By the Select Committee appointed to consider Science and Technology.

ORDERED TO REPORT

  1.1     Antibiotics have saved countless lives and transformed the practice of medicine since the first flowering of antimicrobial chemotherapy in the 1930s and '40s.[1] Many people are old enough to remember when these and other antimicrobial drugs were not available. Their memories include patients with pulmonary tuberculosis isolated in sanatoria until either they died or their disease healed itself; frequent postoperative wound infections; bone infections (osteomyelitis) followed by discharging sinuses requiring drainage for year after year; syphilis advancing to its late stages and ending in insanity despite the use of arsenical drugs; cases of tuberculous meningitis, invariably fatal; and simple cuts and scratches giving rise to fatal septicaemia.

Box 1

HISTORY AND TERMINOLOGY

Historically the concept of attacking invading organisms without harming the host was introduced at the turn of the century by the German Paul Ehrlich. This concept he called chemotherapy. The invading organisms he first studied were not bacteria but rather the protozoa that cause malaria and sleeping sickness; but in 1910 he made his great discovery of salvarsan (the 606th synthetic chemical he had tried) which was effective in treating the spirochaete (a type of bacterium) which causes syphilis. He called it a "magic bullet". In the 1930s the sulphonamide drugs were introduced: they were the first effective drugs that attacked the common bacteria such as streptococci and could cure pneumonia and meningitis, although they caused serious problems and side effects. They were not called antibiotics; they were known as "chemotherapeutic agents".

"Antibiotic" was the term originally applied to naturally occurring compounds such as penicillin which attacked infecting bacteria without harming the host. "Antibiotic" is now regularly used to refer to synthetic compounds as well as natural compounds, and to refer to antiviral as well as antibacterial drugs. In the public mind, however, "antibiotics" are still largely equated with penicillin.

Penicillin, the first antibiotic, was identified in a mould by Alexander Fleming in 1928; but it was not available for use until Florey and Chain and their colleagues purified it in 1940 and showed how effective it could be. Unlike the sulphonamides it seemed completely harmless to the host and very effective against many bacteria. As it was a naturally occurring product, not a synthetic chemical, it was not called a chemotherapeutic drug, although that would have been a perfectly correct description. It would also have been a correct general description to include not only all antibacterial agents but also agents against viruses, protozoa, worms and other parasites, with all of which our report is concerned. However, the word "chemotherapy" is now used and recognised by the public as the term to describe the drug treatment of cancer.

"Cancer chemotherapy" is a legitimate term if we regard cancerous cells as invasive, being therefore, like infecting organisms, foreign to the host. Cancer chemotherapy thus seeks to attack the invader without damaging the host. Chemotherapy against microbial infection is referred to as antimicrobial chemotherapy.

This report is concerned with various forms of antimicrobial chemotherapy, and mainly with antibacterial antibiotics, or antibacterials. It deals also with antiviral antibiotics, or antivirals; and with antimalarial and anthelmintic drugs.

For an historical account of the development of resistance to antibiotics, see the evidence of Professors Phillips and Roberts of the Royal College of Pathologists, p 453.

  1.2     L P Garrod wrote in 1968, "No one recently qualified, even with the liveliest imagination, can picture the ravages of bacterial infection which continued until little more than 30 years ago". Since then, many new antibacterial agents have been developed and antiviral chemotherapy, then in its infancy, has become possible for an increasing range of viral diseases. As well as its uses in the direct treatment of infection, antimicrobial chemotherapy has also helped to make possible medical advances such as transplantation and the treatment of many forms of cancer which carry a special risk of infection.

  1.3     But the worm in the bud emerged early when, during the development of penicillin, the enzyme which destroys it was isolated and it was presciently predicted (by Abraham and Chain) that penicillin resistance would become a problem. So it has, and so also, at greatly varying intervals following its introduction, has resistance to each new antibiotic.

