CHAPTER 1 INTRODUCTION (continued)|
1.16 Although antibiotic
resistance is encountered everywhere, there are special problems
in hospitals and other health care institutions. Many organisms
which are part of the normal commensal flora of the body pose
an important threat to patients whose resistance is lowered by
reason of illness, surgery, administration of immunosuppressant
drugs, or extremes of age. Many of these organisms, such as VRE
are highly resistant, and even previously susceptible species
can easily be replaced by resistant strains.
1.17 The hospital environment,
especially in departments such as intensive care units and neonatal
units, operates as an epidemiological pressure cooker for the
emergence of resistance, combining high infective risks in immunologically
compromised patients who are also undergoing invasive procedures,
frequent spread of infection, and high usage of antibiotics exerting
strong selective pressure on the microbial population.
1.18 Some organisms
causing hospital infection, such as MRSA (methicillin-resistant
Staphylococcus aureussee below), may also become
a significant problem outside hospitals; and, even if they do
not, their presence in the normal flora of people in the community
is an important factor in the dissemination of these resistant
1.19 Antibiotic resistance
threatens mankind with the prospect of a return to the pre-antibiotic
era. This will not, of course, happen overnight. It is a relatively
slow but inexorable process, patchy in its effects but already
under way. The options available for the treatment of infections
have everywhere become constrained. In some locations, the organisms
causing several life-threatening infections are now resistant
to all available antibiotics, so that for patients suffering these
illnesses the antibiotic era has already ended. Some examples
will serve to emphasise the great importance of resistance in
bacterial, viral and parasitic disease.
1.20 The organisms
causing gut infections such as typhoid and bacillary dysentery
are peculiarly liable to become antibiotic resistant. These organisms
also acquire resistance to several antibiotics (multiple drug
resistance, MDR) with great facility, so that Salmonella species,
for example, can become resistant to 8 or 10 antibiotics. The
genes conferring these properties are transferred together as
a package, and infections caused by these strains are untreatable
by any of the antibiotics involved. Thus, when it became possible
to treat typhoid fever with antibiotics, chloramphenicol and later
amoxycillin or trimethoprim were widely and successfully used.
Resistance to all these agents emerged so that in recent years
it has been necessary to employ ciprofloxacin as the only effective
agent remaining to us. Now ciprofloxacin-resistant typhoid has
emerged in many places and is at present causing an epidemic in
(Streptococcus pneumoniae) is a universal organism
often carried in the nose and throat of healthy people. It is
the most common cause of pneumonia in adults and children throughout
the world, a major cause of otitis media, and one of the three
most common causes of bacterial meningitis. Pneumococcal meningitis
is an especially serious form, with a high mortality and a high
probability of deafness and other neurological consequences in
its survivors. For nearly 40 years after penicillin was introduced,
the pneumococcus remained fully susceptible. Resistance then emerged
and is now in the process of disseminating throughout the world.
In some countries resistant strains are already dominant; in the
United Kingdom at present they are an increasing problem. A few
penicillin-resistant pneumococci are highly resistant and these
strains often show multiple resistance to other antibiotics. Few
options are available for treating meningitis caused by such strains,
and the agents remaining are unavailable in many poorer countries,
so that pneumococcal meningitis has become effectively untreatable
in these places.
1.22 The lives of patients
with meningococcal meningitis were first saved by sulphonamides
in the late 1930s. By the 1970s too many strains were sulphonamide-resistant
for these drugs to remain in use for a life-threatening infection
and penicillin became universally, and effectively, the treatment
of choice. Penicillin resistance in meningococci has now emerged
in a few places. Its presence anywhere is serious; spread to the
meningitis belt of Africa (a wide geographical area subject to
large epidemics every few years) would constitute a major disaster
in world health.
are omnipresent on our skins; they are normally benign but capable
of causing infections ranging from a boil to life-threatening
septicaemia. Methicillin-resistant Staphylococcus aureus
(MRSA), often also resistant to many other antibiotics, has
become highly prevalent in many hospitals and nursing homes.
