a Burnthouse, Burnthouse Lane, Cowfold, Horsham, Sussex RH13 6DH; b Journal of Antimicrobial Chemotherapy, 11 The Wharf, 16 Bridge Street, Birmingham B1 2JS, UK
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Abstract |
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Introduction |
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The hope and intention, frequently stated,25 is that results obtained from surveillance systems can help provide a better understanding of the problems, and thus may assist in controlling the spread of resistance. An additional aim is to aid improvements in prescribing.
The House of Lords Select Committee on Science and Technology published a third report in March 2001 entitled Resistance to Antibiotics and Other Antimicrobial Agents, in which progress since the publication of the first report was considered.6 The Committee highlighted a number of aspects and expressed concern over the time taken to implement some of the recommendations of the first report. The Department of Health (DH) arranged a closed meeting, held at the Royal Society of Medicine on 28 March 2001, to discuss the current situation with regard to the surveillance of resistance. The aim of the meeting was to clarify the extent to which the needs of clinicians, microbiologists, public health specialists and policy makers are currently being addressed, and to consider future developments. Approximately 70 experts in the field of human and veterinary medicine were invited. The programme is given in the Appendix.
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The reasons for surveillance |
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Clearly it will not be practical or cost-effective to attempt to survey all organisms from all infections for their susceptibility to all antimicrobial agents. Choices have to be made, and certain organisms have already been given priority in many surveillance systems, either because they are known to have developed resistance to many agents and are clinically common or difficult to treat, or because they are a major public health concern. Leese listed the species that she regarded as important in this context: Escherichia coli, Staphylococcus spp., Streptococcus pneumoniae, Salmonella spp., Mycobacterium tuberculosis, Neisseria gonorrhoeae, and HIV. In addition, choices have to be made as to whether surveillance will be local, regional, national or international.
It is generally claimed that the results obtained from surveillance studies are needed by clinicians, by the public health authorities and by the scientific community. The information acquired should lead to action, a point emphasized by Palmer and one that has been highlighted previously by others,25 but unfortunately this is frequently overlooked. The clinician may want to change clinical practice by adapting infection control or antibiotic-use guidelines in order to optimize the use of antimicrobials. The public health community may institute a variety of control measures to contain outbreaks or to improve prescribing. Where resistance is considered a major problem, the use of vaccines may be an option. The scientific community will want to investigate resistance mechanisms and to discover new targets for antibacterials
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Current systemsdo they fulfil the perceived requirements? |
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The acquisition of information in itself is of little value unless it is put to some good purpose. Palmer quoted Rose,7 who stated that We need to stop admiring information. In itself it is clutter and it should be tolerated only if it has a purpose. Two other speakers had similar views, with Webb stating that there was information overload and Nathwani saying that although a vast amount of information had been accumulated, much of it was of little value. Several speakers suggested that the resources were frequently not sufficient for establishing good surveillance systems. Access to the results was perceived by many of those present as being poor and not always available to those most in need of them.
There is often confusion between epidemiological studies and surveillance, and Palmer highlighted a number of differences between the two. Epidemiological studies were often more complex, complete and were sporadic, generally with a time limit and were targeted towards an academic and clinical audience, whereas surveillance studies are more simple, incomplete and descriptive, and they need to be regular or continuous.
For a surveillance system to be successful the objectives need to be stated clearly at the outset. These must include a clear definition of the data required, which should be minimal. There needs to be a simple method of capturing these data, and good and timely analysis and reporting of them. The requirements for surveillance differ with varying audiences. Thus the DH needs information at a national level to allow it to plan ahead and decide priorities, whereas the needs at a local level are quite different. This point was emphasized by various members of the audience.
Although surveillance seems to have a high profile, with systems running in many countries, Williams said that when the WHO requested feedback from these, they had a very disappointing response with only 15 reports from 74 participants. The more successful surveillance studies are those on specific diseases, such as tuberculosis, gonorrhoea and malaria, probably because it is easier to decide what the questions are and there are only limited numbers of compounds to test.
