Superbugs – the problem of antimicrobial resistance

This essay was written by Roger Buxton and was first published in the 2001 Mill Hill Essays.

We can close the book on infectious disease

U.S. Surgeon General testifying before Congress, 1969

This enquiry has been an alarming experience, which leaves us convinced that resistance to antibiotics and other anti-infective agents constitutes a major threat to public health and ought to be recognised as such more widely than it is at present

Resistance to antibiotics and other antimicrobial agents. Report of House of Lords Select Committee on Science and Technology, 1998

Following a car accident Ed Hill was taken to the local hospital and was in intensive care for nine days. He seemed to be recovering well and was then transferred to another ward where he deteriorated. Ed became confused and at some points he lost consciousness. Eventually he was found to have MRSA [methicillin-resistant Staphylococcus aureus]. He was put on a course of Vancomycin and kept in hospital for another two weeks

BBC News report, 2000

Nine out of one hundred patients in Britain acquire an infection whilst in hospital resulting in the loss of five thousand lives and a cost to the National Health Service of one billion pounds a year. The most worrying aspect of this is that many of these infections can no longer be treated with the usual antibiotics because the bacteria that cause them have become resistant to antibiotic attack. Resistance to the antibiotic methicillin among infections due to the bacterium Staphylococcus aureus increased from one point seven percent in nineteen ninety to three point eight percent in nineteen ninety-three, but rose steeply to thirty-four percent in nineteen ninety-eight. The problem is not confined to hospitals. One in twenty patients discharged from hospitals have been reported to carry antibiotic-resistant bacteria. Should we be concerned about this and what can we do about it? Are we looking at a nightmare scenario of multiresistant bacteria laying waste the human race or will scientists always come up with ideas for new drugs to combat infections? What has gone wrong since the optimistic statement of the U.S. Surgeon General in nineteen sixty-nine? In general the answer is that we are using too many antimicrobial drugs for the wrong reasons. The biggest single factor in the spread of antibiotic resistance is the huge quantity of antibiotics used in human medicine and agriculture.

How do antibiotics work and why are they such a special form of treatment against bacterial infections? After all it is not difficult to kill most forms of bacteria, you can just soak them in bleach. The problem is that bleach will kill you along with the bacteria. Antibiotics, however, are substances produced by living organisms that kill bacteria but leave the patient alive. The reason for this apparently amazing selectivity is really very simple. It is because many of the chemical processes in bacteria are so very different from those in man or indeed in any animal. Penicillin for example, works by interfering with the growth of the wall that surrounds bacterial cells. This wall is made of a substance quite unlike anything in animals or plants. Other antibiotics work by interfering with other parts of the bacterial biochemistry that are also distinct from animal processes.

Antibiotics completely revolutionised the practice of medicine and have saved untold numbers of lives. A graphic description of the relationship between doctor and patient before the advent of antibiotics is given by Ronald Hare, himself the son of a doctor, in his book “The Birth of Penicillin“. He describes the doctor’s visit in those days as a morale boosting procedure carried out with little in the way of examination. The doctor almost invariably visited the patient, but was usually called only as a last resort. After antibiotics came into use the doctor became much more popular. So much so that he could not see all patients in their own homes, they now had to visit him and wait. The reason for this popularity was that doctors could now make a real difference to the patient’s well being and were therefore sought out much sooner by the patients. Diseases that had been completely incurable were now treated with antibiotics without even a hospital visit. Ronald Hare notes that hospitals became transformed through the use of antibiotics. “Patients with all the many forms of tuberculosis, the tertiary stages of syphilis, the cardiac complications of rheumatic fever, osteomyelitis, deep abcesses, carbuncles, and meningitis have become increasingly unusual. Compound fractures still become infected and patients with appendicitis or acute peritonitis still appear in the wards, but with an antibiotic to help them they are seldom in danger and generally recover quickly.” And even now antibiotic therapy is still developing. In nineteen eighty-two it was shown that the leading cause of peptic ulcers was a bacterium, Helicobacter pylori, and that antibiotic therapy could be used successfully in a disease previously attributed to “stress”. Other diseases not previously thought of as being affected by bacterial infection may also benefit from antibiotic therapy. A recent example is the use of antibiotics to treat patients at risk of heart disease. It seems that some types of heart disease may be made worse by bacterial infections. So antibiotics continue to be effective in ways previously not thought of. They are a success story of twentieth century medicine, and many other advances in medicine, particularly surgery, would have been impossible without their use.

