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Antibacterial resistance and antibacterial prescribing.
- Peter A Riley (6 November 2001)
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Cross-sectional surveys cannot assess causation
- Christopher Cates (7 November 2001)
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Without penicillin post-streptococcal-reactive disease will emerge again!
- Friedrich Flachsbart (7 November 2001)
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Routinely collected data do not represent true resistance rates.
- Derelie Richards, Les Toop (12 November 2001)
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Antibacterial prescribing and antibacterial resistance in English general practice
- Ian M Gould (19 November 2001)
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Prescribing in General Practice as a force for the generation of anti-microbial resistance
- Stephen Conaty (29 November 2001)
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Surveillance of Antimicrobial Resistance - does a broad brush paint a better picture?
- Martin C J Wale (14 December 2001)
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Peter A Riley, Consultant Microbiologist Mayday Hospital
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In their study of antibacterial prescribing and antibacterial resistance in English general practice, Priest et al(1) conclude that routine microbiological isolates should not be used for surveillance of antibacterial resistance in the community. I would agree, since as Wise reports in his accompanying commentary (2), the dynamics of the interplay between prescribing and resistance are exceedingly complicated. In their study Priest at al have laudably tried to keep things simple, but they have not considered all of the factors that may account for antibacterial resistance in uropathogens. The first part of their study examined the relationship between amoxycillin/ampicillin and trimethoprim resistance rates in coliforms and the prescribing rates of these antibiotics. In urinary tract infections the majority of coliform isolates are Escherichia coli and the determinants of urovirulence in E. coli are well understood e.g. adhesive fimbriae, haemolysins and siderophores such as aerobactin (3). Many of these urovirulence factors are plasmid mediated and these plasmids commonly also have determinants for antibiotic resistance (4). This linkage of urovirulence genes to antibiotic resistance genes may result in artificially high rates of antibiotic resistance that are not related to selection following antibiotic usage. To clarify the situation what we also need to know is whether the antibiotic resistant rates are the same in isolates of E. coli that do not harbour plasmids with urovirulence genes. Priest et al also state in their study design that since resistance to ampicillin and amoxycillin can be due to production of beta lactamase, the use of any beta lactam antibacterial could potentially select for or induce this resistance. Consequently they also examined the association between ampicillin and amoxycillin resistance and prescribing of all beta lactam antibiotics. Their assertion is only partly true. Most urinary isolates of amoxycillin or ampicillin resistant E. coli produce relatively narrow spectrum beta lactamases such as TEM-1 and will therefore be susceptible to most of the other commonly used beta lactams in general practice. What Priest at al should have also eaxmined is the association of amoxycillin or ampicillin resistance with the use of non beta lactam antibacterials. This is because plasmids from urinary isolates of E. coli encoding resistance to amoxycillin and trimethoprim commonly also have resistance determinants for other non â lactam antibiotics such as tetracycline, chloramphenicol and sulphonamides (4). Use of these non-beta lactams antibiotics may consequently select for resistance to amoxycillin and ampicillin. Although the use of these other antibacterials may not be that common in general practice, use in agriculture may be higher (5). Finally I would make a plea for the use of the term coliform to be discouraged. It is unclear from the study of Priest at al what exactly they mean by the term coliform. The term is commonly used (almost exclusively in Britain) to describe a group of bacteria that share some basic phenotypic properties that are easily and cheaply recognised in a routine diagnostic microbiology laboratory. The term coliform is not synonymous with E. coli and the use of the term probably varies from one laboratory to another. Coliforms are made up of a highly heterogeneous population of different bacterial species. Isolates of E. coli, Klebsiella sp., Citrobacter sp. Enterobacter sp. May all be described as coliforms. Amongst these different bacterial species, rates of antibiotic resistance may vary greatly, for example virtually all isolates of Klebsiella sp. are resistant to amoxycillin, and isolates of Enterobacter sp. will almost always be resistant to amoxycillin co-amoxiclav and cephalosporins. Although E. coli is likely to be the commonest coliform isolated from urinary tract infection, changes in isolation rates of these other species may have significant effects on resistance rates of “coliforms” . In the study of Priest at al it would be impossible to tell whether there are unusual rates of isolation of these more commonly antibacterial- resistant organisms. References 1. Priest P, Yudkin P, McNulty C, Mant D. Antibacterial prescribing and antibacterial resistance in English general practice: cross sectional study. BMJ 2001; 323: 1037-1041. 2. Wise R. Commentary: antibiotic resistance is a dynamic process. BMJ 2001; 323: 1041. 3. Johnson JR. Virulence factors in Escherichia coli urinary tract infections. Clin Microbiol Rev 1991; 4: 80-128. 4. Riley PA, Threlfall EJ, Cheasty T, Wooldridge KG, Willimas PH, Phillips I. Occurrence of FIme plasmids in multiply antimicrobial- resistant Escherichia coli isolated from urinary tract infection. Epidemiol Infect 1993;110:459-68. 5. Standing Medical Advisory Committee on Antimicrobial Resistance. The path of least resistance. London: Stationery Office, 1998. |
