On a spring morning in 1980, I was driving to work; it was still cold in Atlanta. I worked for more than two months in the hot regions of Bangladesh and India and returned to the center for disease control and prevention with great relief. In the office greeted her with the familiar, sorted mail and started to work, but the day felt a strange aching bones. It’s probably the jet lag – arrived only last night and haven’t acclimatized yet. But my health was getting worse, my forehead was hot. After about an hour decided to go home. Maybe he caught the flu on the plane or during a long transplant in England? I couldn’t remember when I felt so bad before that I couldn’t work. I have to go to bed, and it’ll be better by morning.
It did not: the temperature rose to 38.3 ° C. At the CDC, I was an expert on infectious diseases, so I knew malaria could start just like the flu: fever, headache, bone aches, muscle aches. Could I have caught it? Travelers usually die from this disease because it is too late to be diagnosed and treated. But I probably just have the flu. On reflection, I called a colleague from the Department of parasitic diseases, Dr. Isabel Guerrero, and asked him to take my blood smear for malaria.
Half an hour later she arrived. Punctured a finger, smeared some blood on a glass plate and said she’d report the results right away.
Called in an hour.
You don’t have malaria.
Encouraged by these words, I prepared to lie at home with the flu. By this time, a small cough had started.
I was still sick Wednesday morning. I felt good, but the temperature was still good. The wife was advised to go to the doctor-infektsionist Carl Perlino. He did an examination: except that the temperature mysteriously disappeared during the visit, all the tests showed that I was healthy. Even blood.
On Thursday, the temperature and a weak cough also did not go away. The entire day has lain in bed, and at night saw very colorful nightmare. I don’t remember who was chasing me, but I woke up in a cold sweat. The sheets are all wet. And even in delirium immediately realized what is really sick: typhoid fever! I’ve been to Bangladesh and India, where impurities sometimes get into food. The symptoms are the same, though unclear, started about a week after returning, the fever lasts a few days and raises. There were no other options.
The next morning I was very weak. The temperature rose to 40 ° C. Had no strength even to button a shirt or to sit in the car upright, not leaning on the door. I knew that without antibiotic treatment I could die with a 10-20% chance. Pain, sweating, loss of strength, lack of appetite, despite the fact that I have not eaten for several days – all the signs of an acute stage of the disease. As we drove that beautiful spring day down the street, planted with flowering magnolias, I thought that to die in thirty-one years would not be too pleasant.
When we got to the hospital, I cringed and shivered from the cold. I had to sit in a wheelchair. It was terrible that Dr. Perlino did not understand how strong the disease is, and sent home. The irony of fate: I knew perfectly well that hospitals can be dangerous – patients fall from their beds, get the wrong drugs, pick up new diseases-but desperately wanted to be put there and begin to be treated.
Fortunately, the doctor looked at me and immediately said that hospitalization is required. Another irony: my main job at the CDC is a consultant on Salmonella. Doctors from all over the country called and asked for advice on patients and epidemics of salmonellosis. And here the doctor asked what antibiotic I want to be treated with. I knew that Salmonella typhi, the main causative agent of typhoid fever, could be controlled with ampicillin, an advanced form of penicillin. He saved the lives of millions of people. But the problem was that by 1980, this antibiotic had been used so often that many strains had become resistant. The treatment could have been completely ineffective.
So recommended a new formula of sulfa – co-trimoxazole. It combined two tools developed in the 1960s and worked very well at the same time (however, resistance developed to it later). It seems, despite the high temperature, I have not lost the ability to think. Even if I was wrong about typhus, I was so seriously ill that the doctors just couldn’t help but give me something in case there were some other unfriendly bacteria in my blood system.
Medical students came to take blood samples for the microbiological laboratory. If it is typhoid, Salmonella typhi will grow in Petri dishes. Then put on a drip. I realized the odds were rising. The probability of death was decreasing by the hour. Here it is, the miracle of antibacterial agents that were first discovered in the early 1930s.
I fell asleep and slept long. But the next morning it didn’t get any better. Still in pain, I asked the doctors.:
- What’s in my blood cultures?
– Nothing grows.
Am I wrong in my own diagnosis? It’s not typhus? But the tests only took about twelve hours ago, so maybe it’s too early. In a strange dual position of the patient and the specialist doctor, I recommended to continue the course of treatment, and the treating team agreed.
The next morning the doctors came to the ward.
