Antibiotics

Almost exactly 100 years ago, physicians began to treat syphilis, a bacterial infection, with compounds containing arsenic. They had some success and such treatment marked the first time that a chemical compound had been used specifically to kill microorganisms. A dozen or so years later, chemicals were discovered as a byproducts of the aniline dye industry that had similar properties. Prontosil rubra was the first of the sulphonamide drugs and was used successfully to successfully treat a number of infections during the 1930s. In 1928, Alexander Fleming made his chance observation of a bacterial colony in a petri dish that had been accidentally exposed to a mould. He noticed that the growth of bacteria was inhibited by the mould.  This finding subsequently led to the discovery of penicillin which was introduced into clinical practice for the first time in 1942.

The following twenty years saw the discovery of many more so-called antibiotics, which were grouped into classes depending upon their modes of action. The term ‘antibiotic' means against life and was coined because substances were available to kill or inhibit the growth and actions of microorganisms that heretofore were responsible for so many serious illnesses that killed people. Before the antibiotic era, a person could sustain  a pricked thumb, whilst pruning rosebushes, which could lead to a fatal septicaemia.  Once antibiotics were freely available such an outcome was very much less likely. By 1962, twenty classes of antibiotics had been developed were and used during the subsequent fifty years. Only two more were discovered, but none for the past thirty years. By 2010, over one hundred different antibiotic compounds were in regular clinical use.

Very shortly after the introduction of penicillin, the phenomenon of antibiotic resistance was noticed. Drugs that had previously been effective against certain organisms, no longer were so. This led to the common clinical practice of prescribing more than one drug for a particular infection. A prime example of such a strategy can be seen in the management of tuberculosis. Streptomycin, introduced in the late 1940s, was found to be very effective against the organism responsible for the disease. Unfortunately, it turned out to be a very toxic drug and so its usefulness as a single therapy was short lived. When given in combination with paraminosalicylic acid and isoniazid, it worked much better and its toxic effects were lessened. There are several other examples of drugs being used in combination and thereby slowing the development of bacterial resistance.

The last ten years have seen the emergence of multi-drug resistant bacteria - the so-called super bugs. Some of these are just about beyond  the reach of any of the currently available agents. This phenomenon is giving rise to great anxiety and is thought by some to presage the end of the antibiotic era and a return to the times when simple infections could prove fatal. The great advances in medical and surgical treatment of so many diseases require the use of antibiotic cover. For example, powerful chemotherapeutic drugs used against cancer affect sufferers' autoimmune systems leaving them prone to infections. Often, chemotherapy is given with antibiotic cover to prevent this. The use of implants of one sort or another in treating various cardiac and orthopaedic conditions has become very common. These, too, are often require  the administration of antibiotics to prevent secondary infection. Organ transplants: heart, kidney, liver, for example, entail the use of immunosuppressants to lessen the chance of transplant rejection. Organ recipients are therefore prone to infection and require antibiotics. If and when all available antibiotics have lost their effectiveness,  such medical advances as these will no longer be safely available. A potential very grave health crisis is looming.

Bacterial resistance to antibiotics is attributed to many factors. Microorganisms, when faced with drugs designed to kill them, mutate and form strains that are drug resistant. They reproduce extremely rapidly and generations are measured in minutes rather than years or decades as is the case with more advanced creatures: mammals in general and primates in particular. This ability facilitates the speedy acquisition of drug resistance. It is also said that antibiotics have been used carelessly both by the medical profession and the general population. In the past, penicillin was handed out to just about anyone with a fever. Upper respiratory infections are extremely common and caused by viruses against which antibiotics are useless. Patients became very demanding and expected to receive a course of antibiotics more or less as a routine.  Research has shown that many such courses were never completed; patients stopped using the drugs as soon as they began to feel better. The use of antibiotic drugs has also become very common in agribusiness because they were found to increase yields and profits. In summary, widespread use of antibiotics, often inappropriately, has led to universal drug resistance.

The biology of microorganisms has been extensively studied and metabolic pathways identified that could be attacked by drugs resulting in the death of the organisms. Roughly a score of such pathways have been attacked. Microorganisms have responded by repairing these pathways and achieving resistance. Presumably, any new antibiotics that are introduced will have to be directed at other as yet unknown metabolic mechanisms. Rather more than twenty classes of antibiotics have kept  humanity safe from bacterial assault during the past fifty or sixty years and it is presumed that a  further twenty will be necessary to ensure safety over the next half century.

Generally, the discovery, introduction and marketing of drugs have been left in the hands of ‘Big Pharma’.  Large drug companies like all other capitalist enterprises have one main aim: engrossing the net wealth of shareholders. This is important. Antibiotics are not money spinners. They are given in short courses to multiple patients. Contrast this with drugs that are used against the so-called metabolic diseases. For example, patients in their mid-50s might be found to have hypertension, hypercholesterolaemia or type II diabetes. Such conditions can be controlled but not cured so consequently sufferers are required to take regular medications for thirty years or more. As a commercial proposition that  beats antibiotics out of sight. If then, twenty new classes of antibiotics must be developed in short order and Big Pharma does not see any great commercial advantage accruing from that enterprise, how can it be achieved? So far, health authorities and health systems around the world have been flagging a looming disaster but governments and the drug companies do not seem to have responded. Is a completely new approach is required?

I suggest that a consortium of carefully selected nations set up an independent organisation to grapple with the problem. Ideal candidates would include Australia, Canada, New Zealand, the United Kingdom, Israel, Germany, Switzerland and Finland. This group would assemble its leading microbiologists to begin work very urgently on developing new antibiotics. The task would prove very costly and the money could readily come from each country’s overseas development aid budget. The United Kingdom, for example, devotes 0.7% of its gross domestic product to overseas aid  – it spends more on aid than on its Home Office, its ministry of internal affairs – and a good deal this money finds its way into the pockets of the kleptocrats that rule so many developing countries. All too commonly, many projects are found to be ill thought out and a waste of money. A glaring example  can be found in the useless airport recently completed on the island of St Helena at a cost of £250 million. The countries listed above all  spend handsome sums annually to a variety of projects and much of this money is either wasted or stolen. Were it instead to be devoted to antibiotic development, short term aid would suffer but the Third World, along with everyone else, would benefit greatly in due course.

The countries that I have suggested that form the consortium all have outstanding records of medical research and development. They could, of course, hire other eminent scientists from other nations and pay them handsomely. I have not included the United States on my list because I would not want the consortium to  become enmeshed in American legal and political labyrinths; furthermore, international co-operative ventures are not being looked upon favourably by the current administration, which could be in place for most of the next decade and we do not have that amount of time to waste. However, many American medical scientists are outstanding and it would be foolish not to hire some if they were willing to work for such a scheme. President John F. Kennedy in the early 1960s declared that his country would put a man on the moon before the decade was out. He succeeded. Huge sums of government money were thrown at the project.  I think that the discovery and introduction of new antibiotics is probably a good deal more crucial than a vanity space project. It will be difficult and very costly and the sooner some such scheme, as the one outlined, is introduced the more likely it is that a  disastrous healthcare catastrophe will be avoided. Few people alive today have  any experience of how things were before the antibiotic era. But a world in which a trifling gardening accident might prove fatal is not one we should aspire to.

Comments, please.

Those interested in a recent scholarly article on this problem might care to try  <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085877/>

David Amies

Lethbridge, AB,

April 27, 2017