Good afternoon ladies and gentlemen. I am privileged to have been invited to speak to the Association this afternoon. I recognise that the association is primarily interested in political and social issues but this afternoon I am going to talk about a medical issue which has perhaps got political and social consequences. I have taken my title from the title of a publication produced in the United Kingdom by the Standing Medical Advisory Committee to the Department of Health and which has generated a great deal of interest and concern in the medical profession.

I am going to tell you a story of scientific search and enquiry, discovery laced with a little serendipity which led to, what I believe, is one of the greatest medical discoveries of the 20th century without which much modern technological medicine would not be possible. It is also a story of arrogance and complacency and possible disaster. I am going to talk about antibiotics.

Antibiotic comes from the Greek work "anti" meaning against and "bios" meaning life. The unique quality of antibiotics, which are naturally occurring substances, is that they have the property of selective toxicity. That means that they are toxic to certain microbes and infecting agents while being less toxic or non-toxic to the human host. They are not new in the microbiological world they have been around for millions of years and presumably confer some advantage to the microbes that can produce them. In comparison to microbes, we humans are relative newcomers to this planet. Homosapians has been around for just 150,000 years and the earliest records of the use of anti-infective substances come from the middle ages when plant extracts and moulds were used to combat infective disease.

In the 18th century heavy metals such as mercury were used in the treatment of venereal infection but it was in the 20th century that antibiotics as we understand them came into use in medicine. They have been widely used for only 50 years and yet we are in a position in which we may loose their usefulness to the development of resistance in the microbial population. We could after just 50 short years be looking at a post antibiotic era in medicine. In the early decades of the 20th century the first compounds were the arsenic derivative Salversan and the sulpha derivative Prontosil and the earliest recorded episode of treatment failure due to acquired resistance in microbes was a case of Prontosil failure in the treatment of gonorrhea which was reported in the Lancet by Surgeon Commander Crean in 1937 but it is really thanks to Penicillin that much of our modern attitude towards antibiotics and antibiotic therapy have been derived.

Penicillin, which is the product of a fungal mould, was first observed by Alexander Fleming in St Mary's Hospital in 1929 but was exploited for therapeutic use by Professor Florey and Dr Chain in 1940. The properties of powerful antibacterial action and very low toxicity led to very wide spread use and in the medical profession an assumption that antibiotics were easy to prescribe and easy to take and that the use carried no negative consequences. This belief I think persists in the medical profession to this very day.

During the 1950s and 1960s there was an explosive enlargement in the number and range of antibiotics available to doctors and extremely high antibiotic prescription and high consumption has become the norm in medical practice both in hospital and the community worldwide. There are regional differences throughout the world, for example, the United States and Japan which comprise 10 per cent of the world's population consumes 60 per cent of the world's antibiotics. In Europe consumption is rather lower being most constrained in Northern Europe and Scandinavia and most profligate in Southern Europe. It is notable that in many Southern European countries antibiotics are widely available over the counter and it is in these regions that antibiotic resistance is most widely seen.

It is estimated that there are 200 million prescriptions per year in Europe for respiratory infections and over the counter consumption would add substantially to this figure. In the United Kingdom antibiotic prescribing is 50 per cent in man and 50 per cent in animals and this mirrors the situation in all developed countries where the use of antibiotics in animal husbandry is very high indeed. In this context the most controversial use of antibiotics is as feed additives to promote growth and weight gain. This has been practised for the last 30 or 40 years and evidence is increasing that this practice may be giving rise to a reservoir of antibiotic resistant microorganisms that are finding their way into the human food chain. It is interesting that the European Union has legislated against the use of antibiotics in animal feed in the last couple of years and this is a welcome development.

However, paradoxically when antibiotic growth promoters were banned in Sweden there was initially a rise in antibiotic consumption, which has now reduced again. One possible explanation is that antibiotics were being used as a substitute for good husbandry in some situations and there is a lesson there. In human medicine the 50 per cent of antibiotics in the UK consumed are overwhelmingly consumed in the community and not as you might imagine in hospitals. Eighty per cent of human antibiotic consumption is in the community and half of that is for respiratory infection. Despite the fact that the overwhelming majority of respiratory infections are caused by viruses which do not respond to antibiotic therapy. This is not a consequence of ignorance on the part of doctors but is substantially due to demand driven by the patients for prescriptions for relatively minor, self limiting complaints. It is hardly surprising that the prevalence of antibiotic resistance in the microbes, which cause respiratory infection, is now rising steeply and has been doing so for the last decade.

How have we got into such a mess in only 50 short years? One reason is that bacteria reproduce very quickly. Some microbes, which commonly cause infection in the urinary tract, can reproduce every twenty minutes. Bacteria divide by binary fission, that is one cell gives rise to two cells which give rise to four and so on. If this process is happening every 20 minutes the potential for genetic adaptation to an altered environment is simply enormous. Furthermore bacteria are very clever. They have evolved many different ways of manipulating their own genes. They have many mechanisms by which they can transfer DNA one to another.

