How to describe the euphoria of those old days? It was 1945. The second world war is over. We have defeated the forces of evil; a more just society has won. Americans were overwhelmed with optimism. Then many children were born – including me. Within 5 years after the war, the Americans bought 20 million refrigerators, 21.4 million cars and 5.5 million gas stoves. That was the era when so much appeared for the first time: Tupperware, “fins” on cars, sprawling suburbs, fast food restaurants, television and, of course, miracle drugs.
Since they were effective and did not present an obvious risk, doctors and patients began to ask: can we solve all the problems with their help? For example, urinary tract infections or cystic fibrosis? Can we relieve discomfort from nasal or dental infections, correct appearance, spoiled by severe acne? Very often the answer was positive.
Sometimes the benefits were huge-for example, before surgery they were used as a prevention of infections. In other cases, this benefit was very small, but since the costs (toxicity) were considered minimal, even the smallest was worth it. For example, for decades, dentists have been giving antibiotics to people with little heart murmur to prevent an incredibly low risk of endocarditis.
I do not question their effectiveness in treating a minority of people hospitalized with pneumonia, postpartum sepsis, meningitis and other serious diseases. It is only about the use in the treatment of millions of healthy people with less serious infections and minor complaints like runny nose or skin irritation. The United States alone prescribes antibiotics to tens of millions of people every year.
This problem is especially acute for children. They are vulnerable on sides that we could not have imagined.
The most obvious example of abuse is the treatment of common diseases known collectively as upper respiratory infections. Parents of young children are well aware of the symptoms: sore throat, runny nose, stuffy nose, pain in the ears and sinuses, just feeling unwell. Sometimes there’s a temperature, sometimes not. Most suffer from SARS two or three times a year for up to three years. By the age of three, up to 80% of children suffer from acute otitis at least once. More than 40% to seven years carry six such ear infections.
In fact, all-both adults and children – more or less regularly suffer from upper respiratory tract infections. Such a situation can not be avoided-it is a product of our complex social networks, where there is a constant collision with microbes that people emit when coughing, sneezing and just breathing. Infections will be with us as long as we live close to each other, and that is how the majority wants to live – next to loved ones, friends, classmates. When scientists go to isolated colonies in Antarctica for the winter, upper respiratory infections circulate between them for a month or two and then die. As in the case of hunter-gatherers: first ill all those who are susceptible, and then the pathogen has nowhere to go – there are no new carriers. Only when the next plane or ship arrives new people with new infectious microbes, the cycle will repeat.
But … you know what? Upper respiratory infections are mainly caused by viruses. The reason for more than 80 % of them-microbes with exotic names like “rhinovirus“, “Astrovirus“, “metapneumovirus” and “parainfluenza“. (The term computer virus is derived from these highly contagious human viruses.) When we catch one of the pathogens, we say that we have a cold or flu. But after a few days of being somewhere between “slight indisposition” and “terrible”, almost all are recovering gradually. The disease is ” self-limiting.” Even the most stubborn and protracted cough passes by itself a maximum of a couple of weeks. But if you go on for a week and you can’t see the end of it, you call the doctor and say, “That’s it, I’m tired. Give me an antibiotic.” Although in fact they do not affect the development of viral infections.
When it comes to such cases, the main difference to be taken into account is between bacteria and viruses. The first are cells. They eat, move, breathe, reproduce. Give them the right nutrients and a good home – like a warm corner, a glacier, or a volcano – and they will multiply.
Viruses, on the other hand, are smaller and simpler. They need media. They can only live inside cells – human or any other (animals, plants or bacteria). The cellular mechanisms of the carrier are used for their own purposes – including for reproduction, because they cannot exist by themselves. Sometimes they sleep in the carrier for decades, and sometimes kill the cells in which they settled.
Because viruses don’t have the walls that we’ve talked about, antibiotics like penicillin don’t work on them. The synthesis of their proteins is completely dependent on the synthesis of the carrier, so it is necessary to inhibit the second process to suppress the virus. When they parasitize on human cells-for example, colds, herpes, influenza and many others – we can not suppress the synthesis of carrier proteins, because they are ourselves. That is, in this case, poison their own bodies. Some drugs still prevent certain infections to get in and out of cells or to reproduce. For example, acyclovir, which is used in the treatment of herpesviruses, or drugs designed to disrupt the life cycle of HIV. Viruses can be suppressed, but it is almost impossible to cure them. And at the same time, antibiotics can cure almost all bacterial infections.
