17 March 1998
By the Select Committee appointed
to consider Science and Technology.
RESISTANCE TO ANTIBIOTICS
OTHER ANTIMICROBIAL AGENTS
CHAPTER 1 INTRODUCTION
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. 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.
|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.
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.
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:
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.
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.
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".
1.15 Because the amount
of interaction between human populations, and with them their
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.
For terminology, see Box 1, and the glossary in Appendix 8. Back
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
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
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