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3: The Story So Far: A Brief History of Antibiotic Use

Before looking at antibiotics themselves, we should briefly examine antibacterial approaches, some of which are still in use, which preceded the discovery of antibiotics.

Before 1935 there were few successful medical methods for treating infections apart from procedures which went back hundreds of years, such as the use of an extract of cinchona bark for the treatment of malaria (from which quinine was eventually derived) and the use of ipecacuanha for some forms of dysentery.

During the early 20th century a few medications were developed in Germany for treatment of parasitic infections, but there were no antibacterial medications as such until the discovery of sulfur drugs, which were able to save lives in conditions which had previously been virtually untreatable.

The Sulfur Drugs

In 1935 it was announced that a drug had been developed, in Germany, of a sulfur derivative which could be used to treat commonly fatal streptococcal infections such as puerperal fever.

In the early 1930s over 1,000 young women were dying every year, in the UK, after childbirth because of infection of the bloodstream, from puerperal fever. Well over 100 out of every 100,000 births resulted in the mother becoming fatally infected in this way at this time.

When the new sulfonamide antibiotics were introduced in the mid-1930s, the figures for deaths from puerperal fever dropped dramatically, so that by 1940 the figure was down to around 20 deaths per 100,000 births. After the introduction of penicillin in the early 1940s, this figure dropped further so that there were fewer than 10 deaths per 100,000 births by 1950.

It was soon shown by research that the antibacterial effect of this drug resulted from the release from it, in the body, of a sulfur compound (sulfanilamide). This led to further research resulting in the production of sulfapyridine in 1938, which was capable of strong antibacterial effects against the microorganism responsible for pneumococcal pneumonia (see Chapter 2).

Research into sulfur drugs continued (and continues, although many scientists believe that drugs of this sort are no longer of much importance or usefulness). Professor Richard Lacey, writing in Geoffrey Cannons’s comprehensive examination of the phenomenon of resistance, Superbugs (Virgin, 1995) says

Avoid all sulphonamides, except co-timoxazole in one special special situation – Pneumocystis carinii which is common in AIDS patients. [These drugs are] relatively toxic [many ill-effects]; obsolete. Better restricted for use in agriculture, as long as resultant meat and other human food contains no residues.1

So what are the side-effects of sulfur drugs, which are still widely used?^2,3,4

Formation of crystals can take place in the urine, which causes kidney blockage. This is said to be rare nowadays if the correct dosage is taken, but very serious if it does occur. Blood in the urine is an early sign.

A moderately severe fever and skin rash and damage to blood cells is an uncommon but possible hypersensitivity reaction.

Rarely, a severe reaction can occur in which a fever plus a skin rash also involves extensive ulceration of the mouth and/or the vagina. The eyes may become involved, leading commonly to blindness. This sometimes fatal condition is known as the Stevens-Johnson syndrome and usually relates to long-acting sulfur drugs, and is more common in young patients than adults. It is important to realize the degree of rarity of this sort of reaction – with an estimate of between 1 and 2 cases per 10 million doses prescribed.

Inflammation of the arteries can occur, as can inflammation of the heart muscle.

Damage to the bone marrow may occur, leading to several conditions – some serious – involving different blood cells, reduction in white blood cell levels, and various forms of anemia.

Liver damage may occur, as may lung diseases, but reports of these are extremely rare.

WHEN ARE SULFUR DRUGS NOW USED?

urinary tract infections – in combination with other drugs in treatment of Pneumocystis carinii, commonly in people with immune deficiency

sometimes in recurrent ear infections in children

previously widely used in meningitis and bacterial infections of the intestines, but less so now because of widespread resistance by the bacteria

for some sexually transmitted diseases such as chlamydia

sometimes in treating malaria and for some parasitic infections

in long-term control of conditions such as ulcerative colitis and Crohn’s disease.

Much of the early research into antibiotics was diligent and painstaking, although some of the discoveries were almost accidental:

Fleming’s original revelation of the antibacterial effect of penicillin was a stroke of luck rather than genius. The spores of the mold from which the first penicillin was extracted had apparently floated out of one window (of a room where molds were being studied) in St. Mary’s Hospital in London and onto culture dishes lying in Fleming’s laboratory.

Later another mold, now used for penicillin production (Penicillium chrysogenum), was discovered on a moldy melon (cantaloupe) found in a market in Peoria, Illinois.

In 1953 an antibiotic (Helenine) which was used to treat some viral infections was isolated from Penicillium funiculosum after being noticed growing on the transparent (isinglass) cover of a photograph of the wife of the discoverer, a Dr Shope (his wife’s name was Helen, hence the name given the antibiotic).

Many antibiotics have been discovered in molds which live in the soil, where for millions of years microorganisms have competed with each other for nutrients and territory, and so have developed ways of attacking each other and of defending themselves. Not surprisingly, out of the tens of thousands of chemicals which these organisms produce to harm each other or defend themselves, some have been found which can be used in humans, to kill or damage other microorganisms which may be causing infection – without causing (too much) harm to the person being treated (though this is the hope rather than the reality, as we shall see).

