JHI paper Structure by 5th March first draft 2nd July 2012
Joint Working Party on Multi resistant Gram-negative Infection: Treatment Peter Hawkey*David EnochCliodna McNultyDavid M LivermoreRoderick WarrenJonathan OtterSusan BennettJennifer BostockMaria CannPeter Wilson* Corresponding author: Peter M Hawkey, Professor of Clinical and Public Health Bacteriology, Consultant Medical Microbiologist, and Lead Public Health Microbiologist (West Midlands)Address: Public Health Laboratory, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK. Tel: +44 (0) 121 424 1240E-mail address: peter.hawkey@heartofengland.nhs.uk (Peter Hawkey)Peter Hawkey, Professor of Clinical and Public Health Bacteriology, Institute of Microbiology and Infection, University of Birmingham, and Consultant Medical Microbiologist, Public Health England, Public Health Laboratory, Birmingham Heartlands Hospital, Bordesley Green East, BirminghamDavid A Enoch, Consultant Microbiologist, Public Health England, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, CambridgeDavid Livermore, Professor of Medical Microbiology, Norwich Medical School, University of East AngliaCliodna McNulty, Head of Primary Care Unit, Public Health England, and Honorary Visiting Professor Cardiff University, Microbiology Dept, Gloucester Royal Hospital, GloucesterRoderic Warren, Retired Consultant Microbiologist, Shrewsbury and Telford Hospital NHS TrustJonathan Otter, Epidemiologist, Infection Prevention and Control, Imperial College Healthcare NHS Trust, London, UKProf Peter Wilson, Consultant Microbiologist & Professor of Microbiology, Department Microbiology & Virology, University College London Hospitals, LondonPatient representatives: Susan Bennett, Member of Health Care Acquired Infections, Service Users Research Forum, Leicester, UKJennifer Bostock, Member of Health Care Acquired Infections, Service Users Research Forum, Leicester, UKMaria Cann, Trustee, MRSA Action, Kirkham, UKNICE accreditation has been applied for. Table of Contents TOC \o "1-4" \h \z \u 1Executive Summary PAGEREF _Toc448397710 \h 52Lay Summary PAGEREF _Toc448397711 \h 53Introduction PAGEREF _Toc448397714 \h 54Guideline Development Team PAGEREF _Toc448397715 \h 64.1 Guideline Advisory Group PAGEREF _Toc448397716 \h 64.2 Acknowledgements PAGEREF _Toc448397717 \h 64.3 Source of funding PAGEREF _Toc448397718 \h 64.4 Disclosure of Potential Conflict of Interest PAGEREF _Toc448397719 \h 74.5 Relationship of Author with Sponsor PAGEREF _Toc448397720 \h 74.6 Responsibility for Guidelines PAGEREF _Toc448397721 \h 75. The Working Party report PAGEREF _Toc448397722 \h 75.1 What is The Working Party report? PAGEREF _Toc448397723 \h 85.2 Why do we need a Working Party Report for these infections? PAGEREF _Toc448397724 \h 85.3 What is the purpose of the Report’s recommendations? PAGEREF _Toc448397725 \h 85.4 What is the scope of the guidelines? PAGEREF _Toc448397726 \h 85.5 What is the evidence for these guidelines? PAGEREF _Toc448397727 \h 95.6 Who developed these guidelines? PAGEREF _Toc448397728 \h 95.7 Who are these guidelines for? PAGEREF _Toc448397729 \h 95.8 How are the guidelines structured? PAGEREF _Toc448397730 \h 95.9 How frequently are the guidelines reviewed and updated? PAGEREF _Toc448397731 \h 95.10 Aim PAGEREF _Toc448397732 \h 96 Summary of Guidelines PAGEREF _Toc448397733 \h 107. Implementation of these guidelines PAGEREF _Toc448397736 \h 147.1 How can the guidelines be used to improve clinical effectiveness? PAGEREF _Toc448397737 \h 147.2How much will implementation of the guidelines cost? PAGEREF _Toc448397738 \h 157.3 Summary of audit measures PAGEREF _Toc448397739 \h 157.4 E-learning tools PAGEREF _Toc448397740 \h 158.Methodology PAGEREF _Toc448397741 \h 158.1 Evidence appraisal PAGEREF _Toc448397742 \h 158.2 Consultation process PAGEREF _Toc448397743 \h 179. Rationale for recommendations PAGEREF _Toc448397744 \h 189.1 Epidemiology PAGEREF _Toc448397745 \h 189.1.1 What is the Definition of Multidrug-resistant Gram-negative bacteria? PAGEREF _Toc448397746 \h 189.1.2 What is the global epidemiology of MRGNB? PAGEREF _Toc448397747 \h 20 HYPERLINK \l "_Toc448397748" 9.1.3 How do Multi-Resistant Enterobacteriaceae differ from non-fermenters in terms of their prevalence and associated resistance genes? PAGEREF _Toc448397748 \h 249.1.4 What impact have returning travellers made on UK epidemiology? PAGEREF _Toc448397749 \h 25 HYPERLINK \l "_Toc448397750" 9.1.5 What is the clinical importance of carbapenemase versus Amp C and CTX-M producing strains? PAGEREF _Toc448397750 \h 26 HYPERLINK \l "_Toc448397751" 9.2 Treatment options for Multi resistant Gram-negative bacteria: What is the efficacy of carbapenems, mecillinam, temocillin, fosfomycin, colistin and other antibiotics against specific MRGNB and what are the recommended antibiotics for secondary/tertiary care? PAGEREF _Toc448397751 \h 279.2.1 Intravenous antibiotics for secondary and tertiary care PAGEREF _Toc448397752 \h 279.2.2 Oral agents for secondary/tertiary care treatment PAGEREF _Toc448397753 \h 529.2.3 Treatment of carbapenemase-producers with combination therapy PAGEREF _Toc448397759 \h 539.3What are the recommended antibiotics for community care, including care homes? PAGEREF _Toc448397760 \h 569.3.1 What are the risk factors for patients with urinary infections caused by MDRGNB in the UK? PAGEREF _Toc448397761 \h 569.3.2 Which oral antibiotics are preferred for use in treating uncomplicated UTIs in the community due to MDRGNB? PAGEREF _Toc448397763 \h 589.4Treatment of pyelonephritis and complicated UTI caused by MDR Gram- negative bacteria PAGEREF _Toc448397764 \h 659.5What is the threshold level of resistance for changing the choice of empirical treatment for urinary tract infections? PAGEREF _Toc448397765 \h 679.6 What effect does good antibiotic stewardship have on rates of MRGNB? PAGEREF _Toc448397766 \h 689.6.1 The impact of good antibiotic stewardship in secondary/tertiary care facilities PAGEREF _Toc448397767 \h 689.6.2Antibiotic stewardship in the community and care homes to reduce MDR Gram-negative infections PAGEREF _Toc448397768 \h 7510.Further Research PAGEREF _Toc448397769 \h 82_Toc448397770Appendix 1 - Glossary PAGEREF _Toc448397774 \h 114Appendix 2 PAGEREF _Toc448397775 \h 1162.1Guideline Development PAGEREF _Toc448397776 \h 1192.2Conflict of Interests PAGEREF _Toc448397777 \h 1192.3Infection Control -Systematic Review Process PAGEREF _Toc448397778 \h 1192.3.1PICO: PAGEREF _Toc448397779 \h 1192.3.2Systematic Review Questions PAGEREF _Toc448397780 \h 1192.4Antimicrobial Chemotherapy -Systematic Review Process PAGEREF _Toc448397781 \h 1212.4.1Systematic Review Questions PAGEREF _Toc448397782 \h 1212.5Databases and Search terms Used 23/5/14 PAGEREF _Toc448397783 \h 121Appendix 3: Consultation stakeholders PAGEREF _Toc448397784 \h 123Appendix 4: CPD material PAGEREF _Toc448397785 \h 1474Appendix 6. Search Strategy PAGEREF _Toc448397787 \h 1234.1Medline (January 1946 to December 2012) PAGEREF _Toc448397788 \h 141Executive SummaryMulti-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 best practice in antimicrobial prescribing in treatment of infections caused by these organisms. Methods for systematic review 1946-2014 were in accordance with SIGN 50 (Scottish Intercollegiate Guidelines Network 2014) and the Cochrane Collaboration; (Higgins 2010) critical appraisal was applied using AGREEII ADDIN REFMGR.CITE <Refman><Cite><Author>Brouwers</Author><Year>2010</Year><RecNum>3065</RecNum><IDText>AGREE II: advancing guideline development, reporting and evaluation in health care</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3065</Ref_ID><Title_Primary>AGREE II: advancing guideline development, reporting and evaluation in health care</Title_Primary><Authors_Primary>Brouwers,M.C.</Authors_Primary><Authors_Primary>Kho,M.E.</Authors_Primary><Authors_Primary>Browman,G.P.</Authors_Primary><Authors_Primary>Burgers,J.S.</Authors_Primary><Authors_Primary>Cluzeau,F.</Authors_Primary><Authors_Primary>Feder,G.</Authors_Primary><Authors_Primary>Fervers,B.</Authors_Primary><Authors_Primary>Graham,I.D.</Authors_Primary><Authors_Primary>Grimshaw,J.</Authors_Primary><Authors_Primary>Hanna,S.E.</Authors_Primary><Authors_Primary>Littlejohns,P.</Authors_Primary><Authors_Primary>Makarski,J.</Authors_Primary><Authors_Primary>Zitzelsberger,L.</Authors_Primary><Date_Primary>2010/12/14</Date_Primary><Keywords>Canada</Keywords><Keywords>Delivery of Health Care</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Manuals as Topic</Keywords><Keywords>methods</Keywords><Keywords>Practice Guidelines as Topic</Keywords><Keywords>Program Development</Keywords><Keywords>standards</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>E839</Start_Page><End_Page>E842</End_Page><Periodical>CMAJ.</Periodical><Volume>182</Volume><Issue>18</Issue><ZZ_JournalStdAbbrev><f name="System">CMAJ.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brouwers et al. 2010). 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 for specific organisms are given where there are species differences. Lay SummaryMulti-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 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. Infection happens when the bacteria enters the body through an open wound or through a medical device such as a catheter. When patients develop infection and require antibiotic treatment, selecting the correct antibiotic can be difficult. This report provides the advice on the best choice agents currently available. Introduction This guidance has been prepared by the Working Party to provide advice on the treatment of infectious caused by MDR Gram-negative bacteria. The guidance also describes best-practice in antimicrobial prescribing. There is an accompanying guideline describing appropriate infection prevention and control precautions, including hand hygiene, equipment and environmental cleaning and guidance on screening for MDR Gram-negative bacteria PFJlZm1hbj48Q2l0ZT48QXV0aG9yPldpbHNvbjwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Wilson et al. 2016). It should be used in conjunction with this document. There is a glossary for techinical terms (Appendix 1).