Resistance is useless

We’ve “never had it so good”, said Tory Prime Minister Harold Macmillan in the 1950s and in at least one sense we have never had it so good. Few of us can remember a time when people could die from trivial injuries or infections which now respond to antibiotics. The World Health Organisation estimates that drugs like penicillin and streptomycin have added some 20 years to our life expectancy. And yet it could all go wrong.

Antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are the problem that could end our complacency and make even routine operations hazardous. Already, hospital-acquired infections by MRSA and Clostridium difficile are a major difficulty (hence alcohol-based disinfectant gels in hospitals and hand-washing campaigns). In fact, a scarier problem is that of multidrug-resistant bacteria or “superbugs”. In the worst cases, bacteria may be resistant to all common antibiotics, as is the case with some strains of tuberculosis. Some 5000 people per year die in the UK because they are infected by resistant bacteria. In the US, some 2 million are infected each year, with 23000 deaths.

The problem of resistance has been known since the birth of medical antibiotics but has recently been highlighted, most notably by the UK Chief Medical Officer Sally Davies in a report published Mar 2013.1

Fifteen months later, David Cameron publicly recognised the problem and announced an inquiry (funded and hosted by the Wellcome Trust) into

(a) the spread of drug-resistant bacteria;

(b) the over-use of antibiotics; and

(c) the “market failure” whereby no new classes of antibiotic have been introduced for some 25 years.

Furthermore, the new Longitude Challenge has chosen as its focus, after a public vote, the development of a cheap, accurate, rapid, easy-to-use test for infections, so that bacteria may be targeted quickly with the appropriate antibiotic.

But why do we need new antibiotics to keep being found or made? The answer is evolution. Alexander Fleming, discoverer of penicillin 85 years ago, warned that, if misused, resistance would soon develop in its bacterial targets and it would become useless. If just one bacterium among a population of trillions mutates to become resistant, it will survive. If not dealt with by the immune system (perhaps weakened for some other reason) and doubling every hour, its descendants will number trillions again in less than two days. And we will need a different antibiotic as the previous one will not work.

The early antibiotics were naturally-occurring compounds produced by moulds or bacteria to inhibit competition from other bacteria (Fleming famously discovered accidentally that Penicillium bread mould inhibited the growth of bacteria on a nutrient gel). Bacteria did not stand idly by and mutations that conferred antibiotic resistance evolved and spread in nature. Bacteria have an extra string to their bow in that drug resistance can spread not just “vertically” (from parent to offspring) but “horizontally” by exchange of fragments of DNA called plasmids, within species and even between species. This allows resistance to spread much faster.

The chance of resistance developing is increased if insufficient antibiotic is used because more bacteria survive and the chance of a resistant mutation is increased. As Fleming said in his 1945 Nobel Prize lecture2, “if you use penicillin, use enough”. The first patient treated with penicillin died only because there was not enough then available to kill all the bacteria in his bloodstream.3 Mass production began in 1943 and in only four years resistance began to appear. This was due partly to a black market in the still scarce penicillin where the stolen drug was diluted to increase sales. Art was to imitate life with the 1949 Graham Greene book and film The Third Man.4

Yet, in another sense, there is over-use of antibiotics. They are frequently prescribed for virus infections (such as colds and influenza) for which they are ineffective. They can also be bought over the counter in some countries and taken inappropriately. This allows resistance to develop among the body’s natural skin and gut bacteria. A subsequent injury allows an infection to occur which can no longer be treated with the antibiotic in question. Also, if the whole course of treatment is not taken (often because the patient feels better already), the remaining bacteria have a greater chance of a resistant mutation. And, with even less justification except for profit, enormous amounts of antibiotics are given to farm animals because they enhance rates of growth – more scope for resistance to develop.

So far, so bad but we have the greatest global economy ever, with enormously successful pharmaceutical companies. Nevertheless, no new class of antibiotic has been introduced since 1985. Surely the capitalist market will supply a product for which there is a demand. This is certainly the expectation of those incorrigible optimists at spiked! (“Humanity is under-rated”), the website founded by members of the erstwhile Revolutionary Communist Party. Their correspondent Robin Walsh, a trainee doctor, accused CMO Sally Davies of “fear-mongering”: new drugs would rapidly follow if the government would alter its payment policy to the drug companies.5 This would manipulate the ”demand”, at present limited since antibiotics need to be used sparingly, restricting the profits to be made.

Unfortunately, financial incentives are not necessarily going to solve the problem. Drug industry insider Derek Lowe who blogs and writes In The Pipeline for Chemistry World6 points out that virtually all targets in bacteria have already been attacked and no new targets have come up. This is despite knowledge of bacterial genomes which has yielded nothing of use in 20 years. He ruefully admits that it’s easy to come up with drugs that kill all cells but difficult to find those that attack only bacteria.

Finally, any new antibiotic would rapidly come up against the same problem of resistance. This is because we are exerting “the most concentrated Darwinian selection pressure on pathogens” which leaves survivors very well-equipped to defeat future attacks. Lowe doesn’t think that money is the problem: it’s more that resistant bacteria are a very hard target! This is highlighted by another recent finding that antibiotic resistance genes are widespread in nature. Looking at 71 environments across the world, ranging from oceans to soil to human faeces, a French research team found resistance genes relevant to human and veterinary medicine everywhere.7

To reiterate, in order to generate profits, companies need to sell more of their products at as high a price as possible. That works for chronic illnesses, male impotence, headaches, diseases of the well-off, and so on, but not for bacterial infections. The more antibiotics you use, the quicker resistance evolves in bacteria. Antibiotics need to be used as sparingly as possible – not a recipe for generating profits. And when resistance has developed, there is little incentive to look for new antibiotics when they will be only a temporary solution.

New Scientist magazine is confident that solutions can be found to the drug-resistance crisis but that the free market needs to be replaced by “socially-motivated medicine makers”. This goes against the worship of the market by the main political parties and certainly against extending the role of the private sector in health, as even Labour has done. Other solutions include much more sparing use of antibiotics in medicine, banning their use in farming, much more rigorous hygiene in hospitals, development of new vaccines, and quicker tests to identify bacteria so that more appropriate antibiotics can be used straight away (the Longitude Challenge). There really isn’t “a pill for every ill”.

1CMO’s 2011 Report, Part 2: https://www.gov.uk/government/publications/chief-medical-officer-annual-report-volume-2

2http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.html

3Reserve Constable Albert Alexander had developed septicaemia following a scratch from a rose thorn and was dying in an Oxford hospital in 1941. He started rapidly recovering when given penicillin but when it ran out he worsened again and died.

4The anti-hero Harry Lime (Orson Welles) steals, adulterates and sells penicillin on the black market. Asked about the victims of his crimes, Lime dismisses them as insignificant as scurrying ants. Highly recommended (the film, not Lime’s views!).

5http://www.spiked-online.com/newsite/article/13447#.U_IhhhbaaX0

6http://www.rsc.org/chemistryworld/2013/03/derek-lowe-antibiotics-research-pharma-business

7http://www.cell.com/current-biology/abstract/S0960-9822(14)00328-5

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