a Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT; b IMS-HEALTH UK, 107 Marsh Road, Pinner, Middlesex HA5 5HQ; c Public Health Laboratory Service Headquarters, 61 Colindale Avenue, London NW9 5HT, UK
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Abstract |
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Introduction |
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The present study was prompted by review of bacteraemia data reported to the Public Health Laboratory Service (PHLS) by laboratories in England. This revealed wide and consistent regional variation in the prevalence of resistance to ampicillin and trimethoprim among Escherichia coli isolates between 1990 and 1997. E. coli was further chosen for analysis as the most frequent pathogen from bacteraemic patients in England,4 and as one where most infection arises endogenously.5 Multi-resistant clones, which might be expected to be local, only account for a small proportion of E. coli infections. The antibacterial agents considered, ampicillin and trimethoprim, are heavily used drugs to which resistance is frequent and is reliably detected by routine laboratories.6 The objective was to test whether this regional variation in resistance could be related to variation in prescribing.
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Materials and methods |
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Since 1989, up to 209 hospitals in England and Wales have voluntarily reported their antibiotic susceptibility results for isolates from blood and cerebrospinal fluid (CSF) to the PHLS.4 The data collected were sorted according to the old Health Regions, which were in official use until 1994.
Hospitals in the UK speciate Enterobacteriaceae isolates from blood cultures, mostly using API20E strips (bioMérieux, La Balme les Grottes, France). They perform susceptibility tests by their own choice of method, and with various ranges of antibiotics. Most (>90%) use variants of Stokes' comparative technique, but minorities undertake KirbyBauer type disc tests, with the control on a separate plate to the test isolate, or perform breakpoint dilution tests.7,8 The media, supplements and inoculum preparation are at the discretion of the laboratory; most use IsoSensitest or DST agars with semi-confluent lawns of bacteria, but with much variation in the details of the methodology.8 Isolates reported as intermediate were counted as resistant, since some laboratories distinguish these categories whereas others do not. Susceptibility reports for ampicillin and amoxycillin were pooled as these drugs have equal activity against E. coli and are compromised by the same resistance mechanisms.9 All the hospitals participate in the National External Quality Assurance Scheme, which has found better than 95% accuracy in the routine laboratory detection of ampicillin and trimethoprim resistances in Enterobacteriaceae.6 A recent analysis confirms the view that routine diagnostic laboratories accurately detect resistance to ampicillin and trimethoprim in E. coli.6
Prescribing of ampicillin analogues and of trimethoprim
The numbers of prescriptions written by region for ampicillin analogues and trimethoprim between 1987 and 1997 were projected from IMS-HEALTH's Medical Data Index (MDI), which collects prescribing data from 500 general practitioners (GPs). The average number of participating GPs in each region in 1987 was 39 (range 2071) and these numbers have not changed significantly since then. From 1987 to 1994, the weekly prescribing data were collected quarterly from a representative sample of 250 panel doctors and 250 sample doctors selected at random. Each doctor and his or her receptionist were asked to record details in a specially designed diary for all patients seen or contacted in any way for seven consecutive days. The number of prescriptions written by the representative sample of GPs was compared with the total number of prescriptions in the UK, as given by the Prescription Pricing Authority (PPA), so as to give a projection factor to allow estimation of total community prescribing in the UK. This one factor was used to project for all therapy classes or conditions. Since 1994, the prescribing data have been collected continuously from the practice computers of a panel of 500 GPs. The data collection method conforms to the recommendations of the joint British Medical Association and Royal College of General Practitioners Committee on Standards of Data Extraction, and no patient-identifiable data are collected. The projection methodology also changed from 1994, with a switch to regional projection factors based on the number of sample doctors in each region as a proportion of the total number of doctors in each region. The resulting figures are then adjusted to reflect the UK total, as measured by the PPA.
For the present analysis, ampicillin and analogues included (i) generic ampicillin and amoxycillin, (ii) ampicillin and amoxycillin under various trade names, (iii) ampicillin and amoxycillin esters (e.g. pivampicillin and bacampicillin) and (iv) proprietary combinations of ampicillin or amoxycillin with anti-staphylococcal penicillins. Combinations of ampicillin and amoxycillin with ß-lactamase inhibitors (e.g. co-amoxiclav and ampicillinsulbactam) were excluded, since these largely exert a different selective pressure from that of unprotected penicillins (see Discussion). Data for trimethoprim prescribing included the compound itself under generic and trade names, and as co-trimoxazole. In the earlier years of the study, most trimethoprim use was as co-trimoxazole but uncombined trimethoprim has predominated since 1992 (see Discussion).
