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Prevention and Control of multi-drug resistant (MDR) Gram-negative Bacteria –
Recommendations from a Joint Working Party
A.P.R. Wilson*, D.M. Livermore, J.A. Otter, R.E. Warren, P. Jenks, D.A. Enoch, W.
Newsholme, B. Oppenheim, A. Leanord, C. McNulty, G. Tanner, S. Bennett, M.
Cann, J. Bostock, E. Collins, S. Peckitt, L. Ritchie, C. Fry, P. Hawkey
* Corresponding author. Address: Department of Microbiology & Virology, University
College London Hospitals, 60 Whitfield Street, London W1T 4EU, UK. Tel.: +44 (0)
2034479516
E-mail address: [email protected] (Peter Wilson)
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Prof Peter Wilson, Consultant Microbiologist, Department Microbiology & Virology,
University College London Hospitals, London
David Livermore, Professor of Medical Microbiology, Norwich Medical School,
University of East Anglia
Jonathan Otter, Research Fellow, Centre for Clinical Infection and Diagnostics
Research, Department of Infectious Diseases, Guy’s and St. Thomas’ NHS
Foundation Trust and King’s College London.
Roderic Warren, Retired Consultant Microbiologist, Shrewsbury and Telford
Hospital NHS Trust
Peter Jenks, Consultant Microbiologist, Plymouth Hospitals NHS Trust
David Enoch, Consultant Microbiologist, Public Health England, Addenbrooke’s
Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge
William Newsholme, Consultant in Infectious Diseases, Infection Control & General
Medicine, Dept. of Infection, St Thomas' Hospital, London
Beryl Oppenheim, Cons Microbiologist, University Hospitals Birmingham NHS
Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre,
Birmingham,
Prof Alistair Leanord, Consultant Microbiologist, Southern General Hospital,
Glasgow
Cliodna McNulty, Head of Primary Care Unit, Public Health England, and Honorary
Visiting Professor Cardiff University, Microbiology Dept., Gloucester Royal Hospital,
Gloucester
Elizabeth Collins, Clinical Lead Infection Prevention, University Hospitals of
Leicester, Leicester Royal Infirmary, Leicester
Sue Peckitt, Infection Prevention and Control Lead for North Yorkshire and Humber
Commissioning support Unit
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Lisa Ritchie, Nurse Consultant Infection Control, Infection Control Team/HAI Group,
Health Protection Scotland, Glasgow
Carole Fry, Nursing Officer – Communicable Diseases Infectious Diseases & Blood
Policy, Department of Health, Room 101, Richmond House, London
Peter Hawkey, Professor of Clinical and Public Health Bacteriology, Consultant
Medical Microbiologist, Public Health Laboratory, Birmingham Heartlands Hospital,
Bordesley Green East, Birmingham
Patient representatives:
Graham Tanner, Susan Bennett, Jennifer Bostock
Maria Cann, Trustee, MRSA Action UK
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Table of contents
1 Executive Summary.........................................................................................................................7
2 Lay Summary...................................................................................................................................7
3 Introduction......................................................................................................................................8
4 Guideline Development Team.........................................................................................................8
4.1 Guideline Advisory Group.......................................................................................................8
4.2 Acknowledgements..................................................................................................................8
4.3 Source of Funding....................................................................................................................9
4.4 Disclosure of Potential Conflict of Interest.............................................................................9
4.5 Relationship of Author with Sponsor....................................................................................10
4.6 Responsibility for Guidelines................................................................................................10
5 The Working Party Report.............................................................................................................10
5.1 Aim........................................................................................................................................12
6 Summary of Guidelines.................................................................................................................12
7 Implementation of these Guidelines..............................................................................................15
7.1 How can the guidelines be used to improve clinical effectiveness?......................................15
7.2 How much will implementation of the guidelines cost?........................................................16
7.3 Summary of Audit Measures.................................................................................................16
7.4 E-learning tools......................................................................................................................16
8 Methodology..................................................................................................................................17
8.1 Evidence Appraisal................................................................................................................17
8.2 Consultation process..............................................................................................................18
9 Rationale for Recommendations....................................................................................................19
9.1 Epidemiology.........................................................................................................................19
9.1.1 What is the definition of MDR Gram-negative bacteria?..............................................19
9.1.2 Which Gram-negative bacteria cause infection control problems?...............................19
9.1.3 What are the relative contributions of community and hospital acquisition?................19
9.1.4 What is the evidence for reservoir and spread of MDR Gram-negative bacteria in care homes and secondary care?............................................................................................................20
9.1.5 Multi-resistance in the community................................................................................24
9.1.6 What is the role of agricultural use of sewage and antibiotic treatment in veterinary practice in spreading ESBLs?........................................................................................................25
9.1.7 What insights has national E. coli bacteraemia surveillance provided?........................26
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9.1.8 Is there evidence for high/low risk areas within a healthcare facility?..........................27
9.2 Is there evidence of differences between organisms in respect of transmission, morbidity and mortality?....................................................................................................................................27
9.2.1 Resistant Enterobacteriaceae.........................................................................................27
9.2.2 Acinetobacter baumannii...............................................................................................28
9.2.3 Pseudomonas aeruginosa..............................................................................................29
9.3 Surveillance...........................................................................................................................30
9.3.1 Selection of samples and antimicrobials to test.............................................................30
9.3.2 What national surveillance is performed and how should it be developed?..................34
9.3.3 How should we undertake local screening, why is it important and how should it be interpreted?....................................................................................................................................36
9.3.4 At what point should passive surveillance switch to active surveillance (screening)?. 37
9.4 What is the evidence that infection prevention and control precautions prevent transmission?.....................................................................................................................................37
9.4.1 Are standard infection control precautions sufficient to stop transmission?.................38
9.4.2 Screening.......................................................................................................................41
9.4.3 Isolation and segregation...............................................................................................52
9.4.4 Hand hygiene.................................................................................................................58
9.4.5 Environmental hygiene..................................................................................................59
9.4.6 Selective decontamination: Why is it not used? Is there a role?...................................68
9.5 What are the minimum standards to stop spread in public areas, primary care or care homes?...............................................................................................................................................70
9.6 Are there organisational structures within a healthcare facility that play a role in the successful control of MDR Gram-negative bacilli?..........................................................................71
10 Further research.........................................................................................................................72
11 Appendix 1 - Glossary...............................................................................................................90
12 Appendix 2.................................................................................................................................93
12.1 Guideline Development.........................................................................................................93
12.2 Conflict of Interests...............................................................................................................93
12.3 Infection Control -Systematic Review Process.....................................................................93
12.3.1 PICO:.............................................................................................................................93
12.3.2 Systematic Review Questions........................................................................................94
12.4 Antimicrobial Chemotherapy -Systematic Review Process..................................................95
12.4.1 Systematic Review Questions........................................................................................94
12.5 Databases and Search terms Used 23/5/14............................................................................95
13 Appendix 3: Consultation stakeholders.....................................................................................97
14 Appendix 4: CPD material.........................................................................................................99
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15 Appendix 5: Working Party Scope..........................................................................................100
16 Appendix 6. Search Strategy...................................................................................................103
16.1 Medline (January 1946 to December 2012)........................................................................119
17 References.......................................................................................................................................125
Further information on excluded studies, evidence tables, stakeholder consultation/peer review comments, scope, and conflict of interests are contained in online appendices A-E.
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1 Executive Summary
Multi-drug-resistant (MDR) Gram-negative bacterial infections have become
prevalent in some European countries. Moreover, increased use of broad-spectrum
agents selects organisms with resistance and, by increasing their numbers, also
increases their chance of spread. This Report describes measures that are clinically
effective for preventing transmission when used by healthcare workers in acute and
primary healthcare premises. Methods for systematic review 1946-2014 were in
accordance with SIGN 501 and the Cochrane Collaboration;2 critical appraisal was
applied using AGREEII.3 Accepted guidelines were used as part of the evidence
base and to support expert consensus. Questions for review were derived from the
Working Party Group, which included patient representatives, in accordance with
Patient Intervention Comparison Outcome. 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.
2 Lay Summary
Multi-drug resistant (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, but can cause infection at other body sites, mostly in
1
?. Scottish Intercollegiate Guidelines Network. SIGN 50: A guideline developer's handbook.
Edinburgh: Healthcare Improvement Scotland; 2014. Revised edition. Available at:
http://www.sign.ac.uk. Last accessed 10th December 2014.
2. Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions
version 5.1.0. Updated March 2011. London: Cochrane Collaboration; 2011.
3. Brouwers M, Kho ME, Browman GP, et al.; AGREE Next Steps Consortium. AGREE II:
advancing guideline development, reporting and evaluation in healthcare. CMAJ
2010;182:E839–E842.
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patients who are made vulnerable by other underlying disease, injury or
hospitalisation. 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 which
should be used in conjunction with this document.
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 SURF (Healthcare-acquired
Infection Service Users Research Forum), patient charities and/or through
involvement in the development of NICE guidelines.
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4 Guideline Development Team
4.1 Guideline Advisory Group
Martin Kiernan, Nurse Consultant, Prevention and Control of InfectionSouthport and Ormskirk NHS Trust, UK
Phil Wiffen, Cochrane Pain, Palliative and Supportive Care Group Pain
Research, Churchill Hospital Oxford, Nuffield Dept. of Clinical Neurosciences,
Oxford, UK.
Karla Soares-Wieser, Enhance Reviews, Ltd, Wantage,UK.
4.2 Acknowledgements
We would like to acknowledge the support of the Infection Prevention Society 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 part supported by National Institute for Health Research University
College London Hospitals Biomedical Research Centre.
4.3 Source of Funding
A grant funded equally by British Infection Association, Healthcare Infection Society,
and British Society for Antimicrobial Chemotherapy. The grant funded Karla Soares-
Wieser and others at Enhance Reviews Lt, Lyford, Wantage and Paul Wiffen to
perform the systematic review.
4.4 Disclosure of Potential Conflict of Interest
PH: Consultancy: BioMerieux, Becton-Dickinson, Eumedica, Merck, Novartis,
MagusCommunications, Pfizer, Wyeth; director of ModusMedica (medical education
company); Funded research: Merck, Novartis, and Pfizer.
APRW: Consultant on Drug Safety Monitoring Boards for Roche and Genentech,
Advisory Panel for 3M.
DL: Advisory Boards or consultancy – Achaogen, Adenium, Alere, Allecra,
AstraZeneca, Basilea, Bayer, BioVersys, Cubist, Curetis, Cycle, Discuva, Forest,
GSK, Longitude, Meiji, Pfizer, Roche, Shionogi, Tetraphase, VenatoRx, Wockhardt,
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paid lectures – AOP Orphan, AstraZeneca, Bruker, Curetis, Merck, Pfizer, Leo,
Relevant shareholdings in– Dechra, GSK, Merck, Perkin Elmer, Pfizer collectively
amounting to <10% of portfolio value
BO: Advisory Board Astellas, Forrest. Lecture Alere
DAE: ECCMID conference attendance funded by Astellas and Eumedica
CM: Travel expenses Merieux Diagnostics
JO: part-time employment at Bioquell; paid lectures for 3M; research funding from
Pfizer and the Guy’s & St Thomas’ Charity
MC: IPS conference attendance funded by corporate sponsorship from Mölnlycke
Healthcare
PJ: Advisory Board for Baxter
All other authors no conflicts declared.
4.5 Relationship of Author with Sponsor
The British Society of Antimicrobial Chemotherapy (BSAC), British Infection
Association (BIA) and Healthcare Infection Society (HIS) commissioned the authors
to undertake the Working Party report. The Infection Prevention Society (IPS)
provided additional panel members 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 after
consultation have been endorsed by the sponsoring societies.
5 The Working Party Report
Date of Publication:
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).
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. Antimicrobial chemotherapy is 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.
Why do we need a Working Party Report for these infections?
Colonization and infection by multi-resistant 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% rise 2013 vs. 2010).4 The spread
of these infections risks increasing the length of hospital stay and adversely affects
the quality of care of patients. Public awareness of resistance and hospital-acquired
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 multi-resistant strains occur, there is a considerable
financial, physical and psychological cost. Unless controlled, outbreaks are likely to
become more common and multi-resistant strains will become endemic. Evidence-
based infection prevention and associated quality improvement methods are
effective in reducing the number of infections with these organisms.
What is the purpose of the Report’s recommendations?
The Report describes measures that are clinically effective for preventing infections
when used by healthcare workers in acute and long-term healthcare.
What is the scope of the guidelines?
4. Public Health England. English surveillance programme for antimicrobial utilisation and
resistance (ESPAUR). London PHE; 2014. Available at:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/362374/
ESPAUR_Report_2014__3_.pdf. Last accessed 23rd October 2014.
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Two sets of guidelines have been developed. This document includes appropriate
infection prevention and control precautions. The other publication describes best-
practice antimicrobial prescribing.5
What is the evidence for these guidelines?
In the preparation of these recommendations, systematic reviews were performed of
peer-reviewed research. Expert opinion was also derived from published guidelines
subjected to validated appraisal.Error: Reference source not found Evidence was
assessed for methodological quality and clinical applicability according to SIGN
protocols.
Who developed these guidelines?
A group of medical microbiologists, scientists, infectious disease physicians,
infection control practitioners, epidemiologists, and patient representatives.
Who are these guidelines for?
Any healthcare practitioner can use these guidelines and adapt 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
understand the methods available to prevent acquisition of antibiotic resistant
bacteria.
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.
How frequently are the guidelines reviewed and updated?
The guidelines will be reviewed at least every 4 years and updated if change(s) in
the evidence are sufficient to require a change in practice.
5.1 Aim
The primary aim of the review was to assess the current evidence for prevention and
control of MDR Gram-negative infections.
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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:
Surveillance
1,2 Susceptibility tests performed on significant Gram-negative isolates
should include meropenem; plus cefpodoxime for Enterobacteriaceae and
ceftazidime for Pseudomonas . Strong
3. Travel history (i.e. countries or known endemic area visited within a year)
should be collected for all patients with carbapenemase producing Gram
negative bacteria. Strong
4. Each healthcare organisation should have access to robust microbiological
arrangements for detecting and reporting all multi-drug resistant Gram-
negative organisms in routine clinical samples and for screening, using
highly-sensitive tests with a diagnostic turnaround time of <48h.
Conditional
Screening
5. Active screening rather than passive surveillance is recommended for high-
risk specialties. Conditional
6. Patients at high risk for carbapenem-resistant organisms include those
admitted to ICU 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
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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 A. baumannii and MDR P aeruginosa is required in management of outbreaks. Strong
10.A rectal swab (with visible material) or stool sample (and urine if catheter
present) should be used for screening for multiresistant Enterobacteriaceae
and Pseudomonas aeruginosa. For Acinetobacter, sample skin sites or if a
catheter or endotracheal tube is present, urine or respiratory secretion.
Conditional
11. In the event of secondary cases of carbapenem-resistant Enterobacteriaceae,
Standard Infection Control Precautions (SICP) and Contact Precautions
should be monitored and reinforced 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.Those with previous samples with carbapenem-resistant or other MDR Gram-
negative bacteria should be screened at the time of admission.
Conditional
Prevention of transmission
13. In addition to SICP, 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
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 ESBL-
Enterobacteriaceae, P. aeruginosa. Strong
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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 Klebsiella sp, carbapenemase-
producing P. aeruginosa, ESBL E. coli and other Enterobacteriaceae, AmpC
Enterobacteriaceae. Strong
17. If there are insufficient rooms 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
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 hand wash sinks Strong
21.For P. aeruginosa including multiresistant 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 infections rise to
determine if point-of-use filters should be installed or if taps need to be
changed. Strong
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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
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 both in terms of economics and
quality of life. Screening and isolation where this is not currently practiced will result
in significant cost pressures 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.
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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 are tested)
The microbiology laboratory reports all patients infected or colonized with
carbapenemase producing Gram-negative bacteria to Public Health England or an
equivalent body
All patients colonized or infected with carbapenem-resistant Enterobacteriaceae and
A. baumannii are placed under Contact Precautions within 6 hours 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 obtained at time of admission for all acute hospital patients, and
screened if from endemic area
7.4 E-learning tools
CPD questions and model answers are listed for self assessment in Appendix 4.
8 Methodology
8.1 Evidence Appraisal
Methods were in accordance with SIGN 50Error: Reference source not found and
the Cochrane CollaborationError: Reference source not found and critical appraisal
was applied using AGREEII.Error: Reference source not found 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 Patient Intervention Comparison Outcome
(PICO).Error: Reference source not found
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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 (RCT) and observational
studies were included and assessed by two reviewers. In context, observational
studies included non-randomised controlled studies, controlled before-and-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 Cochrane Library
(Issue 11 2012), Medline (1946-2012), Embase (1980-2012) and Cumulated Index of
Nursing and Allied Health Literature (CINAHL) (1984-2012). On 23/5/14 an update
search was conducted on Medline only using the same strategy for references after
1/1/13. References 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. Pre-tested data extraction forms were used and study
characteristics and results collected. Data were extracted from observational studies
for multiple-effect estimates: the number of patients, adjusted and unadjusted effect
estimates with standard error or 95% confidence interval, confounding variables and
the 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.Error: Reference source not
found,6 Quality was judged by report of 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, treatment effectiveness, 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
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by specific Gram-negative pathogens. For dichotomous variables, risk ratios were
used and, for continuous outcomes, mean differences with 95% confidence
intervals.7 Analyses were performed in Revman 5.2.8 SIGN summary tables were
used.
Evidence tables and judgement reports were presented and discussed by the
Working Party and guidelines 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 (Table II). The grading relates to the strength of the supporting
evidence and predictive power of the study designs, not the importance of the
recommendation. Any disagreements between members were resolved by
discussion. For some areas only expert opinion is available such that a Good
practice recommendation is made.
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 MDR Gram-negative bacteria?
For the purposes of this guideline, multi-drug resistant 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.Error: Reference source not found
9.1.2 Which Gram-negative bacteria cause infection control problems?
Opportunistic Gram-negative bacteria that present increasing resistance issues
include Enterobacteriaceae (Escherichia coli, Klebsiella spp., Enterobacter spp.,
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Serratia spp., Citrobacter spp., Proteeae), and the non-fermenters: Pseudomonas
aeruginosa, and Acinetobacter baumannii. Stenotrophomonas maltophilia is
inherently multi-resistant in most cases but a less common cause of cross infection.
Gonococci are Gram-negative and are increasingly resistant but were excluded
because relevant public health control actions are substantially different.
Emphasis here is placed on of strains resistant to -lactams, including carbapenems,
cephalosporins and β-lactamase inhibitor combinations, and on those resistant to
fluoroquinolones insofar as these are the core components of most therapies for
severe infections. Aminoglycosides are most often used as adjuncts to -lactam
therapy in severe infection whereas polymyxins are mostly used in cases where -
lactams cannot be used owing to resistance. Resistance to these latter groups of
agents should nevertheless prompt concern, especially where it is coupled to
resistance to multiple -lactams, as is often the case. Means of infection control
remain the same 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.Error: Reference source not found 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,9 and with
hospital stays becoming shorter, so that hospital-acquired infections often become
apparent after hospital discharge,10 or on readmission. 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 utilise different intervals when classifying infection diagnosed in the
community as ‘hospital-acquired’. Intervals of 1 to 3 months are commonly used to
distinguish community acquisition from that acquired during hospital admission, but
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the literature shows that carriage, and the potential for infection, can persist for much
longer periods (commonly a year), and we recommend that this longer period be
used.11
9.1.4 What is the evidence for reservoir and spread of MDR Gram-negative bacteria
in care homes and secondary care?
Enterobacteriaceae, P. aeruginosa and Acinetobacter, whether resistant or not, can
all be transferred among vulnerable patients by staff vectors and contaminated
equipment, leading to well-defined local clonal outbreaks.12 Both A. baumannii and
K. pneumoniae (by virtue of their capsules) can survive on dry surfaces, including
hands.13,14 MDR Enterobacteriaceae can colonize the gut, providing – without any
symptoms – a reservoir for transfer to other body sites, where infection may ensue,
or to other patients, with the transmission risk increased if the carrier experiences
diarrhoea or incontinence.
In general, and excluding particular high-risk clones discussed below, there is no
evidence that multi-resistant strains are more likely to be associated with cross-
infection than other strains. Enterobacteriaceae that owe carbapenem resistance to
combinations of extended spectrum beta lactamases (ESBL) 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.15,16,17 In a nested case-control study in USA, mechanical ventilation,
pulmonary disease, days of antibiotic treatment and colonization pressure were
associated with acquisition of carbapenem-resistant Enterobacteriaceae.18 Typing of
Klebsiella 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.19 For example:
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The majority of fluoroquinolone-resistant ESBL-producing E. coli causing
infection both in hospitals and the community belong to sequence type (ST)
131-B2-O25b.20,21
The growing prevalence of KPC carbapenemase-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.22
In Russia, Belarus and Kazakhstan, there is extensive nosocomial spread of
ST235 P. aeruginosa with VIM-2 carbapenemase susceptible only to
colistin.23
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, though both ST258 K. pneumoniae and ST235 P. aeruginosa have been
recorded.Error: Reference source not found,24 National clones that have achieved
considerable traction in the UK include A. baumannii OXA-23 clone 1, recorded at
>60 hospitals.Error: Reference source not found,25 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. Focussing infection control on specific types rather than resistances has not
been explored for ESBL-producing E.coli.
Escherichia coli sequence type 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.26 The lineage can be
distinguished by serotyping and PCR.27 Among faeces sent for culture from
international travellers returning to UK, many from the Indian sub-continent, 18%
contained ESBL E. coli, mostly with CTX-M-15 enzymes and 2.1% had ST131
strains with ESBL.28
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.29,30 This is the case, for example in the current
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spread of pKpQIL plasmids encoding KPC carbapenemases in and around
Manchester.31 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 (though rarely proven), that frequent plasmid transfer among gut bacteria
leads to the diversity of strains involved.32 Since 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 SICP is
extremely important.
9.1.4.3 Outbreaks due to P. 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.Error: Reference source not found However a different epidemiology is
sometimes seen, particularly with P. aeruginosa (multi-resistant 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.33,34 Such
instances often reflect contamination of the hospital plumbing system by the
Pseudomonas clone(s), and control may require modification/assessment, including
e.g. 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 minimise flooding.35,36
9.1.4.4 Long term care facilities and the spread of MDR Enterobacteriaceae
Long-term care facilities (LTCF) are increasingly identified as reservoirs of antibiotic
resistance, in particular with colonization rather than infection. 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 LTCFs increased from 0.07 in 1996 to 0.28 in 2005. This largely
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reflected the proliferation of E. coli with CTX-M enzymes, which were later
recognised as representatives of the international ST131 clone.37,38
Long-term care facilities range from establishments offering assisted-living to largely
independent residents through to those providing complex medical support.39,40 This
spectrum of care varies among countries, reflecting healthcare organisation and
cultural factors.41,42,43
The distribution of incontinent and catheterised residents is likely to influence the
transmission of Gram-negative bacteria, including those with multi-resistance.
Variation may be very local: thus March et al. found that gut carriage of resistant
bacteria varied across five sub-units in one long-term care facility in Bolzano, Italy.44
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 LTCF vs. 22% of 45 in geriatric unit). In contrast, Gruber
et al. in Germany found higher carriage rates of multi-resistant bacteria in geriatric
units (32.6%) than in nursing homes (18.5%) or ambulatory care (15.6%).45
Whilst most resistance studies on LTCFs relate to those catering 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.46
The literature supporting the view that LTCFs constitute a reservoir of multi-
resistance comprises, firstly, numerous analyses showing that previous stay in a
LTCF is a risk factor for later infections with MDR Gram-negative bacteria, including
those with ESBLs and carbapenemases and, secondly, of multiple snapshot surveys
showing frequent (though very variable) gut carriage of ESBL-producing E. coli and
Klebsiella spp. among LTCF residents, including in Australia, Belgium, France,
Germany, Israel, Japan, Malaysia, the UK, Italy and the USA where these enzymes
have already proliferated in hospitals.Error: Reference source not found,47,48,49,50,51
Accumulation of MDR Gram-negative bacteria in LTCFs probably reflects a
combination of
(i) the frequent transfer into LTCFs of patients/residents who were initially
colonized or infected in hospitals,
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(ii) oro-faecal transfer within LTCFs, reflecting breakdowns of personal
hygiene in populations with high rates of dementia and incontinence and
(iii) frequent antibiotic use and its contingent selection pressure on the gut
flora.
(iv) High rates of urinary tract catheterisation
Only one sizeable UK study of the carriage of MDR Gram-negative bacteria by
nursing home residents has been published.Error: Reference source not found
This was conducted in Belfast from 2004-6, early in the national dissemination of
E. coli with CTX-M ESBLs. This study included 16 LTCFs and found E. coli that
were both ciprofloxacin-resistant and produced ESBLs in faeces from 119/294
residents (40.5%). This was a 40-fold higher carriage rate than for diarrhoeal
samples from community patients. Virtually all (99%) of these multi-resistant
isolates belonged to the ST131: half belonged to the CTX-M-15-positive ‘strain A’
variant frequent elsewhere in the UK.52,53 Two small (6 and 12 bed) LTCFs had no
colonized residents; others had up to 75% (18/24) colonized, 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
multivariate model.Error: Reference source not found Duration of the nursing
home residency did not correlate with an increased likelihood of carriage;
although it seems likely that carriers commonly have acquired their organism
within their LTCFs.
9.1.5 Multi-resistance in the community
Multi-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, UK, rising to 22.8% of those with
surnames suggesting a Middle Eastern or South Asian patrimony vs. 8.1% among
those names suggesting European patrimony. This differential perhaps reflects
frequent travel to parts of the world where ESBLs are common outside the hospital.54
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
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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 by these organisms,
typically with the particular ESBL type prevalent in the country visited.55
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.Error: Reference source not found, 56,57,58
_ENREF_1 However, in areas of high-prevalence, particularly parts of the Indian sub-
continent, 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.59,60
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.61 Cross infection occurs62 and can be interrupted by segregation of colonized
and non-colonized cystic fibrosis patients.63 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.64
9.1.6 What is the role of agricultural use of sewage and antibiotic treatment in
veterinary practice in spreading ESBLs?
Gut E. coli are ubiquitous in mammals, and multi-resistant strains are repeatedly
reported in both food and companion animals.65 Johnson et al. demonstrated that the
same ESBL-producing E. coli strains can be shared among household members and
their pet dog, though the direction of transmission is uncertain.66 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.67
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.68 However, the ESBLs in retail chicken in the UK are
predominantly CTX-2 or -14-like69,70 and their host strains are non-clonal, whereas
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clonal ST131 E. coli with CTX-M-15 enzyme predominates among human ESBL
isolates and are 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.71
9.1.7 What insights has national E. 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 Public Health England, most cases
arose in elderly patients in the community who had visited their GP (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.72 A third
of patients with bacteraemia had received antibiotics for genitourinary infection in the
past 4 weeks but the adequacy of treatment was not known. There is a notable rise
in incidence in the summer for all Gram-negative bacteraemias,73,74,75,76 and a number
of hypotheses are possible, including the role that hydration status in the elderly has
to play in predisposition to infection. Reporting of resistance data in E. coli
bacteraemia helps in making local risk assessments on patients transferred from
other hospitals.77
9.1.8 Is there evidence for high/low risk areas within a healthcare facility?
Sharing a room with a colonized patient and admission to ICU are risk factors for
acquisition of carbapenem-resistant organisms.78,79,80 A German point prevalence
study in 2011 of 56 hospitals showed that, overall, prevalence of resistance was
highest on intensive care wards (ESBL E. coli 2.5% on ICU) and higher on medical
wards compared with surgical wards81 as also seen in a UK study.82 A European
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survey of 19,888 patients, mainly in Belgium and France, showed the highest
prevalence of hospital-acquired infection in intensive care units (28.1%).83
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.84,85 In one series of
carbapenem-resistant Acinetobacter and Klebsiella isolates over half were obtained
from patients admitted from long-term acute care facilities.86
Evidence
The intensive care unit in acute hospitals and any long-term care facility have higher
prevalence of MDR Gram-negative bacteria than general wards. 2+
Recommendation
Patients at high risk for carbapenem-resistant organisms include those admitted to
ICU 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).
