Volume 2 No 3 ;18 January 2008
The Health Protection Agency, the National Public Health Service of Wales and Health Protection Scotland are investigating an outbreak of Salmonella Anatum affecting England, Wales and Scotland. The geographic distribution of cases is shown in figure 1.
Figure 1. Geographic distribution of cases of Salmonella Anatum in England, Wales, and Scotland received by LEP or SSRL since 1 November 2007
Since 1 November 2007, there have been 84 primary indigenous cases (54 England, 8 Wales, 22 Scotland), with the most recent onset date of 17 December 2007 (figure 2).
Figure 2. Epicurve for cases of Salmonella Anatum in England, Wales and Scotland, received by LEP or SSRL since 01 November 2007
Pulsed-field gel electrophoresis has been conducted on 23, 4, and 20 isolates (England, Wales, and Scotland, respectively) and are of the strain designated SANTXB.0012. The ages for all cases range from 4 months to 92 years of age, though the older age-groups are more affected (figure 3). More women are affected than men (ratio 1.6:1).
Figure 3. Age disribution of cases of Salmonella Anatum in England, Wales and Scotland, received by LEP or SSRL since 01 November 07
Ten trawling questionnaires have been administered in England, and four in Scotland. These have not produced a formal hypothesis to test, and any possible hypotheses will be difficult to test due to recall bias (both due to time lag and memory of respondents).
The investigation team will continue to conduct the trawling questionnaire, focussing on younger cases and those most recent, to minimise the risk of recall bias among respondents.
The increasing burden of Clostridium difficile infection (CDI) is compounded by the lack of treatment choices. Two main options exist comprising either oral metronidazole or vancomycin. Metronidazole is generally favoured for the majority of CDI episodes that are non-severe. To date there has been little evidence for the emergence of resistance in C. difficile to either of these antibiotics, and confirmation of resistance has generally been limited to occasional strains with reduced susceptibility to metronidazole [1,2].
Ongoing surveillance for antibiotic resistance in C. difficile has now identified the emergence of reduced susceptibility to metronidazole. Recently isolated (2005-2006) C. difficile strains from symptomatic patients in Leeds were screened and results compared with those from repeat testing of historic isolates (1995-2001) . Isolates of C. difficile ribotypes 001 (n=87), 106 (n=81), 027 (n=48), the most common types seen in the United Kingdom (UK), and ten other prevalent ribotypes (n=57) were examined initially using a spiral gradient endpoint (SGE) method. No reduced susceptibility to metronidazole was observed in C. difficile ribotype 106 or 027 isolates (geometric mean minimum inhibitory concentrations [MICs] by SGE were 1.1 mg/L and 0.9 mg/L, respectively). By contrast, 21 (24%) of C. difficile ribotype 001 isolates had reduced susceptibility to metronidazole by SGE (geometric mean MIC was 3.5 mg/L (P<0.001). No reduced susceptibility to vancomycin was observed.
Those isolates displaying a metronidazole MIC =6 mg/L, as determined by SGE, were analysed further by agar incorporation and E-test methods. Results varied according to the method used, and both the agar base and broth used to prepare inocula affected the metronidazole MIC values for C. difficile . Neither E-test nor Clinical and Laboratory Standards Institute methods detected the C. difficile strains with reduced susceptibility to metronidazole. Reduced susceptibility to metronidazole was, however, confirmed using an agar dilution method . Briefly, strains were cultured in pre-reduced Schaedler's anaerobic broth (Oxoid, UK) at 37° C for 24hr, followed by multipoint inoculation of 104 cfu per spot onto Wilkins-Chalgren agar (Oxoid) and anaerobic culture at 37° C for 48hr. Using this method the geometric mean MICs of C. difficile ribotype 001 isolates from 1995-2001 (n=72) and those identified by SGE with reduced susceptibility to metronidazole (n=19) were 1.03 and 5.9 mg/L, respectively (P<0.001). Highly discriminatory DNA fingerprinting using multilocus variable number of tandem repeat analysis (MLVA ) of 22 resistant isolates and six susceptible isolates revealed three subgroups with highly genetically related strains (summed tandem-repeat difference [STRD] <2) of ribotype 001 isolates. The subgroups differed from one another at two loci with 3-12 STRD. Of 22 resistant strains, 18 belonged to one of the subgroups, whereas only two of six susceptible strains were genetically related. This is suggestive of the dissemination of clones with reduced metronidazole resistance phenotype. The mechanism of reduced susceptibility to metronidazole remains to be determined.