But there is another difficulty: they cause less than 20% of upper respiratory diseases. The microorganisms that live in your throat and nose can be permanent residents, migrants, or temporary settlers – something like long-term tenants. Among the most important – Streptococcus pneumoniae or pneumococcus, the pathogen number one in the upper respiratory tract and lungs, which causes, respectively, or otitis media, or pneumonia. Streptococcus pyogenes, or Streptococcus group A, causes acute pharyngitis. Staphylococcus aureus, is the majority of staphylococcal infections. And Haemophylus infl uenzae, which used to regularly cause otitis media and sometimes meningitis in children, until a vaccine appeared.
These four types of bacteria are often found in upper respiratory tract infections. But do not jump to conclusions – sometimes they cause disease, but most often not. The apparent contradiction is that these germs with ominous names may have hit you or your child a long time ago. You were not infected, and colonized-usually such an event is harmless. This is an incredibly important difference that is often overlooked.
Colonization means they just live in you and on you, but do no harm. Their presence, of course, is a necessary condition for the disease, but not enough. Most of these people are completely healthy. For example, Staphylococcus aureus can last a lifetime colony in your nose, and you do not know anything. For most, it is only part of the microbiome. To sum up, our nose and throat are home to a large community of bacteria, both friendly and potentially pathogenic.
Moreover, some have proven to help stay healthy by containing “enemies” and modulating the immune system. One of the most interesting examples is Streptococcus viridans, a group of streptococcal bacteria that lives peacefully in everyone’s mouth. Initially, they were considered pathogenic because they were the main cause of endocarditis. But gradually it became clear that these are normal residents of the oral cavity and only sometimes get into the blood and are planted on the damaged heart valve. Now we know: if you mix harmless “green” streptococci and pathogenic Streptococcus group A, win the first. So a bacterium, sometimes a pathogen, actually turns out to be a serious protector of our health. This dichotomy is an important model for the evaluation of many other microorganisms that live in us.
But back to the original topic: when do potential upper respiratory pathogens cause problems for children? When should they be treated with antibiotics? If at the same time another infection like “gastric flu” appears, or the immune system is subjected to additional stress, for example, Allergy blocks the Eustachian tubes, they become vulnerable to more serious ear or lung infections. In rare cases, severe complications develop, for example, pneumonia or mastoiditis, inflammation of the cavities adjacent to the ear canals.
Infections can live in healthy-looking children. If thousands of babies in your city catch the same respiratory virus or bacteria at the same time – which is not uncommon in winter – the results will be different. Some people have no symptoms at all – these are just carriers. Other symptoms last a day, the third-two or three days. After four or five the number of patients is dramatically reduced, but several infection necessarily delayed. The distribution resembles a familiar bell-shaped curve: some do not get sick, some tolerate calmly, some get sick hard.
The doctor can recognize an acute infection, but can not predict who will have problems with recovery. So, although the number of severe cases is low, about 5-10%, 60-80% of children whose parents lead to a doctor with complaints of severe pain in the throat or ear, prescribe antibiotics. And in most cases, doctors do not even know the bacterial infection or viral.
They have one good reason to reflexively prescribe such medications: fear of acute rheumatic fever. This is a very serious inflammatory disease that resembles rheumatism; it manifests itself approximately two to three weeks after a short-term streptococcal pharyngitis. Antibodies raised “on alert” against Streptococcus, cross – react to the tissues of the heart, joints, skin and brain of the child-a tragic case of mistaken identity.
Previously, it developed in every three-hundredth child with streptococcal infection, or, if the streptococcal strain was particularly aggressive, – in every thirtieth. Now doctors prescribe antibiotics for acute pharyngitis not to reduce the duration of the disease, because they just almost do not affect, but to prevent rheumatic fever. Most people (and even some doctors) do not understand that they are prescribed for prevention.
But here lies the problem. Group a streptococci often colonize children, especially in winter. This condition can last two months, and they remain healthy carriers. But imagine that a child at this time picks up a common cold virus, and he begins to hurt his throat. You take him to the doctor, he does a swab of the throat, and voila-in the culture found Streptococcus. It is reasonable to prescribe an antibiotic to prevent acute rheumatic fever, although in fact the infection was caused by a virus.
