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Prevention and control of multi-drug-resistant Gram-negative bacteria: recommendations from a Joint Working Party

Published:November 15, 2015DOI:https://doi.org/10.1016/j.jhin.2015.08.007

      1. Executive summary

      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 50
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      and the Cochrane Collaboration;
      critical appraisal was applied using AGREEII.
      • Brouwers M.
      • Kho M.E.
      • Browman G.P.
      • et al.
      AGREE Next Steps Consortium
      AGREE II: advancing guideline development, reporting and evaluation in healthcare.
      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.

      2. Lay summary

      MDR Gram-negative bacteria are bacteria (or germs) that are resistant to at least three different antibiotics. These bacteria are commonly found in the gut, where they do no harm; however, they can cause infection at other body sites, mainly in patients who are vulnerable due to other underlying diseases, injury or hospitalization. Infection often happens when the bacteria enter the body through an open wound or via a medical device such as a catheter. Infections caused by MDR Gram-negative bacteria are difficult to treat, and can cause additional pain to patients with slow wound healing and other complications such as pneumonia or infection in the blood. This can prolong the length of stay in hospital and, in some cases, can cause death.
      Some types of resistant Gram-negative bacteria can be carried on the skin rather than the gut, again with no obvious signs or symptoms. ‘Colonization’ describes this carriage of bacteria in the gut, on the skin or in the nose, throat or elsewhere on the body. Although the patients lack symptoms of infection, they may still need to be isolated/segregated and/or other contact precautions may be necessary in order to stop their resistant bacteria spreading to others.

      3. Introduction

      This guidance has been prepared by the Working Party to provide advice on screening (testing), treatment and precautions needed to prevent the spread of MDR Gram-negative bacteria. The guidance describes appropriate infection prevention and control precautions to include hand hygiene, equipment and environmental cleaning and guidance on screening for MDR Gram-negative bacteria. There is an accompanying guideline describing best practice in antimicrobial prescribing and stewardship which should be used in conjunction with this report.
      The Working Party comprises a group of medical microbiologists and scientists, infectious disease physicians, infection control practitioners, epidemiologists and patient representatives. The patient representatives are lay members and have direct experience of the treatment of healthcare-associated infections through personal experience and/or through membership of the Healthcare-acquired Infection Service Users Research Forum, patient charities and/or through involvement in the development of National Institute for Health and Care Excellence (NICE) guidelines.

      4. Guideline Development Team

      4.1 Guideline Advisory Group

      • Martin Kiernan, Nurse Consultant, Prevention and Control of Infection, Southport and Ormskirk NHS Trust, Southport, UK
      • Phil Wiffen, Cochrane Pain, Palliative and Supportive Care Group Pain Research, Churchill Hospital Oxford, Nuffield Department of Clinical Neurosciences, Oxford, UK
      • Karla Soares-Wieser, Enhance Reviews Ltd, Wantage, UK

      4.2 Acknowledgements

      The authors would like to acknowledge the support of the Infection Prevention Society (IPS) for their input into the development of these guidelines, as well as the associations, societies, Royal Colleges and patient groups who helped with the external review. APRW was supported, in part, by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The authors wish to thank Claire Brown, Senior Nurse Infection Control Health Protection Scotland for help in writing the staff and patient information leaflets.

      4.3 Source of funding

      A grant from the British Infection Association (BIA), the Healthcare Infection Society (HIS) and the British Society for Antimicrobial Chemotherapy (BSAC) funded Karla Soares-Wieser and others at Enhance Reviews Ltd, Lyford, Wantage and Paul Wiffen to perform the systematic review.

      4.4 Disclosure of potential conflict of interest

      • APRW: Consultant on Drug Safety Monitoring Boards for Roche and Genentech. Advisory panel for 3M.
      • DML: Advisory boards or consultancy for Achaogen, Adenium, Alere, Allecra, AstraZeneca, Basilea, Bayer, BioVersys, Cubist, Curetis, Cycle, Discuva, Forest, GSK, Longitude, Meiji, Pfizer, Roche, Shionogi, Tetraphase, VenatoRx and Wockhardt. Paid lectures for AOP Orphan, AstraZeneca, Bruker, Curetis, Merck, Pfizer and Leo. Relevant shareholdings in Dechra, GSK, Merck, Perkin Elmer and Pfizer (collectively amounting to <10% of portfolio value).
      • JAO: Part-time employment at Bioquell during the production of these guidelines. Paid lectures for 3M. Research funding from Pfizer and the Guy's and St Thomas' Charity.
      • PJ: Advisory board for Baxter.
      • DAE: ECCMID conference attendance funded by Astellas and Eumedica.
      • BO: Advisory board for Astellas and Forest. Lecture for Alere.
      • CM: Travel expenses funded by Mérieux Diagnostics.
      • MC: IPS conference attendance funded by corporate sponsorship from Mölnlycke Healthcare.
      • PH: Consultancy for bioMérieux, Becton-Dickinson, Eumedica, Merck, Novartis, MagusCommunications, Pfizer and Wyeth. Director of ModusMedica (medical education company). Research funded by Merck, Novartis and Pfizer.
      • All other authors declared no conflict of interest.

      4.5 Relationship of authors with sponsors

      BSAC, BIA and HIS commissioned the authors to undertake the Working Party Report. IPS provided additional panel members and financial support for them to attend meetings. The authors are members of these societies.

      4.6 Responsibility for guidelines

      The views expressed in this publication are those of the authors, and have been endorsed by the sponsoring societies following consultation.

      5. Working Party Report

      Date of publication: January 2016 (published online 16th November 2015)

      5.1 What is the Working Party Report?

      This report is a set of recommendations covering prevention of transmission of MDR Gram-negative bacteria (i.e. resistant to at least three different antibiotics).
      Antimicrobial chemotherapy and stewardship are covered in a separate publication.
      The Working Party recommendations have been developed systematically through a multi-professional group based on published evidence. They should be used in the development of local protocols for all acute and long-term healthcare settings.

      5.2 Why do we need a Working Party Report for these infections?

      Colonization and infection by MDR Gram-negative bacteria have become prevalent in some European countries. Heavy use of broad-spectrum agents selects for organisms with resistance, and increases their chance of spread. National antibiotic consumption is increasing in the UK (6% increase in 2013 compared with 2010).
      • Public Health England
      English surveillance programme for antimicrobial utilisation and resistance (ESPAUR).
      The spread of these infections risks increasing the length of hospital stay, and has an adverse effect on the quality of care of patients. Public awareness of resistance and healthcare-associated infections is increasing, and the paucity of new antimicrobial agents to treat these infections has resulted in the formulation of the five-year Antimicrobial Resistance Strategy by the Department of Health for England to address the problem. When outbreaks of infection involving MDR strains occur, there is a considerable financial, physical and psychological cost. Unless controlled, outbreaks are likely to become more common and MDR strains will become endemic. Evidence-based infection prevention and associated quality improvement methods are effective in reducing the number of infections with these organisms.

      5.3 What is the purpose of the Working Party Report's recommendations?

      This report describes measures that are clinically effective for preventing infections when used by healthcare workers in acute and long-term health care.

      5.4 What is the scope of the guidelines?

      Two sets of guidelines have been developed. This report includes appropriate infection prevention and control precautions. The other report describes best-practice antimicrobial prescribing and stewardship.
      • Hawkey P.
      Treatment of multi-drug resistant (MDR) Gram-negative bacteria – recommendations from a Joint Working Party.

      5.5 What is the evidence for these guidelines?

      In the preparation of these recommendations, systematic reviews of peer-reviewed research were undertaken. Expert opinion was also derived from published guidelines subjected to validated appraisal.
      • Brouwers M.
      • Kho M.E.
      • Browman G.P.
      • et al.
      AGREE Next Steps Consortium
      AGREE II: advancing guideline development, reporting and evaluation in healthcare.
      Evidence was assessed for methodological quality and clinical applicability according to the protocols of the Scottish Intercollegiate Guidelines Network (SIGN).

      5.6 Who developed these guidelines?

      A group of medical microbiologists, scientists, infectious disease physicians, infection control practitioners, epidemiologists and patient representatives.

      5.7 Who are these guidelines for?

      Any healthcare practitioner can use these guidelines and adapt them for local use. Users are anticipated to include clinical staff (i.e. medical, nursing and paramedical staff) as well as healthcare infection prevention and control teams. The guidelines should be used to improve practice of infection prevention, and to help patients and their carers to understand the methods available to prevent acquisition of antibiotic-resistant bacteria.

      5.8 How are the guidelines structured?

      Each section comprises an introduction, a summary of the evidence base with levels, and a recommendation graded according to the available evidence.

      5.9 How frequently are the guidelines reviewed and updated?

      The guidelines will be reviewed at least every four years and updated if change(s) in the evidence are sufficient to require a change in practice.

      5.10 Aim

      The primary aim of this report was to assess the current evidence for prevention and control of MDR Gram-negative infections.

      6. Summary of guidelines

      The guidelines relate to MDR Gram-negative bacteria and have been derived from current best peer-reviewed publications and expert opinion. Table IV contains expert opinion. Each recommendation is associated with a class of supporting evidence, as follows.

      6.1 Surveillance

      • 1,2.
        The minimum susceptibility tests performed on all significant Gram-negative isolates should include meropenem; in addition, cefpodoxime should be tested for Enterobacteriaceae, and ceftazidime should be tested for Pseudomonas spp.Strong
      • 3.
        Travel history (i.e. countries or known endemic areas visited within previous year) should be collected for all patients with carbapenemase-producing Gram-negative bacteria.Strong
      • 4.
        Each healthcare organization should have access to robust microbiological arrangements for detecting and reporting all MDR Gram-negative organisms in routine clinical samples and for screening using highly-sensitive tests with a diagnostic turnaround time of <48h.Conditional

      6.2 Screening

      • 5.
        Active screening rather than passive surveillance is recommended for high-risk specialties.Conditional
      • 6.
        Patients at high risk of colonization or infection with carbapenem-resistant organisms include those admitted to intensive care units (ICUs) and from long-term care facilities (e.g. care homes).Conditional
      • 7.
        Screening for rectal and wound carriage of carbapenemase-producing Enterobacteriaceae should be undertaken in patients at risk.Strong
      • 8.
        All patients transferred from, or with a history of admission to, healthcare facilities with known endemic carbapenemase-producing Enterobacteriaceae in the preceding year should be screened.Strong
      • 9.
        Screening for carbapenem-resistant Acinetobacter baumannii and MDR Pseudomonas aeruginosa is required in the management of outbreaks.Strong
      • 10.
        A rectal swab (with visible material) or stool sample (and urine sample if catheter present) should be used for screening for MDR Enterobacteriaceae and P. aeruginosa. For Acinetobacter spp., skin sites should be sampled, or, if a catheter or endotracheal tube is present, urine or respiratory secretions should be sampled.Conditional
      • 11.
        In the event of secondary cases of carbapenem-resistant Enterobacteriaceae, standard infection control precautions (SICPs) and contact precautions should be monitored and re-inforced among clinical staff. Screening of patients not identified as carriers should be repeated weekly and on discharge from affected units until no new cases are identified for more than seven days.Strong
      • 12.
        Patients with previous samples with carbapenem-resistant or other MDR Gram-negative bacteria should be screened at the time of admission.Conditional

      6.3 Prevention of transmission

      • 13.
        In addition to SICPs, apply contact precautions for those patients who present an infection risk.Strong
      • 14.
        Where possible, single-room isolation should be provided for patients with MDR Gram-negative bacterial infection/colonization, and contact precautions should be continued for the duration of their stay.Conditional
      • 15.
        Use disposable gloves and gowns or aprons to care for patients with MDR Gram-negative bacteria: A. baumannii, carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, P. aeruginosa.Strong
      • 16.
        Identify and place infected and colonized patients in single rooms where available in this order of priority: carbapenem-resistant Enterobacteriaceae, carbapenem-resistant A. baumannii, ESBL-producing Klebsiella spp., carbapenemase-producing P. aeruginosa, ESBL-producing Escherichia coli and other Enterobacteriaceae, AmpC Enterobacteriaceae.Strong
      • 17.
        If insufficient rooms are available, cohort patients following local risk assessment.Conditional
      • 18.
        Hand hygiene is required before and after direct patient contact; after contact with body fluids, mucous membranes and non-intact skin; after contact with the immediate patient environment; and immediately after the removal of gloves.Strong

      6.4 Cleaning and environment

      • 19.
        Environmental screening should be considered where there is unexplained transmission of MDR Gram-negative organisms or a possible common source for an outbreak.Strong
      • 20.
        Respiratory and other contaminated equipment should be decontaminated (or respiratory secretions discarded) away from the immediate bed area in designated cleaning sinks and not in handwash sinks.Strong
      • 21.
        For P. aeruginosa, including MDR strains, at a minimum, in accordance with the organization's water safety plan, a risk assessment should be made when levels of patient colonization or infection rise in order to determine if point-of-use filters should be installed or if taps need to be changed.Strong
      • 22.
        Terminal disinfection of vacated areas with hypochlorite should be used in the control of outbreaks of infection due to MDR Gram-negative bacteria.Conditional
      • 23.
        Hydrogen peroxide vapour should be considered as an adjunctive measure following cleaning of vacated isolation rooms/areas.Conditional
      • 24.
        The routine use of selective decontamination of the mouth or digestive tract is not recommended for control of MDR Gram-negative bacteria.Conditional

      6.5 Miscellaneous

      • 25.
        Monitor hand hygiene of all staff when patient cohorting is being applied.Strong

      7. Implementation of these guidelines

      7.1 How can the guidelines be used to improve clinical effectiveness?

      The guidelines can be used to inform local infection prevention and control guidance, and to direct clinical decision-making. They provide a framework for clinical audit tools aiming to achieve quality improvement.