Cephalosporin antibiotics – such as the widely used antibiotics cefaclor and cefoxitin – were originally derived from microbes (molds) found in sewage.

There are now literally tens of thousands of different antibiotic variations (see Chapter 4 for a summary of the differences and details of some of the major versions) and hundreds on the market, leading to great confusion in the minds of those who have to prescribe them. It is hard to know which (if any) is superior in many cases. Sometimes such decisions are easy and clear, but more often the doctor who has to prescribe has to make choices based on inadequate information. As Professor Garrod has stated,⁵ ‘A confident choice between them, for any given purpose, is one which few prescribers are qualified to make – indeed no one may be, since there is often no significant difference between the effects to be expected.’

The laws of natural selection (and survival of the fittest) teach us that when assaulted by a toxic (to them) substance such as an antibiotic, some bacteria will survive, because they already have, or will develop, a natural immunity to the antibiotic. Those bacteria that survive will then be able to transmit this resistance to their descendants – this process lies at the heart of the superbug problem.

Antibiotics

Although there are a few records on the use of substances extracted from various molds to treat infection, going back thousands of years to ancient Egypt and indeed throughout recorded history, the modern era of antibiotic use dates back to around 1940.

PENICILLIN

Fleming had identified the antibiotic penicillin effect in 1929, however it was not until 1941 that extracts of the mold microbe Penicillium notatum were ready for use to treat infection. When enough of the first penicillin had been painstakingly gathered by the early researchers to treat patients, they were faced with the problem of too great a demand and too slow a production, especially after some of the initial cures, which were dramatic and newsworthy.

Conditions such as meningitis, septicemia and pneumonia became controllable for the first time, the early antibiotics proving superior in their effects to the sulfur drugs.

One early method of ‘recycling’ penicillin was to extract traces of it from the patient’s urine and re-use it. After some years, methods of production improved and this recycling was stopped.

Penicillin was initially used widely in childhood infections as well as for serious life-threatening infections in adults.

Penicillin, and all antibiotics, are of no value whatever in treatment of viral illnesses, and yet in the early days through ignorance, and right up to the present, antibiotics were and are regularly prescribed for conditions not caused by bacteria at all.

Allergic reactions to penicillin, as well as other types of reactions (usually mild and short-lived) including diarrhea and nausea, became (and remain) extremely common.

One result of the enthusiastic and excessive use of penicillins was that by the late 1940s many disease-causing organisms had developed resistance to the early versions, and the energies of the pharmaceutical manufacturers were focused on the never-ending job of finding new variations which could control the resistant bacteria. In his prophetic book When Antibiotics Fail, Marc Lappe of the University of Illinois College of Medicine points out that over 23,000 different forms of penicillin had been developed during the period 1975 to 1986 (plus over 7,000 cephalosporins, 1,500 rifamycins, 3,000 tetracyclines, 750 lincomycins, 300 streptomycins and a further 1,000 aminoglycosides!).⁶

The painful truth is that the fortunes of many drug companies depend upon new resistances developing, new drugs appearing, and the cycle continuing forever. The problem for them is that it cannot, as options are increasingly limited in terms of new antibiotics. Other strategies will have to be found to deal with the super-resistance of the superbugs and the health crisis this is causing.

STREPTOMYCIN

By 1944 streptomycin had been developed (from the bacteria Streptomycaes griseus) – a breakthrough as this was able to treat tuberculosis effectively – for a while. It was not long, just a few years, before resistant strains appeared of Mycobacterium tuberculosis.

Streptomycin was also soon found to be extremely toxic and is in decline in usefulness in Western industrialized countries, although in many under-developed countries it is widely and inappropriately used (along with other antibiotics) – often without the need for prescription – causing a potential disease time-bomb in often malnourished populations.

According to the British Medical Association,

These potent drugs are effective against a broad range of bacteria, but they are not as widely used as some other antibiotics because they have to be given by injection, and they also have potentially serious side-effects.

Their use is therefore limited to hospital treatment of serious infections.

Possible adverse effects include:

damage to the nerves of the ear

damage to the kidneys

severe skin rashes.

Over the more than 50 years since penicillin and streptomycin appeared, a host of new antibiotics have emerged and continue to reach the market every year.

CHLORAMPHENICOL

In the late 1940s came the chloramphenicol drugs, a ‘broad-spectrum’ antibiotic which was apparently effective against many different microorganisms. These drugs were originally widely and enthusiastically used to treat everything from gonorrhea to blood infections and gastroenteritis.