- Positive for Salmonella. Germs to grow.
Still typhus.
The next day I was in for a little surprise. It was not Salmonella typhi, the usual causative agent of typhoid fever, but Salmonella parotyphi A, in fact, twin. But the textbooks say that the course of the disease is almost indistinguishable, and I guarantee it.
Thanks to treatment, despite some complications, gradually began recovery. A week later I was discharged, and another week I spent at home, recovering. Three weeks-a serious was disease. I can’t imagine what would have happened to me if it wasn’t for the cure.
A few years later, we discussed this case with a colleague who worked in Asia for many years. I said that as far as I remember, the only food negligence that was allowed a few weeks before the illness happened on a hot evening in Bombay. I was walking down the street and saw a Hawker selling watermelon slices. His tray didn’t inspire much confidence, so I had to ask him to cut me off a piece of the whole watermelon. I thought it was a precaution. It was nine days before the disease – classical incubation period.
“Of course it’s the watermelon,” said the colleague. – You see, in India they sell them by weight. So farmers inject water to make them weigh more. And the liquid, of course, take from rivers and streams flowing next to the fields.
I have a sick feeling in my stomach: a watermelon was contaminated with sewage. Typhoid infected by eating food or drinking water, infected with the feces of the carrier of the disease.
I remembered the most famous host, Mary Mallon, better known as Typhoid Mary, an Irish immigrant who worked as a cook in wealthy new York families in the early twentieth century. After in the house where she worked, the epidemic of typhus began, the woman passed to other family. And there, sooner or later, also started the epidemic, etc. did she Know that is their reason, not entirely clear. Typhoid was a fairly common disease then; hospitals were full, about a quarter were dying. Famous medical detective George Soper was able to discover that the cause of the epidemic was Mary, and forced her to give up the job as a cook. She was a carrier: she felt perfectly healthy and was perfectly healthy. Carriers do not get sick, but only carry microorganisms.
The woman denied any connection to previous cases and soon broke her promise. Started a new epidemic. Sopher found her again. There was a difficult dilemma: she was perfectly healthy, but at the same time represented a threat to society, and no less than shooting at the crowd with a gun. Typhus is a serious disease; several people died after eating cooked food. In the end, the judge decided: Mary was quarantined on the island of North brother, which is located in the new York Strait East river. She spent the rest of her life there, assuring everyone of her innocence. In our time, we could probably cure her by removing the gallbladder and giving her antibiotics. And all those it has infected.
Fast forward from Atlanta to twelve years, in may 1992, when I was asked to speak at a conference on advances in understanding and treating infectious diseases. The topic was the revealed relationship between the recently discovered gastric bacterium Helicobacter pylori and gastric cancer – a common and intractable malignant tumor {55}. We thought it was a new pathogen, and people were interested in learning more about it.
A Symposium at Yale University was held in honor of the fiftieth anniversary of the first use of penicillin in the United States. The presenter began by telling about the case of Ann Miller, a 33-year-old nurse who had a miscarriage in 1942. She suffered from a serious illness for a month, with temperatures up to 41.6 ° C, delirium and symptoms of streptococcal infection. She had a delivery fever, or, in doctor’s terminology, postpartum sepsis. This infamous disease has killed many young women. Miller lay dying, and then lost consciousness, came to himself.
Thanks to incredible luck, her doctor was able to get access to one of the first small batches of penicillin, which has not even entered the commercial sale. Medicine using aircraft and police officers were taken to hospital at Yale – new haven and introduced Miller.
The recovery began a few hours later. The temperature went down, the delirium ended, she was able to eat, and a month later fully recovered. It was the scientific equivalent of a miracle. All changed 5.5 grams of penicillin, about a teaspoon, which was added to her saline. The drugs were so small then that Miller’s urine was preserved and sent back to Merck’s pharmaceutical company in new Jersey, where it was isolated from penicillin, which was then given to another patient.
While the presenter was telling the details of this dramatic story, it was so quiet in the hall that a paper clip would have fallen – it would have been heard. And then after a little pause, he said, ” Patient, stand up, please.“
I turned around. In the third row, a petite, graceful old woman with short grey hair stood up and looked around the hall with her bright eyes. Anne Miller, who was already over eighty – the miracle of penicillin gave her fifty years of life. I still remember that humble smile. She lived another seven years and died at ninety.
