5
Pharmaceutical Antibiotics
Their History and Effects
Antibiotics, the medications that are used to kill germs, are actually produced by the germs themselves. How is this possible?
A germ is never by itself; it is always surrounded by a crowd of its fellow germs, which, like it, are trying to occupy a specific place from which they can take nourishment. Consequently, the countless germs that live on the earth and everything on it inevitably enter into competition with other types of germs. In this struggle for survival, they secrete poisons to kill their rivals. These substances are harmless to them but toxic to their neighbors. Because they work against (anti) something that is living (bio = “life”), we call them antibiotics.
The antibiotic substances that are released by germs act either by preventing the multiplication of their neighbors—which prevents them from being overwhelmed by neighboring microbes—or by killing them—which frees up living space and resources. Harvested in large quantity from cultures that are specially prepared for this purpose, they can then be used as medications.
Several thousand different antibiotic substances are known today, though a vastly greater number could exist given the number of germs that exist. However, only a hundred of these antibiotics are used in medicine, and only around fifty are used on human beings.
To be of any use in therapy, antibiotics must possess precise characteristics. For example, they must have an effect on the germs that attack human beings. They must be distributed easily in the body in order to reach the site of the infection; once there, they must be able to make contact with the microbial cell, if not gain entrance to it. Antibiotic substances must also retain their composition when they come into contact with bodily fluids or enzymes, or else they will lose their therapeutic properties.
When the antibiotic reaches the germ, it takes action against it in several ways. One of the antibiotic’s primary targets is the outer membrane of the germ cell; if the antibiotic wounds the membrane, the cell loses its cytoplasm and organelles and dies. Another target is the organelle responsible for breathing; by destroying it, the antibiotic causes the germ to asphyxiate. Another organelle that the antibiotic sets its sights on is the ribosome, which is responsible for the production of proteins. Its neutralization will cause fatal deficiencies for the germ.
The germ’s genetic code is yet another target of antibiotics. Like all cells, each germ cell holds its genetic coding in the deoxyribonucleic acid (DNA) found in its nucleus. That information is transmitted to the various organelles by the cell’s ribonucleic acid (RNA). Taking action against one of these two molecules—which a variety of antibiotics do—is a sure way to hamper the growth of germ populations.
Because they act against the various parts of a microbial cell, antibiotics are effective against bacteria and, to a lesser degree, protozoans and fungi, as they are all single-celled organisms. To the contrary, they have absolutely no effect against viruses, which are only molecules and not cells.
Antibiotics also do not work against toxins, which are just molecules and not cells. They are certainly effective at killing germs that emit toxins—for example, the bacilli responsible for cholera, anthrax, and typhoid—but they do not combat the toxins that these bacilli produce.
In nature, the various germs manufacture antibiotic substances that are tailored to the threats each germ must face. These antibiotic substances, therefore, can vary depending upon the species that produces them and the other species that that species competes against. A distinction is made between narrow-spectrum antibiotics, which are given that name because they are only effective against a single species or small number of germs, and broad-spectrum antibiotics, which kill a large variety of germs.
While all antibiotics work against one or more bacteria, few among them have any effect on protozoans, and an even smaller number have shown any effectiveness when dealing with fungi. And, let me repeat, they are completely useless against viruses.
THE HISTORY OF ANTIBIOTICS
When the existence of germs and the role they play in the incubation of infectious diseases was discovered in the nineteenth century, researchers began looking for methods to kill them. For this purpose, researchers perfected procedures for creating germ cultures so that they could have a large number of specimens at their disposal. They would place these microbial cultures in contact with all kinds of substances to learn which would destroy them. During one of these tests in 1877, two French researchers, Louis Pasteur and Jules Francois Joubert, put harmless bacteria in contact with the bacilli responsible for anthrax. They had the immense satisfaction of observing that these bacilli did not survive this contact. A first step was made!
