Antibiotic

The production of antibiotics has become a multibillion-dollar industry that continues to grow each year.

An antibiotic is a chemical substance made by a living microorganism (a living thing that is so small it can only be seen through a microscope), such as a fungus or mold, that is harmful to another microorganism that causes diseases. An antibiotic drug can stop the growth of harmful bacteria and other microorganisms, or destroy them. More than ten thousand antibiotic substances have been found. Scientists can also make antibiotics synthetically (artificially) from chemicals or from a combination of chemicals and natural substances (semisynthetic drugs). The production of antibiotics has become a multibillion-dollar industry that continues to grow each year.

Over 2,500 years old

Although the process by which antibiotics fight disease-causing bacteria was not discovered until the twentieth century, the Chinese had used antibiotics about 2,500 years ago. They discovered that applying the moldy curd of soybeans to the body could heal certain infections (conditions resulting from the body's invasion by disease-causing microorganisms).

Other cultures are also known to have used antibiotic-type substances to cure illnesses. The Sudanese-Nubian civilization used a type of tetracycline antibiotic as early as 350 c.e. (common era). In Europe during the Middle Ages (476–1453), crude plant extracts and cheese curds were used to fight infections.

Modern antibiotics

Modern antibiotics resulted from the work of several individuals who demonstrated that materials derived from certain microorganisms could be used to cure infectious diseases. In 1877, French chemist and microbiologist Louis Pasteur (1822–1895) discovered that disease-causing anthrax bacteria could be prevented from multiplying by Saprophyte bacteria living on dead and decaying organisms. Anthrax, a disease that dates back to biblical times, can be fatal, sometimes affecting a large number of animals. The disease also affects humans.

The first miracle drug

In 1928, Scottish bacteriologist Alexander Fleming (1881–1955) made one of the most important contributions to the field of antibiotics. While culturing (growing) Staphyloccus bacteria in a laboratory dish, Fleming made a remarkable discovery. He found that mold, which had grown on some bacteria, prevented their growth. Upon further investigation, Fleming found that a substance in the mold Penicillium notatum could destroy many disease-producing bacteria without harming healthy body cells.

However, Fleming was unable to develop penicillin for medical use. It was not until 1941 that Ernst Chain (1906–1979) and Howard Florey (1898–1968), continuing Fleming's work, developed the drug penicillin. Penicillin was later called the "miracle drug" because of its role in saving millions of human lives. Penicillin remains one of the effective treatments for such bacterial infections as pneumonia, strep throat, and syphilis.

Other antibiotics

Since the development of penicillin, other antibiotic substances have been found. In 1939, research began on identifying possible antibiotic materials from the soil bacteria Streptomyces. In 1943, Ukrainian-born American microbiologist Selman Waksman (1888–1973) developed the drug streptomycin from soil bacteria. It was the first antibiotic found effective in treating tuberculosis.

In 1941, Waksman coined the term antibiotic—from the Greek anti, meaning against, and bios, meaning life. The term describes the drug's function of fighting bacteria either by killing them or by preventing them from multiplying.

After World War II (1939–1945), the search for molds and other soil bacteria led to the development of other antibiotics, including erythromycin and cephalosporin that can each be used in patients allergic to penicillin. Quinolone, which was developed during the 1960s, has been used in treating urinary-tract infections and infectious diarrhea. Since the 1970s, most antibiotics produced have been the synthetic types.

How antibiotics work

Antibiotics fight harmful bacteria in different ways. Some antibiotics destroy bacteria by weakening their cell walls, causing the walls to burst. Certain antibiotics damage the exterior of bacterial cells, causing the contents of the cells to leak. Still other antibiotics interfere with the bacteria's metabolism, the chemical processes in the cells needed by the bacteria to multiply and function. For example, tetracycline interferes with the production of proteins, which not only make up structural parts of the bacteria but also perform important functions.

Raw Materials

Antibiotics are produced using a fermentation process. The substances that make up the fermentation broth are the raw materials needed to manufacture antibiotics. This broth contains all the ingredients needed to promote the growth of the specific antibiotic-producing microorganisms.

The fermentation broth typically contains a carbon source, such as molasses or soy meal, which are made up of lactose and glucose. These are the food sources for the microorganisms. Ammonia is added for its nitrogen, which the organisms need for metabolism. Trace elements are added for proper growth. They include phosphorus, sulfur, magnesium, zinc, iron, and copper. Anti-foaming substances are added to prevent foaming.