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Methods used in surveillance, and their merits and drawbacks |
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The PHLS surveys are valuable in detecting increases in resistance to important antibacterial agents in certain species. For example, the numbers of methicillin-resistant Staphylococcus aureus isolated from blood and CSF samples have risen from less than 5% in 1990 to approximately 12% in 1995, increasing to over 40% in 2000. Similarly, the numbers of vancomycin-resistant Enterococci, which were rare up to 1992, have also increased. Most of this increase is accounted for by Enterococcus faecium strains (30% resistance in 2000), with a modest increase in resistant strains of Enterococcus faecalis. An additional 1015% of resistant strains are unspeciated, illustrating a problem with some routine surveys where speciation is either not done or is inaccurate. The increase in resistance among E. faecalis strains was stated by Livermore probably to be a consequence of poor speciation rather than a real increase, and he used this to emphasize the importance of accurate speciation. A number of studies have claimed to have found ampicillin-resistant strains of E. faecalis, but in the UK, none of these has been confirmed to date, indicating incorrect speciation. Similar problems occur when identification is restricted to coliform rather than speciating accurately. Resistance among E. coli is generally lower than among Klebsiella spp., with Enterobacter spp. having far higher levels of resistance.
Care has to be taken in combining or pooling data derived from routine surveys, as it is not always appropriate to do so. The purposes of the studies and their approaches may differ. One laboratory may for example test drug A against all organisms, another may just test drug A against organisms resistant to the related drug B, and others may only test if requested by a clinician. Attempting to combine such results could be misleading.
Sentinel surveys are generally far more detailed than routine ones employing data collection, and they produce high quality data, which are often linked to molecular studies on the mode of resistance. Their coverage, however, is more restricted and care has to be taken in the use of results derived from such surveys, as they can also be misleading. They are often carried out by teaching hospitals, as these institutions have the infrastructure to perform such surveys, and consequently the sample bias may be high, with an over-representation of certain populations.
Alternative sources of surveillance data include learned societies, independent companies, such as GR Micro (based in the UK) and Focus Technologies (formerly MRL, with centres in the USA and Holland), and the pharmaceutical industry. Increasingly the pharmaceutical industry is funding surveillance studies, partly for marketing purposes but also now as a requirement for drug registration. Some of these are point prevalence studies while others are ongoing. Such studies described by Felmingham include one sponsored by Bayer, looking at the susceptibility to 21 antibacterial agents (including a new fluoroquinolone) of 5000 nosocomial pathogens isolated in 30 European centres. Another is sponsored by Aventis Pharma, looking at the susceptibility to 10 antibacterials (including a ketolide) of 2000 respiratory tract isolates from paediatric patients in 30 centres in the UK and the Republic of Ireland. Astra Zeneca are sponsoring a longitudinal study, called MYSTIC (Meropenem Yearly Susceptibility Test Information Collection), of susceptibility to meropenem and five other antibacterial agents among isolates from severely ill hospital patients. The Alexander Project, funded by GlaxoSmithKline, and instituted by SmithKline Beecham in 1992, is following trends over a number of years in the susceptibility to a number of antibacterial agents (currently 22) among lower respiratory tract isolates (S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis). A major asset of input from the pharmaceutical industry in surveillance is that it provides much needed funding for what is always an expensive exercise. There are, however, possible problems with industry-funded surveillance systems in that the data are owned by the company paying for the study and are thus not necessarily in the public domain. Additionally, the choice of antibacterial agents will inevitably be influenced by the marketing needs of the company.