      7.2 How much will implementation of the guidelines cost?

      In most areas, there are no anticipated additional costs unless existing practice falls well below currently-accepted best practice. Failure to implement the recommendations would result in greater costs in terms of economics and quality of life. Screening and isolation will result in significant cost pressures where they are not currently practised, but these costs are set against reduced transmission and fewer cases needing antibiotic treatment. Prolonged isolation can have adverse effects on a patient's psychological health, so may have additional unexpected costs.

      7.3 Summary of audit measures

      The following are expressed as percentage compliance:
      • All Gram-negative isolates requiring antibiotic treatment are to be tested for susceptibility to meropenem (or all blood isolates should be tested).
      • The microbiology laboratory reports all patients infected or colonized with carbapenemase-producing Gram-negative bacteria to Public Health England (PHE) or an equivalent body.
      • All patients colonized or infected with carbapenem-resistant Enterobacteriaceae and A. baumannii are placed under contact precautions within 6h of identification.
      • All patients colonized or infected with carbapenem-resistant Enterobacteriaceae and A. baumannii are placed under contact precautions in a single room or cohort for the duration of their stay.
      • Travel history is obtained at the time of admission for all acute hospital patients, and patients from endemic areas are screened.

      7.4 E-learning tools

      Continuing Professional Development questions and model answers are listed for self-assessment in Appendix 4.

      8. Methodology

      8.1 Evidence appraisal

      Methods were in accordance with SIGN 50
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      and the Cochrane Collaboration,
      and critical appraisal was applied using AGREEII.
      • Brouwers M.
      • Kho M.E.
      • Browman G.P.
      • et al.
      AGREE Next Steps Consortium
      AGREE II: advancing guideline development, reporting and evaluation in healthcare.
      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 PICO process.
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      K. Soares-Wiesner of Enhance Reviews Ltd and Dr P. Wiffen of Pain Research and Nuffield Department of Clinical Neurosciences, Oxford University used a systematic review process. Guidelines and research studies were identified for each search question. Systematic reviews, randomized controlled trials and observational studies were included and assessed by two reviewers. In context, observational studies included non-randomized controlled studies, controlled before–after studies and interrupted time series.
      All languages were searched. Search strategies for each area are given in the sections below. MeSH headings and free-text terms were used in the Cochrane Library (Issue 11 2012), Medline (1946–2012), Embase (1980–2012) and Cumulated Index of Nursing and Allied Health Literature (CINAHL) (1984–2012). On 23rd May 2014, an update search was conducted on Medline alone using the same strategy for references after 1st January 2013. Reference lists of included studies were searched. Two review authors independently screened all citations and abstracts identified, and screened full reports of potentially eligible studies (those that addressed review questions in primary or systematic secondary research or a clinical or in-use study). Disagreements were resolved by discussion, and rationales for exclusion of studies were documented. Pretested data extraction forms were used, and study characteristics and results were collected. Data were extracted from observational studies for multiple-effect estimates: number of patients, adjusted and unadjusted effect estimates with standard error or 95% confidence interval (CI), confounding variables and methods used to adjust the analysis. If available, data were extracted from contingency tables. Risk of bias was assessed using SIGN critical appraisal checklists. Interrupted time series were assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Group.
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      • Cochrane Effective Practice and Organisation of Care Review Group
      EPOC resources.
      Quality was judged by reported details of protection against secular changes (intervention independent of other changes) and detection bias (blinded assessment of primary outcomes and completeness of data). For outbreak patterns associated with particular pathogens, the Working Party made additional searches of descriptive studies to extract effective interventions.
      Clinical outcomes were mortality, effectiveness of treatment and length of hospital stay. Microbial outcome measures were decreases in the prevalence of multi-drug resistance among Gram-negative bacteria, or decreases in colonization or infection by specific Gram-negative pathogens. Risk ratios (RR) were used for dichotomous variables, and mean differences with 95% CI were used for continuous outcomes.
      • Borenstein M.
      • Hedges L.V.
      • Higgins J.P.T.
      • Rothstein H.R.
      Introduction to meta-analysis.
      Analyses were performed using Revman 5.2.
      SIGN summary tables were used.
      Evidence tables and judgement reports were presented and discussed by the Working Party, and guidelines were prepared according to the nature and applicability of the evidence, patient preference and acceptability, and likely costs. The strength of evidence was defined by SIGN (Table I), and the strength of recommendation was adopted from GRADE (Grading of Recommendations Assessment, Development and Evaluation) (Table II). The grading relates to the strength of the supporting evidence and predictive power of the study designs, rather than the importance of the recommendation. Any disagreements between members were resolved by discussion. For some areas, only expert opinion is available; in such cases, a good practice recommendation has been made.
      Table ILevels of evidence for intervention studies
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      • Cochrane Effective Practice and Organisation of Care Review Group
      EPOC resources.
      1++High-quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias.
      1 +Well-conducted meta-analyses, systematic reviews or RCTs with a low risk of bias.
      1 −Meta-analyses, systematic reviews or RCTs with a high risk of bias.
      Studies with an evidence level of ‘1−‘ and ‘2−‘ should not be used as a basis for making a recommendation.
      2++High-quality systematic reviews of case–control or cohort studies.

      High-quality case–control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal.

      Interrupted time series with a control group: (i) there is a clearly defined point in time when the intervention occurred; and (ii) at least three data points before and three data points after the intervention.
      2+Well-conducted case–control or cohort studies with a low risk of confounding or bias, and a moderate probability that the relationship is causal.

      Controlled before–after studies with two or more intervention and control sites.
      2−Case–control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal.

      Interrupted time series without a parallel control group: (i) there is a clearly defined point in time when the intervention occurred; and (ii) at least three data points before and three data points after the intervention.

      Controlled before–after studies with one intervention and one control site.
      3Non-analytic studies (e.g. uncontrolled before–after studies, case reports, case series).
      4Expert opinion. Legislation.
      RCT, randomized controlled trial.
      a Studies with an evidence level of ‘1−‘ and ‘2−‘ should not be used as a basis for making a recommendation.
      Table IIRecommendation grading
      • Scottish Intercollegiate Guidelines Network
      SIGN 50: a guideline developer's handbook.
      Recommendation
      Undesirable consequences clearly outweigh

      desirable consequences
      Strong recommendation against
      Undesirable consequences probably outweigh

      desirable consequences
      Conditional recommendation against
      Balance between desirable and undesirable

      consequences is closely balanced or uncertain
      Recommendation for research and possibly

      conditional recommendation for use restricted to trials
      Desirable consequences probably outweigh

      undesirable consequences
      Conditional recommendation for
      Desirable consequences clearly outweigh

      undesirable consequences
      Strong recommendation for

      8.2 Consultation process

      On completion, these guidelines were opened to consultation with the stakeholders listed in Appendix 1. The draft report was placed on the HIS website for one month. Views were invited on format, content, local applicability, patient acceptability and recommendations. The Working Party considered and collated comments, and agreed revisions.

      9. Rationale for recommendations

      9.1 Epidemiology

      9.1.1 What is the definition of multi-drug-resistant Gram-negative bacteria?

      For the purposes of this guideline, MDR Gram-negative bacteria were defined as having three or more antimicrobial resistance mechanisms affecting different antibiotic classes. For a full discussion of the definitions in use, please refer to the companion paper.
      • Hawkey P.
      Treatment of multi-drug resistant (MDR) Gram-negative bacteria – recommendations from a Joint Working Party.

      9.1.2 Which Gram-negative bacteria cause infection control problems?

      Opportunistic Gram-negative bacteria that present increasing resistance issues include Enterobacteriaceae (E. coli, Klebsiella spp., Enterobacter spp., Serratia spp., Citrobacter spp., Proteeae) and the non-fermenters, P. aeruginosa and A. baumannii. Stenotrophomonas maltophilia is inherently MDR in most cases, but a less common cause of cross-infection. Gonococci are Gram-negative bacteria and are increasingly resistant, but were excluded because relevant public health control actions are substantially different.
      In this report, emphasis is placed on strains resistant to β-lactams, including carbapenems, cephalosporins and β-lactamase inhibitor combinations, and strains resistant to fluoroquinolones insofar as these are the core components of most therapies for severe infections. Aminoglycosides are most often used as adjuncts to β-lactam therapy in severe infection, whereas polymyxins are mainly used in cases where β-lactams cannot be used due to resistance. Resistance to these latter groups of agents should nevertheless prompt concern, especially where it is coupled with resistance to multiple β-lactams, as is often the case. Means of infection control remain the same irrespective of the specific resistance.

      9.1.3 What are the relative contributions of community and hospital acquisition?

      The mechanisms and time course of resistance accumulation by Gram-negative opportunists, both internationally and in the UK, are reviewed in a companion paper.
      • Hawkey P.
      Treatment of multi-drug resistant (MDR) Gram-negative bacteria – recommendations from a Joint Working Party.
      This introduction, rather, is concerned with the distribution of these resistance types in hospitals, long-term care facilities and the community. The distinction between these sectors is increasingly blurred, with many elderly patients moving back and forth between hospital and care homes,
      • Rooney P.J.
      • O'Leary M.C.
      • Loughrey A.C.
      • et al.
      Nursing homes as a reservoir of extended-spectrum beta-lactamase (ESBL)-producing ciprofloxacin-resistant Escherichia coli.
      and with hospital stays becoming shorter, so that healthcare-associated infections often become apparent after hospital discharge
      • Leaper D.
      • Tanner J.
      • Kiernan M.
      Surveillance of surgical site infection: more accurate definitions and intensive recording needed.
      or on re-admission. Consequently, MDR Gram-negative bacteria – including those producing carbapenemases – are increasingly seen in general practice specimens, principally urine samples. Careful enquiry often reveals that the patient recently received secondary care. The period of time that may elapse from acquisition in hospital, often in colonization sites, to the development of an obvious infection in the community is variable, and different papers use different intervals when classifying infection diagnosed in the community as ‘healthcare-associated’. Intervals of one to three months are commonly used to distinguish community acquisition from that acquired during hospital admission, but the literature shows that carriage, and the potential for infection, can persist for much longer periods (commonly one year); it is recommended that this longer period should be used.
      • Zimmerman F.S.
      • Assous M.V.
      • Bdolah-Abram T.
      • Lachish T.
      • Yinnon A.M.
      • Wiener-Well Y.
      Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge.

      9.1.4 What is the evidence for reservoirs and spread of multi-drug-resistant Gram-negative bacteria in care homes and secondary care?