Even if acute pharyngitis is really caused by bacteria, the disease usually does not last long, and almost all recover in a day or two. But if your child receives the medicine and recovers, then you will definitely think that it was the medicine that cured him. This is a classic example of the law “correlation does not imply causation”. Children do feel better after a few doses of amoxicillin, so the correlation is obvious. But this does not prove that the recovery is caused by the medicine.
How, then, to distinguish a mild, self-limiting bacterial or viral infection from a more serious one? Or colonization from infection? This is a critical question, because the answer, which, unfortunately, is unclear at this point, will help put an end to the excessive use of antibiotics. The discerning Clinician knows that most children at risk of serious complications have special warning signals (though not always). They have a higher temperature, symptoms last longer, the number of white blood cells is abnormal, and they look worse. But many cases fall into the”gray zone”.
It’s important. Until doctors learn to distinguish viral respiratory infection from bacterial infection at once, they will choose the safest course of action. And there’s not much time. Doctors examine patients at five children per working hour, and paper to fill out. The lack of practical, fast, inexpensive and accurate diagnostic tools and the constant lack of time are two factors leading to over – treatment. New diagnostic tools that can improve the situation have already been invented, but have not yet been put into effect; in the current climate, no one wants to pay for them.
In addition, over the shoulder of the doctor is always the looming silhouette of a lawyer. What if he doesn’t treat the baby and it’s a disaster? What if the court asked, ” Why didn’t you give this child an antibiotic for otitis media, which as a result turned into meningitis, paralyzing him?»
The complex dynamic described above is unprecedented – for all children around the world for generations. The cycle repeats and even, perhaps, amplifies. Millions of patients are being treated for bacterial infections they don’t have – it’s not hard to guess that this will lead to big problems.
The scale of antibiotic use is huge and growing every year. In 1945, an article in the prestigious Journal of Clinical Investigation spoke about the excellent effectiveness of penicillin – 64% cured of pneumonia. This equated to a miracle. But in 2010, health care providers prescribed 258 million courses of antibiotics to US residents. The scale increased by four million times – for every thousand inhabitants of the country had 833 prescriptions. We don’t know if all courses have been completed, but most are accurate. About a quarter were discharged by family doctors, a little less – pediatricians and therapists. Dentists-10 %, about 25 million a year.
The highest percentage of prescriptions is for children under two years of age: 1,365 per 1,000 children. This means that the average American child up to two years receives about three courses. Over the next eight years of life on average eight. Extrapolating the current statistics Of the center for disease control and prevention, we find that children receive about seventeen courses of antibiotics before the age of 20. This is a large number, but it is consistent with previous studies in the US and other developed countries.
In the period from 20 to 40 years receive another thirteen courses. That is, in General, up to forty years, Americans receive 30 courses of powerful drugs. Naturally: someone more, someone-less. But the consequences are significant. Many young women will become mothers of the next generation, and it is from them that children will receive the first microbiomes. And how that treatment will affect the transfer?
The first recognized problem caused by overuse of antibiotics is resistance. Simply put, the more often we and our children take them, the more likely the bacteria that are able to resist the action of these drugs are selected. Many people are not well aware of what resistance is. They believe that they “have acquired immunity to antibiotics”, while in fact it was acquired by bacteria.
Here is one possible algorithm. The child receives an antibiotic, such as amoxicillin, to treat the infection. This penicillin derivative is the most commonly prescribed antibiotic for children in many countries. When used (most often a liquid of the color of chewing gum), it is absorbed in the intestine and enters the bloodstream. From there begins a journey through all the organs and tissues – the stomach, lungs, mouth, throat, skin, ears, etc. – and destroys the bacteria that meets along the way. So – called broad-spectrum antibiotics like amoxicillin are very skilled killers.
But the problem is that they take a lot of innocent “civilians“. Among the huge bacterial population there are both vulnerable and resistant bacteria. The drug destroys vulnerable microbes throughout the body-along with the pathogen, which is most often concentrated in one place. It’s something of a carpet bombing run when you really need a laser point strike.
Here and begin problems. The number of vulnerable species is reduced (sometimes to zero), the population of resistant species increases (the fewer competitors, the more they thrive). In this case, it is luck, because it is their offspring will be the most numerous. Resistant can be a pathogen, which, in fact, wanted to destroy, and many “civilians”.
