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Summary Background The global prevalence of extended-spectrum beta-lactamase-producing Escherichia coli is rising and is dominated by blaCTX-M spread by plasmids. Travellers to South Asia from Western Europe have high rates of acquisition of faecal CTX-M-producing E. coli (CTX-M-EC). Aims To determine the conjugative ability of CTX-M-EC acquired by healthy volunteers after travel to South Asia, the proportion of travel-acquired CTX-M-EC where blaCTX-M is encoded on a plasmid vs on the bacterial chromosome, and the relatedness of travel-acquired CTX-M-EC plasmids to previously sequenced plasmids. Methods Faecal samples were collected pre- and post-travel from 23 volunteers who visited South Asia, and CTX-M-EC were cultured. After short- and long-read sequencing, 10 plasmid sequences were identified and compared with previously sequenced plasmids in GenBank. Conjugation to E. coli K-12 was undertaken using filter mating. Findings Thirty-five percent of CTX-M-EC isolates tested transferred the blaCTX-M plasmid by conjugation. Travel-acquired CTX-M-EC carried blaCTX-M on a plasmid in 62% of isolates, whereas 38% of isolates had blaCTX-M on the chromosome. CTX-M-EC plasmids acquired after travel to South Asia had close homology to previously described epidemic plasmids which are widely disseminated in humans, animals and the natural environment. Conclusion Globally successful epidemic plasmids are involved in the spread of CTX-M-EC. Targeted strategies may be used to displace such plasmids from the host strain as part of efforts in infection prevention and control in healthcare settings. Bacteria with blaCTX-M plasmids were readily acquired by healthy volunteers, and were carried on return to the UK, providing opportunities for onward dissemination.

BACKGROUND: Coronavirus disease-19 (COVID-19) pandemic caused delays in definitive treatment of patients with prostate cancer. Beyond the immediate delay a backlog for future patients is expected. Such delays can lead to disease progression. OBJECTIVE: We aimed to develop guidance on criteria for prioritization for surgery and reconfiguring management pathways for non-metastatic stage of prostate cancer who opt for surgical treatment. A second aim was to identify the infection prevention and control (IPC) measures to achieve low likelihood of COVID-19 hazard if radical prostatectomy was to be carried out during the outbreak and whilst the disease is endemic. DESIGN, SETTING AND PARTICIPANTS: An accelerated consensus process and systematic review. We conducted a systematic review of the evidence on COVID-19 and reviewed international guidance on prostate cancer. These were presented to an international prostate cancer expert panel (n=34) through an online meeting. The consensus process underwent three rounds of survey in total. Additions to the second- and third-round surveys were formulated based on the answers and comments from the previous rounds. OUTCOME MEASURES: Consensus opinion was defined as ≥80% agreement, which were used to reconfigure the prostate cancer pathways. RESULTS: Evidence on the delayed management of patients with prostate cancer is scarce. There was 100% agreement that prostate cancer pathways should be reconfigured and develop measures to prevent nosocomial COVID-19 for patients treated surgically. Consensus was reached on prioritization criteria of patients for surgery and management pathways for those who have delayed treatment. IPC measures to achieve a low likelihood of nosocomial COVID-19 were coined as "COVID-19 cold sites". CONCLUSION: Re-configuring management pathways for prostate cancer patients is recommended if significant delay (>3-6 months) in surgical management is unavoidable. The mapped pathways provide guidance for such patients. The IPC processes proposed provide a framework for providing radical prostatectomy within an environment with low COVID-19 risk during the outbreak or when the disease remains endemic. The broader concepts could be adapted to other indications beyond prostate cancer surgery.

Summary Background Pseudomonas aeruginosa is a common opportunistic pathogen and molecular typing in outbreaks has linked patient acquisition to contaminated hospital water systems. Aim To elucidate the role of P. aeruginosa transmission rates in non-outbreak augmented care settings in the UK. Methods Over a 16-week period, all water outlets in augmented care units of four hospitals were sampled for P. aeruginosa and clinical isolates were collected. Outlet and clinical P. aeruginosa isolates underwent whole-genome sequencing (WGS), which with epidemiological data identified acquisition from water as definite (level 1), probable (level 2), possible (level 3), and no evidence (level 4). Findings Outlets were positive in each hospital on all three occasions: W (16%), X (2.5%), Y (0.9%) and Z (2%); and there were 51 persistently positive outlets in total. WGS identified likely transmission (at levels 1, 2 and 3) from outlets to patients in three hospitals for P. aeruginosa positive patients: W (63%), X (54.5%) and Z (26%). According to the criteria (intimate epidemiological link and no phylogenetic distance), approximately 5% of patients in the study ‘definitely’ acquired their P. aeruginosa from their water outlets in the intensive care unit. This study found extensive evidence of transmission from the outlet to the patients particularly in the newest hospital (W), which had the highest rate of positive outlets. Conclusions The overall findings suggest that water outlets are the most likely source of P. aeruginosa nosocomial infections in some settings, and that widespread introduction of control measures would have a substantial impact on infections.

Highlights • In response to the dramatic impact of the COVID-19 pandemic on health care pathways and delivery, including delays in management of aggressive cancers, an international expert panel was convened to address the management pathways for patients with penile cancer. • This study reports the statements developed by the panel to reconfigure the management pathways for penile cancer patients during the COVID-19 acute waves. • The adaptation of the EAU and NCCN penile cancer guidelines for use in the setting of COVID-19 acute waves was guided mainly by 2 necessities: To minimize the numbers of hospital visits and hospitalization and to prevent COVID-19-related complications attributed to cancer treatment • A consensus was reached regarding multiple items related to the diagnosis and management of penile cancer throughout the COVID-19 acute waves. • Non-urgent procedures should be postponed and non-invasive procedures should be encouraged to delay or avoid the need for procedures that require general anesthesia because of the morbidity associated with perioperative severe acute respiratory syndrome coronavirus 2 infection., Objectives To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. Materials and methods A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. Results Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. Conclusions The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

