The risk of an end to the human race may sound like science fiction. However, there are only a small number of threats that could theoretically lead to the extinction of mankind. The four main concerns that most experts share are:
1. Nuclear war.
2. Deadly plague that cannot be treated by drugs or prevented by vaccines.
3. A potent poison being widely disseminated.
4. Earth being struck by a large meteor.
Drug-resistant plague poses one of the most serious, potential challenges to mankind. The final responsibility for coordinating a response rests with governments. The dangers are being increasingly recognised by politicians with the British Prime Minister helping to lead the way and a far-reaching British enquiry planned. All Infections are caused by “pathogens”, which are usually bacteria, viruses, tiny fungi or other microscopic parasites. Bacteria are a specific type of one-cell living organism and can be seen with an optical microscope. Viruses are much smaller and comprise largely genetic material that enters human cells and tricks them into making more viruses. Fungal infections are relatively rare but do arise e.g. thrush. Malaria is an example of a microscopic parasite that does not fall into the other categories. All pathogens mutate so that their properties gradually change. As the reproductive cycle is short many generations can occur in a small period of time. Pathogens that have mutated in a way that makes them more able to resist the actions of drugs are more likely to survive in patients being treated with the products. Growing drug resistance in the community and hospitals results.
Resistant viruses are probably a greater threat to mankind than resistant bacteria, fungi or microscopic parasites. Viruses are necessarily harmful because they take over healthy human cells and use them to produce new viruses. They are often transmitted between people in specific ways e.g. by sneezing and absorbing viruses through the nose in the case of ‘flu or the common cold; through blood or sexual activity in the case of AIDS; through animal bites with rabies. Once viruses have entered the body they frequently target a particular organ or class of cell e.g. a type of white blood cell for AIDS; the liver for hepatitis. New viruses generally require the discovery of new drugs or vaccines to treat or prevent infections whereas a new strain of bacteria is generally treatable by existing antibiotics (antibacterials). Bacterial infections are normally curable whilst viral infections vary in this respect. Fortunately, viral infections that are easy to transmit and mutate rapidly tend to cause less serious infections (e.g. the common cold, ‘flu). However, there is no reason as to why this pattern will continue. The risk for mankind is the evolution of a virus that is as easy to transmit and that mutates as readily as the common cold or ‘flu but is also invariably deadly. There is no reason why such a virus will not emerge and why drug development might not turn out to be too slow to provide an effective response.
Resistance to existing drugs is growing in the case of all pathogens. The problem is arguably potentially more serious for antiviral drugs than for antibiotics because there are far fewer of the former from which to choose in practical clinical situations. Nevertheless, antibiotic resistance is a growing and serious problem that can lead to deaths when hygiene has proved inadequate and the right combination of antibiotics is not found in time for a specific patient’s infection.
What should governments, doctors and regulators do?
In my experience drug companies have not become more reluctant to research potential breakthrough antibiotics. The reasons why the pace of antibiotic drug discovery has slowed are partly the increased bureaucracy within drug companies affecting R&D productivity in all drug classes and partly a big reduction in the number of good ideas for new antibiotics for reasons relating to antibiotic science. Most antibiotics including all penicillins, cephalosporins, monobactams and carbapenems have what is known as a beta-lactam ring in their chemical structure. Such antibiotics are collectively known as beta-lactams. The commonest way in which bacteria become resistant to beta-lactams is by starting to make a substance belonging to a chemical family known as “beta-lactamases”, which destroy the beta-lactam ring in beta-lactam antibiotics and so render them useless. Antibiotic R&D since the 1950’s has been largely about testing many different beta-lactams with the object of finding chemical structures whose beta-lactam ring is more stable in the presence of beta-lactamases. Most possible structures have been considered so that discovering new antibiotics is now much harder. In addition, many beta-lactams have been subject to resistance from the beginning because they can be destroyed by beta-lactamases that are already encountered. Antibiotics that are not beta-lactams typically see just as much resistance develop in other ways, have higher side effects and work in a narrower range of bacteria.
Incentivising drug companies to develop new antibiotics would have limited effect since the industry is running out of good ideas for designing new antibiotics. Policies in the UK for rewarding drug companies cannot alone be of great importance on the world stage. It would certainly be fair and helpful to compensate companies for lost sales of any drugs that are held in reserve in case resistance to presently used products becomes unmanageable. However, this idea is not a solution in itself because of the limitations of current ideas for new antibiotics, although coordinated support from other countries would help.
The most constructive way in which governments can help in the discovery of antibiotics and antivirals is by funding academic research and courses relating to bacteria, viruses and microbiology in the hope of generating ideas that the industry can pursue and increasing the number of appropriately skilled scientists. In the meantime governments, doctors and managers should work to minimise resistance in the following ways:
1. Detailed, high-level, expert guidance is required on the best prescribing practice to provide the most appropriate treatment for patients with the least development of resistance.
