Scottish Surveillance of Healthcare Associated Infection Programme (SSHAIP)

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SSHAIP

07 July 2010

Quarterly report on the Surveillance of Clostridium difficile infection (CDI) in Scotland, January 2010-March 2010

Please note CDI rates in this report have been updated due to a subsequent revision of the national figures of hospital activity.
Please go to http://www.hps.scot.nhs.uk/haiic/sshaip/publicationsdetail.aspx?id=50174 for the revised data.

Executive summary

  • This report provides CDI data for the first quarter of 2010 (January-March 2010) in 14 NHS boards. Results in the age groups 15-64 and those aged 65 and over are included.
  • Incidence rates in patients aged 65 and over are compared to previous quarters, including comparison with annual rates, whereas the rates in the age group 15-64 are compared with the previous quarter only. Cases from NHS Golden Jubilee National Hospital are reported separately.
  • A total of 641 new cases of CDI, in persons aged 65 and over, were reported during the first quarter of 2010, which is a 5% decrease from the fourth quarter (October-December 2009) where 672 cases were reported.
  • The overall rate for Scotland in persons aged 65 and over was 0.49 cases of CDI per 1000 total occupied bed days (OCBDs), representing a decrease of 6% compared to the previous quarter’s rate of 0.52 per 1000 OCBDs. This is the eighth consecutive drop in rates since the beginning of 2008, and is the lowest overall rate reported so far.
  • Overall for Scotland, comparison of yearly rates in persons aged 65 and over between April 2008-March 2009 and April 2009-March 2010 shows a reduction of 44%.
  • In the 15-64 age group, there were 194 cases of CDI reported compared to 235 in the previous quarter, which is a 17% decrease. The distribution of cases in this age group is skewed with 67% of the cases aged 50-64 and 85% aged 40-64.
  • The overall rate in the 15-64 age group was 0.50 cases of CDI per 1000 acute occupied bed days (AOBDs) compared to 0.62 per 1000 AOBDs in the fourth quarter, which is a 19% decrease. These rates are not comparable to rates in the 65 or over age group (see caveats in the Discussion).
  • Results in the 15-64 age group should be interpreted with caution as there may be increased case ascertainment due to heightened awareness of the new testing criterion, variance in board compliance with the expanded surveillance programme, bias due to differences in patient population characteristics among boards, and the potential for false positives to have an exaggerated effect due to the lower prevalence in this age group.
  • For this quarter, none of the NHS boards were above the upper 95% confidence limits of the funnel plot of total rates in either age group.
  • Trend analysis in patients aged 65 and over for the period April 2009 to March 2010 shows that 13 NHS boards have downward trends. NHS Dumfries & Galloway is static, although rates have decreased over the last two quarters.
  • Based on submissions for C. difficile culture from severe cases and outbreaks to the reference laboratory (clinical surveillance), ribotype 106 (29%) remains the most common type reported in Scotland followed by ribotype 001 (22%). The cumulative frequency of reports of types 027 (12%) and 078 (3%) has not changed significantly. All ribotypes were sensitive to metronidazole and vancomycin.
  • Results of the representative surveillance (snapshot programme) for the first quarter of 2010 show that the relative frequencies of the three most common types associated with outbreaks and severe cases are lower in this more representative sample (although ribotypes 106 and 001 remain the two most common strains, respectively). There is a higher prevalence of other types such as 020, 015 and 023 compared to the proportions seen in the clinical surveillance. The proportion of ribotype 027 reported in this quarter (7%) is the same as in the previous quarter.
  • Consensus guidance on diagnostic testing (‘Recommended protocol for testing for Clostridium difficile and subsequent culture’) has been developed by the Scottish Salmonella Shigella and Clostridium difficile Reference Laboratory (SSSCDRL), HPS and representatives from the Scottish Microbiology Forum (SMF). This guidance was distributed in December 2009.
  • The national surveillance programme is retrospective (i.e. three months in arrears) and does not obviate the need for local monitoring of cases of CDI.

1. Introduction

The surveillance programme monitors the occurrence of CDI in all patients aged 15 and over, with diarrhoea, and who have been in contact with the healthcare system, including acute and non-acute hospitals and primary care.

This report covers data for the first quarter of 2010 (January-March 2010) from 14 NHS boards. Cases from NHS Golden Jubilee National Hospital are not included in the analysis of Scottish CDI data due to differences in patient population and later inclusion in the mandatory surveillance. This is currently under review.

This report also includes data from the C. difficile snapshot programme (representative surveillance) for the first quarter of 2010. Details of the programme and the methods of data collection can be accessed from: http://www.hps.scot.nhs.uk/haiic/sshaip/guidelinedetail.aspx?id=40550.