However other ESBL Enterobacteriaceae appear less likely to spread. It remains
unclear why the E. coli ST131 lineage has been so successful compared with many
other ESBL-producing strains.87 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).Error: Reference source
not found,Error: Reference source not found,88,89 Infection prevention and control relies on the
consistent application of SICPs e.g. hand hygiene, appropriate use of personal
protective equipment (PPE), and ensuring a clean and well-maintained care
environment. Patient screening, used as part of a bundle of infection prevention and
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control measures, is effective in identifying carriage of ESBLs by E. coli, Klebsiella
pneumoniae and Enterobacter spp.90,91,92
For colonization or infection with ESBL-producing bacteria, the presence of a
gastrostomy, urinary catheter or a nasogastric tube were risk factors.93,94,95 Antibiotic
treatment has been shown to select for ESBL-producing E. coli in a variety of
healthcare setting.96 For some strains, piperacillin-tazobactam can select for
quinolone-resistant bacteria that produce CTX-M97 and carbapenem use is
associated with acquisition of carbapenem resistant E. coli.98
Screening for carriers with subsequent isolation of those identified is effective in
preventing transmission and is important for early recognition.99 Awareness of
carriage is important and, therefore, communications regarding those identified to be
infected or colonized with multi-resistant 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.Error: Reference source not found,100 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.Error:
Reference source not found
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 workers101
and ensuring the aseptic care of vascular catheters and endotracheal tubes.Error:
Reference source not found Increased cleaning of the general care environment has
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been the next-most-frequent outbreak intervention,Error: Reference source not found
reflecting the concern that Acinetobacter spp. can survive for months on wet or dry
surfaces, thereby facilitating nosocomial transmission.102 Disinfection regimens used
on surfaces include 0.1% hypochlorite,103,104 and, increasingly, hydrogen peroxide
vapour.105,106,107,108,109
Screening of the patient is suggested in a number of studies.Error: Reference source
not found,110,111 Several also advocate reduced prescribing of broad-spectrum
antibiotics, such as fluoroquinolones or carbapenems.Error: Reference source not
found,112 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.113,114,115
Often, the use of a multifactorial or ‘bundle’ approach is the most effective way of
controlling this organism.116
9.2.3 Pseudomonas aeruginosa
Sources and mechanisms of transmission vary, and surveillance is complicated by
the close association of patient and environmental isolates. Association with moist
environmental sources is well documented, though significant persistence on dry
surfaces including hospital linen and floors with a range of 6 hours to 16 months is
reported.117 Water systems act as a source of infection, or indicate environmental
contamination from other sources e.g. staff hands or reusable care equipment being
cleaned in hand-wash sinks.Error: Reference source not found Levels of sink
colonization are higher in critical care areas than general wards.118
Transmission occurs via the hands of healthcare workers, contaminated either from
patients or from the environment and has been reviewed systematically by
Loveday.Error: Reference source not found,119,120,121,122,123,124 Pseudomonal carriage
on hands may be less persistent than with other Gram-negative bacteria, but other
factors such as glove usage and artificial nails contribute.Error: Reference source
not found,125,126,127 Patient to patient transmission can occur via the air among cystic
fibrosis patients, with evidence of infectious droplet nuclei128 or via patient hand and
environmental contamination.129,130
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Sporadic and epidemic strains tend to co-exist and may be difficult to track without
molecular typing.Error: Reference source not found,131 There is no evidence for the
effect of routine surveillance on the control of MDR Pseudomonas, but reports of
outbreak interventions support the utility of screening.132,133
There is little evidence that isolating patients in single rooms reduces endemic multi-
resistant Pseudomonas levels. In outbreak settings, use of isolation measures as
part of a multi-facetted infection control regime is usual, but direct evidence for the
impact of isolation alone is lacking.Error: Reference source not found,134,135,136,137,138
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.Error: Reference source not found,Error: Reference source not found,Error: Reference
source not found,Error: Reference source not found,139 Care should be exercised with production, storage
and turnover of cleaning products, since the organism has a degree of disinfectant
tolerance and there is evidence for pseudomonal contamination of detergent-type
cleaning products.140,141
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 permitting spread of such infections being
detected earlier. 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,
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algorithms for testing need to be developed, if universal testing is not applied.
Testing only cephalosporin-resistant isolates 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.142
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.143 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
meropenem MIC >0.12 mg/L should be treated with suspicion, not just those with
MICs above the clinical breakpoint of 2 mg/L; the screening MIC of >0.12 mg/L
equates to a zone <25 mm diameter on Mueller-Hinton agar.144 Ertapenem is a more
sensitive indicator of carbapenemase production than meropenem or imipenem but
is less specific as it is more-affected 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.Error: Reference source not found
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 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
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available for specific carbapenemase gene detection, but are not yet widely used.
Most meropenem resistance in Pseudomonas aeruginosa is due to loss of OprD
porin and not carbapenemase. Sensitivity to ceftazidime, piptazobactam and
carbenicillin despite meropenem resistance suggests this mechanism and that
neither high level infection control action nor submission to a reference laboratory is
needed.
To detect ESBLs, E. coli, Klebsiella spp. and P. mirabilis should be screened for
clavulanate-reversed resistance to ceftazidime and cefotaximeError: Reference
source not found or cefpodoxime. AmpC producers are resistant to cefotaxime
(reversed by cloxacillin) but susceptible (or intermediate) to cefepime. For AmpC-
inducible genera, such as Enterobacter and C. 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 the cephalosporin alone and those discs containing
clavulanic acid. A zone expansion of >5 mm indicates ESBL production.
Alternatively, an Etest strip is used to demonstrate at least 8-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 24 hours. Detection within a few
hours is possible if molecular tests are applied directly to the clinical specimen,
though 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. Those media seeking ESBL producers often have good sensitivity but
poor specificity in distinguishing these organisms from strains that hyperproduce
AmpC enzyme.145,146,147 The sensitivity of media seeking carbapenemases varies with
the particular enzyme,148 with OXA-48 the hardest to detect owing 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:
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(i) The chromogenic oxyimino-cephalosporin HMRZ-86 turns from yellow to red
on hydrolysis.149 If used in combination with inhibitors, it can be used to
distinguish strains with AmpC, ESBLs or metallo-carbapenemases, though
KPC enzymes may be confused with AmpC and it is unclear whether OXA-48
is detected.
(ii) Acidimetric -lactamase tests can be adapted to detect carbapenemase
producers, as in the ‘Carba-NP’ test where, again, some authors report
problems in detecting OXA-48.150,151,152
(iii) MALDI-ToF assays for carbapenemase activity, exploiting the molecular
mass change that occurs when the -lactam molecules are hydrolysed.153
Molecular tests can be used to seek -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.154
PCR may be used directly on rectal swabs, without culture and can give results
within 1h from the specimen being taken.155 Sensitivity and specificity are good,
though positive results are often obtained for patients from whom the laboratory fails
to grow a carbapenemase-producing pathogen.156 This is a wider issue with
molecular diagnostics, when used directly on specimen and may either indicate a
poor positive predictive value or that culture is not the ‘gold standard’.157
Recommendation
The minimum susceptibility tests performed on Gram-negative bacteria from any site
should include meropenem; in addition for Enterobacteriaceae, cefpodoxime, and,
for Pseudomonas aeruginosa, ceftazidime. Strong
9.3.1.1 When to seek reference laboratory typing of isolates
To inform cross-infection and outbreak investigation
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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. pneumoniae 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.158 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 falsely being linked, 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 as to a source, since the isolate is likely to have come from
the patient rather than the patient having acquired it from 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 organisations and
commissioners of healthcare. The World Health Organisation (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 CSF isolates across Europe.159 EARS-NET
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identified the early accumulation of carbapenemases in K. pneumoniae in Greece,160
though they are now also proliferating in other countries such as Italy. Hence travel
history on admission can be a useful indicator of risk of carriage of multi-resistant
organisms.
In the UK (except Scotland), Public Health England collects susceptibility data in a
voluntary scheme for bloodstream isolates of all species. A web-based database
application, AmWeb, will facilitate electronic submission of antimicrobial susceptibility
data for all bacterial isolates, regardless of whether these are from blood,Error:
Reference source not found but there is wide variation in participation, mostly due to
the range of different laboratory information systems in use. AmWeb will integrate
with the Second-Generation Surveillance System to be introduced in 2015 to provide
data linkage to other PHE databases. Electronic Reporting System for meropenem
resistance is being introduced. In addition, the BSAC Resistance Surveillance
Project (http://www.bsacsurv.org) tracks prevalence of antibiotic resistance for a
range of species and antibiotics in bacteraemia and lower respiratory tract infection,
based on collection and central testing of isolates from a panel of 40 laboratories
across the UK and Ireland.
Evidence
There is a significant increasing trend of carbapenem-resistant K. pneumoniae and
other Gram-negative bacteria in most European countries, with major proliferation in
Greece and Italy, suggesting a risk of occurrence in UK 2+
Recommendation
Laboratories should test meropenem susceptibility in all clinically significant Gram-
negative isolates. Strong
Travel history (i.e. countries or known endemic area visited within a year) should be
collected for all patients with carbapenemase producing Gram-negative bacteria.
Strong
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9.3.3 How should we undertake local screening, why is it important and how should
it be interpreted?
Screening at hospital level is useful for infection control, and to track resistance
types (e.g. carbapenemase producers) by rectal swab or stool on admission, weekly
during hospital stay and at discharge (Table III). Rectal swabs have maximum
sensitivity for multi-resistant pathogens (other than Acinetobacter), but it is critical to
ensure the compliance of staff with guidance on how and when to take samples by
means of audit and feedback as well the specific actions arising from a positive
result.161 When a carbapenem-resistant organism is identified (or an isolate with any
other index resistance sought), any epidemiologically-linked patients should be
screened. Screening of other patients depends on an assessment of risk of shedding
of the organism and duration of exposure and is less likely to be required if the
patient has been isolated from admission.162
The primary purpose of local screening is the detection of outbreaks of resistant
colonizing or infecting organisms with minimum delay. Few hospitals have sufficient
single rooms to allow segregation of all patients at risk when they are admitted.
Therefore, local identification of carriers allows prioritisation of single rooms,
potentially limiting spread. Hospital level surveillance provides faster notification of
an emergent problem than awaiting results from the reference laboratory, particularly
if a single clone and species is responsible. Passive surveillance of clinical infections
alone will be too delayed to help to limiting spread. In an outbreak, isolation and
infection control precautions are only effective if combined with active
surveillance.Error: Reference source not found A plasmid-based outbreak (e.g.
carbapenemase producers) can be more difficult to recognise because multiple
bacterial species may be involved.
9.3.4 At what point should passive surveillance switch to active surveillance
(screening)?
Examination of routine diagnostic tests or discharge summaries requires little
resource, compared with screening an entire ‘at risk’ group. However screening
quickly identifies patients colonized with MDR Gram-negative pathogens who require
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38
source isolation but who otherwise might be placed in a shared bay. Choosing to
screen depends on available resources, outbreak progression and clinical
characteristics. Current national advice to screen patients at risk for carbapenemase-
producing Enterobacteriaceae is made despite a low prevalence of these organisms
in most UK centres because the clinical risk of spread is thought to be high.Error:
Reference source not found
Passive surveillance of routine cultures did not distinguish 12 (86%) of 14 patients
later found to have faecal carriage of carbapenemase-producing Klebsiella
pneumoniae.163 MIC was highly dependent on the inoculum. Routine cultures identify
patient carriage of ESBL Enterobacteriaceae on average 3 days later than active
screening.164 The virulence of the strain and the host susceptibility as well as the
sensitivity of the diagnostic method will affect the efficiency of passive identification
of patients.Error: Reference source not found Hence no single recommendation can
be made.
Evidence
Passive surveillance is less sensitive and slower in identifying outbreaks of MDR
Gram-negative infections than active screening. 3
Recommendation
Active screening rather than passive surveillance is recommended for high-risk
specialties. Conditional
9.4 What is the evidence that infection prevention and control precautions prevent transmission?
Trials of infection control strategies are difficult to mount with sufficient power to
determine efficacy, and most trials use a package of measures, so the effect of
single interventions cannot be extracted. A systematic review of infection control
precautions in cancer patients and stem cell recipient care settings showed a
combination of prophylactic antibiotics, control of air quality and isolation in a room
was associated with a lower rate of mortality (0.60 95% CI 0.50-0.72) at 30 days.165
Gram-negative bacteraemia was reduced by the package of measures. Gram-
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negative infections also were significantly less common in patients who were isolated
but there were insufficient data to assess the specific effect on multi-resistant strains.
Environmental cleaning and screening are discussed in other sections.
9.4.1 Are standard infection control precautions sufficient to stop transmission?
Existing national guidelines are unequivocal that Standard Infection Control
Precautions (SICPs) should be used by all staff, in all care settings, at all times, for all patients – adults, children and infants, whether infection is known to be present or
not, to ensure the safety of those being cared for, staff and visitors in any
environment where care is given. SICPs are the basic infection prevention and
control measures necessary to reduce the risk of transmission of infectious agent
from both recognised and unrecognised sources of infection.
Sources of (potential) infection include blood and other body fluids secretions or
excretions (excluding sweat), non-intact skin or mucous membranes and any
equipment or items in the care environment that could have become contaminated.
To be effective in protecting against infection risks, SICPs must be used
continuously by all staff. Patients who move frequently between the hospital, the
community and long term care facilities may render location-based screening
inadequate as a means to identify outbreaks.
However, as underscored by recent systematic reviews,166,167 there is a paucity of
evidence directly testing infection prevention and control advice as related to Gram-
negative organisms, particularly multi-resistant strains. A similar lack of evidence
was noted in the ESCMID guidelines on preventing transmission of MDR Gram-
negative bacteria.Error: Reference source not found Nevertheless, the European
Centre for Disease Prevention and Control (ECDC) risk assessment on
carbapenemase-producing Enterobacteriaceae showed that there was agreement
across Europe that SICPs are an essential integral part of any strategy to control
multi-drug resistant Gram-negative organisms.168 The supporting European survey of
carbapenemase-producing Enterobacteriaceae emphasised the importance of
diagnosis, early containment through patient screening, and SICP.169
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A number of authoritative bodies have produced detailed guidance on
carbapenemase-producing Enterobacteriaceae in particular based on expert
consensus; these emphasise the importance of continuous implementation of SICPs,
with a particular emphasis on hand hygiene.Error: Reference source not found,Error:
Reference source not found,170,171 Public Health England, Centers for Disease Control and
ESCMID all recommend Contact Precautions (patient isolation) in addition to SCIPs
for all colonized or infected patients with MDR Gram-negative bacteria, as well as
those previously colonized and not known to be free of these bacteria.Error:
Reference source not found,Error: Reference source not found,Error: Reference source not found All patients
should be assessed for transmission risk on or before arrival at the care area and
reviewed for any changes in the risk during their stay.
In an endemic setting (with constant challenge from admissions of colonized or
infected patients), ESCMID does not recommend isolation for ESBL-E. coli. Other
guidance emphasizes basing isolation on a risk assessment while maintaining high
levels of hand-hygiene compliance and environmental cleaning.Error: Reference
source not found The ST131 clone of E. coli appears more readily transmissible and
further study is needed.
Other guidelines use general principles based on a range of pathogens. Both
National Evidence-Based Guidelines (EPIC 3) and Health Protection Scotland’s
National Infection Prevention and Control Manual specify good-practice standards
based predominantly on expert consensus or Health and Safety legislation rather
than evidence from controlled trials.Error: Reference source not found,172
Standard Infection Control Precautions (SICPs) includeError: Reference source not
found,173 the following elements:
Hand hygiene;
Environmental cleanliness, including the decontamination of patient care
equipment, the safe management of linen and disposal of healthcare (clinical)
waste;
Safe use and disposal of sharps;
Aseptic practice.
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Respiratory hygiene
Assessment of infection risk, use of personal protective equipment and patient
placement
Contact Precautions entail donning personal protective equipment on room entry and
discarding before exiting the patient room. A single room is preferred.Error:
Reference source not found Hand hygiene is performed before touching patient and
prior to wearing gloves for touching the patient and the patient’s environment.
Strategies to minimise the transmission of pathogens, including MDR Gram-negative
bacteria, will only be successful if there is a reliable high level of compliance to SICP
and Contact Precautions by all healthcare workers.174,175 Training, education, audit
and feedback are therefore important. Low levels of compliance to hand hygiene and
inappropriate glove usage are commonly described.Error: Reference source not
found,176 Invasive medical devices breach the body’s natural defence mechanisms
and increase the likelihood of infection and colonization, therefore device avoidance
and minimisation are important.
Evidence
Consistent application of SICP with Contact Precautions for patients colonized or
infected with MDR Gram-negative pathogens reduces transmission 3
Recommendations
In addition to Standard Infection Control Precautions, apply Contact Precautions for
those patients who present an infection risk Strong
Good Practice RecommendationsError: Reference source not found
Apply and maintain Standard Infection Control Precautions (SICP) in all care
settings, at all times, for all patients.
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9.4.2 Screening
9.4.2.1 What is the role of screening in patients and staff?
Early detection of patients colonized or infected with MDR Gram-negative organisms
is important for managing their status effectively and for implementing timely
interventions to prevent subsequent spread. Screening of potential colonization sites
of patients, e.g. faeces, is essential in limiting the spread of carbapenemase-
producers in hospitals. Identification of other MDR Enterobacteriaceae is useful to
identify those patients whoC e.g. may need carbapenems if treated empirically.
Although ESBL E. coli are often resistant to ciprofloxacin, the proportion varies
widely by country.Error: Reference source not found,177,178
In a multicentre German study of screening of patients with haematological
malignancies, colonization rates with ESBL Enterobacteriaceae varied between 5.3
and 21.8% of patients.179 In a Korean study of ICU patients, 28% of 347 were found
to have ESBL Enterobacteriaceae faecal carriage on admission and another 12%
acquired these organisms during follow-up in ITU. As assessed by PFGE, none of
the acquisitions were nosocomial transmissions, but the methods used would not
have readily identified plasmid outbreaks.180 Routine screening of urine for ESBL E.
coli and Klebsiella spp. followed by single-room isolation of carriers did not result in
any significant reduction in numbers of ESBL producers isolated from non-urinary
sites in hospital.181 Against the background high prevalence of ESBL
Enterobacteriaceae in Korea, routine screening of carriage sites was not cost-
effective in intensive care units.Error: Reference source not found The risk of
dissemination in the local community was high. In Europe ST131 CTX-M-15 strains
are common but specific screening for that strain has not been studied.
A nationwide intervention in Israel against a clonal outbreak of carbapenem-resistant
ST258 K. pneumoniae with a KPC carbapenemase was successful because it
depended on mandatory patient screening and isolation, and patient and staff
cohorting.Error: Reference source not found Short- and long- term care facilities
were involved, as the latter were a reservoir for reintroduction to acute units.
Compliance with national guidelines was reinforced by visits to facilities, reporting of
carrier and isolation status and contact tracing. In high-intensity units such as
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intensive care, rectal swabs from the all the patients on the ward were screened.
Two rectal swabs negative by culture and one by PCR were required before
screening was discontinued for an individual patient in any ward. The programme
successfully reduced acquisition of carbapenem-resistant organisms from 55.5 to 4.8
instances per 100,000 patient days. Screening for non-fermenters such as
Pseudomonas or Acinetobacter is not supported by high quality evidence, but may
be performed in outbreaks (Tables III and IV).
There is usually no indication for screening faecal cultures from healthcare workers
or family members, though good personal hygiene should be emphasised. Outbreak
investigations that do not identify a single environmental source suggest
transmission is occurring via the hands of hospital staff, but hand cultures are usually
negative, presumably because contamination is transient.182 Gram-negative
organisms isolated from nurses’ hands are in most cases different from those
causing significant infections in patients.Error: Reference source not found,183
However outbreak reports are selective and open to bias.
Evidence
Mandatory screening and full implementation of SICP combined with Contact
Precautions throughout the area of care is effective in controlling clonal outbreaks of
carbapenemase-producing pathogens 2++
Routine screening of carriage sites for ESBL-producing Enterobacteriaceae for
infection control purposes may not be cost effective if community transmission and
carriage is frequent. Screening and isolation of carriers of ESBL Klebsiella, is more
likely to be useful than that for ESBL Enterobacter, Serratia or E. coli. However,
specific screening for specific clones has not been studied. 3
Recommendation
Screening for rectal and wound carriage of carbapenemase-producing
Enterobacteriaceae should be undertaken in patients at risk Strong
Good Practice recommendation
Routine screening of family contacts and staff is not recommended
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9.4.2.2 What organisms should screening include?
Enterobacteriaceae and non-fermenters (i.e. A. baumannii and P. aeruginosa)
constitute the majority of MDR Gram-negative pathogens causing healthcare-
acquired infections. Carbapenem-resistant organisms should have priority, as
meropenem is currently the most widely used broad-spectrum antibiotic of last
resort. Some multi-resistant strains are readily transmissible and require patient
isolation. Most carbapenem resistance seen in Enterobacteriaceae, at least among
reference laboratory submissions, is now associated with production of KPC, OXA-
48, NDM and VIM carbapenemases; almost all carbapenem resistance in A.
baumannii is associated with OXA-23, 40, 51 and 58-related carbapenemases.
Carbapenem resistance in P. aeruginosa may involve carbapenemase production
but is more commonly related to porin loss, which confers a narrow spectrum
carbapenem-specific resistance profile.
ESBL producers and plasmid or chromosomal AmpC Enterobacteriaceae are
resistant to a number of antibiotics and infection control precautions are used to
prevent transmission. A major driver for the use of carbapenems is the suspicion of
the presence of ESBL. Screening for ESBL producers thus may be useful in guiding
and thereby limiting empirical carbapenem use, although there are no confirmatory
reports available. Where isolation facilities are limited, cephalosporin-resistant
Enterobacteriaceae cases and carriers should have a lower priority than patients
carrying a carbapenem-resistant Enterobacteriaceae. Subject to local risk
assessment, colonized patients with diarrhoea or discharging wounds would usually
take precedence for single rooms over patients without those characteristics but the
same multi-resistant organism.
Recommendation
Screening for carbapenem-resistant A. baumannii and MDR P aeruginosa is required in management of outbreaks. Strong
9.4.2.3 Who, how and when to screen patients for MDR Gram-negative bacilli?
9.4.2.3.1 Whom to screenThe potential risk factors identified for colonization or infection with MDR Gram-
negative organisms are similar and wide ranging and include recent antimicrobial
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treatment, presence of indwelling devices, severity of illness, admission to an ICU,
transfer between hospital units, residence in long-term care facilities; previous
surgery, hospital inpatient stay within the preceding year (particularly overseas in an
endemic area), recent solid organ or stem cell transplantation, presence of wounds,
presence of biliary catheter and mechanical ventilation.Error: Reference source not
found,Error: Reference source not found
Although there are only limited data available from studies on inter-healthcare
transmission of carbapenem-resistant Gram-negative bacteria within countries, a
number of descriptive studies indicate that cross-border transfer of patients is
associated with a risk of transmission of carbapenem-resistant organisms,
particularly in respect of patients coming from Middle East, India, Pakistan, Italy and
Greece.Error: Reference source not found This applies to patients transferred from
endemic areas to healthcare facilities in another country and where patients had
received medical care abroad in areas with high rates of carbapenem-resistant
organisms. Based on this, a recent ECDC report recommended that all countries
should develop guidance for active screening of faeces of all patients transferred
from any healthcare facility in an endemic area.Error: Reference source not found
Among the first 250 patients in the UK with an isolate producing the NDM
carbapenemase, 100 had a travel history, with half of these having travelled to the
Indian subcontinent.184
All patients with epidemiologic links (same hospital unit or care home) to an index
and secondary cases should be screened to determine the extent of secondary
transmission. However carriage may be prolonged in the community (especially in
patients with urinary catheters) and the chronology can be difficult to determine.
Hence isolation is started on readmission. Admission screening by rectal swab (or
axilla/groin swab for Acinetobacter) is required for patients transferred from countries
or institutions (including those in the UK) with a prevalence of epidemic or endemic
carbapenem-resistant Gram-negative pathogens, as well as those patients with
previous colonization or infection. However that assumes the receiving area
(infection control practitioner) has been informed appropriately of prior hospitalisation
and carriage data and where endemic or epidemic problems are present.
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Given reported prolonged gastrointestinal carriage of MDR Gram-negative
organisms, clearance samples are not recommended. Patient isolation should
continue for the duration of the inpatient stay unless there is extensive spread and
large numbers of colonized or infected patients. Cohorting affected patients together
may then be needed. Colonized or infected patients should be isolated if re-admitted
as emergency cases and should then be screened. Previously colonized or infected
patients should be screened as outpatients if admission is planned and isolated on
admission if screening yields the relevant organism. A method of flagging records is
needed.185
9.4.2.3.2 How to screen
As the intestinal flora is the main source of MDR Gram-negative bacilli (except
Acinetobacter), a rectal swab (or stool ) is preferred for ease of collection handling
and processing,Error: Reference source not found,186 but faecal material must be
visible on the swab before putting into transport medium. A stool sample may be
used if there is a risk of mucosal trauma. Rectal or perirectal swabs or stool samples
have higher yield than testing of other body sites.Error: Reference source not found
In patients with indwelling devices, specimens from the related site should be
screened. Skin swabs, urine and sputum should be checked in those with chronic
wounds, indwelling urinary catheters, or endotracheal intubation. Acinetobacter is
best detected in axilla, groin or wound swabs.187
Screening tests should have a turnaround time of less than 48 hours. Confirming the
specific carbapenemases is important, but requires molecular methods which often
limit availability to reference laboratories. Nevertheless, locally performed phenotypic
tests can be extremely helpful as the report is available without delay. These tests
are easy to implement for most laboratories provided that the resources are available
and laboratory staff have been trained.Error: Reference source not found,Error: Reference
source not found If carbapenemase confirmation is not possible, isolates should be sent to
reference laboratories, though infection control precautions should not be delayed.
These tests can prove even more useful if they are interpreted in conjunction with
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data on the background prevalence of carbapenem-resistant organisms in a specific
region. Fast diagnostic turnaround time and timely communication of laboratory
results to physicians, nurses and the infection control team are extremely important
for infection prevention and control and clinical therapy
Commercial media for detection of carbapenemase-producing Enterobacteriaceae
are increasingly available. In a comparison of four chromogenic media used to detect
carbapenemase-producing Enterobacteriaceae, chromID Carba had the best
sensitivity and specificity though this may not be adequate for OXA-48.Error:
Reference source not found Disk or tablet diffusion synergy tests use meropenem
combined with boronic acid to inhibit KPC carbapenemases or EDTA to inhibit
metallo (IMP, NDM, and VIM) carbapenemases). Cloxacillin inhibits AmpC but not
KPC, facilitating discrimination between isolates with these types of enzyme in an
Etest.Error: Reference source not found High-level temocillin and
piperacillin/tazobactam resistance without potentiation of meropenem by EDTA is a
marker of OXA-48. Molecular confirmation tests show high sensitivity and specificity
and are used in reference laboratories but are expensive and will not detect novel
genes. Although several pseudomonas-selective media are marketed, there are no
specific data on screening methodology, frequency or duration with respect to P.
aeruginosa.Error: Reference source not found P. aeruginosa resistant to
carbapenems but susceptible to other -lactams can be assumed not to have
carbapenemases and do not warrant reference investigation.
