The History of Antibiotics

Antibiotics, in one form or another, have been in use for centuries. Prehistoric man may not have realized why or how the wide variety of organic and inorganic substances he used worked. The important thing was that these substances did, indeed, work. Before the advent of commercial antibiotics, a common-sense approach to infection was obviously being used: do little to treat the infection initially, allow the body to fight it naturally, and in so doing, build up one's natural resistance to it. Only when the body clearly was not winning the battle was intervening action taken.

In general, people depended on herbal medicines and folk cures. Ireland had a strong tradition of herbal medicine, with a doctor or herbalist ready to help in the treatment of infections. As in many other cultures, the knowledge of growing and using herbal medicines was handed down from generation to generation. Doctors depended, to a great extent, on natural substances such as iron, mercury, and antimony.

It was not until the nineteenth century that scientists began to closely examine various curative substances in order to understand exactly how and why they were effective. In the course of this study, scientists discovered that there were beneficial bacteria. They began to experiment, isolating the "good" bacteria and encouraging their growth in the laboratory. These bacterial agents were then tested for their ability to treat disease. This pattern of research and clinical trials continued into the twentieth century (and, in fact, continues today), leading to the production of the first antibiotic drugs.

From ancient times to the 19-th century

The earliest evidence of humans using plants or other natural substances for therapeutic purposes, comes from the Neanderthals, who lived over 50,000 years ago. In northern Iraq, archaeologists uncovered evidence of human remains that had been buried with a range of herbs, some of which are now known to be antibacterial-that is, used to kill bacteria or to prevent them from multiplying. Many of these herbs are still used by the inhabitants of this region today. And in other regions, many other antibacterial substances-both organic and inorganic-have been used over time.

The first prescription for treating infections may well have come from the Egyptians around 1550 BC. Written as "mrht," "byt," and "ftt," it was a mixture of lard, honey, and lint, and was used as an ointment for dressing wounds.
We know that honey is antibacterial-it kills bacterial cells by drawing water out of them. In addition, the enzyme inhib- ine, which is found in honey, converts glucose and oxygen into hydrogen peroxide, a well-known disinfectant.
At the present time wounds are very resistant to treatment with antibiotics, but honey heals them with little difficulty. Honey is also excellent for treating infected varicose ulcers.
Tincta in melle linamenta was a regular prescription in Roman times. It is essentially the same ointment that the Egyptians used, with honey as the active ingredient. The Greeks also used honey in wound dressings, often combining it with copper oxide. More recently, during World War II, an ointment of honey and lard was used in Shanghai to treat wounds and skin infections, and with very good results.

Honey was not the only antibacterial substance used by the Egyptians. Fragrant resins, such as frankincense and myrrh, were used to preserve human remains. Onions, which also have antibacterial properties, have often been found in the body cavities of mummies.
The anti-infective properties of onions and garlic were confirmed by researchers in the 1940s. A substance called allicin was isolated in these plants and was shown to be highly effective in killing bacteria.
Another herb, the radish, is also thought to have been used therapeutically by the Egyptians. The anti-infective property of this herb was confirmed with the isolation of raphanin, a substance that has significant antibacterial activity against a broad range of infections.

The work of Alexander Fleming in the 1920s showed that molds, such as Penicillium spp., can produce antibacterial chemicals. But the use of molds dates back to the ancient Egyptians, and perhaps even earlier. An Egyptian physician, quoted in the Ebers Papyrus around 1550 BC, stated that if a "wound rots. ..then bind on it spoiled barley bread." Indeed, the Egyptians used all kinds of molds to treat surface infections. The ancient Chinese also used molds to treat boils, carbuncles, and other skin infections.

Wine and vinegar have been popular treatments for infected wounds since the time of Hippocrates. Vinegar is an acid and a powerful antiseptic-a substance that kills the germs that cause disease. The antibacterial properties of wine cannot be fully attributed to its alcohol content, as this is very low. Recent chemical analysis of wine has brought to light the presence of an antibacterial substance called malvoside. It is this substance that is now thought to give wine its antibacterial properties.

Inorganic substances have also been used to treat infections throughout the ages. Copper was widely used by the Egyptians, Greeks, and Romans, often in combination with honey. Modern scientific tests have proven that copper is indeed antibacterial. For example, a skin infection known as impetigo, which is caused by the Staphylococcus aureus bacteria, is being treated in France with Eau Dalibour, a combination of zinc and copper. This prescription dates from the time of Jacques Dalibour, surgeon general of the army of Louis XIV, but it may well have been part of French folk medicine long before this.

