you think of the conjugative transfer of

resistance genes as bacterial sex, you have to think

of tetracycline as the aphrodisiac, " she says. When

Salyers exposes Bacteroides to other bacteria such as

Escherichia coli under the disinhibiting influence of

antibiotics, she has witnessed the step-by-step

process by which the bacteria excise and transfer the

tetQ gene from one species to another.

Nor is Bacteroides the only intestinal resident with

such talents. " In June 2002, we passed a particularly

frightening milestone, " Salyers says. That summer,

epidemiologists discovered hospital-bred strains of

the gut bacterium enterococcus harboring a gene that

made them impervious to vancomycin. The bacterium may

have since passed the gene to the far more dangerous

Staphylococcus aureus, the most common cause of fatal

surgical and wound infections.

" I am completely mystified by the lack of public

concern about this problem, " she says.

With no simple solution in sight, Salyers continues to

advise government agencies such as the Food and Drug

Administration and the Department of Agriculture to

reduce the use of antibiotics in livestock feed, a

practice banned throughout the European Union. She

supports the prescient efforts of Tufts University

microbiologist Stuart Levy, founder of the Alliance

for the Prudent Use of Antibiotics, which has been

hectoring doctors to use antibiotics more judiciously.

Yet just when the message appears to be getting

through—judging by a small but real reduction in

antibiotic prescriptions—others are calling for an

unprecedented increase in antibiotic use to clear the

body of infections we never knew we had. Among them is

, a Vanderbilt University chlamydia

specialist. If antibiotics ever do prove effective for

treating coronary artery disease, he says, the results

would be " staggering. We're talking about the majority

of the population being on long-term antibiotics,

possibly multiple antibiotics. "

Hudson cautions that before we set out to eradicate

our bacterial fellow travelers, " we'd damn well better

understand what they're doing in there. " His interest

centers on chlamydia, with its maddening ability to

exist in inactive infections that flare into problems

only for an unlucky few. Does the inactive form cause

damage by secreting toxins or killing cells? Or is the

real problem a disturbed immune response to them?

Lately Hudson has resorted to a device he once shunned

in favor of DNA probes: a microscope, albeit an exotic

$250,000 model. This instrument, which can magnify

organisms an unprecedented 15,000 times, sits in the

laboratory of Hudson's spouse, Judith Whittum-Hudson,

a Wayne State immunologist who is working on a

chlamydia vaccine. On a recent afternoon, Hudson

marveled as a shimmering chlamydia cell was beginning

to morph from its infectious stage into its mysterious

and bizarre-looking persistent form. " One minute you

have this perfectly normal, spherical bacterium and

the next you have this big, goofy-looking doofus of a

microbe, " he says. He leans closer, focusing on a

roiling spot of activity. " It's doing something. It's

making something. It's saying something to its host. "

YOUR BODY'S ABUNDANT BACTERIA

More than 100 trillion bacteria inhabit your body. And

they aren't just silent partners. They digest your

food, make vitamins, and protect you from pathogens. A

recent study has found they may even play a role in

regulating appetite and weight. —Jocelyn Selim

EYES Natural antibiotics in tears kill most organisms,

but the eyes are home to a few hardy forms—mostly

harmless strains of Staphylococcus, such as S.

epidermis, and Streptococcus—that keep more virulent

strains, such as pinkeye-causing Moraxella or

Chlamydia trachomatis, at bay.

EARS Although waxy secretions contain antibacterial

components, more than 200 bacterial species normally

maintain residence in the outer ear.

NOSE At least 20 percent of us carry a virulent strain

of Staphylococcus aureus. Normally it's not much of a

problem, unless a cut lets it into the bloodstream.

Then it can be serious and even fatal. All of us

harbor less harmful strains of Staphylococcus,

Neisseria, and Corynebacterium that provide a buffer

against colonization by such pathogens as

Streptococcus pneumonia.

MOUTH Of the estimated 500 microbial species in the

human mouth, only 150 have ever been cultured in

laboratories. On your teeth, Actinomyces viscosus

secrete plaque, which traps volatile sulfur producers

and acid-leaking Streptococcus mutans, the cause of

bad breath and cavities.

SKIN Relatively low moisture, a low pH, and high

salinity make most areas inhospitable to all but a few

species.

ARMPITS Most of the 12 trillion or so total skin

bacteria prefer the moist climate of the armpits and

groin, where urea, protein, salts, and lactic acid

leak out of sweat ducts and gather around hair

follicles. Some people are hosts to more of the

Corynebacterium species that feast on these odorless

compounds and convert them to 3-methyl-2-hexenoic

acid, the volatile compound that makes armpits smell

distinctive.

STOMACH Once thought too acidic to harbor life, it is

now known to harbor the bacterium Helicobacter pylori,

which can cause ulcers in some people.

SMALL INTESTINE Bile and antimicrobial mucus keep the

small intestine sparsely populated, but Bacteroides,

streptococci, bifidobacteria, and clostridia remain. A

November 2002 study showed that one of these,

Bacteroides thetaiotaomicron, sends signals needed for

the blood vessels of the bowels to develop properly

after birth.

COLON There are over two pounds of bacteria in your

colon, and they make up a third of human feces by

weight. Predominantly composed of the anaerobic

members of the phyla Bacteroidetes and Firmicutes,

these organisms metabolize bile acids, break down

indigestible parts of our food, and produce vitamins K

and B12. A study last February identified a strain

capable of contributing to obesity by disrupting the

appetite-regulating hormone ghrelin.

URINARY TRACT The urethra is normally sterile, except

for the half inch near the exit. Urinary tract

infections occur when certain strains of

colon-dwelling Escherichia coli bacteria manage to

colonize the opening and migrate upward.

REPRODUCTIVE TRACT Various species of Lactobacillus

keep the vagina at a slightly acidic pH ranging from 4

to 5. If the bacteria are killed off, the pH goes up,

encouraging the overgrowth of Candida fungus.

FEET Various species of moisture-loving bacteria

flourish between the toes. Some ferment acids,

producing the smell of sweaty feet.

STERILE AREAS liver, gall bladder, brain, thymus,

blood, lower lungs