Pursuing their research, they observed that the inoculation of fatal doses of anthrax bacilli would not trigger any kind of disorder when those bacilli were combined with the same harmless bacteria. Something in this mixture had an inhibitory effect on the anthrax germs. What could it be? No one knew, but similar experiments strengthened researchers’ conviction that germs could be defeated and that infectious diseases were not an inescapable fatal occurrence.
In 1890 the first antibiotic substance was isolated from a bacteria culture: pyocyanase. This product demonstrated effectiveness against diphtheria and other diseases, but it proved to be highly toxic and its use was abandoned.
In 1929 Alexander Fleming, an English bacteriologist, discovered that the staphylococcus he was cultivating would break down in a particular nutritive culture. Seeking to learn why, he discovered that a mold (Penicillium notatum) that had accidentally contaminated his culture was responsible. The antibiotic substance he extracted from this mold is called penicillin. Although Fleming suggested in the records of his discovery that this substance be used against all infectious diseases, it would not be attempted for another seventeen years.
In 1939 two English researchers, H. Florey and E. Chain, tested the therapeutic value of Fleming’s penicillin in experiments using mice as test subjects. These experiments were crowned with success, and the first use of penicillin on a human being was attempted in 1941. The person selected was a policeman stricken with septicemia and at death’s door. Every three hours for a period of three days, he received an intramuscular injection of penicillin. After twenty-four hours, sure signs of improvement were visible. On the fourth day, the patient’s fever dropped and he could eat again. The researchers were ecstatic; no remedy had ever had such a profound effect on an infection. Unfortunately, the penicillin supply ran out on the fifth day and the infection roared back to life. The patient’s state deteriorated and he died.
However, the therapeutic effect of penicillin had been proven. The problem of supplying a sufficient amount of this product was resolved thanks to the development of processes for producing cultures.
In later experiments, penicillin was shown to be effective against many infections: pneumonia, diphtheria, gonorrhea, acute articular rheumatism, scarlet fever, angina, and so forth.
The world was then gripped by euphoria. A miracle remedy had been found, one that could cure everything! Infectious diseases—which had claimed so many victims, without anyone ever being able to do anything about them—had become easy to cure thanks to penicillin. Its use spread rapidly. In addition to its medical use, throat lozenges, toothpaste, cosmetic creams, and more were made from it. For years, products with a penicillin base, which could be bought directly by anyone, without a doctor’s prescription, flooded the market.
This free trade was brought to an end, though, in 1955, after which time its use became tightly monitored. Penicillin now could only be purchased with a prescription. The number of germs that had become resistant to this antibiotic—as well as an entire series of antibiotics that had been discovered in the meantime—had risen to dangerous levels.
THE RESISTANCE OF GERMS TO ANTIBIOTICS
Like all living entities that are confronted with mortal danger, the germs under attack by antibiotics sought a means of survival. To protect themselves against antibiotics, they had to develop specific properties or defense mechanisms to counter them.
Germs that are able to survive an assault by antibiotics are said to have developed a resistance to them. What this means is that the antibiotic in question no longer has any destructive effect on the germ. This resistance is called simple resistance when it only concerns one antibiotic and multiple resistance when it concerns several different kinds. When a microbe becomes resistant to more than one type of antibiotic, it is said to have multiple drug resistance, or multi-drug resistance.
Microbes may have a natural resistance to certain kinds of antibiotics, or they may acquire resistance through genetic mutation or through sharing genetic material with other microbes. They may also show cross resistance, in which they manifest resistance to a drug that they have never faced before because they have been exposed to a similar drug with similar action, and therefore have developed the mechanisms to resist that type of action.
A germ will resort to various strategies to protect itself from the destructive activity of antibiotics. The bulk of its efforts are directed at the protection of its outer membrane, as it is often the target of antibiotics. That membrane is also the protective layer that an antibiotic substance must pass through to enter the germ cell. So the germ’s defense here consists of reinforcing its outer membrane to make it resistant to the destructive attempts of antibiotics and/or making it impermeable so that antibiotics are unable to travel through it. Another strategy is the development of enzymes that neutralize the aggressive properties of antibiotics. In this latter case, when the antibiotics make direct contact with the germ, they are deactivated by its enzymes.
