Education of healthcare professionals and the public.

In the winter of 2007-08 a new public-facing antimicrobial campaign was agreed by the Advisory Committee on Antimicrobial Resistance and Healthcare-Associated Infection (ARHAI) Education sub-Group (later divided into subgroups for professional and public education): it comprised posters with a positive message on how the public could help themselves when they had a cold. However, the poster campaign, used in isolation in England, did not improve antibiotic use; therefore, the Public Education sub-Group took forward educational approaches to change the behaviour of the public and health professionals. Professionals have been encouraged to give patients clear information about the likely duration of symptoms, self-care, and benefits and harms of antibiotics, reinforcing the public poster campaigns in surgeries, hospitals and pharmacies. Since 2008, campaigns have been launched in England to coincide with European Antibiotic Awareness Day (EAAD) on 18 November, using Department of Health and EAAD materials. Professional education has been facilitated by the 2008 National Institute for Health and Clinical Excellence respiratory tract infection delayed prescribing guidance for general practitioners. A toolkit of materials for medicines management teams, to facilitate good antimicrobial stewardship in primary care (ASPIC), is being taken forward by the Public Education sub-Group and professional societies. After advice from ARHAI, in 2009 the General Medical Council requested that all postgraduate deans and Royal Colleges ensure infection prevention and control and antimicrobial prescribing become standard practice implemented in all clinical settings, and that they are emphasized strongly in undergraduate and postgraduate medical training. ARHAI has also taken a keen interest in reviewing, advising and leading on a number of European Union initiatives dealing with professional education.

Polyclonal multiply antibiotic-resistant methicillin-resistant Staphylococcus aureus with Panton-Valentine leucocidin in England.

OBJECTIVES: Community-associated methicillin-resistant Staphylococcus aureus (MRSA) including those encoding Panton-Valentine leucocidin (PVL) are often described as more susceptible to a range of antibiotics than their hospital-associated counterparts. Recent scattered reports of the emergence of multiresistant PVL-MRSA have highlighted the potential for resistance to emerge. Here we detail polyclonal multiply antibiotic-resistant PVL-MRSA occurring in England. METHODS: PVL-MRSA from community-based and hospitalized patients located across England were identified by PCR. Isolates were characterized via MIC determinations, toxin gene profiling, PFGE, SCCmec, spa and agr typing. Multilocus sequence typing (MLST) was performed on selected isolates. Patient demographic and available disease data were retained for analysis. RESULTS: Seventy-six PVL-MRSA isolates resistant to three further classes of antibiotic were identified between 2005 and 2008 from centres in each of the Health Protection Agency's geographic regions in England. Patient demographics were typical for PVL-MRSA, and some travel associations were identified along with clonal spread. One instance of familial transmission in the community was detected. PVL-MRSA belonging to MLST clonal complex (CC) 1 (sequence type 772) were consistently highly resistant; multiply antibiotic-resistant representatives of CCs 5, 8, 22, 59 and 80 were also identified. Ciprofloxacin resistance was common amongst the study isolates (51 of 76 isolates). CONCLUSIONS: Genetically diverse multiply antibiotic-resistant PVL-MRSA were identified, and included representatives of a recently emerged multiresistant clone (dubbed the Bengal Bay clone). Risk factors and disease presentations were typical for PVL-MRSA infections. This work highlights the diminishing utility of ciprofloxacin susceptibility for putative identification of PVL-MRSA.

Decline of EMRSA-16 amongst methicillin-resistant Staphylococcus aureus causing bacteraemias in the UK between 2001 and 2007.

OBJECTIVES: Between 1998 and 2000, 95.6% of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemias in the UK were due to two epidemic strains, namely EMRSA-15 or EMRSA-16 (60.2% and 35.4%, respectively). We sought to determine the proportions of these strains before and after the general decline in MRSA bacteraemia that began around 2004. METHODS: Consecutive MRSA isolates collected in 2001, 2003, 2005 and 2007 by the BSAC Bacteraemia Surveillance Programme were categorized to multilocus sequence typing (MLST) clonal complex and to SCCmec type by PCR. MICs were determined by the BSAC method. Data trends were tested for significance using a generalized linear regression model. RESULTS: Collectively, EMRSA-15 and EMRSA-16 consistently accounted for approximately 95% of MRSA studied between 2001 and 2007, but the proportions of EMRSA-16 declined from 21.4% in 2001 to 9% in 2007 (P < 0.05), whilst the proportion of EMRSA-15 rose commensurately, accounting for 85% of MRSA in 2007. Ciprofloxacin and erythromycin resistance were common amongst both EMRSA-15 and EMRSA-16. CONCLUSIONS: EMRSA-15 and EMRSA-16 remain the main MRSA strains in bacteraemia in the UK, but the proportion of EMRSA-16 declined from the late 1990 s, thus preceding the general decline in MRSA bacteraemias that began in the middle of the present decade.

Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community.

These guidelines have been developed by a Working Party convened on behalf of the British Society for Antimicrobial Chemotherapy. Their aim is to provide general practitioners and other community- and hospital-based healthcare professionals with pragmatic advice about when to suspect MRSA infection in the community, when and what cultures should be performed and what should be the management options, including the need for hospitalization.

The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection.

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals, and researchers. The ORION (Outbreak Reports and Intervention Studies Of Nosocomial infection) statement consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a "work in progress", which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

Antibody-directed photodynamic therapy of methicillin resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a world-wide public health problem, causing nosocomial and community-acquired infections. Furthermore, MRSA is increasingly resistant to many conventional antimicrobials, so there is a real need to develop alternative approaches for MRSA decolonization and treatment. Previously, we have demonstrated that MRSA can be killed with an immunoglobulin G (IgG)-SnCe6 conjugate and red light, but effectiveness was dependent on the particular strain and the growth phase. In this investigation, we used an antibody raised against MRSA to make an Ab-SnCe6 conjugate capable of targeting many MRSA strains in all growth phases. To suspensions of important epidemic MRSA, each grown to stationary, lag, or exponential phase, the Ab-SnCe6 conjugate was added and samples exposed to red light. Survivors were then enumerated. This treatment was very effective at killing all the different MRSA strains tested, in all growth phases. The Ab-SnCe6 conjugate was able to kill EMRSA-16 selectively in a mixed suspension of EMRSA-16 and Escherichia coli, and was much better at killing EMRSA-16 than a coagulase-negative staphylococcus, S. epidermidis. These results demonstrate that photodynamic therapy of MRSA is very effective when the photosensitizer is targeted to the pathogen using a suitable antibody and may be a good candidate for a novel treatment of MRSA infections.

Use of semi-quantitative and quantitative culture methods and typing for studying the epidemiology of central venous catheter-related infections in neonates on parenteral nutrition.

To study the epidemiology - especially the impact of contaminated stopcocks - on central venous catheter (CVC) infection and catheter-related sepsis (CRS), semi-quantitative (SQ) and quantitative (Q) culture methods and typing of coagulase-negative staphylococci (CNS) were employed in 49 neonates with clinical signs of sepsis while receiving parenteral nutrition in the paediatric intensive care unit. The patients were divided into two groups according to stopcock contamination: group A consisted of 18 patients (36%) with contaminated stopcocks and group B consisted of 31 patients (64%) with sterile stopcocks. Five specimens were obtained from each patient, in addition to that from the stopcock: a swab taken from the skin surrounding the catheter puncture site; the CVC tip; the intradermal segment (IDC); and samples of parenteral fluid and blood. A total of 294 specimens (392 sites) was cultured and micro-organisms were identified. All CNS isolated were typed by biotyping, antibiogram, plasmid analysis and pulsed-field gel electrophoresis (PFGE), and the discriminatory power of the typing methods was compared. The CVC tips were infected in 25 patients (51%); 15 (83%) in group A and 10 (32%) in group B. Sepsis was detected in 24 neonates (49%), 13 in group A and 11 in group B. This was catheter-related in 15 patients (63%), 12 in group A and 3 in group B. CNS were recovered from 13 (52%) of 25 infected CVCs, nine in group A and four in group B. Sixty-five CNS isolates were recovered from these patients and belonged to 14 biotypes, 22 antibiograms, 22 plasmid profiles and 26 PFGE types. Typing showed that in six of nine patients in group A, CNS of the same type were recovered from the catheter tip and the stopcock, in one patient the catheter tip and skin isolates were the same and in two others the catheter tip isolates were different from stopcock and skin isolates. In all four patients in group B, different CNS types were recovered from CVC tips and skin. Bacteraemia was caused by CNS in 14 patients (58%), six in group A and eight in group B. Typing confirmed that nine cases (six in group A and three in group B) were catheter-related but five were not. SQ and Q culture methods and typing, especially by PFGE, allowed the study to determine that bacteria from contaminated stopcocks were frequently the source of CVC infection and CRS.