The clinical implications of these results are unclear, but are of concern for several reasons. Metronidazole achieves relatively poor concentrations in the colonic lumen during CDI; mean concentrations of 9.3 mg/kg have been measured, but these are lower in some individuals, and notably decrease as diarrhoea resolves . Recent evidence suggests that vancomycin is superior to metronidazole for the treatment of severe but not mild/moderate CDI . A wholesale switch to using oral vancomyin for CDI is not recommended given the pressure this would generate for the emergence of resistance to this remaining therapeutic option for CDI. Also, evidence to date has suggested that treatment failure in CDI was not linked with metronidazole resistance [3,6]. However, these latest results mean that clinicians need to be alert for evidence of increased treatment failure. It is not routine to carry out antibiotic susceptibility testing of C. difficile , not least because microbiology laboratories conventionally assay for toxin and do not culture the bacterium. The method used to measure metronidazole susceptibility is important, and increased vigilance is needed to identify reduced antibiotic susceptibility in C. difficile. Further surveillance is planned to monitor this development.
1. Barbut F, Decre D, Burghoffer B, Lesage D, Delisle F, Lalande V, et al . Antimicrobial susceptibilities and serogroups of clinical strains of Clostridium difficile isolated in France in 1991 and 1997. Antimicrob Agents Chemother 1999;43:2607-11.
2. Peláez T, Alcalá L, Alonso R, Rodríguez-Créixems M, García-Lechuz JM, Bouza E. Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrob Agents Chemother 2002; 46: 1647-50 .
3. Freeman J, Stott J, Baines CD, Fawley WN, Wilcox MH. Surveillance for resistance to metronidazole and vancomycin in genotypically distinct and UK epidemic Clostridium difficile isolates in a large teaching hospital. J Antimicrob Chemother 2005; 56: 988-9.
4. Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile . Gut 1986; 27: 1169-72.
5. Sanchez JL, Gerding DN, Olson M, Johnson S. Metronidazole susceptibility in Clostridium difficile isolates recovered from cases of C. difficile -associated disease treatment failures and successes. Anaerobe 1999; 5: 201-204.
6. Zar FA , Bakkanagari SR , Moorthi KM , Davis MB . A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile -associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45: 302-7.
The Department of Health has announced changes to the mandatory surveillance of C. difficile infection in a CMO/CNO letter published on 16 January .
In order to deliver these changes, the Healthcare-associated infections (HCAI) Data Capture System has been extensively revised. The main system changes are:
Details of the system changes can be found in the CMO/CNO letter  and the HCAI user manual on the HCAI Data Capture System website .
1. Changes to the mandatory healthcare associated infection surveillance system for Clostridium difficile infection (CDI) from 1 January 2008 PL CMO (2008)1. London : Department of Health, 2008. Available at <http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars/
2. HCAI User manual v3.0 ( C. difficile , MRSA and MSSA). Available at <https://nww.hpanw.nhs.uk/MRSA/default.asp>.
Guidance for the management of Panton-Valentine leukocidin (PVL) Staphylococcus.aureus infection in the United Kingdom is now available for consultation on the HPA website until 28 February 2008. The guidance has been updated by a subgroup of the Steering Group on Healthcare Associated Infections (SG-HCAI) at the request of the Department of Health (DH) and updates existing guidance available on the DH website.
The guidance aims to provide healthcare professionals with easily accessible advice to assist the recognition, investigation, and management of PVL S.aureus cases. It complements more detailed guidance on diagnosis and the principles of management that has recently been produced by the British Society for Antimicrobial Chemotherapy ( BSAC).
The guidance and details of how to submit your comments can be found at <http://www.hpa.org.uk/consultations/default.htm>.