Introduction Although faecal microbiota transplantation (FMT) appears to hold therapeutic potential for ulcerative colitis (UC), the optimal administration route and dose of FMT is unknown. This pilot trial aimed to identify the optimal route of administration to further test in an RCT. Methods In this prospective, three-centre, open-label, randomised study (STOP-Colitis pilot), we compared delivery of FMT via the naso-gastric (NG) or colonic (COLON) route in adult patients with active UC. Participants were administered 8 infusions of FMT over an 8 week period. Clinical response was defined as ≥3 point and ≥30% reduction in Mayo score at week 8 compared to baseline. Clinical remission was defined as Mayo score of ≤2, with no subscore >1 at week 8. The primary outcome was based on clinical response and safety at weeks 8 and 12, along with qualitative assessment of acceptability. Results 30 participants were randomised between March 2018 and April 2019; 16 to NG; 14 to COLON. 8 in NG arm and 2 patients in the COLON arm withdrew from the study before completion. Clinical response was achieved in more participants who received FMT via COLON compared with NG (9/12 [75%] vs 2/8 [25%]; adjusted relative risk [RR] 2.94 [95% CI, 0.84, 10.30]). Clinical remission was observed in more participants undergoing FMT via COLON compared to NG (6/12 [50%] vs 2/8 [25%] respectively; RR 1.89 [95% CI, 0.51, 6.99]). IBDQ and SF-36 scores at week 8 and 12 were similar in NG and COLON groups. Qualitative analysis showed greater patient and clinician acceptability for colonic delivery. There were three serious adverse events (one considered a serious adverse event) in 2 participants in the NG arm, and none in the COLON arm. Conclusion This pilot study suggests that in patients with active UC, FMT delivered via the COLON route appears to be safe and better tolerated with signals suggesting greater efficacy compared to the NG route. A randomised, double-blind, placebo-controlled trial of colonic delivery of FMT is now underway to determine clinical efficacy and safety.

Background Clostridioides difficile infection (CDI) is a hospital acquired disease associated with significant morbidity, hospitalisation and mortality. Almost 30% of treated patients experience at least one recurrence after treatment of their first episode. Treatment of recurrent CDI (rCDI) utilises vancomycin or fidaxomicin, however, a newer treatment option is faecal microbial transplantation (FMT) administered by nasogastric tube (NGT) or colonoscopy. It is associated with higher cure and lower recurrence rates than fidaxomicin or vancomycin. The aim of this analysis is to evaluate the cost effectiveness of FMT for rCDI using the latest and best evidence. Method A cost utility analysis was conducted using a decision model representing the cost per additional Quality Adjusted Life Year (QALY) from a National Health Service (NHS) perspective. A Markov model was constructed to compare FMT NGT and colonoscopy to antibiotic treatment (fidaxomicin or vancomycin). The model was informed by a literature review of clinical evidence, specifically focussing on hospitalised patients with rCDI over 65 years. Both deterministic and probabilistic sensitivity analyses were performed to assess uncertainties around the model inputs and assumptions. Findings The base case analysis showed that FMT is a less costly and more effective treatment than either fidaxomicin or vancomycin. FMT colonoscopy was slightly more effective than FMT NGT leading to an additional 0.012 QALYs but more expensive and the incremental cost effectiveness ratio (ICER) was £242,514/QALY. The Probabilistic sensitivity analysis based on 10,000 simulations suggested the probability of FMT NGT being cost effective was almost 78% at £20,000/QALY Willingness–To-Pay (WTP) threshold. Interpretation FMT is both more effective and less costly option than antimicrobial therapy. FMT NGT was the preferred route of administration and is likely to be considered the most cost-effective strategy by decision makers given current acceptable thresholds.

Introduction: Faecal microbiota transplantation (FMT) is an effective and licensed treatment for recurrent and refractory Clostridium difficile infection (CDI) and has shown encouraging signals for treatment of ulcerative colitis (UC). Access to FMT has been limited by the introduction of new regulations in the UK. Centres producing FMT are now required to hold a manufacturing licence from the Medicines and Healthcare products Regulatory Agency (MHRA). Methods:The first licenced FMT service in UK - University of Birmingham Microbiome Treatment Centre (UoBMTC) was launched in 2017. Policies and procedures were developed in accordance with MHRA ‘Good Manufacturing Practice’ guide. Results: Since August 2018, 132 FMT aliquots have been supplied for recurrent and refractory CDI to 39 NHS Trusts across UK. Twenty-nine of these Trusts did not have access / perform FMT prior to this service. In all cases, FMT was delivered within 48 hours (unless delayed delivery was requested). The service is the sole supplier of FMT since 2018 via an NHS Innovation and Technology Tariff. UoBMTC has also to date supplied 360 FMT aliquots for a multi-centre trial of FMT in UC (STOP-Colitis). Furthermore, the service has provided FMT to other refractory conditions within clinical settings. Conclusions: Development of a licenced FMT facility has greatly enhanced equality of access for this treatment across the NHS. FMT is provided at a zero-cost model for CDI and is available within 48 hours of request. UoBMTC continues to facilitate research in this field by providing FMT for clinical trials exploring its use for other indications.

The faecal, intestinal and mucosal microbiome, and manipulation of it, is the subject of intense categorisation, collation and study. Advances have been aided by novel culture-independent analytical techniques and a focus on how aberrations in the microbiome are associated with many diseases. Dramatic manipulation of the microbiome is possible using faecal microbiota transplantation (FMT). FMT has been shown to have a definite clinical role in treating recurrent Clostridium difficile infection, and there is accumulating clinical data for a possible role in treating ulcerative colitis. FMT preparation can only take place in a laboratory with licensed facilities and equipment allowing safe treatment and processing of appropriate donor samples. The future of FMT treatment may involve diseases of extra-intestinal origin. This review clarifies recent developments in research and provides a how-to guide for interested clinicians.

Objectives Although carbapenem susceptibility testing has been recommended for all Enterobacteriaceae from clinical specimens, for practical reasons a carbapenem is not included in many primary antibiotic panels for urine specimens. The 'iCREST' study sought carbapenemase-producing Enterobacteriaceae (CPE) in routine urine specimens yielding Gram-negative growth in five diagnostic laboratories in the UK. We sought also to compare locally and centrally determined MICs of meropenem and ceftazidime/avibactam. Methods Positive growth from up to 2000 urine specimens per laboratory was plated onto chromID® CARBA SMART agar. Suspected CPE colonies were tested locally by Etest for susceptibility to meropenem and ceftazidime/avibactam, and referred to central laboratories for PCR confirmation of CPE status and microbroth MIC determination. Results Twenty-two suspected CPE were identified from 7504 urine specimens. Ten were confirmed by PCR to have NDM (5), IMP (2), KPC (2) or OXA-48-like (1) carbapenemases. Locally determined ceftazidime/avibactam MICs showed complete categorical agreement with those determined centrally by microbroth methodology. The seven ceftazidime/avibactam-resistant isolates (MICs ≥256 mg/L) had NDM or IMP metallo-carbapenemases. Conclusions The frequency of confirmed CPE among Gram-negative urinary isolates was low, at 0.13% (10/7504), but CPE were found in urines at all five participating sites and the diversity of carbapenemase genes detected reflected the complex epidemiology of CPE in the UK. These data can inform local policies about the cost-effectiveness and clinical value of testing Gram-negative bacteria from urine specimens routinely against a carbapenem as part of patient management and/or infection prevention and control strategies.