The Feedback Intervention Trial (FIT)--improving hand-hygiene compliance in UK healthcare workers: a stepped wedge cluster randomised controlled trial.

INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10-13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards. CONCLUSION: Despite difficulties in implementation, intention-to-treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN65246961.

Screening, isolation, and decolonisation strategies in the control of meticillin resistant Staphylococcus aureus in intensive care units: cost effectiveness evaluation.

OBJECTIVE: To assess the cost effectiveness of screening, isolation, and decolonisation strategies in the control of meticillin resistant Staphylococcus aureus (MRSA) in intensive care units. DESIGN: Economic evaluation based on a dynamic transmission model. SETTING: England and Wales. Population Theoretical population of patients on an intensive care unit. MAIN OUTCOME MEASURES: Infections, deaths, costs, quality adjusted life years (QALYs), incremental cost effectiveness ratios for alternative strategies, and net monetary benefits. RESULTS: All decolonisation strategies improved health outcomes and reduced costs. Although universal decolonisation (regardless of MRSA status) was the most cost effective in the short term, strategies using screening to target MRSA carriers may be preferred owing to the reduced risk of selecting for resistance. Among such targeted strategies, universal admission and weekly screening with polymerase chain reaction coupled with decolonisation using nasal mupirocin was the most cost effective. This finding was robust to the size of intensive care units, prevalence of MRSA on admission, proportion of patients classified as high risk, and precise value of willingness to pay for health benefits. All strategies using isolation but not decolonisation improved health outcomes but costs were increased. When the prevalence of MRSA on admission to the intensive care unit was 5% and the willingness to pay per QALY gained was between £20,000 (€23,000; $32,000) and £30,000, the best such strategy was to isolate only those patients at high risk of carrying MRSA (either pre-emptively or after identification by admission and weekly screening for MRSA using chromogenic agar). Universal admission and weekly screening using polymerase chain reaction based detection of MRSA coupled with isolation was unlikely to be cost effective unless prevalence was high (10% of patients colonised with MRSA on admission). CONCLUSIONS: MRSA control strategies that use decolonisation are likely to be cost saving in an intensive care unit setting provided resistance is lacking, and combining universal screening using polymerase chain reaction with decolonisation is likely to represent good value for money if untargeted decolonisation is considered unacceptable. In intensive care units where decolonisation is not implemented, evidence is insufficient to support universal screening for MRSA outside high prevalence settings.

Technical note: Assessment of blinding of hand hygiene observers in randomized controlled trials of hand hygiene interventions.

Trials evaluating interventions to improve health care workers' hand hygiene compliance use directly observed compliance as a primary outcome measure. Observers should be blinded to the intervention and the effectiveness of blinding assessed to prevent systematic bias. The literature has not addressed this issue, and this study describes a robust and pragmatic method for assessing the adequacy of blinding in hand hygiene intervention trials.

Antibiotic Resistance Surveillance and Control in the Mediterranean region: report of the ARMed Consensus Conference.

Antimicrobial resistance has become a global threat to effective health care delivery. This is particularly the case within the Mediterranean region, where data from recent studies suggests the situation to be particularly acute. A better knowledge base, as well as a collaborative effort, is therefore required to address this ever increasing challenge to effective patient care. Over its four-year period, the Antibiotic Resistance Surveillance and Control in the Mediterranean Region (ARMed) project investigated the epidemiology of antimicrobial resistance, as well as its contributory factors, in a number of countries in the southern and eastern Mediterranean region through the collection of comparable and validated data. The project culminated in a consensus conference held in Malta in November 2006. The conference provided a forum for expert delegates to agree on a number of priority strategic recommendations that would be relevant to resistance containment efforts in the region. There was general agreement on the need for surveillance and audit to underpin any intervention to tackle antimicrobial resistance, both to monitor changing epidemiological trends in critical pathogens as well as to identify antibiotic consumption practices and effectiveness of prevention and control of health care associated infections. In addition, the importance to convey these data to key users was also stressed in all workshops, as was better education and training of health care workers. The recommendations also made it clear that ownership of the problem needs to be improved throughout the region and that resources, both financial as well as human, must be allocated by the respective policy makers in order to combat it.

