Penicillins

Definition

Penicillins are a group of closely related antibiotics that kill bacteria.

Description

There are several types of penicillins, each used to treat different kinds of infections, such as skin infections, dental infections, ear infections, respiratory tract infections, urinary tract infections, gonorrhea, and other infections caused by bacteria. These drugs will not work for olds, flu, and other infections caused by viruses.

Examples of penicillins are penicillin V (Beepen-VK, Pen-Vee K, V-cillin K, Veetids) and amoxicillin (Amoxil, Polymox, Trimox, Wymox). Penicillins are sometimes combined with other ingredients called beta-lactamase inhibitors, which protect the penicillin from bacterial enzymes that may destroy it before it can do its work. The drug Augmentin, for example, contains a combination of amoxicillin and a beta-lactamase inhibitor, clavulanic acid. Penicillins are available only with a prescription.

The original form of penicillin is called penicillin G. It is a narrow-spectrum antibiotic, which can be destroyed by stomach acid, but it is still useful against anaerobic bacteria (bacteria that can live in the absence of air). Newer penicillins are resistant to stomach acid, such as penicillin V, or have a broader spectrum, such as ampicillin and amoxicillin.

General use

Penicillins are useful against infections in many parts of the body, including the mouth and throat, skin and soft tissue, tonsils, heart, lungs, and ears. However, since many bacteria are resistant to penicillin, it is often wise to do a culture and sensitivity test before using penicillins. In some cases, there are only a few types of bacteria that are likely to be a problem, and so it is appropriate to use a penicillin without testing. For example, dentists often prescribe penicillin to prevent infections after dental surgery.

Precautions

Penicillins are usually very safe. The greatest risk is an allergic reaction, which can be severe. People who have been allergic to cephalosporins are likely to be allergic to penicillins. Moreover, people with certain medical conditions or who are taking certain other medicines can have problems if they take penicillins. Before taking these drugs, patients should be sure to let the physician know about any of the following conditions.

Low-sodium diet

Some penicillin medicines contain large enough amounts of sodium to cause problems for people on low-sodium diets. Parents of children on on such a diet should make sure that the physician treating the infection knows about the special diet.

Diabetes

Penicillins may cause false positive results on urine sugar tests for diabetes. People with diabetes should check with their physicians to see if they need to change their diet or the doses of their diabetes medicine.

Phenylketonuria

Some formulations of Augmentin contain phenylalanine. People with phenylketonuria (PKU) should consult a physician before taking this medicine.

Side effects

The most common side effect of penicillin is diarrhea . Nausea , vomiting , and upset stomach are also common. With some penicillins, particularly the broad spectrum products, there is a risk of increased growth of organisms that are not affected by penicillin. This situation can lead to candidal infections of the mouth and vagina.

Most side effects of penicillin cannot be prevented. Amoxicillin has a lower incidence of diarrhea than ampicillin and is the preferred drug in most cases.

Interactions

Birth control pills may not work properly when taken at the same time as penicillin. Penicillins may also interact with many other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. People who take penicillin should let their physician know all other medicines they are taking. Among the drugs that may interact with penicillins are the following:

• acetaminophen (Tylenol) and other medicines that relieve pain and inflammation
• medicine for overactive thyroid
• other antibiotics
• blood thinners
• antiseizure medicines such as Depakote and Depakene
• blood pressure drugs such as Capoten, Monopril, and Lotensin

The list above does not include every drug that may interact with penicillins. A physician or pharmacist should be consulted before a patient combines penicillins with any other prescription or nonprescription (over-the-counter) medicine.

Parental concerns

Parents should verify that their children have an infection requiring antibiotic therapy. Unnecessary use of antibiotics leads to development of bacterial resistance, while it subjects the child to some needless risk of adverse effects and wastes money.

Liquid forms of penicillin should be refrigerated after reconstitution. These preparations must be shaken well before use and measured with a medicinal teaspoon, not a household teaspoon.

Any adverse effects should be discussed with the prescriber. Penicillin should not be used in patients allergic to the drug; however, an incorrect report of an allergy to penicillin may cause prescribers to select a different drug which may cause even more severe side effects.