Resistance spreads through bacterial communities in two main ways. The first is the growth of organisms that have already acquired it – the so-called vertical transmission. The genes travel from parents to children, from children to their children, etc. When the environment get antibiotics resistant bacteria behave in a similar way. Unlike the vulnerable who die, these continue to divide and multiply.
The second-sex – so-called horizontal transmission. Some bacteria behave like hermits, but many are promiscuous and constantly have sex. But this is not what you imagined – they do not shove into each other strange processes, lying on a microscopic bed. Bacteria get genes or exchange them like baseball cards, and many provide resistance. In the presence of resistance genes and antibiotics there is a natural selection in favor of the former. Thus, the survivors adapt to the drug created for their destruction, which becomes less effective, if not useless. In the presence of antibiotics, selection in the microbial population encourages resistance.
The dynamics of the emergence of resistant bacteria is very instructive. For example, a small dose of amoxicillin is enough to kill the encountered pneumococci. But not all. In a population of a million may be one “outsider” with a small, accidentally appeared genetic variation, which gave him resistance. After the remaining 999 999 999 bacteria die, the” outsider ” reproduces, occupying an empty niche. It becomes dominant. The resistant bacterium is then passed from one to the other by coughing or sneezing. Now let’s imagine that the other is also given a large dose of amoxicillin. He’s got all the vulnerable pneumococci dying again. In the population of resistant there is an option that is able to resist more effectively, besides armed with all the usual bacterial Arsenal. And so on.
Resistance either grows in small steps or very quickly. Sometimes a resistant strain gets new genes from another bacterium after “sex” and literally simultaneously produces this property to a whole class of drugs. In many cases, bacteria receive genes from” civilians ” who have survived the previous attack with antibiotics.
While amoxicillin is given to our children, who have pneumococci in their nose and throat, whether harmless or not, resistance will inevitably appear. However, of course, not at all and not after each course of treatment. This is a kind of casino: for each individual child, and for each community. Much depends on random factors. Resistant bacteria can fail and become extinct; probably more often than not. But some last for years.
In a global sense, bacteria that have gained resistance to penicillin in this way have been spreading slowly and inexorably in recent decades. And this is just one example. Similarly, resistance to macrolides (erythromycin, clarithromycin, azithromycin), tetracyclines (doxycycline), fluoroquinolones (ciprofloxacin) and nitroimidazoles (metronidazole) is increasing.
One of the problems – parents do not know or do not pay due attention to this phenomenon, rapidly developing in society. Let’s go back to the example of otitis media and imagine a possible conversation in the doctor’s office:
DOCTOR: your daughter is restless because she has otitis media.
MOTHER: I never understood – she has had ear infections before. Can I give her an antibiotic?
DOCTOR: more than eighty percent of infections are caused by a virus, so antibiotics won’t work.
MOTHER: what about the other twenty percent?
DOCTOR: We excessively use antibiotics. And the more, the better bacteria learn to resist them and spread more widely in society.
Mother’s doing a little counting. “Society” is other children. But her child may be among the remaining 20%. “Antibiotics won’t hurt, and I want the best treatment.”
The doctor also makes a small calculation. Yes, indeed: antibiotics may not help, but certainly not hurt. “Well, I’ll prescribe a course of amoxicillin for ten days.”
The second crisis is coming, which only emphasizes the excessive use of drugs and resistance to them: pharmaceutical companies do not have time to produce new antibiotics that act on resistant bacteria. Some modern infections can no longer be cured with their help, and, most likely, new ones will soon appear.
Antibiotics are narrow-spectrum (kill only a few species of bacteria) and broad (kill many types of microbes). Most pharmaceutical companies prefer the latter because the more widely used they are, the better they sell. Doctors also like them, and not without reason: sometimes it is very difficult to determine what exactly is caused by the infection-Streptococcus, Staphylococcus, or E. coli, and these drugs act on both, and on others, and on the third. But there is a significant drawback: the wider the range of action, the more active is the selection of resistance.
It is obvious that the more we use antibiotics, the faster the resistance will develop, so the useful life will be reduced. At the beginning of the era, scientists were able to keep the gap, regularly developing new drugs. But now the conveyor is gradually slowing down. All “simple” are already open. Now pharmaceutical companies are more likely to change the glaze on the same cakes: a little change the existing recipes without developing new ingredients.