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p

Limited data are available on temocillin susceptibilities in Enterobacteriaceae from Asian countries where antimicrobial resistance is prevalent. The in vitro activities of temocillin and 15 commonly used antimicrobials against 613 non-duplicate blood (n = 310) and urine (with clinically significant bacteriuria; n = 303) isolates of Enterobacteriaceae from patients who attended 3 out of 7 clusters of public hospitals of the Hospital Authority, Hong Kong, during 2015/2016 were tested. Minimum inhibitory concentrations (MICs) were determined by Clinical and Laboratory Standards Institute (CLSI) microbroth dilution (agar dilution with fosfomycin). For temocillin, MICs were also obtained using the British Society of Antimicrobial Chemotherapy (BSAC) microbroth dilution method and interpreted using the BSAC breakpoints. Overall, 93.0% (570) isolates were susceptible to temocillin using BSAC systemic breakpoint (≤8 mg/L) and all except 2 isolates were susceptible using the urinary breakpoint (≤32 mg/L). The extended spectrum beta-lactamase (ESBL) positivity rate was 23.2% (118 out of 508 E. coli, Klebsiella spp., Proteus spp.). Temocillin resistance rate to ESBL-positive isolates was 16.1% using the systemic breakpoint of ≤8 mg/L (MIC50 and MIC90 were 8 mg/L and 16 mg/L respectively). Two isolates (1 E. coli, temocillin MIC 64 mg/L, 1 Klebsiella sp., MIC 32 mg/mL) were resistant to meropenem and possessed the NDM-5 and KPC-2 genes respectively. Other susceptibility rates were: amoxicillin/clavulanate (59.1%), trimethoprim/sulfamethoxazole (62.5%), ciprofloxacin (71.5%), ceftriaxone (75.4%), nitrofurantoin (76.4%), gentamicin (78.3%), cefepime (81.1%), ceftazidime (83.5%), piperacillin/tazobactam (86%), colistin (88.8%), tigecycline (89.4%), fosfomycin (92.8%), ertapenem (99.0%), amikacin (99.2%) and meropenem (99.7%). Temocillin may be a useful alternative for the treatment of infections caused by ESBL and multi-drug-resistant Enterobacteriaceae in Hong Kong, particularly as resistance rates to ciprofloxacin, nitrofurantoin and piperacillin/tazobactam are high. Electronic supplementary material The online version of this article (10.1007/s10096-017-3091-8) contains supplementary material, which is available to authorized users

Globally, rates of ESBL-producing Enterobacteriaceae are rising. We undertook a literature review, and present the temporal trends in blaCTX-M epidemiology, showing that blaCTX-M-15 and blaCTX-M-14 have displaced other genotypes in many parts of the world. Explanations for these changes can be attributed to: (i) horizontal gene transfer (HGT) of plasmids; (ii) successful Escherichia coli clones; (iii) ESBLs in food animals; (iv) the natural environment; and (v) human migration and access to basic sanitation. We also provide explanations for the changing epidemiology of blaCTX-M-2 and blaCTX-M-27. Modifiable anthropogenic factors, such as poor access to basic sanitary facilities, encourage the spread of blaCTX-M and other antimicrobial resistance (AMR) genes, such as blaNDM, blaKPC and mcr-1. We provide further justification for novel preventative and interventional strategies to reduce transmission of these AMR genes.

Background Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile. There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial. Objectives To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients. Design Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio. Setting A total of 93 NHS hospitals throughout England, Northern Ireland and Wales. Participants A total of 977 patients with newly diagnosed symptomatic myeloma. Intervention Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year. Main outcome measures The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond. Results In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival (p = 0.94). Limitations Short duration of prophylactic antibiotics and cost-effectiveness. Conclusions During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04). Trial registration Current Controlled Trials ISRCTN51731976. Funding details This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.

Introduction Faecal Microbiota Transplant (FMT) is an efficacious treatment for recurrent Clostridium difficile infection (CDI) and has shown encouraging signals for inflammatory bowel disease. Access to FMT services in the NHS has been limited by the regulation of FMT as a medicinal product in the UK. To enable inter-institution supply, FMT manufacturers are required to hold a Specials licence from The Medicines and Healthcare products Regulatory Agency. Methods In 2017 the first licenced FMT service in UK was created at the University of Birmingham Microbiome Treatment Centre. Policies and procedures were developed using the Rules and Guidance for Pharmaceutical Manufacturers and Distributors (Orange Guide), which were used and maintained within a quality management system. The frozen FMT bank utilises anonymous unrelated healthy donors and provides FMT on a named patient basis for the treatment of CDI and supplies clinical trials via an investigational medicinal product (IMP) licence. Results Since August 2018, 53 faecal microbiota transplants have been supplied for recurrent and refractory CDI to 21 NHS Trusts across England and Wales. Twelve of these Trusts did not have access or perform FMT prior to the introduction of this service. In 98% (52/53) of cases FMT was delivered either within 48 hours or on the day of request if >48 hours from request. Clinical response to treatment was observed in 76% (16/21) of patients, with 88% (14/16) of these patients remaining symptom free at 90 days. In 2018 the service became the sole supplier of FMT under the 201–019 NHS Innovation and Technology Tariff. Under the IMP licence the service has successfully supplied over 360 faecal microbiota transplants for the pilot stage of a multi-centre trial of FMT in UC (STOP-Colitis). Conclusions Development of a licenced FMT facility at the University of Birmingham has improved equality of access to this novel treatment across the NHS. FMT has been provided within a zero cost model for CDI and is available generally within 48 hours of request. Patients with CDI benefit from improved care from this service, which limits morbidity and mortality from this severe infection. Supply via an IMP licence has enabled the required FMT infrastructure to be developed to support prospective FMT research in the UK.

Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. There are approximately 5,500 new UK cases of myeloma per annum; a quarter will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection and early death but this may be associated with healthcare-associated infections (HCAI). Methods: The TEAMM trial was a multicentre randomised, double-blind, placebo-controlled trial in newly-diagnosed myeloma patients randomised to receive Levofloxacin or placebo for 12 weeks at the start of anti-myeloma treatment. Follow-up was 4-weekly to 16 weeks and again at 1 year. The primary outcome was time to first febrile episode or death in the first 12 weeks from start of trial treatment. Secondary outcomes included number of infections, deaths, healthcare-associated organism carriage and invasive infections, and overall survival (OS). Findings: 977 patients were randomised (489 levofloxacin, 488 placebo). Primary events (febrile episodes, deaths, febrile episodes with death) in levofloxacin versus placebo arms were 19% vs 27% (87, 4, 4 vs 112, 15, 7), respectively; HR=0.66 (95% CI 0.51-0.86) p=0.002. There was no difference for new acquisitions of clostridium difficile, Methicillin-resistant Staphylococcus aureus and Extended Spectrum Beta Lactamase-positive (ESBL) Gram-negative coliforms when assessed up to 16 weeks. There was an OS benefit at 12 weeks (p=0.008) but not at one year (p=0.94). Interpretation: The addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths without increasing healthcare associated infections or carriage. Trial Registration Number: ISRCTN number: ISRCTN51731976 and EudraCT number: 2011-000366-35. Funding Statement: Funded by NIHR Health Technology Assessment Programme. 08/116/69. Declaration of Interests: None. Ethics Approval Statement: Approved by the UK Coventry & Warwickshire Multi-Research Ethics Committee on 29th July 2011. All patients provided written informed consent.