Penicillins should be administered exactly as directed. Users should never give larger, smaller, more frequent, or less frequent doses. To make sure the infection clears up completely, patients should take the medicine for as long as it has been prescribed. They should not stop taking the drug just because symptoms begin to improve. This point is important with all types of infections, but it is especially important with strep infections, which can lead to serious heart problems if they are not cleared up completely.

This medicine should be used only for the infection for which it was prescribed. Different kinds of penicillins cannot be substituted for one another. Do not save some of the medicine to use on future infections. It may not be the right treatment for other kinds of infections, even if the symptoms are the same.

KEY TERMS

Anaerobic —An organism that grows and thrives in an oxygen-free environment.

Beta-lactamase —An enzyme produced by some bacteria that destroys penicillins.

Broad spectrum —A term applied to antibiotics to indicate that they are effective against many different types of bacteria.

Enzyme —A protein that catalyzes a biochemical reaction without changing its own structure or function.

Microorganism —An organism that is too small to be seen with the naked eye, such as a bacterium, virus, or fungus.

Mononucleosis —An infection, caused by the Epstein-Barr virus, that causes swelling of lymph nodes, spleen, and liver, usually accompanied by extremely sore throat, fever, headache, and intense long-lasting fatigue. Also called infectious mononucleosis.

Resources

BOOKS

Beers, Mark. H., and Robert Berkow, eds. The Merck Manual, 2nd home ed. West Point, PA: Merck & Co., 2004.

Mcevoy, Gerald K., et al. AHFS Drug Information 2004. Bethesda, MD: American Society of Healthsystems Pharmacists, 2004.

Siberry, George K., and Robert Iannone, eds. The Harriet Lane Handbook, 15th ed. Philadelphia, PA: Mosby Publishing, 2000.

PERIODICALS

Apter Andrea J., et al. "Represcription of penicillin after allergic-like events." Journal of Allergy and Clinical Immunology 113, no. 4 (April 2004): 764–770.

ORGANIZATIONS

American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007–1098. Web site: <www.aap.org>.

Centers for Disease Control. 200 Independence Avenue, SW, Washington, DC, 20201. Web site: <www.cdc.gov>.

WEB SITES

"Penicillins (Systemic)." Available online at <www.nlm.nih.gov/medlineplus/druginfo/uspdi/202446.html> (accessed September 29, 2004).

"Treat Sore Throat without Penicillin." Available online at <www.medicinenet.com/script/main/art.asp?articlekey=25627> (accessed September 29, 2004).

Nancy Ross-Flanigan Samuel Uretsky, PharmD

Penicillin

One of the major advances of twentieth-century medicine was the discovery of penicillin. Penicillin is a member of the class of drugs known as antibiotics . These drugs either kill (bacteriocidal) or arrest the growth of (bacteriostatic) bacteria and fungi (yeast ), as well as several other classes of infectious organisms. Antibiotics are ineffective against viruses . Prior to the advent of penicillin, bacterial infections such as pneumonia and sepsis (overwhelming infection of the blood) were usually fatal. Once the use of penicillin became widespread, fatality rates from pneumonia dropped precipitously.

The discovery of penicillin marked the beginning of a new era in the fight against disease. Scientists had known since the mid-nineteenth century that bacteria were responsible for some infectious diseases, but were virtually helpless to stop them. Then, in 1928, Alexander Fleming (1881–1955), a Scottish bacteriologist working at St. Mary's Hospital in London, stumbled onto a powerful new weapon.

Fleming's research centered on the bacteria Staphylococcus, a class of bacteria that caused infections such as pneumonia, abscesses, post-operative wound infections, and sepsis. In order to study these bacteria, Fleming grew them in his laboratory in glass Petri dishes on a substance called agar . In August, 1928 he noticed that some of the Petri dishes in which the bacteria were growing had become contaminated with mold , which he later identified as belonging to the Penicillum family.

Fleming noted that bacteria in the vicinity of the mold had died. Exploring further, Fleming found that the mold killed several, but not all, types of bacteria. He also found that an extract from the mold did not damage healthy tissue in animals. However, growing the mold and collecting even tiny amounts of the active ingredient—penicillin—was extremely difficult. Fleming did, however, publish his results in the medical literature in 1928.