  1.4     "Resistance" means that an organism ceases to be killed or inhibited by a drug. While antibiotics can cause, as can all active therapies, a wide range of adverse effects ranging from trivial to fatal, resistance is a special problem, since the agent loses its former efficacy and the future treatment of other patients is therefore jeopardised.[2] The problem of antibiotic resistance has now become a major concern in medicine throughout the world.

  1.5     The fact of antibiotic resistance is widely known, though not so widely understood. In the United Kingdom, the aspect most talked about among the public at large is probably MRSA (methicillin-resistant Staphylococcus aureus), an infection associated principally with hospitals and nursing homes. Other aspects of the problem are familiar to the people affected: for instance, resistant TB (tuberculosis) is a major threat to people with AIDS, while resistant malaria is the scourge of Africa and the Far East. Both Houses of Parliament have debated MRSA and other resistant infections in the past year or two (the Commons on 19 March 1997, the Lords on 4 November 1996). The Government are seized of the issue: it features in the Chief Medical Officer's annual reports for 1995 and 1996, and Ministers are awaiting advice on different aspects of it from the Standing Medical Advisory Committee and the Advisory Committee on the Microbiological Safety of Food (p 373). So we bring the matter before the House confident that it deserves Parliamentary time and attention. 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.

  1.6     We begin our report with a brief account of what resistance is and why it matters; for more on these questions, we refer the reader to a recent report by the Parliamentary Office of Science and Technology, Diseases Fighting Back (October 1994). We consider how far resistance can be controlled, and how. We then proceed to consider the evidence we have received on the various means of control: prudent use of antimicrobial agents in human medicine (Chapter 2) and in animals (Chapter 3); infection control (Chapter 4) and disease surveillance (Chapter 5); and development of new drugs (Chapter 6) and vaccines (Chapter 7). Chapter 8 considers the special problems of resistance in viruses, and Chapter 9 considers international issues including malaria. Chapter 10 considers the sources of support for research and data-collection. Our recommendations are set out in Chapter 11, and summarised in Chapter 12. Appendix 7 contains notes on some important antimicrobial agents, Appendix 8 a glossary of other terms, and Appendix 9 a list of acronyms.

What is resistance?

  1.7     All antibiotic resistance has a genetic basis. Some organisms are inherently resistant to many antibiotics ("innate resistance"). This resistance probably evolved as a response to exposure to antibiotics present in the natural environment. Many such organisms pose no threat to healthy people, but may become important pathogens in vulnerable patients in hospital. Examples include the Pseudomonas species and some Enterococci.

  1.8     Acquired resistance can arise by a number of diverse mechanisms:

      (i)  Mutational resistance. These mutations have occurred randomly in a small proportion of the particular bacterial population. The most familiar example is seen in the bacterium causing tuberculosis, where a few organisms are naturally resistant to, for example, streptomycin. In the presence of streptomycin as a single antibiotic these resistant organisms soon become the dominant population.

      (ii)  By horizontal transfer of genes determining resistance from one organism to another. This can occur by the direct transfer (conjugation) between bacteria of genetic material carried on small pieces of DNA (plasmids) situated within the bacterial cell but outside the bacterial chromosome, or by similar pieces of DNA carried on a bacterial virus, a bacteriophage (transduction), or by direct transfer of naked DNA (transformation).

  1.9     While these mechanisms have been known for many years, what has emerged more recently is knowledge of the great frequency and flexibility with which bacteria are able to exchange genetic material. and the crucial importance of these mechanisms in bacterial evolution. It is now known, for example, that genetic interchange can take place between a much more diverse variety of organisms than was formerly thought. and is probably a common event in the natural world. There is a global pool of resistance genes which can spread between different bacterial populations occupying different habitats, e.g. between man, animals and the environment. Genes carrying antibiotic resistance factors are easily able to spread if the host organism gains an evolutionary advantage in acquiring them. The importance of these processes for antibiotic resistance in man and animals is that, by whichever process genes for resistance have been acquired, the presence of an antibiotic in the environment of the bacterium imposes "selection pressure" and encourages resistance to spread. The antibiotic kills all susceptible bacteria, thereby "selecting out" the resistant strain; in this way a previously minor population of antibiotic-resistant organisms rapidly becomes dominant. Although there are enormous variations in the speed with which resistance to any antibiotic emerges, and in its geographical spread once it has emerged, it is indisputable that resistance has developed to many new agents after their introduction, with consequent diminution or actual loss of their former value to medicine. Thus has appeared the vicious circle repeatedly witnessed during the last half century, in which the value of each new antibiotic has been progressively eroded by resistance, leading to the introduction of a new and usually more expensive agent, only for this in its turn to suffer the same fate.