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The influence of methodology on results |
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Bias is inherent in any surveillance system and this was noted by a number of speakers. A major bias is in the sampling: normally the only samples tested are those submitted to a laboratory, and these represent only a small proportion of infected patients. Thus, approximately 50% of those with urinary tract infections visiting a doctor have a sample collected and only about 3% of those with respiratory tract infections.8 Patients visiting a doctor do not represent the total of those with an infection. Samples tend to be taken from patients who are not responding to therapy or have recurring infections, increasing the chance that the sample contains resistant organisms. Livermore quoted a study where a resistance rate of 22% was found among H. influenzae isolates, but when consecutive patients were sampled, this fell to 11%.
There is evidence that samples are collected more often from elderly patients with respiratory tract infections than from younger patients.4,8 Grüneberg noted in one of the discussions that the current emphasis of surveillance was on hospital isolates. He highlighted the fact that there is a fundamental problem in the lack of data from the many subjects in the community with infections who do not seek treatment and therefore from whom no samples are collected. There is thus a great lack of knowledge regarding the susceptibility of normal or commensal flora. There is no commercial interest in this aspect, and currently no evidence of any interest from public health authorities. A similar point was made by Johnstone and Lambert with regard to organisms of animal origin.
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The impact of surveillance on antibiotic policies |
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There are recommendations that hospitals monitor the relationship between antimicrobial use and resistance, but Nathwani and Webb both suggested that the resources available were inadequate. Nathwani indicated that many of the necessary data are not available and are frequently difficult to collect. Data were often lacking on antibiotic usage and clinical details, although information was more often available on the susceptibility of the pathogen. The quality of the latter data, however, is generally very variable and often poor. A contributing factor is the low profile that infection control has in many hospitals, with many clinicians not perceiving that there is a problem.
The use of surveillance data to influence prescribing can be a two-edged sword, as Webb pointed out that making such data available to clinicians without interpretative support may lead to inappropriate changes in prescribing behaviour. The presentation of surveillance data needs to be graphical (not as MICs), contain clear but brief explanations and be linked explicitly with guidelines. Most importantly, such information must reach junior medical staff if it is to have any impact.
Outside hospitals, general practitioners need to be given the support to resist inappropriate patient demands. Webb described one successful model in which local practices involved all of their staff in a multidisciplinary approach. The initiative was GP led and involved holding a meeting one afternoon every month for discussions. This allowed for the sharing of best practice and also served the purpose of curriculum development. Peer support was an essential part of this system.
The discussion revealed that many in the audience thought that clarification was needed as to the purpose of surveillance. Was it aimed simply at reducing antimicrobial use overall or was it aimed at improving the use of antimicrobials, i.e. moving towards a more rational use? Reducing overall use at least has the merit that it reduces cost and this is an easy and effective message to convey. In contrast, rational or appropriate prescribing was a more difficult concept. Who decides what is appropriate? In some situations the most appropriate treatment would be more not less of an antibacterial. As had been noted by several speakers, a link between prescribing and outcomes was also felt by many to be an area sadly lacking, both in the community and in hospitals. Grüneberg suggested that more radical political decisions should be taken as to what is done with the increasingly large amount of data that is accumulating.
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Surveillance in the veterinary field |
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There are differences in the purposes of testing of samples from farm animals compared with those from humans. The primary purpose generally in the veterinary field is one of identification rather than for the determination of susceptibility. Nevertheless, Johnstone explained that a number of programmes of susceptibility testing of a number of important pathogens have been established for some years. These include Salmonella spp. (common in small animals, including reptiles), Staphylococcus spp. (causing skin infections and mastitis), Streptococcus spp. (causing joint infections and mastitis) and various organisms causing pneumonia.
Although theoretically it is easier to collect samples from healthy animals for background information than it is from humans, this is not done regularly and there is a lack of knowledge of the background resistance among veterinary pathogens, echoing the point made earlier for human surveillance. There are some exceptions, with routine samples from farm animals being collected as part of herd health schemes. Most of these samples are tested in the Veterinary Investigation Centres, but Johnstone said that these are poorly funded. Samples from companion animals, such as horses, cats, dogs and exotics, are tested in private laboratories, but there is currently no formal mechanism for the exchange of data between these laboratories and DEFRA (formerly MAFF). A point made by both Johnstone and Pfeiffer was that a number of new initiatives in this area have been set back by the outbreak of classical swine fever in 2000 and the recent outbreak of foot and mouth disease.