Total antibacterial prescribing
Data on total prescribing of antibacterial agents [as defined in the British National Formulary (BNF)10] for the financial years (AprilMarch) 19951996, 19961997 and 19971998 were obtained from the PPA, and are based on totals of prescriptions returned to pharmacies for dispensing. The raw data received were based on new (i.e. post-1995) Health Regions, but were subdivided by Health Districts, allowing re-aggregation by old Regions and comparison with the resistance data and MDI data.
Population estimates
Population data were obtained from the National Statistics Office and were based on census returns. Estimates for old (pre-1994) Health Regions ceased to be available after 1995, so 1995 data were used for the subsequent 2 years, with the assumption that the populations remained unchanged.
Statistical analyses
Rates of resistance in individual English regions were compared with the overall rate by chi-squared tests. When examining resistance trends over time, chi-squared for trend was calculated, with only the trend component being reported. Regions were also ranked by resistance rates and the rankings in different years were compared by calculation of Kendall's Coefficient of Concordance and by calculation of Friedman's statistic.11 Statistical calculations were done using Microsoft Excel or with Statview SE+Graphics.
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Results |
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Tables I and II show regional resistance data for ampicillin/ amoxycillin and for trimethoprim, respectively. At least 3300 isolates were tested with each antibacterial in each of the eight study years. The resistance rates cited for individual regions are based on at least 100 reports per year, except for trimethoprim in East Anglia in 1996 (43 reports), South Western in 1997 (94), Wessex in 1997 (83), Yorkshire in 1997 (78), and ampicillin analogues in East Anglia in 1996 (76) and Yorkshire in 1997 (95). The low numbers of reports in these years probably reflected losses in the switch to electronic reporting, not a paucity of infection or testing. Problems with this change also account for the lack of data for the Yorkshire region in 1995 and 1996.
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There were considerable and consistent regional differences in the proportions of organisms reported as resistant (Tables I and II), and this observation provided the impetus for the study. Most strikingly, the proportions of E. coli isolates reported to be resistant to ampicillin analogues in the Trent and Northern regions never fell below 59%, whereas that in East Anglia exceeded 42% only in 1996 and that in the South Western region never rose above 50%. The prevalence of trimethoprim resistance fluctuated between 14.6 and 21.8% in the East Anglia and South Western regions, whereas the prevalence of trimethoprim resistance in NE Thames and North Western regions rose steadily, and exceeded 28% from 1994 onwards.
Taking the 8 year study period as a whole, statistical analysis confirmed that the prevalence of resistance to ampicillin analogues was significantly lower in East Anglia and South Western than in any other regions (P < 0.01 for all comparisons, and <0.0001 for all comparisons except with the Oxford region; Table III). The prevalence of trimethoprim resistance was also lower in East Anglia than any other region except South Western and Wessex (P < 0.01, as compared with all regions except South Western, Wessex and Trent). The resistance rate to trimethoprim in South Western was significantly lower than in any region except East Anglia, Wessex and Trent (P < 0.01; Table IV
). Rates of resistance to ampicillin analogues also remained significantly lower in Oxford and SE Thames than in 10 and nine other regions, respectively (P < 0.01) and rates of resistance to trimethoprim remained lower in Wessex and Trent than in eight other regions (P < 0.05). At the other extreme, the prevalence of resistance to ampicillin analogues remained significantly higher in Northern and Trent (P < 0.0001; Table III
) than in any other region, and the prevalence of trimethoprim resistance was higher in NE Thames and North Western than in any other region (P < 0.05 for all comparisons, and P
0.0005 for all comparisons except with NW Thames; Table IV
).
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Prescribing of ampicillin analogues and trimethoprim
Regional prescribing data for ampicillin analogues and trimethoprim from the MDI are presented in Tables V and VI, respectively. The sharp apparent declines in prescribing between 1993 and 1994 are artefacts of the changed method of data collection (see Materials and methods). Under-reporting of prescriptions for chronic conditions by receptionists is suspected in the period to 1994, when data collection was with the specially designed diaries. The projection methodology during this period overestimated the number of prescriptions for acute conditions, including those for antibiotics. In 1995, following the switch to electronic reporting in 1994, an audit of the completeness of data collection was undertaken, using the MediPlus UK Primary Care Database, from which the MDI is derived. MediPlus represents approximately 560 partners, nearly 2 million patient records, and over 58 million prescriptions. Comparison of MediPlus and published PPA figures at BNF chapter level revealed good correlations, but there appeared to be under-reporting of antibacterial prescribing. Further analysis at practice level of over 2 million prescriptions issued in the first two quarters of 1995 by 75 practices indicated that 96.3% of all prescriptions reaching the PPA were recorded in the MediPlus database but that the figure
for antibacterial prescriptions was only 87.8%. Under-reporting was particularly apparent for ampicillin analogues, and this deficit was attributed to these antibiotics often being used on home visits and not being entered on to practice computers. Strenuous efforts are being made to improve recording in this area. Although this factor does mean that the prescription rates in Tables V (especially) and VI
are underestimates, there is no reason to suppose that underestimation should vary with the Region.