2. Methods

2.1 Laboratory testing

Diarrhoeal stools from patients, aged 15 and older, were tested for toxin A and B using either an immunoassay or a cytotoxicity assay. A diarrhoeal stool is defined as a specimen that takes the shape of its container. A case of CDI is someone in whose stool C. difficile toxin has been identified at the same time as they have diarrhoea not attributable to any other cause, or from patients from whose stool C. difficile has been cultured at the same time as they have been diagnosed with pseudomembranous colitis (PMC).

Isolates of C. difficile were typed using PCR ribotyping according the method described by O’Neill et al.1 Variable-length intragenic spacer regions of the rRNA complex were amplified by PCR, and ribotype patterns were compared directly with those of reference strains obtained from the Anaerobe Reference Laboratory (ARL) in Cardiff. The isolates were further susceptibility tested against nine antibiotics using Etest (AB Biodisk, Solna, Sweden). Breakpoints were derived from the Clinical and Laboratory Standards Institute (CLSI) criteria and aligned with those used in England and Wales. Antibiotics tested included: cefotaxime, (CEFO), (64µg/ml), clindamycin, (CLIN), (≥8µg/ml), erythromycin, (ERYT), (≥8µg/ml), levofloxacin, (LEVO), (≥8µg/ml), meropenem, (MERO), (≥16µg/ml), metronidazole, (METR) (≥32µg/ml), moxifloxacin, (MOXI), (≥8µg/ml), piperacillin-tazobactam (PIP/T), (≥128µg/ml), and vancomycin (VANC), (≥16µg/ml).

2.2 Reporting

Incidence rates of CDI are presented by NHS board. Each case is allocated to an NHS board based on the location of the diagnostic laboratory where the specimen was tested. The surveillance does not distinguish between cases from acute, non-acute hospitals, and the community. It is currently assumed that all cases have been in contact with the healthcare system within 12 weeks of acquiring CDI and therefore can be classified healthcare associated cases. Duplicates have been removed. If a case is diagnosed twice within a 28-day period the second toxin positive test will be considered a duplicate.

Where available, de-duplicated ECOSS data are used for calculating the total number of cases for the national dataset.

The exact date of onset of illness is not reported; instead, the date of collecting specimen from the patient is taken as a proxy for the onset of illness for the ECOSS reports. When this date is not available the date of receiving the specimen or date of reporting is used. Before entering the data into the dataset each diagnostic laboratory has the opportunity to review the data originating from themselves.

2.3 Data analysis

Calculation of rates

The incidence rate of CDI per NHS board area for patients aged 65 and older was calculated as follows:

Rate per 1000 total occupied bed days = number of CDI cases * 1000 / OCBDs ≥65 in board area 

The denominator for patients aged 65 or older (total occupied bed days (OCBDs)) includes patients in acute hospitals and patients in non-acute geriatric medicine and geriatric long-term stay wards except for psychiatry and obstetrics. Acute rates are not calculated separately for the age group 65 or older, as these rates were found to be unsuitable for monitoring CDI in Scotland.

The incidence rate of CDI per NHS board area for patients aged 15-64 was calculated as follows:

Rate per 1000 acute occupied bed days = number of CDI cases * 1000 / AOBDs 15-64 years in board area

The denominator for patients aged 15-64 (acute occupied bed days (AOBDs)) includes patients in acute hospitals only, as so few CDI patients in this age group are found in the non-acute setting.

The bed day data used here were from the period January-March 2009. In addition to the rates per occupied bed days, the rate of disease was also calculated per 100,000 inhabitants for each NHS board.

Identification of outliers

A funnel plot was produced for the incidence rates of CDI in 14 NHS boards in the period January-March 2010. Funnel plots are a type of control chart in which the observed event (in this instance rates of CDI cases) is plotted against a measure of its precision (in this case the sample size as measured by occupied bed days). The statistical analysis was based on an over-dispersed Poisson regression model with the logarithm of the occupied bed days as an offset. In the funnel plot, the incidence rates of CDI per 1000 OCBDs are plotted against the number of OCBDs in 1000s along with 95% confidence limits. Incidence rates outside of the 95% confidence limits are considered outliers.

Analysis of trends

Analysis of trends in the incidence rates of CDI in patients aged 65 and over was also carried out using an over-dispersed model as above, including terms for NHS board, Year and Quarter. Hypothesis tests were carried out using F tests based upon the large sample approximation to the normal distribution. Model checking was accomplished using residual plots and these demonstrated that the model assumptions were reasonable. The trend analysis is based upon the most recent eight quarters of data.