Unfortunately however for the manufacturers of chloramphenicol, some extremely serious side-effects soon began to appear – albeit in only a small number of patients – including potentially fatal aplastic anemia. It also caused major problems when used to treat young children, and so chloramphenicol’s use in industrialized nations has now diminished to very special situations only, such as:

typhoid fever (which means that it is still widely used in underdeveloped countries where typhoid is widespread)

some forms of meningitis

life-threatening chest infections

where nothing else is working to control a serious bacterial infection, so that there is little to lose by trying something as potentially dangerous as a form of chloramphenicol.

The irony here is that because chloramphenicol antibiotics are now used so rarely, bacterial resistance has not been developing against them as rapidly, making these highly toxic drugs possible choices if superinfection occurs. This leads to the thought that if the bug doesn’t get you, the treatment just might.

TETRACYCLINES

In the late 1940s, new antibiotics derived from soil microorganisms appeared. These have an even wider target range than the chloramphenicol drugs – and are known as tetracyclines. One of the most popular of the tetracyclines first appeared in 1950 – oxytetracycline, which is still very much in use.

These antibiotics were and are used to treat infections of many sorts, including those of the eyes, ears, throat, digestive and urinary tracts, acne and a number of sexually transmitted diseases. Unfortunately, as with many other antibiotics, tetracyclines are also widely used in agriculture and have entered the food chain.

The excessive and indiscriminate use of these extremely broad-spectrum antibiotics has resulted in bacterial resistance appearing which limits their use – though, given their side-effects, some might consider this a blessing.

Side-effects to tetracycline drugs are numerous according to the British Medical Association, which summarizes them thus:

A major drawback to the use of tetracycline antibiotics in young children and pregnant women is that they can discolour developing teeth. When given by mouth they have to be administered in high doses to reach effective levels in the blood (because they are poorly absorbed through the intestines). Such high doses increase the likelihood of diarrhoea.

Short-term reactions include:

allergic reactions

sore and itchy rectum

sore tongue

swallowing difficulties.

Long-term problems relate to the demolition job that tetracyclines do on the bowel flora, the friendly bacteria which detoxify our intestines and manufacture B-vitamins for us, and above all which keep yeasts under control.

When tetracycline drugs are used, often for months on end to treat acne, for example, an overgrowth of yeast in the bowel is almost certain, and it can take years to put this right. (See Chapters 7 and 8 for details of aspects of these effects and what you can do about them, as well as Chapter 9 for probiotic strategies to help reverse this damage.)

CEPHALOSPORINS

As mentioned above, the cephalosporins (such as cefaclor) were first extracted from fungal spores found in sewage in the mid-1940s. They were initially fairly toxic, but with steady development of more refined versions they have become less so.

Cephalosporins act in similar ways to penicillin-type drugs, have a wide spectrum and are fairly well tolerated. Their use is mainly in treatment of infections of the chest, urinary tract, liver and gall bladder, as well as for gonorrhea. They are commonly being used prophylactically, before surgery for example, and are frequently used when penicillin antibiotics fail to control infection. They can be administered either by mouth or by injection.

Side-effects include:

allergy – relatively common – in up to 10 percent of patients, in the form of rashes, fever and sickness

severe blood clotting problems – relatively rare.

Resistance is gradually building to many of the major drugs in this group, in a number of important disease-causing microbes, including Staphylococcus aureus, Klebsiella, E. coli and Pseudomonas aeruginosa.

THE MACROLIDE, GLYCOPEPTIDES AND LINCOSAMIDE DRUGS

In the early 1950s, drugs in the class of broad-spectrum antibiotics known as macrolides appeared. The most notable of these, and the only one still in major use, is erythromycin.

Erythromycin is used as an alternative to penicillin and cephalosporin drugs and has a particular usefulness in the treatment of Legionnaires’ disease (a rare form of pneumonia). It carries risks relating to liver damage and so is used cautiously.

The glycopeptide drugs include the toxic, expensive and hence very rarely used vancomycin. Its potency against superbugs such as S. aureus (see Chapter 2) makes this a drug held in reserve, and because of this resistance to it is low. Once again we see the irony of the savior drug being so toxic that it carries dangers all its own.

Among the side-effects of vancomycin are:

a bright red flushing (combined with severe itching) of all or part of the body (‘red-man’ reaction)

swelling of the mucous membranes

cardiovascular collapse (rare)

damage to the ears possibly leading to irreversible deafness

damage to the kidneys

serious blood diseases involving the white blood cells.

But remember – it could save your life at the same time.

The lincosamide drugs such as lincomycin appeared in the early 1960s, and are used mainly for treatment of extremely serious infections of bones, joints and the abdomen which fail to respond to other antibiotics. They too are therefore ‘kept in reserve’ because of their side-effects.

As the British Medical Association explains, ‘they are more likely to cause serious disruption of bacterial activity in the bowel than other antibiotics.’ This highlights the vital importance of maintaining the health of the friendly bacteria, and since all antibiotics damage these it is safe to assume that the lincosamide antibiotics are absolutely devastating.