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.Guideline Development Team4.1 Guideline Advisory GroupPhil Wiffen, Cochrane Pain, Palliative and Supportive Care Group Pain Research, Churchill Hospital Oxford, Nuffield Dept of Clinical Neurosciences, Oxford.Karla Soares-Wieser, Enhance Reviews, Ltd, Wantage4.2 Acknowledgements We would like to acknowledge the support of 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 and PMH was part supported by the National Institute for Health Research Centre for Surgical Reconstruction and Microbiology, University of Birmingham. 4.3 Source of fundingA grant funded equally by British Infection Association, Healthcare Infection Society, and British Society for Antimicrobial Chemotherapy. The grant funded Karla Soares-Wieser and other at Enhance Reviews Lt, Lyford, Wantage and Paul Wiffen to perform the systematic review.4.4 Disclosure of Potential Conflict of InterestAPRW: Consultant on Drug Safety Monitoring Boards for Roche and Genentech. Advisory Panel for 3M. DAE: Received funding to attend conferences from MSD, Eumedica, Gilead and Astellas.DML: Advisory Boards or consultancy – Achaogen, Adenium, Alere, Allecra, AstraZeneca, Basilea, Bayer,?BioVersys, Centauri, Cubist, Discuva, GSK, Meiji, Merck, Nordic, Pfizer, Roche,?Shionogi, Tetraphase, VenatoRx, Wockhardt, Zambon; paid lectures – AstraZeneca, Merck, Nordic, Pfizer; Relevant shareholdings in–?Dechra, GSK, Merck, Perkin Elmer, Pfizer?collectively amounting to <10% of portfolio value. Contract research: Achaogen, AstraZeneca, Melinta, Medicines Co., Meiji, Merck, Roche, Venato Rx??CM: Travel expenses Merieux DiagnosticsMC: IPS conference attendance funded by corporate sponsorship from M?lnlycke Healthcare PH: Consultancy: BioMerieux, Becton-Dickinson, Eumedica, Merck, Novartis, MagusCommunications, Pfizer, Wyeth; director of ModusMedica (medical education company); Funded research: Merck, Novartis, and Pfizer.All other authors no conflicts declared.4.5 Relationship of Author with SponsorThe BSAC, BIA and HIS commissioned the authors to undertake the Working Party Report. All authors are members of one or more of these societies.4.6 Responsibility for GuidelinesThe views expressed in this publication are those of the authors and have been endorsed by the three sponsoring societies following consultation.5. The Working Party reportDate of publication: TBC 2016 (Published online TBC)5.1 What is The Working Party report?This Report is a set of recommendations covering the treatment of infections caused by MDR Gram-negative bacteria (i.e. resistant to at least three different antibiotics). Prevention of transmission is covered in a separate publication PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5XaWxzb248L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA (Wilson et al. 2016).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 acute and long-term healthcare settings.5.2 Why do we need a Working Party Report for these infections?Multi-resistant Gram-negative pathogens have become prevalent internationally, including the UK and Europe. The increased use of broad-spectrum agents encourages their proliferation ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Public Health England (PHE)</Author><Year>2014</Year><RecNum>3503</RecNum><IDText>English Surveillance Programme For Antimicrobial Utilisation and Resistance (ESPAUR)</IDText><Prefix>Public Health England (ESPAUR)</Prefix><MDL Ref_Type="Report"><Ref_Type>Report</Ref_Type><Ref_ID>3503</Ref_ID><Title_Primary>English Surveillance Programme For Antimicrobial Utilisation and Resistance (ESPAUR)</Title_Primary><Authors_Primary>Public Health England (PHE)</Authors_Primary><Date_Primary>2014</Date_Primary><Reprint>Not in File</Reprint><Publisher>Public Health England</Publisher><Web_URL><u>;(Public Health England (ESPAUR) 2014). The spread of these pathogens affects the length of hospital stay and adversely affects the quality of life of patients. Public awareness has been increasing, and the relative lack of new antimicrobial agents to treat infections due to Gram-negative bacteria has resulted in the formulation of the five-year Antimicrobial Resistance Strategy by the UK Department of Health to address the problem ADDIN REFMGR.CITE <Refman><Cite><Author>Department of Health</Author><Year>2013</Year><RecNum>3502</RecNum><IDText>UK Five Year Antimicrobial Resistance Strategy 2013 to 2018</IDText><MDL Ref_Type="Online Source"><Ref_Type>Online Source</Ref_Type><Ref_ID>3502</Ref_ID><Title_Primary>UK Five Year Antimicrobial Resistance Strategy 2013 to 2018</Title_Primary><Authors_Primary>Department of Health</Authors_Primary><Date_Primary>2013</Date_Primary><Reprint>Not in File</Reprint><Authors_Secondary>Department for Environment,Food and Rural Affairs</Authors_Secondary><Publisher>Department of Health</Publisher><Web_URL><u>;(Department of Health 2013). Where outbreaks have occurred there is a considerable financial, physical and psychological cost. Evidence-based treatment regimens and associated quality improvement methods are effective in improving the outcome of infections due to these bacteria. 