The accuracy of carbapenemase detection may be affected by the species and
origin of the pathogen, type of carbapenemase and other resistance properties, such
as porin loss or ESBL production. Phenotypic confirmatory tests such as the
Modified Hodge test are within the capability of most local laboratories but
derepressed AmpC enzymes (and sometimes ESBLs) are associated with weak
false positive Modified Hodge tests, especially with ertapenem. The test can be
difficult to interpret. Colorimetric and MALDI-ToF methods can be used.188 Some
organisms with OXA-48-like carbapenemases exhibit only low-level carbapenem
resistance without cephalosporin resistance so escaping the standard identification
methods.Error: Reference source not found
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High sensitivity and specificity in detecting ESBLs can be achieved using
chromogenic selective media, despite mixed flora in catheter urine or faeces.
However, competitive bacterial flora resistant to multiple antibiotics, especially
cephalosporins, can reduce the specificity of selective media. The use of CTX-M
Chromagar (CHROMagar, Paris, France) is superior to ESBL chromogenic agars if
seeking cases with a CTX-M ESBL in an outbreak, but the medium is less suitable
where, for example, TEM 10 ceftazidime-ase is present.
Screening for carriage of MDR A. baumannii has been described using a variety of
media with samples from various body sites including the axilla, groin, wounds,
rectum or pharynx.Error: Reference source not found,Error: Reference source not found,189,190,191,192
There is no consensus on site or method for screening for Acinetobacter, and
sensitivity is poor.193 Most carbapenem resistance involves OXA-23/40/51/58/143-
like carbapenemases whilst a few isolates have metallo-carbapenemase.194,195
9.4.2.3.3 When to screenThere is insufficient evidence to mandate routine screening of all patients for
colonization by all MDR Gram-negative organisms. However screening of high-risk
patients is used in control efforts for carbapenem-resistant Enterobacteriaceae, e.g.
patient transfers from hospitals where these organisms are prevalent. The
contribution of this practice to decreasing transmission is unknown. Nevertheless
identifying patients who are at high risk of colonization or infection with MDR
organisms (including carbapenem-resistant organisms) and performing screening by
rectal swab (or skin for Acinetobacter) on admission to healthcare facilities is
recommended, and is now becoming more widespread in healthcare setting.Error:
Reference source not found Patients at high risk include patients admitted to ICU
and from long-term care facilities e.g. care homes or endemic areas.
Screening for carriage of ESBL Enterobacteriaceae can identify patients in whom
empirical treatment with meropenem is justified, thus supporting antimicrobial
stewardship. Discharge screening for ESBL or carbapenem-resistant organisms is
appropriate when admission screening is practiced or if a colonized patient is likely
to be readmitted for further procedures or is going to a long-term care facility.
Patients with carbapenem-resistant organisms should have notes flagged pending
readmission or if they transfer to long-term care facilities, where there is a risk of
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further spread. Long-term care facilities should be informed of positive results of
discharge screening on their transferees and may need to consider if their routine i.e.
standard infection control precautions are robust enough in caring for these patients.
Good Practice Recommendations:
Effective communications between healthcare settings will help facilitate efficient
patient transfers and are crucial in reducing spread.
Local screening policies should be developed to define those patients at high risk of
carriage of, for example, carbapenemase-producers.
9.4.2.4 What can be done in the case of patients unable or unwilling to consent to a
rectal swab?
On being admitted to hospital, a patient consents to receive those diagnostic and
screening tests that are deemed necessary to the management of their presenting
problem. In situations where a patient is incapacitated, those giving care may
proceed with any interventions deemed necessary to provide medical treatment for
the patient's well-being. This follows the principles of ‘implied consent’, i.e. it is
reasonable to assume the person would consent if they were not incapacitated and
able to do so. Implied consent is already used for MRSA screening even for patients
who have capacity to consent for themselves.
Screening as part of the ward/hospital policy to guide antimicrobial therapy and/or
prevent disease transmission does not require specific written consent but verbal
agreement from the patient, wherever possible, before sampling is conducted is
required. Individual, religious and societal concerns have to be respected. Patients
should be informed, whenever possible, of the need and reason for screening i.e.
that it is for their benefit and that of other patients, and what it involves. They should
be given the option of who carries it out, including self-screening but only after
assessment of patient’s ability and willingness to comply and safety of the
procedure. The option of a same sex healthcare practitioner should be provided.
Some patients may be unwilling to accept a rectal swab but will provide a stool
sample, though this may result in delay or absence of a sample. Ideally, patients
should be placed pre-emptively in an isolation room while the screening results are
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awaited but this is unlikely to be practicable in many high turnover wards. Patients
having chemotherapy or with an underlying bowel condition (stoma, colon cancer,
recent anal or rectal surgery) may be more easily screened using stool.
Nevertheless, rectal swabs can be safely collected in haematology patients.196
9.4.2.5 How frequently does screening need to be performed?
Extensive active screening during outbreaks due to carbapenem-resistant organism
is recommendedError: Reference source not found (e.g. follow-up screening of
negative cases at weekly intervals and/or for all in-patient contacts with confirmed
cases). Although such accounts must be interpreted with caution, experience from
outbreaks of MDR Gram-negative organisms, including carbapenemase- and ESBL-
producing Enterobacteriaceae, in acute healthcare settings suggests that the
implementation of screening for early detection and isolation of colonized patients
coupled with Contact Precautions can help control transmission.Error: Reference
source not found,Error: Reference source not found,197 Screening of those not known to be carriers
for carbapenem-resistant organisms in an endemic situation is advisable at least
weekly and on discharge.
9.4.2.6 Is there evidence for effective interventions on positive patients i.e. can
carriage be cleared?
A number of studies have evaluated the duration of colonization with MDR Gram-
negative bacteria. Studies of hospital inpatients suggest they tend to remain
colonized for the duration of their stay.Error: Reference source not found,198,199,200
Most studies evaluating the duration of colonization outside of acute settings for a
range of MDR Gram-negative bacteria have identified mean durations of colonization
of months rather than days.Error: Reference source not found,201,202,203,204 This
duration is anyway likely to reflect the particular strain, not its resistance.
Several studies have investigated the duration of colonization with carbapenem-
resistant Enterobacteriaceae following discharge from acute care facilities. Risk
factors for prolonged carriage of MDR Gram-negative bacteria tend to be associated
with healthcare-contact, underlying medical conditions and the presence of invasive
devices.Error: Reference source not found,Error: Reference source not found,Error: Reference source not
found,205 For example, Lubbert et al. evaluated prolonged colonization following an
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outbreak of carbapenem-resistant K. pneumoniae following discharge from an acute
hospital.Error: Reference source not found Although 26 (31%) of the 84 patients
included tested negative for carbapenem-resistant K. pneumoniae at one month post
discharge, 45% remained colonized at 6 months and one patient remained positive
for almost 40 months. Two other studies found that around half of patients colonized
at the time of hospital discharge were spontaneously free by 6 months.Error:
Reference source not found,Error: Reference source not found However, a number of studies
identified patients who retested positive after negative screens, suggesting the
gastrointestinal colonization is suppressed rather than eliminated in many
cases.Error: Reference source not found,Error: Reference source not found For this reason, the
authors of these studies recommend at least 3 consecutive negative screens
separated by at least 24 hours before a patient could be considered
‘decolonized’.Error: Reference source not found,Error: Reference source not found,Error: Reference source not
found In practice, colonized inpatients should be considered carriers during the rest of
their hospital admission. The risk period from previous hospitalization exceeds one
year.
There is no effective equivalent of the topical suppression used to reduce shedding
of MRSA in the healthcare environment. Attempts at eradication of MDR Gram-
negative organisms from the gastrointestinal tract have not been
successful.206,207,208,209 Selective decontamination of the digestive tract can produce
some temporary reduction in the number of organisms in faeces (see section 9.4.6).
Evidence-based criteria for discontinuing Contact Precautions for carbapenem-
resistant Gram-negative organisms in acute care settings have not been developed.
Given the likelihood for prolonged gastrointestinal carriage by these organisms and
risk of spread, organizations should be cautious in discontinuing Contact Precautions
(patient isolation). In most cases, Contact Precautions should continue for the
duration of the hospitalization during which the organism was first found on culture.
Patients readmitted within 12 months of that hospitalization should be considered
probably colonized and managed with Contact Precautions until at least one
negative screen is available.
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Evidence
Early recognition of patients infected with multi-drug resistant Gram-negative
organisms and implementation of rigorous infection control interventions is
usually associated with reduced secondary transmission. 3
Screening (except Acinetobacter) is most sensitive when performed on rectal
(or perirectal) swabs, or stool specimens. 3
Patients transferred from, or who have received medical care in a healthcare
facility in an endemic area in the UK or abroad, are at high risk of carriage of
carbapenemase-resistant organisms. 2++
Recommendations
A rectal swab (with visible material) or stool sample (and urine if catheter present)
should be used for screening for multiresistant Enterobacteriaceae and
Pseudomonas aeruginosa. For Acinetobacter, sample skin sites or if a catheter or
endotracheal tube is present, urine or respiratory secretion. Conditional
Each healthcare organisation should have access to robust microbiological
arrangements for detecting and reporting multi-drug resistant Gram-negative
organisms in routine clinical samples and for screening using highly-sensitive tests
with a rapid diagnostic turnaround time of <48h. Conditional
All patients transferred from, or with a history in the preceding year of admission to,
healthcare facilities with known endemic carbapenemase-producing
Enterobacteriaceae should be screened. Strong
In the event of secondary cases of carbapenem-resistant Enterobacteriaceae, SICP
and Contact Precautions should be monitored and reinforced with 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
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Where possible, single room isolation should be provided for patients with MDR
Gram-negative bacterial infection/colonization and Contact Precautions continued for
the duration of their stay. Conditional
Those with previous samples with carbapenem-resistant or other MDR Gram-
negative bacteria should be screened at the time of admission.
Conditional
9.4.3 Isolation and segregation
A long-standing principle of infection prevention and control is to physically
segregate those known to be infected or colonized with a pathogen of
epidemiological importance from those who are not infected or colonized. However
critical appraisal is difficult as segregation is usually assessed as part of a package
of measures. This physical separation can be achieved through: placing patients with
known/suspected infection in single rooms, and/or identifying and isolating patients
with the same, confirmed pathogen in a cohort room/area. An additional cohort
measure (nursing staff numbers permitting) is to identify staff to care for those
patients placed in cohorts. The implementation of screening cultures at the time of
admission or during a patient’s stay on a particular ward is a way to improve the
impact of physical segregation by identifying those who are colonized with the
pathogen of concern.
Placing patients known to be infected or colonized with MDR Gram-negative bacteria
in single rooms reduces transmission. Several studies have reported the impact of
converting a unit from multi-occupancy to single rooms on rates of MDR Gram-
negative infection/colonization.210,211,212,213,214 A Canadian study reported the
acquisition rate ratio of various Gram-negative bacteria, comparing an intervention
unit, which was converted to single rooms, with a control unit in a sister hospital,
which was not converted to single rooms.Error: Reference source not found The
number of Acinetobacter species, Klebsiella species, and Enterobacter species fell
significantly but Pseudomonas species and Escherichia species did not. A 20 year
before-after study from a US burns ICU that was converted to single rooms reported
a significant reduction in Gram-negative bacteraemia, the time to a first positive
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Gram-negative culture and mortality.Error: Reference source not found Significant
reductions were also reported in bloodstream infections due to P. aeruginosa, K.
pneumoniae, E. cloacae, E. coli and Providencia stuartii. However, there was no
control unit and improvements in burn care during the study may have contributed to
these reductions. A separate study from the same renovation reported an overall
reduction in infection rates and mortality and in non-enteric Gram-negative
species.Error: Reference source not found One study from a US ICU reported no
significant reduction in overall infection rates, or in rates of E. coli, Pseudomonas
species, Acinetobacter species, Klebsiella species or Serratia species.Error:
Reference source not found Again, this study did not include a control ward. Hand
hygiene compliance was low and did not increase when the unit was converted to
single rooms, in contrast to other studies.215,216
The impact of enhancing patient isolation aside from other interventions has been
evaluated. A French study in 2001 found that introducing patient isolation to care for
ESBL carriers resulted in a sequential reduction in ESBL incidence and hospital
acquisition.217 However this preceded emergence of CTX-M and Escherichia coli as
dominant factors. A study in a Vietnamese ICU found that improving patient isolation
by reinforcing hand hygiene, and limiting exchange of equipment, materials and staff
between patients did not reduce exogenous transmission of various Gram-negative
bacteria (gentamicin-resistant K. pneumoniae, ESBL-Enterobacteriaceae, amikacin-
resistant Acinetobacter species and P. aeruginosa), whereas rates of MRSA fell
significantly. However, this study did not include physical segregation of patients or
the use of gowns or aprons.218
Various studies have evaluated switching from a multi-occupancy ward to a single
occupancy ward. An Israeli study showed that there were significantly fewer
acquisitions of resistant organisms when an ICU was converted from a multi-
occupancy bay to single rooms.Error: Reference source not found The study
included a control ward, which was not converted. Patients in the single-room plan
ICU had a significantly lower acquisition rate of resistant organisms when compared
with the control multi-occupancy ICU during the same period (3/62 (5%) versus 7/39
(18%), respectively, P = 0.043). SICP were applied throughout, but hand hygiene
compliance was better in the single rooms. Although MDR Gram-negative organisms
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were included, the significant changes related to Gram-positive pathogens. Another
study found that the mean number of nosocomial infections and length of stay were
reduced significantly when multi-occupancy PICU was converted to single
occupancy.219 However, no control ward was used and no specific data on MDR
Gram-negative pathogens were reported.
Although these studies suggest that converting multi-occupancy wards to single
rooms reduces the spread of MDR Gram-negative pathogens, there are several
limitations. First, most studies do not include a control ward (although the two studies
that include a control ward both show a significant reduction in transmission).Error:
Reference source not found,Error: Reference source not found Second, hand hygiene compliance
is higher in a single room format compared with a multi-occupancy setting.Error:
Reference source not found,Error: Reference source not found Thus, it could be that improved
hand hygiene rather than improved physical segregation is the critical factor for
reducing transmission. All of the studies have been performed in an ICU setting,
limiting their applicability to settings outside of critical care. Converting wards to
single rooms often include other changes, such as the size of each bedspace and
the location and number of hand hygiene facilities, which could influence
transmission rates.Error: Reference source not found Single rooms are associated
with a number of drawbacks, particularly an increased risk of adverse events due to
reduced observation and psychological effects, so the requirement for patient
observation is a key consideration when deciding on the optimal configuration of
wards.220 Finally, patients are increasingly moved around the hospital for procedures
and investigations, challenging their segregation.
9.4.3.1 Cohorting staff
No studies have evaluated the impact of cohorting staff aside from other
interventions, but several have reported cohorting staff as an element of a successful
multifaceted strategy.Error: Reference source not found,Error: Reference source not found,221,222
9.4.3.2 Disposable aprons and gloves
Data are limited in terms of the most appropriate personal protective equipment to
use when caring for patients with MDR Gram-negative bacteria
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Studies have evaluated interventions that have included the use of gloves and
gowns or aprons as an element of contact precautions.Error: Reference source not
found,Error: Reference source not found,223,224 Hands and uniforms (or gloves and gowns or aprons
if worn) can become contaminated with MDR organisms.Error: Reference source not
found,Error: Reference source not found,225,226,227,228,229,230
The use of gloves is an essential part of prevention of transmission of infection and
the evidence has been reviewed elsewhere.Error: Reference source not found While
they protect hands from contamination with biological fluids and microorganisms,
they are not a substitute for hand hygiene and unnecessary use can result in
increased cross contamination. Loveday et al. recommended they should be
removed immediately after the activity has been completed and the hands then
decontaminated to prevent transmission as they may be contaminated during glove
use or during removal.Error: Reference source not found
Evidence
Units composed of single rooms have less transmission of MDR-GNR: A.
baumannii, ESBL-producing (and, by inference carbapenemase-producing)
Enterobacteriaceae, P. aeruginosa 3
Recommendation
Use disposable gloves and gowns or aprons to care for patients with MDR
Gram-negative bacteria: A. baumannii, carbapenem-resistant and ESBL-
Enterobacteriaceae, P. aeruginosa Strong
9.4.3.3 What is the role of isolation in the care home/hospital settings?
Current practices for the identification and isolation of patients with MDR Gram-
negative bacteria (in either single rooms or cohorts) vary widely among healthcare
facilities.231,232 A survey of 66 hospitals in 26 US states and 15 other countries found
that 74.2% isolated those with ESBLs, 93.9% carbapenem-resistant organisms,
81.8% MDR Pseudomonas species, and 84.9% MDR Acinetobacter species. There
was considerable variation in the duration of isolation and few facilities performed
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screening. Isolation of patients in long term care facility rooms may not be
practicable for psychological reasons.
A number of studies have evaluated the impact of isolating patients with ESBL
Enterobacteriaceae aside from other interventions.Error: Reference source not
found,233,234,235,236 A 6-year Canadian study evaluated the impact of placing patients
with ESBL Enterobacteriaceae in single rooms for the duration of their stay, and
applying contact precautions for symptomatic patients.Error: Reference source not
found There was an overall increase in ESBL Enterobacteriaceae
colonizations/infections, but a relative decrease in cases attributable to the hospital,
suggesting that local transmission was reduced. A 2-year before-after study in
France before the proliferation of CTX-M -lactamases found that the introduction of
admission and weekly surveillance combined with isolation of carriers resulted in a
significant reduction in the percentage of patients infected or colonized with ESBL
Enterobacteriaceae.Error: Reference source not found There was a significant
reduction in ESBL-producing K. pneumoniae but not MDR E. aerogenes. The study
has a number of important confounders, including an intervention to reduce
imipenem use, encouraging prompt discharge, and chlorhexidine bathing for isolated
patients. A study in a French paediatric hospital evaluated a sequential change in
isolation policy from placing patients in a single room to placing them in a cohort
block, applying modelling to test the impact on transmission of ESBL
producers.Error: Reference source not found No significant difference was identified
between the two isolation protocols, but the model suggested that single room or
cohort isolation reduced transmission of ESBL producers. Finally, a 12-month cluster
randomised study in 13 European ICUs evaluated chromogenic agar screening for
ESBL Enterobacteriaceae on admission and isolation of carriers vs. no admission
screening.Error: Reference source not found A hand hygiene improvement
programme for staff and chlorhexidine body washing for patients preceded the trial.
Of the 2129 Enterobacteriaceae resistant to third and fourth generation
cephalosporins found on screening, 29% were resistant to carbapenems. Screening
and source isolation was not associated with any trend (during the intervention
period) or step-change (compared with a baseline period) in rate of ESBL
transmission. However individual species were not analysed separately.
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Two studies have evaluated the impact of isolation on the transmission of A.
baumannii and P. aeruginosa.Error: Reference source not found,Error: Reference source not found
A 7-year before-after study in France evaluated across the whole hospital the
introduction of contact precautions, which included placing the patient in a single
room or cohort with other patients, and the use of gloves and gowns or aprons on A.
baumannii transmission.Error: Reference source not found Isolation precautions
were implemented for 2 years, then stopped for three years, then re-implemented for
2 years; the incidence of A. baumannii was significantly lower during the two periods
when isolation precautions were in use. The implementation of isolation precautions
was the only variable associated with lower A. baumannii incidence in multivariate
analysis. A follow-up study from the same group reported similar findings.237 A study
from an ICU in Brazil evaluated the introduction of contact isolation, including the use
of gloves and gowns or aprons, cohorting of medical items (stethoscopes etc), daily
surface cleaning and disinfection on the rates of MDR A. baumannii and P.
aeruginosa.Error: Reference source not found Bloodstream infections reduced
significantly during the intervention but species were not analysed separately. The
study compared rates of infections at two points during the intervention, with no
baseline period.
A number of other studies have implemented complex interventions that included
increased isolation of patients.Error: Reference source not found,Error: Reference source not
found,Error: Reference source not found,Error: Reference source not found,238 One study in a US ICU implemented
a multifaceted intervention centred on improved isolation of patients, including
admission screening for carbapenem-resistant K. pneumoniae but not for A.
baumannii or P. aeruginosa.Error: Reference source not found There was a
significant reduction in the rate of carbapenem-resistant K. pneumoniae but no
change in the rate of A. baumannii or P. aeruginosa. A study of various interventions
in six US hospitals found the only consistent predictor of successful control of K.
pneumoniae with KPC carbapenemases was a shorter length of stay.Error:
Reference source not found Three studies have evaluated the impact of a
multifaceted intervention to control the spread of A. baumannii. An intervention at US
field hospitals in Iraq including improved hand hygiene, contact precautions,
cohorting patients and staff resulted in a significant reduction in A. baumannii
ventilator-associated pneumonia.Error: Reference source not found A bundle of
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interventions including Contact Precautions, screening (on occasion), and regular
staff briefings significantly reduced the rate of MDR A. baumannii infections overall,
and in particular bloodstream infections due to the organisms in a Spanish
hospital.Error: Reference source not found Finally, a study in a Thai ICU reported a
significant reduction in MDR A. baumannii associated with the introduction of contact
precautions, cohorting colonized patients, screening and environmental disinfection
using bleach.Error: Reference source not found However Acinetobacter infections
are more common in Thailand than in UK.
Studies that have evaluated the impact of isolating patients in either single rooms or
cohorts generally lack a concurrent control unit, making it difficult to be certain that
changes in rate are attributable to isolation alone. The one study that included a
concurrent control ward demonstrated no significant decrease in transmission of
ESBL-producing Enterobacteriaceae.Error: Reference source not found
Evidence
Transmission of MDR Gram-negative bacteria is reduced by identifying
patients who are infected or colonized and placing them in single rooms or
cohorts. 3
Recommendations
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 Klebsiella sp, carbapenemase-
producing P. aeruginosa, ESBL E. coli and other Enterobacteriaceae, AmpC
Enterobacteriaceae. Strong
If there are insufficient rooms available, cohort isolate following local risk
assessment Conditional
Good Practice recommendation
Establish a flagging system for patient notes Conditional
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9.4.4 Hand hygiene
Hand hygiene is an essential part of prevention of transmission of infection in
healthcare and has already been reviewed in Loveday et al.Error: Reference source
not found Transient flora, including MDR Gram-negative bacteria, is acquired from
touching the patient or environment and is easily transferred to the next patient or
surface. In turn, this causes colonization and later (potentially) infection. Use of
alcohol hand rub (or liquid soap and water if hands visibly soiled) has been shown to
reduce the carriage of potential pathogens on the hands and therefore is likely to
reduce the number and likelihood of healthcare acquired infections.Error: Reference
source not found,Error: Reference source not found Hand decontamination is considered to have a
high impact on outcomes that are important to patients.239 Training of all care
workers, combined with audit and feedback of compliance rates, is central to current
guidance on prevention of infection. The WHO Five Moments for Hand Hygiene has
been widely used and supported by National Institute for Health and Care Excellence
(NICE) and describes the points at which hand hygiene is required.Error: Reference
source not found Hand hygiene is often missed as the worker enters or leaves the
patient environment and on contact with potentially contaminated surfaces240,241,242
Despite many activities around hand hygiene product improvement, introduction of
alcohol based hand rubs/gel, improving environmental factors, extensive marketing
and education campaigns evidence of sustained compliance improvement is lacking.
Hand hygiene compliance globally is variable with Creedon243 and Larson et al.244
suggesting it is approximately 50%. Improving hand hygiene compliance is reliant
upon an understanding of the interactions within healthcare between the individuals,
the practices and procedures they perform, the environment that they work in, and
the culture and safety awareness of the organisation. These human factors should
be applied to the infection prevention agenda to ensure that meaningful, sustainable
interventions are adopted reliably to produce the greatest impact.245
Evidence
Hand hygiene is associated with reduction of carriage of potential pathogens
on the hands 2+
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Recommendation
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
9.4.5 Environmental hygiene
9.4.5.1 When should the environment be sampled?
The role of the environment in the transmission of healthcare acquired infection
remains controversial and difficult to study. In recent years much of the research
around this has focused on high-profile Gram-positive pathogens such as MRSA,
Clostridium difficile and glycopeptide-resistant enterococci, where a significant body
of evidence for the importance of environmental sources has started to
accumulate.246,247 Reservoirs can be identified when infection control has failed to
control an outbreak.Error: Reference source not found The general view has been
that Gram-negative bacteria, particularly members of the Enterobacteriaceae, are
not as successful at surviving in the environment for prolonged periods, and
generally are relatively easily removed by appropriate conventional cleaning and
drying.Error: Reference source not found Nevertheless, Enterobacteriaceae,
including carbapenem-resistant strains, are able to survive on dry surfaces for
extended periods, sometimes measured in weeks and months.248,249 Some strains of
Escherichia coli carrying ESBLs for example can survive for a median of 10 days in
the environment.250 In favourable conditions, E. coli, Klebsiella spp. and
Pseudomonas spp. can survive for even longer.Error: Reference source not found
Acinetobacter has the capacity for long-term survival on dry surfaces.Error: Reference source
not found,251,252,253 Pseudomonas is more traditionally associated with moist environments
and will be found around hand wash basins and respiratory equipment.Error:
Reference source not found,254 There is considerable evidence that P. aeruginosa
can contaminate waste water systems and spread from them, with these sometimes
acting as reservoirs for carbapenemase-producing strains causing prolonged
outbreaks.255 Endoscopes if not adequately decontaminated including the hand piece
have been responsible for outbreaks.256
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MDR Gram-negative bacteria, including carbapenem-resistant organisms,
Enterobacteriaceae and A. baumannii, can be cultured from sites surrounding
infected and or colonized patients.Error: Reference source not found,257 Several
studies have found that environmental contamination with resistant K. pneumoniae is
more common than contamination with resistant E. coli.258,259,260 No controlled studies
have shown that an environmental intervention reduces the transmission of multi-
drug-resistant Gram-negative rods. However, contamination with MDR Gram-
negative bacteria can persist despite cleaning and disinfection.Error: Reference
source not found,261,262 Epidemiological data suggest that admission to an ICU room
previously occupied by patients infected or colonized with A. baumannii or P.
aeruginosa presents an increased risk for acquiring these organisms.Error:
Reference source not found A significant correlation was noted between the number
of environmental swabs in monthly screening and number of patients with
colonization/infection in the same month (P=0.004).Error: Reference source not
found However, this association was not seen for resistant Enterobacteriaceae,
suggesting that the environment is less important in their transmission,Error:
Reference source not found,263 albeit with the caveat that these studies did not
stratify by species of Enterobacteriaceae, which may be important given the
increased capacity for K. pneumoniae, in particular, to contaminate and survive on
hospital surfaces.