Ten years later, other researchers picked up where Fleming had left off. Working in Oxford, England, a team led by Howard Florey (1898–1968), an Australian, and Ernst Chain, a refugee from Nazi Germany, came across Fleming's study and confirmed his findings in their laboratory. They also had problems growing the mold and found it very difficult to isolate the active ingredient

Another researcher on their team, Norman Heatley, developed better production techniques, and the team was able to produce enough penicillin to conduct tests in humans. In 1941, the team announced that penicillin could combat disease in humans. Unfortunately, producing penicillin was still a cumbersome process and supplies of the new drug were extremely limited. Working in the United States, Heatley and other scientists improved production and began making large quantities of the drug. Owing to this success, penicillin was available to treat wounded soldiers by the latter part of World War II. Fleming, Florey, and Chain were awarded the Noble Prize in medicine. Heatley received an honorary M.D. from Oxford University in 1990.

Penicillin's mode of action is to block the construction of cell walls in certain bacteria. The bacteria must be reproducing for penicillin to work, thus there is always some lag time between dosage and response.

The mechanism of action of penicillin at the molecular level is still not completely understood. It is known that the initial step is the binding of penicillin to penicillin-binding proteins (PBPs), which are located in the cell wall. Some PBPs are inhibitors of cell autolytic enzymes that literally eat the cell wall and are most likely necessary during cell division. Other PBPs are enzymes that are involved in the final step of cell wall synthesis called transpeptidation. These latter enzymes are outside the cell membrane and link cell wall components together by joining glycopeptide polymers together to form peptidoglycan . The bacterial cell wall owes its strength to layers composed of peptidoglycan (also known as murein or mucopeptide). Peptidoglycan is a complex polymer composed of alternating N-acetylglucosamine and N-acetylmuramic acid as a backbone off of which a set of identical tetrapeptide side chains branch from the N-acetylmuramic acids, and a set of identical peptide cross-bridges also branch. The tetrapeptide side chains and the cross-bridges vary from species to species, but the backbone is the same in all bacterial species.

Each peptidoglycan layer of the cell wall is actually a giant polymer molecule because all peptidoglycan chains are cross-linked. In gram-positive bacteria there may be as many as 40 sheets of peptidoglycan, making up to 50% of the cell wall material. In Gram-negative bacteria, there are only one or two sheets (about 5–10% of the cell wall material). In general, penicillin G, or the penicillin that Fleming discovered, has high activity against Gram-positive bacteria and low activity against Gram-negative bacteria (with some exceptions).

Penicillin acts by inhibiting peptidoglycan synthesis by blocking the final transpeptidation step in the synthesis of peptidoglycan. It also removes the inactivator of the inhibitor of autolytic enzymes, and the autolytic enzymes then lyses the cell wall, and the bacterium ruptures. This latter is the final bacteriocidal event.

Since the 1940s, many other antibiotics have been developed. Some of these are based on the molecular structure of penicillin; others are completely unrelated. At one time, scientists assumed that bacterial infections were conquered by the development of antibiotics. However, in the late twentieth century, bacterial resistance to antibiotics—including penicillin—was recognized as a potential threat to this success. A classic example is the Staphylococcus bacteria, the very species Fleming had found killed by penicillin on his Petri dishes. By 1999, a large percentage of Staphylococcus bacteria were resistant to penicillin G. Continuing research so far has been able to keep pace with emerging resistant strains of bacteria. Scientists and physicians must be judicious about the use of antibiotics, however, in order to minimize bacterial resistance and ensure that antibiotics such as penicillin remain effective agents for treatment of bacterial infections.

See also Antibiotic resistance, tests for; Bacteria and bacterial infection; Bacterial adaptation; Bacterial growth and division; Bacterial membranes and cell wall; History of the development of antibiotics

Penicillins

Definition

Penicillins are medicines that kill bacteria or prevent their growth.

Purpose

Penicillins are antibiotics (medicines used to treat infections caused by microorganisms). There are several types of penicillins, each used to treat different kinds of infections, such as skin infections, dental infections, ear infections, respiratory tract infections, urinary tract infections, gonorrhea, and other infections caused by bacteria. These drugs will not work for colds, flu, and other infections caused by viruses.

Description

Examples of penicillins are penicillin V (Beepen-VK, Pen-Vee K, V-cillin K, Veetids) and amoxicillin (Amoxil, Polymox, Trimox, Wymox). Penicillins are sometimes combined with other ingredients called beta-lactamase inhibitors, which protect the penicillin from bacterial enzymes that may destroy it before it can do its work. The drug Augmentin, for example, contains a combination of amoxicillin and a betalactamase inhibitor, clavulanic acid.