      Enterobacteriaceae, P. aeruginosa and Acinetobacter spp., whether resistant or not, can all be transferred among vulnerable patients by staff vectors and contaminated equipment, leading to well-defined local clonal outbreaks.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      Both A. baumannii and Klebsiella pneumoniae (by virtue of their capsules) can survive on dry surfaces, including hands.
      • Casewell M.W.
      • Desai N.
      Survival of multiply-resistant Klebsiella aerogenes and other Gram-negative bacilli on finger-tips.
      • Jawad A.
      • Seifert H.
      • Snelling A.M.
      • Heritage J.
      • Hawkey P.M.
      Survival of Acinetobacter baumannii on dry surfaces: comparison of outbreak and sporadic isolates.
      MDR Enterobacteriaceae can colonize the gut, providing – without any symptoms – a reservoir for transfer to other body sites where infection may ensue, or transfer to other patients. The risk of transmission is increased if the carrier experiences diarrhoea or incontinence.
      In general, and excluding particular high-risk clones discussed below, there is no evidence that MDR strains are more likely to be associated with cross-infection than other strains. Enterobacteriaceae that owe carbapenem resistance to combinations of ESBLs or AmpC β-lactamase activity together with porin loss are often thought to have impaired fitness, and to be less likely to spread among patients than those with carbapenemases, but cross-infection by porin-deficient Enterobacteriaceae has been reported from Italy, Korea and Portugal.
      • Novais A.
      • Rodrigues C.
      • Branquinho R.
      • Antunes P.
      • Grosso F.
      • Boaventura L.
      Spread of an OmpK36-modified ST15 Klebsiella pneumoniae variant during an outbreak involving multiple carbapenem-resistant Enterobacteriaceae species and clones.
      • Suh B.
      • Bae I.K.
      • Kim J.
      • Jeong S.H.
      • Yong D.
      • Lee K.
      Outbreak of meropenem-resistant Serratia marcescens comediated by chromosomal AmpC beta-lactamase overproduction and outer membrane protein loss.
      • García-Fernández A.
      • Miriagou V.
      • Papagiannitsis C.C.
      • et al.
      An ertapenem-resistant extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae clone carries a novel OmpK36 porin variant.
      In a nested case–control study in the USA, mechanical ventilation, pulmonary disease, days of antibiotic treatment and colonization pressure were associated with acquisition of carbapenem-resistant Enterobacteriaceae.
      • Swaminathan M.
      • Sharma S.
      • Poliansky Blash S.
      • et al.
      Prevalence and risk factors for acquisition of carbapenem-resistant Enterobacteriaceae in the setting of endemicity.
      Typing of K. pneumoniae in this study suggested clonal transmission within and between hospitals.

      9.1.4.1 High-risk clones

      Bacterial typing has revealed the role of ‘high-risk clones’ in the international spread of resistance.
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      For example:
      • The majority of fluoroquinolone-resistant ESBL-producing E. coli causing infection in hospitals and the community belong to sequence type (ST) 131-B2-O25b.
        • Banerjee R.
        • Johnston B.
        • Lohse C.
        • Porter S.B.
        • Clabots C.
        • Johnson J.R.
        Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant clonal group associated with healthcare and elderly hosts.
        • Xu L.
        • Shabir S.
        • Bodah T.
        • et al.
        Regional survey of CTX-M-type extended-spectrum β-lactamases among Enterobacteriaceae reveals marked heterogeneity in the distribution of the ST131 clone.
      • The growing prevalence of K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae in hospitals (e.g. in Israel, Italy and the USA) substantially reflects the clonal expansion of ST258 variants with KPC-2 or -3 enzymes.
        • Munoz-Price L.S.
        • Poirel L.
        • Bonomo R.A.
        • et al.
        Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      • In Russia, Belarus and Kazakhstan, there is extensive nosocomial spread of ST235 P. aeruginosa, with VIM-2 carbapenemase only susceptible to colistin.
        • Edelstein M.V.
        • Skleenova E.N.
        • Shevchenko O.V.
        • et al.
        Spread of extensively resistant VIM-2-positive ST235 Pseudomonas aeruginosa in Belarus, Kazakhstan, and Russia: a longitudinal epidemiological and clinical study.
      Except in the case of ST131 E. coli (where infection may be preceded by a long period of innocuous gut carriage), UK hospitals are minimally affected by these lineages, although both ST258 K. pneumoniae and ST235 P. aeruginosa have been recorded.
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      • Wright L.L.
      • Turton J.F.
      • Livermore D.M.
      • Hopkins K.L.
      • Woodford N.
      Dominance of international ‘high-risk clones’ among metallo-β-lactamase-producing Pseudomonas aeruginosa in the UK.
      National clones that have achieved considerable traction in the UK include A. baumannii OXA-23 clone 1, recorded at >60 hospitals.
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      • Coelho J.M.
      • Turton J.F.
      • Kaufmann M.E.
      • et al.
      Occurrence of carbapenem-resistant Acinetobacter baumannii clones at multiple hospitals in London and Southeast England.
      It remains uncertain whether this prevalence reflects site-to-site transfer via colonized patients, or the selection, at multiple sites, of a pre-existing but previously rare subtype of this very clonal species. Focusing infection control on specific types rather than resistances has not been explored for ESBL-producing E. coli.
      E. coli ST131 has spread globally, and is transmitted within hospitals, families, through pets and long-term care facilities whilst being very rare in food animals. It is often resistant to fluoroquinolones and multiple other antimicrobials, as well as producing CTX-M ESBLs.
      • Colpan A.
      • Johnston B.
      • Porter S.
      • et al.
      VICTORY (Veterans Influence of Clonal Types on Resistance: Year 2011) Investigators. Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veterans.
      The lineage can be distinguished by serotyping and polymerase chain reaction (PCR).
      • Novais A.
      • Sousa C.
      • de Dios Caballero J.
      • et al.
      MALDI-TOF mass-spectrometry as a tool for the discrimination of high-risk Escherichia coli clones from phylogenetic groups B2 (ST131) and D (ST69, ST405,ST393).
      Among faeces sent for culture from international travellers returning to the UK, many of which were from the Indian subcontinent, 18% contained ESBL E. coli, mainly with CTX-M-15 enzymes, and 2.1% had ST131 strains with ESBL.
      • Dhanji H.
      • Patel R.
      • Wall R.
      • et al.
      Variation in the genetic environments of bla(CTX-M-15) in Escherichia coli from the faeces of travellers returning to the United Kingdom.

      9.1.4.2 Plasmid outbreaks

      In this situation, a plasmid or family of related plasmids disseminate(s) among strains of one or more species in a locale.
      • Vlek A.L.M.
      • Cooper B.S.
      • Kypraios T.
      • Cox A.
      • Edgeworth J.D.
      • Auguet O.T.
      Clustering of antimicrobial resistance outbreaks across bacterial species in the intensive care unit.
      • Conlan S.
      • Thomas P.J.
      • Deming C.
      • et al.
      Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae.
      This is the case, for example, in the current spread of pKpQIL plasmids encoding KPC carbapenemases in and around Manchester.
      • Munoz-Price L.S.
      • Fajardo-Aquino Y.
      • Arheart K.L.
      • et al.
      Aerosolization of Acinetobacter baumannii in a trauma ICU.
      Unlike in a clonal outbreak, the isolates are diverse in terms of species, strain and in their antibiograms, which also reflect the host strain and any other plasmid(s) carried. Single-strain clusters occur within this overall diversity, but do not come to dominate the picture as in a classical single-strain outbreak. It is inferred (although rarely proven) that frequent plasmid transfer among gut bacteria leads to the diversity of strains involved.
      • Gijón D.
      • Curiao T.
      • Baquero F.
      • Coque T.M.
      • Cantón R.
      Fecal carriage of carbapenemase-producing Enterobacteriaceae: a hidden reservoir in hospitalized and nonhospitalized patients.
      As there is no single ‘outbreak’ organism to target this scenario, it is more challenging for infection control teams than a classical outbreak. Moreover, it presents a greater recognition challenge to the microbiology laboratory; consequently, reliable and consistent application of SICPs is extremely important.

      9.1.4.3 Outbreaks due to Pseudomonas aeruginosa contamination of water systems

      Classical clonal outbreaks of hospital infection have a clear train of transmission if carriage is taken into account, and, assuming consistent application of contact precautions, can be controlled in a relatively short time if the strain(s) are not re-introduced.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      However, a different epidemiology is seen occasionally, particularly with P. aeruginosa (MDR or not), when a single clone or small number of clones causes infections in multiple patients in a unit or hospital, often without obvious links, over a prolonged period, sometimes extending over several years and with gaps of months between cases.
      • Crespo M.P.
      • Woodford N.
      • Sinclair A.
      • et al.
      Outbreak of carbapenem-resistant Pseudomonas aeruginosa producing VIM-8, a novel metallo-beta-lactamase, in a tertiary care center in Cali, Colombia.
      • Loveday H.P.
      • Wilson J.A.
      • Kerr K.
      • Pitchers R.
      • Walker J.T.
      • Browne J.
      Association between healthcare water systems and Pseudomonas aeruginosa infections: a rapid systematic review.
      Such instances often reflect contamination of the hospital plumbing system by the pseudomonas clone(s), and control may require modification/assessment, including, for example, replacing sinks and toilets with easier-to-clean models less prone to splashback, educating staff to reduce blockages and inappropriate storage, reviewing cleaning protocols, and reducing shower flow rates to minimize flooding.
      • Breathnach A.S.
      • Cubbon M.D.
      • Karunaharan R.N.
      • Pope C.F.
      • Planche T.D.
      Multidrug-resistant Pseudomonas aeruginosa outbreaks in two hospitals: association with contaminated hospital waste-water systems.
      • Department of Health
      Pseudomonas aeruginosa – advice for augmented care units.