Of course, developing resistance to antibiotics is nothing new for germs. They do it all the time in nature to ensure their survival in the face of the vast number of other germs they encounter that secrete antibiotic substances in order to eliminate them.
There are three physiological phenomena that come into play when germs make the transformations necessary to acquire antibiotic resistance: plasmid mutations, transposon mutations, and spontaneous mutations.
Plasmid Mutations
Plasmids are little rings of DNA that appear in the cytoplasm of microbial cells. In contrast to the genetic information of the cell’s nucleus, which is fixed and will change only under exceptional circumstances, the genetic coding of the plasmids changes often and in reaction to the environment in which the cell finds itself. Informed of all changes affecting the living conditions of the germ, the plasmid expels genes that have become unusable or acquires new genes in order to direct the adaptation process accordingly.
Thanks to the plasmids and their ability to encode the adaptations that are necessary for the cell to survive an assault by antibiotics, germs rapidly develop antibiotic resistance. Because the information carried by the plasmids is transmitted to the daughter cells during cellular multiplication, the resistance developed by the mother cell becomes those of its thousands of descendants.
Plasmids also have the peculiar ability to leave their home germ and make their way into another kind of germ. The consequence of plasmid transfer is that the resistance developed by one germ can be transmitted to another without the latter germ having any contact with the antibiotic in question!
Transposon Mutations
The second method relies on the transposons, free DNA strands that float in the microbial cell’s cytoplasm. Transposons act in the same way as plasmids, but they are even more effective and rapid, accelerating the adaptation and manufacturing processes at work in creating resistance.
Spontaneous Mutations
The third method by which microbes develop antibiotic resistance is passive and results from natural selection. From time to time, germs will experience spontaneous mutations in their genetic coding as they multiply. This is how an individual germ can appear whose genetic heritage is different from that of its mother cell. When that germ multiplies, it transmits this new characteristic to all of its descendants and creates a new strain. This is a natural phenomenon that takes place in all plant and animal organisms. But in germs, these mutations occur frequently because the germs multiply so rapidly. Out of the naturally high number of mutations that occur, it can happen that one of them will cause the appearance of a strain of germs that are resistant to an antibiotic.
Normally cellular mutants vanish quickly, as they are in the minority among cells carrying the exact genetic coding of their forebears, with whom they are competing. Now, let’s imagine that these germs were the source of an infection, that the infection was treated with antibiotics, and that the mutant germs were the only ones able to resist the antibiotics. The cells carrying the nonresistant coding would be destroyed, but the mutants would survive, as would their descendants. When these surviving mutant germs multiplied, this new strain would spread through the body, and the antibiotics would be powerless to stop it. Later, when these germs left the organism to infect another one, they would carry antibiotic resistance with them.
The same process takes place with saprophytic microbes during an antibiotic treatment. Although these microbes may not be the antibiotic’s intended targets, it will kill some of them and leave behind those that are resistant to it. That resistant strain will multiply. If, for some reason or other, that saprophytic microbe becomes virulent and triggers an infection, the antibiotic in question will not be able to contain it.
When resistance appears by mutation, it is only transmitted to the descendants of the mutant germ; it remains within the strain. When the plasmids and transposons intervene, the resistance overflows and spreads to other strains and kinds of germs.
THE CAUSES OF RESISTANCE
The reason for the current epidemic of numerous resistances on the part of germs and growing difficulty in finding effective antibiotics is not to be found in the reasonable use of antibiotics but in their improper and exorbitant use.
Like all medications, antibiotics need to be used correctly to ensure that all their effectiveness comes into play and to limit their negative side effects. They should only be used against germs on which they have an effect, and only at the dosage and duration of time that is needed to kill them. They should only be prescribed in cases of absolute necessity, when all other less dangerous therapeutic methods have been proven insufficient. Alas, these criteria for proper use are often not respected.