When the girl was rescued, medicine was just learning to fight bacterial infections. Pneumonia, meningitis, abscesses, infections of the urinary tract, bones, sinuses, eyes, ears – Yes, in General, all diseases are still treated with ineffective and questionable methods. When George Washington got an infection in his throat, the surgeon bled him. This method of treatment is very trusted, but perhaps he only accelerated the death of the President. Bloodletting was treated in the XX century.
Some methods helped, but not much, and the side effects of proprietary remedies were almost worse than the diseases themselves. Many contained large amounts of arsenic. Despite a significant improvement in technique, surgeons had to constantly worry about infections – they could turn a successful operation into a disaster. In particularly unlucky patients, removal of the ingrown toenail led to amputation of the entire foot. Endocarditis was fatal in 100 % of cases-worse than cancer.
During the American Civil war, more soldiers died from typhoid and dysentery than from bullets. Nobody was protected. Leland Stanford, Jr., son of the Governor of California, after whom the University is named, died of typhoid fever in Italy. He was fifteen years old. In the First world war, the statistics were about the same. In 1918 and 1919, the Spanish epidemic swept the world; 500 million people were infected, about a quarter of the then world population. 20-40 million died, often due to complications like bacterial pneumonia.
Scientists in the late nineteenth and early twentieth centuries worked feverishly on methods of struggle against infectious diseases. They had one guiding star: the theory of microbes, the idea that many diseases are caused by the presence and actions of microorganisms, especially bacteria.
A small group of great scientists, titans in their fields, showed the way to all. In 1857, French chemist Louis Pasteur proved that fermentation and decay are caused by invisible organisms floating in the air. He demonstrated that rotting meat is caused by microbes, and diseases can be explained by the multiplication of harmful microbes in the body. Following the example of the Hungarian doctor Ignaz Semmelweis, who demanded that obstetricians wash their hands and thereby reduced the number of deaths from birth fever, the British doctor Joseph Lister revolutionized surgery, introducing new principles of purity. Inspired by Pasteur, he began soaking bandages in carbolic acid (a kind of coal tar with antiseptic properties) before applying them to wounds, and thus improved their healing ability. Finally, Robert Koch, a German physician, developed methods for determining whether a given microorganism causes any particular disease; today, these criteria are known as “Koch’s postulates.” In addition, he developed dyes to visualize the bacteria that cause tuberculosis and cholera under a microscope.
The theory of microbes, of course, led to better sanitation and better understanding of disease, but it did not revolutionize it. The fact that bacteria could now be seen and even grown on their own did not mean that it is just as easy to find ways to get rid of them. Another pioneer, Paul Ehrlich, who worked in the bacteriological laboratory of Koch, was looking for “magic bullets” – paints, poisons, heavy metals-that will not only stain specific microbes, but also kill them.
No one thought to look in nature living organisms that can destroy pathogens. What for? It’s now that we’re beginning to understand how incredibly diverse the microbial world is.
This was the mood in the scientific community when Alexander Fleming, a Scotsman wearing a bow tie who worked at St. Mary’s hospital in London, made a discovery that changed the world. Like many contemporaries, he was looking for ways to kill bacteria and conducted classical experiments: placed jelly-like environment for cultivation (agar-agar and heated blood) in shallow round transparent saucers, which are called “Petri dishes”, and then did the sowing of bacteria. Microorganisms, too small to be seen with the naked eye, love to eat agar-agar. And by eating it, they reproduce. After all, agglomerations of millions of bacteria form a colony that is visible to the naked eye. By placing the cups in a warm incubator overnight, Fleming grew huge, well-visible Golden colonies of Staphylococcus aureus and others, which he then tried to kill with enzymes isolated from white blood cells and saliva.
In August 1928, Fleming went on holiday to France. Returning in early September, he found several Petri dishes that he had forgotten to throw away. They were sown Staphylococcus aureus, and they stood for a month on the desktop. Throwing away useless cups, the scientist paid attention to one of them. There was a strip of blue-green gun-the usual bread mold, fungus Penicillum. He noticed that the luxurious glade of Staphylococcus aureus, a multi-layered film of billions of bacterial cells that filled the Cup to the brim, disappeared next to the mold. Around there was a kind of halo – a substance in the environment seemed to prevent the microorganism to grow.