      9.1.4.4 Long-term care facilities and the spread of multi-drug-resistant Enterobacteriaceae

      Long-term care facilities are increasingly identified as reservoirs of antibiotic resistance, particularly for colonization. The data to support this view are considerable but are not based on systematic surveillance, except in France, where the incidence of ESBL-producing Enterobacteriaceae infection per 1000 days in long-term care facilities increased from 0.07 in 1996 to 0.28 in 2005. This largely reflected the proliferation of E. coli with CTX-M enzymes, which were later recognized as representatives of the international ST131 clone.
      • Nicolas-Chanoine M.H.
      • Jarlier V.
      Extended-spectrum beta-lactamases in long-term-care facilities.
      • Brisse S.
      • Diancourt L.
      • Laouénan C.
      • et al.
      Coli β Study Group
      Phylogenetic distribution of CTX-M- and non-extended-spectrum-β-lactamase-producing Escherichia coli isolates: group B2 isolates, except clone ST131, rarely produce CTX-M enzymes.
      Long-term care facilities range from establishments offering assisted living to largely independent residents through to those providing complex medical support.
      • Centers for Disease Control and Prevention
      Guidance for control of carbapenem-resistant Enterobacteriaceae.
      • Lievesley N.
      • Crosby G.
      • Bowman C.
      The changing role of care homes.
      This spectrum of care varies between countries, reflecting healthcare organization and cultural factors.
      • Frijters D.H.M.
      • van der Roest H.G.
      • Carpenter I.G.I.
      • et al.
      The calculation of quality indicators for long term care facilities in 8 countries (SHELTER project).
      • World Health Organization
      Key policy issues in long-term care.
      The distribution of incontinent and catheterized residents is likely to influence the transmission of Gram-negative bacteria, including those with multi-drug resistance. Variation may be very local; March et al. found that gut carriage of resistant bacteria varied across five subunits in one long-term care facility in Bolzano, Italy.
      • March A.
      • Aschbacher R.
      • Dhanji H.
      • et al.
      Colonization of residents and staff of a long-term-care facility and adjacent acute-care hospital geriatric unit by multiresistant bacteria.
      Overall, carriage was higher than in the hospital's geriatric unit, which perhaps had more knowledge and reliable application of infection prevention and control precautions (75% of 111 in long-term care facility vs 22% of 45 in geriatric unit). In contrast, Gruber et al. in Germany found higher carriage rates of MDR bacteria in geriatric units (32.6%) than in nursing homes (18.5%) or ambulatory care (15.6%).
      • Gruber I.
      • Heudorf U.
      • Werner G.
      • et al.
      Multidrug-resistant bacteria in geriatric clinics, nursing homes, and ambulant care – prevalence and risk factors.
      While most resistance studies on long-term care facilities relate to those caring for the elderly, spread of carbapenemase producers as gut colonizers has also been recorded in a care home for children and young adults with neurodevelopmental problems.
      • Viau R.A.
      • Hujer A.M.
      • Marshall S.H.
      • et al.
      ‘Silent’ dissemination of Klebsiella pneumoniae isolates bearing K. pneumoniae carbapenemase in a long-term care facility for children and young adults in Northeast Ohio.
      The literature supporting the view that long-term care facilities constitute a reservoir of multi-drug resistance comprises, firstly, numerous analyses showing that previous stay in a long-term care facility is a risk factor for later infections with MDR Gram-negative bacteria, including those with ESBLs and carbapenemases; and, secondly, multiple snapshot surveys showing frequent (although very variable) gut carriage of ESBL-producing E. coli and Klebsiella spp. among residents in long-term care facilities, including in Australia, Belgium, France, Germany, Israel, Japan, Malaysia, the UK, Italy and the USA where these enzymes have already proliferated in hospitals.
      • March A.
      • Aschbacher R.
      • Dhanji H.
      • et al.
      Colonization of residents and staff of a long-term-care facility and adjacent acute-care hospital geriatric unit by multiresistant bacteria.
      • Feldman N.
      • Adler A.
      • Molshatzki N.
      • et al.
      Gastrointestinal colonization by KPC-producing Klebsiella pneumoniae following hospital discharge: duration of carriage and risk factors for persistent carriage.
      • Mavroidi A.
      • Miriagou V.
      • Malli E.
      • et al.
      Emergence of Escherichia coli sequence type 410 (ST410) with KPC-2 β-lactamase.
      • Lin M.Y.
      • Lyles-Banks R.D.
      • Lolans K.
      • et al.
      Centers for Disease Control and Prevention Epicenters Program. The importance of long-term acute care hospitals in the regional epidemiology of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae.
      • Prabaker K.
      • Lin M.Y.
      • McNally M.
      • et al.
      Centers for Disease Control and Prevention Epicenters Program
      Transfer from high-acuity long-term care facilities is associated with carriage of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae: a multihospital study.
      • Aschbacher R.
      • Pagani L.
      • Doumith M.
      • et al.
      Metallo-β-lactamases among Enterobacteriaceae from routine samples in an Italian tertiary-care hospital and long-term care facilities during 2008.
      Accumulation of MDR Gram-negative bacteria in long-term care facilities probably reflects a combination of:
      • the frequent transfer into long-term care facilities of patients/residents who were initially colonized or infected in hospitals;
      • oro-faecal transfer within long-term care facilities, reflecting breakdowns of personal hygiene in populations with high rates of dementia and incontinence;
      • frequent antibiotic use and its contingent selection pressure on the gut flora; and
      • high rates of urinary tract catheterization.
      Only one sizeable UK study of the carriage of MDR Gram-negative bacteria by nursing home residents has been published.
      • Rooney P.J.
      • O'Leary M.C.
      • Loughrey A.C.
      • et al.
      Nursing homes as a reservoir of extended-spectrum beta-lactamase (ESBL)-producing ciprofloxacin-resistant Escherichia coli.
      This was conducted in Belfast from 2004 to 2006, early in the national dissemination of E. coli with CTX-M ESBLs. This study included 16 long-term care facilities, and found E. coli that were both ciprofloxacin-resistant and produced ESBLs in faeces from 119 of 294 residents (40.5%). This was a 40-fold higher carriage rate than for diarrhoeal samples from community patients. Virtually all (99%) of these MDR isolates were ST131 variants; half belonged to the CTX-M-15-positive ‘strain A’ variant that is common elsewhere in the UK.
      • Dhanji H.
      • Doumith M.
      • Rooney P.J.
      • et al.
      Molecular epidemiology of fluoroquinolone-resistant ST131 Escherichia coli producing CTX-M extended-spectrum beta-lactamases in nursing homes in Belfast, UK.
      • Doumith M.
      • Dhanji H.
      • Ellington M.J.
      • Hawkey P.
      • Woodford N.
      Characterization of plasmids encoding extended-spectrum β-lactamases and their addiction systems circulating among Escherichia coli clinical isolates in the UK.
      Two small (six- and 12-bed) long-term care facilities had no colonized residents, and others had up to 75% (18/24) colonized residents, with considerable diversity among the ST131 variants at many sites. Fluoroquinolone use and a history of urinary tract infection were independently associated with carriage in a multi-variate model.
      • Rooney P.J.
      • O'Leary M.C.
      • Loughrey A.C.
      • et al.
      Nursing homes as a reservoir of extended-spectrum beta-lactamase (ESBL)-producing ciprofloxacin-resistant Escherichia coli.
      Duration of nursing home residency did not correlate with increased likelihood of carriage, although it seems likely that carriers commonly acquire their organism within their long-term care facilities.

      9.1.5 Multi-drug resistance in the community

      Multi-drug resistance remains uncommon among true community-acquired infections in the UK, and few studies have correlated resistance in clinical infections and faecal carriage in these cases. Nevertheless, stool carriage of ESBL-producing faecal E. coli was found in 11.3% of patients in Birmingham, rising to 22.8% in those with surnames suggesting a Middle Eastern or South Asian patrimony compared with 8.1% among names suggesting European patrimony. This differential perhaps reflects frequent travel to parts of the world where ESBLs are common outside the hospital setting.
      • Wickramasinghe N.H.
      • Xu L.
      • Eustace A.
      • Shabir S.
      • Saluja T.
      • Hawkey P.M.
      High community faecal carriage rates of CTX-M ESBL-producing Escherichia coli in a specific population group in Birmingham, UK.
      A few references specifically indicated travel to South or East Asia as a risk factor for acquisition of ESBL-producing E. coli in faeces. Carriage is often persistent and, in Canada, prior travel to a country with a high prevalence of ESBL-producing E. coli was identified as a risk factor for subsequent urinary infection with these organisms, typically with the particular ESBL type prevalent in the country visited.
      • Pitout J.D.
      • Campbell L.
      • Church D.L.
      • Gregson D.B.
      • Laupland K.B.
      Molecular characteristics of travel-related extended-spectrum-beta-lactamase-producing Escherichia coli isolates from the Calgary Health Region.
      Most cases of infection or colonization by carbapenemase-producing Enterobacteriaceae and non-fermenters occur in hospital and healthcare settings, at least in Europe and North America.
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      • Gupta N.
      • Limbago B.M.
      • Patel J.B.
      • Kallen A.J.
      Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention.
      • Canton R.
      • Akova M.
      • Carmeli Y.
      • et al.
      Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe.
      • Higgins P.G.
      • Dammhayn C.
      • Hackel M.
      • Seifert H.
      Global spread of carbapenem-resistant Acinetobacter baumannii.
      However, in areas of high prevalence, particularly parts of the Indian subcontinent, it seems that a large reservoir of community carriers of carbapenemase-producing Enterobacteriaceae has been established, which likely eclipses the hospital-based reservoir in terms of numbers, but not risk.
      • Day K.M.
      • Ali S.
      • Mirza I.A.
      • et al.
      Prevalence and molecular characterization of Enterobacteriaceae producing NDM-1 carbapenemase at a military hospital in Pakistan and evaluation of two chromogenic media.
      • Perry J.D.
      • Naqvi S.H.
      • Mirza I.A.
      • et al.
      Prevalence of faecal carriage of Enterobacteriaceae with NDM-1 carbapenemase at military hospitals in Pakistan, and evaluation of two chromogenic media.
      MDR P. aeruginosa and other non-fermenters are an important problem in patients with cystic fibrosis, who also span the hospital/community divide. There is a growing prevalence of high-risk clones, such as the Liverpool epidemic P. aeruginosa strain.
      • Aaron S.D.
      • Vandemheen K.L.
      • Ramotar K.
      • et al.
      Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis.
      Cross-infection occurs
      • Fothergill J.L.
      • Walshaw M.J.
      • Winstanley C.
      Transmissible strains of Pseudomonas aeruginosa in cystic fibrosis lung infections.
      and can be interrupted by segregation of colonized and non-colonized patients with cystic fibrosis.
      • Ashish A.
      • Shaw M.
      • Winstanley C.
      • Humphreys L.
      • Walshaw M.J.
      Halting the spread of epidemic Pseudomonas aeruginosa in an adult cystic fibrosis centre: a prospective cohort study.
      Resistance is often extensive but evolves very variably in the individual patient, and there is no specific resistance pattern associated with any of the successful cystic fibrosis lineages.
      • Ashish A.
      • Paterson S.
      • Mowat E.
      • Fothergill J.L.
      • Walshaw M.J.
      • Winstanley C.
      Extensive diversification is a common feature of Pseudomonas aeruginosa populations during respiratory infections in cystic fibrosis.

      9.1.6 What is the role of agricultural use of sewage and antibiotic treatment in veterinary practice in spreading extended-spectrum β-lactamases?

      Gut E. coli are ubiquitous in mammals, and MDR strains are reported repeatedly in both food and companion animals.
      • Ewers C.
      • Bethe A.
      • Semmler T.
      • Guenther S.
      • Wieler L.H.
      Extended-spectrum β-lactamase-producing and AmpC-producing Escherichia coli from livestock and companion animals, and their putative impact on public health: a global perspective.
      Johnson et al. demonstrated that the same ESBL-producing E. coli strains can be shared among household members and their pet dog, although the direction of transmission is uncertain.
      • Johnson J.R.
      • Clabots C.
      • Kuskowski M.A.
      Multiple-host sharing, long-term persistence, and virulence of Escherichia coli clones from human and animal household members.
      Transmission of resistant E. coli down the food chain can occur. At a population level, fluoroquinolone-resistant E. coli from chickens and humans were reportedly more similar than fluoroquinolone-resistant and -susceptible E. coli from humans.
      • Warren R.E.
      • Ensor V.M.
      • O'Neill P.M.
      • et al.
      Imported chicken meat as a potential source of quinolone-resistant Escherichia coli producing extended-spectrum beta-lactamases in the UK.
      However, sequence typing needs to be examined. In the Netherlands, the same E. coli strains, plasmids and ESBL genes (blaCTX-M-1 and blaTEM-52) were found in humans, broilers and retail chicken meat.
      • Leverstein-van Hall M.A.
      • Dierikx C.M.
      • Cohen Stuart J.
      • et al.
      National ESBL surveillance group. Dutch patients, retail chicken meat and poultry share the same ESBL genes, plasmids and strains.
      However, the ESBLs in retail chicken meat in the UK are predominantly CTX-2 or -14-like,
      • Randall L.P.
      • Clouting C.
      • Horton R.A.
      • et al.
      Prevalence of Escherichia coli carrying extended-spectrum beta-lactamases (CTX-M and TEM52) from broiler chickens and turkeys in Great Britain between 2006 and 2009.
      • Dhanji H.
      • Murphy N.M.
      • Doumith M.
      • et al.
      Cephalosporin resistance mechanisms in Escherichia coli from raw chicken imported into the UK.
      and their host strains are non-clonal, whereas clonal ST131 E. coli with CTX-M-15 enzyme predominates among human ESBL isolates and is very rare in chicken meat.
      Recently, a large UK, German and Dutch study found that only 1.2% of ESBL-producing E. coli from food animals resembled human ESBL-producing isolates. The authors concluded that human-to-human faecal-oral or plasmid transmission was considerably more important than food chain transmission, but noted that food animals represent a reservoir (and evolution site) for resistant strains that may pose future challenges in humans.
      • Wu G.
      • Day M.J.
      • Mafura M.T.
      • et al.
      Comparative analysis of ESBL-positive Escherichia coli isolates from animals and humans from the UK, The Netherlands and Germany.

      9.1.7 What insights have national Escherichia coli bacteraemia surveillance provided?

      Bacteraemias caused by E. coli result from a variety of aetiologies including pre-existing urinary tract infection, indwelling urinary catheters and biliary-related infection. In sentinel surveillance undertaken by PHE, most cases arose in elderly patients in the community who had visited their general practitioner at least once in the preceding weeks with urinary tract infection, suggesting that co-morbidity or treatment failure may be a significant factor.
      • Kiernan M.
      ARHAI E. coli Subgroup final report.
      One-third of patients with bacteraemia had received antibiotics for genitourinary infection in the preceding four weeks, but the adequacy of treatment was not known. There is a notable rise in incidence in the summer for all Gram-negative bacteraemias,
      • Freeman J.T.
      • Anderson D.J.
      • Sexton D.J.
      Seasonal peaks in Escherichia coli infections: possible explanations and implications.
      • Perencevich E.N.
      • McGregor J.C.
      • Shardell M.
      • et al.
      Summer peaks in the incidences of Gram-negative bacterial infection among hospitalized patients.
      • Al-Hasan M.N.
      • Lahr B.D.
      • Eckel-Passow J.E.
      • Baddour L.M.
      Seasonal variation in Escherichia coli bloodstream infection: a population-based study.
      • Wilson J.
      • Elgohari S.
      • Livermore D.M.
      • et al.
      Trends among pathogens reported as causing bacteraemia in England, 2004–2008.
      and a number of hypotheses are possible, including the role that hydration status in the elderly has to play in predisposition to infection. Reporting resistance data in E. coli bacteraemia helps in making local risk assessments on patients transferred from other hospitals.
      • Schwaber M.J.
      • Carmeli Y.
      An ongoing national intervention to contain the spread of carbapenem-resistant Enterobacteriaceae.

