Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (9 page)

A handful of brilliant scientists, the giants in their field, led the way. In 1857, French chemist Louis Pasteur showed that fermentation and putrefaction are caused by invisible organisms floating in the air. He demonstrated that meat decay was caused by microbes and that disease could be explained by the multiplication of germs in the body. Following Hungarian physician Ignatz Semmelweis, who markedly reduced deaths due to childbirth fever by requiring hand washing, the British doctor Joseph Lister revolutionized surgical practice by introducing new principles of cleanliness. Inspired by Pasteur, he soaked dressings with carbolic acid (a form of coal tar with antiseptic properties), covered infected wounds, and thereby improved their healing. And Robert Koch, a German doctor, developed methods to assess whether a particular microorganism causes a specific disease; these criteria are known today as Koch’s postulates. He also developed stains for visualizing the bacteria that cause tuberculosis and cholera under the microscope.

But while germ theory led to improved sanitation and a better understanding of disease, it did not revolutionize treatment. Just because it was possible to see and grow bacteria did not mean that finding ways to kill them would be easy. Another pioneer, Paul Ehrlich, who worked in Koch’s bacteriology lab, was searching for “magic bullets”—dyes, poisons, and heavy metals—that would stain specific germs and then, in a double whammy, attach to the germs and kill them.

But no one thought to look in the natural world for living organisms that would knock back pathogens. Why would they? The astonishing diversity of the microbial world is only now becoming appreciated.

Such was the mind-set of the scientific community when Alexander Fleming, a bow-tie-clad Scotsman working in St. Mary’s Hospital in London, made a discovery that changed the world. Like many of his contemporaries, he was looking for ways to kill bacteria. In classically designed experiments, he placed a jellylike growth medium (agar and heated blood) into shallow, circular, transparent plates, called petri dishes, and then inoculated the medium with bacteria. Bacteria, which are too small to be seen with the naked eye, love to eat agar. As they ate, they divided again and again. Eventually agglomerations of millions of bacteria formed a colony that could be seen by the naked eye. After putting the plates into a warm incubator overnight, Fleming was able to grow huge, clearly visible, gold-colored colonies of
Staphylococcus aureus
and other bacteria that he would try to kill with enzymes derived from white blood cells and from saliva.

In August 1928, Fleming went on vacation to France. When he returned in early September, he found several petri dishes that he had neglected to throw out. They had been inoculated with
Staph
and then they sat on his lab bench for the month he was away. As Fleming was tossing out the now useless plates, one of them caught his eye. It was flecked with a patch of blue-green fuzz, which he recognized as the common bread mold
Penicillium.
He saw that the luxuriant lawn of golden
Staph
, the filmy layer of billions of bacterial cells growing wall-to-wall on the plate, had disappeared near the mold. There was a kind of halo around the mold delineated by something in the medium that had prevented the
Staph
from growing.

Fleming’s trained eye immediately recognized what had happened. The mold, which is a fungus that also likes agar, had produced a substance that had diffused into the agar and killed the
Staph
. That substance, the first-identified true antibiotic, dissolved bacterial cells, just as did lysozyme, an enzyme he had discovered in saliva in his experiments years earlier. It wiped them out, scorched earth–style. Fleming thought his “mold juice” contained an enzyme (like lysozyme), although it was later learned that the substance was not an enzyme but nevertheless disrupts the ability of bacteria to build their cell walls, causing them to burst.

The miraculous mold was identified as
Penicillium notatum.
Actually the antibacterial effects of
Penicillium
molds had been known since the seventeenth century but not to Fleming or any of his contemporary physicians. Ancient Egyptians, Chinese, and Central American Indians all used molds to treat infected wounds. But it was Fleming’s training as a scientist that enabled him to move the fungus from a folk remedy into the scientific spotlight.