Self-protection as a driver for hand hygiene among healthcare workers.

A total of 2,725 healthcare workers in 8 Mediterranean countries replied to a self-assessment questionnaire that assessed their perceptions on hand hygiene. Responses revealed that rates of hand hygiene compliance before patient contact were significantly less than rates after patient contact (P < .001) and that use of soap and water was preferred over use of alcohol-based hand rub. These findings suggest that self-protection could be a major subliminal driver for performance of hand hygiene.

Health care worker perceptions of hand hygiene practices and obstacles in a developing region.

A structured self-assessment questionnaire was distributed to 8 southern and eastern Mediterranean hospitals to identify perceived obstacles to hand hygiene (HH). An insufficient number of sinks and alcohol handrub stations was rated by the vast majority of respondents as the most critical impediment, whereas improved availability of HH products was deemed the key intervention to increase compliance. The least importance and relevance were given to HH auditing and collegial reminders. While initiatives to improve HH compliance clearly must address infrastructural inadequacies, sociocultural issues also need to be considered when transposing initiatives found to be successful in Western countries to less-developed regions, to ensure that campaigns are not compromised by perceptual undercurrents.

Evaluation of molecular typing methods in characterizing a European collection of epidemic methicillin-resistant Staphylococcus aureus strains: the HARMONY collection.

We analyzed a representative sample of methicillin-resistant Staphylococcus aureus (MRSA) from 11 European countries (referred to as the HARMONY collection) using three molecular typing methods used within the HARMONY group to examine their usefulness for large, multicenter MRSA surveillance networks that use these different laboratory methodologies. MRSA isolates were collected based on their prevalence in each center and their genetic diversity, assessed by pulsed-field gel electrophoresis (PFGE). PFGE groupings (< or = 3 bands difference between patterns) were compared to those made by sequencing of the variable repeats in the protein A gene spa and clonal designations based on multilocus sequence typing (MLST), combined with PCR analysis of the staphylococcal chromosome cassette containing the mec genes involved in methicillin resistance (SCCmec). A high level of discrimination was achieved using each of the three methodologies, with discriminatory indices between 89.5% and 91.9% with overlapping 95% confidence intervals. There was also a high level of concordance of groupings made using each method. MLST/SCCmec typing distinguished 10 groups containing at least two isolates, and these correspond to the majority of nosocomial MRSA clones described in the literature. PFGE and spa typing resolved 34 and 31 subtypes, respectively, within these 10 MRSA clones, with each subtype differing only slightly from the most common pattern using each method. The HARMONY group has found that the methods used in this study differ in their availability and affordability to European centers involved in MRSA surveillance. Here, we demonstrate that the integration of such technologies is achievable, although common protocols (such as we have developed for PFGE) may also be important, as is the use of centralized Internet sites to facilitate data analysis. PFGE and spa-typing data from analysis of MRSA isolates from the many centers that have access to the relevant equipment can be compared to reference patterns/sequences, and clonal designations can be made. In the majority of cases, these will correspond to those made by the (more expensive) method of choice-MLST/SCCmec typing-and these alternative methods can therefore be used as frontline typing systems for multicenter surveillance of MRSA.

Development of a novel targeting system for lethal photosensitization of antibiotic-resistant strains of Staphylococcus aureus.