      9.1.8 Is there evidence for high-/low-risk areas within a healthcare facility?

      Sharing a room with a colonized patient and ICU admission are risk factors for acquisition of carbapenem-resistant organisms.
      • Lepelletier D.
      • Cady A.
      • Caroff N.
      • et al.
      Imipenem-resistant Pseudomonas aeruginosa gastrointestinal carriage among hospitalized patients: risk factors and resistance mechanisms.
      • Hussein K.
      • Sprecher H.
      • Mashiach T.
      • Oren I.
      • Kassis I.
      • Finkelstein R.
      Carbapenem resistance among Klebsiella pneumoniae isolates: risk factors, molecular characteristics, and susceptibility patterns.
      • Sheng W.H.
      • Liao C.H.
      • Lauderdale T.L.
      • et al.
      A multicenter study of risk factors and outcome of hospitalized patients with infections due to carbapenem-resistant Acinetobacter baumannii.
      A German point prevalence study of 56 hospitals in 2011 showed that, overall, prevalence of resistance was highest in ICUs (ESBL-producing E. coli 2.5% on ICU) and higher on medical wards compared with surgical wards,
      • Wegner C.
      • Hübner N.O.
      • Gleich S.
      • Thalmaier U.
      • Krüger C.M.
      • Kramer A.
      One-day point prevalence of emerging bacterial pathogens in a nationwide sample of 62 German hospitals in 2012 and comparison with the results of the one-day point prevalence of 2010.
      as also seen in a UK study.
      • Moore L.S.
      • Freeman R.
      • Gilchrist M.J.
      • et al.
      Homogeneity of antimicrobial policy, yet heterogeneity of antimicrobial resistance: antimicrobial non-susceptibility among 108 717 clinical isolates from primary, secondary and tertiary care patients in London.
      A European survey of 19,888 patients, mainly in Belgium and France, showed the highest prevalence of healthcare-acquired infection in ICUs (28.1%).
      • Zarb P.
      • Coignard B.
      • Griskeviciene J.
      • et al.
      National Contact Points for the ECDC pilot point prevalence survey; Hospital Contact Points for the ECDC pilot point prevalence survey
      The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcare-associated infections and antimicrobial use.
      Long-term care facilities report high prevalence of colonization with MDR Gram-negative bacteria in residents compared with acute hospitals, associated with prolonged stay, antimicrobial treatment and faecal incontinence.
      • O'Fallon E.
      • Schreiber R.
      • Kandel R.
      • D'Agata E.M.
      Multidrug-resistant Gram-negative bacteria at a long-term care facility: assessment of residents, healthcare workers, and inanimate surfaces.
      • Endimiani A.
      • Depasquale J.M.
      • Forero S.
      • et al.
      Emergence of blaKPC-containing Klebsiella pneumoniae in a long-term acute care hospital: a new challenge to our healthcare system.
      In one series of carbapenem-resistant Acinetobacter and Klebsiella isolates, over half were obtained from patients admitted from long-term acute care facilities.
      • Perez F.
      • Endimiani A.
      • Ray A.J.
      • et al.
      Carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae across a hospital system: impact of post-acute care facilities on dissemination.
      Evidence
      ICUs in acute hospitals and any long-term care facilities have higher prevalence of MDR Gram-negative bacteria than general wards.2+
      Recommendation
      Patients at high risk for colonization or infection with carbapenem-resistant organisms include those admitted to ICUs and from long-term care facilities (e.g. care homes).Conditional

      9.2 Is there evidence of differences between organisms in respect of transmission, morbidity and mortality?

      9.2.1 Resistant Enterobacteriaceae

      Enterobacteriaceae are part of the gastrointestinal flora of humans and animals, and some are readily transmitted, particularly in the healthcare setting (Table III). It remains unclear why the E. coli ST131 lineage has been so successful compared with many other ESBL-producing strains.
      • Nicolas-Chanoine M.H.
      • Bertrand X.
      • Madec J.Y.
      Escherichia coli ST131, an intriguing clonal group.
      Transmission from patient to patient is believed to be mainly via hands of staff, although common environmental sources have occasionally been described and should be sought where no other plausible vectors can be found (e.g. ventilator equipment or water supply).
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      • Breathnach A.S.
      • Cubbon M.D.
      • Karunaharan R.N.
      • Pope C.F.
      • Planche T.D.
      Multidrug-resistant Pseudomonas aeruginosa outbreaks in two hospitals: association with contaminated hospital waste-water systems.
      • Wang S.A.
      • Levine R.B.
      • Carson L.A.
      • et al.
      An outbreak of Gram-negative bacteremia in hemodialysis patients traced to hemodialysis machine waste drain ports.
      • Bancroft E.A.
      • English L.
      • Terashita D.
      • Yasuda L.
      Outbreak of Escherichia coli infections associated with a contaminated transesophageal echocardiography probe.
      Infection prevention and control relies on the consistent application of SICPs (e.g. hand hygiene, appropriate use of personal protective equipment, and ensuring a clean and well-maintained care environment). Patient screening, used as part of a bundle of infection prevention and control measures, is effective for identifying carriage of ESBLs by E. coli, K. pneumoniae and Enterobacter spp.
      • Soulier A.
      • Barbut F.
      • Ollivier J.M.
      • Petit J.C.
      • Lienhart A.
      Decreased transmission of Enterobacteriaceae with extended-spectrum beta-lactamases in an intensive care unit by nursing reorganization.
      • van der Zwet W.C.
      • van Riessen N.
      • Bergervoet P.W.
      • van der Laan J.R.
      • Savelkoul P.H.
      • Sebens F.W.
      Outbreak of multiresistant Escherichia coli on a surgical ward: course, measures and consequences for future admissions of contaminated patients.
      • Warren R.E.
      • Harvey G.
      • Carr R.
      • Ward D.
      • Doroshenko A.
      Control of infections due to extended-spectrum beta-lactamase-producing organisms in hospitals and the community.
      Table IIIDissecting the epidemiology of multi-drug-resistant (MDR) Gram-negative rods
      Resistant EnterobacteriaceaeMDR non-fermenters
      AmpC, ESBLCPEAcinetobacter baumannii
      From a taxonomic viewpoint, four species are virtually indistinguishable (A. baumannii, Acinetobacter calcoaceticus, genomic species 3 and genomic species 13TU) so are grouped together as ‘A. calcoaceticus–A. baumannii complex’; however, A. baumannii is by far the most important human pathogen in this group. However, as methods commonly used to speciate Acinetobacter spp. in the clinical laboratory are unable to distinguish these species, the relative contribution of each to the burden of human disease is difficult to establish.
      Pseudomonas aeruginosaStenotrophomonas maltophilia
      MicrobiologyFermentative, oxidase-negative, motile or non-motile, facultatively anaerobic, rodsNon-fermentative, oxidase-negative, non-motile, obligate aerobic, coccobacilli
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      Non-fermentative, oxidase-positive, motile, aerobic, rods
      • Lister P.D.
      • Wolter D.J.
      • Hanson N.D.
      Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms.
      Non-fermentative,
      Recent data indicate that the ‘non-fermentative’ status of S. maltophilia should be re-assessed.
      ,
      • Carmody L.A.
      • Spilker T.
      • LiPuma J.J.
      Reassessment of Stenotrophomonas maltophilia phenotype.
      motile, oxidase +/−, obligate aerobic, rods
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      ReservoirsHuman and animal gastrointestinal tract, waterRespiratory and gastrointestinal tract, dry surfaces
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      Ubiquitous: plants, animals, moist environments
      • Lister P.D.
      • Wolter D.J.
      • Hanson N.D.
      Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms.
      Ubiquitous: plants, animals, humans, moist environments
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      Sites of colonizationGastrointestinal tract
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      Skin, respiratory and gastrointestinal tract
      • Apisarnthanarak A.
      • Warren D.K.
      Screening for carbapenem-resistant Acinetobacter baumannii colonization sites: an implication for combination of horizontal and vertical approaches.
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      • Medina-Presentado J.C.
      • Seija V.
      • Vignoli R.
      • et al.
      Polyclonal endemicity of Acinetobacter baumannii in ventilated patients in an intensive care unit in Uruguay.
      Gastrointestinal tract, moist body sites (throat, nasal mucosa, axillary skin, perineum)
      • Paterson D.L.
      The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
      Respiratory and gastrointestinal tract
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      • Apisarnthanarak A.
      • Fraser V.J.
      • Dunne W.M.
      • et al.
      Stenotrophomonas maltophilia intestinal colonization in hospitalized oncology patients with diarrhea.
      Duration of colonizationMonths to more than one year
      • Strenger V.
      • Feierl G.
      • Resch B.
      • et al.
      Fecal carriage and intrafamilial spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae following colonization at the neonatal ICU.
      • Apisarnthanarak A.
      • Bailey T.C.
      • Fraser V.J.
      Duration of stool colonization in patients infected with extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.
      • Haverkate M.
      • Dautzenberg M.
      • Ossewaarde T.
      • et al.
      Within-host and population transmission of OXA-48.
      Days to weeks
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      Clinical manifestationUrinary tract (e.g. E. coli), pneumonia (e.g. K. pneumoniae and Enterobacter spp.), intra-abdominal infection
      • Paterson D.L.
      The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
      • Peleg A.Y.
      • Hooper D.C.
      Hospital-acquired infections due to Gram-negative bacteria.
      Ventilator-associated pneumonia, catheter-related bloodstream and urinary tract infections, wound infections
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      Pneumonia, urinary tract, surgical site, bloodstream infections, cystic fibrosis lung, burns
      • Lister P.D.
      • Wolter D.J.
      • Hanson N.D.
      Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms.
      Pneumonia, bloodstream infections; less commonly, urinary tract and wound infections
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      Environmental survivalHours to weeks on dry surfaces;
      • Kramer A.
      • Schwebke I.
      • Kampf G.
      How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.
      contaminated environment likely to play a minor role in transmission
      • Nseir S.
      • Blazejewski C.
      • Lubret R.
      • Wallet F.
      • Courcol R.
      • Durocher A.
      Risk of acquiring multidrug-resistant Gram-negative bacilli from prior room occupants in the intensive care unit.
      • Ajao A.O.
      • Johnson J.K.
      • Harris A.D.
      • et al.
      Risk of acquiring extended-spectrum beta-lactamase-producing Klebsiella species and Escherichia coli from prior room occupants in the intensive care unit.
      Weeks to months on dry surfaces;
      • Kramer A.
      • Schwebke I.
      • Kampf G.
      How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.
      • Wagenvoort J.H.
      • Joosten E.J.
      An outbreak of Acinetobacter baumannii that mimics MRSA in its environmental longevity.
      difficult to remove from surfaces by cleaning and disinfection
      • Denton M.
      • Wilcox M.H.
      • Parnell P.
      • et al.
      Role of environmental cleaning in controlling an outbreak of Acinetobacter baumannii on a neurosurgical intensive care unit.
      • Manian F.A.
      • Griesenauer S.
      • Senkel D.
      • et al.
      Isolation of Acinetobacter baumannii complex and methicillin-resistant Staphylococcus aureus from hospital rooms following terminal cleaning and disinfection: can we do better?.
      Contaminates moist hospital environments: tap aerators, respiratory therapy equipment
      • Paterson D.L.
      The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
      Contaminates moist hospital environments; can form biofilms on surfaces; low biocide susceptibility
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      Transmission routesHands (++), contaminated surfaces (+/−)
      • Palmore T.N.
      • Henderson D.K.
      Managing transmission of carbapenem-resistant Enterobacteriaceae in healthcare settings: a view from the trenches.
      Contaminated surfaces (++), hands (+), air (+/−)
      • Munoz-Price L.S.
      • Fajardo-Aquino Y.
      • Arheart K.L.
      • et al.
      Aerosolization of Acinetobacter baumannii in a trauma ICU.
      • Nseir S.
      • Blazejewski C.
      • Lubret R.
      • Wallet F.
      • Courcol R.
      • Durocher A.
      Risk of acquiring multidrug-resistant Gram-negative bacilli from prior room occupants in the intensive care unit.
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      Hands (+), contaminated moist surfaces (+), air (+/−), water systems
      • Paterson D.L.
      The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
      • Wainwright C.E.
      • France M.W.
      • O'Rourke P.
      • et al.
      Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis.
      Hands (+), contaminated moist surfaces (+), air (+/−)
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Wainwright C.E.
      • France M.W.
      • O'Rourke P.
      • et al.
      Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis.
      Antimicrobial resistance – intrinsicAmpicillin, first- and second-generation cephalosporins.
      • Magiorakos A.P.
      • Srinivasan A.
      • Carey R.B.
      • et al.
      Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.
      Serratia and Proteeae spp. are intrinsically resistant to polymyxins
      Ampicillin, amoxicillin-clavulanate, cefazolin, cefotaxime, ceftriaxone, ertapenem, trimethoprim, fosfomycin
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      Some β-lactams and fluoroquinolones, macrolides, tetracyclines, cotrimoxazole
      • Driscoll J.A.
      • Brody S.L.
      • Kollef M.H.
      The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections.
      Most agents except cotrimoxazole
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      Antimicrobial resistance – acquiredPenicillins (except temocillin), ESBLs, carbapenems (through mechanisms other than more common acquired carbapenemases), aminoglycosides, sulphonamides, quinolones
      • Magiorakos A.P.
      • Srinivasan A.
      • Carey R.B.
      • et al.
      Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.
      • Paterson D.L.
      Resistance in Gram-negative bacteria: Enterobacteriaceae.
      Most or all β-lactams, carbapenems, polymyxins (rarely) (exact profile depends on particular carbapenemase and any co-produced ESBL)
      • Munoz-Price L.S.
      • Fajardo-Aquino Y.
      • Arheart K.L.
      • et al.
      Aerosolization of Acinetobacter baumannii in a trauma ICU.
      • Bogdanovich T.
      • Adams-Haduch J.M.
      • Tian G.B.
      • et al.
      Colistin-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the international epidemic clone ST258.
      Quinolones, aminoglycosides, β-lactams (including carbapenems), polymyxins, tigecycline
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      • Diancourt L.
      • Passet V.
      • Nemec A.
      • Dijkshoorn L.
      • Brisse S.
      The population structure of Acinetobacter baumannii: expanding multiresistant clones from an ancestral susceptible genetic pool.
      Aminoglycosides, β-lactams (including carbapenems), monobactams, fluoroquinolones, polymyxins
      • Driscoll J.A.
      • Brody S.L.
      • Kollef M.H.
      The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections.
      Trimethoprim/sulfamethoxazole
      Common acquired resistance enzymesAmpC (intrinsic in Enterobacter), ESBLs (TEM, SHV, CTX-M), various aminoglycoside-modifying enzymesCarbapenemases (KPC, VIM, IMP, NDM)
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      Various aminoglycoside-modifying enzymes or ribosomal methyltransferase, class-D OXA type carbapenemases
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      • Peleg A.Y.
      • Seifert H.
      • Paterson D.L.
      Acinetobacter baumannii: emergence of a successful pathogen.
      Metallo-β-lactamases (VIM and IMP)
      • Driscoll J.A.
      • Brody S.L.
      • Kollef M.H.
      The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections.
      sul genes (resistance to sulphonamide)
      Mortality (bacteraemia)Moderate/substantial increase in attributable mortality
      • Peleg A.Y.
      • Hooper D.C.
      Hospital-acquired infections due to Gram-negative bacteria.
      • Shorr A.F.
      Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit.
      Stark increase in attributable mortality
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      • Snitkin E.S.
      • Zelazny A.M.
      • Thomas P.J.
      • et al.
      Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing.
      • Patel G.
      • Huprikar S.
      • Factor S.H.
      • Jenkins S.G.
      • Calfee D.P.
      Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies.
      Minimal increase in attributable mortality
      • Shorr A.F.
      Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit.
      Moderate/substantial increase in attributable mortality depending on type of infection
      • Shorr A.F.
      Review of studies of the impact on Gram-negative bacterial resistance on outcomes in the intensive care unit.
      • Hirsch E.B.
      • Tam V.H.
      Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes.
      Minimal increase in attributable mortality
      • Falagas M.E.
      • Kastoris A.C.
      • Vouloumanou E.K.
      • Rafailidis P.I.
      • Kapaskelis A.M.
      • Dimopoulos G.
      Attributable mortality of Stenotrophomonas maltophilia infections: a systematic review of the literature.
      Risk factorsHospital: prolonged hospital stay, prior hospitalization, previous use of antibiotics, presence of indwelling catheters, mechanical ventilation