The UK Veterinary Medicines Directorate has a role in collecting and collating results on animal pathogens and there are a number of European initiatives, with data on zoonoses now being collated in Berlin. Some surveillance studies have been instituted including a 2 year study on resistance in E. faecium, and testing of E. coli, Campylobacter and Salmonella spp. A major study on E. faecium isolated from pigs and poultry carried out by FEFANO (Federation of European Feed Manufacturers Associations) has just been completed. This involved six countries, and 4500 isolates were tested for susceptibility to a range of antibacterial agents, including growth promoters. The glycopeptide growth promoter avoparcin was banned just before the study commenced and, although the link between avoparcin and vancomycin resistance in E. faecium remains highly controversial, the results of this study indicate a drop in vancomycin-resistant enterococci (VRE).
Pfeiffer emphasized the need for epidemiological studies in the veterinary field to improve knowledge of the factors leading to resistance. There is also a lack of risk assessment in the veterinary field, and he quoted a study from the USA that attempted to assess the risk of eating poultry meat contaminated with fluoroquinolone-resistant Campylobacter resulting in human illness.10 Lambert pointed out that although risk assessment was needed, these studies have to be carried out with care. The American study quoted was flawed, as many of the people contracting infections proved to have eaten poultry abroad. There is a need to link surveillance of human and animal pathogens, which is currently lacking. An attempt to do this is the DANMAP scheme funded by the Danish Government,11 which is collecting samples from humans, animals and food. Under this scheme Salmonella, Campylobacter and Yersinia enterocolitica isolates are being tested for susceptibility to a range of antibacterials.
In the discussion McKellar and Pfeiffer highlighted the high density of stocking of animals in many countries abroad as being a risk factor for the importation of resistant organisms in spite of our best efforts. Again the point was raised as to what level of resistance requires action, who should decide and what action should be taken. Duerden emphasized the need for good quality risk assessment.
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The future? |
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Although PK/PD can assist in the choice and use of agents, this approach is not without its drawbacks. PD parameters such as the area under the inhibition curve (AUIC) can be misleading. An example was quoted of some new fluoroquinolones with improved AUIC values against pneumococci, but these agents have poorer activity than the older agents against Gram-negative bacilli. It is thus possible that their use may increase resistance to fluoroquinolones in gut organisms.
Wise also raised the issue of breakpoints, and queried whether a different approach should be taken in deciding these. Currently MIC values are used, but it could be argued that a better value might be the mutant prevention concentration, as this may be a closer reflection of the ability of organisms to develop resistance.
Vaccination was noted by a number of participants as the possible way forward for coping with resistance in some organisms. Wise said that the use of vaccines can reduce the carriage of penicillin-resistant pneumococci, and Newman said that vaccination should be considered by the DH when a major problem was identified.
There has been great interest in the use of rapid methods of identification in recent years with the burgeoning of molecular methods and technological advances. The question was posed by Borriello of how rapid is rapid? as many of the techniques still require days rather than hours to perform. These methods of identification and determination of resistance can have a role to play in recognizing novel modes of resistance, but it is questionable whether they have an impact on surveillance. The more exciting developments are the near patient techniques currently under development. Borriello said that such methods could contribute only if the results influenced prescribing. They could offer advantages for example in distinguishing between viral and bacterial infections; techniques are now available for rapid distinction between influenza and group A streptococcal infections.