Many doctors and scientists have opinions about what constitutes wise and responsible prescribing of antibiotics and antivirals. Nearly all experts agree that antibiotics should not normally be given to patients whose infection is obviously viral since antibiotics are not effective against viruses. The only exception arises when an antibiotic is needed as a preventative measure. Opinions vary considerably over more detailed matters where there is often little hard data and practice varies from country to country, region to region and doctor to doctor. Some of these differences reflect different types of infection and varying patterns of resistance. However, most differences reflect the impressions of doctors in the absence of conclusive evidence. For example, a standard course of most antibiotics in the UK lasts five days. In Spain the same drugs are usually taken for four days (i.e. a day less) but at double the daily dose. Which practice carries the lower risk of resistance developing and whether the position is the same for all antibiotics is simply not known reliably.
The assumption is often made that resistance will build up more slowly if antibiotics are used less. Certainly if they are never used resistance will be held in check. However, it is not true that the lowest dose will cause the least resistance. The dose must be high enough for relatively resistant bacteria to be unlikely to survive and patients should complete the course, once started.
The initial choice of drug given to a patient is important. If the original therapy works poorly the patient will benefit little from it and the scope for increasing resistance is high.
The consequences of using combinations of antibiotics or of antivirals require detailed modelling. Bacteria and viruses find it harder to become resistant to two drugs at the same time than one but if resistance does develop more than one drug stands to be compromised.
Certain combinations represent special cases. For example, in both AIDS and infections caused by a class of bacteria known as Pseudomonas a combination has always been needed to achieve high levels of effectiveness.
An interesting debate is ongoing about whether Augmentin should generally be prescribed in preference to amoxicillin. Augmentin is a mixture of amoxicillin, the most widely prescribed antibiotic in General Practice, and a substance known as a “beta-lactamase inhibitor”. The latter product has minimal antibiotic activity of its own but neutralises beta-lactamases and can therefore restore the lost potency of amoxicillin. Resistance to amoxicillin can only develop from the use of Augmentin if the beta-lactamase inhibitor fails to do its job. Use of Augmentin rather than amoxicillin alone should slow down the development of resistance to amoxicillin but risks introducing resistance to the beta-lactamase inhibitor.
Much work needs to be done, preferably at national level. New studies need to be carried out. The NHS needs to supply whatever data is reasonably required. A suitable agency to coordinate the necessary work might be NICE. This national responsibility could transform NICE from an organisation that carries out unnecessary studies relating to drug pricing with no effect on the NHS drug bill to a body at the forefront of helping mankind.
2. Development of quicker tests for identifying bacterial susceptibility to antibiotics
At present it usually takes at least 48 hours to test bacterial samples from a patient to determine what antibiotics will work against a patient’s infection. As a result the patient may initially be given ineffective medication with little benefit and a high risk of adding to resistance. Side effects may also result from combinations of antibiotics designed to increase the chance that an effective product may be included.
Whilst good ideas for promising new antibiotics are rare, the reasons for diagnostic companies not developing much quicker tests to determine the choice of antibiotic are commercial. Improved, very quick, accurate tests have the potential to have a significant impact on the development of resistance. A major drive to develop such tests and get them accepted is appropriate with either public funding or special arrangements to ensure an attractive financial return. The arrangements could be self-financing because of the reduced use of ineffective, expensive products and shorter stays in hospital.
3. Hospital Hygiene
Although viruses often enter the patient’s body in specific ways (e.g. through someone else sneezing) bacteria are often transferred through lapses in hygiene. Resistant bacteria are found most frequently in hospitals because vulnerable patients may be in close proximity, potent antibiotics are widely used and some facilities require to be sterile (e.g. operating theatres). Every case of suspected poor hospital hygiene should be independently investigated and recommendations made.
4. Isolation of sufferers from deadly new viruses
Robust plans are needed to put sufferers from new deadly viruses into isolation quickly and efficiently. Doctors must record details relevant to learning about the virus and send them to a national monitoring and coordinating centre. Scientists should start immediate work to see whether there is the potential to develop a useful vaccine rapidly.
The new virus currently posing the greatest threat is Ebola, which was first identified in 1976 and was very rare until this year. From 1976 to 2013 fewer than 1,000 people per year have been infected. The World Health Organization (WHO) has now declared an International Public Health Emergency and ruled that it is ethical to make untested vaccines available to patients. Checking whether an antiviral or antibiotic is active against the intended pathogens can be tested relatively quickly in early-stage laboratory research before work is done to confirm that the product can be safely used in humans and reaches the required parts of the body.
Whilst few good ideas for new antibiotics exist, antiviral R&D is thriving. Since the emergence of AIDS in the 1980’s drugs have been found that in combination make life expectancy in HIV positive patients fairly normal. Strong progress has been made in the treatment of Hepatitis B and Hepatitis C. Gilead’s Sovaldi, also known as sofosbuvir, for Hepatitis C was provisionally recommended for use in the UK by NICE last week at a cost of approximately £30,000 for a 12-week course. The drug is set to become the best-selling medicine ever.
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