      Community: older age, recurrent urinary tract infections/prior invasive procedures (e.g. catheterization), known faecal carriage, contact with healthcare facilities, antimicrobial treatment
      • Joint Working Group of DARC and ARHAI, 2012
      ESBLs – a threat to human and animal health?.
      Prior antimicrobial use, length of stay, severity of illness, mechanical ventilation, admission to ICU, high procedure score, presence of wounds, positive culture from a blood isolate, transfer between hospital units within the same hospital, prior surgery, prior hospital stay, proximity to other colonized/infected patients, presence of a biliary catheter and recent transplantation.
      • European Centre for Disease Control and Prevention
      Risk assessment on the spread of carbapenemase-producing Enterobacteriaceae (CPE) through patient transfer between healthcare facilities, with special emphasis on cross-border transfer.
      For NDM, prior hospitalization on Indian subcontinent; for OXA-48, prior hospitalization in Middle East
      (i) Major trauma, particularly burns, surgery and battlefield injury; (ii) previous antimicrobial therapy; (iii) prolonged hospital and ICU stay; (iv) mechanical ventilation, drainage tubes and indwelling catheters; (v) high prevalence of MDR Acinetobacter spp. on the unit; (vi) proximity to other colonized/infected patients
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      • Peleg A.Y.
      • Seifert H.
      • Paterson D.L.
      Acinetobacter baumannii: emergence of a successful pathogen.
      (i) Prior use of antibiotics; (ii) mechanical ventilation; (iii) prolonged hospital and ICU stay; (iv) co-morbidities (e.g. cystic fibrosis, burns units)
      • Hirsch E.B.
      • Tam V.H.
      Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes.
      • Falagas M.E.
      • Kopterides P.
      Risk factors for the isolation of multi-drug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa: a systematic review of the literature.
      Severely compromised health status, malignancy, indwelling devices (such as intravascular catheters and ventilation tubes), exposure to broad-spectrum antimicrobials, long hospital stay, ICU stay
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      At-risk populationPatients in acute, long-term and community settings; patients travelling to areas of high prevalence
      • Gupta N.
      • Limbago B.M.
      • Patel J.B.
      • Kallen A.J.
      Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention.
      Patients in acute settings, particularly those with recent travel to areas of high prevalence
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      • Ahmed-Bentley J.
      • Chandran A.U.
      • Joffe A.M.
      • French D.
      • Peirano G.
      • Pitout J.D.
      Gram-negative bacteria that produce carbapenemases causing death attributed to recent foreign hospitalization.
      Immunocompromised patients in the ICU and burns units;
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      rare cause of community-acquired infection
      • Dijkshoorn L.
      • Nemec A.
      • Seifert H.
      An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii.
      • Eveillard M.
      • Kempf M.
      • Belmonte O.
      • Pailhories H.
      • Joly-Guillou M.L.
      Reservoirs of Acinetobacter baumannii outside the hospital and potential involvement in emerging human community-acquired infections.
      Immunocompromised patients in the ICU and burns units; patients with cystic fibrosis;
      • Driscoll J.A.
      • Brody S.L.
      • Kollef M.H.
      The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections.
      rare cause of community-acquired infection
      • Paterson D.L.
      The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
      Immunocompromised patients in the ICU; patients with cancer and cystic fibrosis; rare cause of community-acquired infection
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Safdar A.
      • Rolston K.V.
      Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer.
      Common international clonesE. coli ST131 with CTX-M ESBLs
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      K. pneumoniae ST258 with KPC enzymes
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      • Munoz-Price L.S.
      • Poirel L.
      • Bonomo R.A.
      • et al.
      Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
      International clones I–III
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      • Karah N.
      • Sundsfjord A.
      • Towner K.
      • Samuelsen O.
      Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii.
      Clonal diversity.
      • Woodford N.
      • Turton J.F.
      • Livermore D.M.
      Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance.
      A few international high-risk clones [e.g. ST111 (serotype O12)] acquire multi-drug resistance; spread of ST235 with VIM carbapenemase in Russia, Belarus and Kazakhstan
      Clonal diversity
      • Brooke J.S.
      Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.
      • Looney W.J.
      • Narita M.
      • Muhlemann K.
      Stenotrophomonas maltophilia: an emerging opportunist human pathogen.
      KPC, Klebsiella pneumoniae carbapenemase; E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae; ESBL, extended-spectrum β-lactamase; CPE, carbapenem-producing Enterobacteriaceae; ICU, intensive care unit.
      a From a taxonomic viewpoint, four species are virtually indistinguishable (A. baumannii, Acinetobacter calcoaceticus, genomic species 3 and genomic species 13TU) so are grouped together as ‘A. calcoaceticus–A. baumannii complex’; however, A. baumannii is by far the most important human pathogen in this group. However, as methods commonly used to speciate Acinetobacter spp. in the clinical laboratory are unable to distinguish these species, the relative contribution of each to the burden of human disease is difficult to establish.
      b Recent data indicate that the ‘non-fermentative’ status of S. maltophilia should be re-assessed.
      For colonization or infection with ESBL-producing bacteria, the presence of a gastrostomy, urinary catheter or nasogastric tube were risk factors.
      • Ena J.
      • Arjona F.
      • Martinez P.C.
      • Lopez-Perezagua M.D.
      • Amador C.
      Epidemiology of urinary infections caused by extended-spectrum beta-lactamase-producing Escherichia coli.
      • Wiener J.
      • Quinn J.P.
      • Bradford P.A.
      • et al.
      Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes.
      • Peña C.
      • Gudiol C.
      • Tubau F.
      • et al.
      Risk-factors for acquisition of extended-spectrum beta-lactamase-producing Escherichia coli among hospitalised patients.
      Antibiotic treatment has been shown to select for ESBL-producing E. coli in a variety of healthcare settings.
      • Siedelman L.
      • Kline S.
      • Duval S.
      Risk factors for community- and health facility-acquired extended-spectrum-lactamase-producing bacterial infections in patients at the University of Minnesota Medical Center, Fairview.
      For some strains, piperacillin-tazobactam can select for quinolone-resistant bacteria that produce CTX-M,
      • Han J.H.
      • Kasahara K.
      • Edelstein P.H.
      • Bilker W.B.
      • Lautenbach E.
      Risk factors for infection or colonization with CTX-M extended-spectrum-lactamase-positive Escherichia coli.
      and carbapenem use is associated with acquisition of carbapenem-resistant E. coli.
      • Jeon M.H.
      • Choi S.H.
      • Kwak Y.G.
      • et al.
      Risk factors for the acquisition of carbapenem-resistant Escherichia coli among hospitalized patients.
      Screening for carriers with subsequent isolation of those identified is effective in preventing transmission, and is important for early recognition.
      • Mitchell S.L.
      • Shaffer M.L.
      • Loeb M.B.
      • et al.
      Infection management and multidrug-resistant organisms in nursing home residents with advanced dementia.
      Awareness of carriage is important and, therefore, communications regarding those identified to be infected or colonized with MDR strains is essential when transferring patients within and between institutions.