Every antibiotic is effective against specific germs and has absolutely no effect on others. We should therefore always be certain that the antibiotic we select clearly matches the germs we want to attack. The antibiogram, a laboratory test, makes it possible to verify which antibiotics will work against the germ in question. The germ responsible for the infection is extracted from the secretions of the patient, allowed to multiply in an appropriate germ culture, and then tested against different antibiotics. This test can clearly show which antibiotics are effective, and out of these, which one has the most potent effect.
Another way of proceeding is to identify the germ responsible for the infection in the patient’s secretions (urine, phlegm, or stools, according to the case). An antibiotic that is known to be effective against that germ can then be prescribed.
However, these two methodologies are not always practiced. And when the prescribed antibiotic is not the right one, the infection will not be arrested, or it will be only partially arrested. The pathological germs that survive will thereby be given the chance to develop a resistance to the antibiotic that has been used against them.
In some cases a broad-spectrum antibiotic is prescribed. This will certainly increase the chances that the infection will be eradicated, but the number of germs this antibiotic attacks will also be higher. This will compel them to develop resistance, and consequently the risk that a larger number of germs will now be resistant to this antibiotic will be greater.
The prescription of antibiotics to fight viral diseases like the flu is another cause for the development of these resistances. The characteristics of these products make them entirely useless against viruses. The saprophytic germs are therefore needlessly confronted by an antibiotic and will work to develop resistance against it.
The use of antibiotics as a preventive measure is another cause of resistance. The intention of this practice is to head off the arrival of an infection and kill germs as soon as they appear. This procedure is to help people suffering from a viral infection from contracting a bacterial infection because of their weakened state. But in this case, the antibiotic is chosen without knowing which germ the patient might come into contact with—or even whether the patient really would develop a secondary infection. Again, here saprophytic microbes are needlessly placed in contact with antibiotics.
A lack of respect for dosage is another case for resistance. Sometimes patients take it upon themselves to reduce their antibiotic dosages in order to reduce the negative side effects. However, antibiotic dosages are calculated quite precisely in order to supply a sufficient quantity of poison to kill the germs. When patients take less than the prescribed dosage, some of these germs will survive and could then develop resistance. The same thing occurs when an antibiotic treatment is not followed for its full course.
As we’ve discussed, a saprophytic microbe is a beneficial member of our intestinal flora. At first glance, antibiotic resistance in a saprophytic microbe might seem to matter little. But a saprophytic microbe can become virulent and pathological if the terrain is altered or if, for one reason or another, it makes its way into another part of the body. In addition, even if the microbe in question never becomes virulent itself, its resistance can be transmitted by its plasmids or transposons to pathological germs traveling through the body.
THE HARMFUL EFFECTS OF RESISTANCE
The development of resistance by germs is the source of two serious problems:
Although antibiotics can provide invaluable help in dealing with serious infections, they still also possess a number of harmful side effects. Now, while it is worth the trouble of putting up with these harmful effects for severe disorders, this is not the case for simple infections.
The loss of effectiveness in antibiotics can be shown by the fact that as time has passed, the dosage we require for a therapeutic effect has had to be increased. In his book Aromathérapie, Dr. Jean Valnet describes how in the middle of the twentieth century, the dosage of penicillin necessary for a therapeutic treatment totaled between 100,000 and 200,000 units. Thirty years later it was several million units, and what’s more, that was the daily dosage.
In concrete terms, the loss of antibiotic effectiveness means, for example, that a woman suffering from cystitis or a child with rhinopharangytis would not be completely and definitively healed after a first session of antibiotic therapy. In the absence of a clear cure, the treatment will need to be repeated at an elevated dosage or with a different antibiotic. In fact, it is common for patients today to ingest several different antibiotics during the same year, and for simple infections!