Penicillins are available only with a physician's prescription. They are sold in capsule, tablet (regular and chewable), liquid, and injectable forms.

Recommended dosage

The recommended dosage depends on the type of penicillin, the strength of the medicine, and the medical problem for which it is being taken. Check with the physician who prescribed the drug or the pharmacist who filled the prescription for the correct dosage.

Always take penicillins exactly as directed. Never take larger, smaller, more frequent, or less frequent doses. To make sure the infection clears up completely, take the medicine for as long as it has been prescribed. Do not stop taking the drug just because symptoms begin to improve. This is important with all types of infections, but it is especially important with "strep" infections, which can lead to serious heart problems if they are not cleared up completely.

Take this medicine only for the infection for which it was prescribed. Different kinds of penicillins cannot be substituted for one another. Do not save some of the medicine to use on future infections. It may not be the right treatment for other kinds of infections, even if the symptoms are the same.

Penicillins work best when they are at constant levels in the blood. To help keep levels constant, take the medicine in doses spaced evenly through the day and night. Do not miss any doses.

Some penicillins, notably penicillin V, should be taken on an empty stomach, but others may be taken with food. Check package directions or ask the physician or pharmacist for instructions on how to take the medicine.

Precautions

Symptoms should begin to improve within a few days of beginning to take this medicine. If they do not, or if they get worse, check with the physician who prescribed the medicine.

Penicillins may cause diarrhea. Certain diarrhea medicines may make the problem worse. Check with a physician before using any diarrhea medicine to treat diarrhea caused by taking penicillin. If diarrhea is severe, check with a physician as soon as possible. This could be a sign of a serious side effect.

Penicillins may change the results of some medical tests. Before having medical tests, patients who are taking penicillin should be sure to let the physician in charge know that they are taking this medicine.

Special conditions

People with certain medical conditions or who are taking certain other medicines can have problems if they take penicillins. Before taking these drugs, be sure to let the physician know about any of these conditions:

ALLERGIES. People who have hay fever, asthma, eczema, or other general allergies (or who have had such allergies in the past) may be more likely to have severe reactions to penicillins. They should be sure their health care provider knows about their allergies.

Anyone who has had unusual reactions to penicillins or cephalosporins in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

LOW-SODIUM DIET. Some penicillin medicines contain large enough amounts of sodium to cause problems for people on low-sodium diets. Anyone on such a diet should make sure that the physician treating the infection knows about the special diet.

DIABETES. Penicillins may cause false positive results on urine sugar tests for diabetes. People with diabetes should check with their physicians to see if they need to change their diet or the doses of their diabetes medicine.

PHENYLKETONURIA. Some formulations of Augmentin contain phenylalanine. People with phenylketonuria (PKU) should consult a physician before taking this medicine.

OTHER MEDICAL CONDITIONS. Before using penicillins, people with any of these medical problems should make sure their physicians are aware of their conditions:

• bleeding problems
• congestive heart failure
• cystic fibrosis
• kidney disease
• mononucleosis ("mono")
• stomach or intestinal problems, especially ulcerative colitis

USE OF CERTAIN MEDICINES. Taking penicillins with certain other drugs may affect the way the drugs work or may increase the chance of side effects.

Side effects

The most common side effects are mild diarrhea, headache, vaginal itching and discharge, sore mouth or tongue, or white patches in the mouth or on the tongue. These problems usually go away as the body adjusts to the drug and do not require medical treatment unless they continue or they are bothersome.

More serious side effects are not common, but may occur. If any of the following side effects occur, get emergency medical help immediately:

• breathing problems, such as shortness of breath or fast or irregular breathing
• fever
• sudden lightheadedness or faintness
• joint pain
• skin rash, hives, itching, or red, scaly skin
• swelling or puffiness in the face

Other rare side effects may occur. Anyone who has unusual symptoms after taking penicillin should get in touch with his or her physician.

Interactions

Birth control pills may not work properly when taken at the same time as penicillin. To prevent pregnancy, use additional methods of birth control while taking penicillin, such as latex condoms or spermicide.