Background Transmission patterns in high tuberculosis incidence areas in England are poorly understood but need elucidating to focus contact tracing. We study transmission within and between age, ethnic and immigrant groups using molecular data from the high incidence West Midlands region. Methods Isolates from culture-confirmed tuberculosis cases during 2007–2011 were typed using 24-locus Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats (MIRU-VNTR). We estimated the proportion of disease attributable to recent transmission, calculated the proportion of isolates matching those from the two preceding years (“retrospectively clustered”), and identified risk factors for retrospective clustering using multivariate analyses. We calculated the ratio (RCR) between the observed and expected proportion clustered retrospectively within or between age, ethnic and immigrant groups. Results Of the 2159 available genotypes (79% of culture-confirmed cases), 34% were attributed to recent transmission. The percentage retrospectively clustered decreased from 50 to 24% for 0–14 and ≥ 65 year olds respectively (p = 0.01) and was significantly lower for immigrants than the UK-born. Higher than expected clustering occurred within 15–24 year olds (RCR: 1.4 (95% CI: 1.1–1.8)), several ethnic groups, and between UK-born or long-term immigrants with the UK-born (RCR: 1.8 (95% CI: 1.1–2.4) and 1.6 (95% CI: 1.2–1.9) respectively). Conclusions This study is the first to consider “who clusters with whom” in a high incidence area in England, laying the foundation for future whole-genome sequencing work. The higher than expected clustering seen here suggests that preferential mixing between some age, ethnic and immigrant groups occurs; prioritising contact tracing to groups with which cases are most likely to cluster retrospectively could improve TB control. Electronic supplementary material The online version of this article (10.1186/s12879-018-3585-8) contains supplementary material, which is available to authorized users.

Summary Faecal samples from 1365 healthy asymptomatic volunteers from four regions in England were screened for the presence of Clostridium difficile between December 2013 and July 2014. The carriage rate of C. difficile in healthy patients was 0.5%, which is lower than reported previously. This study demonstrates that the true community reservoir of C. difficile in the healthy UK population is very low and is, therefore, unlikely to be a reservoir for infections diagnosed in the hospital setting.

Background Faecal Microbiota Transplant (FMT) has improved outcomes for the treatment of Clostridioides difficile infection (CDI) compared to antibiotic therapy. FMT is classified as a medicinal product in the United Kingdom, similar to the USA and Canada, limiting supply via stool banks without appropriate licencing. In the largest UK cohort to date, we describe the clinical outcomes for 124 patients receiving FMT for recurrent or refractory CDI and present a framework to produce FMT as a licenced medicinal product. Methods Anonymous unrelated healthy donors, screened via health assessment and microbiological testing donated stool. In aerobic conditions FMT aliquots were prepared for immediate use or frozen storage, following a production framework developed to comply with Good Manufacturing Practice. Outcome measures were clinical response to FMT defined as resolution of diarrhoea within seven days and clinical cure defined as response without diarrhoea recurrence at 90 days. Findings Clinical response was 83·9% (95% CI 76·0%–90·0%) after one treatment. Clinical cure was 78·2% (95% CI 67·4%–89·0%) across the cohort. Refractory cases appeared to have a lower initial clinical response rate compared to recurrent cases, however at day 90 there were no differences observed between these groups. Interpretation The methodology developed here enabled successful licencing of FMT by The Medicines and Healthcare products Regulatory Agency as a medicinal product. This has widened the availability of FMT in the National Health Service via a stool bank and can be applied in other centres across the world to improve access to safe and quality assured treatments.

The widespread use of antibacterial drugs over the last 70 years has brought immense benefits to human health at the price of increasing drug inefficacy. Antibacterial agents have a strong selective effect in both favouring resistant strains and allowing particular species and families of bacteria to prosper, especially in the healthcare setting. Whilst important Gram-positive bacterial pathogens such as Staphylococcus aureus and Streptococcus pneumoniae caused concern over the last 20 years because of the spread of antibiotic-resistant strains, Enterobacteriaceae have become the biggest challenge. They have very efficient mechanisms for genetic exchange, as illustrated by the emergence and rapid spread of CTX-M β-lactamases and the carbapenemases. The unique epidemiology of Enterobacteriaceae, with substantial numbers colonizing the mammalian gut and subsequent release into and spread in the environment, presents a significant threat to human health because of the high levels of exposure for the whole community. The use of antimicrobials in agriculture combined with global movements of people, animals and food, arising from worldwide industrialization, generates a diversity and level of resistance not seen previously. Control will require globally coordinated interventions similar to those needed to ameliorate climate change.

Interest in the therapeutic potential of faecal microbiota transplant (FMT) has been increasing globally in recent years, particularly as a result of randomised studies in which it has been used as an intervention. The main focus of these studies has been the treatment of recurrent or refractoryClostridium difficileinfection (CDI), but there is also an emerging evidence base regarding potential applications in non-CDI settings. The key clinical stakeholders for the provision and governance of FMT services in the UK have tended to be in two major specialty areas: gastroenterology and microbiology/infectious diseases. While the National Institute for Health and Care Excellence (NICE) guidance (2014) for use of FMT for recurrent or refractory CDI has become accepted in the UK, clear evidence-based UK guidelines for FMT have been lacking. This resulted in discussions between the British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS), and a joint BSG/HIS FMT working group was established. This guideline document is the culmination of that joint dialogue.

Hospital-acquired infection is a major cause of morbidity and mortality, and regimes to prevent infection are crucial in infection control. These include the decolonization of vulnerable patients with methicillin-resistant Staphylococcus aureus (MRSA) carriage using antiseptics, including chlorhexidine and octenidine. Concern has been raised, however, regarding the possible development of biocide resistance. In this study, we assembled a panel of S. aureus isolates, including isolates collected before the development of chlorhexidine and octenidine and isolates, from a major hospital trust in the United Kingdom during a period when the decolonization regimes were altered. We observed significant increases in the MIC and minimum bactericidal concentration (MBC) of chlorhexidine in isolates from periods of high usage of chlorhexidine. Isolates with increased MICs and MBCs of octenidine rapidly emerged after octenidine was introduced in the trust. There was no apparent cross-resistance between the two biocidal agents. A combination of variable-number tandem repeat (VNTR) analysis, PCR for qac genes, and whole-genome sequencing was used to type isolates and examine possible mechanisms of resistance. There was no expansion of a single strain associated with decreased biocide tolerance, and biocide susceptibility did not correlate with carriage of qac efflux pump genes. Mutations within the NorA or NorB efflux pumps, previously associated with chlorhexidine export, were identified, however, suggesting that this may be an important mechanism of biocide tolerance. We present evidence that isolates are evolving in the face of biocide challenge in patients and that changes in decolonization regimes are reflected in changes in susceptibility of isolates. IMPORTANCE Infection in hospitals remains a major cause of death and disease. One way in which we combat this is by decolonizing at-risk patients from carriage of bacteria which can cause disease such as MRSA. This is done with antiseptics, including chlorhexidine and octenidine. There is concern, however, that bacteria may be able to become resistant to these antiseptics. In this study, we looked at isolates of MRSA and found that there was a correlation between the use of antiseptics and increased resistance in the isolates. We also suggest that the mechanism by which these more tolerant isolates may become resistant to antiseptics is that of changing a transport pump that exports these agents. This information suggests that we need to study the impact of antiseptics on clinically important bacteria more closely.