5.3 What is the purpose of the Report’s recommendations?The Report describes appropriate antimicrobial chemotherapy for MDR Gram –negative infections.5.4 What is the scope of the guidelines?Two sets of guidelines have been developed. This document includes evolution and global spread, best practice for antimicrobial prescribing and antimicrobial stewardship. The other document includes appropriate infection control principles, best practice hand hygiene, screening and environmental cleaning PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5XaWxzb248L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA (Wilson et al. 2016). The detailed scope for this guideline is given in Appendix 2 and the review questions in Appendix 3.5.5 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.(Brouwers 2010) Evidence was assessed for methodological quality and clinical applicability according to protocols of the Scottish Intercollegiate Guidelines Network ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Scottish Intercollegiate Guidelines Network</Author><Year>2014</Year><RecNum>3469</RecNum><IDText>SIGN 50: a guideline developer's handbook. revised Edition.</IDText><Prefix>SIGN</Prefix><MDL Ref_Type="Online Source"><Ref_Type>Online Source</Ref_Type><Ref_ID>3469</Ref_ID><Title_Primary><f name="Times New Roman">SIGN 50: a guideline developer's handbook. revised Edition.</f></Title_Primary><Authors_Primary>Scottish Intercollegiate Guidelines Network</Authors_Primary><Date_Primary>2014</Date_Primary><Reprint>Not in File</Reprint><Authors_Secondary>Healthcare Improvement Scotland: 2014</Authors_Secondary><Pub_Place>Edinburgh</Pub_Place><Web_URL><f name="Times New Roman"><u>;(SIGN 2014). The search is given in Appendix 4.5.6 Who developed these guidelines?A group of medical microbiologists, scientists, infectious disease physicians, infection control practitioners, epidemiologists, and patient representatives.5.7 Who are these guidelines for?Any hospital or general practitioner can use these guidelines and adapt them for local use. Expected users include clinical medical, nursing, antimicrobial pharmacy and paramedical staff. The guidelines should be used to improve the treatment of both presumptive and confirmed cases of infection by multidrug resistant Gram-negative bacteria.5.8 How are the guidelines structured?Each area (defined by questions) comprises an introduction, a summary of the evidence base with levels and a recommendation graded according to the available evidence. 5.9 How frequently are the guidelines reviewed and updated?The guidelines will be reviewed and updated every 4 years if warranted by sufficient changes in the evidence.5.10 AimThe primary aim of the review was to assess the current evidence for antimicrobial prescribing in the treatment of MDR Gram-negative infections. The secondary aims were: (a) To evaluate the efficacy of antibiotics to treat community, and secondary- or tertiary-care infections caused by MDR Gram-negative bacteria. (b) To evaluate the impact of educating and providing support to professionals and/or patients to reduce unnecessary use of antibiotics leading to a reduction in the selective pressure for resistance, i.e., antibiotic stewardship.6Summary of GuidelinesThe guidance has been derived from current best peer-reviewed publications and expert opinion. Each recommendation is associated with a class of supporting evidence or it is presented as a Good Practice Point. Temocillin can be used as a carbapenem-sparing agent against Enterobacteriaceae. ConditionalAmpicillin-sulbactam can be used against multi-resistant Acinetobacter baumannii isolates based on susceptibility results. ConditionalAmoxicillin-clavulanate should not be used to treat infection with known ESBL-producing organism unless sensitivity known ConditionalPiperacillin-tazobactam can be considered for use in mild-moderate infections (i.e. not severe sepsis) due to ESBL-producing Enterobacteriaceae if supported by susceptibility results.ConditionalPiperacillin-tazobactam can be considered for use in treating infections caused by Pseudomonas aeruginosa of all types of severity based on susceptibility results. However combination with an aminoglycoside is advisable for severe infections. ConditionalCarbapenems should be used to treat serious ESBL-producing Gram-negative infections subject to antibiotic stewardship to minimize the risk of developing resistance StrongErtapenem is effective in treatment of infections with multi-resistant Enterobacteriaceae apart from carbapenemase producers. StrongIn view of the once daily dosing regimen, ertapenem should be preferred for outpatient antibiotic treatment (OPAT) ConditionalAlthough it retains good efficacy against infections with Pseudomonas aeruginosa, ceftazidime is not recommended for the treatment of