From the discovery of penicillin to contemporary problems, Sean Naughton analyses the considerable influence antibiotics have had on modern medicine.
In one of its first major uses, penicillin proved highly effective preventing wound infections in soldiers in World War II.
In 1920, if you got a cut or a graze that became infected, there were only two things you could do – the first being to hope that your immune system could fight it off, the other was pray.
With no effective treatment for bacterial infections, many ailments that are now considered simple to treat, could quickly lead to death. One form of bacteria, Streptococcus pyogenes, caused half of all post-birth deaths and was a major cause of death from burns. Another common form of bacteria, Staphylococcus aureus, was fatal in 80 per cent of infected wounds and the tuberculosis and pneumonia bacteria were famous killers.
Everything was to change however, in 1928, with a chance observation by Alexander Fleming. On returning from holiday to his laboratory, he noticed that one of his bacterial cultures, which he had left by the window, had become contaminated with a fungus. More interestingly however was the fact that the bacteria immediately surrounding the fungus had been destroyed, whereas those further away were unaffected.
Fleming realised that this fungus was producing a chemical that could kill the bacteria on his plate and after some months of calling it “mould juice,” he named this new substance penicillin.
Fleming ran into problems turning penicillin into a drug, because he was unable to purify and concentrate the substance. That could have been the end of the discovery, but in 1940, Howard Florey and Ernst Chain began to experiment with penicillin at Oxford University.
After many experiments, the duo succeeded in purifying penicillin, and began testing it on mice. Seeing that it caused few side effects in the mice, they began testing it on humans. With the outbreak of World War II and great numbers of soldiers with wounds that were ripe for infection, the need for a bacteria-killing agent was greater than ever. Florey and Chain’s team of workers rushed to develop penicillin in large quantities.
By 1942, penicillin was being produced en masse by British pharmaceutical companies. Many soldiers were saved from infections that developed after they were wounded in battle. Penicillin also reduced the rate at which people died from bacterial pneumonia – where once pneumonia killed 60 to 80 per cent of the people who came down with the lung infection, penicillin lowered the rate to between one and five per cent. In 1945, Fleming, Florey and Chain were awarded the Nobel prize for their revolutionary discovery.
The golden age of antibiotics had begun and soon floods of new natural and man-made antibiotics were being produced to combat a host of different illnesses that caused bacteria. Antibiotics were hailed as wonder drugs because of their stunning record for safety and effectiveness.
Between 1944 and 1972, human life expectancy jumped by eight years, an increase largely credited to the introduction of antibiotics. Many could be forgiven for thinking that man had finally conquered bacteria. Indeed in 1969, the then-US Surgeon General, William Stewart, boldly told the US Congress it was time to “close the books on infectious diseases”.
However, things were not quite so simple. As early as 1949, drug resistant strains of bacteria were being noticed. In 1953 during an outbreak in Japan, the strain of the bacteria responsible was isolated and found to be resistant to multiple drugs. Despite these problems, in the 1950s and 1960s, resistant bacteria seemed to matter little since there was always a new antibiotic being developed to combat them.
Resistance is not a problem while new antibiotics are available, but by the end of the 1960s, the development of new classes of antibiotics was stagnating. Instead, most work involved slightly altering existing antibiotics to reduce toxicity and to revive drugs rendered ineffective by the emergence of resistance. Drug companies had turned their attention elsewhere to areas such as viral infections. By the 1970s, penicillin resistant strains of one of the most common causes of pneumonia, Streptococcus pneumoniae, as well as many venereal diseases spread around the world.
Bacteria are subject to the same natural selection pressures that shaped human evolution, namely ‘survival of the fittest’. Millions of individual bacteria in the same colonies are competing for scarce food and energy resources, and those with genetic advantages that help them survive will flourish at the expense of less well-adapted bacteria.
There are however two important differences between bacterial evolution and human evolution. The first is that bacteria reproduce at a comparatively rapid pace, with some colonies doubling their numbers every thirty minutes. This allows for the rapid selection of the most resistant bacteria. The second is that bacteria have ways of passing antibiotic resistant genes between each other. In a process known as horizontal transmission, these resistance genes can be passed between non-related bacteria and become incorporated into their DNA.
With ample means of developing resistance and multiple cases being identified, you would think that sufficient precautions are being taken to avoid the emergence of bacteria that are resistant to all antibiotics. It has always been known that the key to preventing the development of resistance is to limit the use of antibiotics to when they are really needed and to ensure that an adequate length of treatment is given to ensure all bacteria are killed. Adherence to these guidelines would greatly slow the emerging problem. Unfortunately, these guidelines have been roundly ignored.
Of all the antibiotics produced, humans take only 30 per cent. The remaining 70 per cent are used in animal feed, not just to treat infection, but to promote growth. This sets up enormous scope for the development of resistant bacteria.
In Denmark in 1995, following years of using antibiotics in chicken feed, it was found that 72 per cent of chickens were infected with antibiotic resistant bacteria known as VRE (vancomycin-resistant enterococcus) – bacteria that also affects humans. In fact, in all the areas where this antibiotic was being used the most in animals, the rate of VRE in humans was highest.
In contrast, in the US, where this antibiotic had never been approved as a growth promoter in animals, detection of VRE in the community was rare. Following a ban on the animal use of this antibiotic in Denmark, the number of chickens carrying the drug resistant VRE fell to five per cent in 2000.
Human use is still a major problem however, due to poor prescribing practices and little knowledge among the public with regard to the limitations of antibiotics. For example, antibiotics are useful only for treating bacterial infections; they have no effect on viral illnesses such as the common cold.
Despite such findings, a third of people believe that they are effective for this purpose and often feel they have not got value for money from their doctor unless they leave with a prescription for something. It is this mentality which causes doctors to prescribe antibiotics that they know will have no effect, because they do not have the time to explain why they are unnecessary.
A recent study showed that doctors were more likely to prescribe an antibiotic for a viral case on a Friday evening than they were on a Monday morning, because they were less inclined to refuse the patient’s request at that time. There is also the temptation to use them as a placebo, as many know that simple viral illnesses will be self-limiting and that having any medicine will be a comfort to the patient.
Patient practices are also implicated. When patients are prescribed antibiotics for bacterial infections, they often fail to complete the course of drugs by stopping once they feel better. This provides ample opportunity for the remaining bacteria to rebound and flourish.
The emergence of bacteria that are resistant to multiple antibiotics is a truly frightening prospect. Methicillin-resistant Staphylococcus aureus, or MRSA (which first appeared in the 1960s) is now commonplace. MRSA accounted for 37 per cent of fatal blood stream infections in 1999 in the UK, up from just four per cent in 1991.
The only antibiotic effective against MRSA was vancomycin. However, in 2002 vancomycin-resistant Staphylococcus aureus (VRSA) was documented in the US. This left the newly developed linezolid as the only antibiotic with any effect against this bacterium. In 2003, linezolid-resistance in Staphylococcus aureus was reported. As Joshua Lederberg, a well-known molecular biologist, said in 1994: “We are running out of bullets for dealing with a number of infections. Patients are dying because we no longer in many cases have antibiotics that work.”
The development of antibiotics heralded a new era in medicine. It freed us from the constant threat of infectious diseases. It allowed the development of chemotherapy and radical surgical procedures without the fear of opportunistic infections. It increased the average lifespan by ten years. In contrast, curing all forms of cancer would only extend the average lifespan by three years.
Therefore, there are advances that we risk obfuscating if we do not change our use of antibiotics. Alternatively, if such initiatives are implemented, we can perhaps avoid a future where the only things we have to use against bacterial infections are our rosary beads.