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Christopher Cates, General Practitioner Bushey Health Centre, Hertfordshire WD23 2NN
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EDITOR - Antibiotics are prescribed in primary care for a variety of indications in different patient populations. Urinary tract infections are relatively unusual because they are more liable to occur in younger women, whereas the other main area of usage of beta-lactam antibiotics is for chest infections (often in older men). The data presented by Priest et al do not distinguish the target populations for the antibiotics prescribed, and along with the 30 fold range in the sending of microbiological specimens for analysis and the cross-sectional design of the study it is hard to be sure what these results mean. We audited the resistance of urine specimens sent for analysis in our practice in 1994 and 1995 and at that time found substantial levels of resistance to amoxicillin (20% to 50%). Although amoxicillin remains a popular choice of antibiotic for other conditions (such as chest infections) we have long since abandoned it for suspected urinary tract infection. Total practice amoxicillin prescribing is therefore a very poor marker for the antibiotic load (both type and quantity) on younger women with urinary tract infections and it is not too surprising that the correlation with amoxicillin resistance in urinary coliforms is poor. The authors conclude that this is a very unreliable way to assess the impact of changes in antibiotic prescribing on resistance levels in general practice. What puzzles me is how they can then go on to suggest that “ trying to reduce the overall level of antibiotic prescribing in UK general practice may not be the most effective strategy for reducing antibiotic resistance in the community”. They appear to be able to make a conclusion on effective strategies without presenting any data at all on the results of this strategy or any other comparative strategy. No interventions are assessed in this paper and the study type (cross -sectional survey) is unsuitable for drawing conclusions about causation in either direction. The tendency for higher antibiotic prescribing to induce resistance might be balanced by the tendency for reported resistance in the specimens to reduce the likelihood of that antibiotic to be prescribed! Do the authors have other data from prospective studies comparing the results of different approaches to reducing antibiotic resistance in the community to support their final conclusion? I would be particularly interested to know the evidence to support the use of 3 day courses of antibiotics for urinary infections as opposed to 5 day courses for example. |
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Friedrich Flachsbart, general medicine Göttingen
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Dear Sir, there is increasing resistance following the suboptimal therapy (erythromycin against streptococci). But I see a much greater danger in not-treating streptococci. The reemergence of post-streptococcal-reactive disease is induced by horizontal-gene-transfer of pathogenic factors. But not treating a strep- throat means a three percent probability of inducing post-streptococcal- reactive disease like nephritis or carditis. We should not laugh about flu, cold, influenza like illness. Prof. Dr. W. H. Veil, Jena described the problems 62 years ago and I see his patients in my practice. And thanks to Prof. Fleming I am able to help!! 1. W. H. Veil: Der Rheumatismus und die streptomykotische Symbiose. F. Enke, Stuttgart, 1939 Sincerely Yours
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Derelie Richards, lecturer in general practice (D. Richards) professor of general practice (L.Toop) Department of Public Health and General Practice, Christchurch School of Medicine & Health Sciences, Les Toop
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We read with interest the article by Priest et al describing the link between antibiotic prescribing and antibacterial resistance in English general practice(1). We agree wholeheartedly for the call to use more accurate data to estimate community levels of antibiotic resistance. The results of a recent study in Christchurch New Zealand support this (2). Using samples collected by GPs in the Christchurch Sentinel Network we found a significant discrepancy between reported rates of resistance to trimethoprim based on routinely collected data (19.0%) and our representative sample ( 11.5%). Clinical behaviour is changing; the move toward empiric therapy results in a greater proportion of specimens sent being for complicated infections and treatment failures, thus creating potential for a bias towards higher reported rates of antibiotic resistance(3). We also agree with the point made in the discussion by Priest et al about potential sources of bias in cross sectional studies on prescribing and antibiotic resistance. The link between prescribing and resistance is two way - prescribing changes in response to reported local resistance patterns - an apparent increase in resistance to an antibiotic may lead to a decrease in prescription of that antibiotic. These kind of trends cannot be captured in cross sectional studies, highlighting further the need for systematic collection of accurate data on antibiotic resistance patterns in the community and their relationship to prescribing. Our experience indicates that it is essential that when apparent increases in resistance are reported from routine data efforts are made to eliminate sources of bias before recommending changes in prescribing practice. Derelie Richards, lecturer in general practice Les Toop, professor of general practice Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, PO Box 4345, Christchurch, New Zealand no competing interests References 1. Priest P, Yudkin P, McNulty C, Mant D, Wise R. Antibacterial prescribing and antibacterial resistance in English general practice: cross sectional study. BMJ 2001; 323: 1037-1041 2. Richards DA, Toop LJ, Chambers ST, Sutherland MG, Harris BH, Ikram RB, et al. Antibiotic resistance in uncomplicated urinary tract infection: problems with interpreting cumulative resistance rates from local community Laboratories. New Zealand Medical Journal 2001 (in press). 3. Livermore DM, Macgowan AP, Wale MCJ. Surveillance of antimicrobial resistance. BMJ 1998;317:614-615. |