The 19-th and early 20-th centuries

The nineteenth and early twentieth centuries saw the discovery and development of many new antibiotics. Most were discovered as doctors and scientists worked to isolate and develop "good" bacteria that could be used in the treatment of infectious diseases. Many different antibiotic substances were discovered and developed.

Homeopathy is the use of minute amounts of substances that would normally cause illness in a healthy person to accelerate the disease process in a sick person in order to treat the illness. In Germany, there is a tradition of homeopathic medicine. Many doctors were trained in the art of homeopathy, and there were a number of lay homeopaths as well.
From the mid-1800s until the turn of the century, homeopathic medicine was extremely popular in Europe and North America. However, as pharmaceutical companies began to rise, conventional medicine began to take a stronghold on medical care. Much of the infrastructure associated with conventional medicine-hospitals, medical schools, research and diagnostic facilities, X-ray machines, etc.-were sponsored by pharmaceutical companies, so as pharmaceutical companies began to dominate the medical field, so, too, did conventional medicine. In the early 1900s, the American Medical Association (AMA) secured a strong political lobby to close many homeopathic colleges and hospitals. By 1920, the number of these American hospitals had dropped to a mere seven.
The AMA had found a powerful ally in pharmaceutical companies, which may explain the AMA's considerable political clout. It may also explain why most medical research is sponsored by pharmaceutical companies and why medical students are taught pharmacology (the use of drugs) as the primary means of treating patients.

During the nineteenth century, various experiments were done in an attempt to find a magic, powerful antibacterial substance that would rid humankind of the scourge of infection. In 1877, experiments in Paris demonstrated the benefits of using harmless, "good" bacteria to treat pathogenic or harmful bacteria. These experiments did indeed prove that harmless bacteria could be used to compete with pathogens (harmful bacteria), although they did not kill the pathogens.
Also in Paris, Louis Pasteur described the beneficial effects of injecting animals with harmless soil bacteria to combat anthrax. Many other experiments on anthrax and cholera confirmed these findings and proved that harmless bacteria can inhibit the growth of disease-causing bacteria.

In Germany in 1888, an antibacterial substance called pyocyanase was isolated. Animal trials of this substance showed it to be very effective. In fact, the results were so exciting that trials were undertaken in humans suffering from a variety of infections. However, the results of the human trials were very disappointing-pyocyanase was found to be too toxic. Consequently, all research on this substance halted.

In 1910, a more promising agent called salvarsan, which was actually a dye, was shown to be effective in the treatment of syphilis, a common sexually transmitted disease at the time. Again, toxicity in humans was a major barrier to its development and widespread use.
The problem of toxicity and the failure to find other antimicrobial agents were the two factors hindering the progress of researchers. Enthusiasm began to wane in the search for the "magic bullet" that would rid humanity of infectious diseases, many of which were major causes of death at that time.