The evidence for the benefit of environmental screening is limited and, in itself
environmental sampling will not limit transmission of MDR Gram-negative bacteria.264
The purpose of screening may be to draw attention to failure of clearance of an
outbreak strain by cleaning, or to point to a possible common source for a cluster or
outbreak. Most of the evidence surrounding environmental screening is within
reports of management of outbreaks, and there is often very little detail on sites
sampled, sampling technique, or method of culture.265 When looking for small
numbers of organisms or bacteria living in biofilms the yield can be improved by
using enriched culture but this precludes quantitation. An alternative to specifically
seeking the multi-resistant outbreak strain(s) itself is to assess the degree of
microbiological contamination by using surface contact plates and undertaking
quantitative bacterial culture.266 Surface contact plates using selective media for
specific pathogens can suffer from low sensitivity but use with non-selective media
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may be helpful. Choosing sites for sampling remains problematic as any sampling
can only reflect a very small fraction of the relevant environment.267 The general
approach should be to choose sites that are likely to be relevant for cross
transmission such as work surfaces close to the patient and equipment/surfaces
which are likely to be touched frequently, (e.g. computer keyboards, bed rails and
door handles).Error: Reference source not found,268
Given the difficulties with microbiological sampling of the environment, there has
been considerable interest in the availability of technologies that can indirectly
assess microbial contamination. Adenosine triphosphate (ATP) bioluminescence has
been used for many years in the food industry, where visual assessment is
considered insufficient to assess the risk of infection from contaminated surfaces. It
has a number of potential benefits, including simplicity and immediacy of feedback;
however, it can give only indirect information on the likelihood of bacterial
contamination and bacteria themselves are not isolated for investigation and
comparison to those causing outbreaks. Its use in hospitals can be problematic, as
values can be variable, and there is little consensus on an appropriate benchmark
value to indicate inadequate cleanliness.Error: Reference source not found,269,270
Results are prone to interference by different disinfectants.271 Where ATP
bioluminescence has been used most successfully has been on a continuous basis
to improve compliance through feedback and improved cleaning.272,273 Other
methods of controlling the process of cleaning, such as the use of fluorescent gel
markers, can be useful in auditing the cleaning process and feedback to cleaning
staff.274
Evidence
Transmission of multiply resistant Gram-negative bacteria, particularly non-
fermenters has been associated with contamination of the environment, water
systems or equipment 2-
Sampling of the environment can be useful in identifying sources of ongoing
transmission or a single common source for an outbreak 2-
Recommendation
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Environmental screening should be considered where there is any unexplained
transmission of MDR Gram-negative organisms or a possible common source for an
outbreak. Strong
9.4.5.2 What is the evidence that respiratory equipment contributes to transmission?
The respiratory tract of ventilated patients in critical care units is a frequent site of
carriage of MDR Gram-negative bacteria. In one study in India, 87% of samples from
ventilators, humidifiers, nebulizers and other respiratory equipment showed bacterial
colonization and 17/42 Gram-negative isolates were multi-drug resistant.275
Endotracheal suctioning is a potential cause of cross infection, as disconnection of
the system may allow airborne spread to the patient’s skin, staff hands and the
immediate environment. In a cross-over study in the Netherlands, there was no
significant difference in acquisition of Gram-negative bacteria during periods of using
closed suction vs. open suction in ventilated patients.276 However antibiotic
resistance rates were low and similar in each group. Comparing ventilated with non-
ventilated patients in the ICU, non-fermenting and enteric Gram-negative bacilli were
more frequently reported in ventilator-associated pneumonia, but this reflected the
number of samples cultured per patient. The overall proportions of different
pathogenic species were similar.277
Inappropriate washing of ventilator or endotracheal tubing in hand-wash sinks risks
the spread of Gram-negative pathogens. Environmental sampling in two outbreaks of
MDR P. aeruginosa showed it to have colonized the waste water system, with
blockages, splashback and spillage from showers being possible modes of
spread.Error: Reference source not found Direction of water directly into the outlet
caused spread of organisms from the sink drain trap. Sinks were fitted with a
horizontal drain outlet at the back of the basin, resolving the problem. Sterile fluids
(not tap water) must be used to clear suction equipment, as the latter may be
contaminated with pseudomonads or Enterobacteriaceae and these can be
disseminated when the equipment is next used, including when catheters are
changed.
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Evidence
Gram-negative bacteria colonize respiratory equipment and may be washed into sink
traps 2+
Recommendation
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 hand wash sinks Strong
Good practice recommendation
Do not discard patient wash water, body fluids, secretions or exudates into hand
wash basins.
9.4.5.3 What is the evidence that sensor taps contribute to transmission?
P. aeruginosa, including multi-resistant strains, in water sources in intensive care
units has long been recognised as being associated with the development of
bacteraemia and pneumonia in patients.278 A recent systematic review demonstrated
evidence of transmission of P. aeruginosa from water systems to patients and vice
versa.Error: Reference source not found Point-of-use filters and increasing chlorine
disinfection were effective interventions. Non-touch taps were identified as probable
risk factors for biofilm formation and subsequent transmission to patients. Sinks and
a nurse’s hands have been identified as possible vectors. In a neonatal unit, four
neonates were infected and 44 colonized by cross infection with one clone.Error:
Reference source not found In another neonatal unit in Germany, P. aeruginosa was
isolated from the nasal prongs of 22 babies and from 9 respiratory water
reservoirs.279 The hands of staff were the likely means of transmission. Other
outbreaks have been due to contaminated detergent-disinfectant solution used in
cleaning surfaces.280 Studies confirm the effectiveness of point-of-use filters on water
outlets in reducing infection in critical care units, but were descriptive cohort studies,
and so are subject to temporal variation.281,282,283 Filters have to be replaced regularly,
are expensive and can themselves be the source of contamination. P. aeruginosa is
found in biofilm in flow straighteners, metal support collars and the adjacent parts of
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the tap bodies. The level of contamination with Pseudomonas is highest on complex
flow straighteners, integrated mixers and solenoids.Error: Reference source not
found
Sensor taps have been implicated in some outbreaks of Pseudomonas bacteraemia
and other infections in augmented care units as the flow is slow and controlled and
the internal mechanism complex. Decontamination of sensor taps can be
performed284 and, in one major outbreak, all taps, mixer valves, flexible hoses and
flow straighteners were replaced with simpler designs.Error: Reference source not
found
Where there are vulnerable patients (i.e. augmented care), the Department of Health
in England recommends a regular water-testing regimen but clinical surveillance is
sufficient elsewhere. The frequency of testing depends on previous isolation of the
organism and proximity to patients at risk e.g. neonates. The purpose is to prevent
colonization before patient infection develops. A risk assessment to mitigate risks
and a Water Safety Plan are advised including consideration of removal of
thermostatic mixer valves and flow straighteners and the design of the sink.Error:
Reference source not found Infrequently-used taps should be flushed at full flow for
one minute daily or removed altogether. In the event of contaminated supplies,
sterile water should be used for neonates and single-use wipes for other patient
hygiene together with additional hand hygiene using alcohol gel after washing.
Evidence
The presence of infections with P. aeruginosa in patients is commonly associated
with isolation of these bacteria from unit taps. 2-
The installation of point-of-use filters is associated with a reduction in pseudomonal
infections. 3
Recommendation
For P. aeruginosa including multiresistant strains, at a minimum in accordance with
the organization’s water safety plan, a risk assessment should be made when levels
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of patient colonization or infections rise to determine if point-of-use filters should be
installed or taps changed. Strong
9.4.5.4 Is there any cleaning method more effective than others at removing the
MDR Gram-negative bacilli from the environment?
The importance of persistence in the environment in transmission of MDR Gram-
negative bacteria remains uncertain.Error: Reference source not found,285 However,
maintaining a clean environment and appropriately decontaminating all relevant
equipment is an essential component of any infection prevention and control
programme. The cleanliness of healthcare premises is an important component in
the provision of clean safe care.286 In England, the NHS Constitution pledges ‘The
NHS commits to ensure that services are provided in a clean and safe environment
that is fit for purpose, based on national best practice’.287 Whilst there have been
significant improvements in the cleanliness of English healthcare premises, there is
still room for improvement.Error: Reference source not found
The optimal methods for cleaning have been poorly studied with respect to MDR
Gram-negative bacteria. Poor cleaning practice, such as inappropriate dilution of
cleaning agent or inactivation of disinfectant by organic matter, is more likely to
reduce cleaning efficacy than theoretical cross-resistance between disinfectant and
antibiotic.288 In extreme cases, agents used for cleaning can even become
contaminated with Gram-negative bacteria, especially pseudomonads.Error:
Reference source not found,289,290,291
Conventional decontamination is carried out by a human operator, and the reliance
on the operator to select the correct product, dilution, distribution and surface contact
time has the potential for decontamination failure. Debate around the use of
chemical disinfectants versus detergents for routine cleaning is gathering momentum
with concerns regarding chemical resistance, optimum disinfectant contact times,
allergies amongst users and patients and costs. In short, practice varies widely and
monitoring is traditionally by a visual inspection, which can be subjective. Efficacy is
rarely measured.
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Although persistence of Gram-negative organisms on reuseable bedpans is a
potential mode of spread, there are no recent reviews of performance with respect to
Gram-negative bacteria. In automated washer disinfectors, a combination of alkaline
detergent and temperature over 85ºC for one minute is sufficient to eliminate C
difficile spores.292 However visible faecal soil can remain on 7-33% of bedpans, so
appropriate education is importance to ensure good practice.293 Early studies showed
failure to attain 80C was associated with persistence of Escherichia coli and
Pseudomonas aeruginosa.294 Transmission of pathogens via contaminated
endoscopes is usually due to failure to comply with appropriate reprocessing practice
guidelines.295 Although some cases of transmission have been known, relatively few
are reported in peer reviewed journals.
Assessment of the activity of disinfectants against MDR Gram-negative bacteria is
hampered by the differences between testing against organisms in suspension and
on a surface. Acinetobacter and Pseudomonas may survive in the ward environment
even after bleach disinfection and increase the risk of acquisition by patients.Error:
Reference source not found,Error: Reference source not found In a prospective cohort study,
cleaning the environment with sodium hypochlorite instead of detergent-disinfectant
plus chlorhexidine bathing of patients reduced the risk of colonization with MDR A.
baumannii becoming established beyond that achieved by improved contact
precautions, cohorting, screening and antimicrobial stewardship.296 Termination of
Acinetobacter outbreaks has been associated with closure and cleaning of units, and
removal of a reservoir has been associated with termination of outbreaks for a
variety of organisms.Error: Reference source not found
Most interventions to improve cleaning have been accompanied by a package of
infection control precautions. Education campaigns and use of audit tools such as
marking surfaces with fluorescent dye reduce contamination, but their effect may be
transient.
There has recently been significant interest in the role of ‘no touch’ automated
disinfection systems as an additional measure for terminal cleaning of single rooms
or hospital areas affected by clusters or outbreaks.297 There are a number of types of
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these systems currently marketed, including aerosolised or vapourised hydrogen
peroxide, and ultraviolet radiation. Each has distinct microbiological and practical
characteristics. A number of studies have shown improved efficacy of killing of
various pathogens compared with cleaning alone, particularly in outbreaks, but there
are limited data on whether this reduces rates of acquisition of pathogens.298,299,300
Hydrogen peroxide vapour from 30% H2O2 and in one case, aerosolized hydrogen
peroxide from 5% H2O2 have been used successfully as part of a bundle of
interventions to prevent transmission of MDR Acinetobacter in outbreaksError:
Reference source not found,Error: Reference source not found,Error: Reference source not found,Error: Reference source not
found and hydrogen peroxide vapour has been used to help control outbreaks of
resistant Enterobacteriaceae, including CRE.Error: Reference source not found,301,302
Patients admitted to rooms exposed to hydrogen peroxide vapour were significantly
less likely to acquire any multi-drug-resistant organisms than in hydrogen peroxide
vapour untreated rooms in a cohort intervention study.Error: Reference source not
found K. pneumoniae, P. aeruginosa and A. baumannii in suspension are all
susceptible to low concentrations of hydrogen peroxide but efficacy is significantly
reduced when the organisms were in biofilm; some P. aeruginosa in biofilm had
prolonged survival following hydrogen peroxides exposure in the laboratory.303
Hydrogen peroxide vapour (from 30% H2O2) is more effective in eradicating surface
A. baumannii than aerosolised hydrogen peroxide (from 5% H2O2) (>6 log vs. 1-4 log
reduction).304 It is essential to ensure that the area has been thoroughly cleaned first,
because efficacy is affected by the presence of organic soiling.
Evidence
Cleaning is important in the control of outbreaks due to MDR Acinetobacter and
failure to clean specific areas or pieces of equipment has been associated with
transmission of other MDR Gram-negative bacteria. However evidence derived from
before and after studies and outbreak reports and is open to bias. 2-
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Hydrogen peroxide vapour is effective in reducing environmental reservoirs of
Acinetobacter and other Gram-negative bacteria on surfaces (but not sink traps), if
used in addition to standard cleaning 2+
Recommendation
Terminal disinfection of vacated areas with hypochlorite should be used in the
control of outbreaks of MDR Gram-negative infection Conditional
Hydrogen peroxide vapour should be considered as an adjunctive measure to
following cleaning of vacated isolation rooms/areas. Conditional
Good Practice Recommendation
Increase cleaning frequency to at least twice daily and every 4 hours for high contact
surfaces in the presence of resistant Enterobacteriaece and Acinetobacter sp
9.4.6 Selective decontamination: Why is it not used? Is there a role?
Selective decontamination of the digestive tract (SDD) is an intervention that aims to
reduce mortality and morbidity due to hospital-acquired infection in intensive care
units. It comprises application of non-absorbable antibiotics to the mouth and
stomach together with a course of broad-spectrum intravenous antibiotic. A
modification uses only the topical element of decontamination (SOD). The practice
has been extensively investigated, largely in the Netherlands, and at least 12 meta-
analyses of published papers have been produced.305 Almost one third of the trials
suggest a significant reduction in the incidence of Gram-negative pneumonia and
one large randomised study demonstrated a small but significant reduction in
mortality in a country with low levels of antibiotic resistance.306 Despite issues with
blinding, heterogeneity and compliance, both SDD and SOD appear to be associated
with a reduction in pneumonia (OR 0.32 95% CI 0.26-0.38) and mortality (0.75 95%
CI 0.65-0.87).307
Nevertheless only 5% of UK ICUs use SDD, largely because universal use of
prophylactic antibiotics is counter to the tenets of antibiotic stewardship.308,309 In
some studies with long-term surveillance, both SDD and SOD were associated with
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an increase in resistance to ceftazidime in Gram-negative flora of the respiratory
tract although in many cases systemic antibiotics were also given.310,311,312 In the
short term, however, a systematic review found a significant reduction in resistance
of Gram-negative bacilli to third- generation cephalosporins during the use of
selective decontamination.Error: Reference source not found The relevance of
findings from one country to another is unclear when patterns and prevalence rates
of resistant Gram-negative bacteria vary so widely. Preparation requires suitable
manufacturing units, and administration can be labour intensive.
Recent high-quality studies have provided evidence that daily bathing using
chlorhexidine gluconate in ICU helps to reduce bacteremia but there is limited
evidence of its specific effect on MDR Gram negative bacterial infection.313,314,315,316 It
has formed part of successful bundles of interventions but has not tested as an
isolated measure.Error: Reference source not found,Error: Reference source not found,317,318,319
Some studies that have evaluated chlorhexidine as a single intervention including
randomization have failed to demonstrate a reduction on Gram-negative
bacteremia.Error: Reference source not found,Error: Reference source not found,320 There is no
strong evidence that chlorhexidine daily bathing reduces Gram-negative infection or
colonization. There is a risk of development of resistance.Error: Reference source
not found The routine use of oropharyngeal chlorhexidine has been associated with
an increase in mortality in one systematic review.321
Selective decontamination can temporarily suppress excretion of carbapenem-
resistant organisms from the gastrointestinal tract and possibly supplement
SICP.Error: Reference source not found In a retrospective analysis of a German
outbreak, selective digestive decontamination with colistin and gentamicin as oral
solution and gel was used in 14 patients with proven carriage of carbapenemase-
producing K. pneumoniae KPC-s-KP ST258.Error: Reference source not found Loss
of carriage, as defined by three PCR screens 48 hours apart, was found at a mean
of 21 days in 6 treated patients (43%) but also in 30% of controls. Resistance to
colistin and gentamicin in post treatment isolates of K. pneumoniae rose 19% and
45% respectively, compared to controls. In a randomised placebo-controlled trial of a
regimen based on colistin and neomycin plus treatment of bacteriuria with
nitrofurantoin, the detection of ESBL Enterobacteriaceae in rectal swabs was not
affected significantly.322 A randomised trial against placebo used oral gentamicin and
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72
topical oropharyngeal gentamicin and colistin for a week and was directed against
carbapenem-resistant K. pneumoniae carriage. It produced a significant reduction in
carriage at 2 weeks but not at 6 weeks.Error: Reference source not found Mortality
was not affected significantly, but throat carriage was reduced from 30% to zero in
the intervention versus 35% to 30% with placebo (p<0.0001). Isolates did not
develop resistance. A lower-quality controlled study reported reductions in faecal and
pharyngeal carriage of Acinetobacter during colistin/tobramycin selective
decontamination.323 Against, colistin/neomycin/nalidixic acid did not reduce infections
or mortality due to MDR Enterobacteriaceae compared with no prophylaxis, but
carriage was reduced (n=86, RR0.28 95%CI 0.03-2.28).324
Evidence
The use of SDD or SOD is associated with a reduction in the incidence of
pneumonia due to Gram-negative bacteria. 1+
The use of SDD or SOD is associated with a reduction in the mortality rate. 1+
SOD can be used to reduce excretion of MDR Gram-negative bacteria during an
outbreak, but no effect on transmission of infection has been demonstrated and
application can be logistically difficult. 3
Recommendation
The routine use of selective decontamination of the mouth or digestive tract is not
recommended for control of MDR Gram-negative bacteria.
Conditional
9.5 What are the minimum standards to stop spread in public areas, primary care or care homes?
Care homes are recognised as potential reservoirs of multi-resistant pathogens,
which can spread among residents, generally as colonizers, and can be reintroduced
into hospital.325 Publicity may alarm residents, their relatives and carers. Clear
information on the standards of infection prevention and control should be available
to promote confidence in the quality of care provided. Despite the relatively poor
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2158
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73
evidence base, guidelines are available for managers and carers.Error: Reference
source not found,326 In England, the Code of PracticeError: Reference source not
found defines what is required to ensure compliance with Care Quality Commission
(CQC) registration requirements for cleanliness and infection control. Following
general principles, owners are encouraged to contact the local health protection
team in the event of outbreaks of infection, increase cleaning and hand hygiene
compliance by patients and staff, conduct root cause analyses and train staff in
infection prevention and control. The prevalence of ESBL Enterobacteriaceae in the
care home is usually unknown and sporadic. The need for a urinary catheter if
present should be reviewed regularly and it should be removed as soon as it is not
needed. The appropriate use of such devices to prevent healthcare-acquired
infection has been reviewed elsewhere.Error: Reference source not found Residents
with diarrhoea should be isolated in their room with a dedicated commode if no en
suite facilities are available. This isolation may require additional psychological
support for the resident. Colonization with multi-resistant organisms should not be
construed as a reason to isolate or screen other residents. Standard Infection
Control Precautions must continue to be applied.
Evidence
Institutionalized patients/residents are more likely to carry multi-resistant organisms
and present a risk on readmission to hospital 2+
Good Practice recommendation
Care homes should adopt national recommendations for environmental and
equipment cleanliness and infection prevention and control
Clear patient information on MDR Gram-negative infection must be provided in
accessible formats to encourage good hand hygiene by patients and staff
9.6 Are there organisational structures within a healthcare facility that play a role in the successful control of MDR Gram-negative bacilli?
In Israel, with prevalent ST258/KPC K. pneumoniae, a self-contained nursing unit
with dedicated staff for patients carrying carbapenem-resistant Enterobacteriaceae
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2200
2201
2202
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2209
2210
2211
2212
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74
was effective as part of a package of measures including mandatory reporting and a
centralised national monitoring system.Error: Reference source not found In the
same way, a centralised national system was effective in the control of MRSA in UK.
Outbreaks of carbapenemase-producing K. pneumoniae appear to have been
controlled by a package of measures including nursing infected patients in separate
units with different staff until discharge or cohorting.Error: Reference source not
found,Error: Reference source not found,327,328,329 The nursing units could be single rooms, cohorts
or wards but the nurse did not cross between units during the shift. A sequential
intervention study found control was effective when patients were nursed in
separated locations with dedicated nursing personnel. The shared medical staff had
contact precautions vetted by the dedicated nurse before entering the area.Error:
Reference source not found However, the intervention also included education,
training, cleaning and screening.
Evidence
A separate unit with dedicated nursing staff rather than in a part of the ward with
shared staff is effective in control packages 3
Recommendation
Monitor hand hygiene of all staff when patient cohorting is being applied. Strong
10 Further research
1. PCR-based tests for swift detection of MDR Gram-negative pathogens require
further testing and development to allow cost effective and rapid screening
and detection of carriers.
2. Consideration should be given to further investigation of screening of long-
term care facility patients as a means of tracking movement and defining
reservoirs of organisms. Longitudinal assessment of patients carrying ESBL-
producing organisms, particularly E.coli ST131, should be made on admission
and discharge to hospitals and nursing homes to detect infection and
spontaneous clearance of carriage.
3. The risk factors for development of infection such as urinary catheterisation
should be separated from the risk factors for carriage including hospitalisation.
160161
2217
2218
2219
2220
2221
2222
2223
2224
2225
2226
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2228
2229
2230
2231
2232
2233
2234
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2236
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2238
2239
2240
2241
2242
2243
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2245
2246
2247
2248
2249
75
Household contacts of cases of infection with E. coli ST131 or carbapenem-
resistant K. pneumoniae should be examined for evidence of spread or
subsequent infection.
4. Given the recent changes in the prevalence of e.g. ESBL-producing E. coli
ST131 and K. pneumoniae ST258 with KPC carbapenemases the potential
for screening patients for particular clones as means of controlling
transmission in hospitals should be assessed. MALDI-ToF, serological and
DNA-based detection methods should be developed together with selective or
indicator media for quinolone-resistant Enterobacteriacae.
5. Bacteraemia surveillance including sequence typing for strains resistant to
cephalosporins, quinolones and carbapenems should be expanded and open
to public and commissioning groups. This is essential for accurate risk
assessment of patients transferred between healthcare facilities. In localities
with outbreaks, typing and infection control should be extended to isolates
from other anatomical sites.
6. Randomised intervention studies of the efffectiveness measures including
single-room isolation in prevention of transmission or Gram-negative bacterial
infection.
7. The potential for endoscopes to disseminate MDR Gram negative pathogens
requires better understanding with reference to complex instruments such as
those with wire-containing channels.
162163
2250
2251
2252
2253
2254
2255
2256
2257
2258
2259
2260
2261
2262
2263
2264
2265
2266
2267
2268
2269
2270
76
Table I
Levels of evidence for intervention studiesError: Reference source not found,Error: Reference source not found
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*
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
164165
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2272
2273
2274
77
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
3 Non-analytic studies (e.g. uncontrolled before–after studies, case reports,
case series)
4 Expert opinion. Legislation
*Studies with an evidence level of ‘1-‘ and ‘2-‘ should not be used as a basis for making a recommendation.
RCT, randomised controlled trial.
166167
2275
2276
78
Table II
Recommendation gradingError: Reference source not found
Recommendation
Undesirable consequences clearly outweighdesirable consequences
Strong recommendation against
Undesirable consequences probably outweighdesirable consequences
Conditional recommendation against
Balance between desirable and undesirableconsequences is closely balanced or uncertain.
Recommendation for research and possiblyconditional recommendation for use restricted totrials
Desirable consequences probably outweighundesirable consequences
Conditional recommendation for
Desirable consequences clearly outweighundesirable consequences
Strong recommendation for
168169
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2278
2279
2280
2281
79
Table III
Dissecting the epidemiology of multi-drug-resistant Gram-negative rods
Resistant Enterobacteriaceae Multi-drug-resistant non-fermenters
AmpC, ESBLa CPEb A. baumanniic P. aeruginosa Stenotrophomonas maltophilia
Microbiology Fermentative, oxidase-negative, motile or non-motile, facultatively
anaerobic, rods.
Non-fermentative, oxidase-
negative, non-motile, obligate
aerobic, coccobacilli.330
Non-fermentative, oxidase-
positive, motile, aerobic,
rods.331
Non-fermentative,d,332 motile,
oxidase +/-, obligate aerobic,
rods.333
Reservoirs Human and animal gastrointestinal tract, water. Respiratory and
gastrointestinal tract, and dry
surfaces.Error: Reference
source not found,334
Ubiquitous: plants, animals,
and moist environments. Error:
Reference source not found
Ubiquitous: plants, animals,
humans and moist
environments.Error: Reference
source not found,335
Sites of colonization
Gastrointestinal tract.Error: Reference source not found Skin, respiratory and
gastrointestinal tract.Error:
Reference source not found,Erro
r: Reference source not found,336
Gastrointestinal tract and
moist body sites (throat, nasal
mucosa, axillary skin
perineum).337
Respiratory and
gastrointestinal tract.Error:
Reference source not found,Error:
Reference source not found,338
Duration of colonization
Months to >1 year.339,340,341 Days to weeks.Error:
Reference source not found
- -
Clinical manifestation
Urinary tract (e.g. E. coli), pneumonia (e.g. K. pneumoniae and
Enterobacter spp.), intra-abdominal infection.Error: Reference source
not found,342
Ventilator-associated
pneumonia, catheter-related
bloodstream
and urinary tract infections,
wound infections.Error:
Reference source not found,Erro
Pneumonia, urinary tract,
surgical site, bloodstream
infections cystic fibrosis lung,
burns.Error: Reference source
not found
Pneumonia and bloodstream
infection; less commonly
urinary tract and wound
infections.Error: Reference
source not found,Error: Reference source
not found
170171
2282
2283
2284
2285
80
Resistant Enterobacteriaceae Multi-drug-resistant non-fermenters
Environmental survival
Hours to weeks on dry surfaces;Error: Reference source not found
contaminated environment likely to play a minor role in
transmission.Error: Reference source not found,Error: Reference source not found
Weeks to months on dry
surfaces;Error: Reference
source not found,Error: Reference
source not found difficult to remove
from surfaces by cleaning and
Contaminates moist hospital
environments: tap aerators,
respiratory therapy
equipment.Error: Reference
source not found
Contaminates moist hospital
environments; can form
biofilms on surfaces; low
biocide susceptibility.Error:
Reference source not found,Error:
330. Karah N, Sundsfjord A, Towner K, Samuelsen O. Insights into the global molecular epidemiology of carbapenem non-susceptible clones of
Acinetobacter baumannii. Drug Resist Updat 2012;15:237–247.
331. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of
chromosomally encoded resistance mechanisms. Clin Microbiol Rev 2009;22:582–610.
332. Carmody LA, Spilker T, LiPuma JJ. Reassessment of Stenotrophomonas maltophilia phenotype. J Clin Microbiol 2011;49:1101–1103.
333. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev 2012;25:2–41.
337. Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin
Infect Dis 2006;43(Suppl. 2):S43–S48.
5. Hawkey P. Treatment of multi-drug resistant (MDR) Gram-negative bacteria – recommendations from a joint working party. J Antimicrob
Chemother 2015 (submitted).
7. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Chichester: John Wiley & Sons Ltd; 2009.
8. Review Manager (RevMan) Version 5.1. Copenhagen: Nordic Cochrane Centre, Cochrane Collaboration; 2011.
176177
178
179
180
181
182
183
186
187
188
189
190
191
81
disinfection.Error: Reference
source not found,Error: Reference
source not found
Transmission routes
Hands (++), contaminated surfaces (+/-).Error: Reference source not
found
Contaminated surfaces (++),
hands (+), air (+/-).Error:
Reference source not found,Erro
r: Reference source not found,Error: Reference
source not found
Hands (+), contaminated moist
surfaces (+), air (+/-). Water
systems.Error: Reference
source not found,343
Hands (+), contaminated moist
surfaces (+), air (+/-).Error:
Reference source not found,Error:
Reference source not found
Antimicrobial resistance - intrinsic
Ampicillin, first- and second-generation cephalosporins.344 Serratia
and Proteeae are intrinsically resistant to polymyxins.
Ampicillin, amoxicillin-
clavulanate, cefazolin,
cefotaxime, ceftriaxone,
ertapenem, trimethoprim, and
fosfomycin.Error: Reference
source not found
Some β-lactams and
fluoroquinolones, macrolides,
tetracyclines, trimethoprim/
sulfamethoxazole.345
Most agents except
cotrimoxazole.Error: Reference
source not found,Error: Reference source
not found
Antimicrobial resistance - acquired
Penicillins (except temocillin),
extended-spectrum β-lactams,
carbapenems (through
mechanisms other than
commoner acquired
carbapenemases),
aminoglycosides,
sulphonamides,
quinolones.Error: Reference
source not found,346
Most or all beta-lactams,
carbapenems, polymyxins (rarely)
(exact profile depends on
particular carbapenemase and any
co-produced ESBL).Error:
Reference source not found,347
Quinolones, aminoglycosides,
β-lactams (including
carbapenems), polymyxins,
tigecycline.Error: Reference
source not found,348
Aminoglycosides, β-lactams
(including carbapenems),
monobactams,
fluoroquinolones,
polymyxins.Error: Reference
source not found
Trimethoprim/
sulfamethoxazole (TMP/SMX).