Light-activated antimicrobial agents (photosensitizers) are promising alternatives to antibiotics for the treatment of topical infections. To improve efficacy and avoid possible damage to host tissues, targeting of the photosensitizer to the infecting organism is desirable, and this has previously been achieved using antibodies and chemical modification of the agent. In this study we investigated the possibility of using a bacteriophage to deliver the photosensitizer tin(IV) chlorin e6 (SnCe6) to Staphylococcus aureus. SnCe6 was covalently linked to S. aureus bacteriophage 75, and the ability of the conjugate to kill various strains of S. aureus when exposed to red light was determined. Substantial kills of methicillin- and vancomycin-intermediate strains of S. aureus were achieved using low concentrations of the conjugate (containing 1.5 microg/ml SnCe6) and low light doses (21 J/cm2). Under these conditions, the viability of human epithelial cells (in the absence of bacteria) was largely unaffected. On a molar equivalent basis, the conjugate was a more effective bactericide than the unconjugated SnCe6, and killing was not growth phase dependent. The conjugate was effective against vancomycin-intermediate strains of S. aureus even after growth in vancomycin. The results of this study have demonstrated that a bacteriophage can be used to deliver a photosensitizer to a target organism, resulting in enhanced and selective killing of the organism. Such attributes are desirable in an agent to be used in the photodynamic therapy of infectious diseases.

A new UK strain of epidemic methicillin-resistant Staphylococcus aureus (EMRSA-17) resistant to multiple antibiotics.

An extensive outbreak in a hospital on the south coast of England in 2000, involving a multi-resistant strain of methicillin-resistant Staphylococcus aureus (MRSA) phenotypically similar to a strain periodically seen in several hospitals in that region since 1996, prompted a study to characterize the strain and determine the extent of its spread. Sixty-nine isolates with related phage patterns obtained between 1997 and 2000 from 19 hospitals were selected for study. Of these, 55 isolates had an identical PFGE profile (designated F1), and eight shared five other PFGE profiles (designated F2-F6), which differed from that of F1 by no more than three bands and were considered related. Six isolates had PFGE profiles that differed from F1-F6 by 9-18 bands and were considered to be distinct strains. The 63 isolates of profiles F1-F6 were considered to comprise a single strain and were phenotypically identical, being urease positive and resistant to multiple antibiotics including methicillin, ciprofloxacin, erythromycin, fusidic acid, rifampicin, gentamicin, kanamycin, neomycin, streptomycin and tetracycline, with or without high- or low-level mupirocin resistance. Borderline resistance to teicoplanin was also commonly noted. All but one of these 63 isolates contained the gene sea, with five also carrying the genes seg and sei, and two carrying tst. The isolates of this strain had been referred from 13 different hospitals, seven of which were on or near the south coast, four from London, one from the Midlands and one from the north of England. The isolates were thus considered to comprise an epidemic MRSA (EMRSA) strain, which has been designated EMRSA-17. The six non-EMRSA-17 isolates identified in the study were sensitive to fusidic acid and rifampicin, and came from six geographically diverse hospitals including three in Northern Ireland.

Selective lethal photosensitization of methicillin-resistant Staphylococcus aureus using an IgG-tin (IV) chlorin e6 conjugate.

OBJECTIVES: The growing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to conventional antimicrobial agents necessitates the development of alternative approaches to preventing and treating infections. One such approach is photodynamic therapy, whereby target cells are treated with light-activated drugs (photosensitizers). This investigation aimed to determine whether the ability of MRSA to express the IgG-binding protein, protein A, could be exploited to enable selective lethal photosensitization of the organism with a photosensitizer [tin (IV) chlorin e6; SnCe6] linked to IgG. METHODS: Various strains of MRSA were exposed to light from a helium/neon laser in the presence of an IgG-SnCe6 conjugate and the survivors enumerated by viable counting. Controls consisted of suspensions irradiated in the presence or absence of the conjugate and suspensions kept in the dark in the presence of the conjugate. Similar experiments were also carried out using the unconjugated photosensitizer. The experiments were repeated using a suspension consisting of both EMRSA-16 and Streptococcus sanguis. RESULTS: EMRSA-16 was killed by IgG-SnCe6 and SnCe6 in a light-dose- and photosensitizer-dependent manner. Greater kills were achieved with the IgG-SnCe6 than with the unconjugated SnCe6 using the same light energy dose and photosensitizer concentration. Furthermore, the IgG-SnCe6 conjugate, but not SnCe6, was able to kill EMRSA-16 selectively in a suspension that also contained S. sanguis without any reduction in the viable count of the latter. CONCLUSION: These results demonstrate that selective lethal photosensitization of MRSA can be achieved using an IgG-tin (IV) chlorin e6 conjugate. The effectiveness of killing was dependent, in part, on the particular MRSA strain used, with the clinically important EMRSA-16 strain being the most susceptible.