Penicillins may interact with many other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Anyone who takes penicillin should let the physician know all other medicines he or she is taking. Among the drugs that may interact with penicillins are:

• Acetaminophen (Tylenol) and other medicines that relieve pain and inflammation
• medicine for overactive thyroid
• male hormones (androgens)
• female hormones (estrogens)
• other antibiotics
• blood thinners
• Disulfiram (Antabuse), used to treat alcohol abuse
• antiseizure medicines such as Depakote and Depakene
• blood pressure drugs such as Capoten, Monopril, and Lotensin

KEY TERMS

Enzyme— A type of protein that brings about or speeds up chemical reactions.

Microorganism— An organism that is too small to be seen with the naked eye.

Mononucleosis— An infectious disease with symptoms that include severe fatigue, fever, sore throat, and swollen lymph nodes in the neck and armpits. Also called "mono."

The list above does not include every drug that may interact with penicillins. Be sure to check with a physician or pharmacist before combining penicillins with any other prescription or nonprescription (over-the-counter) medicine.

Penicillin

OVERVIEW

The penicillins (pen-uh-SILL-ins) are a class of antibiotic compounds derived from the molds Penicillium notatum and Penicillium chrysogenum. The class contains a number of compounds with the same basic bicyclic structure to which are attached different side chains. That basic structure consists of two amino acids, cysteine and valine, joined to each other to make a bicyclic ("two-ring") compound. The different forms of penicillin are distinguished from each other by adding a single capital letter to their names. Thus: penicillin F, penicillin G, penicillin K, penicillin N, penicillin O, penicillin S, penicillin V, and penicillin X. A number of other antibiotics, including ampicillin, amoxicillin, and methicillin, have similar chemical structures.

KEY FACTS

OTHER NAMES:

Not applicable; see Overview

FORMULA:

(CH₃)₂C₅H₃NSO(COOH)NHCOR, where R represents any one of a number of substituted groups; see Overview

ELEMENTS:

Carbon, hydrogen, oxygen, nitrogen, sulfur

COMPOUND TYPE:

Bicyclic acid (organic)

STATE:

Solid

MOLECULAR WEIGHT:

Varies; see Overview g/mol

MELTING POINT:

Varies; see Overview

BOILING POINT:

Not applicable; all forms decompose when heated above their melting points

SOLUBILITY:

Slightly soluble in water; soluble in ethyl alcohol, ether, chloroform and most organic solvents

Penicillin was discovered accidentally in 1928 by the Scottish bacteriologist Alexander Fleming (1881–1995). Fleming noticed that a green mold, which he later identified as Penicillium notatum, had started to grow on a petri dish that he had coated with bacteria. As the bacteria grew towards the mold, they began to die. At first, Fleming saw some promise in this observation. Perhaps the mold could be used to kill the bacteria that cause human disease. His experiments showed, however, that the mold's potency declined after a short period of time He was also unable to isolate the antibacterial chemical produced by the mold. He decided that further research on Penicillium was probably not worthwhile.

As a result, it was not until a decade later that Penicillium's promise was realized. In 1935, English pathologist Howard Florey (1898–1968) and his biochemist colleague Ernst Chain (1906–1970) came across Fleming's description of his experiment and decided to see if they could isolate the chemical product produced by Penicillium with anti-bacterial action. They were eventually successful, isolating and purifying a compound with anti-bacterial action, and, in 1941, began trials with human subjects to test its safety and efficacy (ability to kill bacteria). The successful conclusion of those trials not only provided one of the great breakthroughs in the human battle against infectious diseases, but also won for Florey, Chain, and Fleming the 1945 Nobel prize for Physiology or Medicine.

HOW IT IS MADE

Penicillins are classified as biosynthetic or semi-synthetic. Biosynthetic penicillin is natural penicillin. It is produced by culturing molds in large vats and collecting and purifying the penicillins they produce naturally. There are six naturally occurring penicillins. The specific form of penicillin produced in a culturing vat depends on the nutrients provided to the molds. Of the six natural penicillins, only penicillin G (benzylpenicillin) is still used to any extent.

Semi-synthetic penicillins are produced by making chemical alterations in the structure of a naturally occurring penicillin. For example, penicillin V is made by replacing the -CH₂C₆H₅ group in natural penicillin G with a -CH₂OC₆H₅ group.