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Substantial year-to-year fluctuations in regional prescribing were apparent in the MDI, especially for trimethoprim, and this variation was confirmed by cross reference to another IMS database, the British Pharmaceutical Index, which records 97% of purchases by retail pharmacies. Nevertheless, prescribing of ampicillin and its analogues per head of population was consistently high in the Mersey, Oxford, Northern and NE/NW Thames regions, and consistently low in South Western, Wessex and Trent/East Anglia. In the case of trimethoprim, prescribing seemed heaviest in the Mersey, Oxford and South Western regions and lowest in the West Midlands in the early years, but these patterns changed from 19921993, with West Midlands and North Western becoming the heaviest prescribers whilst Wessex and Yorkshire tended to be the lowest prescribers.
Regional resistance rates in each year were correlated with regional prescribing rates for the corresponding agents, taken from the MDI database. Since resistance might be predicted to lag use, usage in the same year and mean usage in that year and the three preceding years were both used in these comparisons. Except in the case of trimethoprim in 1994 and 1995, the correlation coefficients within years between percentage resistance and prescriptions per person per annum were less than 0.7 (not shown). Nevertheless, the South Western region consistently reported low rates of resistance to ampicillin and its analogues and was a low prescriber of these agents (cf. Tables I and V).
Total antibiotic prescribing by region
Total antibiotic prescribing by Regional Health Authority is shown in the Figure for the financial years from 19951996 to 19971998, and is based on PPA data. Earlier data were not available. Three points are striking. First, the rank order of regions by prescribing level was broadly stable across all 3 years. Second, antibacterial prescribing was highest in the Regions covering the northern half of England (viz. Mersey, North Western, Northern, West Midlands, Yorkshire and Trent) and lowest in those covering the southern half (viz. East Anglia, Oxford, Wessex, South Western and the four Thames regions). Thirdly, there was as much divergence between the highest and lowest prescribing Health Districts within regions as between the regions. Thus, although the Mersey region had the highest prescribing and South Western the lowest prescribing, the highest prescribing district in the South Western region prescribed more than the lowest prescribing district in the Mersey region.
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Discussion |
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We attempted to relate these differences in the prevalence of resistance to prescribing data drawn from two sources: the IMS-HEALTH MDI database and the PPA. We believe that these are the best prescribing data available, but they were not collected for relating to resistance data. Several constraints need highlighting. First, MDI pools several pairs of Health Regions so as to prevent deductive disclosure of participating GPs. Most critically, it pools the East Anglia and Trent regions, which had among the lowest and highest resistance rates to ampicillin, respectively. The consequent loss of these regions from comparisons is unfortunate. Secondly, the PPA data were available only for the three most recent years. This is unfortunate since resistance might be expected to lag usage. Third, the PPA data on total usage may conceal regional differences in the types of antimicrobials used. Fourth, the units of prescribing used here, prescriptions per person per annum, take no account of dosage, duration or compliance, although it is unlikely that these vary greatly with geography. Finally, the PPA data were organized according to the British financial year (AprilMarch) not the calendar years used for the other data. The representativeness of the MDI was considered in detail, allowing that it comprises only about 500 practitioners out of a national total of c. 32000. Until 1994 the sample of doctors was stratified by region and years since qualified so as to be representative of the total GP population. Following the change in data collection method, data are derived from the MediPlus UK Primary Care Database. There is a very good correlation between patient age in MediPlus and national age across the range of patient ages. A similar picture is seen in the split of males and females. The MediPlus panel of GPs is broadly representative of the GP population of the UK, although there is some slight under-representation of smaller practices and a slight over-representation of younger doctors. The practices have been recruited to be nationally representative of the geographical distribution of GPs among Regional Health Authorities.