Common acquired AmpC (intrinsic in Carbapenemases (KPC, VIM, Various aminoglycoside- Metallo-β-lactamases (VIM sul genes (resistance to
11. Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well Y. Duration of carriage of carbapenem-resistant
Enterobacteriaceae following hospital discharge. Am J Infect Control 2013;41:190–194.
12. Villegas MV, Hartstein AI. Acinetobacter outbreaks, 1977–2000. Infect Control Hosp Epidemiol 2003;24:284–295.
192193
194
195
196
82
resistance enzymes Enterobacter), ESBLs (TEM,
SHV, CTX-M). Various
aminoglycoside-modifying
enzymes (AMEs).
IMP, NDM).Error: Reference
source not found
modifying enzymes (AMEs) or
ribosomal methyltransferase,
class-D OXA type
carbapenemases.Error:
Reference source not found,349
and IMP).Error: Reference
source not found
sulphonamide).
Mortality Moderate/substantial increase Stark increase in attributable Minimal increase in Moderate/substantial increase Minimal increase in attributable
13. Casewell MW, Desai N. Survival of multiply-resistant Klebsiella aerogenes and other Gram-negative bacilli on finger-tips. J Hosp Infect
1983;4:350–360.
14. Jawad A, Seifert H, Snelling AM, Heritage J, Hawkey PM. Survival of Acinetobacter baumannii on dry surfaces: comparison of outbreak and
sporadic isolates. J Clin Microbiol 1998;36:1938–1941.
15. 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. Eur J Clin Microbiol Infect Dis
2012;31:3057–3063.
16. Suh B, Bae IK, Kim J, Jeong SH, Yong D, Lee K. Outbreak of meropenem-resistant Serratia marcescens comediated by chromosomal AmpC
beta-lactamase overproduction and outer membrane protein loss . Antimicrob Agents Chemother 2010;54:5057–5061.
17. García-Fernández A, Miriagou V, Papagiannitsis CC, et al. An ertapenem-resistant extended-spectrum-beta-lactamase-producing Klebsiella
pneumoniae clone carries a novel OmpK36 porin variant. Antimicrob Agents Chemother 2010;54:4178–4184.
18. Swaminathan M, Sharma S, Poliansky Blash S, et al. Prevalence and risk factors for acquisition of carbapenem-resistant Enterobacteriaceae in
the setting of endemicity. Infect Control Hosp Epidemiol 2013;34:809–817.
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199
200
201
202
203
204
205
206
207
208
209
210
211
83
(bacteraemia) in attributable mortality.Error:
Reference source not found,350
mortality.Error: Reference source
not found,Error: Reference source not found,351
attributable mortality.Error:
Reference source not found
in attributable mortality
depending on type of
infection.Error: Reference
source not found,352
mortality.353
Risk factors Hospital: prolonged hospital
stay, prior hospitalization,
Prior antimicrobial use, length of
stay, severity of illness,
(i) Major trauma, particularly
burns, surgery, and battlefield
(i) Prior use of antibiotics (ii)
mechanical ventilation (iii)
Severely compromised health
status, malignancy, indwelling
19. Woodford N, Turton JF, Livermore DM. Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic
resistance. FEMS Microbiol Rev 2011;35:736–755.
20. Banerjee R, Johnston B, Lohse C, Porter SB, Clabots C, Johnson JR. Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant
clonal group associated with healthcare and elderly hosts. Infect Control Hosp Epidemiol 2013;34:361–369.
21. 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. J Antimicrob Chemother 2011;66:505–511.
22. Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
Lancet Infect Dis 2013;13:785–796.
23. Edelstein MV, Skleenova EN, Shevchenko OV, et al. Spread of extensively resistant VIM-2-positive ST235 Pseudomonas aeruginosa in
Belarus, Kazakhstan, and Russia: a longitudinal epidemiological and clinical study. Lancet Infect Dis 2013;13:867–876.
26. 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. Clin Infect Dis 2013;57:1256–
1265.
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215
216
217
218
219
220
221
222
223
224
225
226
84
previous use of antibiotics,
presence of indwelling
catheters and mechanical
ventilation.
Community: older age,
recurrent UTIs/prior invasive
procedures (e.g.
catheterisation), known faecal
carriage, contact with
mechanical ventilation, admission
to the 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
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 on the unit (vi)
proximity to other colonized
infected patients.Error:
prolonged hospital and ICU
stay (iv) co-morbidities e.g.
cystic fibrosis, burns
units.Error: Reference source
not found,354
devices (such as intravascular
catheters and ventilation
tubes), exposure to broad-
spectrum antimicrobials, long
hospital stays, ICU stay.Error:
Reference source not found,Error:
Reference source not found
27. 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). Eur J Clini Microbiol Infect Dis 2014;33:2071–2075.
28. 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. J Antimicrob Chemother 2011;66:1005–1012.
29. Vlek ALM, Cooper BS Kypraios T, Cox A, Edgeworth JD, Auguet OT. Clustering of antimicrobial resistance outbreaks across bacterial
species in the intensive care unit. Clin Infect Dis 2013;57:65–76.
30. Conlan S, Thomas PJ, Deming C, et al. Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-
producing Enterobacteriaceae. Sci Transl Med 2014;6:254ra126.
31. Munoz-Price LS, Fajardo-Aquino Y, Arheart KL, et al. Aerosolization of Acinetobacter baumannii in a trauma ICU. Crit Care Med
2013;41:1915–1918.
32. Gijón D, Curiao T, Baquero F, Coque TM, Cantón R. Fecal carriage of carbapenemase-producing Enterobacteriaceae: a hidden reservoir in
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234
235
236
237
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239
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healthcare facilities
antimicrobial treatment.Error:
Reference source not found
biliary catheter and recent
transplantation.Error: Reference
source not found For NDM, prior
hospitalisation on Indian
subcontinent; for OXA-48 prior
hospitalisation in Middle East.
Reference source not found,Erro
r: Reference source not found
At-risk population Patients in acute, long-term
and community settings;
Patients in acute settings,
particularly those with recent travel
Immunocompromised patients
in the ICU and burns
Immunocompromised patients
in the ICU and burns units,
Immunocompromised patients
in the ICU; patients with cancer
37. Nicolas-Chanoine MH, Jarlier V. Extended-spectrum beta-lactamases in long-term-care facilities. Clin Microbiol Infect 2008;14(Suppl.
1):111–116.
38. 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. J Clin Microbiol
2012;50:2974–2981.
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patients travelling to areas of
high-prevalence.Error:
Reference source not found
to areas of high prevalence.Error:
Reference source not found,355
units;Error: Reference source
not found rare cause of
community-acquired
infection.Error: Reference
source not found,356
patients with cystic
fibrosis;Error: Reference
source not found rare cause of
community-acquired
infection.Error: Reference
source not found
and cystic fibrosis; rare cause
of community-acquired
infection.Error: Reference
source not found,357
Common international clones
E. coli ST131.with CTX-M
ESBLs.Error: Reference source
K. pneumoniae ST258 with KPC
enzymes.Error: Reference source
International clones I–III.Error:
Reference source not found,Erro
Clonal diversity.Error:
Reference source not found A
Clonal diversity.Error:
Reference source not found,Error:
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http://www.who.int/chp/knowledge/publications/policy_issues_ltc.pdf. Last accessed 12th June 2014.
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54. Wickramasinghe NH, Xu L, Eustace A, Shabir S, Saluja T, Hawkey PM . High community faecal carriage rates of CTX-M ESBL-producing
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87
not found not found,Error: Reference source not found few international high risk
clones, e.g. ST111 (serotype
O12) acquire multi-resistance.
Spread of ST235 with VIM
carbapenemase in Russia,
Belarus and Kazakhstan.
aExtended-spectrum β-lactamase.bCarbapenem-producing Enterobacteriaceae.
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cFrom a taxonomic viewpoint, three four species are virtually indistinguishable (A. baumannii, A. calcoaceticus, genomic species 3 and genomic species 13TU) so are grouped together as ‘A. calcoaceticus-A. baumannii (Acb) complex’; however, A. baumannii is by far the most important human pathogen in this group. However, since methods commonly used to speciate acinetobacters 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. dRecent data indicate that the ‘non-fermentative’ status of S. maltophilia should be re-assessed.
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Table IV
Infection prevention and surveillance by organism: recommendations by organism/resistance
Recommendation Application in respect of
Resistant Multi-drug-resistant non-fermenters
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Enterobacteriaceae (AmpC, ESBL & carbapenem-resistant organisms)
A. baumannii P. aeruginosa
1,2. Laboratory test for Test susceptibility to Test susceptibility to Test susceptibility to
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91
susceptibility to meropenem for
all significant Gram-negative
isolates
Meropenem + cefpodoxime meropenem.
Usually confined to ICU.
meropenem + ceftazidime
Most carbapenem resistance
is via loss of OprD and is less
important for infection control
than carbapenemases.
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92
Carbenicillin and ceftazidime
sensitivity indicates OprD
loss.
3. Request international travel
history for patients with
Find and record Not usually required – local
acquisition
Find and record
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93
carbapenemase producing Gram
negative bacteria
4. Diagnostics: detect and report
all MDR Gram-negative
Early recognition and infection
control intervention to reduce
Early recognition and infection
control intervention to reduce
Early recognition and infection
control intervention to reduce
98. Jeon MH, Choi SH, Kwak YG, et al. Risk factors for the acquisition of carbapenem-resistant Escherichia coli among hospitalized patients.
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organisms (≥3 resistance
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transmission transmission transmission
5. Active screening rather than Case finding/screening for In outbreaks, case Poor evidence for screening–
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monitoring of laboratory reports
for high-risk specialities
carbapenemase for ICU and
other high risk patients but not
routinely recommended for
ESBL/AmpC.
finding/screening for ICU and
other high risk patients.
Otherwise monitor laboratory
reports.
may be appropriate in high-
risk units e.g. cystic fibrosis
units, burns haematology
units, or in context of
outbreak.
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metallo-β-lactamase.
6. Risk assessment on
admission to ICU and from long-
term care facility
Risk assess on admission for
carriage of carbapenem-
Not recommended on
admission except when
outbreak in referring ward or
Not recommended on
admission except when
outbreak in referring ward or
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ESBLs – not recommended
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admission from long stay units
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7.8. Screen patients at risk for
carbapenem-resistant
Enterobacteriaceae
Screen patients assessed as
at risk/coming from endemic
Screen in outbreaks Screen in outbreaks
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Screening not recommended
for family contacts or staff
Screening not recommended
for family contacts or staff
Screening not recommended
for family contacts or staff
9. Type of sample for screening Rectal/stool Skin sites or if a catheter or
endotracheal tube is present,
Rectal/stool
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secretion.
10. Screen patients with stay in
healthcare facility with endemic
Carbapenem-resistant -
targeted screening of patients
Carbapenem-resistant -
targeted screening of patients
Carbapenem-resistant -
targeted screening of patients
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carbapenemase producing
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high-risk areas i.e endemic
not just sporadic cases e.g.
India, Manchester in UK.
with history of healthcare in
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local knowledge of referring
centres.
with history of healthcare in
high-risk areas i.e. based on
local knowledge of referring
centres.
11. Monitor SICP and Contact Carbapenem-resistant – Carbapenem-resistant – No high quality evidence for
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Precautions during outbreaks;
repeat screening of negative
patients weekly and on
discharge until no new cases for
7 days.
during outbreak screen all
patient contacts in ward of a
new case
during outbreak consider
screening all patient contacts
in bay/ward of non- isolated
case. No evidence for regular
admission, ongoing or
discharge screening except in
patient contact screening, but
consider screening of all
patient contacts in bay/ward in
outbreak. No evidence for
regular admission, ongoing or
discharge screening except in
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outbreaks outbreaks
12. Screen at admission those
with previous carbapenem-
resistant or other MDR Gram-
Screen all with known
previous carriage or infection
Screen all with known
previous carriage or infection
Screen all with known
previous carriage or infection
59. Day KM, Ali S, Mirza IA, et al. Prevalence and molecular characterization of Enterobacteriaceae producing NDM-1 carbapenemase at a
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105
negative bacteria
13. Contact precautions for
patients who present an infection
risk
Carbapenem resistant - pre-
emptive isolation of previous
positive patients pending
screening
Carbapenem resistant
organisms pre-emptive
isolation of high risk patients
pending screening
No evidence for pre-emptive
isolation. Extrapolation from
evidence for other multi-
resistant organisms suggests
that isolation or cohorting of
103. Denton M, Wilcox MH, Parnell P, et al. Role of environmental cleaning in controlling an outbreak of Acinetobacter baumannii on a
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Restrict unnecessary patient
movements where possible.
Restrict unnecessary patient
movements where possible.
known cases with contact
precautions and restrictions
on unnecessary movement
are appropriate
14. Patients colonized with MDR
Gram-negative organisms in
single room for duration of stay
No recommendations for tests
of clearance – assume long -
term carriage during the same
inpatient stay
No recommendation for test of
clearance
No recommendation for test of
clearance
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15. Personal protective
equipment: Use disposable
gloves and gown/apron in caring
for patients.
Apron/gown and gloves for all
patient interactions. No
requirement for facemasks or
respirators.
Use apron/gown and gloves
for all patient interactions, No
requirement for facemasks or
respirators.
Apron/gown and gloves for all
patient interactions. No
evidence for the effectiveness
of respiratory precautions
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spread by droplet nuclei in
cystic fibrosis patients
16. Prioritise single room
accommodation. (Local risk
assessment to determine priority
First priority: Carbapenem-
resistant Enterobacteriaceae
Carbapenem-resistant
Second priority: Carbapenem-resistant
Third priority: Carbapenemase-
producing Pseudomonas
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against other pathogens but
carbapenem-resistant
Enterobacteriaceae usually
higher than C difficile or MRSA)
Enterobacteriacae: single
room, preferably with en-suite
facilities, throughout
admission.
Acinetobacter sp
These are usually confined to
ICU.
Carbapenem-resistant: single
aeruginosa. Other MDR
Pseudomonas (e.g.
permeability variant) use
single room if available.
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All other patients with
mulitresistant
Enterobacteriaceae should be
isolated where possible
according to assessment of
risk of spread, otherwise
room, preferably with en-suite
facilities, throughout
admission
Other MDR Acinetobacter:
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contact precautions.
17. Cohort isolate if insufficient
single rooms
Consider cohorting patients
whose isolates have the same
phenotypic resistance pattern.
Consider cohorting patients
whose isolates have the same
phenotypic resistance
Extrapolation from other
infections suggests their staff
cohorting may be useful in
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Consider staff cohorting where
feasible and education of staff
in infection control
mechanism. Level of evidence
for staff cohorting low.
controlling outbreaks
18. Hand hygiene before and
after direct patient contact
Contact precautions; ensure
high awareness of need for
attention to hand hygiene,
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Low level evidence. Ensure
high awareness of need for
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especially with soap and
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19. Environmental screening
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Persistence in environment in
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Environmental persistence,
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Association with persistently
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equipment. surfaces. Bed rails, bed side
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HEPA filters and extract vents
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equipment
20. Decontaminate equipment in
designated cleaning sinks
Indirect evidence for
transmission via equipment
Some evidence for
transmission through
equipment
Evidence for transmission
through equipment
contamination e.g. ventilators,
demonstrates importance of
dedicated & single use
equipment and
decontamination of reusable
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equipment by appropriate
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21. Risk assess point of use
filters for taps if rising P
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Not applicable Not applicable Effective in reducing infection
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22. Terminal disinfection with
hypochlorite in outbreak control
Increase cleaning frequency
to at least twice daily and
every 4 hours for high contact
surfaces
Increase cleaning frequency
to at least twice daily and
every 4 hours for high contact
surfaces
Some evidence that cleaning
protocols have role for
controlling spread in outbreak
settings
23. Consider hydrogen peroxide
vapour as adjunct to cleaning
Effective in reducing
reservoirs
Effective in reducing
reservoirs
Effective in reducing
reservoirs on surfaces but not
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taps or sink traps
24. Routine use of selective
digestive decontamination not
recommended
Not normally recommended
as contrary to antibiotic
Not recommended Not normally recommended
as contrary to antibiotic
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stewardship. stewardship.
25. Monitor hand hygiene of all
shared staff in cohort isolation
Self contained nursing unit is
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Self contained nursing unit is
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No direct evidence
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11 Appendix 1 - Glossary
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Augmented care area: units where medical/nursing procedures render the patients
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Beta-lactamases: Enzymes produced by some bacteria that confer resistance to β-
lactam antibiotics such as penicillins and cephalosporins, by breaking down the
central structure of the antibiotic.
Carbapenemases: These are β-lactamases that inactivate carbapenems such as
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Care area: any portion of a healthcare facility where patients are intended to be
examined or treated.
Cleaning: Methods that physically remove soil, dust and dirt from surfaces or
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Cohorting: imposed grouping within an area of a hospital ward of patients or staff
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Community-associated: usually defined as infection or colonization detected in an
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Contact precautions: hand hygiene is performed before touching patient and prior to
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(q.v.) they do not attack carbapenems
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Long-term care facility (care home/nursing home) provides accommodation and
meets the needs of patients with chronic illness or disability who cannot care for
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Screening of patients: sampling potential colonization sites for MDR Gram-negative
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decontamination of the digestive tract in UK critical care units. Br J Anaesth 2014;113:610–
617.
309. Bastin AJ, Ryanna KB. Use of selective decontamination of the digestive tract in United
Kingdom intensive care units. Anaesthesia 2009;64:46–49.
317. Hayden MK, Lin MY, Lolans K, et al. Prevention of colonization and infection by
Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae in long term acute care
hospitals. Clin Infect Dis 2015;60:1153–1161.
318. Munoz-Price LS, Hayden MK, Lolans K, et al. Successful control of an outbreak of
Klebsiella pneumoniae carbapenemase-producing K. pneumoniae at a long-term acute care
hospital. Infect Control Hosp Epidemiol 2010;31:341–347.
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12 Appendix 2
12.1 Guideline Development
The subject was identified by the Scientific Development Committee of the
Healthcare Infection Society in February 2011 and approved by HIS in May 2011.
The BSAC Council agreed a similar proposal at the same time. BIA Council agreed
319. Palmore TN, Henderson DK. Managing transmission of carbapenem-resistant
Enterobacteriaceae in healthcare settings: a view from the trenches. Clin Infect Dis
2013;57:1593–1599.
320. Camus C, Bellissant E, Sebille V, et al. Prevention of acquired infections in intubated
patients with the combination of two decontamination regimens. Crit Care Med
2005;33:307–314.
321. Price R, MacLennan G, Glen J; SuDDICU Collaboration. Selective digestive or
oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of
death in general intensive care: systematic review and network meta-analysis. BMJ .
2014;348:g2197.
322. Huttner B, Haustein H, Uckay I, et al. Decolonization of intestinal carriage of extended-
spectrum beta-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a
randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother 2013;68:2375–
2382.
323. Agustí C, Pujol M , Argerich MJ , et al. Short-term effect of the application of selective
decontamination of the digestive tract on different body site reservoir ICU patients colonised
by multiresistant Acinetobacter baumannii. J Antimicrob Chemother 2002;49:205–208.
324. Brun-Buisson C, Legrand P, Rauss A, et al. Intestinal decontamination for control of
nosocomial multiresistant Gram-negative bacilli. Study of an outbreak in an intensive care
unit. Ann Intern Med 1989;110:873–881.
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to join in September 2011. The members were chosen to reflect the range of
stakeholders and not limited to members of the three Societies. The questions were
decided at the first meeting of the Group in November 2011 from issues presented to
the members and patient representatives by staff and patients in the preceding
months. Each was debated by the Group before adoption. Enhance Reviews was
paid for the serach and data extraction. Working Party members were not paid
except for travel expenses.
325. Eveillard M, Lafargue S, Guet L, et al. Association between institutionalization and
carriage of multiresistant bacteria in the elderly at the time of admission to a general hospital.
Eur J Clin Microbiol Infect Dis 1999;18:133–136.
326. Health Protection Agency. Prevention and control of infection in care homes – an
information resource. London: HPA; 2013. Available at:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/214929/Care-
home-resource-18-February-2013.pdf. Last accessed 8th August 2014.
327. Carbonne A, Thiolet JM, Fournier S, et al. Control of a multi-hospital outbreak of KPC-
producing Klebsiella pneumoniae type 2 in France, September to October 2009. Euro Surveill
2010;15:pii=19734.
328. Ciobotaro P, Oved M, Nadir E, Bardenstein R, Zimhony O. An effective intervention to
limit the spread of an epidemic carbapenem-resistant Klebsiella pneumoniae strain in an
acute care setting: from theory to practice. Am J Infect Control 2011;39:671–677.
329. Schwaber MJ, Lev B, Israeli A, et al.; Israel Carbapenem-Resistant Enterobacteriaceae
Working Group. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella
pneumoniae in Israeli hospitals via a nationally implemented intervention. Clin Infect Dis
2011;52:848–855.
334. Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrug-resistant
Acinetobacter baumannii. Nat Rev Microbiol 2007;5:939–951.
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12.2 Conflict of Interests
Conflicts of interest were registered at the outset and renewed during the process.
They are stated in the Report. In the event of a potential conflict being identified, the
Working Party agreed that the member should not contribute to the section affected.
335. Looney WJ, Narita M, Muhlemann K. Stenotrophomonas maltophilia: an emerging
opportunist human pathogen. Lancet Infect Dis 2009;9:312–323.
336. Medina-Presentado JC, Seija V, Vignoli R, et al. Polyclonal endemicity of Acinetobacter
baumannii in ventilated patients in an intensive care unit in Uruguay. Int J Infect Dis
2013;17:e422–427.
338. Apisarnthanarak A, Fraser VJ, Dunne WM, et al. Stenotrophomonas maltophilia intestinal
colonization in hospitalized oncology patients with diarrhea. Clin Infect Dis 2003;37:1131–
1135.
342. Peleg AY, Hooper DC. Hospital-acquired infections due to Gram-negative bacteria. N
Engl J Med 2010;362:1804–1813.
343. Wainwright CE, France MW, O'Rourke P, et al. Cough-generated aerosols of
Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic
fibrosis. Thorax 2009;64:926–931.
346. Paterson DL. Resistance in Gram-negative bacteria: Enterobacteriaceae. Am J Infect
Control 2006;34:S20–S28; discussion S64–S73.
347. Bogdanovich T, Adams-Haduch JM, Tian GB, et al. Colistin-resistant, Klebsiella
pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the
international epidemic clone ST258. Clin Infect Dis 2011;53:373–376.
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12.3 Infection Control -Systematic Review Process
12.3.1 PICO:
Patients: All patient groups were included. The guideline is careful not to make recommendations which may prejudice clinical care based on gender, age, ethnicity or socio-economic status.
Interventions: interventions were identified in the literature to generate intervention specific recommendations
Comparisons: comparisons between intervention and standard management were used;
348. 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. PLoS One 2010;5:e10034.
349. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful
pathogen. Clin Microbiol Rev 2008;21:538–582.
350. Shorr AF. Review of studies of the impact on Gram-negative bacterial resistance on
outcomes in the intensive care unit. Crit Care Med 2009;37:1463–1469.
351. Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-
resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive
therapies. Infect Control Hosp Epidemiol 2008;29:1099–1106.
352. Hirsch EB, Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on
patient outcomes. Expert Rev Pharmacoecon Outcomes Res 2010;10:441–451.
354. Falagas ME, Kopterides P. Risk factors for the isolation of multi-drug-resistant
Acinetobacter baumannii and Pseudomonas aeruginosa: a systematic review of the literature.
J Hosp Infect 2006;64:7–15.
355. Ahmed-Bentley J, Chandran AU, Joffe AM, French D, Peirano G, Pitout JD. Gram-
negative bacteria that produce carbapenemases causing death attributed to recent foreign
hospitalization. Antimicrob Agents Chemother 2013;57:3085–3091.
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Outcomes were objective referring to length of hospital stay, mortality, rate of acquisition or infection.
12.3.2 Systematic Review Questions
1. What is the definition of MDR Gram-negative bacilli?
2. What Gram-negative bacilli cause infection control problems?
3. What are the relative contributions of community and hospital acquisition?
4. What is the evidence for reservoir and spread of mulitresistant Gram-
negatives in Care Homes and secondary care?
5. What is the role of agricultural use of sewage and antibiotic treatment in
veterinary practice in spreading ESBL?
6. What insights has national E. coli bacteraemia surveillance provided?
7. What is the role for screening in patients and staff?
8. What organisms should screening include?
9. Who, how and when to screen patients for MDR Gram-negative bacilli?
10.What can be done concerning patients unable to consent to a rectal swab?
11.How frequently does screening need to be performed?
12. Is there evidence for effective interventions on positive patients i.e. can
carriage be cleared?
13.Selective decontamination: Why is it not used? Is there a role?
14.When should the environment be sampled?
15.What is the evidence that respiratory equipment contributes to transmission?
16.What national surveillance is performed and how should it be developed?
17.What is the evidence that sensor taps contribute to transmission?
356. Eveillard M, Kempf M, Belmonte O, Pailhories H, Joly-Guillou ML. Reservoirs of
Acinetobacter baumannii outside the hospital and potential involvement in emerging human
community-acquired infections. Int J Infect Dis 2013;17:e802–e805.
357. Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious
bacterial pathogen in patients with cancer. Clin Infect Dis 2007;45:1602–1609.
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18. Is there any cleaning method more effective than others at removing the MDR
Gram-negative bacilli from the environment?
19.What is the evidence that infection control precautions prevent transmission?
20. Are standard infection control measures sufficient to stop transmission?
21.What are the minimum standards to stop spread in public areas, primary care
or care homes?
22. Is there evidence for high/low risk areas within a healthcare facility?
23.Are there any organisational structures within a healthcare facility that play a
role in the successful control of multi-resistant Gram-negative bacilli?
24.How should we undertake local screening, why is it important and how should
it be interpreted?
25.At what point should passive surveillance switch to active surveillance i.e.
screening?
26.What is the role of isolation in the care home/hospital settings?
27. Is there evidence of differences between organisms in respect of
transmission, morbidity and mortality:
12.4 Antimicrobial Chemotherapy -Systematic Review Process
12.4.1 Systematic Review Questions
1. What is the clinical importance of carbapenemases versus Amp C and
CTX-M strains?
2. What impact have returning travellers made on UK epidemiology?
3. What is the global epidemiology of MDR-GNR?
4. How do MDR Enterobacteriaceae differ from the non-fermenters in
terms of their prevalence and associated resistance genes?
5. What is the efficacy of carbapenems, mecillinam, temocillin, fosfomycin
and colistin against specific pathogens?
6. What are the recommended antibiotics for
community/secondary/tertiary care?
7. What is the threshold level of resistance for changing choice of
empirical treatment for urinary infection?
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12.5 Databases and Search terms Used 23/5/14358
Databases
The Cochrane Library; MEDLINE; EMBASE; CINAHL
MeSH Terms see Appendix 1
Free text terms. See Appendix 1
Search Date: Medline 1946-2014; Embase 1980-2012; CINAHL (1984-2012)
Search Results (Fig 1)
Total number of articles located after duplicates removed = 2523
Sift 1 Criteria
Abstract screening: Systematic review, primary research, infection relates to MDR
Gram-negative infection, informs one or more review question
Articles Retrieved
Total number of studies selected = 597
Sift 2 Criteria
Full text confirms that the article is primary research (randomised controlled trial,
non-randomised controlled trials, controlled before and after studies, interrupted time
series, case control study, case series, prospective cohort, systematic review;
informs one or more of the review questions.
Articles selected for appraisal (10 full text publications could not be retrieved)
Total number of studies selected = 49
Critical appraisal
Articles presenting primary research or a systematic review and meeting the sift
criteria were critically appraised by two reviewers using SIGN and EPOC criteria.