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Ian M Gould, Consultant Microbiologist Dept. of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN
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Editor - While enjoying the study reported by Priest et al (1) on the relationships between antibiotic prescribing and bacterial resistance in English general practice, I disagree with two of their three conclusions. Surveillance of routine isolates may not be the most sensitive of techniques for establishing the subtleties of relationships between antibiotic consumption and resistance but it does give a useful snapshot of the worst case scenario which can be used in guiding empiric treatment in appropriate patient populations and detecting problems of emerging resistance. Given the general ease of availability of such data, I firmly believe its analysis is worthwhile, while accepting that targeted surveillance data also needs to be collected and improved laboratory susceptibility testing methods used in our battle to control antibiotic resistance (2). The authors final conclusion, that trying to reduce the overall level of antibiotic prescribing in UK general practice may not be the most effective strategy for reducing resistance in the community is also not warranted. There are several examples in the literature where just such a strategy has been successful (3). The disappointingly small differences in resistance rates between patient isolates in low and high prescribing practices may well be more a reflection of individual patient selection and widespread environmental pollution by antibiotics, resistant bacteria and their resistant determinants. It is only by reducing community prescribing that significant inroads will be made into the antibiotic resistance problem for the majority of community resistant problems. The efforts of general practitioners to reduce antibiotic prescribing are to be applauded and should continue (4). Comparison with prescribing data from Holland suggests there is further room for improvement (5). At the same time high quality diagnosis of serious bacterial infection must remain a priority so that there is no increase in untreated, invasive, community acquired sepsis (4). 1. Priest, P., Yudkin, P., McNulty, C. & Mant, D. (2001) Antibacterial prescribing and antibacterial resistance in English general practice: cross sectional study. British Medical Journal 323 1037- 1041. 2. Gould, I.M. (2000) Towards a common susceptibility testing method? Journal of Antimicrobial Chemotherapy 45 757-762. 3. Kristinsson, K.G. (2001) Mathematical models as tools for evaluating the effectiveness of interventions: A comment on Levin. Clinical Infectious Diseases 33 S174-S179. 4. Gould, I.M., Clarke, R., Hutchinson, S. & Davey, P (2001) Variation in European antibiotic use. The Lancet 358 1273. 5. Cars, O., Mölstad, S., Melander, A. (2001) Variation in antibiotic use in the European Union. The Lancet 357 1851-53. |
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Stephen Conaty, Lecturer in Infectious Disease Epidemiology Primary Care and Population Science, Royal Free, London NW3 2PF
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Editor-The BMJ has now published two cross-sectional ecological studies showing a modest but significant correlation between practice levels of prescribing and antimicrobial resistance to amoxy/ampicillin in urinary coliforms. (1,2) However, the conclusions drawn differ. Magee et al seem to emphasise the seriousness of the problem while Priest et al venture that the problem may be over-emphasised. What are GPs and policy- makers to make of this? There are at least two reasons for thinking that cross-sectional ecological studies such as these may underestimate the true effect. Firstly, the interpretation of ecological data is not straightforward. Sometimes a weak relationship at an ecological level of data obscures a stronger relationship at a lower level. (3) This may be the case if, hypothetically, resistant UTIs are predominantly generated in an epidemiologically distinct segment of the population (such as young women living with young families). If much of the variation in measured exposure (prescribing) between the units studied (practices) is because of exposure in another group (such as the elderly) and practices differ in their population make-up then a strong relationship may be obscured when data is aggregated. Secondly, after introduction of a resistant organism it takes time for equilibrium (a stable relationship between prescribing and resistance levels) to develop. We do not know how long this process takes so it is difficult to guess what stage of the process we may be at. As Priest et al acknowledge, their argument that a 20% decrease in prescribing might result in a decrease in resistance of only 1% holds only if the resistant population has reached equilibrium and the communities from which the estimates are derived are independent. The closer we are to approaching equilibrium the more