When antibiotics are taken this way, they affect not just the germ responsible for the infection but also a host of other species. Those latter species will develop resistance—unless they simply receive them ready-made from plasmids and transposons. When several germs have become resistant to a given antibiotic, it becomes useless. It must therefore be replaced by another antibiotic, which in its own turn can be outstripped in short order because of the improper usage of these kinds of remedies.
How many antibiotics do we have at our disposal to carry out these ongoing treatments and continuous replacements? Very few! Several dozen, at most. And only a few of these will be effective against the particular germ we are trying to destroy. The possibilities for replacement are therefore limited . . . and diminishing.
Of course the search for new antibiotics is always taking place. But the rhythm of discoveries is slower than that of the development of resistance. The alarm bell is regularly sounded by many figures of the medical world and international health organizations. Many experts fear that one day antibiotic resistance will have developed to such an extent that we will have no effective means left to us to treat some infectious diseases.
A variety of events give us the impression that this day may not be far off. In 1980 an epidemic of Staphylococcus aureus erupted in several hospitals in the city of Melbourne, Australia. An increasing number of patients were affected by it. The problem continued growing in size and the death toll kept growing. The antibiotics used until then to curb this infection had no result. Others were tried, but each proved to be equally ineffective. A great fear began spreading among the nursing staff: When would this epidemic be stopped? Even more importantly, what would stop it? Finally, an effective antibiotic was found: vancomycin. Although fairly toxic and quite taxing to humans, it had to be used, as it was the only remedy found to be effective.
Vancomycin remained the antibiotic of last resort until 2002. That was the year when the first case of vancomycin resistance was detected. If this resistance spreads, how will we contend with this problem?
Since the 1960s research has been oriented toward the production of altered antibiotics—that is, antibiotics whose molecular structure has been modified in order to bypass the obstacle of resistance. These new kinds of antibiotics include molecules produced artificially in the laboratory, and so they are sometimes called semisynthetic antibiotics. They are also called second-generation antibiotics, as opposed to the firstgeneration antibiotics whose origins are entirely microbial.
These second-generation antibiotics were effective at first, but germs’ abilities to adapt soon came into play against them. New resistances appeared that in turn caused these antibiotics to lose their effectiveness.
To get around these deficiencies, a third generation of entirely synthetic antibiotics, on a base consisting solely of laboratory-crafted molecules, was created starting around 1980. Because these new forms of antibiotics were entirely new to the germs, they should have been able to disarm the germs’ counterattack. It has been seen, however, that the adaptive capabilities of germs also apply to these new kinds of molecules, and they are developing resistance to combat them.
To contend with this resistance, a new strategy has been crafted: instead of using only one antibiotic at a time, as in the past, two or three are given at the same time.
In addition to the problems connected to the development of germ resistance, antibiotics—which are among the most heavily prescribed remedies today—possess numerous side effects that also contraindicate their overuse.
THE HARMFUL EFFECTS OF ANTIBIOTICS
Thousands of antibiotics have been discovered, but only a minority—around eighty—are used for therapeutic purposes. This simple fact speaks volumes about the toxicity of these kinds of remedies. This does not mean, though, that they should never be used.
In certain cases antibiotics are absolutely necessary, despite their harmful side effects, and we can only be grateful that they exist. But these cases are rare and much less numerous than those cases for which antibiotics are often prescribed even though they could be treated by simpler, nonharmful methods.
The best-known side effect of antibiotics is the destruction of a portion of the saprophytic microbes of the intestinal flora. Generally only some of these microbes will be sensitive to any particular antibiotic. When those microbes (which have nothing to do with the infection) are killed but other microbes that are less sensitive to the antibiotic survive, the microbial populations are thrown out of balance. Microbes that might normally make up only a small proportion of the intestinal flora witness a sharp increase in their population, while others, with whom they are in competition, are decimated.
