WRITTEN EVIDENCE RECEIVED
UP TO 18 FEBRUARY 2003
Memorandum by Professor S.G.B. Amyes,
University of Edinburgh
1. MAIN PROBLEMS
1.1 There is no doubt that we face a crisis
in our capability to manage many infectious diseases. A great
deal of attention is focused on "new" pathogens and
the document "Getting Ahead of the Curve" does identify
some. However, the impact of some of these pathogens is minimal
compared with more widespread pathogens that have now become increasingly
difficult to treat.
1.2 The management of hospital-acquired
infection probably has the greatest impact in our decreasing capability
to deal with infectious diseases. Many of the infectious agents
that we were once able to treat adequately are now increasingly
problematic. The decreasing capability of control measures, whether
they are antibiotic therapy or other methods, is the major obstacle
in the management of Infectious Diseases in the 21st Century.
If we look at the main pathogens still responsible for severe
infection in this country, these are mainly associated with bacterial
infections in patients at both extremes of age and in patients
severely compromised by other medical conditions. The improvements
in medical procedures, particularly those involving chemotherapy
and transplantation, have resulted in a renaissance of some bacteria
as pathogens. The multi antibiotic resistant bacterial pathogens
such as Staphylococcus aureus, Enterococcus faecium, Acinetobacter
baumannii, Klebsiella species, Pseudomonas aeruginosa,
within the hospital population and Streptococcus pneumoniae,
Burkholderia cepacia and Mycobacterium tuberculosis mainly
in the community. These bacteria are already, in some areas, impossible
to treat and are likely to become significant problems within
this country. The Department of Health has suggested that 5,000
people a year die directly from hospital acquired infection and
that the deaths of 15,000 may be promoted by hospital acquired
infection. In such a case, approximately 5 per cent of the population
will die from hospital-acquired infection, which might translate
to around 60 patients per day. This should be compared with the
total number of cases of vCJD or even HIV.
1.3 Our surveillance procedures might be
adequate to identify these problems as they emerge but they have
not had significant success in reversing the decreasing capability
to treat infections caused by these bacteria. We are often not
sure how closely related individual strains of bacteria are to
each other. We speciate bacteria with tests that often were devised
over 100 years ago, but we type bacteria with molecular biology
tests that can virtually prove two bacteria colonies are identical.
Why is it important to provide better speciation of bacteria?
Largely it is because all surveillance of bacteria groups them
within these species. If these species comprise a heterogeneous
population of bacteria, then we are comparing unlike bacteria
with one another. There have been some significant advances in
molecular taxonomy but these are very slow to be implemented within
routine diagnostic laboratories.
1.4 We are often surprisingly ignorant about
the dissemination of bacteria and the causes of their spread.
It is easy for us to suppose that the use of antibiotics is solely
responsible for the emergence of antibiotic resistance. However,
there are very few robust studies that can prove this directly.
We often cannot prove whether resistant bacteria have evolved
directly from the sensitive bacteria that we have previously observed
in the clinic. This information would have an enormous impact
on the way that we would use antibiotics. Other factors must play
a role, but we often do not know what they might be. We do not
know what contribution modern hospital design plays in the spread
of resistant (or sensitive) bacteria from patient to patient.
Certainly resistant bacteria seem to spread more rapidly through
hospitals of modern design than in those where more traditional
nursing techniques have been retained.
2.1 I do not believe that the document Getting
Ahead of the Curve does really address the problems, at least
as far as bacterial infections are concerned and particularly
those that are becoming multi-drug resistant. The document calls
for better surveillance but we have been performing widespread
surveillance for most of the last century. We have a Public Health
Laboratory Service that is the envy of many other countries. However,
this service and the reporting streams did not cover the whole
of the United Kingdom and different techniques have been used
north and south of the border. A true surveillance system must
be uniform for the whole country and probably for the whole continent.
The Americans can achieve this, so should the Europeans. We should
identify the problem as a global one and probably deal with it
as a European one.
2.2 We probably have not been ahead of the
Curve because we have only had vague ideas of our goals. We really
need to redefine what information we want to obtain. If resistance
emerges in a population, we need to know where it comes from,
what promotes it, how it spreads, on what genetic form it is carried,
and how it has been controlled in other areas. There has been
relatively little progress in the methods and the analyses that
we have performed on bacteria. This has largely been caused by
reluctance to fund research into the problems of bacterial diseases,
which has been a result of complacency about our capability to
treat all bacterial infections. If as many people were to die
from vCJD as die from hospital-acquired infection then we would
consider that we were in the middle of pandemic and extraordinary
measures would be introduced to try and control it. Actually we
probably know the causes of vCJD but we often do not know how
patients acquire multi-drug resistant bacteria. The major problem
is really that many do not recognise that there even is a problem.
2.3 In the recent meeting hosted by the
Institute of Biology, I was asked to raise issues for policy makers:
I suggested that we should increase radically our research into
this area. All the grant-funding bodies see the need for this
and now have initiatives for research into antibiotic resistance.
The problem is that these initiatives are often under-subscribed
because we have allowed the number of researchers in this area
to decline as they found increasing difficulty to obtain funding.