Huge efforts and costs associated with the development of fundamentally new antibiotics, companies are simply unprofitable – especially a narrow range. There is a wish to develop those which will accept millions of people for many years-for example, means from high cholesterol, diabetes or hypertension. It’s profitable.
A few years ago, when I was working for the American society of infectious diseases (AOI), one of my tasks was to try to convince the U.S. Congress to pass laws that would help to get the stuck conveyor running again. We are very concerned about stopping the development of new drugs, because we know very well that this process takes years. We cannot wait for the emergence of a new easily transmitted bacteria that will not be treated with any existing antibiotics. I traveled regularly to Washington for several years and worked with other members of the AOI team, other organizations pursuing similar goals, and family members of patients who died or were severely injured by antibiotic-resistant microorganisms. In all possibilities, we were in the Congress in briefings or formal meetings of committees.
Stories about young, healthy people struck by the vicious, merciless infection, it was sad and frightening. One day, Brandon noble, an American football player who played for the Washington Redskins, told his story. He was a real star, everybody knew him. Like many professional athletes, he suffered a series of injuries, in his case – knee. And like everything, went to the hospital to heal torn ligaments, this is a relatively routine procedure. Such operations are carried out thousands a year. But in his knee was resistant to antibiotics Staphylococcus aureus (so-called methicillin-resistant Staphylococcus aureus, or MRSA). The knee had to be cleaned many times; despite the necessary treatment, the moving parts were irreversibly crippled. When the infection was finally cured, noble could no longer walk normally, his career was over. Seeing how this man limps to the microphone, we immediately realized how strong the damage was. Later he said, “The worst and unexpected thing I encountered during his football career, little thing that I see-and could not”.
The next speaker was a woman from a small town in Pennsylvania, who told about her son Ricky Lanetti, a senior football player from College. While preparing for the playoff games of the third division of NCAA he noticed inflammation on the buttock. A little abscess, nothing special in appearance, no more pimple. No one, including himself, is not particularly worried, once-in front of a big game.
A few days later, the young man died of a severe MRSA infection, which spread from the abscess throughout the body. His immune system couldn’t handle it, couldn’t save even large doses of antibiotics. We listened in silence to the mother’s grief. She showed a beautiful photo, which stood with her son. He towered over her, dressed in a football uniform. And now his not was.
When Congress considers an issue, stakeholders are sometimes invited to a round table organized by a Subcommittee of the Senate or House of representatives. The meetings are held in large halls with classic layout and furniture, symbolizing the strength of our democracy. All are seated in accordance with the hierarchy of power: congressmen in front of the Department, in front of them tables, which are speakers. In the far part of the room chairs where people sit waiting for their turn, congressmen assistants and just curious spectators.
Three or four groups, organized according to the topics of discussion, often speak at the hearing. The first are congressmen and celebrities, then – their friends, then – interested organizations. I have spoken on this issue many times, but AOI, the professional organization with the most interest and the most knowledge on the subject, always reads the reports at the end. By this time, after several hours of dull speeches, eulogies and breaks, the hall is almost empty. Most congressmen disagree, but the Chairman remains to make a final conclusion on issues of concern to the nation.
Exactly the same scenario took place and the round table. Finally it came to me. I prepared a speech about why you need to run the antibiotic conveyor again and how to do it better. The only remaining Congressman was the Chairman of the Subcommittee, an elderly man with a southern accent. Before I had a chance to start, he said he was happy to hear the presentation on this issue. Then he continued: “a Few weeks ago I was playing Golf with a friend. He complained to me that his knee was hurting and said he had signed up for knee replacement surgery. Next time I saw him at the funeral. During the operation, MRSA-the infection that killed him – got so simple. He had nothing to treat. So I know what you’re talking about.”
There were only a handful of people left in the room, but this Congressman understood perfectly well why it was necessary to do something. His Committee spoke in support of the bill, which, in the end, turned to the Federal law on encouraging development of new medicines. However, the paradox still has not gone away: we have much more antibiotics than we need, but not enough “right” ones that can cure resistant infections. And the problems are connected: the first generates the second.
But resistance is not only due to the excessive use of antibiotics. This is also due to the way we treat animals on farms.