time will have elapsed for mixing of people and microbes and the less the independence assumption can be justified. This may account for the larger correlations between prescribing and resistance obtained using a larger unit of analysis (primary care groups) as the assumption of independence may be more justified. Of course it may be the case that both papers have got the right answer, especially for antibiotics like amoxycillin which have been heavily prescribed for many years and where resistance levels are already high, but we cannot assume that the observed association between prescribing of amoxy/ampicillin and resistance is generalisable to other antibiotics. For newer antibiotics (such as the quinolones) we are at a much earlier stage of the development of resistance so control of prescribing now is likely to prevent or defer escalation of the problem in the future. In order to address these questions in a more valid way we need more detailed longitudinal data where there is less biased sampling and better characterisation of the individuals and groups within practices who receive antibiotics and who develop resistance. We also need to supplement our insights from other sources of data - such as European data - where variation in prescribing (and resistance) is greater. (4) (5) Stephen Conaty, Lecturer in Infectious Disease Epidemiology Andrew Hayward, Senior Lecturer in Infectious Disease Epidemiology Richard Morris, Senior Lecturer in Medical Statistics Department of Primary Care and Population Science, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF Ben Cooper, Research Fellow
References 1. Priest P, Yudkin P, McNulty C, Mant D. Antibacterial prescribing and antibacterial resistance in English General Practice: cross sectional study. BMJ 2001; 323: 1037-41. 2. Magee JT, Pritchard EL, Fitzgerald KA, Dunstan FDJ, Howard J. Antibiotic prescribing and antibiotic resistance in community practice: retrospective study, 1996-8. BMJ 1999; 319: 1239-40. 3. Morris RW, Whincup PH, Lampe FC, Walker M, Wannamethee, SG, Shaper AG. Geographic variation in incidence of coronary heart disease in Britain: the contribution of established risk factors. Heart 2001; 86: 277-283. 4. Kahlmeter G. The ECO.SENS Project: a prospective, multinational, multicentre epidemiological survey of the prevalence and antimicrobial sensitivity of urinary tract pathogens - interim report. J Antimicrob Chemother 2000; 46(S1): 15-22. 5. Cars O, Molstad S, Melander A. Variation in antibiotic use in the European Union. Lancet 2001; 357: 1851-3. |
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Martin C J Wale, Consultant Regional Epidemiologist and Head of PHLS Antimicrobial Susceptibility Surveillance Unit CDSC Trent, Public Health Laboratory, Queens Medical Centre, Nottingham NG7 2UH
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Dear Sir In their paper on "Antibacterial prescribing and antibacterial resistance in English general practice: cross sectional study" (BMJ 232, 3rd November 2001) Priest et al conclude that routine microbiological isolates should neither be used for the surveillance of antimicrobial resistance in the community, nor for monitoring the outcome of changes in antibacterial prescribing by general practitioners. Whilst we agree that approaching individual laboratories for data on a few antibiotic/organism combinations and linking this data to that on prescribing would not be a cost-effective approach to surveillance, their conclusion is over generalised, based as it was on a short duration study. The key question is "does improved prudent prescribing slow down or reverse the effects of antimicrobial resistance and how can this be measured?" To answer this, surveillance has to involve sustained susceptibility data collection for a given population over a substantial time period, allowing the monitoring of trends and an investigation of the relationship with prescribing over several years. The automatic electronic mapping of laboratory sensitivity data onto populations would enable better monitoring of levels of resistance for both community and hospitals from local to national level. Complete coverage across a given geographical area overcomes difficulties with ill- defined laboratory catchment areas, and enables the use of population denominators and comparison with existing public health data sets e.g. prescribing data. A system has been developed (and piloted in Trent Region) by the Public Health Laboratory Service Antimicrobial Susceptibility Surveillance Unit to collect all routinely generated susceptibility data from hospital microbiology laboratories with a view to facilitating the above. Such "broad-brush" information can then be used to identify areas that need further investigation and it is at this point that sentinel studies are required. The dynamics between hospital and community resistance patterns mandate the need for better sampling protocols, and effects of interventions in prescribing can be studied using this approach. To solely initiate a series of sentinel GP practices would introduce bias in terms of geographical area, environmental factors, caseload and enthusiasm of participants, thus extrapolation of interventions carried out in these different populations could be seriously misleading. However, a sentinel practice is a valuable tool to focus on an area or to investigate a given problem. Yours faithfully Dr Martin CJ Wale Consultant Regional Epidemiologist and Head of the PHLS Antimicrobial Susceptibility Surveillance Unit (AmSSU). Mr Peter R Ridout Manager, AmSSU Dr Joan A Birkin Scientist, AmSSU PHLS Antimicrobial Susceptibility Surveillance Unit (AmSSU). CDSC Trent Public Health Laboratory Queens Medical Centre Nottingham NG7 2UH Correspondence to Dr Joan A Birkin at jbirkin@cdsctrent.phls.nhs.uk Competing interests - None |
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