The tide began to change when Alexander Fleming discovered penicillin. After distinguishing himself in his medical studies, Dr. Fleming started research work in pathology in 1908. His early work led to the isolation of lysozyme, an enzyme in human tears and nasal mucus. This enzyme proved to be mildly antibacterial, but it was not very effective against most human infections.
In 1928, while attempting to grow the bacteria Staphylococcus spp. on an agar plate (a dish used for preparing bacterial cultures), Fleming noticed that the growth of this bacterium was inhibited by a mold that had accidentally contaminated the plate. He decided to identify the mold, which was eventually called Penicillium notatum. Fleming was excited by this discovery. He cultured the mold in a special broth and injected the broth into some of his patients, who had various infectious diseases. The results were encouraging, and the broth proved to be nontoxic. Unfortunately, though, Fleming had not made enough of this broth, making his experiment rather limited. When he presented a paper on his findings in 1929, his colleagues in the medical profession were not particularly impressed or interested.
It took two other gifted researchers-Doctors Florey and Chain, working at Oxford University in the late 1930s and early 1940s-to realize the importance of Dr. Fleming's findings. It was their pioneering work that brought penicillin into clinical use. Florey, an Australian doctor, had gone to Oxford on a scholarship to study pathology. Chain was a German chemist who had fled from the Nazis in the 1930s and had come to rest in England.
Florey was eager to form a group of researchers who were interested in finding effective antibacterial substances. He was the microbiologist and clinician, while Chain was the chemist capable of isolating, purifying, and studying the properties of such substances. Their research team was made up of twenty of the best scientists in Britain at that time. They focused their attention on the work of Alexander Fleming and worked at purifying penicillin and testing its effectiveness.
In one laboratory experiment, the team injected fifty mice with a lethal dose of the Streptococci spp. bacteria. Twenty-five of these animals received frequent injections of penicillin. The control group (the other twenty-five mice) was not injected with penicillin. After ten days, twenty-four of the twenty-five penicillin-treated mice had survived. All mice in the control group were dead. These startling results were reported in the well-known medical journal The Lancet on August 24,1940.
In 1941, the Oxford group conducted their first clinical trial of penicillin. Their patient was a 43-year-old policeman who was suffering from septicemia (blood poisoning). The man was dying, so Florey and Chain decided to try the seemingly drastic measure of injecting penicillin intramuscularly every three hours for five days. Within twenty-four hours, there was a marked improvement in the man's condition. By the fourth day, his fever was gone and he was eating again. However, after the fifth day, the supply of penicillin ran out and the patient's condition started to deteriorate again. He eventually died. Despite his death, it was clear to all that penicillin was extremely effective at fighting infection.
The Oxford group's next challenge was finding a way to produce penicillin in large, economical quantities. All efforts to get industrial support for their research in Britain were fruitless, so in the summer of 1941, they went to the United States. Here they succeeded in getting a number of pharmaceutical companies involved in the industrial production of penicillin, including Merck, Squibb, Pfizer, Abbott, Winthrop, and Commercial Solvents. It was these American pharmaceutical companies that made penicillin a therapeutic reality.
Subsequent clinical trials produced spectacular results. Penicillin demonstrated remarkable effectiveness against a range of infections, including pneumonia, septicemia, scarlet fever, strep throat, diphtheria, gonorrhea, and rheumatic fever. There was a general belief that it could help treat any disease-a myth that still exists today. Tremendous publicity surrounded this new "miracle drug," and in 1945, Fleming, Florey, and Chain were jointly awarded the Nobel Prize in Physiology and Medicine.
Penicillin was later produced in oral form and was added to many products, including salves, throat lozenges, nasal ointments, and cosmetic creams. Prior to 1955, its sale was not controlled, so anyone could buy it over the counter without a prescription. This excessive and uncontrolled use led to the overgrowth of resistant bacteria, and the damage had been done. Resistance had become a major problem, and epidemics of staphylococcal-resistant infections began to emerge in hospitals.

In 1935, a German researcher showed that a dye called Prontosil Red cured mice that were infected with Streptococcus spp. (the bacteria that causes strep throat). Prontosil Red was the precursor of a group of antibiotic-like drugs called sulfonamides, or sulfa drugs. These drugs are still in use today. Septra, for example, which contains sulfamethoxazole, is used to treat respiratory and urinary tract infections.

Microbiologists have long known that soil contains very few bacteria that are capable of causing infections in humans. The study of soil bacteria and the reasons why they are not more capable of causing disease was the lifelong work of Selman Waksman, a research scientist at Rutgers University in New Jersey.
In 1939, Merck and Company provided Waksman with financial assistance to mount a search for antibiotics in soil microorganisms. In 1943, this search culminated in the isolation of streptomycin, the first antibiotic to offer hope to patients with tuberculosis (TB). This antibiotic is still used today in the treatment of TB.
After clinical use in tuberculosis patients, it was soon realized that streptomycin caused side effects not seen with penicillin, including kidney damage and deafness. However, the main problem encountered in the use of streptomycin, and the one that restricted its effectiveness, was resistance. The speed at which bacteria were able to develop resistance to the drug was a surprise to Waksman and his coworkers. Because of this, they were prompted to search for other antibiotics. This search resulted in the development of neomycin, a drug commonly used in antibacterial ointments today.

In 1947, the antibiotic chloramphenicol was used in a clinical trial to treat an epidemic of typhus in Bolivia. Its success in curbing the epidemic led to its use on the other side of the world-treating scrub typhus in Malaysia.
In the Bolivian epidemic, all twenty-two patients who received chloramphenicol recovered. Of the fifty patients for whom the antibiotic was unavailable, fourteen died. The trial in Bolivia is not the only South American link with this antibiotic. Chloramphenicol was first isolated from a soil sample in Caracas, Venezuela, a discovery that was important in two ways. First, it identified a new antibiotic substance; second, as the clinical trial showed, chloramphenicol could cure previously untreatable diseases, such as typhus. Later, this same antibiotic showed remarkable results in the treatment of typhoid fever. At last scientists were finding effective substances that could treat serious infections.
The euphoria surrounding the discovery of chloramphenicol was dampened somewhat when it was shown to cause serious side effects. By 1950, many investigators had become alarmed by the mounting evidence linking it with serious blood disorders, including anemia and leukemia.
Today, the use of chloramphenicol is limited in developed countries, where more expensive but safer drugs are available. In developing countries, however, it is still widely used because it is so inexpensive to produce. It is used mainly to treat typhus, typhoid fever, meningitis, and brucellosis, but it can also be used for other infections. You may have used it yourself-in ear drops or eye drops.