      9.2.2 Acinetobacter baumannii

      Infection control precautions against A. baumannii have been adapted following experience with outbreaks, and generally address the organism's major epidemic modes of transmission and the excessive use of broad-spectrum antibiotics (Table III). Control can sometimes be achieved when a common source is identified and eliminated.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      • Fournier P.E.
      • Richet H.
      The epidemiology and control of Acinetobacter baumannii in health care facilities.
      A review of 51 hospital outbreaks showed that 25 had common sources. Of these, 13 outbreaks were predominantly respiratory tract infections, and 12 were predominantly bloodstream or other infections. They were controlled by removal or disinfection and sterilization of contaminated ventilator (or related) equipment or contaminated moist fomites.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      When neither common sources nor environmental reservoirs are identified, control has depended on surveillance and isolation of colonized and infected patients, along with promoting improvements in the hand hygiene practices of healthcare workers,
      • Roberts S.A.
      • Findlay R.
      • Lang S.D.
      Investigation of an outbreak of multi-drug resistant Acinetobacter baumannii in an intensive care burns unit.
      and ensuring the aseptic care of vascular catheters and endotracheal tubes.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      Increased cleaning of the general care environment has been the next most common outbreak intervention,
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      reflecting the concern that Acinetobacter spp. can survive for months on wet or dry surfaces, thereby facilitating nosocomial transmission.
      • Wendt C.
      • Dietze B.
      • Dietz E.
      • Rüden H.
      Survival of Acinetobacter baumannii on dry surfaces.
      Disinfection regimens used on surfaces include 0.1% hypochlorite
      • Denton M.
      • Wilcox M.H.
      • Parnell P.
      • et al.
      Role of environmental cleaning in controlling an outbreak of Acinetobacter baumannii on a neurosurgical intensive care unit.
      • Enoch D.A.
      • Summers C.
      • Brown N.M.
      • et al.
      Investigation and management of an outbreak of multidrug-carbapenem-resistant Acinetobacter baumannii in Cambridge, UK.
      and, increasingly, hydrogen peroxide vapour.
      • Ray A.
      • Perez F.
      • Beltramini A.M.
      • et al.
      Use of vaporized hydrogen peroxide decontamination during an outbreak of multidrug-resistant Acinetobacter baumannii infection at a long-term acute care hospital.
      • Manian F.A.
      • Griesenauer S.
      • Senkel D.
      • et al.
      Isolation of Acinetobacter baumannii complex and methicillin-resistant Staphylococcus aureus from hospital rooms following terminal cleaning and disinfection: can we do better?.
      • Landelle C.
      • Legrand P.
      • Lesprit P.
      • et al.
      Protracted outbreak of multidrug-resistant Acinetobacter baumannii after intercontinental transfer of colonised patients.
      • Chmielarczyk A.
      • Higgins P.G.
      • Wojkowska-Mach J.
      • et al.
      Control of an outbreak of Acinetobacter baumannii infections using vaporized hydrogen peroxide.
      • Barbut F.
      • Yezli S.
      • Mimoun M.
      • Pham J.
      • Chaouat M.
      • Otter J.A.
      Reducing the spread of Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus on a burns unit through the intervention of an infection control bundle.
      Patient screening has been suggested in a number of studies.
      • Enoch D.A.
      • Summers C.
      • Brown N.M.
      • et al.
      Investigation and management of an outbreak of multidrug-carbapenem-resistant Acinetobacter baumannii in Cambridge, UK.
      • Ayats J.
      • Corbella X.
      • Ardanuy C.
      • et al.
      Epidemiological significance of cutaneous, pharyngeal, and digestive tract colonization by multiresistant Acinetobacter baumannii in ICU patients.
      • Valencia R.
      • Arroyo L.A.
      • Conde M.
      • et al.
      Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii in a tertiary care university hospital.
      Several studies also advocate reduced prescribing of broad-spectrum antibiotics, such as fluoroquinolones or carbapenems.
      • Villegas M.V.
      • Hartstein A.I.
      Acinetobacter outbreaks, 1977–2000.
      • Corbella X.
      • Montero A.
      • Pujol M.
      • et al.
      Emergence and rapid spread of carbapenem resistance during a large and sustained hospital outbreak of multiresistant Acinetobacter baumannii.
      Antibiotic exposure is often a risk factor for an outbreak; however, the use of multiple interventions and historical controls complicates interpretation of these studies. Patient decolonization by skin cleansing with chlorhexidine or the use of polymyxin on wounds, orally or by inhaled aerosol, has been an occasional adjunctive control measure but may be a risk for development of resistance.
      • Urban C.
      • Segal-Maurer S.
      • Rahal J.J.
      Considerations in control and treatment of nosocomial infections due to multidrug-resistant Acinetobacter baumannii.
      • Otter J.A.
      • Patel A.
      • Cliff P.R.
      • Halligan E.P.
      • Tosas O.
      • Edgeworth J.D.
      Selection for qacA carriage in CC22, but not CC30, methicillin-resistant Staphylococcus aureus bloodstream infection isolates during a successful institutional infection control programme.
      • Suwantarat N.
      • Carroll K.C.
      • Tekle T.
      • et al.
      High prevalence of reduced chlorhexidine susceptibility in organisms causing central line-associated bloodstream infections.
      Often, the use of a multi-factorial or ‘bundle’ approach is the most effective way of controlling this organism.
      • Rodríguez-Baño J.
      • García L.
      • Ramírez E.
      • et al.
      Long-term control of hospital-wide, endemic multidrug-resistant Acinetobacter baumannii through a comprehensive ‘bundle’ approach.

      9.2.3 Pseudomonas aeruginosa

      Sources and mechanisms of transmission vary, and surveillance is complicated by the close association between patient and environmental isolates. Association with moist environmental sources is well documented, although significant persistence on dry surfaces, including hospital linen and floors, with a range of 6 h to 16 months is reported.
      • Kramer A.
      • Schwebke I.
      • Kampf G.
      How long do nosocomial pathogens persist on inanimate surfaces? A systematic review.
      Water systems act as a source of infection, or indicate environmental contamination from other sources (e.g. staff hands or re-usable care equipment being cleaned in handwash sinks).
      • Loveday H.P.
      • Wilson J.A.
      • Kerr K.
      • Pitchers R.
      • Walker J.T.
      • Browne J.
      Association between healthcare water systems and Pseudomonas aeruginosa infections: a rapid systematic review.
      Levels of sink colonization are higher in critical care areas than general wards.
      • Dancer S.J.
      • Coyne M.
      • Robertson C.
      • Thomson A.
      • Guleri A.
      • Alcock S.
      Antibiotic use is associated with resistance of environmental organisms in a teaching hospital.
      Transmission occurs via the hands of healthcare workers, contaminated either from patients or from the environment, and has been reviewed systematically by Loveday.
      • Loveday H.P.
      • Wilson J.A.
      • Kerr K.
      • Pitchers R.
      • Walker J.T.
      • Browne J.
      Association between healthcare water systems and Pseudomonas aeruginosa infections: a rapid systematic review.
      • Widmer A.F.
      • Wenzel R.P.
      • Trilla A.
      • Bale M.J.
      • Jones R.N.
      • Doebbeling B.N.
      Outbreak of Pseudomonas aeruginosa infections in a surgical intensive care unit: probable transmission via hands of a health care worker.
      • Foca M.
      • Jakob K.
      • Whittier S.
      • et al.
      Endemic Pseudomonas aeruginosa infection in a neonatal intensive care unit.
      • Nogueras M.
      • Marinsalta N.
      • Roussell M.
      • Notario R.
      Importance of hand germ contamination in health-care workers as possible carriers of nosocomial infections.
      • Waters V.
      • Larsen E.
      • Wu F.
      • et al.
      Molecular epidemiology of Gram-negative bacilli from infected neonates and health care workers' hands in neonatal intensive care units.
      • Rogues A.M.
      • Boulestreau H.
      • Lasheras A.
      • et al.
      Contribution of tap water to patient colonisation with Pseudomonas aeruginosa in a medical intensive care unit.
      • Crivaro V.
      • Di Popolo A.
      • Caprio A.
      • et al.
      Pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures.
      Pseudomonal carriage on hands may be less persistent than for other Gram-negative bacteria, but other factors such as glove usage and artificial nails contribute.
      • Casewell M.W.
      • Desai N.
      Survival of multiply-resistant Klebsiella aerogenes and other Gram-negative bacilli on finger-tips.
      • Moolenaar R.L.
      • Crutcher J.M.
      • San Joaquin V.H.
      • et al.
      A prolonged outbreak of P. aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission?.
      • Morgan D.J.
      • Liang S.Y.
      • Smith C.L.
      • et al.
      Frequent multidrug-resistant Acinetobacter baumannii contamination of gloves, gowns, and hands of healthcare workers.
      • Morgan D.J.
      • Rogawski E.
      • Thom K.A.
      • et al.
      Transfer of multidrug-resistant bacteria to healthcare workers' gloves and gowns after patient contact increases with environmental contamination.
      Patient-to-patient transmission can occur via the air among patients with cystic fibrosis, with evidence of infectious droplet nuclei,
      • Saiman L.
      Infection prevention and control in cystic fibrosis.
      or via patient hand and environmental contamination.
      • Clifton U.
      • Pecham D.G.
      Defining routes of airborne transmission of Pseudomonas aeruginosa in people with cystic fibrosis.
      • Tingpej P.
      • Elkins M.
      • Rose B.
      • et al.
      Clinical profile of adult cystic fibrosis patients with frequent epidemic clones of Pseudomonas aeruginosa.
      Sporadic and epidemic strains tend to co-exist and may be difficult to track without molecular typing.
      • Crivaro V.
      • Di Popolo A.
      • Caprio A.
      • et al.
      Pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures.
      • Peña C.
      • Suarez C.
      • Tubau F.
      • et al.
      Nosocomial spread of Pseudomonas aeruginosa producing the metallo-beta-lactamase VIM-2 in a Spanish hospital: clinical and epidemiological implications.
      There is no evidence for the effect of routine surveillance on the control of MDR Pseudomonas spp., but reports of outbreak interventions support the utility of screening.
      • Cortes J.A.
      • Cuervo S.I.
      • Urdaneta A.M.
      • et al.
      Identifying and controlling a multiresistant Pseudomonas aeruginosa outbreak in a Latin-American cancer centre and its associated risk factors.
      • Nagao M.
      • Iinuma Y.
      • Igawa J.
      • et al.
      Control of an outbreak of carbapenem-resistant Pseudomonas aeruginosa in a haemato-oncology unit.
      There is little evidence that isolating patients in single rooms reduces endemic MDR Pseudomonas spp. levels. In outbreak settings, use of isolation measures as part of a multi-faceted infection control regime is usual, but direct evidence for the impact of isolation alone is lacking.
      • Cortes J.A.
      • Cuervo S.I.
      • Urdaneta A.M.
      • et al.
      Identifying and controlling a multiresistant Pseudomonas aeruginosa outbreak in a Latin-American cancer centre and its associated risk factors.
      • Richard P.
      • Le Floch R.
      • Chamoux C.
      • Pannier M.
      • Espaze E.
      • Richet H.
      Pseudomonas aeruginosa outbreak in a burn unit: role of antimicrobials in the emergence of multiply resistant strains.
      • Bert F.
      • Maubec E.
      • Bruneau B.
      • Berry P.
      • Lambert-Zechovsky N.
      Multiresistant Pseudomonas aeruginosa outbreak associated with contaminated tap water in a neurosurgery intensive care unit.
      • Richet H.
      • Escande M.C.
      • Marie J.P.
      • Zittoun R.
      • Lagrange P.H.
      Epidemic Pseudomonas aeruginosa serotype 016 bacteraemia in hematology-oncology patients.
      • Martins S.T.
      • Moreira M.
      • Furtado G.H.
      • et al.
      Application of control measures for infections caused by multiresistant Gram-negative bacteria in intensive care unit patients.
      • Kohlenberg A.
      • Weitzel-Kage D.
      • van der Linden P.
      • et al.
      Outbreak of carbapenem-resistant Pseudomonas aeruginosa infection in a surgical intensive care unit.
      There is a risk of bias in outbreak reports, and balance between desirable and undesirable effects of physical isolation should be considered. There is a poor level of specific evidence as to the effect of hand hygiene, but expert opinion extrapolated from other situations supports the use of this measure as part of a wider infection prevention strategy.
      • Crespo M.P.
      • Woodford N.
      • Sinclair A.
      • et al.
      Outbreak of carbapenem-resistant Pseudomonas aeruginosa producing VIM-8, a novel metallo-beta-lactamase, in a tertiary care center in Cali, Colombia.
      • Cortes J.A.
      • Cuervo S.I.
      • Urdaneta A.M.
      • et al.
      Identifying and controlling a multiresistant Pseudomonas aeruginosa outbreak in a Latin-American cancer centre and its associated risk factors.
      • Nagao M.
      • Iinuma Y.
      • Igawa J.
      • et al.
      Control of an outbreak of carbapenem-resistant Pseudomonas aeruginosa in a haemato-oncology unit.
      • Kohlenberg A.
      • Weitzel-Kage D.
      • van der Linden P.
      • et al.
      Outbreak of carbapenem-resistant Pseudomonas aeruginosa infection in a surgical intensive care unit.
      • Peña C.
      • Dominguez M.A.
      • Pujol M.
      • Verdaguer R.
      • Gudiol F.
      • Ariza J.
      An outbreak of carbapenem-resistant Pseudomonas aeruginosa in a urology ward.
      Care should be exercised with production, storage and turnover of cleaning products as the organism has a degree of tolerance to disinfectants, and there is evidence for pseudomonal contamination of detergent-type cleaning products.
      • Medcraft J.W.
      • Hawkins J.M.
      • Fletcher B.N.
      • Dadswell J.V.
      Potential hazard from spray cleaning of floors in hospital wards.
      • Werry C.
      • Lawrence J.M.
      • Sanderson P.J.
      Contamination of detergent cleaning solutions during hospital cleaning.