There simply is not the research base for this type of initiative
in this country. I assess for a number of grant-awarding bodies
and most of the applications are of a low standard. We need to
train microbiologists and infectious disease physicians and we
should probably move towards the American model where microbiologists
are science graduates with PhDs and that infectious disease specialists
are those who are medically-qualified. Microbiology should now
be leading-edge science, which relies largely on the advances
in molecular biology. For this we need scientists trained in the
3. ADVANCES IN
3.1 For the reasons listed above, I do not
believe that we have benefited from the implementation in new
techniques. Most of these techniques are molecular biological;
they require not just expensive equipment but also considerable
expertise in molecular biology. This expertise is not readily
available in all laboratories. We now have the techniques to track
individual clones of bacteria through the human population; however,
many diagnostic and some reference laboratories are still using
phenotypic techniques that have been shown to be less reliable
4.1 Vaccines appear to be an attractive
alternative to antibiotics. I can only comment on vaccines against
bacterial infections and there are actually relatively few effective
vaccines against these micro-organisms. Vaccines require prediction
of the problem and then an informed vaccination campaign. There
are possibly two problems with this. Vaccination is not popular
amongst the general population, particularly if it is perceived
that only a small minority of individuals would benefit immediately.
In the control of hospital-acquired infections, vaccination may
not prove effective because many patients are immunocompromised
and also it is difficult to predict what infections they might
be prone to. The main problem with vaccines is that they have
to be administered pre-infection and, as there are so many possible
infectious agents, this could incur a heavy burden on individuals.
5.1 The largest threats appear to be an
inability to treat the infections that we once were able to control.
If the situation continues then we shall reach a situation that
certain bacterial infections become effectively untreatable. This
will not happen with all bacterial infections but certainly with
some of the bacteria that cause hospital-acquired infection. We
know already that methicillin-resistant Staphylococcus aureus
can aquire the glycopeptide resistance genes of enterococci,
not just in the laboratory but also recently within clinical bacteria.
If this organism became widely disseminated it would radically
affect the procedures that hospitals and individuals would be
prepared to undertake. How many people would be willing to have
a hip-replacement if any resultant infection would be likely to
be untreatable? Many procedures in hospitals are performed because
the risk analysis makes the hazards an acceptable price for success.
However, in an environment of untreatable bacterial infection,
a very different risk analysis would result.
6. POLICY INTERVENTIONS
6.1 I do not believe that we yet have sufficient
information to make good policy interventions. There are many
preconceptions about bacterial infections and the development
and spread of resistance but actually surprising little data to
support them. Before we make policy interventions, we should have
more robust information.
6.2 In the recent meeting hosted by the
Institute of Biology, I was asked to raise issues for policy makers
and I proposed some issues that should be addressed: we need answers
to some basic questions and we need those answers supported by
good molecular data obtained, if possible, by prospective study.
How does resistance develop within
the bacterial population?
What is the link between antibiotic
usage and resistance?
Does antibiotic use in husbandry
and agriculture cause Resistance?
For this we need good epidemiology. Not simply
surveillance but the type of epidemiological analysis that demonstrated
the pivotal cases of the recent foot-and-mouth epidemic or the
case 0 for HIV infection in the USA. We have to understand how
bacteria are transported, why some survive better, what other
factors besides antibiotic usage promotes their survival. This
can only be achieved by prospective study by teams that are simply
focused on this goal. It cannot be achieved as a sideline to routine
diagnostic work nor even reference laboratory studies, which by
their nature only get the most difficult strains, thus are examining
a biased population. Epidemiology is important science and should
undertaken by experts trained in it.
6.3 We also need to establish the factors
involved in the culture of antibiotic prescribing:
Are antibiotics really used inappropriately?
How can we promote rational antibiotic
Are they simply not up to the job?
It is often said that antibiotics are used inappropriately.
This may be true but there are very few studies that demonstrate
this clearly. We need to know if, by changing our behaviour, we
could reduce the spread of resistance. In this case we could then
promote rational antibiotic use. A question we should ask is whether
antibiotics are really the suitable agents for the role that we
now expect them to perform. For instance, when they were first
used their role was essentially to stop bacteria from an acute
infection from dividing, the immune system would then take over.
Now we expect them to keep patients alive while they are immunosuppressed.
Once we establish the crucial factors involved in prescribing
there should be incentives for good prescribing.
6.4 Part of the crisis in the treatment
of bacterial infections comes from the reluctance of pharmaceutical
companies to place their major research efforts in this area.
The merger of pharmaceutical companies has resulted in very little
research still being performed in this country. As a major industrial
power, we should try to reverse this. Not only would it bring
prestige but also give British scientists some influence in the
development of this crucial market. However, the industry needs:
Incentives for antibiotic development.
Extension of antibiotic patent life.
The former could come from tax incentives that
some other countries provide. We still have the scientific training
base in this country but we do not have the commercial research
laboratories to place these graduates. Scientific research could
also be performed with Centres of Excellence in the Universities;
some such as the University of Edinburgh are already initiating
Centres of Infectious Diseases. This would also allow commercial/academic
partnerships; however, such initiatives are often shunned by the
stigma with which they are viewed by some academic institutions,
as well as the hefty overheads that some universities impose (up
to 110 per cent in this country compared with figures as low as
20 per cent in come institutions in the USA). Possibly the greatest
incentive for antibiotic development would be the extension of
the patent life. The patent life of antibiotics is often the same
as other pharmaceuticals but, unlike other pharmaceuticals, the
success of antibiotics is sensitive to the manner in which they
are prescribed. Widespread prescription is thought to lead to
widespread resistance. Slower introduction over a longer time
period is likely to reduce the emergence of resistance. The companies
have no incentives for delaying the introduction of their new
antibiotics. If the patent life of these unique pharmaceuticals
was extended, research into new development and a more measured
introduction would be much more attractive.
6.5 The other areas that require rapid development
are research into:
Prediction of resistance development
in new drugs.
Possibilities to slow this process,
both medical and social.
and the implementation of:
Rapid diagnosis and molecular taxonomy.
Rapid resistance identification leading
to rational prescribing.
Professor S.G.B. Amyes