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For Question #7

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For Question #6

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Towards The Next 80 Years of Penicillin Production

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Penicillins and synthetic beta-lactam antibiotics have dramatically transformed health care and quality of life in the 80 years since Alexander Fleming's discovery of Penicillium. Large-scale production of beta-lactam antibiotics is the result of sustained industrial strain improvement, representing numerous rounds of mutagenesis and selection. Penicillin titers and productivities have increased by at least three orders...

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For Question #4

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In 1928, Alexander Fleming noted that mold belonging to the genus Penicillium inhibited the growth of bacteria. Fleming called this unknown antibacterial substance penicillin. Ten years later, a group at Oxford University began to investigate penicillin in laboratory mice. Penicillin was hailed as a miracle drug and saved countless lives in World War II.

Penicillins are antibiotics used to treat bacterial infections that are derived from the antibiotic penicillin.

Today, many derivatives of penicillin have been developed that inhibit more types of bacteria than the original life-saving drug. Penicillin itself is active against

streptococci (including Streptococcus pneumoniae),

Listeria, Neisseria gonorrhoeae,

Clostridium,

Peptococcus, and

Peptostreptococcus.

However, most staphylococci now are resistant to penicillin.
Other penicillin antibiotics are effective against

Penicillin antibiotics are used to treat many types of infections caused by susceptible bacteria. They are used to treat infections of the middle ear, sinuses, stomach and intestines, bladder, and kidney. They also are used for treating

penicillin V

penicillin G (Pfizerpen, Permapen)

amoxicillin/clavulonate (Augmentin)

ampicillin (Unasyn)

nafcillin (Nallpen)

oxacillin (Bactocill)

dicloxacillin (Dycill, Dynapen are discontinued brands in the US; generic is available)

cloxacillin (discontinued in the US)

piperacillin (Pipracil)

piperacillin/tazobactam (Zosyn)

ticarcillin (Ticar) (Discontinued in the US; ; generic is not available))

ticarcillin/clavulonate (Timentin) (Discontinued in the US and a generic is not available.)

Side effects of penicillin antibiotics include

Individuals who are allergic to the cephalosporin class of antibiotics, which are related to the penicillins, for example, cefaclor (Ceclor), cephalexin ( Keflex), and cefprozil ( Cefzil), may or may not be allergic to penicillins.

Serious but rare reactions include

Like other antibiotics, penicillin antibiotics can alter the normal bacteria in the colon and encourage overgrowth of some bacteria such as Clostridium difficile, which causes inflammation of the colon (C. difficile colitis or pseudomembranous colitis).

Signs and symptoms of C. difficile colitis include

Penicillin antibiotics have few important drug interactions.

Probenecid (Benemid) causes an increase in the amount of penicillins in the body by preventing excretion of penicillin by the kidneys.

Combining ampicillin with allopurinol (Zyloprim) can increase the incidence of drug-relatedskin rash.

Penicillin antibiotics may reduce the effect of BCG live vaccine and typhoid live vaccine.

Penicillin antibiotics are available as

tablets,

capsules,

powder for oral suspension, and

powder for injection.

Penicillin antibiotics are considered safe to use during pregnancy.

Although small amounts of penicillins pass into breast milk they are considered safe to use while breastfeeding.

Penicillin antibiotics stop bacteria from multiplying by preventing bacteria from forming the walls that surround them. The walls are necessary to protect the bacteria from their environment, and to keep the contents of the bacterial cell together. Bacteria cannot survive without a cell wall. Penicillin antibiotics are most effective when bacteria are actively multiplying and forming cell walls.

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Penicillin Inventor, Brand Names, Uses, Side Effects & Allergy

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In 1928, Alexander Fleming noted that mold belonging to the genus Penicillium inhibited the growth of bacteria. Fleming called this unknown antibacterial substance penicillin. Ten years later, a group at Oxford University began to investigate penicillin in laboratory mice. Penicillin was hailed as a miracle drug and saved countless lives in World War II.

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For Question #3

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Aztreonam is a monobactam antibiotic that contains a betalactam ring. However, unlike other beta-lactam antibiotics, aztreonam does not contain a bicyclic-ring structure ( 6). To date, aztreonam has not demonstrated clinical cross-reactivity in penicillin-allergic patients ( 2, 8). Ceftazidime has a side chain identical to that of aztreonam, and clinical cross-reactivity has been demonstrated in vitro ( 8, 9).

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For Question #2

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The discovery of penicillin, one of the world's first antibiotics, marks a true turning point in human history - when doctors finally had a tool that could completely cure their patients of deadly infectious diseases.