Clinical resistance

  1.10     Bacterial species differ greatly in their inherent susceptibility or resistance to various antibiotics. There is also a range of susceptibility within any species, so that some organisms are more susceptible than others. Clinical resistance, i.e. whether the antibiotic will or will not work in a patient or animal, is a more complex concept in which many other factors are involved such as the precise location of the infection, the distribution of the drug in body fluids and the state of the patient's immune system.

  1.11     Resistance is measured in the clinical microbiology laboratory by qualitative or quantitative methods which attempt to relate the test results to the expected effect in clinical practice, taking into account such factors as the range of serum concentrations achieved when the antibiotic is administered. Most laboratories use an agar disc susceptibility test in which isolates (i.e. samples) are categorised as susceptible, resistant or intermediate.

  1.12     There is much continued discussion about the best methods of antibiotic testing, about quality control and about international agreement on methods. In practice, the results of these pragmatic tests often relate well to clinical success or failure, for example in tuberculosis and in gonorrhoea.

  1.13     At a more basic level, the biochemical mechanisms responsible for antibiotic resistance have been analysed in great detail. Resistance arises (i) if the bacteria can inactivate the drug before it reaches its target within the bacterial cell; (ii) if the outer layers of the cell are impermeable, and prevent the drug from entering; (iii) if the drug enters but is then pumped back out again ("efflux"); (iv) if the target is altered so that it is no longer recognised by the antibiotic, or (v) if the bacteria acquire an alternative metabolic pathway that renders the antibiotic's target redundant ("by-pass"). Although some hundreds of resistances are known, virtually all can be ascribed to one of these five broad types of mechanism. See Figure 1, which represents the antibiotic as a bullet and the target as a roundel.[3]

Cross-infection

  1.14     Bacteria inhabit a global environmental pool in which resistant bacteria, and genes transferring antibiotic resistance between bacteria, can and do spread easily between people and animals. A continuous process of exchange of genes takes place within the microbial world. The two variable factors affecting the spread of antibiotic resistance are the selection pressure exerted by antibiotic use, and the ease with which resistant organisms are able to spread between people by "cross-infection".

The international dimension

  1.15     Because the amount of interaction between human populations, and with them their commensal[4] microbes, varies greatly, the type and frequency of antibiotic resistance in any particular organism differs greatly between geographical locations. In the longer term, however, once antibiotic resistance is established in an organism, it spreads with lesser or greater speed throughout the world. Modern methods of molecular epidemiology have enabled the spread of bacteria to be tracked and it is clear that bacteria, some of them carrying antibiotic resistance factors, can spread between countries and continents with phenomenal speed in this era of mass travel.

2   Resistance should be distinguished from tolerance. When a patient develops tolerance to a drug, no other patient is affected; but a resistant organism can infect others. Back

3   We are indebted for this simple account of a complex matter, and for the Figure, to Dr David Livermore, Head of the PHLS Antibiotic Reference Unit. See also Diseases Fighting Back, Parliamentary Office of Science and Technology, October 1994; and the memoranda of the Association of Medical Microbiologists (p 2) and the Society for General Microbiology (p 485). Back

4   Commensal microbes, or "flora", are the numerous and diverse micro-organisms which inhabit the skin, nose, mouth and gut. They do not normally cause disease in healthy people. Back