Background ESBL-producing Enterobacteriaceae (ESBLPE) are increasing in prevalence worldwide and are more difficult to treat than non-ESBLPE. Their prevalence in the UK general population is unknown, as the only previous UK ESBLPE faecal colonization study involved patients with diarrhoea. Objectives To estimate the prevalence of CTX-M ESBLPE faecal colonization in the general adult population of England in 2014, and investigate risk factors. Methods A stratified random sample of 58 337 registered patients from 16 general practices within four areas of England were invited to participate by returning faeces specimens and self-completed questionnaires. Specimens were tested for ESBLPE and carbapenemase-producing Enterobacteriaceae (CPE). Results 2430 individuals participated (4% of those invited). The estimated prevalence of colonization with CTX-M ESBLPE in England was 7.3% (95% CI 5.6%-9.4%) (Shropshire 774 participants, 4.9% colonization; Southampton City 740 participants, 9.2%; Newham 612 participants, 12.7%; Heart of Birmingham 234 individuals, 16.0%) and was particularly high in: those born in Afghanistan (10 participants, 60.0% colonization, 95% CI 29.7%-84.2%); those born on the Indian subcontinent (India, Pakistan, Bangladesh or Sri Lanka) (259 participants, 25.0% colonization, 95% CI 18.5%-32.9%); travellers to South Asia (India, Pakistan, Bangladesh, Sri Lanka or Nepal) in the last year (140 participants, 38.5% colonization, 95% CI 27.8%-50.5%); and healthcare domestics (8 participants, unweighted 37.5% colonization, 95% CI 8.5%-75.5%). Risk factors identified included: being born in the Indian subcontinent (aOR 5.4, 95% CI 3.0-9.7); travel to South Asia (aOR 2.9, 95% CI 1.8-4.8) or to Africa, China, South or Central America, South East or Pacific Asia or Afghanistan (aOR 2.6, 95% CI 1.7-4.1) in the last year; and working as a healthcare domestic (aOR 6.2, 95% CI 1.3-31). None of the 48 participants who took co-amoxiclav in the last year was colonized with CTX-M ESBLPE. blaCTX-M-15 accounted for 66% of CTX-M ESBLPE positives. 0.1% (two participants) were colonized with CPE. Conclusions CTX-M ESBLPE are established in the general population in England and prevalence is particularly high in people from certain countries of birth or with recent travel. We recommend that these findings be taken into account in guidance on the empirical management of patients presenting with a likely Enterobacteriaceae infection.

The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use.

Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum β-lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid-mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase--and highlights the importance of control of antibiotic use.

To determine if local transmission was responsible for rising tuberculosis incidence in a recently dispersed migrant community in Birmingham, UK, during 2004-2013, we conducted enhanced epidemiologic investigation of molecular clusters. This technique identified exact locations of social mixing and chains of apparent recent transmission, which can be helpful for directing resources.

We analyzed China’s current use of and microbial resistance to antibiotics, and possible means of reducing antimicrobial resistance. Interventions like executive orders within clinical settings and educational approach with vertical approaches rather than an integrated strategy to curb the use of antimicrobials remain limited. An underlying problem is the system of incentives that has resulted in the intensification of inappropriate use by health professionals and patients. There is an urgent need to explore the relationship between financial and non-financial incentives for providers and patients, to eliminate inappropriate incentives. China’s national health reforms have created an opportunity to contain inappropriate use of antibiotics through more comprehensive and integrated strategies. Containment of microbial resistance may be achieved by strengthening surveillance at national, regional and hospital levels; eliminating detrimental incentives within the health system; and changing prescribing behaviors to a wider health systems approach, to achieve long-term, equitable and sustainable results and coordinate stakeholders’ actions through transparent sharing of information.

ObjectivesThis study aims to highlight problems with recruiting to an English stool sample community prevalence study. It was part of a larger cross-sectional research to determine the risk factors for the presence of extended-spectrum beta-lactamase and carbapenemase-producing coliforms in stool samples of the asymptomatic general English population.SettingFour National Health Service primary care trusts (PCTs) of England representing a different section of the population of England: Newham PCT; Heart of Birmingham Teaching PCT; Shropshire County PCT; and Southampton City PCT.ParticipantsSixteen general practices across the four PCTs were purposefully selected. After stratification of GP lists by age, ethnicity and antibiotic use, 58 337 randomly selected patients were sent a postal invitation.Patients who had died, moved to a different surgery, were deemed too ill by their General Practitioner or hospitalised at the time of mailing were excluded.ResultsStool and questionnaire returns varied by area, age, gender and ethnicity; the highest return rate of 27.3% was in Shropshire in the age group of over 60 years; the lowest, 0.6%, was in Birmingham in the age group of 18–39 years. Whereas only 3.9%(2296) returned a completed questionnaire and stool sample, 94.9% of participants gave permission for their sample and data to be used in future research.ConclusionResearchers should consider the low stool specimen return rate and wide variation by ethnicity and age when planning future studies involving stool specimen collection. This is particularly pertinent if the study has no health benefit to participants. Further research is needed to explore how to improve recruitment in multicultural communities and in younger people.

Objectives To assess the effect of general practice characteristics and antibiotic prescribing on the number of non-susceptible Escherichia coli isolated from urine specimens submitted from community settings, we undertook an ecological study of the general practice population in the West Midlands. Methods Descriptive analysis and multilevel modelling of temporal trends in antibiotic prescribing and non-susceptibility of E. coli urine isolates to a range of antibiotics prescribed in the community over a 4 year period. Results Nine of the 16 antibiotic prescribing/non-susceptibility combinations demonstrated a significant statistical linear correlation with non-susceptibility either for prescribing in a quarter or for prescribing within the previous 12 months. The magnitude of the effect varied, from a 0.3% increase in the odds of non-susceptibility to ampicillin/amoxicillin (when prescribing ampicillin/amoxicillin) to a 6.3% increase in the odds of non-susceptibility to nitrofurantoin (when prescribing nitrofurantoin) for an increase of 50 DDDs per 1000 practice population within a quarter (equivalent to ∼10 courses of antibiotics). In all 16 models, single-handed general practices were shown to have a significant association with increased numbers of non-susceptible E. coli urine isolates (adjusted ORs 1.083-1.657). Increased prescribing of ampicillin/amoxicillin in winter periods was associated with increased non-susceptibility of E. coli isolated from urine specimens. Conclusions Small increases in antibiotic prescribing in individual general practices reduce the number of susceptible bacteria in the practice population. To maintain the effectiveness of available treatment, antibiotic stewardship should be encouraged and supported within each practice.