Many school children can recite the basics. Penicillin was discovered in London in September of 1928. As the story goes, Dr. Alexander Fleming, the bacteriologist on duty at St. Mary's Hospital, returned from a summer vacation in Scotland to find a messy lab bench and a good deal more.

Upon examining some colonies of Staphylococcus aureus, Dr. Fleming noted that a mold called Penicillium notatum had contaminated his Petri dishes. After carefully placing the dishes under his microscope, he was amazed to find that the mold prevented the normal growth of the staphylococci.

It took Fleming a few more weeks to grow enough of the persnickety mold so that he was able to confirm his findings. His conclusions turned out to be phenomenal: there was some factor in the Penicillium mold that not only inhibited the growth of the bacteria but, more important, might be harnessed to combat infectious diseases.

As Dr. Fleming famously wrote about that red-letter date: "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer. But I guess that was exactly what I did."

Fourteen years later, in March 1942, Anne Miller became the first civilian patient to be successfully treated with penicillin, lying near death at New Haven Hospital in Connecticut, after miscarrying and developing an infection that led to blood poisoning.

But there is much more to this historic sequence of events.

Actually, Fleming had neither the laboratory resources at St. Mary's nor the chemistry background to take the next giant steps of isolating the active ingredient of the penicillium mold juice, purifying it, figuring out which germs it was effective against, and how to use it. That task fell to Dr. Howard Florey, a professor of pathology who was director of the Sir William Dunn School of Pathology at Oxford University. He was a master at extracting research grants from tight-fisted bureaucrats and an absolute wizard at administering a large laboratory filled with talented but quirky scientists.

This landmark work began in 1938 when Florey, who had long been interested in the ways that bacteria and mold naturally kill each other, came across Fleming's paper on the penicillium mold while leafing through some back issues of The British Journal of Experimental Pathology. Soon after, Florey and his colleagues assembled in his well-stocked laboratory. They decided to unravel the science beneath what Fleming called penicillium's "antibacterial action."

One of Florey's brightest employees was a biochemist, Dr. Ernst Chain, a Jewish German émigré. Chain was an abrupt, abrasive and acutely sensitive man who fought constantly with Florey over who deserved credit for developing penicillin. Despite their battles, they produced a series of crude penicillium-mold culture fluid extracts.

During the summer of 1940, their experiments centered on a group of 50 mice that they had infected with deadly streptococcus. Half the mice died miserable deaths from overwhelming sepsis. The others, which received penicillin injections, survived.

It was at that point that Florey realized that he had enough promising information to test the drug on people. But the problem remained: how to produce enough pure penicillin to treat people. In spite of efforts to increase the yield from the mold cultures, it took 2,000 liters of mold culture fluid to obtain enough pure penicillin to treat a single case of sepsis in a person.

In September 1940, an Oxford police constable, Albert Alexander, 48, provided the first test case. Alexander nicked his face working in his rose garden. The scratch, infected with streptococci and staphylococci, spread to his eyes and scalp. Although Alexander was admitted to the Radcliffe Infirmary and treated with doses of sulfa drugs, the infection worsened and resulted in smoldering abscesses in the eye, lungs and shoulder. Florey and Chain heard about the horrible case at high table one evening and, immediately, asked the Radcliffe physicians if they could try their "purified" penicillin.

After five days of injections, Alexander began to recover. But Chain and Florey did not have enough pure penicillin to eradicate the infection, and Alexander ultimately died.

Another vital figure in the lab was a biochemist, Dr. Norman Heatley, who used every available container, bottle and bedpan to grow vats of the penicillin mold, suction off the fluid and develop ways to purify the antibiotic. The makeshift mold factory he put together was about as far removed as one could get from the enormous fermentation tanks and sophisticated chemical engineering that characterize modern antibiotic production today.

In the summer of 1941, shortly before the United States entered World War II, Florey and Heatley flew to the United States, where they worked with American scientists in Peoria, Ill., to develop a means of mass producing what became known as the wonder drug.

Aware that the fungus Penicillium notatum would never yield enough penicillin to treat people reliably, Florey and Heatley searched for a more productive species.

One hot summer day, a laboratory assistant, Mary Hunt, arrived with a cantaloupe that she had picked up at the market and that was covered with a "pretty, golden mold." Serendipitously, the mold turned out to be the fungus Penicillium chrysogeum, and it yielded 200 times the amount of penicillin as the species that Fleming had described. Yet even that species required enhancing with mutation-causing X-rays and filtration, ultimately producing 1,000 times as much penicillin as the first batches from Penicillium notatum.