Within a couple of years of the first use of antibiotics, however, resistant bacteria were found and they have continued to spread. The reasons for this are linked to two special properties of bacteria: their ability to exchange genetic material with other bacteria and their incredibly fast growth. Antibiotic resistance arises either through changes called mutations in their genetic material, DNA, or by the acquisition of mutant DNA from other organisms by transfer of genetic material. In the case of new mutations, bacteria are at an immense advantage since they grow so fast. A standard laboratory bacterium divides into two new cells in the course of twenty to thirty minutes, and these two cells are each immediately ready to grow and divide into two more cells in the next twenty minutes. A single bacterium therefore can produce more than a million cells in the course of twelve hours. If an antibiotic is present in the growth medium then only the rare bacterium that has acquired a mutation making it resistant to the antibiotic will be able to grow. To acquire mutations by genetic transfer, bacteria have evolved a number of methods by which new genes are transferred from other bacteria. One way involves the release of DNA from bacteria into the environment. This DNA may then be taken up by other bacteria. Another is by insertion of small circular molecules of DNA called plasmids directly from one bacterial cell into another. Genes producing resistance to antibiotics, which occur naturally in organisms in the environment, can be carried by plasmids. Resistance can be rapidly transferred through a population of bacteria so that transfer itself is infectious. Many resistance genes are thought to have come originally from other bacteria in the soil or in the guts of humans or animals.

Whatever antibiotic is used, resistant mutants will be obtained. Mutations provide resistance in a number of different ways. Some result in the antibiotic being pumped out of the bacteria, others change the target so that it is no longer blocked by the antibiotic, and in others the antibiotic is chemically inactivated. Scientists have been very active in finding new antibiotics and in making chemical modifications to old ones, but we have reached a point where no new classes of antibiotics have been discovered in the last twenty years. However, with the new knowledge of the complete DNA sequence of many bacteria it is now becoming possible to design new classes of antibiotics that, for example, target the regulation of chemical processes in the bacterium. Nevertheless, mutations will still arise. Killing bacteria is like hitting a moving target – just when you think you’ve got them, they mutate. There will therefore be no “final victory” in the war against microbes; there can only be a continual antimicrobial “arms race”. Research into new types of antimicrobial agents will still be necessary in the future, as well as research into other forms of therapy such as the development of vaccines against particular types of bacteria.

Knowledge of how and why bacterial antibiotic resistance mutations occur helps us to identify practices in the use of antibiotics which have increased the spread of resistance. Spread has not been uniform in all countries of the world. In Denmark for example, only zero point two percent of Staphylococcus aureus bacteria are resistant to methicillin, but this rises to forty percent in Greece and eighty percent in Japan. Parts of the former Soviet Union also have a high rate of resistance. Undoubtedly these differences are related to both the availability of antibiotics and their method of use. In many of the countries with high rates of methicillin resistant Staphylococcus aureus, antibiotics can be freely purchased without a doctor’s prescription. They may then be used for incorrect periods of time and in inappropriate situations. Mutations leading to antibiotic resistance are much more likely to occur if the bacteria are exposed to low doses of drug since the bacteria can then accumulate a series of mutations gradually. Similarly, if the antibiotic is taken for too long, the chance of resistance developing increases, and on the other hand, if a treatment course is not completed, drug-resistant organisms may more easily survive. The same can happen if the course of treatment involves more than one antibiotic, as does the current therapy for tuberculosis. If the drugs are taken one after the other, rather than all at once, an antibiotic-resistant organism can emerge which can then accumulate further mutations when it is exposed to the next antibiotic. On the other hand if the antibiotics are taken together, the chance of a mutation giving resistance to all the antibiotics at the same time is vanishingly small.

Antibiotics should therefore be more and more regarded as precious drugs requiring careful regulation. Even in Britain antibiotics are often prescribed unnecessarily for infections that are caused by viruses rather than by bacteria. Upper respiratory tract infections or bronchitis, which are mostly viral in origin, account for more than one fifth of all antibiotic prescriptions, and it has been estimated that between ten and fifty percent of outpatient antibiotic prescriptions are unnecessary. Improved diagnostic procedures would help to alleviate this over-prescribing since doctors sometimes write a prescription “just in case” bacteria are involved in a disease. Increasing patients’ understanding of these problems would also help to dampen down expectations that an antibiotic will always be prescribed.

Perhaps more controversial is the use of antibiotics in agriculture and veterinary practice. Besides being given to combat specific disease conditions, antibiotics are given at high doses to prevent infections occurring. This provides strong selective pressure for resistant organisms, especially in the conditions of close animal proximity common in many modern farming practices. Lower doses are also given to enhance food conversion. The appearance of Enterococcus faecium resistant to the antibiotic vancomycin, the “antibiotic of last resort” for the treatment of methicillin resistant Staphylococcus aureus, is a particularly ominous example of a resistant bacterium appearing in animals that subsequently was transferred to humans; its emergence in food can be traced to the widespread use of a type of vancomycin in livestock. However, since antibiotics are of such financial benefit to agriculture it is most unlikely that their use will be eliminated. But prudence demands that, as is the case in Britain, only antibiotics not used in human medicine or those which do not select for cross resistance with antibiotics used in humans are used for this kind of performance enhancement.