Consensus was achieved through discussion
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Accepted and Rejected Evidence
No meta analyses were available
Accepted after critical appraisal 49
Rejected after critical appraisal 0
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13 Appendix 3: Consultation stakeholders
Antimicrobial Resistance and Hospital Acquired Infection
Advisory Committee (ARHAI)
British Medical Association
British Society of Antimicrobial Chemotherapy
British Infection Society
C Diff Support
European Society of Clinical Microbiology and Infectious Diseases
Faculty of Intensive Care Medicine
Foundation Trust Network
Hand Hygiene Alliance
Healthcare Infection Society
Infection Prevention Society
Lee Spark Foundation
MRSA Action UK
NHS Confederation
NHS England
NHS Trust Development Authority
Patient’s Association
Public Health England/ Wales/ Scotland/ Northern Ireland
Royal College of Pathologists
Royal College of General Practitioners
Royal College of Nursing
Royal College of Physicians
Royal College of Surgeons
Service User Research Forum Healthcare acquired Infections
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UK Clinical Pharmacists Association
Unison
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14 Appendix 4: CPD material
1. In deciding which patients to screen for carbapenem resistant organisms which two groups should take priority:
a) Admitted to Intensive Careb) Admitted to Surgical wardc) Admitted from Long term care facilityd) Admitted to Medical warde) Discharge to community
A C
2. For the purposes of national surveillance, which two antimicrobial susceptibilities for Gram-negative pathogens are most important to test
a. Meropenem b. Amoxicillinc. Trimethoprimd. Gentamicine. Cefpodoxime
A E
3. To prevent spread of MDR Gram-negative pathogens:
a. Assess all patients for risk of infection on arrival b. Maintain standard infection control precautions in only those patients at high
risk c. Do not discard body fluids into hand basinsd. Minimise invasive medical device usee. Audit and feedback staff compliance
A C D E
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15 Appendix 5: Working Party Scope
Joint BSAC/HIS Working Party on Multi-resistant Gram-negative bacteriaA proposal for the Councils to consider
1. Guideline titlePrevention and Control of MDR Gram-negative bacteria – recommendations from a Joint
Working Party
1.1 Short title
Multi-resistant Gram-negative bacteria
2. The remit
To examine and make recommendations both for treatment and prevention of transmission of multi-resistant-Gram-negative infections, resulting in the publication of guidelines on:A Current epidemiology and infection control issues.B Therapeutic issues and antibiotic guidance for treating infections caused by multi-resistant Gram-negatives.
3. Clinical need for the guideline3.1 Epidemiology There are a rising number of MDR Gram-negative infections in critical care
units and the dual problems of finding an appropriate antibiotic and preventing spread.
ARHAI has recently produced brief guidelines on infection control and treatment options for these infections.
There was a significant interest attracted by the May 2010 BSAC conference examining the lack of development of new antibiotics effective against Gram-negative bacteria.
The recent outbreaks of Gram-negative infections related to infrared taps in neonatal units causing cross infections and deaths led to the Department of Health’s decision to review advice on tap design.
The Department of Health’s recognised that whilst control of MRSA and C difficile has been relatively successful, Gram-negative infections have continued to increase. Consequent to this is the surveillance subcommittee of ARHAI recommendation that E. coli bacteraemia be included in mandatory reporting from April 2011, a recommendation that has received ministerial approval.
Outbreaks of multi-resistant Acinetobacter spp. have been very troublesome in critical care units from time to time but control measures appear poorly effective.
3.2 Current practice
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Members of BSAC and HIS, with the knowledge of the Councils of each, have been discussing the issues surrounding the recent increase in infections with multi-resistant Gram-negative bacteria in UK hospitals.
Following discussions and consideration of the forthcoming ARHAI report we now believe it an appropriate time to set up a Joint Working Party to look at making authoritative recommendations both for treatment and prevention of transmission of these infections.
4. The guidelineThe guideline development process is described on the NICE website. The scope defines what the guideline will and will not examine and what the guideline developers will consider. The scope is based on the referral from the three Societies.4.1 Population
4.1.1 Groups that will be covereda) Adultsb) Children over 1 month oldc) Particular consideration given to patients of 65 years and older,
people at high risk of acquiring multi-resistant bacteria such as those requiring care in hospital settings
4.1.2 Groups that will not be covereda) Cystic fibrosisb) Community outbreaks
4.2 Healthcare settinga) All settings in which NHS care is received
4.3 Clinical management4.3.1 Key clinical issues that will be covered
a) Consideration will be given to laboratory testing and susceptibility testing, although only screening and confirmatory tests available in a general microbiology laboratory and not those limited to reference laboratories.
b) The use of antibiotic combinations in the therapy of infections will be considered, particularly oral combinations that can be used in the outpatient setting.
c) Mainly infections in critical and non-critical care patients in secondary care. However the same general principles would apply in community settings, particularly in areas where inappropriate treatment is encouraging selection.4.3.2 Clinical issues that will not be covered
A) Children younger than 1 month (neonates). This group has physiologically different needs and care is very specialised.
B) people with cystic fibrosis, who need specialised careC) people , who receive community health care in nursing homes
4.4 Main outcomes
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Outputs will be the production of guidelines, which will be approved via a process of national consultation. The intention is to inform and guide practice but also to highlight areas where more research is needed. The following will be produced and published as indicated:
a) Current epidemiology and infection control issues – Journal of Hospital Infection
b) Therapeutic issues and antibiotic guidance for treating infections caused by multi-resistant Gram-negatives – Journal of Antimicrobial Chemotherapy
c) In addition, it is expected that each Journal will carry a leading article or review article on the guidance that is published by the joint society.
d) The Working Party will follow the SIGN process when developing guidance including the hosting of a national stakeholder meeting as part of the national stakeholder consultation process.
4.5 Economic aspectsDevelopers will take into account both clinical and cost effectiveness when making recommendations involving a choice between alternative interventions.
4.6 Status4.6.1 Scope
Final scope4.6.2 Timing
The work will start in October 2011.
5. Patient Representation And Equality Patient representatives are invited to all meetings and involved in the writing and drafting of the guidelines. As part of these discussions potential impacts on equality of groups sharing protected characteristics are considered and incorporated into the guidelines. Health inequalities associated with socioeconomic factors and with inequities in access for groups to healthcare and social care are considered and opportunities identified to improve health.
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16 Appendix 6. Search Strategy
CINAHL (January 1984-December 2012)
# Query Results
S83 S48 AND S82 275
S82 S55 OR S56 OR S81 515,966
S81 S57 or S58 or S59 or S60 or S61 or S62 or S63 or S64 or S65 or S66 or S67 or S68 or S69 or S70 or S71 or S72 or S73 or S74 or S75 or S76 or S77 or S78 or S79 or S80 471,263
S80
TI ( (time points n3 over) or (time points n3 multiple) or (time points n3 three) or (time points n3 four) or (time points n3 five) or (time points n3 six) or (time points n3 seven) or (time points n3 eight) or (time points n3 nine) or (time points n3 ten) or (time points n3 eleven) or (time points n3 twelve) or (time points n3 month*) or (time points n3 hour*) or (time points n3 day*) or (time points n3 ‘more than’) ) or AB ( (time points n3 over) or (time points n3 multiple) or (time points n3 three) or (time points n3 four) or (time points n3 five) or (time points n3 six) or (time points n3 seven) or (time points n3 eight) or (time points n3 nine) or (time points n3 ten) or (time points n3 eleven) or (time points n3 twelve) or (time points n3 month*) or (time points n3 hour*) or (time points n3 day*) or (time points n3 ‘more than’) )
1,527
S79 TI ( (control w3 area) or (control w3 cohort*) or (control w3 compar*) or (control w3 condition) or (control w3 group*) or (control w3 intervention*) or (control w3 participant*) or (control w3 study) ) or AB ( (control w3 area) or (control w3 cohort*) or (control w3 compar*) or (control w3 condition) or (control w3 group*) or (control w3 intervention*) or (control w3 participant*) or (control w3 study) )
45,564
S78 TI ( multicentre or multicenter or multi-centre or multi-center ) or AB random* 101,899
S77 TI random* OR controlled 94,669
S76 TI ( trial or (study n3 aim) or ‘our study’ ) or AB ( (study n3 aim) or ‘our study’ ) 87,121
S75 TI ( pre-workshop or preworkshop or post-workshop or postworkshop or (before n3 workshop) or (after n3 workshop) ) or AB ( pre-workshop or preworkshop or post-workshop or postworkshop or (before n3 workshop) or (after n3 workshop) )
283
S74 TI ( demonstration project OR demonstration projects OR preimplement* or pre-implement* or post-implement* or postimplement* ) or AB ( demonstration project OR demonstration projects OR preimplement* or pre-implement* or post-implement* or postimplement* )
1,290
S73
(intervention n6 clinician*) or (intervention n6 community) or (intervention n6 complex) or (intervention n6 design*) or (intervention n6 doctor*) or (intervention n6 educational) or (intervention n6 family doctor*) or (intervention n6 family physician*) or (intervention n6 family practitioner*) or (intervention n6 financial) or (intervention n6 GP) or (intervention n6 general practice*) Or (intervention n6 hospital*) or (intervention n6 impact*) Or (intervention n6 improv*) or (intervention n6 individualize*) Or (intervention n6 individualise*) or (intervention n6 individualizing) or (intervention n6 individualising) or (intervention n6 interdisciplin*) or (intervention n6 multicomponent) or (intervention n6 multi-component) or (intervention n6 multidisciplin*) or (intervention n6 multi-disciplin*) or (intervention n6 multifacet*) or (intervention n6 multi-facet*) or (intervention n6 multimodal*) or (intervention n6 multi-modal*) or (intervention n6 personalize*) or(intervention n6 personalise*) or (intervention n6 personalizing) or (intervention n6 personalising) or (intervention n6 pharmaci*) or (intervention n6 pharmacist*) or (intervention n6 pharmacy) or (intervention n6 physician*) or (intervention n6 practitioner*) Or (intervention n6 prescrib*) or (intervention n6 prescription*) or (intervention n6 primary care) or (intervention n6 professional*) or (intervention* n6 provider*) or (intervention* n6 regulatory) or (intervention n6 regulatory) or (intervention n6 tailor*) or (intervention n6 target*) or (intervention n6 team*) or (intervention n6 usual care)
23,198
S72 TI ( collaborativ* or collaboration* or tailored or personalised or personalized ) or AB ( collaborativ* or collaboration* or tailored or personalised or personalized ) 38,021
S71 TI pilot 13,958
11201121
2658
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2661
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# Query Results
S70 (MH ‘Pilot Studies’) 36,433
S69 AB ‘before-and-after’ 17,437
S68 AB time series 1,670
S67 TI time series 359
S66 AB ( before* n10 during or before n10 after ) or AU ( before* n10 during or before n10 after ) 32,982
S65 TI ( (time point*) or (period* n4 interrupted) or (period* n4 multiple) or (period* n4 time) or (period* n4 various) or (period* n4 varying) or (period* n4 week*) or (period* n4 month*) or (period* n4 year*) ) or AB ( (time point*) or (period* n4 interrupted) or (period* n4 multiple) or (period* n4 time) or (period* n4 various) or (period* n4 varying) or (period* n4 week*) or (period* n4 month*) or (period* n4 year*) )
51,050
S64
TI ( ( quasi-experiment* or quasiexperiment* or quasi-random* or quasirandom* or quasi control* or quasicontrol* or quasi* W3 method* or quasi* W3 study or quasi* W3 studies or quasi* W3 trial or quasi* W3 design* or experimental W3 method* or experimental W3 study or experimental W3 studies or experimental W3 trial or experimental W3 design* ) ) or AB ( ( quasi-experiment* or quasiexperiment* or quasi-random* or quasirandom* or quasi control* or quasicontrol* or quasi* W3 method* or quasi* W3 study or quasi* W3 studies or quasi* W3 trial or quasi* W3 design* or experimental W3 method* or experimental W3 study or experimental W3 studies or experimental W3 trial or experimental W3 design* ) )
12,758
S63 TI pre w7 post or AB pre w7 post 9,367
S62 MH ‘Multiple Time Series’ or MH ‘Time Series’ 1,312
S61 TI ( (comparative N2 study) or (comparative N2 studies) or evaluation study or evaluation studies ) or AB ( (comparative N2 study) or (comparative N2 studies) or evaluation study or evaluation studies ) 11,680
S60 MH Experimental Studies or Community Trials or Community Trials or Pretest-Posttest Design + or Quasi-Experimental Studies + Pilot Studies or Policy Studies + Multicenter Studies 34,567
S59 TI ( pre-test* or pretest* or posttest* or post-test* ) or AB ( pre-test* or pretest* or posttest* or ‘post test* ) OR TI ( preimplement*’ or pre-implement* ) or AB ( pre-implement* or preimplement* ) 6,868
S58 TI ( intervention* or multiintervention* or multi-intervention* or postintervention* or post-intervention* or preintervention* or pre-intervention* ) or AB ( intervention* or multiintervention* or multi-intervention* or postintervention* or post-intervention* or preintervention* or pre-intervention* )
151,748
S57 (MH ‘Quasi-Experimental Studies’) 5,747
S56
(TI (systematic* n3 review*)) or (AB (systematic* n3 review*)) or (TI (systematic* n3 bibliographic*)) or (AB (systematic* n3 bibliographic*)) or (TI (systematic* n3 literature)) or (AB (systematic* n3 literature)) or (TI (systematic* n3 review*)) or (AB (systematic* n3 review*)) or (TI (comprehensive* n3 literature)) or (AB (comprehensive* n3 literature)) or (TI (comprehensive* n3 bibliographic*)) or (AB (comprehensive* n3 bibliographic*)) or (JN ‘Cochrane Database of Systematic Reviews’) or (TI (information n2 synthesis)) or (TI (data n2 synthesis)) or (AB (information n2 synthesis)) or (AB (data n2 synthesis)) or (TI (data n2 extract*)) or (AB (data n2 extract*)) or (TI (medline or pubmed or psyclit or cinahl or (psycinfo not ‘psycinfo database’) or ‘web of science’ or scopus or embase)) or (AB (medline or pubmed or psyclit or cinahl or (psycinfo not ‘psycinfo database’) or ‘web of science’ or scopus or embase)) or (MH ‘Systematic Review’) or (MH ‘Meta Analysis’) or (TI (meta-analy* or metaanaly*)) or (AB (meta-analy* or metaanaly*))
59,817
S55 S49 OR S50 OR S51 OR S52 OR S53 OR S54 158,596
S54 TI ( ‘control* N1 clinical’ or ‘control* N1 group*’ or ‘control* N1 trial*’ or ‘control* N1 study’ or ‘control* N1 studies’ or ‘control* N1 design*’ or ‘control* N1 method*’ ) or AB ( ‘control* N1 clinical’ or ‘control* N1 group*’ or ‘control* N1 trial*’ or ‘control* N1 study’ or ‘control* N1 studies’ or ‘control* N1 design*’ or ‘control* N1 method*’ )
1
S53 TI controlled or AB controlled 68,638
S52 TI random* or AB random* 117,418
S51 TI ( ‘clinical study’ or ‘clinical studies’ ) or AB ( ‘clinical study’ or ‘clinical studies’ ) 7,969
11221123
148
# Query Results
S50 (MM ‘Clinical Trials+’) 10,670
S49 TI ( (multicent* n2 design*) or (multicent* n2 study) or (multicent* n2 studies) or (multicent* n2 trial*) ) or AB ( (multicent* n2 design*) or (multicent* n2 study) or (multicent* n2 studies) or (multicent* n2 trial*) ) 8,917
S48 S18 AND S21 AND S47 917
S47 S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 16,726
S46 TI ( (belcomycin or colicort or colimycin* or colisitin or colisticin or Colistin or colistine or colomycin or (coly n1 mycin) or colymicin or colymycin or coly-mycin or multimycin or (Polymyxin n1 E) or totazina) ) OR AB ( (belcomycin or colicort or colimycin* or colisitin or colisticin or Colistin or colistine or colomycin or (coly n1 mycin) or colymicin or colymycin or coly-mycin or multimycin or (Polymyxin n1 E) or totazina) )
171
S45 (MH ‘Colistin’) 134
S44 TI ( ((amdinocillin n1 pivoxil) or (FL n1 ‘1039’) or FL1039 or fl1039 or FL-1039 or pivamdinocillin or Pivmecillinam or Selexid or coactabs or (ro n1 ‘109071’) or (ro10 n1 ‘9071’) or ro109071) ) OR AB ( ((amdinocillin n1 pivoxil) or (FL n1 ‘1039’) or FL1039 or fl1039 or FL-1039 or pivamdinocillin or Pivmecillinam or Selexid or coactabs or (ro n1 ‘109071’) or (ro10 n1 ‘9071’) or ro109071) )
13
S43
TI ( ((Cephalosporanic n1 Acid*) or Cephalosporin* or Cefamandole or Cefoperazone or Cefazolin or Cefonicid or Cefsulodin or Cephacetrile or Cefotaxime or Cephalothin or Cephapirin or Cephalexin or Cefaclor or Cefadroxil or Cephaloglycin or Cephradine or Cephaloridine or Ceftazidime or Cephamycins or Cefmetazole or Cefotetan or Cefoxitin) ) OR AB ( ((Cephalosporanic n1 Acid*) or Cephalosporin* or Cefamandole or Cefoperazone or Cefazolin or Cefonicid or Cefsulodin or Cephacetrile or Cefotaxime or Cephalothin or Cephapirin or Cephalexin or Cefaclor or Cefadroxil or Cephaloglycin or Cephradine or Cephaloridine or Ceftazidime or Cephamycins or Cefmetazole or Cefotetan or Cefoxitin) )
1,569
S42 TI ( (Axepim* or bmy 28142 or bmy28142 or BMY-28142 or Cefepim* or cefepitax or ceficad or cepimax or forzyn beta or maxcef or maxfrom or maxipime or Quadrocef) ) OR AB ( (Axepim* or bmy 28142 or bmy28142 or BMY-28142 or Cefepim* or cefepitax or ceficad or cepimax or forzyn beta or maxcef or maxfrom or maxipime or Quadrocef) )
171
S41 (MH ‘Cephalosporins+’) 2,105
S40
TI ( (berkfurin or biofurin or chemiofuran or dantafur or f 30 or f30 or fua-med or furaben or furadantin* or furadantoin or furadina or furadoine or furadonin or furadonine or furalan or furanpur or furantocompren or furantoin* or furobactina or furofen or furophen or infurin or ituran or ivadantin or macrobid or macrodantin* or macrofuran or macrofurin or micofurantin* or mitrofuratoin or nephronex or nierofu or nifurantin or nifuryl or (nitro n1 macro) or nitrofuracin or nitrofuradantoin or nitrofurantine or nitrofurantoin* or nitrofurin or novofuran or nsc 2107 or nsc2107 or orafuran or parfuran or phenurin or (potassium n1 furagin) or ralodantin or trocurine or urantin or (uro n1 tablinen) or urodil or urodin or urofuran or urolong or urotablinen or uro-tablinen or urotoina or uvamin) ) OR AB ( (berkfurin or biofurin or chemiofuran or dantafur or f 30 or f30 or fua-med or furaben or furadantin* or furadantoin or furadina or furadoine or furadonin or furadonine or furalan or furanpur or furantocompren or furantoin* or furobactina or furofen or furophen or infurin or ituran or ivadantin or macrobid or macrodantin* or macrofuran or macrofurin or micofurantin* or mitrofuratoin or nephronex or nierofu or nifurantin or nifuryl or (nitro n1 macro) or nitrofuracin or nitrofuradantoin or nitrofurantine or nitrofurantoin* or nitrofurin or novofuran or nsc 2107 or nsc2107 or orafuran or parfuran or phenurin or (potassium n1 furagin) or ralodantin or trocurine or urantin or (uro n1 tablinen) or urodil or urodin or urofuran or urolong or urotablinen or uro-tablinen or urotoina or uvamin) )
325
S39
TI ( ((az n1 threonam) or azactam or azenam or azthreonam or aztreonam or (corus n1 ‘1020’) or dynabiotic or primbactam or SQ 26,776 or sq 26,776 or sq 26776 or SQ-26,776 or sq26776 or sq-26776 or urobactam) ) OR AB ( ((az n1 threonam) or azactam or azenam or azthreonam or aztreonam or (corus n1 ‘1020’) or dynabiotic or primbactam or SQ 26,776 or sq 26,776 or sq 26776 or SQ-26,776 or sq26776 or sq-26776 or urobactam) )
96
S38 (MH ‘Aztreonam’) 54
S37 TI ( (fosfocil or fosfocin or fosfocina or fosfomicin or fosfomycin or fosfonomycin or ‘mk 0955’ or mk 955 or mk0955 or mk955 or monuril or phosphomycin or phosphonomycin) ) OR AB ( (fosfocil or fosfocin or fosfocina or fosfomicin or fosfomycin or fosfonomycin or ‘mk 0955’ or mk 955 or mk0955 or mk955 or monuril or phosphomycin or phosphonomycin) )
57
11241125
149
# Query Results
S36
TI ( (akacin or akicin or amicacina or amicasil or amicin or amiglymide v or amikacin* or amikafur or amikalem or amikan or amikayect or amikin or amiklin or amikozit or amiktam or amitracin or amixin or amukin or apalin or bb k 8 or bb k8 or bbk 8 or bb-k 8 or bbk8 or bbk-8 or bb-k8 or biclin or biklin or biokacin or briclin or briklin or chemacin or cinmik or fabianol or gamikal or glukamin or kacinth-a or kanbine or kormakin or likacin or lukadin or miacin or mikasome or onikin or oprad or orlobin or pediakin or pierami or riklinak or savox or selaxa or selemycin or sulfate amikacin or tybikin or vs 107 or vs107 or yectamid) ) OR AB ( (akacin or akicin or amicacina or amicasil or amicin or amiglymide v or amikacin* or amikafur or amikalem or amikan or amikayect or amikin or amiklin or amikozit or amiktam or amitracin or amixin or amukin or apalin or bb k 8 or bb k8 or bbk 8 or bb-k 8 or bbk8 or bbk-8 or bb-k8 or biclin or biklin or biokacin or briclin or briklin or chemacin or cinmik or fabianol or gamikal or glukamin or kacinth-a or kanbine or kormakin or likacin or lukadin or miacin or mikasome or onikin or oprad or orlobin or pediakin or pierami or riklinak or savox or selaxa or selemycin or sulfate amikacin or tybikin or vs 107 or vs107 or yectamid) )
342
S35 (MH ‘Amikacin’) 140
S34
TI ( (adelanin or alcomicin or apigent or apogen or apoten or azupel or bactiderm or biogaracin or bristagen or cidomycin or danigen or dermogen or dianfarma or dispagent or duragentam* or epigent or (frieso n1 gent) or garabiotic or garalone or garamicin* or garamycin or garbilocin or gencin or gendril or genoptic or genrex or gensumycin or gentabiotic or gentabiox or gentac or gentacidin or gentacin or gentacor or gentacycol or gentacyl or gentafair or gentagram or gentak or gental or gentaline or gentalline or gentalol or gentalyn or gentamax or gentame* or gentamicin* or gentamina or gentamycin* or gentamyl or gentamytrex or gentaplus or gentarad or gentasil or gentasol or gentasone or gentasporin or gentatrim or gentavet or genticin* or genticyn or gentiderm or gentimycin or gentocin or gentogram or gentomycin or genum or geomycine or gevramycin or g-mycin or gmyticin or g-myticin or grammicin or hexamycin or jenamicin or konigen or lacromycin or lisagent or martigenta or migenta or miragenta or miramycin or nichogencin or nsc 82261 or nsc82261 or obogen or ocugenta or ocu-mycin or oftagen or ophtagram or opthagen or optigen or opti-genta or ottogenta or pyogenta or refobacin or ribomicin or rigaminol or rocy gen or rovixida or rupegen or sagestam or sch 9724 or sch9724 or sedanazin or servigenta or skinfect or sulmycin or tangyn or u-gencin or versigen or yectamicina) ) OR AB ( (adelanin or alcomicin or apigent or apogen or apoten or azupel or bactiderm or biogaracin or bristagen or cidomycin or danigen or dermogen or dianfarma or dispagent or duragentam* or epigent or (frieso n1 gent) or garabiotic or garalone or garamicin* or garamycin or garbilocin or gencin or gendril or genoptic or genrex or gensumycin or gentabiotic or gentabiox or gentac or gentacidin or gentacin or gentacor or gentacycol or gentacyl or gentafair or gentagram or gentak or gental or gentaline or gentalline or gentalol or gentalyn or gentamax or gentame* or gentamicin* or gentamina or gentamycin* or gentamyl or gentamytrex or gentaplus or gentarad or gentasil or gentasol or gentasone or gentasporin or gentatrim or gentavet or genticin* or genticyn or gentiderm or gentimycin or gentocin or gentogram or gentomycin or genum or geomycine or gevramycin or g-mycin or gmyticin or g-myticin or grammicin or hexamycin or jenamicin or konigen or lacromycin or lisagent or martigenta or migenta or miragenta or miramycin or nichogencin or nsc 82261 or nsc82261 or obogen or ocugenta or ocu-mycin or oftagen or ophtagram or opthagen or optigen or opti-genta or ottogenta or pyogenta or refobacin or ribomicin or rigaminol or rocy gen or rovixida or rupegen or sagestam or sch 9724 or sch9724 or sedanazin or servigenta or skinfect or sulmycin or tangyn or u-gencin or versigen or yectamicina) )