Only vancomycin and related drugs, toxic, expensive and not always
effective agents, remain for their treatment; and the first isolates
of vancomycin-resistant S. aureus
(VRSA) have already been reported in Japan and the USA.
provides one of the clearest examples of the successive loss of
one antibiotic after another because of the inexorable advance
of antibiotic resistance. At first sulphonamides were successful
but resistance rapidly emerged. A form of penicillin resistance
which could be overcome by increasing the dose followed, with
a progressive increase in the amount of penicillin needed to effect
a cure. Later still, gonococci acquired the ability to make penicillinase,
completely vitiating the effect of penicillin in gonococcal infection
caused by these strains. Many other formerly effective agents
have suffered the same fate, leading to the need for progressive
changes in national and WHO recommendations for the treatment
of this common worldwide infection. Many of the changes have involved
increasingly expensive drugs.
(TB) kills around three million people each year, more than any
other infectious disease. Resistance to the first antibiotics
effective against tuberculosis was detected as soon as they were
introduced. How this could be prevented, by using two or three
agents in combination, was then rapidly discovered, and a series
of meticulous trials by the United Kingdom Medical Research Council
established regimens of treatment which were highly successful
both in curing patients and in preventing the emergence of resistance.
Resistance has remained rare in countries such as the United Kingdom,
where these regimens are generally followed under a well-established
system for diagnosis and treatment. Sadly, however, resistance
has become important in many countries because, for many reasons,
the established regimens have often been neglected by doctors
and by patients.
1.26 Multi-drug resistant
(MDR) tuberculosis is a newer and different problem, found especially
but not exclusively in patients with HIV infection, carrying a
high mortality and extremely difficult to treat. Here is another
example, in which our antibiotic options are nearly exhausted
and when tuberculosis again becomes "the captain of all these
men of death".
MDR tuberculosis is at present rare in the United Kingdom.
is thought to cause two million deaths and several hundred million
new infections annually throughout the world. A variety of resistance
patterns has emerged, creating serious constraints on the options
available for both treatment and prevention. In highly endemic
areas it is becoming increasingly difficult to treat life-threatening
disease in children. Most important is chloroquine resistance,
now widespread in many continents. Chloroquine resistance has
necessitated a return to the oldest of all chemotherapeutic agents,
quinine, but multiple resistance, including partial resistance
to quinine, is now a major problem in SE Asia. The consequences
of the current degree of malarial resistance are massive, especially
in Africa where Ministries of Health have annual budgets of a
few dollars per head. See Chapter 9 below.
can also become resistant to the drugs used in their treatment.
This takes place inside the cells of the patient, within which
the virus multiplies. Viruses such as HIV replicate very rapidly
and minor variations of the genome occur with each multiplication,
leading to a genetically heterogeneous population of viral particles.
It is inevitable that, in the presence of an antiviral drug, variants
with increased resistance to its action will show a selective
advantage and will soon become the majority species. Much effort
is now being undertaken to find how best to use antiviral drugs
in ways which make it more difficult for resistance to emerge.
See Chapter 8 below.
1.29 The impact of
antibiotic resistance on our ability to treat some important infections
is summarised in Box 2.
1.30 There are some
exceptions to the general onward march of resistance. For example,
Streptococcus pyogenes (group A haemolytic streptococcus)
has so far remained susceptible to penicillin, although it is
often resistant to several other agents. Likewise, resistance
has rarely been reported among the chlamydia, an important cause
of genital and eye infections including trachoma; and the causative
organism of syphilis (Treponema pallidum) has remained
susceptible to penicillin. We do not attempt to describe the problem
of resistance as it affects all pathogens, but have concentrated
on those of particular importance for world health.
1.31 How to tackle
the problems of resistance depends critically on the answer to
a question on which science is divided: can the rise in the proportion
of resistant strains be reversed, or at least slowed down, or
is it inexorable?
1.32 Professor David
Reeves, President of the Association of Medical Microbiologists
(AMM), is an optimist. "There is plenty of evidence that,
if you remove the selection pressure, the organisms will slowly
revert [to susceptibility], some types of organisms more quickly
than others and to certain antibiotics more quickly than to others"
(Q 23, cp McGavock Q 675). Dr Peter Davey, Reader
in Clinical Pharmacology at Ninewells Hospital, Dundee, gave us
a table of supporting evidence for the proposition that resistance
is dependent on usage (p 145), but produced at least one
potential confounding variable for each point. Professor A Percival,
Professor of Clinical Bacteriology at Liverpool University, put
it starkly: "The concept that antibiotic resistance is related
somehow to the amount of use is critical, because, if it is not
true, then we have no chance of controlling it...Although everybody
believes that, the evidence to support it and to demonstrate it
in a scientifically acceptable way is largely lacking...worldwide"
1.33 In marked contrast
with Professor Reeves' optimism was the approach of Dr Bruce
Levin, a population biologist from Emory University, whom we met
in Atlanta. He believes that resistance is a one-way street: even
if antibiotic use is cut back sharply, the proportion of resistant
strains wanes slowly if at all; even moderate use still imposes
heavy selective pressure; and, if use is resumed, resistance rises
again more rapidly than before. As he put it, "We are committed
to an arms race"; disarmament is not an option. See Appendix 6.
