Select Committee on Science and Technology Seventh Report


CHAPTER 1 INTRODUCTION (continued)

Hospital infection

  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 (vancomycin-resistant enterococcus[5]), 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 aureus—see 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 strains.

Does antibiotic resistance matter?

  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 Tajikistan.

  1.21     Pneumococcus (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.[6] 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.

  1.23     Staphylococci 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.[7] 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[8] (VRSA) have already been reported in Japan and the USA.

  1.24     Gonorrhoea 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.

  1.25     Tuberculosis (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".[9] MDR tuberculosis is at present rare in the United Kingdom.[10]

  1.27     Malaria 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.

  1.28     Viruses 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.

Can resistance be controlled?

  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" (Q 73).

  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).

Box 2

EXAMPLES OF VALUABLE ANTIBIOTIC THERAPIES NOW LOST OR IMPERILLED BY THE SPREAD OF RESISTANCE
Organism Disease Agents lost or threatened[11]
Pneumococcus Pneumonia, otitis, meningitis Penicillin; many others
Meningococcus Meningitis, septicaemia Sulphonamides; (penicillin)
Haemophilus influenzae Meningitis Ampicillin, chloramphenicol
Staphylococcus aureus Wound infection, sepsis Penicillin, penicillinase-resistant penicillins, others
Salmonella typhi Typhoid fever Most relevant agents
Shigella spp. Bacillary dysentery Most relevant agents
Gonococcus Gonorrhoea Sulphonamides, penicillin, tetracycline; (ciprofloxacin)
Plasmodium falciparum Severe malaria 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 bugs".

  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).[12] 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.

Acknowledgements

  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 Health.


5   See the evidence of Dr H F Kennedy and Dr J R Michie of the Royal Hospital for Sick Children, Glasgow (p 549). Back

6   See the evidence of Professor Keith Klugman, Director of the South African Institute for Medical Research (p 426). Back

7   See the evidence of Dr R Hill of King's College Hospital, p 417. Back

8   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

9   John Bunyan, The Life and Death of Mr BadmanBack

10   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

11   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

12   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


 
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