993
S33 (MH ‘Gentamicins’) 808
S32
TI ( (Aminoglycosides or Anthracyclines or Aclarubicin or Daunorubicin or Plicamycin or Butirosin Sulfate or Sisomicin or Hygromycin B or Kanamycin or Dibekacin or Nebramycin or Metrizamide or Neomycin or Framycetin or Paromomycin or Ribostamycin or Puromycin or Spectinomycin or Streptomycin or Dihydrostreptomycin Sulfate or Streptothricins or Streptozocin) ) OR AB ( (Aminoglycosides or Anthracyclines or Aclarubicin or Daunorubicin or Plicamycin or Butirosin Sulfate or Sisomicin or Hygromycin B or Kanamycin or Dibekacin or Nebramycin or Metrizamide or Neomycin or Framycetin or Paromomycin or Ribostamycin or Puromycin or Spectinomycin or Streptomycin or Dihydrostreptomycin Sulfate or Streptothricins or Streptozocin) )
1,269
S31 (MH ‘Aminoglycosides+’) 6,215
S30 TI ( ((chinolone n1 derivative) or fluoroquinolones or (haloquinolone n1 derivative) or ketoquinolines or oxoquinolines or quinolinones or quinolones) ) OR AB ( ((chinolone n1 derivative) or fluoroquinolones or (haloquinolone n1 derivative) or ketoquinolines or oxoquinolines or quinolinones or quinolones) )
834
S29 (MH ‘Quinolines+’) OR (MH ‘Antiinfective Agents, Quinolone+’) 4,842
S28 TI ( (tigecycline or (tbg n1 mino) or tygacil or gar 936 or gar936 or (tert n1 butylglycinamido*)) ) OR AB ( (tigecycline or (tbg n1 mino) or tygacil or gar 936 or gar936 or (tert n1 butylglycinamido*)) ) 208
11261127
150
# Query Results
S27 TI ( ((brl n1 ‘17421’) or brl17421 or (thiophenemalonamic n1 acid) or negaban or temocillin or temopen) ) OR AB ( ((brl n1 ‘17421’) or brl17421 or (thiophenemalonamic n1 acid) or negaban or temocillin or temopen) )
10
S26
TI ( (aclam or aktil or ambilan or amocla or amoclan or amoclav or amoksiklav or amolanic or amometin or (amox n1 clav) or amox-clav or (amoxi n1 plus) or (amoxNear/3clavulan*) or amoxiclav or amoxiclav-bid or amoxiclav-teva or amoxsiklav or amoxxlin or (amoxycillin-clavulanic n1 acid) or ancla or (auclatin n1 duo) or augamox or augmaxcil or augmentan or augmentin* or augmex or augpen or (augucillin n1 duo) or augurcin or ausclav or auspilic or bactiv or bactoclav or bioclavid or (brl n1 ‘25000’) or brl25000 or brl-25000 or cavumox or ciblor or (clacillin n1 duo) or clamax or clamentin or clamobit or clamonex or clamovid or clamoxin or (clamoxyl n1 duo*) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin n1 plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox n1 duo) or clavumox or (co n1 amoxiclav) or (co n1 amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon n1 duo) or (croanan n1 duo) or curam or danoclav or (darzitil n1 plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina n1 plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox n1 cl) or vestaclav or viaclav or vulamox or xiclav or (zami n1 ‘8503’)) ) OR AB ( (aclam or aktil or ambilan or amocla or amoclan or amoclav or amoksiklav or amolanic or amometin or (amox n1 clav) or amox-clav or (amoxi n1 plus) or (amoxNear/3clavulan*) or amoxiclav or amoxiclav-bid or amoxiclav-teva or amoxsiklav or amoxxlin or (amoxycillin-clavulanic n1 acid) or ancla or (auclatin n1 duo) or augamox or augmaxcil or augmentan or augmentin* or augmex or augpen or (augucillin n1 duo) or augurcin or ausclav or auspilic or bactiv or bactoclav or bioclavid or (brl n1 ‘25000’) or brl25000 or brl-25000 or cavumox or ciblor or (clacillin n1 duo) or clamax or clamentin or clamobit or clamonex or clamovid or clamoxin or (clamoxyl n1 duo*) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin n1 plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox n1 duo) or clavumox or (co n1 amoxiclav) or (co n1 amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon n1 duo) or (croanan n1 duo) or curam or danoclav or (darzitil n1 plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina n1 plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox n1 cl) or vestaclav or viaclav or vulamox or xiclav or (zami n1 ‘8503’)) )
805
S25 TI ( (cl 307579 or cl298741 or cl307579 or tazabactam or tazobac* or tazocel or tazocillin* or tazocin or tazomax or tazonam or tazopril or yp 14 or yp14 or ytr 830 or ytr 830h or ytr830 or ytr830h or zosyn) ) OR AB ( (cl 307579 or cl298741 or cl307579 or tazabactam or tazobac* or tazocel or tazocillin* or tazocin or tazomax or tazonam or tazopril or yp 14 or yp14 or ytr 830 or ytr 830h or ytr830 or ytr830h or zosyn) )
247
S24
TI ( (acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin* or pipcil or pipera hameln or piperacil or piperacillin* or piperacin or pipera-hameln or pipercillin or piperilline or pipraci* or pipraks or pipril or piprilin or pitamycin or t 1220 or t1220 or t-1220 or taiperacillin) ) OR AB ( (acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin* or pipcil or pipera hameln or piperacil or piperacillin* or piperacin or pipera-hameln or pipercillin or piperilline or pipraci* or pipraks or pipril or piprilin or pitamycin or t 1220 or t1220 or t-1220 or taiperacillin) )
296
S23
TI ( (Carbapenem* or doripenem or ertapenem or Imipemide or Imipenem or Invanoz or Invanz or meropenem or Merrem or ‘MK 0787’ or MK0787 or MK-0787 or N Formimidoylthienamycin or N-Formimidoylthienamycin or Penem or Ronem or S 4661 or S-4661 or SM 7338 or SM-7338 or Thienamycin*) ) OR AB ( (Carbapenem* or doripenem or ertapenem or Imipemide or Imipenem or Invanoz or Invanz or meropenem or Merrem or ‘MK 0787’ or MK0787 or MK-0787 or N Formimidoylthienamycin or N-Formimidoylthienamycin or Penem or Ronem or S 4661 or S-4661 or SM 7338 or SM-7338 or Thienamycin*) )
974
S22 (MH ‘Carbapenems+’) 559
S21 S19 OR S20 14,473
S20 (MH ‘Drug Resistance, Microbial+’) 14,182
S19 TI ( (multiresistant or (multi n1 resistan*)) ) OR AB ( (multiresistant or (multi n1 resistan*)) ) 604
S18 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 7,706
11281129
151
# Query Results
S17 TI ( ((bacillus n1 morgan*) or (bacterium n1 morgana) or (morganella n1 morgagni*) or (morganella n1 morganii) or (proteus n1 morgagni) or (proteus n1 morgana*) or (salmonella n1 morgana)) ) OR AB ( ((bacillus n1 morgan*) or (bacterium n1 morgana) or (morganella n1 morgagni*) or (morganella n1 morganii) or (proteus n1 morgagni) or (proteus n1 morgana*) or (salmonella n1 morgana)) )
20
S16 TI ( ((Citrobacter n1 freundii) or (bacterium n1 freundii) or (Escherichia n1 freundii)) ) OR AB ( ((Citrobacter n1 freundii) or (bacterium n1 freundii) or (Escherichia n1 freundii)) ) 32
S15 (MH ‘Citrobacter’) 40
S14 TI Serratia OR AB Serratia 238
S13 (MH ‘Serratia’) OR (MH ‘Serratia Infections’) 174
S12 TI Proteus OR AB Proteus 257
S11 (MH ‘Proteus’) OR (MH ‘Proteus Infections’) 118
S10 TI ( (Acinetobacter or mima or mimae or herellea or acinetobacterium) ) OR AB ( (Acinetobacter or mima or mimae or herellea or acinetobacterium) ) 889
S9 (MH ‘Acinetobacter Infections’) 581
S8 TI ‘p. aeruginosa’ OR AB ‘p. aeruginosa’ 610
S7 TI ( ((bacillus n1 pyocyaneus) or (bacterium n1 (aeruginosum or pyocyaneum)) or (blue n1 apus) or (Pseudomonas n1 (aeruginosa or aureofaciens or pyoceaneus or pyocyanea or pyocyaneus))) ) OR AB ( ((bacillus n1 pyocyaneus) or (bacterium n1 (aeruginosum or pyocyaneum)) or (blue n1 apus) or (Pseudomonas n1 (aeruginosa or aureofaciens or pyoceaneus or pyocyanea or pyocyaneus))) )
1,855
S6 TI ( (enterobacter or aerobacter) ) OR AB ( (enterobacter or aerobacter) ) 370
S5 TI ( (‘k. pneumoniae’ or ‘b. friedlander’) ) OR AB ( (‘k. pneumoniae’ or ‘b. friedlander’) ) 200
S4
TI ( (klebsiella or Calymmatobacterium or (aerobacter n1 aerogenes) or ((bacillus or bacterium) n1 pneumonia) or ((friedlaender or Friedlander) n1 bacillus) or (Hyalococcus n1 pneumonia) or Pneumobacillus) ) OR AB ( (klebsiella or Calymmatobacterium or (aerobacter n1 aerogenes) or ((bacillus or bacterium) n1 pneumonia) or ((friedlaender or Friedlander) n1 bacillus) or (Hyalococcus n1 pneumonia) or Pneumobacillus) )
1,039
S3 (MH ‘Klebsiella’) OR (MH ‘Klebsiella Infections’) 835
S2 TI ( (Eaggec or (escherichia n1 coli) or (e n1 coli) or (alkalescens-dispar n1 group) or (bacillus n1 escherichii) or (Coli n1 bacillus) or (Coli n1 bacterium) or colibacillus or (colon n1 bacillus)) ) OR AB ( (Eaggec or (escherichia n1 coli) or (e n1 coli) or (alkalescens-dispar n1 group) or (bacillus n1 escherichii) or (Coli n1 bacillus) or (Coli n1 bacterium) or colibacillus or (colon n1 bacillus)) )
2,914
S1 (MH ‘Escherichia Coli’) OR (MH ‘Escherichia Coli Infections’) 2,983
Cochrane Library (Issue 11, 2012)
ID Search
#1 MeSH descriptor: [Escherichia coli] explode all trees
#2 (Eaggec or (escherichia near/1 coli) or (e near/1 coli) or (alkalescens-dispar near/1 group) or (bacillus near/1 escherichii) or (Coli near/1 bacillus) or (Coli near/1 bacterium) or colibacillus or (colon near/1 bacillus)):ti,ab,kw (Word variations have been searched)
#3 MeSH descriptor: [Klebsiella] explode all trees
11301131
2662
2663
2664
2665
266626672668
2669
152
#4 (klebsiella or Calymmatobacterium or (aerobacter near/1 aerogenes) or ((bacillus or bacterium) near/1 pneumonia) or ((friedlaender or Friedlander) near/1 bacillus) or (Hyalococcus near/1 pneumonia) or Pneumobacillus):ti,ab,kw (Word variations have been searched)
#5 k. pneumoniae or b. friedlander:ti,ab,kw (Word variations have been searched)
#6 MeSH descriptor: [Enterobacter] explode all trees
#7 (enterobacter or aerobacter):ti,ab,kw (Word variations have been searched)
#8 MeSH descriptor: [Pseudomonas aeruginosa] explode all trees
#9 ((bacillus near/1 pyocyaneus) or (bacterium near/1 (aeruginosum or pyocyaneum)) or (blue near/1 apus) or (Pseudomonas near/1 (aeruginosa or aureofaciens or pyoceaneus or pyocyanea or pyocyaneus))):ti,ab,kw (Word variations have been searched)
#10 p. aeruginosa:ti,ab,kw (Word variations have been searched)
#11 MeSH descriptor: [Acinetobacter] explode all trees
#12 (Acinetobacter or mima or mimae or herellea or acinetobacterium):ti,ab,kw (Word variations have been searched)
#13 MeSH descriptor: [Proteus] explode all trees
#14 Proteus:ti,ab,kw (Word variations have been searched)
#15 MeSH descriptor: [Serratia] explode all trees
#16 Serratia:ti,ab,kw (Word variations have been searched)
#17 MeSH descriptor: [Citrobacter freundii] explode all trees
#18 ((Citrobacter near/1 freundii) or (bacterium near/1 freundii) or (Escherichia near/1 freundii)):ti,ab,kw (Word variations have been searched)
#19 MeSH descriptor: [Morganella morganii] explode all trees
#20 ((bacillus near/1 morgan$) or (bacterium near/1 morgana) or (morganella near/1 morgagni$) or (morganella near/1 morganii) or (proteus near/1 morgagni) or (proteus near/1 morgana$) or (salmonella near/1 morgana)):ti,ab,kw (Word variations have been searched)
#21 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
#22 (multiresistant or (multi near/1 resistan$)):ti,ab,kw (Word variations have been searched)
#23 MeSH descriptor: [Drug Resistance, Multiple] explode all trees
#24 #22 or #23
#25 MeSH descriptor: [Colistin] explode all trees
#26 (belcomycin or colicort or colimycin$ or colisitin or colisticin or Colistin or colistine or colomycin or (coly near/1 mycin) or colymicin or colymycin or coly-mycin or multimycin or (Polymyxin near/1 E) or totazina):ti,ab,kw (Word variations have been searched)
#27 MeSH descriptor: [Carbapenems] explode all trees
11321133
267026712672
2673
2674
2675
2676
267726782679
2680
2681
26822683
2684
2685
2686
2687
2688
26892690
2691
269226932694
26952696
2697
2698
2699
2700
270127022703
2704
153
#28 (Carbapenem$ or doripenem or ertapenem or Imipemide or Imipenem or Invanoz or Invanz or meropenem or Merrem or ‘MK 0787’ or MK0787 or MK-0787 or N Formimidoylthienamycin or N-Formimidoylthienamycin or Penem or Ronem or S 4661 or S-4661 or SM 7338 or SM-7338 or Thienamycin$):ti,ab,kw (Word variations have been searched)
#29 MeSH descriptor: [Piperacillin] explode all trees
#30 (acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin$ or pipcil or pipera hameln or piperacil or piperacillin$ or piperacin or pipera-hameln or pipercillin or piperilline or pipraci$ or pipraks or pipril or piprilin or pitamycin or t 1220 or t1220 or t-1220 or taiperacillin):ti,ab,kw (Word variations have been searched)
#31 (cl 307579 or cl298741 or cl307579 or tazabactam or tazobac$ or tazocel or tazocillin$ or tazocin or tazomax or tazonam or tazopril or yp 14 or yp14 or ytr 830 or ytr 830h or ytr830 or ytr830h or zosyn):ti,ab,kw (Word variations have been searched)
#32 MeSH descriptor: [Amoxicillin-Potassium Clavulanate Combination] explode all trees
#33 (aclam or aktil or ambilan or amocla or amoclan or amoclav or amoksiklav or amolanic or amometin or (amox near/1 clav) or amox-clav or (amoxi near/1 plus) or (amoxNear/3clavulan$) or amoxiclav or amoxiclav-bid or amoxiclav-teva or amoxsiklav or amoxxlin or (amoxycillin-clavulanic near/1 acid) or ancla or (auclatin near/1 duo) or augamox or augmaxcil or augmentan or augmentin$ or augmex or augpen or (augucillin near/1 duo) or augurcin or ausclav or auspilic or bactiv or bactoclav or bioclavid or (brl near/1 ‘25000’) or brl25000 or brl-25000 or cavumox or ciblor or (clacillin near/1 duo) or clamax or clamentin or clamobit or clamonex or clamovid or clamoxin or (clamoxyl near/1 duo$) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin near/1 plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox near/1 duo) or clavumox or (co near/1 amoxiclav) or (co near/1 amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon near/1 duo) or (croanan near/1 duo) or curam or danoclav or (darzitil near/1 plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina near/1 plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox near/1 cl) or vestaclav or viaclav or vulamox or xiclav or (zami near/1 ‘8503’)):ti,ab,kw (Word variations have been searched)
#34 ((brl near/1 ‘17421’) or brl17421 or (thiophenemalonamic near/1 acid) or negaban or temocillin or temopen):ti,ab,kw (Word variations have been searched)
#35 (tigecycline or (tbg near/1 mino) or tygacil or gar 936 or gar936 or (tert near/1 butylglycinamido$)):ti,ab,kw (Word variations have been searched)
#36 MeSH descriptor: [Quinolones] explode all trees
#37 ((chinolone near/1 derivative) or fluoroquinolones or (haloquinolone near/1 derivative) or ketoquinolines or oxoquinolines or quinolinones or quinolones):ti,ab,kw (Word variations have been searched)
#38 MeSH descriptor: [Aminoglycosides] explode all trees
#39 (Aminoglycosides or Anthracyclines or Aclarubicin or Daunorubicin or Plicamycin or Butirosin Sulfate or Sisomicin or Hygromycin B or Kanamycin or Dibekacin or Nebramycin or Metrizamide or Neomycin or Framycetin or Paromomycin or Ribostamycin or Puromycin or Spectinomycin or Streptomycin or Dihydrostreptomycin Sulfate or Streptothricins or Streptozocin):ti,ab,kw (Word variations have been searched)
#40 MeSH descriptor: [Gentamicins] explode all trees
11341135
2705270627072708
2709
27102711271227132714
271527162717
2718
271927202721272227232724272527262727272827292730273127322733
27342735
27362737
2738
27392740
2741
2742274327442745
2746
154
#41 (adelanin or alcomicin or apigent or apogen or apoten or azupel or bactiderm or biogaracin or bristagen or cidomycin or danigen or dermogen or dianfarma or dispagent or duragentam$ or epigent or (frieso near/1 gent) or garabiotic or garalone or garamicin$ or garamycin or garbilocin or gencin or gendril or genoptic or genrex or gensumycin or gentabiotic or gentabiox or gentac or gentacidin or gentacin or gentacor or gentacycol or gentacyl or gentafair or gentagram or gentak or gental or gentaline or gentalline or gentalol or gentalyn or gentamax or gentame$ or gentamicin$ or gentamina or gentamycin$ or gentamyl or gentamytrex or gentaplus or gentarad or gentasil or gentasol or gentasone or gentasporin or gentatrim or gentavet or genticin$ or genticyn or gentiderm or gentimycin or gentocin or gentogram or gentomycin or genum or geomycine or gevramycin or g-mycin or gmyticin or g-myticin or grammicin or hexamycin or jenamicin or konigen or lacromycin or lisagent or martigenta or migenta or miragenta or miramycin or nichogencin or nsc 82261 or nsc82261 or obogen or ocugenta or ocu-mycin or oftagen or ophtagram or opthagen or optigen or opti-genta or ottogenta or pyogenta or refobacin or ribomicin or rigaminol or rocy gen or rovixida or rupegen or sagestam or sch 9724 or sch9724 or sedanazin or servigenta or skinfect or sulmycin or tangyn or u-gencin or versigen or yectamicina):ti,ab,kw (Word variations have been searched)
#42 MeSH descriptor: [Amikacin] explode all trees
#43 (akacin or akicin or amicacina or amicasil or amicin or amiglymide v or amikacin$ or amikafur or amikalem or amikan or amikayect or amikin or amiklin or amikozit or amiktam or amitracin or amixin or amukin or apalin or bb k 8 or bb k8 or bbk 8 or bb-k 8 or bbk8 or bbk-8 or bb-k8 or biclin or biklin or biokacin or briclin or briklin or chemacin or cinmik or fabianol or gamikal or glukamin or kacinth-a or kanbine or kormakin or likacin or lukadin or miacin or mikasome or onikin or oprad or orlobin or pediakin or pierami or riklinak or savox or selaxa or selemycin or sulfate amikacin or tybikin or vs 107 or vs107 or yectamid):ti,ab,kw (Word variations have been searched)
#44 MeSH descriptor: [Fosfomycin] explode all trees
#45 (fosfocil or fosfocin or fosfocina or fosfomicin or fosfomycin or fosfonomycin or ‘mk 0955’ or mk 955 or mk0955 or mk955 or monuril or phosphomycin or phosphonomycin):ti,ab,kw (Word variations have been searched)
#46 MeSH descriptor: [Aztreonam] explode all trees
#47 ((az near/1 threonam) or azactam or azenam or azthreonam or aztreonam or (corus near/1 ‘1020’) or dynabiotic or primbactam or SQ 26,776 or sq 26,776 or sq 26776 or SQ-26,776 or sq26776 or sq-26776 or urobactam):ti,ab,kw (Word variations have been searched)
#48 MeSH descriptor: [Nitrofurantoin] explode all trees
#49 (berkfurin or biofurin or chemiofuran or dantafur or f 30 or f30 or fua-med or furaben or furadantin$ or furadantoin or furadina or furadoine or furadonin or furadonine or furalan or furanpur or furantocompren or furantoin$ or furobactina or furofen or furophen or infurin or ituran or ivadantin or macrobid or macrodantin$ or macrofuran or macrofurin or micofurantin$ or mitrofuratoin or nephronex or nierofu or nifurantin or nifuryl or (nitro near/1 macro) or nitrofuracin or nitrofuradantoin or nitrofurantine or nitrofurantoin$ or nitrofurin or novofuran or nsc 2107 or nsc2107 or orafuran or parfuran or phenurin or (potassium near/1 furagin) or ralodantin or trocurine or urantin or (uro near/1 tablinen) or urodil or urodin or urofuran or urolong or urotablinen or uro-tablinen or urotoina or uvamin):ti,ab,kw (Word variations have been searched)
#50 MeSH descriptor: [Cephalosporins] explode all trees
11361137
274727482749275027512752275327542755275627572758275927602761
2762
2763276427652766276727682769
2770
277127722773
2774
277527762777
2778
277927802781278227832784278527862787
2788
155
#51 ((Cephalosporanic near/1 Acid$) or Cephalosporin$ or Cefamandole or Cefoperazone or Cefazolin or Cefonicid or Cefsulodin or Cephacetrile or Cefotaxime or Cephalothin or Cephapirin or Cephalexin or Cefaclor or Cefadroxil or Cephaloglycin or Cephradine or Cephaloridine or Ceftazidime or Cephamycins or Cefmetazole or Cefotetan or Cefoxitin):ti,ab,kw (Word variations have been searched)
#52 MeSH descriptor: [Amdinocillin Pivoxil] explode all trees
#53 ((amdinocillin near/1 pivoxil) or (FL near/1 ‘1039’) or FL1039 or fl1039 or FL-1039 or pivamdinocillin or Pivmecillinam or Selexid or coactabs or (ro near/1 ‘109071’) or (ro10 near/1 ‘9071’) or ro109071):ti,ab,kw (Word variations have been searched)
#54 #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53
#55 #21 and #24 and #54 (21)
Embase (January 1980 to December 1012)
1 exp Escherichia coli/ (255846)
2 (Eaggec or (escherichia adj coli) or (e adj coli) or (alkalescens-dispar adj group) or (bacillus adj escherichii) or (Coli adj bacillus) or (Coli adj bacterium) or colibacillus or (colon adj bacillus)).ti,ab. (240749)
3 exp Klebsiella/ (30199)
4 (klebsiella or Calymmatobacterium or (aerobacter adj aerogenes) or ((bacillus or bacterium) adj pneumonia) or ((friedlaender or Friedlander) adj bacillus) or (Hyalococcus adj pneumonia) or Pneumobacillus).ti,ab. (22836)
5 (‘k. pneumoniae’ or ‘b. friedlander’).ti,ab. (5513)
6 exp Enterobacter/ (12784)
7 (enterobacter or aerobacter).ti,ab. (9700)
8 exp Pseudomonas aeruginosa/ (55073)
9 ((bacillus adj pyocyaneus) or (bacterium adj (aeruginosum or pyocyaneum)) or (blue adj apus) or (Pseudomonas adj (aeruginosa or aureofaciens or pyoceaneus or pyocyanea or pyocyaneus))).ti,ab. (43474)
10 ‘p. aeruginosa’.ti,ab. (17572)
11 exp Acinetobacter/ (12028)
12 (Acinetobacter or mima or mimae or herellea or acinetobacterium).ti,ab. (10917)
13 exp Proteus/ (14447)
11381139
27892790279127922793
2794
279527962797
279827992800
2801
2802
2803
2804
280528062807
2808
280928102811
2812
2813
2814
2815
281628172818
2819
2820
2821
2822
156
14 Proteus.ti,ab. (10461)
15 exp Serratia/ (9507)
16 Serratia.ti,ab. (7407)
17 exp Citrobacter freundii/ (1778)
18 ((Citrobacter adj freundii) or (bacterium adj freundii) or (Escherichia adj freundii)).ti,ab. (1675)
19 exp Morganella morganii/ (1134)
20 ((bacillus adj morgan$) or (bacterium adj morgana) or (morganella adj morgagni$) or (morganella adj morganii) or (proteus adj morgagni) or (proteus adj morgana$) or (salmonella adj morgana)).ti,ab. (804)
21 or/1-20 (396800)
22 (multiresistant or (multi adj resistan$)).ti,ab. (5599)
23 exp multidrug resistance/ (29629)
24 22 or 23 (33705)
25 exp Colistin/ (8049)
26 (belcomycin or colicort or colimycin$ or colisitin or colisticin or Colistin or colistine or colomycin or (coly adj mycin) or colymicin or colymycin or coly-mycin or multimycin or (Polymyxin adj E) or totazina).ti,ab. (3104)
27 exp Carbapenems/ (4745)
28 (Carbapenem$ or doripenem or ertapenem or Imipemide or Imipenem or Invanoz or Invanz or meropenem or Merrem or ‘MK 0787’ or MK0787 or MK-0787 or N Formimidoylthienamycin or N-Formimidoylthienamycin or Penem or Ronem or S 4661 or S-4661 or SM 7338 or SM-7338 or Thienamycin$).ti,ab. (18086)
29 exp Piperacillin/ (14822)
30 (acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin$ or pipcil or pipera hameln or piperacil or piperacillin$ or piperacin or pipera-hameln or pipercillin or piperilline or pipraci$ or pipraks or pipril or piprilin or pitamycin or t 1220 or t1220 or t-1220 or taiperacillin).ti,ab. (6462)
31 exp Amoxicillin-Potassium Clavulanate Combination/ (23616)
32 (aclam or aktil or ambilan or amocla or amoclan or amoclav or amoksiklav or amolanic or amometin or (amox adj clav) or amox-clav or (amoxi adj plus) or (amox adj3 clavulan$) or amoxiclav or amoxiclav-bid or amoxiclav-teva or amoxsiklav or amoxxlin or (amoxycillin-clavulanic adj acid) or ancla or (auclatin adj duo) or augamox or augmaxcil or augmentan or augmentin$ or augmex or augpen or (augucillin adj duo) or augurcin or ausclav or auspilic or bactiv or bactoclav or bioclavid or (brl adj ‘25000’) or brl25000 or brl-25000 or cavumox or ciblor or (clacillin adj duo) or clamax or
11401141
2823
2824
2825
2826
2827
2828
282928302831
2832
2833
2834
2835
2836
283728382839
2840
2841284228432844
2845
28462847284828492850
2851
285228532854285528562857
157
clamentin or clamobit or clamonex or clamovid or clamoxin or (clamoxyl adj duo$) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin adj plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox adj duo) or clavumox or (co adj amoxiclav) or (co adj amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon adj duo) or (croanan adj duo) or curam or danoclav or (darzitil adj plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina adj plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox adj cl) or vestaclav or viaclav or vulamox or xiclav or (zami adj ‘8503’)).ti,ab. (11598)
33 exp Quinolones/ (101072)
34 ((chinolone adj derivative) or fluoroquinolones or (haloquinolone adj derivative) or ketoquinolines or oxoquinolines or quinolinones or quinolones).ti,ab. (15677)
35 exp Aminoglycosides/ (10599)
36 (Aminoglycosides or Anthracyclines or Aclarubicin or Daunorubicin or Plicamycin or Butirosin Sulfate or Sisomicin or Hygromycin B or Kanamycin or Dibekacin or Nebramycin + or Metrizamide or Neomycin or Framycetin or Paromomycin or Ribostamycin or Puromycin or Spectinomycin or Streptomycin or Dihydrostreptomycin Sulfate or Streptothricins or Streptozocin).ti,ab. (56708)
37 exp Gentamicins/ (70647)