Over the next months, Fleming was able to grow the mold in liquid broth, pass the broth through a filter, and isolate a fluid that was rich in antibacterial activity. He called it penicillin. But there were many obstacles to obtaining enough of it. Not all strains of
P. notatum
made penicillin. Fleming was fortunate in that the one that fell onto his petri dish produced penicillin, but the yields remained tiny, unstable, short-lived, and slow acting. Unable to devise ways to make penicillin medically useful, Fleming gave up. After publishing his results, and trying some crude extracts on a few ill patients without any apparent effect, he concluded that his discovery had no practical importance.

But others had noticed. A few years later, a chemist in Germany who worked for the giant I. G. Farben chemical company that made aspirin and dyes used for textile coloring was looking for a dye that would inhibit the growth of bacteria. In 1932, Gerhard Domagk discovered a red dye (called
Prontosil
) that contained a wholly synthetic antibacterial agent, the first sulfonamide. A class of related sulfa drugs followed. These were the first agents that had any sustained and reproducible activity against bacteria and were not so overly toxic to people that they were injured by the side effects. Over the next few years, doctors began to use sulfa drugs to treat infections. But their spectrum of activity was limited. The drugs were good but not good enough.

With the outbreak of World War II, the need for antibacterial agents was urgent. Thousands of soldiers were destined to die from battle wounds, complicating pneumonias, and abdominal, urinary, and skin infections. In 1940 a team at the Sir William Dunn School of Pathology at Oxford University, led by Howard Florey and Ernst Chain, dusted off Fleming’s penicillin and embarked on a journey to develop ways to make it in quantity. Because London was being bombed, they took their project to the Rockefeller Foundation in New York, where they were introduced to several pharmaceutical firms in the area. The companies did not welcome the scientists with open arms, for they knew that penicillin was at a very early experimental stage. Yields rarely exceeded 4 units per milliliter of culture broth—a drop in the proverbial bucket.

So the British scientists took their efforts to Peoria, Illinois, where the new Fermentation Division of the Northern Regional Research Laboratory was gearing up studies about using the metabolism of molds (fermentation) as a source of new microorganisms. Its staff was experienced and had a substantial collection of molds, but few of their strains made penicillin, and none was prolific. Thus the call went out to everyone they knew: send us samples of soil, moldy grain, fruits, and vegetables. A woman was hired to scour the markets, bakeries, and cheese stores of Peoria for samples bearing blue-green mold. She did the job so well they called her Moldy Mary. But in the end, a housewife brought in a moldy cantaloupe that changed the course of history. This particular mold produced 250 units of penicillin per milliliter of broth. One of its mutants churned out 50,000 units per milliliter. All strains of penicillin today are descendants from that 1943 mold.

The scientists ultimately developed methods for making this more potent form of penicillin in quantity. Later the pharmaceutical firm Charles Pfizer & Company used molasses as a way of growing the penicillium molds in bulk. By the time of the invasion of Normandy in June 1944, 100 billion units were being produced each month.

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Penicillin ushered in a golden age in medicine. Here was a drug that could, at last, treat infections caused by deadly bacteria. Because it was so astoundingly effective, it was considered to be truly “miraculous.” What could this wonder drug not do? Press reports heralded “a new era of medicine, the conquest of germs by interfering with their eating and digesting, [that] is sweeping through the military hospitals of America and England.”

In 1943 streptomycin, the first effective agent against
M. tuberculosis
, was developed from soil bacteria. Then came others: tetracycline, erythromycin, chloramphenicol, and isoniazid, which together brought about the antibiotic era. At the same time, new forms of semisynthetic drugs were developed via chemical modification of natural substances, as well as the manufacture of purely synthetic or nonnatural compounds. Today, for convenience, we call all of these drugs antibiotics, although strictly speaking antibiotics are substances made by one living form to fight against another.

Those original antibiotics and their descendant drugs transformed the practice of medicine and the health of the world. Formerly lethal diseases like meningitis, heart valve infection, and childbirth fever could be cured. Chronic bone infections, abscesses, and scarlet fever could be prevented and cured. Tuberculosis could be arrested and cured. Sexually transmitted diseases like syphilis and gonorrhea could be cured. Even my case of paratyphoid could be cured without months of illness and a big risk of dying. Cure also was a great form of prevention, since a cured person would not spread the pathogen to others.