      9.3 Surveillance

      9.3.1 Selection of samples and antimicrobials to test

      In order to support surveillance and infection control, national uniformity is needed in the testing of clinically significant isolates and in the detection of MDR strains. This may involve widespread testing of organisms with antibiotics that would not ordinarily be used in the individual patient.
      In particular, testing of parenteral agents against urinary Gram-negative isolates from community patients is necessary. This may impose costs on diagnostic laboratories without matching benefits beyond earlier detection of spread of such infections. At present, the major requirement is detection of carbapenem-resistant organisms, although detection of quinolone-resistant and ESBL-producing organisms is important. Plasmid transmission of carbapenemases to a wide variety of Gram-negative species makes it difficult to be proscriptive. Validated, sensitive algorithms for testing need to be developed if universal testing is not applied. Testing cephalosporin-resistant isolates solely for carbapenem resistance may miss strains with OXA-48 carbepenemases, but this is a useful minimum standard for detection of other carbapenemases. Wider testing of temocillin may detect more OXA-48-producing strains.
      • Woodford N.
      • Pike R.
      • Meunier D.
      • Loy R.
      • Hill R.
      • Hopkins K.L.
      In vitro activity of temocillin against multidrug-resistant clinical isolates of Escherichia coli, Klebsiella spp. and Enterobacter spp., and evaluation of high-level temocillin resistance as a diagnostic marker for OXA-48 carbapenemase.
      The basic phenotypic strategy to detect carbapenemase producers is to use a carbapenem as an indicator, and then to undertake supplementary tests to distinguish carbapenemase producers from those that have other carbapenem resistance mechanisms.
      • Joint Working Group of DARC and ARHAI, 2012
      ESBLs – a threat to human and animal health?.
      Some carbapenemases may not be associated with clinical resistance to carbapenems, and tests that detect hydrolytic capacity [e.g. the modified Hodge/clover leaf test, or synergy tests between carbapenems and boronates (to inhibit KPC enzymes) or EDTA (to inhibit metallo-carbapenemases)] are more useful in identifying these strains. European Committee on Antimicrobial Susceptibility Testing (EUCAST) advice is that Enterobacteriaceae with a minimum inhibitory concentration (MIC) for meropenem >0.12mg/L should be treated with suspicion, not just those with MICs above the clinical breakpoint of 2mg/L; the screening MIC of >0.12mg/L equates to a zone with a diameter of <25mm on Mueller-Hinton agar.
      • European Committee on Antimicrobial Susceptibility Testing
      EUCAST guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance.
      Ertapenem is a more sensitive indicator of carbapenemase production than meropenem or imipenem, but is less specific as it is affected more than other carbapenems by porin-mediated mechanisms. It is also less used and tested. Meropenem or imipenem have better specificity and are to be recommended for screening for national surveillance. EUCAST screening breakpoints should be used.
      • Joint Working Group of DARC and ARHAI, 2012
      ESBLs – a threat to human and animal health?.
      Many laboratories do not test meropenem susceptibility routinely for all Gram-negative blood isolates. For national surveillance of carbapenem resistance to be effective, phenotypic meropenem resistance must be tested for all blood isolates, and resistance must be reported to central authorities. However, provision for reporting meropenem-resistant Gram-negative isolates from all body sites is important, and should not burden laboratories excessively; electronic and paper reporting systems should be made available. All secondary and tertiary care hospitals, as well as private hospitals, should be included. Monitoring by identifying specific carbapenemases would require reference laboratory reports; therefore, local confirmatory tests are encouraged. Automated PCR methods are being developed or available for specific carbapenemase gene detection, but are not yet widely used. Most meropenem resistance in P. aeruginosa is due to loss of OprD porin and not a carbapenemase. Sensitivity to ceftazidime, piperacillin-tazobactam and carbenicillin despite meropenem resistance suggests this mechanism, and also suggests that neither high-level infection control action nor submission to a reference laboratory is needed.
      To detect ESBLs, E. coli, Klebsiella spp. and Proteus mirabilis should be screened for clavulanate-reversed resistance to ceftazidime and cefotaxime
      • Joint Working Group of DARC and ARHAI, 2012
      ESBLs – a threat to human and animal health?.
      or cefpodoxime. AmpC producers are resistant to cefotaxime (reversed by cloxacillin), but susceptible (or intermediate) to cefepime. For AmpC-inducible genera, such as Enterobacter spp. and Citrobacter freundii, comparison of cefepime and cefepime plus clavulanate discs can be used to detect additional presence of ESBLs. Confirmation of ESBL production is most easily accomplished by comparing inhibition zones for discs with cephalosporin alone with discs containing clavulanic acid. A zone expansion of >5mm indicates ESBL production. Alternatively, an Etest strip is used to demonstrate at least eight-fold reduction in MIC.
      Faster diagnostic methods may be considered, particularly during outbreaks, to allow more rapid isolation. Selective media or combinations of non-selective media and a chromogenic or genetic test achieve a result within 24h. Detection within a few hours is possible if molecular tests are applied directly to the clinical specimen, although this approach is still new.
      Various selective commercial media are available to seek ESBL, CTX-M ESBL or carbapenemase producers directly from clinical specimens or early growth in blood culture bottles. Media-seeking ESBL producers often have good sensitivity but poor specificity in distinguishing these organisms from strains that hyperproduce AmpC enzymes.
      • Réglier-Poupet H.
      • Naas T.
      • Carrer A.
      • et al.
      Performance of chromID ESBL, a chromogenic medium for detection of Enterobacteriaceae producing extended-spectrum beta-lactamases.
      • Huang T.D.
      • Bogaerts P.
      • Berhin C.
      • Guisset A.
      • Glupczynski Y.
      Evaluation of Brilliance ESBL agar, a novel chromogenic medium for detection of extended-spectrum-beta-lactamase-producing Enterobacteriaceae.
      • Färber J.
      • Moder K.A.
      • Layer F.
      • Tammer I.
      • König W.
      • König B.
      Extended-spectrum beta-lactamase detection with different panels for automated susceptibility testing and with a chromogenic medium.
      The sensitivity of media-seeking carbapenemases varies with the particular enzyme,
      • Wilkinson K.M.
      • Winstanley T.G.
      • Lanyon C.
      • Cummings S.P.
      • Raza M.W.
      • Perry J.D.
      Comparison of four chromogenic culture media for carbapenemase-producing Enterobacteriaceae.
      with OXA-48 being the most difficult to detect due to the low levels of resistance often conferred. The alternative approach is to seek ESBL or carbapenemase activity in colonies growing on non-selective agars. Colorimetric and biochemical approaches include the following:
      • The chromogenic oxyimino-cephalosporin HMRZ-86 turns from yellow to red on hydrolysis.
        • Livermore D.M.
        • Warner M.
        • Mushtaq S.
        Evaluation of the chromogenic Cica-beta-test for detecting extended-spectrum, AmpC and metallo-beta-lactamases.
        If used in combination with inhibitors, it can be used to distinguish strains with AmpC, ESBLs or metallo-carbapenemases, although KPC enzymes may be confused with AmpC and it is unclear whether OXA-48 is detected.
      • Acidimetric β-lactamase tests can be adapted to detect carbapenemase producers, as in the ‘Carba-NP’ test where, again, some authors report problems in detecting OXA-48.
        • Rubin F.A.
        • Smith D.H.
        Characterization of R factor beta-lactamases by the acidimetric method.
        • Dortet L.
        • Bréchard L.
        • Cuzon G.
        • Poirel L.
        • Nordmann P.
        Strategy for rapid detection of carbapenemase-producing Enterobacteriaceae.
        • Osterblad M.
        • Hakanen A.J.
        • Jalava J.
        Evaluation of the Carba NP test for carbapenemase detection.
      • MALDI-ToF assays for carbapenemase activity, exploiting the molecular mass change that occurs when the β-lactam molecules are hydrolysed.
        • Burckhardt I.
        • Zimmermann S.
        Using matrix-assisted laser desorption ionization-time of flight mass spectrometry to detect carbapenem resistance within 1 to 2.5 hours.
      Molecular tests can be used to seek β-lactamase genes in overnight cultures. One PCR/array system (Check-MDR CT03) can rapidly detect a wide range of relevant acquired AmpC, ESBL and carbapenemase genes, distinguishing between those encoding classical and extended-spectrum TEM and SHV types.
      • Cuzon G.
      • Naas T.
      • Bogaerts P.
      • Glupczynski Y.
      • Nordmann P.
      Evaluation of a DNA microarray for the rapid detection of extended-spectrum β-lactamases (TEM, SHV and CTX-M), plasmid-mediated cephalosporinases (CMY-2-like, DHA, FOX, ACC-1, ACT/MIR and CMY-1-like/MOX) and carbapenemases (KPC, OXA-48, VIM, IMP and NDM).
      PCR may be used directly on rectal swabs, without culture, and can give results within 1h of the specimen being taken.
      • Tenover F.C.
      • Canton R.
      • Kop J.
      • et al.
      Detection of colonization by carbapenemase-producing Gram-negative bacilli in patients by use of the Xpert MDRO assay.
      Sensitivity and specificity are good, although positive results are often obtained for patients from whom the laboratory fails to grow a carbapenemase-producing pathogen.
      • Lowman W.
      • Marais M.
      • Ahmed K.
      • Marcus L.
      Routine active surveillance for carbapenemase-producing Enterobacteriaceae from rectal swabs: diagnostic implications of multiplex polymerase chain reaction.
      This is a wider issue with molecular diagnostics when used directly on specimens, and may either indicate a poor positive predictive value or that the culture is not the ‘gold standard’.
      • Livermore D.M.
      • Wain J.
      Revolutionising bacteriology to improve treatment outcomes and antibiotic stewardship.
      Recommendation
      The minimum susceptibility tests performed on all significant Gram-negative isolates should include meropenem; in addition, cefpodoxime should be tested for Enterobacteriaceae, and ceftazidime should be tested for Pseudomonas spp.Strong

      9.3.1.1 When to seek reference laboratory typing of isolates

      • To inform cross-infection and outbreak investigations.
      • To seek a particular type associated with specific clinical characteristic(s) (e.g. K1 capsular type of CC 23 of K. pneumoniae associated with hypermucoviscosity and liver abscesses).
      • To provide national/international context (e.g. in tracking the spread of ‘high-risk clones’, such as ST258 K. pneumonia, with KPC carbapenemases).
      Typing results can never stand alone, and need to be interpreted in the context of all available epidemiological, clinical and demographical data.
      • van Belkum A.
      • Tassios P.T.
      • Dijkshoorn L.
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Epidemiological Markers (ESGEM)
      Guidelines for the validation and application of typing methods for use in bacterial epidemiology.
      Typing of isolates is helpful to inform cross-infection and outbreak investigations among groups of patients with potential links. Comparison of isolates without epidemiological linkage information may result in patients being linked in error, simply because they share the same international high-risk clone, or both have representatives of a widespread cluster. Typing of environmental isolates may be helpful, especially where a piece of equipment common to all the affected patients is implicated. However, it may also be confusing and needs to be focused. All environmental samples should have a clear link to an affected patient; there is no point in typing environmental isolates on their own. Isolates from sink plug holes/drains may well match patient isolates, but this provides little information regarding the source as the isolate is likely to have come from the patient rather than the patient having acquired it from a drain. Large-scale environmental sampling is rarely helpful, and there should be a clear hypothesis as to a likely source and the link between that source and the patient(s).

      9.3.2 What national surveillance is performed and how should it be developed?

      National surveillance of antimicrobial resistance is essential in detecting the emergence of new strains and resistance mechanisms, providing information for formularies and assessing the effect of control strategies. Outputs must be timely and tailored to the needs of medical and nursing staff, healthcare organizations and commissioners of health care. The World Health Organization (WHO) provides WHONET database software, which is used for collecting data in some areas, while the European Antimicrobial Resistance Surveillance Network (EARS-NET) provides resistance information on blood and cerebrospinal fluid isolates across Europe.
      • Ironmonger D.
      • Edeghere O.
      • Gossain S.
      • Bains A.
      • Hawkey P.M.
      AmWeb: a novel interactive web tool for antimicrobial resistance surveillance, applicable to both community and hospital patients.
      EARS-NET identified the early accumulation of carbapenemases in K. pneumoniae in Greece,
      • Magiorakos A.
      • Suetens C.
      • Monnet D.L.
      • Carlo Gagliotti C.
      • Heuer O.E.
      EARS-Net Coordination Group and EARS-Net participants
      The rise of carbapenem resistance in Europe: just the tip of the iceberg?.