Both the MDI and PPA data indicated heavier prescribing of antibiotics in the north and west of England than in the south and east, perhaps reflecting social or climatic factors. Taking the eight-year survey period as a whole, ampicillin resistance rates were highest in the Northern, Trent, NE Thames, West Midlands, NW Thames and North Western regions. In all of these regions except NW Thames, the PPA data indicated an antibacterial prescribing rate of at least one course per person per annum in at least 2 of the 3 years with data available. Four of these six regions, Northern, Trent, North Western and West Midlands, consistently featured amongst the six highest prescribing regions. Of the six regions with the lowest overall resistance of ampicillin analogues, East Anglia, South Western, Oxford, SE Thames, SW Thames and Yorkshire, five (the exception being Yorkshire) consistently featured among the lowest prescribers on the PPA data, with treatment rates below 0.9 antibacterial courses per person per annum. Nevertheless, the relationships between prescribing and resistance to ampicillin analogues were imperfect: Mersey and Wessex were among the highest and lowest prescribers, respectively, based on both the PPA and MDI data, yet were mid-ranking for ampicillin resistance. More generally, there was poor correlation (r < 0.7) between resistance rates and prescribing of the corresponding antimicrobials, as measured by the MDI.
The limited relationship between resistance and prescribing is counter-intuitive, but may be explained by several factors. These include (i) the drugs considered as potential selectors, (ii) whether the bacteria reported correspond to those experiencing the selection pressure measured and (iii) whether Health Regions are appropriate units of geography. The choice of drugs to consider as selectors raised several problems. Co-amoxiclav and cephalosporins were excluded when totalling usage of ampicillin analogues, since they are active against most E. coli isolates with TEM-1 ß-lactamase, which is the commonest cause of ampicillin resistance,10,11 and so exert a different selective pressure. Nevertheless, co-amoxiclav and first-generation cephalosporins may exert identical selection pressure to ampicillin and amoxycillin for strains that hyperproduce TEM ß-lactamase or have clavulanate-resistant ß-lactamases, such as the AmpC and OXA types.12 In the case of trimethoprim a complexity arose from the continuing shift from co-trimoxazole to trimethoprim use during the study period. In 1990, 63% of trimethoprim usage was as co-trimoxazole but, by 1997, this proportion had declined to below 2% (IMS-HEALTH data on file). Some authors used to suggest that trimethoprim would be more likely to select resistance than co-trimoxazole, although this view was never substantiated.13,14 More generally, attempts to relate resistance to the use of specific antimicrobials (as with MDI) are bedevilled by the fact that many plasmids encode diverse resistances and may be selected by any of these agents.13 Moreover, resistances may persist long after a selection pressure is removed, as demonstrated by the continued frequency of streptomycin resistance in E. coli.15 Turning to whether the E. coli isolates reported in the PHLS bacteraemia surveillance correspond to those experiencing the selection pressure recorded in the IMS HEALTH and PPA data, it should be emphasized that these databases record community antibiotic usage, whereas the resistance data include (but do not distinguish) hospital bacteraemias. We do not consider this to be an overwhelming problem since 87% of ampicillin analogue use and 70% of trimethoprim use is in the community (based on cost; IMS- HEALTH, data on file, 1998). Moreover, most E. coli bacteraemias involve organisms originating from the patient's own gut flora,5 and the resistances of these are most likely to reflect previous community prescribing. Nevertheless, we cannot discount the possibility that the resistance rates were distorted by hospital strains, although these seem unlikely to have accounted for stable long-term differences in regional resistance rates. Finally, and perhaps most importantly, it may be that Regions were excessively large units to examine. There was considerable variation in prescribing between the districts that compose these regions (Figure), and a closer relationship may exist between resistance and prescribing on a district basis. In a recent study in Wales, Magee et al.16 noted relationships between prescribing and resistance in urinary coliform bacteria only when the data were split to the level of individual general practices. Dividing the present data to smaller units of geography was impossible, since there were too few bacteraemia isolates or MDI-contributing GPs.
In conclusion, these data reveal long-standing regional differences in the prevalence of ampicillin and trimethoprim resistance in E. coli isolates from bacteraemia and CSF infection but these differences showed only weak relationships with the prescribing pressure recorded by the MDI and PPA data.
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Acknowledgments |
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Notes |
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References |
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Magee, J. T., Pritchard, E. L., Fitzgerald, K. A., Dunstan, F. D. J. & Howard, A. J. (1999). Antibiotic prescribing and antibiotic resistance in community practice: retrospective study 19968. British Medical Journal 319, 123940.
Received 21 June 1999; returned 4 January 2000; revised 3 March 2000; accepted 21 May 2000