It is now possible to detect Helicobacter pylori with various types of genotypic resistance to clarithromycin in 1 h from a biopsy using light cycling real-time PCR. Resistance to clarithromycin has increased over recent years and, when present, lowers its efficacy against such strains from 92% to 50%. Gene probes are available for detecting an increasing number of pathogens, including M. tuberculosis and resistance to rifampicin, and HIV and resistance to protease inhibitors. An exciting new method using mass spectrometry can establish identity from a mycobacterial colony in 3 minutes. The major stumbling block to the development and more widespread use of these techniques is funding. A possible impetus to this area, however, is the opportunity to reduce unnecessary prescribing. The kits for detecting influenza are a good example, as the new anti-influenza drugs are expensive and have no effect on other viral or bacterial infections.
Borriello pointed out that these new genotypic techniques detect not resistance but the possibility of resistance and also they can only detect a known resistance mechanism. Phenotypic methods are still of value, however, and it should be noted that genotypic methods cannot detect phenotypic modes of resistance.
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Conclusions |
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Although there were differences of opinion as to how strong the link is between antibacterial use and resistance in the community, there is still general agreement that a reduction in unnecessary use of antibacterials is desirable. Hospital use was often regarded as excessive and inappropriate. Education was quoted many times as an essential part of the package. Lord Soulsby suggested that this should start at the undergraduate level, where both medical and veterinary students should have a better grounding in resistance and the problems it may bring. Education of the public, patients and GPs could help to reduce unnecessary prescribing in the community. In hospitals a greater integration and understanding was required between infection control, and prescribing and resistance needed to have a far higher profile.
Some of the questions that have been highlighted both at this symposium and in previous publications remained unanswered. The purposes of surveillance still need clarification and no real consensus emerged as to the level of resistance that required action, what action should be taken and by whom. Although a considerable effort is being put into various aspects of surveillance, many participants were of the view that not all of this effort was well directed. A major problem identified is the poor availability and dissemination of the information, with many of the data not being accessible to those who most need them. Information technology could have an important role in handling and circulating the data. It was clear that in both the human and veterinary fields, the overwhelming opinion was that funding was inadequate.
The diagnosis and detection of resistance in a pathogen before treatment commences is now a distinct possibility, at least for some organisms, but this, like many other aspects, will need funding. The problem cannot be considered as just a UK or even an EU matter, since bacteria know no boundaries and increased travel allows people to move freely across the world. The import of food from around the world poses a threat since we cannot control animal health and the use of antibacterials in developing nations. Resistance will thus be a continuing and accumulating problem and it will be necessary to use the existing agents prudently.
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Appendix |
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Introduction by Lord Soulsby of Swaffham Prior, Past President of the Royal Society of Medicine
Session chaired by Lord Soulsby
Population based surveillance of communicable diseasethe overall contextProfessor S. Palmer (University of Wales)
Antimicrobial resistance surveillancewhat we need to do and whyDr J. Leese (Department of Health)
Public sector antimicrobial resistance surveillance in the UKstrengths and weaknessesDr D. Livermore (PHLS)
Industry and learned society initiativesD. Felmingham (GR Micro)
Improving prescribingthe role of pharmacokinetics and pharmacodynamicsProfessor R. Wise (City Hospital, Birmingham)
Session chaired by Professor R. Wise
Bringing surveillance into antibiotic policyDr D. Nathwani (Dundee)
Bringing surveillance into bedside practiceDr C. H. Webb (Royal Hospitals NHS Trust, Belfast)
Discussion led by Dr R. Williams (World Health Organisation) and Dr R. Grüneberg (GR Micro)
Session chaired by Dr B. Duerden (PHLS)
Surveillance in animalsthe current positionProfessor A. M. Johnstone (Royal Veterinary College)
Surveillance in animalsis it going to answer our human health problems?Professor D. Pfeiffer (Royal Veterinary College)
Discussion led by Professor Q. McKellar (Moredun Research Institute, Scotland) and Professor H. Lambert (London School of Hygiene and Tropical Medicine)
Rapid recognition of resistanceimplications for surveillanceProfessor P. Borriello (Director, CPHL)
Global issuesLord Soulsby
Discussion led by Dr C. Newman (NHS, Leeds) and Professor S. Palmer
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Notes |
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References |
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