1.34 Countries with
firmer controls on the supply and use of antibiotics, and more
rigorous infection control, have lower rates of resistant strains,
and it is generally assumed that these things are connected. "Holland
and Denmark have amongst the lowest incidence of MRSA, due to
their effective antibiotic and infection control policies"
(PHLS p 42). "Spain has the highest consumption of anti-infectives
per capita in Europe, and one of the worst records of antibiotic
resistance" (ABPI p 176).
EXAMPLES OF VALUABLE ANTIBIOTIC THERAPIES NOW LOST OR IMPERILLED BY THE SPREAD OF RESISTANCE
||Agents lost or threatened
||Pneumonia, otitis, meningitis
||Penicillin; many others
||Wound infection, sepsis
||Penicillin, penicillinase-resistant penicillins, others
||Most relevant agents
||Most relevant agents
||Sulphonamides, penicillin, tetracycline; (ciprofloxacin)
||Chloroquine, pyrimethamine; (mefloquine, quinine)
|E. coli (coliforms)
||Urinary infection, septicaemia
||Ampicillin, trimethoprim, others
1.35 Slowing the take-over
of resistant strains is one thing; eradicating them once they
have arrived is another, and seems to be easier for some organisms
than for others. Resistance in the gonococcus to penicillin (PHLS
p 68), and in Strep. pyogenes to erythromycin (AMM
p 9, Finch p 187), can be reduced; resistance in Staph. aureus
to methicillin (PHLS p 43) and in E. coli to
streptomycin (PHLS p 52), once prevalent, appears to be stable.
1.36 Throughout our
enquiry we have listened for stories of success in reversing the
rise in the proportion of resistant strains. Only two such stories
have been rigorously researched and written up (Anderson Q 687).
In Finland, an increase in resistance of Group A streptococci
to erythromycin around 1990 was countered by a policy restricting
the use of macrolides in favour of alternative drugs. Consumption
was reduced by nearly a half by 1992, and the rate of resistance
was nearly halved by 1996. Dr Davey told a similar tale from
Iceland (Q 261), where a problem with penicillin-resistant
pneumococci was associated with day-care centres for children.
"There was an information campaign aimed at the public and
doctors, saying that giving antibiotics to children too frequently
at day-care centres was not a good idea. They did reduce the antibiotic
prescribing, and they have reduced the transmission of these resistant
1.37 According to the
Department of Health, "The role of the use of antimicrobials
in the development of antimicrobial resistance is undoubted. Those
countries with high usage and uncontrolled availability of `over
the counter' antibiotics tend to have higher levels of antimicrobial
resistance, whereas Denmark for instance has seen a dramatic reduction
in the prevalence of antibiotic resistant micro-organisms since
tight controls on antimicrobial usage, together with strict infection
control procedures, were introduced" (p 342).
On the basis of the Danish experience, the Chief Medical Officer
considers that it should be an objective of Government strategy
"to reduce the prevalence of micro-organisms resistant to
current drugs" (Q 756).
1.38 As for malaria,
Dr David Warhurst of the London School of Hygiene and Tropical
Medicine told us, "There is evidence that, if drugs are not
used, some of these [resistant malarial] organisms will probably
get back to their pre-existing state" (Q 493). Dr Deenan Pillay,
Director of the PHLS Antiviral Susceptibility Reference Laboratory
in Birmingham, told a similar tale from virology (Q 614).
1.39 So what is the
policy-maker to conclude? We suggest that the following propositions
conform with the present state of knowledge:
(i) Any antimicrobial agent
must be expected to encounter resistance sooner or later.
(ii) Resistant strains will take
longer to emerge and spread if antimicrobial use is controlled
and prudent from the start.