NHS Golden Jubilee National Hospital was excluded from the analysis as noted in the introduction.

3. Results

3.1 Surveillance data

CDI incidence in patients aged 65 and over

During the period January to March 2010, HPS received case reports from 25 diagnostic laboratories in 14 NHS boards.

The total number of cases identified in patients aged 65 and over was 641, a 5% decrease on the fourth quarter (October-December 2009) where 672 cases were recorded. Individual rates by NHS board are shown in Figure 1 for this quarter compared with the previous quarter.

One case of CDI in patients aged 65 and over from NHS Golden Jubilee National Hospital was reported this quarter.

The overall rate for Scotland for this quarter was 0.49 per 1000 OCBDs, which is 31% below the annual overall rate for 2009 of 0.71 per 1000 OCBDs (see Table A1 for individual NHS boards in the Appendix).

In comparison with the overall rate for the first quarter of 2009, this quarter’s rate is 44% down (from 0.88 to 0.49 per 1000 OCBDs).

As Figure 1 shows, the rates per 1000 total OCBDs decreased in six boards, increased in seven boards (none of the increases were statistically significant) and remained the same in one board.

Rates of CDI were also calculated using the population aged 65 and older per NHS board area as the denominator (Figure 2). The overall rate per 100,000 persons aged 65 and over has decreased by 5% compared to the previous quarter (from 81 to 77 per 100,000 persons aged 65 and older).

CDI incidence in patients aged 15-64

The total number of cases identified in patients aged 15-64 was 194, representing a decrease of 17% compared to the previous quarter where 235 cases were reported. There were no cases in patients aged 15-64 reported from NHS Golden Jubilee National Hospital.

As Table 1 shows, the distribution of the cases within this age group is skewed, with 130 (67%) of the cases in the 50-64 age group, and 164 (85%) of the total in the 40-64 age group.

Figure 3 shows the individual rates for each NHS board for this quarter compared with the previous quarter (October-December 2009).

The overall incidence rate for Scotland for this quarter was 0.5 per 1000 AOBDs, a 19% decrease compared to the last quarter’s rate of 0.62 per 1000 AOBDs.

As Figure 3 shows, the rates per 1000 AOBDs decreased in eight boards, increased in five boards (none of the increases were statistically significant) and stayed the same in one board.

3.2 Identification of outliers

The funnel plots for the first quarter of 2010 for those aged 65 and over and 15-64 show that the rates in all NHS boards in both age groups are below the upper 95% confidence limit (see Figures 4 and 5).

The precision of these analyses are higher for the NHS boards with large numbers of OCBDs than for those with smaller numbers of OCBDs.

3.3 Identification of trends

Trends of CDI rates for the first 14 quarters of data collection in patients aged 65 and over are shown for the individual NHS boards in the appendix (Figure A1). The overall quarterly rates for Scotland are shown in Figure 6.

Analysis of the trends over the eight quarters from April 2008 to March 2010 shows that NHS Ayrshire & Arran, NHS Borders, and NHS Grampian have seen an initial increase followed by a downward trend in rates. The trend in NHS Dumfries & Galloway is static (although the last two quarters appear to show a developing downward trend), and all other NHS boards have a downward trend in rates (Figure A1).

Comparison of the yearly rates between April 2008-March 2009 and April 2009-March 2010 shows that rates have decreased significantly in NHS Ayrshire & Arran, NHS Borders, NHS Fife, NHS Forth Valley, NHS Grampian, NHS Greater Glasgow & Clyde, NHS Highland, NHS Lanarkshire, NHS Lothian, NHS Orkney and NHS Shetland. Rates in NHS Dumfries & Galloway, NHS Tayside and NHS Western Isles decreased but were not statistically significant. NHS Shetland has reported zero cases in the last four quarters.

Overall for Scotland, comparison of yearly rates between April 2008-March 2009 and April 2009-March 2010, adjusting for NHS board and quarter, shows a reduction of 44% (95% CI 39%, 49%).
Figure 6: Overall quarterly CDI rates for Scotland (per 1000 total OCBDs) for 14 quarters of mandatory surveillance covering the period October 2006-March 2010.

3.4 Typing and susceptibility data

Ribotype data (severe cases and outbreaks)

In the period November 2007-March 2010, 1740 specimens were received by the Scottish Salmonella Shigella and Clostridium difficile Reference Laboratory (SSSCDRL) for ribotyping. Most were ribotype 106 (29%), 001 (22%), 027 (12%), 002 (6%), 015 (4%), 014 (3%), 078 (3%) and 005 (3%). The remaining ribotypes are present at frequencies of less than 3% (see Figure 7).