One of the most effective methods call conjugation can lead to the rapid transfer of the genetic information for multi-antibiotic resistance between bacterial cells and this process occurs in the human gut so the antibiotic tablet that we swallow can have quite unforeseen consequences on the microbial flora in our own bowel. The more antibiotic that we use the more environmental pressure there will be upon the microbial population to adapt and to use survival mechanisms and this is exactly what has happened. Social and political factors have also been at work, if we consider the re-emergence of tuberculosis as an example. This terrifying disease was the scourge of humanity for centuries until in the 1950s effective antibacterial therapy became available and in the late 20th century tuberculosis has been managed routinely in general hospitals. Gone were the sanatoria, gone was the fear. Instead complacency had taken its place but yet in 1996 the World Health Organisation reported that tuberculosis was more prevalent worldwide than at any time in history.

What social factors had contributed to this?

• Poverty and homelessness.
• Population migration.
• The collapse of health care systems.
• Reduced public health budgets in affluent countries.

Multi-drug resistance in tuberculosis is rising in some parts of the world particularly in the former Soviet Union and it has been recognised as a problem in New York City. In the United Kingdom it is relatively uncommon but what does the future hold?

Another example is Staphylococcus aureus this microbe, a normal human parasite, causes a wide range of infections from septic fingers to boils, pneumonia, blood poisoning and of course death. When Penicillin was first introduced in the 1950s its effect on Staphylococcal sepsis was magical but by the early 1960s Penicillin resistance was already a problem and a new derivative called Methicillin came unto the market. Methicillin was active against Penicillin resistant Staphylococci and this drug and its derivatives have served us well for thirty years. This led the medical profession to conclude in the 1970s and 80s that this organism was no longer a problem but the Staphylococci knew better!

In the last 15 years Methicillin resistance has become wide spread and carries with it resistance to a very wide range of antibiotics leading to a situation in which untreatable Staphylococcal infection is now being encountered in our hospitals. Non-the-less the majority of individuals who acquire Methicillin Resistant Staphylococcus Aureus commonly referred to as MRSA do not perish, indeed the vast majority are not clinically ill. Unfortunately this micro-organism has been accorded cult status in the popular media leading to hysteria in some situations when it is encountered but the real lesson from MRSA is that it is only one of a very wide range of disease producing microbes that are beating us in the battle to stay ahead of infection.

You might ask why the medical profession is not more prudent in the use of antibiotics? Some reasons have already been given. Complacency and to a certain extent pressure from patients to prescribe but there are other difficulties. Despite an enormous bulk of scientific literature in relation to antibiotic prescribing there is often a lack of good quality scientific information to direct prescribing decisions. Most clinical trials of antibiotics are promoted by the pharmaceutical industry and are intended to demonstrate equivalence between two drugs. This does not help the medical practitioner who is seeking guidance on optimal therapy in the individual patient.

Secondly many drug licences are constructed around trials which are aimed at the US marked where there is a high prescribing culture and long treatment courses are used. This may not be the most appropriate way to use antibiotics but doctors of course have to prescribe antibiotics in the manner in which they are licensed. In other countries direct advertising aimed at the consumer and also over the counter availability of antibiotics are both powerful mechanisms by which antibiotic consumption is driven upwards. Direct to consumer advertising has been shown to stoke up patient demand and over the counter availability enables patients who are not the best diagnosticians to self medicate. Often the drugs are taken in insufficient dosage and for the wrong duration.

We cannot expect the pharmaceutical industry to promote restrained prescribing they spend colossal sums of money in research and development and they have a responsibility to their shareholders. The responsibility to promote the prudent use of antibiotics lies squarely with Governments, the medical profession and through the medium of education and perhaps also the public.

In the last few years widespread concern has led to some preliminary action in many countries and also by the WHO. In the United Kingdom the House of Lords Select Committee on Science and Technology reported in 1998 on the problem of antibiotic resistance and also the Department of Health Standing Medical Advisory Committee Sub Group on Antimicrobial Resistance produced the document entitled "The Path of Least Resistance" which I have borrowed as the title of this lecture.

The United Kingdom Government has established a National Institute for Clinical Excellence, which may promote the practice of evidence, based medicine in due course. There have been winter advertising campaigns promoted by the Department of Health to educate patients in moderating their demand for antibiotics for minor respiratory infections but this is just a beginning as it has been pointed out in the British Medical Journal the antibiotic resistance question is rather like global warming. The scientific evidence may still be uncertain. There are many vested interests. There are no votes in it and there is certainly no quick fix.

There is a temptation to say that it is somebody else's problem and a feeling of helplessness on the part of the individual doctor to do anything about the problem and yet if we don't many modern technological medical procedures may cease to be viable on a risk versus benefit patient basis. These would include bone marrow transplant and organ transplantation, cancer chemotherapy, prosthetic implant surgery, intensive care management and many forms of elective gastro-intestinal and vascular surgery. In the community many old scourges may come back to haunt us again – pneumonia, tuberculosis, meningitis, salmonelosis, malaria and others. To paraphrase Professor Rennie in the British Journal of Intensive Care in 1998, he said, "Our parents lived in an age in which Paul Erlich's concept of a magic bullet was just a dream until Penicillin".

Given the workings of evolutionary adaptation unless we do something about it our children may find themselves in an era like that of Erlich but with little possibility of a 21st century Penicillin. Unfortunately Western civilisation is built on the principle of exploitation. We are profligate with fossil fuels and we ignore renewable energy. We practice environmental vandalism and ignore bio diversity. What is the probability that we will practice restraint in antibiotic usage in order to conserve this most precious gift?

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