Pneumococcal disease has a high burden in adults in the United Kingdom (UK); however, the total burden is underestimated, principally because most cases of community-acquired pneumonia (CAP) are non-invasive. Research into pneumonia receives poor funding relative to its disease burden (global mortality, disability-adjusted life years, and years lived with disability), ranking just 20 out of 25 for investment in infectious diseases in the UK. The current accuracy of data for establishing incidence rates is questionable, and it is a reflection of the paucity of research that much of the background information available derives from nearly 30 years ago. Given the relationship between CAP and mortality (pneumonia accounts for 29,000 deaths per annum in the UK, and 5–15% of patients hospitalised with CAP die within 30 days of admission), and the increasing threat of antimicrobial resistance associated with inappropriate antibiotic prescribing, such neglect of a highly prevalent problem is concerning. In this Call to Action, we explore the poorly understood burden of CAP in the UK, discuss the importance of an accurate diagnosis and appropriate treatment, and suggest how national collaboration could improve the management of an often life-threatening, yet potentially preventable disease.

IntroductionImbalance of the gut microbiome is key to the pathogenesis of ulcerative colitis (UC). Faecal microbiota transplant (FMT) is the transfer of homogenised and filtered faeces from a healthy individual to the gastrointestinal tract of a patient with disease. Published datasets show a positive signal for the use of FMT to treat UC, but the optimal route and dose of FMT remain unanswered.Methods and analysisThis prospective, multi-centre open-label, randomised pilot study will assess two possible routes of FMT delivery, via the nasogastric (NG) route or by delivery to the COLON, in 30 patients with active UC recruited from three sites in the UK. Stool will be collected from healthy screened donors, processed, frozen and stored under a Medicines and Healthcare products Regulatory Agency (MHRA) “specials” manufacturing licence held at the University of Birmingham Microbiome Treatment Centre. Thawed FMT samples will be administered to patients either via eight nasogastric infusions given initially over 4 days starting on the day of randomisation, and then again for 4 days in week 4 for foregut delivery (total of 240 g of stool) or via one colonoscopic infusion followed by seven weekly enemas according to the hindgut protocol (total of 360 g of stool). Patients will be followed up weekly for 8 weeks, and then at 12 weeks. The aims of this pilot study are (1) to determine which FMT administration route (NG or COLON) should be investigated in a randomised double-blind, placebo-controlled trial and (2) to determine if a full randomised controlled trial is feasible. The primary outcome will be a composite assessment of both qualitative and quantitative data based on efficacy (clinical response), acceptability and safety. At the end of the pilot study, decisions will be made regarding the feasibility of a full randomised double-blind, placebo-controlled trial and, if deemed feasible, which route of administration should be used in such a study.Ethics and disseminationEthical approval for this study has been obtained from the East Midlands-Nottingham Research Ethics Committee (REC 17/EM/0274). At the end of the study, findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals.Trial registration numberNCT74072945

During the past 10 years, multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. Antibiotic resistance develops through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently by acquisition of mobile genes that have evolved over time in bacteria in the environment. The reservoir of resistance genes in the environment is due to a mix of naturally occurring resistance and those present in animal and human waste and the selective effects of pollutants, which can co-select for mobile genetic elements carrying multiple resistant genes. Less attention has been given to how anthropogenic activity might be causing evolution of antibiotic resistance in the environment. Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance.

SETTING Birmingham, United Kingdom, 2010-2014. OBJECTIVE To investigate predictors for clustering of tuberculosis (TB) cases and cluster size and to evaluate the impact of cluster investigation using social network data. DESIGN Retrospective observational cohort study. Prioritised cases linked using 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) were interviewed using a social network approach to find epidemiological links. RESULTS Of 2055 TB cases notified, 56% could be typed. Clustering was associated with younger age, UK birth, Black Caribbean ethnicity, social risk factors, pulmonary TB and negative human immunodeficiency virus status. Only UK birth and presence of more than one social risk factor were associated with larger cluster size, while drug resistance was associated with smaller cluster size. Social network data from 139/431 clustered cases found new epidemiological links in 11/19 clusters with ⩾5 members (undirected median network density 0.09, interquartile range 0.05-0.4). Ninety-eight additional contacts were assessed, with one case of active TB and 24 with latent tuberculous infection diagnosed. CONCLUSION A social network approach increased knowledge of likely transmission events, but few additional TB cases were diagnosed. Obtaining social network data for all typed and untyped TB cases may improve contact tracing and reduce unexpected transmission detected from molecular data.

BACKGROUND: Marked increases in Clostridium difficile infection (CDI) incidence, driven by epidemic strain spread, is a global phenomenon. METHODS: The Clostridium difficile Ribotyping Network (CDRN) was established in 2007 as part of enhanced CDI surveillance in England, to facilitate the recognition and control of epidemic strains. We report on changes in CDI epidemiology in England in the first 3 years of CDRN. RESULTS: CDRN received 12,603 fecal specimens, comprising significantly (P < .05) increasing numbers and proportions of national CDI cases in 2007-2008 (n = 2109, 3.8%), 2008-2009 (n = 4774, 13.2%), and 2009-2010 (n = 5720, 22.3%). The C. difficile recovery rate was 90%, yielding 11,294 isolates for ribotyping. Rates of 9 of the 10 most common ribotypes changed significantly (P < .05) during 2007-2010. Clostridium difficile ribotype 027 predominated, but decreased markedly from 55% to 36% and 21% in 2007-2008, 2008-2009, and 2009-2010, respectively. The largest regional variations in prevalence occurred for ribotypes 027, 002, 015, and 078. Cephalosporin and fluoroquinolone use in CDI cases was reported significantly (P < .05) less frequently during 2007-2010. Mortality data were subject to potential reporting bias, but there was a significant decrease in CDI-associated deaths during 2007-2010, which may have been due to multiple factors, including reduced prevalence of ribotype 027. CONCLUSIONS: Access to C. difficile ribotyping was associated with significant changes in the prevalence of epidemic strains, especially ribotype 027. These changes coincided with markedly reduced CDI incidence and related mortality in England. CDI control programs should include prospective access to C. difficile typing and analysis of risk factors for CDI and outcomes.