other serious infections due to ESBL / AmpC producing Enterobacteriaceae, even if in vitro tests suggest the isolate is susceptible. ConditionalCefepime should not be used for treating infection caused by ESBL, Amp C and carbapenemase-producing Enterobacteriaceae. Strong negative With the exception of infections with metallo-β-lactamase strains, ceftazidime-avibactam, when available, should be used as alternative treatment to carbapenems. Strong Ceftolozane-tazobactam should be used as alternative treatment to carbapenems in treating ESBL-producing Gram negative pathogens (but not carbapenemase producers). Strong Polymyxins should be reserved for infections due to multiresistant strains guided by susceptibility testing and preferably used in combination with other agents. ConditionalRenal function must be closely monitored during polymyxin treatment especially in the elderly, for those receiving high doses for prolonged periods and those on concomitant nephrotoxic agents. StrongFluoroquinolones can be used to treat urinary infection due to multidrug resistant Gram-negative bacteria based on susceptibility results ConditionalTigecycline can be used in combination in the treatment of multiresistant soft tissue, intra abdominal, respiratory and bacteremic infections ConditionalCo-trimoxazole should be used in treatment of infections due to Stenotrophomonas maltophilia ConditionalFosfomycin should be used in treatment of urinary infection due to multiresistant Gram-negative bacteria (oral administration only suitable for lower urinary infection)ConditionalAztreonam should only be used in combination with other agents if resistance or Gram positive pathogens are suspected ConditionalCefixime should not be used for treating infections caused by ESBL-, Amp-C- or CPE producing Enterobacteriaceae. ConditionalWhen a combination of agents is used in the treatment of carbapenem-resistant Enterobacteriacae infections e.g. Klebsiella pneumoniae carbapenemase, a carbapenem should be included with the active agents unless NDM carbapenemase is presentConditionalPolymyxins should be given in combination with other agents if they are used in treating carbapenem-resistant Enterobacteriaceae. StrongMultiresistant organisms do not need to be considered in the empirical treatment of acute uncomplicated urinary infection in younger women without risk factors or recent foreign travelStrongAlways send a urine specimen for culture and susceptibility if an antibiotic-resistant organism is suspected AND the patient is symptomatic StrongThe following antibiotics should be used in urinary infection (guided where possible by sensitivity testing) against suspected antibiotic resistant strains: nitrofurantoin, fosfomycin, pivmecillinam. StrongIn uncomplicated urinary infection due to a proven ESBL-producing organism, treatment is recommended for 7 days to improve bacteriological clearance. ConditionalIn pyelonephritis or complicated urinary infection where MDR Gram negative infection suspected, patients should have a urine sample collected and started on empirical intravenous therapy with ertapenem or meropenem. If known to have sensitive organisms in the last month and well enough for oral therapy then use best choice active agent. If a carbapenem-resistant bacterium is present, treatment is then guided by susceptibility testing and other recent isolates.StrongThe threshold for changing empirical therapy in the face of rising resistance should be determined locally based on the risk of bacteremia and rates of resistance Conditional All hospitals should have an antimicrobial stewardship programmme based on both surveillance and active feedback to prescribers, with monitoring of clinical and prescribing outcomes.StrongOutcomes of bacteraemia in relation to antibiotic treatment should be collected for each hospital and made publicly available as a tabulated comparison by public health authorities, as a measure of the adequacy of treatment of infection.StrongCommissioning and quality organisations should review outcome data linked to antibiotic prescribing to improve quality of care in both hospitals and the communityConditionalRestrictive prescribing policies should be used to reduce the likelihood of new occurrences of MDR Gram-negative infection.StrongHospitals should ensure that new antimicrobials that may be required to treat MDR Gram-negative infections are readily identified through horizon scanning and available/monitored through existing formulary groups and other similar bodies.Conditional Use persuasive and restrictive interventions to reduce the total antibiotic consumption, particularly broad-spectrum antibiotics in the, community and care home setting. StrongUse audit and feedback to reduce antimicrobial use in the community and care home setting.ConditionalFollow local guidance for advice on what antibiotics to prescribe, basing decision on when to prescribe (whatever the age) primarily on symptoms and using dipstick tests only to confirm the diagnosis of urinary infection, especially