217/1740 (12%) cases of infection with the hypervirulent ribotype 027 were reported in the period November 2007-March 2010.

In total, 52 different ribotypes have been reported since November 2007.

Antibiotic susceptibility

The susceptibilities of the isolates were investigated by determining the minimum inhibitory concentration (MIC) for the nine antibiotics previously listed. Figure 8 shows the resistance profiles for the nine antibiotics. All isolates were sensitive to metronidazole (MIC range 0.03-3.0 µg/ml) and vancomycin (MIC range 0.064-3.0 µg/ml).

The highest frequencies of resistance were reported for cefotaxime, erythromycin, and clindamycin.

A single isolate of type 014 was resistant to piperacillin-tazobactam (this isolate was also resistant to cefotaxime, levofloxacin, moxifloxacin and clindamycin).

Antibiotic susceptibility in ribotypes 106, 001 and 027

The majority of isolates of types 106, 001 and 027 are multi-resistant to the antibiotics cefotaxime, moxifloxacin, levofloxacin, erythromycin and clindamycin (Table 2), with >90% of isolates of types 106 and 001 being multi-resistant. Ribotype 027 has a lower frequency of resistance to cefotaxime compared to types 001 and 106, although it is still observed in the majority of isolates (86%).

Ribotype data (representative surveillance - snapshot data)

Between January and March 2010, the reference laboratory received 154 out of a requested 177 samples (87%) from 25 laboratories across Scotland. Of the samples submitted, 135 (88%) were ribotyped (19 isolates were either not C. difficile or did not grow in culture).

As Figure 9 shows, the two most common ribotypes collected during this period were ribotype 106 (20%) and ribotype 001 (12%). Frequencies of other common ribotypes were 002 (7%), 027 (7%), 020 (6%), 015 (6%), 023 (5%) and 014 (3%), with the remaining ribotypes present at frequencies of less than 3% (one sample is awaiting results).

Twenty-eight different types were identified during this period. All types were sensitive to metronidazole and vancomycin.

4. Discussion

A total of 641 cases, in persons aged 65 and over, were identified during this quarter (a 5% decrease compared to last quarter). The overall rate for Scotland was the lowest rate reported since the beginning of the mandatory surveillance and the eighth consecutive drop since 2008. This is a 6% decrease compared to the fourth quarter of 2009 (0.49 per 1000 total OCBDs compared to 0.52), and a 67% decrease compared to the highest rate reported in the first and second quarters of 2007 (1.47 per 1000 total OCBDs).

There is evidence that there has been a reduction in the overall rate of CDI in patients aged 65 and over between the year ending March 2009 and the year ending March 2010, with rates decreasing significantly in NHS Ayrshire & Arran, NHS Borders, NHS Fife, NHS Forth Valley, NHS Grampian, NHS Greater Glasgow & Clyde, NHS Highland, NHS Lanarkshire, NHS Lothian, NHS Orkney and NHS Shetland. NHS Shetland has reported no cases over the last year. There were no boards with a significant increase in rates over this period.

The decreasing trends in rates in most of the Scottish NHS boards are helping to drive the downward trend in the Scottish overall rate; however, all NHS boards need to remain focused on their individual rates as well as the national rate.

In the 15-64 age group, the majority of the cases (85%) were aged 40 or above, reflecting the propensity for CDI to affect older patients. However, the results reveal the presence of CDI in younger age groups; therefore, it is important that the health service is aware of the potential for CDI to infect a younger population and continue to follow the surveillance protocol. The overall rate in this age group has decreased 19% (0.62 to 0.50 per 1000 AOBDs) compared to the previous quarter.

The rates for the two age groups are not directly comparable for the reasons laid out below; however, the rates do suggest a similarity in trends within their respective NHS boards; i.e., boards with higher rates in the patients aged 65 and older also have higher rates in the 15-64 age group.

Results in the 15-64 age group should be interpreted with caution as there may be increased case ascertainment due to heightened awareness of the new testing criteria, variance among boards in complying with the expanded surveillance programme, bias due to differences in patient population characteristics among boards, and the potential for false positives to have an exaggerated effect due to the lower prevalence in this age group.

Typing of selected isolates from suspected outbreaks and cases of severe disease have shown that ribotypes 106, 001 and 027 remain the three most prevalent strains in Scotland. The common European ribotypes, 002, 014 and 015, have emerged in Scotland.