The Manufacturing Process

Although most antibiotics are found in nature, they do not normally occur in the amounts necessary to produce a great quantity. For this reason, a fermentation process has been developed. It involves collecting the microorganism whose antibiotic product is desired, promoting the increase in numbers of the culture (growth of the specific microorganism in a laboratory), and separating the excreted antibiotic product from the fermentation broth.

Starting the culture

1 Before fermentation can begin, the desired antibiotic-producing organism is collected and made to multiply. This is done by producing an initial, or sample, culture. This initial culture is cultivated in a dish with agar (a gelatin-like substance that acts as an environment in which organisms grow). Then, the initial culture is transferred into shake flasks (bottle-like containers) with growth-promoting nutrients added. The starter culture is allowed to multiply some more.

CONSUMERS LACK KNOWLEDGE OF ANTIBIOTIC USE

The misuse and overuse of antibiotics have encouraged the spread of bacterial resistance to antibiotics. Patients sometimes ask their doctors to prescribe antibiotics for the common cold and flu (influenza), which are caused by viruses and cannot be cured by antibiotics. Some doctors tend to prescribe antibiotics for all kinds of symptoms. For an antibiotic to work, the patient has to take the complete prescription. It is very common for patients to stop taking the prescription once the symptoms of the illness have disappeared. Some people do not know that even if they feel better after several days of medication, some of the bacteria that cause the infection live on and continue to multiply. Stopping the medication makes the surviving bacteria resistant to the drug. If the person develops the same illness in the future and is prescribed the same antibiotic, it may not work.

A 1998 survey of the American public by the American Society of Health-System Pharmacists, Bethesda, Maryland, found that:

Over one-third of Americans surveyed said they stopped taking their complete antibiotic prescription because they started feeling better.

About 1 out of 4 people said they saved antibiotics prescribed for one illness and then took them for another illness at a later time.

More than half thought antibiotics are the best medicine for viral infections.

2 The starter culture is transferred to seed tanks for further growth. The seed tanks are steel tanks filled with all the food and nutrients the specific microorganisms need to survive and grow. These include warm water, carbohydrate foods, such as lactose or glucose sugars, and nutrients like those found in the shake flasks. The tanks also contain carbon sources, such as acetic acid, alcohols, or hydrocarbons, as well as nitrogen sources, such as ammonia salts. Air that is sterilized (germ-free) and filtered (rid of impurities) is delivered into the tank, while mixers keep the mixture moving. After about twenty-four to twenty-eight hours, the mixture is transferred to fermentation tanks.

Fermentation

3 The fermentation tank is a bigger version of the seed tank and holds about 30,000 gallons. It is filled with the same ingredients found in the seed tank to encourage further growth of the microorganisms. The tank temperature is kept between 73 to 81 degrees Fahrenheit (23 to 27.2 degrees Centigrade). The mixture is constantly stirred, and sterilized, and filtered air is continuously pumped in. For this reason, antifoaming agents are periodically added. Acids or bases are added as needed to keep a pH balance that is ideal for growth. In this environment, the microorganisms continue to grow and multiply and excrete large quantities of the desired antibiotic.

Isolation and purification

4 After three to five days, when the maximum amount of antibiotic has been produced, the process of collecting the antibiotic from the broth starts. Different purification methods are used, depending on the type of antibiotic produced.

5 For antibiotics that are water-soluble (can be dissolved in water), an ion-exchange method is used. The antibiotic is separated from the waste materials in the fermentation broth. Then, it is separated from other water-soluble materials. For antibiotics that are oil-soluble (can be dissolved in oil), a solvent-extraction method is used. The fermentation broth is treated with butyl acetate or methyl isobutyl ketone, substances that can dissolve the antibiotic. The antibiotic is then collected using chemical means. These methods produce a purified powdered form of the antibiotic, which is further converted into different product forms.

Refining

6 Antibiotics can come in different forms. They can come in solutions for intravenous (given by injection) bags or syringes (needles) and in pill or gel-capsule form. They can be in the form of powders that are added to topical ointments (creams applied to a body part).

Based on the final form of the antibiotic, different refining steps are used. For intravenous bags, the crystalline antibiotic is dissolved in a solution and put in the bag, which is then hermetically sealed (tightly sealed so that air cannot get in). For gel capsules, powdered antibiotic is put into the capsule bottom; the top half of the capsule is then put in place. For topical ointments, the antibiotic is mixed into the ointment.

7 Finally, the antibiotic products are transported to the packaging stations. The products are stacked and put in boxes. They are loaded up on trucks and transported to hospitals, pharmacies, and various distributors.