when symptoms are mild. StrongCommunity onset E. coli bacteraemias are increasing so ALWAYS inform patients what to look out for, how to seek further help and what to expect over time, so that the patient or their carers knows when to reconsult if their symptoms worsen or do not improve. StrongDo not prescribe antibiotics in asymptomatic bacteriuria in older people or those with indwelling catheters. StrongOnly start empirical antibiotics and send urine for culture in an elderly patient if they have two or more signs of infection, especially dysuria, fever > 38 o C or new incontinence ConditionalAlthough daily or post-coital antibiotic prophylaxis is very effective in reducing recurrent UTI, use standby antibiotics as the default.ConditionalDo not give antibiotic prophylaxis for urinary catheter insertion or changes unless previous history of symptomatic urinary infections associated with a catheter change or there is trauma during the catheter insertion. ConditionalLocal surveillance data should be used to inform empirical antibiotic advice for UTI in the community setting. Conditional7. Implementation of these guidelines7.1 How can the guidelines be used to improve clinical effectiveness?The Guidelines can be used to direct and formulate antibiotic policies. They provide a framework for clinical audit tools for quality improvement.7.2How much will implementation of the guidelines cost? The majority of antimicrobial agents described in these guidelines are generic and are currently widely used. Implementation of these guidelines should enable better focused therapy, with no increase in drug utilization and possibly a modest decrease.7.3 Summary of audit measuresTotal antibiotic consumption in defined daily doses reducing by quarter uin accordance with antimicrobial stewardship programmeUse of ertapenem, meropenem and imipenem by quarter stable or reducing annuallyNo antibiotic prescriptions to treat urinary infection in elderly catheterised patient unless bacteraemia suspectedNo antibiotic prophylaxis for urinary catheter insertion or changes unless previous history of symptomatic urinary infections associated with a catheter change or there is trauma during the catheter insertion. 7.4 E-learning toolsContinuing Professional Development questions and model answers are listed for self-assessment in Appendix 5. 8.Methodology8.1 Evidence appraisalMethods were in accordance with SIGN 50 and Cochrane Collaboration criteria ADDIN REFMGR.CITE <Refman><Cite><Author>SIGN</Author><Year>2011</Year><RecNum>3299</RecNum><IDText>Publication No. 50 A Guideline Developer's Handbook.</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3299</Ref_ID><Title_Primary>Publication No. 50 A Guideline Developer's Handbook.</Title_Primary><Authors_Primary>SIGN</Authors_Primary><Date_Primary>2011</Date_Primary><Reprint>Not in File</Reprint><Periodical>Scottish Intercollegiate Guidelines Network</Periodical><Volume>November</Volume><ZZ_JournalFull><f name="System">Scottish Intercollegiate Guidelines Network</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Higgins</Author><Year>2011</Year><RecNum>3300</RecNum><IDText>Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. </IDText><MDL Ref_Type="Book, Whole"><Ref_Type>Book, Whole</Ref_Type><Ref_ID>3300</Ref_ID><Title_Primary><f name="Cambria">Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. </f></Title_Primary><Authors_Primary>Higgins,JPT</Authors_Primary><Authors_Primary>Green,S</Authors_Primary><Date_Primary>2011</Date_Primary><Reprint>Not in File</Reprint><Volume><f name="Cambria">Version 5.1.0 </f></Volume><Publisher><f name="Cambria">The Cochrane Collaboration, 2011</f></Publisher><Web_URL><f name="Cambria"><u>;(Higgins and Green 2011;SIGN 2011) and critical appraisal was applied using AGREEII (Brouwers 2010). Accepted guidelines were used as part of the evidence base and to support expert consensus. Questions for review (appendix 3) were derived from the Working Party Group including patient representatives in accordance with Patient Intervention Comparison Outcome (PICO) (SIGN 2014).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. The latter comprised 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 and in Appendix 4. MeSH headings and free text terms were used in the Cochrane Library (Issue 11 2012), Medline (1946-2012), Embase (1980-2012) and Cumulated Index of Nursing and Allied Health Literature (CINAHL) (1984-2012). On 23rd May 2014, an update search was conducted on Medline alonse using the same strategy for references after 1st January 2013. Reference lists of included studies were searched. Two review authors independently screened all citations and abstracts identified, and screened full reports of potentially eligible studies (those that addressed the 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: these included the number of cases analyzed, adjusted and unadjusted effect estimates, with standard error or 95% confidence interval (CI), confounding variables and methods used to adjust the analysis. If available, data were extracted from contingency tables. Risk of bias was assessed using SIGN critical appraisal checklists. Interrupted time series were assessed using the Cochrane Effective Practice and Organisation of Care (EPOC) Group (SIGN 2014, Cochrane 2013). 