Fleming’s eye was fixed, so he knew right away what had happened. Mold-a fungus that also likes to eat agar-agar-has developed a certain substance that has penetrated into the” delicacy ” and killed Staphylococcus. This substance, the first real antibiotic discovered, dissolved bacterial cells just like lysozyme, an enzyme discovered by Fleming in saliva during experiments a few years earlier. He dissolved the microbes, leaving nothing at all. The scientist believed that his “mold juice” contains an enzyme (like lysozyme) that prevents bacteria from building cell walls, which is why they burst. Later it became clear that this is not an enzyme.
Miraculous mold belonged to the species Penicillum notatum. In fact, its antibacterial effect has been known since the XVII century, but not Fleming and his contemporaries-doctors. The ancient Egyptians, Chinese and Indians of Central America treated its wounds. But it was Fleming’s scientific training that helped turn the fungus from a folk remedy into an advanced medicine.
Over the next few months, the scientist was able to grow mold in a liquid nutrient medium, filtered it and isolated the liquid that showed the greatest antibacterial activity. He called it penicillin. But produce substance in sufficient numbers it turned out it is difficult. Fleming was very lucky that the strain that got into the Petri dish produced it. But the production was small, unstable, short-lived and slow. And not finding ways to make penicillin useful in medicine, the scientist gave up. After publishing the results of his experiments and trying (unsuccessfully) to apply the crude extract to several patients, he concluded that this discovery has no practical value.
But others were not so pessimistic. A few years later, a German chemist who worked for a giant chemical company, Farben, which produced textile dyes and aspirin, decided to find a dye that would slow down the growth of bacteria. In 1932, Gerhard Domagk opened red paint (which is called prontosil), containing the fully synthetic antibacterial agent, the first sulfanilamide. It was followed by a whole class of sulfanilamide drugs. These were the first drugs that had a noticeable and repetitive effect on bacteria and were not so poisonous that people suffered from side effects. In the next few years, doctors began to use them to treat infections. But the range of action was limited. Drugs were not good enough.
After the outbreak of the Second world war, the need for antibacterial agents became urgent. Thousands of soldiers were waiting for death from combat wounds, complications from pneumonia, infections of the abdomen, urinary tract and skin. In 1940, a team from the sir William Dunn school of pathology at Oxford University, headed by Howard Florey and Ernst chain, took out penicillin Fleming from the storerooms and began to look for ways to produce it in large quantities. As London was bombed, they went with their project to the Rockefeller Foundation in new York, where they held talks with representatives of several pharmaceutical companies. They were met not with open arms, because they knew: the production of penicillin is at an early experimental stage. Production rarely exceeded four units per milliliter of nutrient medium-a drop in the sea.
British scientists went to Peoria, Illinois, where the new fermentation Department of the Northern regional research laboratory conducted research on the use of mold metabolism (fermentation) as a source of new microorganisms. Experienced staff have collected a significant collection, but only a few of the strains produced penicillin, moreover, in insufficient quantities. Attracted friends: send samples of soil, moldy grains, fruits, vegetables. One woman was hired to search shops, bakeries and cheese factories in Peoria for samples of blue-green mold. She worked so well, she even got the nickname ” Moldy Mary.” And finally, some housewife brought a cantaloupe melon that changed the course of history. The mold on it produced 250 units of penicillin per milliliter of nutrient medium. One of its mutated strains is 50,000 units. All existing strains are descendants of the same mold of 1943.
After all, scientists have developed methods for producing this more powerful drug in large quantities. Later, the pharmaceutical company Charles Pfi zer & Company began to grow penicillin mold on molasses. By the time Normandy landed in June 1944, 100 billion units of penicillin were produced per month.
It marked the beginning of the Golden age of medicine. Finally, there is a drug that can treat infections caused by deadly bacteria. Because the effectiveness was amazing, it was considered truly “wonderful”. He could do anything. The press proclaimed “a new era in medicine, the victory over microbes that are deprived of the opportunity to eat and digest food, a triumphant March on the military hospitals of America and England.”
In 1943, streptomycin was developed from soil bacteria, the first effective remedy against tuberculosis. It was followed by others – tetracycline, erythromycin, chloramphenicol and isoniazide. The era of antibiotics has come. At the same time, semi-synthetic drugs obtained by chemical modification of natural substances began to appear. In addition, the production of pure synthetic, non-natural compounds began. Today, for convenience, we call all these drugs antibiotics, although, strictly speaking, they are substances that one form of life produces to fight the other {62}.