Quality Control

A germ-free environment has to be maintained throughout the manufacturing process, so that other microorganisms do not contaminate (introduce impurities to) the culture. The culture medium and all the processing equipment are steam-sterilized. Moreover, frequent checks of the condition of the culture during fermentation are conducted. The finished product is further checked for its physical and chemical properties, including pH, melting point, and moisture content.

In the United States, the Food and Drug Administration (FDA) regulates the production of antibiotics. The amount of testing depends on the type of antibiotic and how it will be used. For example, the FDA might require that, for a particular antibiotic, it has to first check each batch for effectiveness and purity before giving its approval for sale to the public.

CLEVER GENES

Bacteria that are capable of resisting the action of an antibiotic may have resistance genes that produce enzymes, or proteins that chemically change the drug or make it powerless. Some resistance genes cause bacteria to mutate (change), leading to new characteristics that the antibiotic cannot attack.

The Future

Since the earliest use of antibiotics against disease-causing bacteria, some of these harmful microorganisms have developed drug resistance so that they cannot be killed or controlled by the antibiotic. Typically, an antibiotic destroys most bacteria that are making a person ill; however, a few bacteria may manage to survive. These bacteria develop resistance genes (basic units of hereditary materials) that are passed down to their offspring or transferred to others within the same species (a group of living things that have similar characteristics). Gene exchange is a common occurrence among organisms. Experts have found that resistant bacteria tend to fight off more than one antibiotic.

A renewed interest

According to the U.S. Centers for Disease Control and Prevention (CDC), cases of antibiotic resistance are increasing. Life-threatening diseases, such as tuberculosis, are on the rise. Realizing the threat to public health, drug companies all over the world are taking up the challenge of developing new antibiotics to fight microorganisms that are resistant to antibiotics.

One area of interest is sparked by the Human Genome Project, an international research program designed to understand the genomes of humans and organisms. (The genome is the complete collection of genes passed down from generation to generation.) For example, some scientists have been able to map out the genome of the bacterium that infects the lungs of cystic fibrosis patients. This antibiotic-resistant bacterium destroys the patient's lungs, eventually causing death. By studying the genome, scientists hope to develop an antibiotic that would target some part of the bacterium, thus destroying it. Researchers continue to look for newer types of antibiotics, as well as a combination of drugs to fight resistant bacteria. Scientists are also trying to develop vaccines to prevent bacterial infections.

agar:

A gelatin-like substance in which scientists grow organisms.

bacteria:

Small, one-celled organisms that can only be seen through a microscope.

culture:

A growth of microorganisms in nutrient.

infection:

Invasion of the body by disease-causing microorganisms.

ion-exchange method:

A method of purifying a water-soluble antibiotic that is collected after fermentation. The antibiotic is first separated from the waste materials in the fermentation broth, then sent through equipment that separates other water-soluble materials from the antibiotic.

microorganism:

A living thing that is so small it can only be seen through a microscope.

nutrient:

A food substance, such as carbohydrate, protein, fat, mineral, vitamin, water, or fiber needed for growth.

organism:

Any living thing.

pH:

A number that shows the acidity or alkalinity of a chemical substance.

semisynthetic antibiotic:

An antibiotic that is made from a combination of chemicals and natural substances.

solvent-extraction:

A method of purifying an oil-soluble antibiotic that is collected after fermentation. The fermentation broth is treated with substances that can dissolve the antibiotic, and the antibiotic is collected using chemical means.

starter culture:

A small growth of microorganisms used to start a larger growth to produce antibiotics.

synthetic antibiotic:

An antibiotic that is made artificially from chemicals.

virus:

A very tiny particle than can grow inside a living cell. Viruses attack the cells of other organisms to make copies of themselves. Outside a cell, viruses are lifeless. Viruses cause such illnesses as the flu, colds, and AIDS.

For More Information

Books

Gottfried, Ted. Alexander Fleming: Discoverer of Penicillin. New York, NY: Franklin Watts, 1997.

Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Endangers TheirCurative Power. Cambridge, MA: Perseus Publishing, 2001.

Periodicals

Bren, Linda. "Antibiotic Resistance From Down on the Chicken Farm." FDA Consumer. (January-February 2001): pp. 10-11

Monroe, Judy. "Antibiotics vs. the Superbugs." Current Health 2. (October 2001): pp. 24-25.

Web Sites

"An Inside Look at FDA On-Site." Center for Drug Evaluation and Research, Food and Drug Administration.http://www.fda.gov/cder/about/whatwedo/testtube-7.pdf (accessed on July 22, 2002).