Our normal digestive processes rely on a balanced microbial population. When our intestinal flora are imbalanced or insufficient, we experience abnormal fermentation and putrefaction processes that cause bloating, indigestion, diarrhea, colic, and abdominal pain, conditions that are sometimes difficult to get rid of.
This is a well-known fact, and many people who are prescribed antibiotics try to counter it by consuming yogurt, lactofermented foods, or brewer’s yeast to encourage regeneration of their intestinal flora. What is less well known, however, is that the rest of the body’s microbial flora—that of the lungs, skin, genital organs, and urinary tract—is thrown out of balance by antibiotic treatment in the same way. The disorders that result are harder to connect with their cause, but the sharp increase in the incidence of infections with Candida albicans—whether it is confined to this or that organ or in the entire body—shows that they can be severe and extremely bothersome.
Depending on the type used, antibiotics can cause headaches, vomiting, balance problems, anemia, and kidney problems. They can also cause allergic reactions, such as respiratory problems, bronchospasms, skin rashes, hives, edemas, states of shock, fevers, malaise, lethargy, and so forth.
The most harmful side effect of antibiotics, however, is the negative effect they have on the immune system. In fact, because of the way they work, antibiotics have an inhibitory effect on one or another part of the body’s defenses. In addition to disrupting the intestinal and cutaneous flora that form part of the immune system’s first line of defense, antibiotics also have the following effects:
With the immune state weakened, the organism’s receptivity to future infections is heightened.
Instead of adding their effects to those of the immune system, antibiotics merely substitute themselves for them. The many ways in which the immune system can parry the attacks of germs are then replaced, in short, by the fairly unilateral and incomplete properties of antibiotics. This kind of therapy should only be chosen with the greatest caution!
REVERSIBILITY
The development of antibiotic resistances, with all the negative side effects that result, is not an insoluble problem, fortunately.
If the selective pressure exerted on germs by antibiotics pushes them to develop resistance, a total and prolonged elimination of these remedies will cause the germs to lose them. No longer having to defend themselves against antibiotics, the germs will no longer need the defenses they created for this purpose. Those properties will atrophy and then vanish, bringing the germs back to their initial sensitivity. The acquisition of resistance is therefore not definitive!
This reversibility has already been observed. For example, doctors in a South African hospital had noted that the bacteria Klebsiella pneumoniae, which is responsible for pulmonary infections, had become resistant to the antibiotic that up until then had been successfully used against them. Because it was now useless, that antibiotic was abandoned completely, and the use of other antibiotics was reduced as a cautionary measure. After a period of around five years, the klebsiella bacteria had regained their sensitivity to the antibiotic whose use had been eliminated earlier. Because they no longer needed to defend themselves against it, they had lost the ability to do so.
Similar observations were recorded in Iceland. In a desire to counter the alarming growth of the number and variety of resistances, authorities there imposed a draconian reduction on the use of antibiotics in all but the most serious cases. Less virulent infections were treated by other means or simply left to the defensive devices of the immune system. The result was that the number of antibiotic-resistant germ strains fell and the number of germs that regained sensitivity to them rose.
To curb the development of new resistances and to reduce or eliminate those that already exist, a long period of antibiotics abolition should take place. Is this possible? What would then become of the people stricken by infections? Would they be left with no treatment options?
This would be the case if there was no alternative to the use of antibiotics. But it so happens that one exists. As we have already seen, infections arise due to the presence of pathological germs and the susceptibility of the terrain. Prescribing antibiotics takes action against just one single cause of the infection. Addressing the second cause—that is, strengthening the terrain to make it less susceptible to infection—is not generally a consideration. Nevertheless, correction of the terrain, by itself, is capable of dealing successfully with a number of simple infections, and all the more because it will also reinforce the body’s defenses! (See chapter 8.)
Furthermore, nature offers us an entire range of natural antibiotics that do not have the drawbacks of conventional antibiotics. They are highly effective, have no side effects, and do not spur germs into developing resistances.