COMMON USES AND POTENTIAL HAZARDS

Penicillins are prescription medications used to treat a variety of bacterial infections, including meningitis, syphilis, sore throats, and ear aches. They do so by inactivating an enzyme used in the formation of bacterial cell walls. With the enzyme inactivated, bacteria can not make cell walls and die off. Penicillins do not act on viruses in the same way they do on bacteria, so they are not effective against viral diseases, such as the flu or the common cold.

Interesting Facts

• The discovery of penicillin's antibacterial action came at just the right time: the onset of World War II. The new drug made possible the saving of untold numbers of lives. As just one example, about three-quarters of all soldiers who developed bone infections as a result of wounds suffered in World War I died of those infections. By contrast, no more than about 5 percent of those who developed similar infections in World War II died. The availability of penicillin to treat those wounds in World War II made the difference in those survival rates.

A number of side effects are related to the use of penicillin. These side effects include diarrhea, upset stomach, and vaginal yeast infections. In those individuals who are allergic to penicillins, side effects are far more serious and include rash, hives, swelling of tissues, breathing problems, and anaphylactic shock, a life-threatening condition that requires immediate medical treatment.

Penicillin may alter the results of some medical tests, such as those for the presence of sugar in the urine. Penicillin can also interact with a number of other medications, including blood thinners, thyroid drugs, blood pressure drugs, birth control pills, and other antibiotics, in some cases decreasing their effectiveness.

Once promoted as wonder drugs, the use of penicillins has declined slowly because of the spread of antibiotic resistance. Antibiotic resistance occurs when new strains of bacteria evolve that are resistant to existing types of penicillin. One reason that antibiotic resistance has become a problem is the extensive and often unnecessary use of penicillins. When they are prescribed for colds and the flu, for example, they have no effect on the viruses that cause those diseases, but they encourage the growth of bacteria more able to survive against penicillins.

Words to Know

BICYCLIC

Refers to a molecule in which the atoms are arranged so as to look like two rings.

BIOSYNTHETIC

Natural; made from a living organism.

SEMI-SYNTHETIC

Produced by making chemical alterations in the structure of a naturally occurring organism.

FOR FURTHER INFORMATION

"β-Lactam Antibiotics: Penicillins." The Merck Manual of Diagnosis and Therapy. Chapter 153. Available online at http://www.merck.com/mrkshared/mmanual/section13/chapter153/153b.jsp (accessed on October 23, 2005).

Chain, E. B. "The Chemical Structure of the Penicillins." Nobel Lecture, March 20, 1945. Available online at http://nobelprize.org/medicine/laureates/1945/chain-lecture.pdf (accessed on October 23, 2005).

Moore, Greogry A., and Ollie Nygren. "Penicillins." The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals. http://ebib.arbetslivsinstitutet.se/ah/2004/ah2004_06.pdf (accessed on October 23, 2005).

Ross-Flanigan, Nancy. "Penicillins." Gale Encyclopedia of Medicine. Edited by Jacqueline L. Longe and Deidre S. Blanchfield. 2nd ed. Detroit, MI: Gale, 2002.

"Tom Volk's Fungus of the Month for November 2003." http://botit.botany.wisc.edu/toms_fungi/nov2003.html (accessed on October 23, 2005).

PENICILLIN.

In the second half of the twentieth century penicillin was the best known of a new class of drugs—antibiotics—that revolutionized the treatment of communicable diseases and allowed doctors to rapidly cure a large number of bacterial infections. Beyond its role as a specific therapy, penicillin, often referred to as the "Wonder Drug," initiated a transformation in the pharmaceutical industry and was the principal symbol of medical progress for a generation.

The word penicillin was coined by the Scots scientist Alexander Fleming (1881–1955) in 1929 for the substance produced by the mold Penicillium that he found to be active against certain disease-causing bacteria. Fleming, like other before him, notably C. G. Paine (1905–?) in Sheffield, England, tried to use the substance therapeutically but had little success and did not pursue the possibility. However, its potential was explored again in the late 1930s by Howard Florey (1898–1968) and Ernst Chain (1906–1979) at Oxford, who were researching naturally occurring antibacterial substances. With the help of Norman Heatley (1911–2004), they improved the purity and hence the activity of extracts from the mold. Penicillin was first tested successfully on mice in the May 1940.