Surgery got safer. Antibiotics could be given pre-operatively to lower the risk of many surgical infections. If infection developed, antibiotics came to the rescue. Surgeons could attempt more sophisticated surgeries to correct a myriad of woes, such as removing brain tumors, correcting deformed limbs, repairing cleft palates. It is fair to say that without antibiotics there would be no open-heart surgery, organ transplantation, or in vitro fertilization.

Similarly, chemotherapies used to fight cancer often suppress the body’s ability to fight infection and lead to bacterial infection. Without antibiotics, leukemias and many other cancers would not be treatable. It would be too dangerous to give the massive amounts of chemotherapy required without the safeguard of antibiotics.

In the 1950s the Chinese government decided to wipe out syphilis. Tens of millions of people were treated with a long-acting form of penicillin. This massive public-health campaign worked. The age-old scourge was virtually eliminated from China. Yaws, a related ancestral disease, was successfully eradicated from vast swaths of Africa after a series of similar campaigns.

How did and how do these drugs perform their miracles? Antibiotics work in three general ways. One, as exemplified by penicillin and its descendants, is by attacking the machinery used by bacteria to create their cell walls. With defective walls, bacterial cells die. Interestingly, they often commit suicide: lack of a cell wall triggers bacterial hara-kiri. We are not certain of the biological reason for their suicide, but nature selected for fungi like the
Penicillium
mold that make these antibiotics and are able to exploit that weakness.

The second mechanism is inhibiting of the way bacteria make the proteins that perform all of the important functions of the bacterial cell. The proteins within a cell are vital for life. Cells need proteins to digest food, build their walls, enable reproduction, defend against invaders and competitors, and help the bacteria move around. Such antibiotics directly target the machinery that allows proteins to be made, crippling the bacteria, and having minimal effects on protein production by human cells.

A third is interfering specifically with the ability of bacteria to divide and reproduce, thereby inhibiting their doubling. With slower growth, they become less of a threat so that the host can mount an immune response to deal with them more easily.

If you think about it, antibiotics are natural substances made by living organisms—fungi and other bacteria—that want to throw a monkey wrench into the workings of their competitors. Their neighboring bacterial cells are little machines, all with multiple moving parts; over the eons, they have found many different ways to attack. And the bacteria have found so many ways to defend, which are the very basis of bacterial resistance to antibiotics. Since time immemorial, it has been an arms race. But for us humans, our development of antibiotics has been like getting the atomic bomb. It has fundamentally changed the playing field. Interestingly, both came on the scene at the same time. The scientific developments of the 1920s and 1930s led to their deployment in the 1940s. As with the atomic bomb, our hope was that it would be a panacea. The threat of the bomb would be so great that we would war no more. Similarly, the power of the antibiotics would once and for all defeat bacteria. Although there is some truth to both, neither has fulfilled that promise, nor could they ever. Both are just tools, and the fundamental causes of war between men and between men and bacteria remain.

*   *   *

As use of antibiotics became more and more widespread, a few side effects appeared, but most were mild—a few days of loose bowel movements, an allergic rash. In nearly all cases, these problems went away as soon as the drug was stopped. A handful of people had serious, sometimes fatal, allergies to penicillin. But the risk of dying from penicillin allergy was, and is, lower than the risk of being struck by lightning. It is a remarkably safe drug.

Other antibiotics did produce adverse effects. Some damaged the auditory nerve; others could not be used in children because it mottled their teeth. A very commonly used antibiotic in the 1950s, chloramphenicol, was found to cause a rare suppression of the bone marrow’s ability to form blood cells, which was fatal about once in forty thousand courses of the drug. For very serious infections, such a low risk of dying from a drug allergy was infinitesimal compared to the risk of dying from the infection. But in some places, hundreds of thousands of healthy young children with mild sore throats were treated with chloramphenicol. For them, the risk clearly exceeded the benefit, and there were lots of alternative antibiotics. Doctors stopped using it almost entirely. Still, for years, I have said to my students that if I were marooned on a desert island and I could have only one antibiotic with me, I would choose chloramphenicol; it is that powerful.