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 treatments for infections caused by bacteria with specific resistance. Clinical outcomes were mortality, effectiveness of treatment , and length of hospital stay. Microbial outcome measures were decreases in the prevalence of multi-drug resistance among Gram-negative bacteria, or decreases in colonization or infection by specific Gram-negative pathogens. Risk ratios (RR) were used for dichotomous variables, and mean differences with 95% CI were used for continuous outcomes. ADDIN REFMGR.CITE <Refman><Cite><Author>Borestein</Author><Year>2009</Year><RecNum>3301</RecNum><IDText>Introduction to Meta- Analysis</IDText><MDL Ref_Type="Book, Whole"><Ref_Type>Book, Whole</Ref_Type><Ref_ID>3301</Ref_ID><Title_Primary><f name="Cambria">Introduction to Meta- Analysis</f></Title_Primary><Authors_Primary>Borestein,M</Authors_Primary><Authors_Primary>Hedges,LV</Authors_Primary><Authors_Primary>Higgins JPT</Authors_Primary><Authors_Primary>Rothstein,HR</Authors_Primary><Date_Primary>2009</Date_Primary><Reprint>Not in File</Reprint><Publisher><f name="Cambria">Chichester: John Wiley & Sons LTD</f></Publisher><ZZ_WorkformID>2</ZZ_WorkformID></MDL></Cite></Refman>(Borestein et al. 2009). Analyses were performed in Revman 5.2 ADDIN REFMGR.CITE <Refman><Cite><Author>Review Manager</Author><Year>2011</Year><RecNum>3302</RecNum><IDText>Review Manager</IDText><MDL Ref_Type="Computer Program"><Ref_Type>Computer Program</Ref_Type><Ref_ID>3302</Ref_ID><Title_Primary>Review Manager</Title_Primary><Authors_Primary>Review Manager</Authors_Primary><Date_Primary>2011</Date_Primary><Reprint>Not in File</Reprint><Issue>5.1</Issue><Publisher><f name="Cambria">Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration</f></Publisher><ZZ_WorkformID>11</ZZ_WorkformID></MDL></Cite></Refman>(Review Manager 2011). SIGN summary tables were used.Evidence tables and judgment 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 recommendation was as defined by SIGN (Table 1), and the strength of recommendation was adopted from GRADE (Grading of Recommendations Assessment, Development and Evaluation) (Table 2) The grading relates to the strength of the supporting evidence and predictive power of the study designs, rather than the importance of the recommendation. Any disagreements between members were resolved by discussion. For some areas, only expert opinion is available; in such cases, a good practice recommendation has been made. A flow chart of the systematic review process is given in Figure 1.8.2 Consultation processOn completion these guidelines were opened to consultation with the stakeholders listed in Appendix 6. The draft report was placed on the BSAC 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 recommendations9.1 Epidemiology9.1.1 What is the Definition of Multidrug-resistant Gram-negative bacteria?Multidrug resistant (MDR) is a vexed term. From 1980 it was used to mean, ‘resistant to multiple agents’ without the number or types of agents being specified. More recently the European Centre for Disease Prevention and Control (ECDC) has attempted to formalise the term as ‘resistant to three or more antibiotic classes’ whilst extremely drug resistant (XDR) is ‘susceptible only to one or two drug classes’ PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNpZXZlcnQ8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Sievert et al. 2013). These definitions, based on those for tuberculosis, are epidemiologically attractive, but run into the sands of practicality. A European consensus is difficult to achieve, as not all products are readily available and therefore tested by laboratories in all countries. Many laboratories do not test the antibiotics required notably fosfomycin. , There is scope for disagreement on on which antibiotics should be considered as separate classes, for example, monobactams behave similarly to oxyimino cephalosporins in respect of most resistance mechanisms but differently in respect of metallo-carbapenemases. A useful pragmatic approach is to consider oral and parenteral drugs separately as, in the UK, these will be largely used in primary and secondary care respectively, with multi resistance constituting different challenges in each setting. For oral drugs multi-resistance might usefully be defined as an organism susceptible to only one readily available oral agent. Such a definition is sensitive to the introduction, or new availability of new oral agents, but this is appropriate and may emphasise the importance of new agents to the licensing authorities. By this definition the following would be classed as multi-resistant isolates for the community:Escherichia coli that are resistant to coamoxiclav, oral cephalosporins, quinolones, trimethoprim