Ribotypes 106, 001 and 027 are multi-resistant to cefotaxime, moxifloxacin, levofloxacin, erythromycin and clindamycin, which may reflect the importance that the use of fluoroquinolones, cephalosporins and clindamycin may play in the spread and persistence of these types in Scotland. A single isolate of ribotype 014 was resistant to piperacillin-tazobactam. All isolates remain susceptible to vancomycin and metronidazole.

In the representative surveillance (snapshot programme), which comprises a cross-section of all diagnosed cases, the most prevalent types were 106, 001, 002 and 027, respectively. The prevalence of ribotype 027 has not changed (7%) compared to the last quarter. There is a greater prevalence of other types such as 020, 015 and 023 reflecting an increased diversity of ribotypes contributing to CDI in Scotland. Further study of the distribution and epidemiology of these emerging types is warranted.

The representative surveillance reflects a range of disease presentations, from mild to severe, whereas clinical submissions reflect outbreaks and severe cases. It is notable that the two most prevalent strains causing severe disease in Scotland (ribotypes 106 and 001) are also the two most prevalent in the representative surveillance, although they represent a lower proportion of the ribotypes in the representative surveillance. Therefore, the representative surveillance results suggest that there is a greater diversity and prevalence of ribotypes causing milder disease than suggested by the clinical submissions. The distribution of ribotypes is not the same across Scotland. The collection of more data will help improve the understanding of the distribution and epidemiology of C. difficile in Scotland.

It is important that the service is aware and remains vigilant to the possibility of outbreaks of C. difficile of any ribotype.

A number of important caveats associated with the data in this report must be highlighted: (a) regional differences in healthcare provision and the age distribution of the population are factors likely to affect the number of persons acquiring CDI in each NHS board area; (b) full compliance with the national surveillance protocol has been achieved gradually at different times in the NHS boards and comparison with previous data could therefore be associated with error; (c) previous validation studies (not mentioned in this report) showed that 9-35% of reported cases had no documented symptoms – some of these cases may have been false-positive cases; (d) the trend analysis is only based upon eight quarters of data as this enables a year on year comparison to be made without any bias associated with seasonal effects. The analysis does not cover data from 2006 as there is evidence of different patterns in rates in many boards in the early part of the surveillance and the recent year on year change is of greater interest than historical comparison. Much of the statistical significance comes from the large numbers of cases which add power to the analysis; (e) some of the samples submitted for the snapshot programme did not grow on culture or were not C. difficile, and some laboratories did not have any samples to send as there were no cases of CDI during the collection period or have experienced technical issues in the preparation of samples; therefore, there is some bias between laboratories. The snapshot data is also, so far, based on small numbers and more data is required to be able to draw further conclusions; (f) case review studies have shown that community-associated CDI varies amongst NHS boards from 0-26%; and (g) the NHS Centre for Evidence-based Purchasing (CEP) has published the results of an evaluation of the performance of commercial kits for the detection of C. difficile toxins and highlights issues related to the sensitivity and positive predictive values of the kits. In the context of widespread testing, this has raised doubts as to the appropriateness of using single tests for toxin detection. A questions and answers document has been drawn up by the CDI Diagnosis Working Group and adapted by HPS. The document may be accessed from: http://www.hps.scot.nhs.uk/haiic/sshaip/guidelinedetail.aspx?id=40852

Following publication of the CEP results, consensus guidance on diagnostic testing (‘Recommended protocol for testing for Clostridium difficile and subsequent culture’) has been developed by the Scottish Salmonella Shigella and Clostridium difficile Reference Laboratory (SSSCDRL), HPS and representatives from the Scottish Microbiology Forum (SMF). This guidance was distributed in December 2009.

Whilst unlikely to impact the current numbers, the new testing guidance may affect numbers reported in future. This is currently under review.

Acknowledgement

We would like to thank all the microbiologists and biomedical scientists who have provided and reviewed data for the CDI surveillance programme and the Scottish C. difficile reference service for providing ribotyping data. Information Services Division of the NHS in Scotland is thanked for providing the hospital activity denominator data for this report. Our thanks also to Chris Robertson (Professor of Public Health Epidemiology, HPS and University of Strathclyde), Gwen Allardice (HPS and University of Strathclyde) and Traini Stari (HPS and University of Strathclyde) for their statistical support, and the continuing hard work of the infection control and antimicrobial management teams in helping to reduce the burden of CDI.

References

O’Neill GL, Ogunsola FT, Brazier JS, Duerden BI. Modification of a PCR ribotyping method for application as a routine typing scheme for Clostridium difficile. Anaerobe 1996; 2; 205-209.

Appendix

Author(s): Prepared by: The HPS C. difficile Working Group Vol: 44 No: 27 Year: 2010 Page:

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