The Oxford group treated their first patient on 12 February 1941, a policeman who was close to death due to an infection. His condition improved while he was being administered penicillin, but he died when supplies ran out. However, other successful cases followed and from the summer of 1941 the Oxford group began working with British companies to develop large-scale production. At this point in World War II, with British industry stretched and suffering regular bombing raids, such opportunities were limited, so Florey approached the United States government for assistance in production. He was referred to the U.S. Department of Agriculture and in turn to the Northern Regional Research Laboratory at Peoria, Illinois. Scientists there had the necessary expertise in fungal fermentation and introduced a number of crucial process innovations that enabled high-volume, high-quality production of pure penicillin. This enabled further clinical trials, all of which showed that penicillin had great advantages over the limited number of existing antibacterial drugs, being less toxic and curing a wider range of infections.

Penicillin was soon being trumpeted as a major boon to the war effort, helping save the lives of combatants and civilians, especially those with wound infections and burns, and as yet another example of the contribution of science to social progress. In 1943 the U.S. government increased the priority given to penicillin, so by the end of the war it was being produced by many companies across the United States and to a lesser extent in Britain. Fleming became something of a celebrity and for a while the role played by Florey, Chain, Heatley, and the Peoria scientists who were all still actively at work on penicillin was eclipsed; however, in 1945 Florey, Chain, and Fleming were jointly awarded the Nobel Prize for Medicine.

In the late 1940s and early 1950s penicillin continued to enjoy a reputation as the "Wonder Drug," with demand outstripping supply. Penicillin had a major impact in saving lives and reducing suffering, and it transformed the image of the doctor from someone who helped patients manage their illnesses to someone who could cure disease. It also reduced the length of stay of surgical and infectious disease patients in hospitals, as secondary infections could be better controlled, although its use in general practice was limited by the fact that administration was by injection. While penicillin enjoyed an almost wholly positive public image, doctors and pharmaceutical companies were aware of two problems: first, penicillin-resistant bacteria, and, second, allergic reactions to the drug. The former had been known about since 1942, but the numbers of bacteria with this property increased with the rapid diffusion of penicillin and were common in hospitals in the 1950s. This led doctors to return to more traditional antiseptic and aseptic techniques and to look to new antibiotics being produced by the pharmaceutical industry. Allergies to penicillin can cause death and were more common in the 1950s, when high doses were used, than they are in the early twenty-first century. Although deaths were relatively rare, they often received wide publicity and, along with greater awareness of bacterial resistance, led to growing anxieties that penicillin might not be that wonderful after all. On balance, public confidence in the drug was not dented, as it was the experience of both patients and doctors that the benefits easily outweighed the risks. Indeed, it seems that penicillin was overused, with many doctors prescribing it for all infections, including viral infections (against which it is ineffective), on the grounds that it might prevent secondary bacterial infections. Another factor is that doctors were under pressure from patients who were unaware of the limitations and problems of the "Wonder Drug."

In the postwar period the huge market for penicillin and the problems with bacterial resistance led pharmaceutical companies to search for other naturally occurring antibiotics. The most important of these was streptomycin, introduced in 1946 as a treatment for tuberculosis, the most serious bacterial infection against which penicillin was ineffective. Scientists also found new penicillins produced by the various species of the Penicillium mold. Research in the 1950s concentrated on refining dosage recommendations and improving methods of administration—the first oral penicillins were introduced in 1954. In the late 1950s, research and development focused on semisynthetic and synthetic penicillins, with scientists offering improvements in administration and effectiveness. The range of new penicillins enabled doctors to keep ahead of bacterial resistance to antibiotics, but this has proved something of a treadmill and over time other drugs have replaced penicillins in the fight against resistant bacteria. However, for many common bacterial infections penicillin-based antibiotics remain the drug of choice at the start of the twenty-first century and continue to be a potent symbol of medical advance.

See alsoPublic Health; Science.

BIBLIOGRAPHY

Masters, David. Miracle Drug: The Inner History of Penicillin. London, 1946. The first detailed account of the development of penicillin.

Wainwright, Milton. Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics. Oxford, U.K., 1990. A detailed study of the development of penicillin and the issues around its development.

Weatherall, Miles. In Search of a Cure: A History of Pharmaceutical Discovery. Oxford, U.K., 1990. Places the history of penicillin in the context of wider developments in pharmaceuticals.

Michael Worboys