In the mid-1940s, Giuseppe Brotzu, rector of the University of Cagliari in Sardinia, isolated an antibiotic-like substance from a mold. He conducted clinical trials with the substance (albeit in an impure form) and achieved very good results, particularly in the treatment of staphylococcal infections and in typhoid fever.
Brotzu published his results in 1948, and his work came to the attention of Florey's research group in Oxford. When they obtained samples of the fungus, they were able to isolate and purify several penicillin-like antibiotics. These were called cephalosporins. The cephalosporins are very effective in treating a wide range of bacterial infections. They destroy bacteria in a manner similar to penicillin and are valuable alternatives, especially where resistance to penicillin is a problem. The added advantage is that they have very low toxicity, although allergic reactions develop in about 5 percent of patients.
Modifications of the basic cephalosporin chemical structure led to the development of a whole range of these antibiotics for clinical use. Research into the development of new cephalosporins continues today.

In 1947, chlortetracycline was isolated from a Missouri River mud sample by Benjamin M. Duggar. Chlortetracycline was the first tetracycline, but Duggar's discovery has led to the isolation and subsequent development of a large number of very powerful antibiotics, which now rank second only to the penicillins in their use worldwide.
Because they are active against a broad range of bacteria and are relatively inexpensive to produce, the tetracyclines quickly gained favor and are now used to treat a long list of infections.
The extensive research done on the tetracyclines has shown them to be effective. However, they are also known to cause a number of toxic side effects. The tetracyclines form calcium complexes in growing bone, which may lead to lifelong discoloration and enamel defects in teeth, as well as reduced bone growth. Tetracyclines also cross the placenta and have a greater toxicity in the fetus. As a result of these side effects, they are prohibited in the treatment of infections in pregnant women and in children below the age of seven, as they may inhibit small children's growth.
Other toxic effects include overgrowth of the Candida spp. and Staphylococcus spp. bacteria in the bowel, leading to chronic infections with these organisms. Liver and kidney damage may also occur in some patients, as may allergic reactions such as hives, skin rash, asthma, and contact dermatitis.
Because the tetracycline antibiotics form complexes with calcium, magnesium, and iron, they should not be taken with dairy products or any mineral and vitamin supplements containing calcium, magnesium, or iron.

Further research took place during the 1960s, which led to the development of the second generation of antibiotics. Among these was methicillin, a semi-synthetic derivative of penicillin produced specifically to overcome the problem of penicillin resistance. Methicillin was hailed as a major breakthrough in the fight against bacterial resistance to penicillin, and scientists believed that they could now win this battle. Unfortunately, bacteria had the last word, and we now have bacteria that are resistant to methicillin.
Ampicillin is also a derivative of penicillin. It was developed to broaden the range of infections that penicillin could treat and has now replaced penicillin to a great extent. It is often the first choice in the treatment of a whole range of infections, including respiratory and urinary tract infections.
Amoxicillin is another widely used penicillin derivative. Like ampicillin, it has a broad range of activity, as it can treat both Gram-positive bacteria (those bacteria that retain the violet stain in a process called Gram's method or Gram's stain, used to classify bacteria-e.g., Streptococcus spp. and Staphylococcus spp.) and Gram-negative bacteria (those bacteria that do not retain the violet stain used in Gram's method-e.g,. E. coli and Haemophilus influenzae).
Gentamicin is in the same family of antibiotics as streptomycin (the anti- TB drug discovered in 1943). It is generally reserved for serious infections, as it can have severe toxic side effects on the ears and kidneys.

Recently, a new family of antibiotics called the fluoroquinolones has been developed by pharmaceutical laboratories. In addition to being effective against a broad range of bacteria, these antibiotics can reach a high concentration in the bloodstream when taken orally. This means that many more infections that may once have required a hospital stay can now be treated at home.
The fluoroquinolones are often used for cases in which long courses of antibiotics (weeks to months) are required. A whole range is now available, and are proving effective against bacteria that were once difficult to treat, such as the leprosy bacteria.

The future

The search for new and more effective drugs, which began with Florey, Chain, and Waksman, continues today. The pace, however, has slowed remarkably, as it is now much more difficult for pharmaceutical companies to get approval for new drugs. The time delay between the discovery of an antibiotic in the laboratory and the approval to produce it commercially is so great that it has led some companies to abandon the marketplace completely. Companies involved in the search for new antibiotics are also finding it increasingly difficult to keep up with the pace at which bacterial resistance renders their findings useless.

Comments