Antibiotics are widely used in human and veterinary medicine for the prevention and treatment of infectious diseases. This practice has led to the emergence of antimicrobial-resistant bacteria in both humans and animals. The potential role that animals, particularly livestock, might play as potential reservoirs of antibiotic resistance genes has been recognized, and it is currently a cause of public health concern. The impact of animal and human antibiotic usage on the emergence and persistence of resistant bacteria and the precise transfer pathways for resistance genes between humans and animals are not currently fully understood. As part of the remit of the UK Advisory Committee on Antimicrobial Resistance and Healthcare-Associated Infection (ARHAI), two main areas were addressed, namely methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Gram-negative bacteria, where both the human and veterinary health sectors share interests. We review the current knowledge of MRSA and resistant Gram-negative bacteria, and provide guidance on occupational risks for veterinary healthcare workers relating to animals infected or colonized with MRSA. Findings and recommendations for further work across disciplines and future research in multidrug-resistant Gram-negative bacteria are also presented. Working collaboratively across disciplines is essential in order to better understand and challenge an important human and animal health problem: antimicrobial resistance.

The impact of human activity on the selection for antibiotic resistance in the environment is largely unknown, although considerable amounts of antibiotics are introduced through domestic wastewater and farm animal waste. Selection for resistance may occur by exposure to antibiotic residues or by co-selection for mobile genetic elements (MGEs) which carry genes of varying activity. Class 1 integrons are genetic elements that carry antibiotic and quaternary ammonium compound (QAC) resistance genes that confer resistance to detergents and biocides. This study aimed to investigate the prevalence and diversity of class 1 integron and integron-associated QAC resistance genes in bacteria associated with industrial waste, sewage sludge and pig slurry. We show that prevalence of class 1 integrons is higher in bacteria exposed to detergents and/or antibiotic residues, specifically in sewage sludge and pig slurry compared with agricultural soils to which these waste products are amended. We also show that QAC resistance genes are more prevalent in the presence of detergents. Studies of class 1 integron prevalence in sewage sludge amended soil showed measurable differences compared with controls. Insertion sequence elements were discovered in integrons from QAC contaminated sediment, acting as powerful promoters likely to upregulate cassette gene expression. On the basis of this data, >1 × 1019 bacteria carrying class 1 integrons enter the United Kingdom environment by disposal of sewage sludge each year.

Summary In the UK, infections due to Panton–Valentine leucocidin-positive community-associated meticillin-resistant Staphylococcus aureus (PVL-MRSA) have been reported sporadically. In September 2006, a fatal PVL-MRSA infection occurred in a Filipino healthcare worker (HCW) after she underwent caesarean section. Throat and nasal swabs were obtained from contacts of cases in community and hospital. MRSA with an antibiogram similar to the PVL-MRSA strain were characterised including toxin gene profiling, polymerase chain reaction- and sequence-based typing. Carriers underwent decolonisation treatment, and HCWs were restricted from patient care until they and their household members were considered negative for PVL-MRSA. The PVL-MRSA belonged to ST30, was protein A gene ( spa ) type t019, SCC mec IVc, agr 3, and resistant only to β-lactam antibiotics. Representatives of the same lineage were identified among a further 16 individuals in community and hospital. Infections likely to be caused by PVL-MRSA had occurred in 12 cases, and were likely to be hospital-acquired in two patients (one fatal) and occupationally acquired in one HCW. Nine cases worked as nursing staff in the hospital. Eight of these had emigrated from the Philippines in the previous five years and were linked socially. Thus, PVL-MRSA-ST30 was detected in a HCW community in the UK. This is the first report of nosocomial transmission of this pandemic clone in the UK associated with a fatality. Increased vigilance in healthcare and community is needed in response to this emerging threat.

In recent years the rates of Clostridium difficile infection (CDI) have increased worldwide with several large outbreaks occurring within the UK. New guidance from the UK Department of Health describes measures to investigate periods of increased incidence (PII) of CDI which include informing staff, ribotyping isolates, enhanced cleaning, audits and monitoring of antibiotic prescribing. This study aimed to determine whether a standardised set of measures could be used to control the incidence of CDI within an acute hospital setting over an 18 month period. During the study period a total of 102 PII involving 439 patients were investigated. The number of PII per month ranged from 14 in February 2008 to one in June 2009. From January 2008 to September 2008, ribotyping of patient isolates was only carried out on PII involving more than 10 patients, but from October 2008 it was carried out on all PII. During the period October 2008 to June 2009, 28 PII were investigated on 21 different wards, with seven wards having two PII. Ribotyping of the isolates confirmed nine (32%) of these PII to be outbreaks, with three being due to ribotype 027, two ribotype 078 and the others distinct ribotypes. Use of a set of standardised interventions has resulted in a decrease in the incidence of PII and a reduction in the number of patients involved. By taking early action with a set of standardised measures the incidence of hospital-acquired CDI can be reduced.

Identification of patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) and subsequent isolation and decolonization is pivotal to the control of cross infection in hospitals. The aim of this study was to establish if early identification of colonized patients using rapid methods alone reduces transmission. A prospective, cluster, two-period cross-over design was used. Seven surgical wards at a large hospital were allocated to two groups, and for the first 8 months four wards used rapid MRSA screening and three wards used a standard culture method. The groups were reversed for the second 8 months. Regardless of the method of detection, all patients were screened for nasal carriage on admission and then every 4 days. MRSA control measures remained constant. Results were analysed using a log linear Poisson regression model. A total of 12 682/13 952 patient ward episodes (PWE) were included in the study. Admission screening identified 453 (3.6%) MRSA-positive patient ward episodes, with a further 268 (2.2%) acquiring MRSA. After adjusting for other variables, rapid screening was shown to statistically reduce MRSA acquisition, with patients being 1.49 times (p 0.007) more likely to acquire MRSA in wards where they were screened using the culture method. Screening of surgical patients using rapid testing resulted in a statistically significant reduction in MRSA acquisition. This result was achieved in a routine surgical service with high bed occupancy and low availability of isolation rooms, making it applicable to the majority of health-care systems worldwide.

The use of successive generations of beta-lactams has selected successive generations of beta-lactamases including CTX-M ESBLs, AmpC beta-lactamases, and KPC carbapenamases in Enterobacteriaceae. Moreover, this cephalosporin resistance, along with rising resistance to fluoroquinolones, is now driving the use of carbapenems and unfortunately the carbapenem resistance has emerged markedly, especially in Acinetobacter spp. due to OXA- and metallo-carbapenemases. The industry responded to the challenge of rising resistance and recently developed some novel beta-lactams such as ceftobiprole, ceftaroline etc. and many beta-lactam compounds, including beta-lactamase-inhibitors, such as BMS-247243, S-3578, RWJ-54428, CS-023, SMP-601, NXL 104, BAL 30376, LK 157, and so on are under trials. This review provides the comprehensive accounts of the developments in penicillins, cephalosporins, carbapenems, and beta-lactamase-inhibitors, and the insight about medicinal chemistry, mechanism(s) of action and resistance, potential strategies to overcome resistance due to beta-lactamases, and also the recent advancements in the development of newer beta-lactam compounds; some of which are still under trials and yet to be classified. This review will fill the gap since previously published reviews and will serve as a comprehensive update on the current topic.