38 (adelanin or alcomicin or apigent or apogen or apoten or azupel or bactiderm or biogaracin or bristagen or cidomycin or danigen or dermogen or dianfarma or dispagent or duragentam$ or epigent or (frieso adj gent) or garabiotic or garalone or garamicin$ or garamycin or garbilocin or gencin or gendril or genoptic or genrex or gensumycin or gentabiotic or gentabiox or gentac or gentacidin or gentacin or gentacor or gentacycol or gentacyl or gentafair or gentagram or gentak or gental or gentaline or gentalline or gentalol or gentalyn or gentamax or gentame$ or gentamicin$ or gentamina or gentamycin$ or gentamyl or gentamytrex or gentaplus or gentarad or gentasil or gentasol or gentasone or gentasporin or gentatrim or gentavet or genticin$ or genticyn or gentiderm or gentimycin or gentocin or gentogram or gentomycin or genum or geomycine or gevramycin or g-mycin or gmyticin or g-myticin or grammicin or hexamycin or jenamicin or konigen or lacromycin or lisagent or martigenta or migenta or miragenta or miramycin or nichogencin or nsc 82261 or nsc82261 or obogen or ocugenta or ocu-mycin or oftagen or ophtagram or opthagen or optigen or opti-genta or ottogenta or pyogenta or refobacin or ribomicin or rigaminol or rocy gen or rovixida or rupegen or sagestam or sch 9724 or sch9724 or sedanazin or servigenta or skinfect or sulmycin or tangyn or u-gencin or versigen or yectamicina).ti,ab. (23700)
39 exp Amikacin/ (28644)
40 (akacin or akicin or amicacina or amicasil or amicin or amiglymide v or amikacin$ or amikafur or amikalem or amikan or amikayect or amikin or amiklin or amikozit or amiktam or amitracin or amixin or amukin or apalin or bb k 8 or bb k8 or bbk 8 or bb-k 8 or bbk8 or bbk-8 or bb-k8 or biclin or biklin or biokacin or briclin or briklin or chemacin or cinmik or fabianol or gamikal or glukamin or kacinth-a or kanbine or kormakin or likacin or lukadin or miacin or mikasome or onikin or oprad or orlobin or pediakin or pierami or riklinak or savox or selaxa or selemycin or sulfate amikacin or tybikin or vs 107 or vs107 or yectamid).ti,ab. (9841)
41 exp Fosfomycin/ (5561)
11421143
285828592860286128622863286428652866
2867
28682869
2870
2871287228732874
2875
287628772878287928802881288228832884288528862887288828892890
2891
2892289328942895289628972898
2899
158
42 (fosfocil or fosfocin or fosfocina or fosfomicin or fosfomycin or fosfonomycin or ‘mk 0955’ or mk 955 or mk0955 or mk955 or monuril or phosphomycin or phosphonomycin).ti,ab. (2386)
43 exp Aztreonam/ (10567)
44 ((az adj threonam) or azactam or azenam or azthreonam or aztreonam or (corus adj ‘1020’) or dynabiotic or primbactam or SQ 26,776 or sq 26,776 or sq 26776 or SQ-26,776 or sq26776 or sq-26776 or urobactam).ti,ab. (3245)
45 exp Nitrofurantoin/ (9724)
46 (berkfurin or biofurin or chemiofuran or dantafur or f 30 or f30 or fua-med or furaben or furadantin$ or furadantoin or furadina or furadoine or furadonin or furadonine or furalan or furanpur or furantocompren or furantoin$ or furobactina or furofen or furophen or infurin or ituran or ivadantin or macrobid or macrodantin$ or macrofuran or macrofurin or micofurantin$ or mitrofuratoin or nephronex or nierofu or nifurantin or nifuryl or (nitro adj macro) or nitrofuracin or nitrofuradantoin or nitrofurantine or nitrofurantoin$ or nitrofurin or novofuran or nsc 2107 or nsc2107 or orafuran or parfuran or phenurin or (potassium adj furagin) or ralodantin or trocurine or urantin or (uro adj tablinen) or urodil or urodin or urofuran or urolong or urotablinen or uro-tablinen or urotoina or uvamin).ti,ab. (3412)
47 exp Cephalosporins/ (150937)
48 (Axepim$ or bmy 28142 or bmy28142 or BMY-28142 or Cefepim$ or cefepitax or ceficad or cepimax or forzyn beta or maxcef or maxfrom or maxipime or Quadrocef).ti,ab. (2995)
49 exp tazobactam/ (3045)
50 (cl 307579 or cl298741 or cl307579 or tazabactam or tazobac$ or tazocel or tazocillin$ or tazocin or tazomax or tazonam or tazopril or yp 14 or yp14 or ytr 830 or ytr 830h or ytr830 or ytr830h or zosyn).ti,ab. (3809)
51 exp temocillin/ (499)
52 ((brl adj ‘17421’) or brl17421 or (thiophenemalonamic adj acid) or negaban or temocillin or temopen).ti,ab. (236)
53 exp tigecycline/ (3876)
54 (tigecycline or (tbg adj mino) or tygacil or gar 936 or gar936 or (tert adj butylglycinamido$)).ti,ab. (1970)
55 exp cefepime/ (9948)
56 ((Cephalosporanic adj Acid$) or Cephalosporin$ or Cefamandole or Cefoperazone or Cefazolin or Cefonicid or Cefsulodin or Cephacetrile or Cefotaxime or Cephalothin or Cephapirin or Cephalexin or Cefaclor or Cefadroxil or Cephaloglycin or Cephradine or Cephaloridine or Ceftazidime or Cephamycins or Cefmetazole or Cefotetan or Cefoxitin).ti,ab. (45983)
57 exp pivmecillinam/ (685)
11441145
29002901
2902
290329042905
2906
290729082909291029112912291329142915
2916
29172918
2919
292029212922
2923
29242925
2926
29272928
2929
2930293129322933
2934
159
58 ((amdinocillin adj pivoxil) or (FL adj ‘1039’) or FL1039 or fl1039 or FL-1039 or pivamdinocillin or Pivmecillinam or Selexid or coactabs or (ro adj ‘109071’) or (ro10 adj ‘9071’) or ro109071).ti,ab. (280)
59 or/25-58 (349366)
60 21 and 24 and 59 (4969)
61 (review or review,tutorial or review, academic).pt. (1901059)
62 (systematic$ adj5 review$).tw,sh. (70959)
63 (systematic$ adj5 overview$).tw,sh. (869)
64 (quantitativ$ adj5 review$).tw,sh. (15516)
65 (quantitativ$ adj5 overview$).tw,sh. (203)
66 (quantitativ$ adj5 synthesis$).tw,sh. (2716)
67 (methodologic$ adj5 review$).tw,sh. (3414)
68 (methodologic$ adj5 overview$).tw,sh. (238)
69 (integrative research review$ or research integration).tw. (94)
70 (meta-analys$ or meta analys$ or metaanalys$).tw,sh. (96394)
71 (meta synthesis or meta synthesis or metasynthesis).tw,sh. (238)
72 (meta-regression or meta regression or metaregression).tw,sh. (2242)
73 (synthes$ adj3 literature).tw. (1448)
74 (synthes$ adj3 evidence).tw. (3583)
75 integrative review.tw. (604)
76 data synthesis.tw. (8747)
77 (research synthesis or narrative synthesis).tw. (547)
78 (systematic study or systematic studies).tw. (7413)
79 systematic comparison$.tw. (1183)
80 comprehensive review$.tw. (6873)
81 critical review.tw. (11216)
82 quantitative review.tw. (488)
83 structured review.tw. (492)
84 realist review.tw. (34)
11461147
293529362937
2938
2939
2940
2941
2942
2943
2944
2945
2946
2947
2948
2949
2950
2951
2952
2953
2954
2955
2956
2957
2958
2959
2960
2961
2962
2963
160
85 realist synthesis.tw. (12)
86 review.ti. (264011)
87 systematic$ literature review$.tw. (3464)
88 ‘systematic review’/ (55637)
89 ‘systematic review (topic)’/ (2885)
90 meta analysis/ (67746)
91 ‘meta analysis (topic)’/ (5552)
92 (synthes$ adj2 qualitative).tw. (428)
93 (systematic adj2 search$).tw. (7848)
94 systematic$ literature research$.tw. (102)
95 (review adj3 scientific literature).tw. (833)
96 (literature review adj2 side effect$).tw. (10)
97 (literature review adj2 adverse effect$).tw. (2)
98 (literature review adj2 adverse event$).tw. (6)
99 (evidence-based adj2 review).tw. (1915)
100 critical analysis.tw. (5559)
101 (review$ adj10 (papers or trials or trial data or studies or evidence or intervention$ or evaluation$ or outcome$ or findings)).tw. (248295)
102 review.ti. (264011)
103 metanaly$.tw. (316)
104 letter.pt. (800258)
105 editorial.pt. (417835)
106 104 or 105 (1218093)
107 or/61-103 (2212977)
108 107 not 106 (2200787)
109 (clin$ adj2 trial).mp. (968683)
110 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. (190403)
111 (random$ adj5 (assign$ or allocat$)).mp. (101920)
112 randomi$.mp. (613392)
11481149
2964
2965
2966
2967
2968
2969
2970
2971
2972
2973
2974
2975
2976
2977
2978
2979
29802981
2982
2983
2984
2985
2986
2987
2988
2989
2990
2991
2992
161
113 crossover.mp. (59181)
114 exp randomized-controlled-trial/ (334017)
115 exp double-blind-procedure/ (112280)
116 exp crossover-procedure/ (35737)
117 exp single-blind-procedure/ (16758)
118 exp randomization/ (60197)
119 or/109-118 (1282139)
120 intervention?.ti. or (intervention? adj6 (clinician? or collaborat$ or community or complex or DESIGN$ or doctor? or educational or family doctor? or family physician? or family practitioner? or financial or GP or general practice? or hospital? or impact? or improv$ or individuali?e? or individuali?ing or interdisciplin$ or multicomponent or multi-component or multidisciplin$ or multi-disciplin$ or multifacet$ or multi-facet$ or multimodal$ or multi-modal$ or personali?e? or personali?ing or pharmacies or pharmacist? or pharmacy or physician? or practitioner? or prescrib$ or prescription? or primary care or professional$ or provider? or regulatory or regulatory or tailor$ or target$ or team$ or usual care)).ab. (175033)
121 (hospital$ or patient?).hw. and (study or studies or care or health$ or practitioner? or provider? or physician? or nurse? or nursing or doctor?).ti,hw. (1363115)
122 demonstration project?.ti,ab. (2081)
123 (pre-post or ‘pre test$’ or pretest$ or posttest$ or ‘post test$’ or (pre adj5 post)).ti,ab. (78013)
124 (pre-workshop or post-workshop or (before adj3 workshop) or (after adj3 workshop)).ti,ab. (673)
125 trial.ti. or ((study adj3 aim?) or ‘our study’).ab. (724065)
126 (before adj10 (after or during)).ti,ab. (394152)
127 (time points adj3 (over or multiple or three or four or five or six or seven or eight or nine or ten or eleven or twelve or month$ or hour? or day? or ‘more than’)).ab. (10006)
128 pilot.ti. (43036)
129 (multicentre or multicenter or multi-centre or multi-center).ti. (34428)
130 random$.ti,ab. or controlled.ti. (819713)
131 review.ti. (264011)
132 *experimental design/ or *pilot study/ or quasi experimental study/ (5205)
133 (‘quasi-experiment$’ or quasiexperiment$ or ‘quasi random$’ or quasirandom$ or ‘quasi control$’ or quasicontrol$ or ((quasi$ or experimental) adj3 (method$ or study or trial or design$))).ti,ab. (105122)
134 or/120-133 (3341084)
11501151
2993
2994
2995
2996
2997
2998
2999
30003001300230033004300530063007
30083009
3010
3011
3012
3013
3014
30153016
3017
3018
3019
3020
3021
302230233024
3025
162
135 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ (18985259)
136 human/ or normal human/ or human cell/ (14037258)
137 135 and 136 (14004971)
138 135 not 137 (4980288)
139 (‘time series’ adj2 interrupt$).ti,ab. (922)
140 134 not (138 or 139) (2996658)
141 108 or 119 or 140 (5157863)
142 60 and 141 (1860)
16.1 Medline (January 1946 to December 2012)
1 exp Escherichia coli/ (224545)
2 (Eaggec or (escherichia adj coli) or (e adj coli) or (alkalescens-dispar adj group) or (bacillus adj escherichii) or (Coli adj bacillus) or (Coli adj bacterium) or colibacillus or (colon adj bacillus)).ti,ab. (226847)
3 exp Klebsiella/ (13720)
4 (klebsiella or Calymmatobacterium or (aerobacter adj aerogenes) or ((bacillus or bacterium) adj pneumonia) or ((friedlaender or Friedlander) adj bacillus) or (Hyalococcus adj pneumonia) or Pneumobacillus).ti,ab. (18345)
5 (‘k. pneumoniae’ or ‘b. friedlander’).ti,ab. (3902)
6 exp Enterobacter/ (5504)
7 (enterobacter or aerobacter).ti,ab. (8130)
8 exp Pseudomonas aeruginosa/ (30232)
9 ((bacillus adj pyocyaneus) or (bacterium adj (aeruginosum or pyocyaneum)) or (blue adj apus) or (Pseudomonas adj (aeruginosa or aureofaciens or pyoceaneus or pyocyanea or pyocyaneus))).ti,ab. (35984)
10 ‘p. aeruginosa’.ti,ab. (14103)
11 exp Acinetobacter/ (5262)
12 (Acinetobacter or mima or mimae or herellea or acinetobacterium).ti,ab. (8005)
13 exp Proteus/ (8091)
14 Proteus.ti,ab. (9496)
15 exp Serratia/ (5505)
16 Serratia.ti,ab. (6720)
11521153
30263027
3028
3029
3030
3031
3032
3033
3034
3035
3036
3037
3038
30393040
3041
30423043
3044
3045
3046
3047
30483049
3050
3051
3052
3053
3054
3055
3056
163
17 exp Citrobacter freundii/ (438)
18 ((Citrobacter adj freundii) or (bacterium adj freundii) or (Escherichia adj freundii)).ti,ab. (1361)
19 exp Morganella morganii/ (133)
20 ((bacillus adj morgan$) or (bacterium adj morgana) or (morganella adj morgagni$) or (morganella adj morganii) or (proteus adj morgagni) or (proteus adj morgana$) or (salmonella adj morgana)).ti,ab. (601)
21 or/1-20 (360253)
22 (multiresistant or (multi adj resistan$)).ti,ab. (3949)
23 exp drug resistance, multiple/ (21763)
24 22 or 23 (24405)
25 exp Colistin/ (2107)
26 (belcomycin or colicort or colimycin$ or colisitin or colisticin or Colistin or colistine or colomycin or (coly adj mycin) or colymicin or colymycin or coly-mycin or multimycin or (Polymyxin adj E) or totazina).ti,ab. (2346)
27 exp Carbapenems/ (6668)
28 (Carbapenem$ or doripenem or ertapenem or Imipemide or Imipenem or Invanoz or Invanz or meropenem or Merrem or ‘MK 0787’ or MK0787 or MK-0787 or N Formimidoylthienamycin or N-Formimidoylthienamycin or Penem or Ronem or S 4661 or S-4661 or SM 7338 or SM-7338 or Thienamycin$).ti,ab. (11771)
29 exp Piperacillin/ (2035)
30 (acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin$ or pipcil or pipera hameln or piperacil or piperacillin$ or piperacin or pipera-hameln or pipercillin or piperilline or pipraci$ or pipraks or pipril or piprilin or pitamycin or t 1220 or t1220 or t-1220 or taiperacillin).ti,ab. (4319)
31 (cl 307579 or cl298741 or cl307579 or tazabactam or tazobac$ or tazocel or tazocillin$ or tazocin or tazomax or tazonam or tazopril or yp 14 or yp14 or ytr 830 or ytr 830h or ytr830 or ytr830h or zosyn).ti,ab. (2217)
32 exp Amoxicillin-Potassium Clavulanate Combination/ (1914)
33 (aclam or aktil or ambilan or amocla or amoclan or amoclav or amoksiklav or amolanic or amometin or (amox adj clav) or amox-clav or (amoxi adj plus) or (amox adj3 clavulan$) or amoxiclav or amoxiclav-bid or amoxiclav-teva or amoxsiklav or amoxxlin or (amoxycillin-clavulanic adj acid) or ancla or (auclatin adj duo) or augamox or augmaxcil or augmentan or augmentin$ or augmex or augpen or (augucillin adj duo) or augurcin or ausclav or auspilic or bactiv or bactoclav or bioclavid or (brl adj ‘25000’) or brl25000 or brl-25000 or cavumox or ciblor or (clacillin adj duo) or clamax or clamentin or clamobit or clamonex or clamovid or clamoxin or (clamoxyl adj duo$) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin adj plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox adj duo) or clavumox or (co adj amoxiclav) or (co adj amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon adj duo) or (croanan adj duo) or curam or danoclav or (darzitil adj plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina adj plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox adj cl) or vestaclav or viaclav or vulamox or xiclav or (zami adj ‘8503’)).ti,ab. (9184)
11541155
3057
3058
3059
30603061
3062
3063
3064
3065
3066
306730683069
3070
307130723073
3074
30753076307730783079
30803081
3082
30833084308530863087308830893090309130923093309430953096
164
34 ((brl adj ‘17421’) or brl17421 or (thiophenemalonamic adj acid) or negaban or temocillin or temopen).ti,ab. (179)
35 (tigecycline or (tbg adj mino) or tygacil or gar 936 or gar936 or (tert adj butylglycinamido$)).ab,ti. (1161)
36 exp Quinolones/ (33277)
37 ((chinolone adj derivative) or fluoroquinolones or (haloquinolone adj derivative) or ketoquinolines or oxoquinolines or quinolinones or quinolones).ti,ab. (11055)
38 exp Aminoglycosides/ (122582)
39 (Aminoglycosides or Anthracyclines or Aclarubicin or Daunorubicin or Plicamycin or Butirosin Sulfate or Sisomicin or Hygromycin B or Kanamycin or Dibekacin or Nebramycin + or Metrizamide or Neomycin or Framycetin or Paromomycin or Ribostamycin or Puromycin or Spectinomycin or Streptomycin or Dihydrostreptomycin Sulfate or Streptothricins or Streptozocin).ti,ab. (52288)
40 exp Gentamicins/ (16678)
41 (adelanin or alcomicin or apigent or apogen or apoten or azupel or bactiderm or biogaracin or bristagen or cidomycin or danigen or dermogen or dianfarma or dispagent or duragentam$ or epigent or (frieso adj gent) or garabiotic or garalone or garamicin$ or garamycin or garbilocin or gencin or gendril or genoptic or genrex or gensumycin or gentabiotic or gentabiox or gentac or gentacidin or gentacin or gentacor or gentacycol or gentacyl or gentafair or gentagram or gentak or gental or gentaline or gentalline or gentalol or gentalyn or gentamax or gentame$ or gentamicin$ or gentamina or gentamycin$ or gentamyl or gentamytrex or gentaplus or gentarad or gentasil or gentasol or gentasone or gentasporin or gentatrim or gentavet or genticin$ or genticyn or gentiderm or gentimycin or gentocin or gentogram or gentomycin or genum or geomycine or gevramycin or g-mycin or gmyticin or g-myticin or grammicin or hexamycin or jenamicin or konigen or lacromycin or lisagent or martigenta or migenta or miragenta or miramycin or nichogencin or nsc 82261 or nsc82261 or obogen or ocugenta or ocu-mycin or oftagen or ophtagram or opthagen or optigen or opti-genta or ottogenta or pyogenta or refobacin or ribomicin or rigaminol or rocy gen or rovixida or rupegen or sagestam or sch 9724 or sch9724 or sedanazin or servigenta or skinfect or sulmycin or tangyn or u-gencin or versigen or yectamicina).ti,ab. (19829)
42 exp Amikacin/ (3372)
43 (akacin or akicin or amicacina or amicasil or amicin or amiglymide v or amikacin$ or amikafur or amikalem or amikan or amikayect or amikin or amiklin or amikozit or amiktam or amitracin or amixin or amukin or apalin or bb k 8 or bb k8 or bbk 8 or bb-k 8 or bbk8 or bbk-8 or bb-k8 or biclin or biklin or biokacin or briclin or briklin or chemacin or cinmik or fabianol or gamikal or glukamin or kacinth-a or kanbine or kormakin or likacin or lukadin or miacin or mikasome or onikin or oprad or orlobin or pediakin or pierami or riklinak or savox or selaxa or selemycin or sulfate amikacin or tybikin or vs 107 or vs107 or yectamid).ti,ab. (7140)
44 exp Fosfomycin/ (1378)
45 (fosfocil or fosfocin or fosfocina or fosfomicin or fosfomycin or fosfonomycin or ‘mk 0955’ or mk 955 or mk0955 or mk955 or monuril or phosphomycin or phosphonomycin).ti,ab. (1779)
46 exp Aztreonam/ (1233)
47 ((az adj threonam) or azactam or azenam or azthreonam or aztreonam or (corus adj ‘1020’) or dynabiotic or primbactam or SQ 26,776 or sq 26,776 or sq 26776 or SQ-26,776 or sq26776 or sq-26776 or urobactam).ti,ab. (2333)
48 exp Nitrofurantoin/ (2253)
11561157
30973098
3099
3100
31013102
3103
3104310531063107
3108
3109311031113112311331143115311631173118311931203121
3122
312331243125312631273128
3129
31303131
3132
313331343135
3136
165
49 (berkfurin or biofurin or chemiofuran or dantafur or f 30 or f30 or fua-med or furaben or furadantin$ or furadantoin or furadina or furadoine or furadonin or furadonine or furalan or furanpur or furantocompren or furantoin$ or furobactina or furofen or furophen or infurin or ituran or ivadantin or macrobid or macrodantin$ or macrofuran or macrofurin or micofurantin$ or mitrofuratoin or nephronex or nierofu or nifurantin or nifuryl or (nitro adj macro) or nitrofuracin or nitrofuradantoin or nitrofurantine or nitrofurantoin$ or nitrofurin or novofuran or nsc 2107 or nsc2107 or orafuran or parfuran or phenurin or (potassium adj furagin) or ralodantin or trocurine or urantin or (uro adj tablinen) or urodil or urodin or urofuran or urolong or urotablinen or uro-tablinen or urotoina or uvamin).ti,ab. (2721)
50 exp Cephalosporins/ (35352)
51 (Axepim$ or bmy 28142 or bmy28142 or BMY-28142 or Cefepim$ or cefepitax or ceficad or cepimax or forzyn beta or maxcef or maxfrom or maxipime or Quadrocef).ti,ab. (1916)
52 ((Cephalosporanic adj Acid$) or Cephalosporin$ or Cefamandole or Cefoperazone or Cefazolin or Cefonicid or Cefsulodin or Cephacetrile or Cefotaxime or Cephalothin or Cephapirin or Cephalexin or Cefaclor or Cefadroxil or Cephaloglycin or Cephradine or Cephaloridine or Ceftazidime or Cephamycins or Cefmetazole or Cefotetan or Cefoxitin).ti,ab. (35099)
53 exp Amdinocillin Pivoxil/ (199)
54 ((amdinocillin adj pivoxil) or (FL adj ‘1039’) or FL1039 or fl1039 or FL-1039 or pivamdinocillin or Pivmecillinam or Selexid or coactabs or (ro adj ‘109071’) or (ro10 adj ‘9071’) or ro109071).ti,ab. (237)
55 or/25-54 (246506)
56 21 and 24 and 55 (3195)
57 exp clinical trial/ (706293)
58 exp randomized controlled trials/ (85563)
59 exp double-blind method/ (118498)
60 exp single-blind method/ (17086)
61 exp cross-over studies/ (30990)
62 randomized controlled trial.pt. (342334)
63 clinical trial.pt. (476450)
64 controlled clinical trial.pt. (85694)
65 (clinic$ adj2 trial).mp. (552367)
66 (random$ adj5 control$ adj5 trial$).mp. (443104)
67 (crossover or cross-over).mp. (59003)
68 ((singl$ or double$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. (162179)
69 randomi$.mp. (509202)
70 (random$ adj5 (assign$ or allocat$ or assort$ or reciev$)).mp. (150717)
71 or/57-70 (968331)
11581159
31373138313931403141314231433144
3145
31463147
3148314931503151
3152
31533154
3155
3156
3157
3158
3159
3160
3161
3162
3163
3164
3165
3166
3167
3168
3169
3170
3171
166
72 (review or review,tutorial or review, academic).pt. (1758734)
73 (systematic$ adj5 review$).tw,sh. (40365)
74 (systematic$ adj5 overview$).tw,sh. (663)
75 (quantitativ$ adj5 review$).tw,sh. (3684)
76 (quantitativ$ adj5 overview$).tw,sh. (153)
77 (quantitativ$ adj5 synthesis$).tw,sh. (1107)
78 (methodologic$ adj5 review$).tw,sh. (2696)
79 (methodologic$ adj5 overview$).tw,sh. (180)
80 (integrative research review$ or research integration).tw. (78)
81 meta-analysis as topic/ (12608)
82 (meta-analys$ or meta analys$ or metaanalys$).tw,sh. (62359)
83 (meta synthesis or meta synthesis or metasynthesis).tw,sh. (215)
84 (meta-regression or meta regression or metaregression).tw,sh. (1650)
85 meta-analysis.pt. (37918)
86 (synthes$ adj3 literature).tw. (1070)
87 (synthes$ adj3 evidence).tw. (2956)
88 integrative review.tw. (583)
89 data synthesis.tw. (6328)
90 (research synthesis or narrative synthesis).tw. (463)
91 (systematic study or systematic studies).tw. (5679)
92 systematic comparison$.tw. (953)
93 systematic comparison$.tw. (953)
94 evidence based review.tw. (965)
95 comprehensive review$.tw. (5290)
96 critical review.tw. (9227)
97 quantitative review.tw. (382)
98 structured review.tw. (376)
99 realist review.tw. (24)
100 realist synthesis.tw. (11)
101 review.ti. (212126)
11601161
3172
3173
3174
3175
3176
3177
3178
3179
3180
3181
3182
3183
3184
3185
3186
3187
3188
3189
3190
3191
3192
3193
3194
3195
3196
3197
3198
3199
3200
3201
167
102 (review$ adj4 (papers or trials or studies or evidence or intervention$ or evaluation$)).tw. (80949)
103 metanaly$.tw. (137)
104 letter.pt. (766872)
105 editorial.pt. (310993)
106 comment.pt. (493546)
107 or/104-106 (1166749)
108 or/72-103 (1897061)
109 108 not 107 (1860495)
110 intervention?.ti. or (intervention? adj6 (clinician? or collaborat$ or community or complex or DESIGN$ or doctor? or educational or family doctor? or family physician? or family practitioner? or financial or GP or general practice? or hospital? or impact? or improv$ or individuali?e? or individuali?ing or interdisciplin$ or multicomponent or multi-component or multidisciplin$ or multi-disciplin$ or multifacet$ or multi-facet$ or multimodal$ or multi-modal$ or personali?e? or personali?ing or pharmacies or pharmacist? or pharmacy or physician? or practitioner? or prescrib$ or prescription? or primary care or professional$ or provider? or regulatory or regulatory or tailor$ or target$ or team$ or usual care)).ab. (128957)
111 (pre-intervention? or preintervention? or ‘pre intervention?’ or post-intervention? or postintervention? or ‘post intervention?’).ti,ab. (7451)
112 demonstration project?.ti,ab. (1742)
113 (pre-post or ‘pre test$’ or pretest$ or posttest$ or ‘post test$’ or (pre adj5 post)).ti,ab. (52427)
114 (pre-workshop or post-workshop or (before adj3 workshop) or (after adj3 workshop)).ti,ab. (472)
115 trial.ti. or ((study adj3 aim?) or ‘our study’).ab. (500725)
116 (before adj10 (after or during)).ti,ab. (314768)
117 (‘quasi-experiment$’ or quasiexperiment$ or ‘quasi random$’ or quasirandom$ or ‘quasi control$’ or quasicontrol$ or ((quasi$ or experimental) adj3 (method$ or study or trial or design$))).ti,ab,hw. (84783)
118 (‘time series’ adj2 interrupt$).ti,ab,hw. (744)
119 (time points adj3 (over or multiple or three or four or five or six or seven or eight or nine or ten or eleven or twelve or month$ or hour? or day? or ‘more than’)).ab. (7043)
120 pilot.ti. (32084)
121 Pilot projects/ (74648)
122 (clinical trial or controlled clinical trial or multicenter study).pt. (595489)
123 (multicentre or multicenter or multi-centre or multi-center).ti. (24301)
124 random$.ti,ab. or controlled.ti. (624993)
125 (control adj3 (area or cohort? or compare? or condition or design or group? or intervention? or participant? or study)).ab. not (controlled clinical trial or randomized controlled trial).pt. (342332)
11621163
3202
3203
3204
3205
3206
3207
3208
3209
3210321132123213321432153216
32173218
3219
3220
3221
3222
3223
32243225
3226
32273228
3229
3230
3231
3232
3233
32343235
168
126 ‘comment on’.cm. or review.ti,pt. or randomized controlled trial.pt. (2652864)
127 (rat or rats or cow or cows or chicken? or horse or horses or mice or mouse or bovine or animal?).ti. (1254855)
128 exp animals/ not humans.sh. (3812817)
129 (or/110-126) not (or/127-128) (3811646)
130 71 or 109 or 129 (4107075)
131 56 and 130 (822)
17 References
11641165
3236
32373238
3239
3240
3241
3242
3243
3244
3245
169
358. Moher D, Liberati A, Tetzlaff J, Altman DG; the PRISMA Group. Preferred Reporting
Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement. PLoS Med
2009;6:e1000097.
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1193
1194
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