In the war, penicillin proved its mettle. Throughout history, the major killer in wars had been infection rather than battle injuries. In World War I, the death rate from bacterial pneumonia was 18 percent; in World War II, it fell, to less than 1 percent.

From January to May in 1942, 400 million units of pure penicillin were manufactured. By the end of the war, American pharmaceutical companies were producing 650 billion units a month.

Ironically, Fleming did little work on penicillin after his initial observations in 1928. Beginning in 1941, after news reporters began to cover the early trials of the antibiotic on people, the unprepossessing and gentle Fleming was lionized as the discoverer of penicillin. And much to the quiet consternation of Florey, the Oxford group's contributions were virtually ignored.

That problem was partially corrected in 1945, when Fleming, Florey, and Chain - but not Heatley - were awarded the Nobel Prize in Physiology or Medicine. In his acceptance speech, Fleming presciently warned that the overuse of penicillin might lead to bacterial resistance.

In 1990, Oxford made up for the Nobel committee's oversight by awarding Heatley the first honorary doctorate of medicine in its 800-year history.

Maybe this September 28, as we celebrate Alexander Fleming's great accomplishment, we will recall that penicillin also required the midwifery of Florey, Chain and Heatley, as well as an army of laboratory workers.
Do you have a question for Dr. Markel about how a particular aspect of modern medicine came to be? Send them to us at onlinehealth@newshour.org.

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The discovery of penicillin, one of the world's first antibiotics, marks a true turning point in human history - when doctors finally had a tool that could completely cure their patients of deadly infectious diseases. Many school children can recite the basics. Penicillin was discovered in London in September of 1928.

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For Question #1

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Alexander Fleming Discovery and Development of Penicillin - Landmark - American Chemical Society

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American Chemical Society: Chemistry for Life.

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For Question #5

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Penicillins are a group of antibiotics used to treat a large range of bacterial infections. They are derived from Penicillium fungi and can be taken orally or via injection.

Penicillin has saved millions of lives since its initial discovery. In 2010, more than 7.3 billion standard units of penicillin (pill, capsule, or ampoule) were consumed, worldwide.

The penicillins were the first antibacterial drugs used by doctors, and they attack a wide range of bacteria. Penicillin's discovery and consequent manufacture have changed the face of medicine.

Fast facts on penicillin

Here are some key points about penicillin. More detail and supporting information is in the main article.

Penicillin was the first antibiotic to be used medically

There are a number of penicillin strains used for different medical applications

Alexander Fleming is credited with penicillin's discovery

Penicillin works by interfering with bacteria cell walls

Less than 1 percent of people are dangerously allergic to penicillin

Penicillin: A short history

The discovery of a mold growing in an uncovered Petri dish led to the use of penicillin to treat bacterial infections.

The discovery of penicillin's antibiotic powers is attributed to Alexander Fleming. The story goes that he returned to his laboratory one day in September 1928 to find a Petri dish containing Staphylococcus bacteria with its lid removed.

The dish had become contaminated by blue-green mold. He noted that there was a clear ring surrounding the mold where the bacteria had been inhibited from growing.

This discovery of the mold - Penicillium notatum - and his recognition of its special powers set the wheels in motion to create one of the most used drugs in medical history.

In March 1942, Anne Miller became the first civilian to be treated successfully with penicillin having almost died from a huge infection following a miscarriage.

Although Fleming often gets the accolade for having invented the first antibiotic, there was a lot of work to do before penicillin could become as commonly used and useful as it is today.

The bulk of the work was eventually carried out by scientists who had a much better-stocked laboratory and a deeper understanding of chemistry than Fleming. Dr. Howard Florey, Dr. Norman Heatley, and Dr. Ernst Chain carried out the first in-depth and focused studies.

Interestingly, and with impressive foresight, Fleming's Nobel Prize acceptance speech warned that the overuse of penicillin might, one day, lead to bacterial resistance.

How penicillin works

Penicillin works by indirectly bursting bacterial cell walls. It does this by acting directly on peptidoglycans, an important part of bacteria's structure.

The peptidoglycan in bacteria's cell walls increases their strength and keeps external fluids and particles from entering them.

Peptidoglycans form a mesh-like structure around the bacteria's plasma membrane.

When a bacterium multiplies, small holes open up in their cell walls as the cells divide. These holes are then backfilled with newly produced peptidoglycans, and the wall is reconstructed. That is unless penicillin is in the vicinity.

