Select Committee on Science and Technology Written Evidence


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.  ADDRESSING GETTING AHEAD OF THE CURVE

  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 area.

3.  ADVANCES IN SURVEILLANCE AND TECHNIQUES

  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 or informative.

4.  VACCINES

  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.  THREATS

  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 use?

    —  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

October 2002


 
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