Not all bacteria cause disease. Bacteria are part of a normal healthy human which, it has been estimated, actually contains more bacterial cells than human cells. It is therefore undesirable, even unhealthy and dangerous to try to sterilise our environment either inside or outside the body. Antibacterial substances are now incorporated into such things as chopping boards, food containers, and even sandals. They are bound to result in the selection of resistant mutants sooner or later, and whilst this may not in itself be detrimental to human health, the danger is that these resistance-causing genes will be transferred to bacteria that do cause disease. Basic hygiene procedures, and infection control procedures in hospitals such as proper use of disinfectants and correct hand washing practices are still absolutely essential to prevent the spread of antimicrobial resistance. In the developing world, simple public health measures such as improving levels of sanitation, access to uncontaminated water and reduction of overcrowding are of far greater benefit to the public health than the widespread use of expensive drugs.

With what infections is antibiotic resistance of most concern? Mention has already been made of methicillin resistant Staphylococcus aureus. Staphylococci are among the most important bacteria that cause disease in man. They are actually normal inhabitants of the upper respiratory tract, skin, intestine and vagina. They can however produce disease in almost every organ and tissue of the body. They multiply and spread in tissues through their production and release of chemicals into the tissues. The classic examples of this disease are localised abscesses and boils, but more serious diseases are toxic shock syndrome and a bone infection called osteomyelitis. Staphylococci are the classic hospital-acquired bacteria which usually produce disease in people whose defensive mechanisms are compromised. Other hospital-acquired infections of concern include Enterococcus faecium that causes colitis and enteritis, since many of these are now resistant to the antibiotic vancomycin.

On a world-wide scale, bacteria causing pneumonia, such as Streptococcus pneumoniae, are now resistant to the first-line of antibiotics, as are bacteria such as Shigella dysenteriae, a cause of diarrhoea particularly in under-developed countries. For non-bacterial infections, mutants of the human immunodeficiency virus, the causative agent of AIDS, are rapidly becoming resistant to antiviral drugs, and amongst the parasitic protozoa resistance to the front-line anti-malarial drugs is now widespread. The human race would not die out if all antimicrobial agents became ineffective but undoubtedly mortality would increase and life would be much more uncomfortable and less predictable than at present.

It is generally agreed that the best way to reduce the emergence of resistance to antimicrobial agents is to reduce usage and to put into place better, more effective prescribing habits together with more effective basic hygiene measures. It may be useful to look at the lessons to be learned from what the city of New York did to counteract the emergence of drug resistant cases of tuberculosis when multi-drug resistance increased from six percent in nineteen eighty-seven to fourteen percent in nineteen ninety-one. At the heart of the epidemic was the failure of patients to comply with the treatment prescribed. This was caused by cuts in tuberculosis control, poor communication between inpatient facilities and community services, and social upheavals that led to increases in overcrowding, homelessness and the spread of HIV that is known to be a fellow traveller with tuberculosis. The city’s public health department overcame the problem by improving infection control in hospitals, improving the co-ordination between health services and especially by improving compliance with the prescribed drug regimen through expanding the directly observed therapy programme. Cases of multidrug resistant tuberculosis fell from four hundred and forty-one in nineteen ninety-two to fifty-six in nineteen ninety-seven. In a wider context the same programme is used for tuberculosis therapy throughout the world under the auspices of the World Health Organisation. It is especially needed for tuberculosis because the therapy takes a long time compared with treatment of most other bacterial diseases. We may indeed see a need to introduce other “simple” measures to combat disease; the use of isolation, formerly a mainstay of tuberculosis therapy immediately springs to mind. Although tuberculosis, perhaps more than most diseases, is as much a social and political disease as a medical one, the lesson from New York points to the importance of adequate surveillance and the need to encourage patients to adhere to treatment. In the end it comes down to cost and organisation. Even back in nineteen fifteen the annual report of the New York City Board of Public Health stated: “The city can have as much reduction of preventable disease as it wishes to pay for. Public health is purchasable; within natural limitations a city can determine its own death rate.” It all depends on how much we are prepared to pay; for the research needed to develop new antimicrobial agents, the development of new vaccines, surveillance systems, infection control nurses, and diagnostic tests for infection. There is no single remedy for antimicrobial resistance, rather a multidisciplinary approach is required to tackle the problem. Above all we should remember that antimicrobial drugs are a resource that must be conserved for future generations.

 

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