This review looks at the challenges facing the worldwide community with the increasing problem of methicillin resistance in Staphylococcus aureus. The epidemiology and natural history of community-associated methicillin-resistant Staphylococcus aureus and the challenge of control is discussed. Options for treatment and review of key antimicrobial agents acting against methicillin-resistant S. aureus, both currently in use and in development, are addressed. There are a number of new agents, the place of which in therapeutic regimens is yet to emerge. The review attempts to inform the reader of the probable position of these agents.

Since the first usage of antimicrobials, the burden of resistance among bacteria has progressively increased and has accelerated within the last 10 years. Antibiotic resistance genes were present at very low levels prior to the introduction of antibiotics and it is largely the selective pressure of antibiotic use and the resulting exposure of bacteria, not only in humans but also in companion and food animals and the environment, which has caused the rise. The increasing mobility across the globe of people, food and animals is another factor. Examples of this are the international pandemic of different genotypes of CTX-M extended-spectrum beta-lactamases (particularly CTX-M-14 and -15) and the emergence of the carbapenemase KPC-1 in both the USA and Israel. This review details examples of both the emergence and dissemination through different genetic routes, both direct and indirect selective pressure, of significance resistance in Staphylococcus aureus, Enterococcus species, Enterobacteriaceae and Pseudomonas/Acinetobacter. The response made by society to reduce resistance involves surveillance, reduced usage, improved infection control and the introduction of new antimicrobial agents. Although efforts are being made in all these areas, there is an urgent need to increase the effectiveness of these interventions or some bacterial infections will become difficult if not impossible to treat reliably.

Staphylococci are a significant cause of hospital-acquired infection. Nasal carriage of Staphylococcus aureus is an important risk factor for infection in surgical patients and coagulase-negative staphylococci (CNS) are a major cause of prosthetic joint infections. The impact that antibiotic surgical prophylaxis has on the nasal carriage of staphylococci has not been studied. Daily nasal swabs were taken from 63 patients who received antibiotic surgical prophylaxis and 16 patients who received no antibiotics. Total aerobic bacterial count, S. aureus and CNS were enumerated by culture from nasal swabs. Representative isolates were typed by staphylococcal interspersed repeat units (SIRU) typing and PFGE, and MICs to nine antibiotics were determined. After antibiotic administration, there was a reduction in S. aureus counts (median - 2.3 log(10)c.f.u. ml(- 1)) in 64.0 % of S. aureus carriers, compared with only a 0.89 log(10)c.f.u. ml(- 1) reduction in 75.0 % of S. aureus carriers who did not receive antibiotics. A greater increase in the nasal carriage rate of meticillin-resistant CNS was observed after antibiotic surgical prophylaxis compared with hospitalization alone, with increases of 16.4 and 4.6 %, respectively. Antibiotic-resistant S. epidermidis carriage rate increased by 16.6 % after antibiotic administration compared with 7.5 % with hospitalization alone. Antibiotic surgical prophylaxis impacts the nasal carriage of both S. aureus and CNS.

Multi-drug-resistant (MDR) Gram-negative bacterial infections have become prevalent in some European countries. Moreover, increased use of broad-spectrum antimicrobial agents selects organisms with resistance and, by increasing their numbers, increases their chance of spread. This report describes measures that are clinically effective for preventing transmission when used by healthcare workers in acute and primary healthcare premises. Methods for systematic review 1946–2014 were in accordance with SIGN 501 and the Cochrane Collaboration;2 critical appraisal was applied using AGREEII.3 Accepted guidelines were used as part of the evidence base and to support expert consensus. Questions for review were derived from the Working Party Group, which included patient representatives in accordance with the Patient Intervention Comparison Outcome (PICO) process. Recommendations are made in the following areas: screening, diagnosis and infection control precautions including hand hygiene, single-room accommodation, and environmental screening and cleaning. Recommendations for specific organisms are given where there are species differences. Antibiotic stewardship is covered in a separate publication.

Heavy antibiotic usage is thought to contribute to the increased bacterial antibiotic resistance reported in intensive care units. Many units use extended-spectrum cephalosporins or fluoroquinolones as the empirical drug of choice; however, there are few reports documenting the effects of a switch from one class of antibiotics to another. A 2-year crossover study was undertaken on 2 large units, where the ecological effect of the implementation of a defined prescribing policy of 2 different antibiotic classes on the microflora of patients was examined. For the first year, cefotaxime or ceftazidime was the drug of choice for empirical treatment of patients. In the second year, this was changed to ciprofloxacin. Bacterial isolates from twice-weekly surveillance specimens and all clinical specimens were collected from 1026 patients. These were identified, and breakpoint susceptibility testing was conducted both during a 3-month baseline period and during the 2-year study period. Patient demographic data and antibiotic usage data were recorded throughout the study. There was a significant increase in the amount of ciprofloxacin used in the second year of the study and a decrease in the amount of cefotaxime or ceftazidime used. The decreased use of cephalosporins was linked with a decrease in ceftazidime-resistant Enterobacteriaceae organisms. The increased use of ciprofloxacin during the second year of the study did not seem to cause any significant rise in ciprofloxacin-resistant isolates. Although reducing the overall selective pressure by cutting antibiotic usage is important for controlling antibiotic resistance, our study illustrates the value of carefully considering which classes of antibiotic should be used for empirical therapy.

Results from clinical diagnostic microbiology laboratories taking part in the UK National Quality Assessment Service (UK NEQAS) scheme for Mycobacteria Culture between 1993 and 2003 were evaluated and assessed to determine whether the perceived increase in the use of rapid methods is improving time-to-positive reporting of results. Four simulated sputum specimens containing mycobacteria in mixed cultures with normal commensal organisms were distributed three times a year. Participating laboratories were required to report on the presence of ‘mycobacteria’ and on the time required to obtain a positive result. The overall level of performance with the mycobacteria culture external quality assessment specimens remained consistently high, with an average success rate of 94% over 10 years. The mean time-to-positive decreased from 24 to 17 days during the previous 8 years. A survey questionnaire, circulated in 2002, addressed the use of continuous automated mycobacterial liquid culture (CAMLiC) and molecular methods. The increase in the use of rapid culture methods for the detection of Mycobacterium tuberculosis has resulted in an overall reduction in time-to-positive data reported by participants, and has provided an indication of participants’ ability to meet the 21-day target recommended by the CDC for the detection and identification of M. tuberculosis.