Penicillins inhibit the protein struts that link the peptidoglycans together in the wall. This inhibition prevents the bacterium from closing the hole in its wall.

Because of the difference in pressure between the inside of the bacterium and the surrounding fluid, water rushes into the hole and the bacterium bursts.

How do bacteria become resistant to penicillin?

Contrary to popular opinion, it is not the patient who develops resistance to penicillin but the bacteria itself.

Bacteria have been around for billions of years. During this time, they have suffered extreme environments and, as such, have a great deal of experience in adapting. Additionally, they regenerate very rapidly, making any genetic changes across a population relatively swift.

There are three common ways in which bacteria can develop an immunity to penicillin:

Penicillinase - sometimes bacteria produce penicillinases (e.g. beta-lactamase), enzymes that degrade penicillin. This ability is then transmitted throughout the bacterial group via a plasmid (a small ring of DNA) in a process called conjugation - the bacterial equivalent of sexual reproduction, where new genetic information is shared between individuals.

Altered bacterial structure - some bacteria subtly change the format of their peptidoglycan wall or the penicillin-binding proteins so that the penicillin can no longer bind to it.

Penicillin removal - other bacteria develop systems to export penicillin. Bacteria have efflux pumps that are used to transport substances out of the cell. Some of these pumps can be repurposed to dispose of penicillin.

Penicillin side effects

Below are some of the side effects that have been noted during penicillin usage:

Common side effects

Headaches are a common side effect of penicillin use.

Less common side effects

Shortness of breath or irregular breathing

Joint pain

Sudden lightheadedness and fainting

Puffiness and redness of the face

Rashes and hives

Scaly, red skin

Rare side effects

Anxiety, fear, or confusion

Sense of impending death

Anxiety and hallucinations

Yellowing of the eyes and skin

Sore throat

Unusual bleeding

Diarrhea and reduced urination

Convulsions

Abdominal cramps, spasms, tenderness, or pain

Nausea and vomiting

Potential problems with penicillin use

Although penicillins are widely used, as with any drug, there can be some issues or contraindications that occur:

Breast-feeding - breast-feeding mothers may pass small amounts of penicillin to their babies. This can result in allergic reactions, diarrhea, fungal infections, and skin rash.

Interactions - some drugs can interact with penicillin. It is important to check with a doctor before taking multiple medications.

Bleeding problems - some penicillins (carbenicillin, piperacillin, and ticarcillin) can make pre-existing bleeding problems worse.

Oral contraceptives - penicillins can impede the effectiveness of oral contraceptives, raising the chances of pregnancy.

Cystic fibrosis - patients with cystic fibrosis are more prone to getting fever and skin rash when taking piperacillin.

Kidney disease - patients with kidney disease have an increased risk of side effects.

Methotrexate - methotrexate interferes with cell growth and is used to treat a number of conditions including leukemia and some autoimmune problems. Penicillin prevents the body from disposing of the drug, potentially leading to serious complications.

Phenylketonuria - some stronger, chewable amoxicillin tablets have high levels of aspartame that the body converts to phenylalanine. This is dangerous for anyone with phenylketonuria.

Gastrointestinal problems - patients with a history of stomach ulcers or other intestinal diseases might be more likely to develop colitis when taking penicillin.

Penicillin allergy

Some people exhibit allergies to penicillin. Allergic reactions normally include hives, wheezing, and swelling, particularly of the face. Around 10 percent of people report an allergy to penicillin but the true figure is closer to 1 percent, and only 0.03 percent exhibit life-threatening allergic effects.

Alcohol and penicillin

Although alcohol does not interact with penicillin, it may alter how effective it is. For this reason, it is not advised that people drink alcohol with penicillin.

Alcohol and penicillin also share side effects in some people - dizziness and nausea, for instance - so in combination, the side effects could be worsened.

It is also worth noting that certain antibiotics do have serious reactions with alcohol, for instance, metronidazole and tinidazole.

Penicillin has saved countless lives throughout its impressive medical career. Modern clinicians, however, worry about the onward march of antibiotic resistance. Only time will tell how the antibiotics of the future will jump this worrying hurdle.

With medical advances moving as swiftly as they currently are, anything could be around the corner. In the words of Fleming: "one sometimes finds what one is not looking for."

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University of Illinois-Chicago, School of Medicine

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Penicillins are a group of antibiotics used to treat a large range of bacterial infections. They are derived from Penicillium fungi and can be taken orally or via injection. Penicillin has saved millions of lives since its initial discovery. In 2010, more than 7.3 billion standard units of penicillin (pill, capsule, or ampoule) were consumed, worldwide.