The first antibiotics and their descendants have transformed the practice of medicine and the health of the world. Once deadly diseases such as meningitis, endocarditis and birth fever became curable. Chronic bone infections, abscesses and scarlet fever have learned to prevent and treat, as well as tuberculosis and venereal diseases like syphilis and gonorrhea. Even from my paratyphoid can be cured without a few months of misery and risk of death. In addition, all this proved to be an excellent method of prevention – the cured patient can no longer infect others.
Surgery has become safer. Patients were given antibiotics before surgery to reduce the risk of infection. There was an opportunity to carry out more complex operations: removal of brain tumors, correction of deformed limbs, treatment of the wolf’s mouth. Without these drugs, there would be no open heart surgery, organ transplantation and in vitro fertilization.
Chemotherapy, which is used to fight cancer, often suppresses the immune system and leads to infections. Without antibiotics, leukemia and many other cancers would be incurable. Chemotherapy would just be too dangerous.
How do these drugs perform miracles? Antibiotics work in three main ways. The first is penicillin and its descendants: they attack the mechanisms that bacteria use to build cell walls. Those who have them defective, die. Interestingly, they often commit suicide: the absence of a cell wall causes the bacterium to make “harakiri”. We do not know the exact biological causes of this phenomenon, but nature has selected fungi like Penicillum, which produce antibiotics and are able to exploit this weakness.
In the 50s, the Chinese government decided to destroy syphilis. Tens of millions of people received long-acting doses of penicillin. And this huge health campaign has worked. As old as the world the disease is virtually destroyed. Yaws, its ancient cousin, just managed to eradicate in the vast expanses of Africa through a series of similar campaigns.
The second-antibiotics prevent bacteria from producing proteins that perform all important functions. Without it in a cage there will be no life because they are necessary for digestion of food, a structure of walls, reproduction, protection from uninvited guests and competitors, the help in movement. Such drugs attack the means of protein production, crippling bacteria, while practically not interfering with their production in human cells.
Third – antibiotics interfere with the bacteria to divide and multiply, slowing the growth of population. Slowly evolving, they are not such a big threat, so the host can prepare an immune response and deal with them easily.
If you think about it, these are natural substances produced by living organisms-fungi and other bacteria – that want to spoil the life of competitors. Neighbor bacterial cells are small machines with many moving parts. Over billions of years, they’ve learned a lot of ways to attack. And bacteria have learned a lot of ways to protect, which are the basis of drug resistance. This arms race has been going on since the beginning.
But for us humans, the discovery of antibiotics can be compared to the invention of the atomic bomb. They have fundamentally changed the “playing field”. Interestingly, both appeared almost at the same time: scientific discoveries of the 20s and 30s led to their introduction in the 40s. As in the case of weapons, we hoped to find a panacea: powerful antibiotics once and for all defeat bacteria! The threat of an atomic bomb is so great that we will never fight again. There is some truth in both statements, but neither the atomic bomb nor the antibiotics lived up to their expectations, and they could not. These are just tools, and the fundamental causes of people’s war with each other and with bacteria have not gone away.
With the spread of drugs began and side effects, initially minor-a few days of liquid stool, allergic rash. In almost all cases, they disappeared immediately after discontinuation of the drug. A small number showed a serious, sometimes even fatal Allergy to penicillin. But the risk of dying from it is less than that from lightning. It’s a very safe drug.
Other antibiotics caused much more serious side effects. Some damaged the auditory nerve, others could not be given to children, because the teeth were covered with spots. Often used in the 1950s, the antibiotic chloramphenicol appeared to be able to inhibit bone marrow’s ability to produce blood cells, leading to death in about one in forty thousand cases. But in some places chloramphenicol was prescribed to hundreds of thousands of young children who just had a sore throat. For them, the risk clearly exceeded the benefit, and there were many alternatives. In the end, the doctors almost said goodbye to this drug. However, I have told students for many years that if I was dropped off on a desert island and offered only one antibiotic, I would choose chloramphenicol – just because of the strength.
The idea that others have significant adverse effects not once were very rare – more than that, it is even seriously considered. If a few days or weeks after taking the drug did not develop allergies, it was considered safe.
Almost all the great achievements of medicine in the second half of the XX century and to this day have been made possible by the use of antibiotics. Then it seemed that their use does not cause any harm. The consequences came much later.