(iii) Improving the control of
antimicrobial use can be expected to slow down the rise in the
proportion of resistant strains. In the case of certain pathogens
(e.g. streptococci, pneumococci, gonococci), the proportion may
even fall; but this must not be expected to happen in every case.
If, following an improvement in control and a fall in resistance,
control is once again relaxed, reversion to high levels of resistance
may be swift.
1.40 Why reducing the
selective pressure of antimicrobials sometimes brings down the
level of resistance and sometimes does not, scientists cannot
yet say with certainty. As noted above, in cases where it does,
it may be because resistance, though in itself an advantage from
the microbe's point of view, confers a collateral burden such
that, in the absence of selective pressure, the resistant strain
is at an evolutionary disadvantage (i.e. in terms of "survival
of the fittest", the resistant strain is less fit), and susceptible
strains take over again. Where resistance does not evolve away,
it may be because the resistant strain has undergone a secondary
adaptation and evolved around the burden, so that in the absence
of selective pressure it is no longer at a disadvantage. Alternatively,
it may be because the plasmid carrying the gene which confers
the resistance in question also carries, as a package, genes which
code for resistance to other agents (e.g. Salmonella may carry
packages of resistance to as many as 10 antibiotics); if just
one of these agents remains in use, selective pressure will keep
all the resistances in the package at high levels.
1.41 These rules of
thumb, though rough and ready, are based on evidence from leaders
in the field in both the United Kingdom and the USA; and those
with whom we have spoken readily admit that knowledge in this
area is incomplete and somewhat anecdotal. The case for continued
research is clear: see Chapter 10 below.
1.42 The enquiry which
led to this report was conducted between July 1997 and March 1998
by Sub-Committee I, whose members are listed in Appendix 1.
They received evidence from the organisations and individuals
listed in Appendix 2, to all of whom we are grateful for
their time and trouble. They paid two visits to the Headquarters
of the Public Health Laboratory Service (PHLS) in Colindale, where
Professor Brian Duerden, Deputy Director, and numerous members
of PHLS staff, were extremely helpful: see Appendices 3 and
4. They visited King's College Hospital, on Denmark Hill; we are
grateful to Professor Mark Casewell, then Professor of Medical
Microbiology, and to members of the medical and nursing staff,
for organising a very informative visit: see Appendix 5.
In November, four members visited the USA: Appendix 6 describes
the visit, and acknowledges the numerous people who gave generously
of their time to make it worthwhile. We acknowledge the help of
Sub-Committee I's Specialist Advisers, Professor Harold
Lambert, Emeritus Professor of Microbial Diseases at St George's
Hospital, Tooting, and Professor Richard Wise, Professor
of Clinical Microbiology at Birmingham City Hospital. Finally,
we are grateful to the Parliamentary Office of Science and Technology
(POST), for the report Diseases Fighting Back noted above,
and for a report on Vaccines and their Future Role in Public
See the evidence of Dr H F Kennedy and Dr J R
Michie of the Royal Hospital for Sick Children, Glasgow (p 549). Back
See the evidence of Professor Keith Klugman, Director of
the South African Institute for Medical Research (p 426). Back
See the evidence of Dr R Hill of King's College Hospital,
p 417. Back
These isolates have also been characterised as "vancomycin-intermediate"
(VISA), because, although their susceptibility is reduced, they
are not absolutely resistant. We were told in the USA that these
isolates, though alarming in their own right, were not what VRSA
had been expected to look like. Back
John Bunyan, The Life and Death of Mr Badman. Back
Dr B Bannister at Coppetts Wood Hospital sees 50 new cases of
TB each year; of these, two or three are MDR-TB, usually in people
from Turkey or central Africa (p 377). Professor D A Mitchison
of St George's Hospital puts the total number of cases of
MDR-TB in the United Kingdom at present at fewer than 20 (p 432). Back
Because of the widely variable distribution of antibiotic resistance
at any time, a clear distinction between `lost' and `threatened'
cannot be made. An antibiotic now useless in one place may still
be valuable in another. Resistance to the agents in parentheses
is so far uncommon. Back
Dr Rosamund Williams of WHO (Q 132) told us that the
Danish strategy included surveillance of resistance and usage,
strict national prescribing guidelines with follow-up of doctors
who infringe them, and isolation and screening of infected persons.
The Minister for Public Health said that the Department of Health
are "very interested" in the Danish approach (Q 755). Back