but susceptible to mecillinam, This would include some ESBL and AmpC producing strains that are difficult to treat if causing upper urinary infection.Pseudomonas aeruginosa resistant to quinolones.This approach could be modified to exclude agents where the mutation frequency is sufficiently high so that resistance emerges during treatment .For parenteral antibiotics a similar approach could be considered. Some oral agents have no licensed (or otherwise available) parenteral form e.g. pivmecillinam and nitrofurantoin and susceptibility to these agents should not be taken into account unless this situation changes. Specific agents to which impaired susceptibility might be significant include carbapenems, temocillin, piperacillin/tazobactam, relevant cephalosporins (cefotaxime for Enterobacteriacae, ceftazidime for P. aeruginosa), colistin fosfomycin, tigecycline and aminoglycosides (including amikacin). Given this greater number of agents and the paucity of new pipeline antibiotics active against Gram-negative species, it is pragmatic to consider ‘multi-resistant’ as isolates where only two chemically unrelated antibiotics are active against the bacterium. By such a definition the following would be considered multi-resistant isolates in hospitals. Acinetobacter baumannii susceptible to two or less of colistin, tigecycline, meropenem or imipenem, third generation cephalosporins, quinolones, trimethoprim.Klebsiella sp. that are susceptible to two or less of meropenem or imipenem, third generation cephalosporins, colistin, tigecycline, quinolones, aminoglycosides and piperacillin/tazobactam.Morganella sp. that are third-generation cephalosporin, aminoglycoside and piperacillin-tazobactam resistant and susceptible only to meropenem.The following would not be regarded as multi-resistant: Escherichia coli that are susceptible to 2 or fewer of coamoxiclav, cephalosporins, piperacillin/tazobactam, quinolones, trimethoprim, but are susceptible to carbapenems, temocillin and colistin. 9.1.2 What is the global epidemiology of MRGNB?Origins and impact of multi-resistanceResistance to multiple agents can develop via successive mutations, through the dissemination of multi resistance plasmids/genes (e.g., transposons) or through a combination of both processes. Resistance narrows antibiotic choices for definitive therapy; more critically, it increases the likelihood that empirical therapy will prove ineffective, increasing mortality in septic patients. Plasmids are the main source of multidrug resistance in Enterobacteriaceae and Acinetobacter spp., except for fluoroquinolones, and for mutational derepression of AmpC β-lactamases (e.g. in Enterobacter spp.). By contrast, sequential accumulation of mutations is paramount in Pseudomonas spp. Some less frequently encountered non-fermenters, e.g. Stenotrophomonas spp, Burkholderia spp and Chryseobacterium spp./Elizabethkingia spp. have exceptional inherent resistance, and are typically susceptible only to co-trimoxazole. Some multidrug resistant clones have spread widely among sites and countries. Resistance may increase their competitiveness, but a disturbing possibility is that antibiotics select not only for multidrug resistance, but also for the ability to accumulate multidrug resistance. 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ADDIN EN.CITE.DATA (Doumith et al. 2012). Finally, integrons, which provide efficient gene capture and expression systems, are now frequent in plasmids but absent from pre-antibiotic plasmid era, providing a mechanism whereby the resistance acquisition has accelerated.Epidemiological trends among multidrug resistant Enterobacteriaceae - cephalosporin and quinolone resistanceThe rise in multidrug resistant Enterobacteriaceae in the UK between 2000-2007 largely reflected the spread of IncF (pEK499 or similar) plasmids, which became particularly associated with the internationally-successful E. coli ST131 lineage (Fig 1). These plasmids encode the CTX-M-15 ESBL, along with resistance to trimethoprim, sulphonamides, tetracyclines and aminoglycosides. Frequent co-carriage of OXA-1 pencillinases impairs susceptibility to β-lactamase-inhibitor combinations. Other factors associated with the rise of multidrug resistant Enterobacteriaceae include the spread of plasmids encoding AmpC cephalosporinase, though these are around 10-fold less frequent than ESBL producers PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBvdHo8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Potz et al. 2006). Mutations can augment multidrug resistance: for example porin loss can engender resistance to ertapenem (and, occasionally, other carbapenems) in ESBL- and AmpC- producing Enterobacteriaceae, whilst mutational up-regulation of ArcAB-mediated efflux compromises tigecycline. Surveillance is limited but reference laboratory submissions suggest that these combined mechanisms are increasingly prevalent. Since approximately 2007 (the date varies with the species and resistance) the rise of cephalosporin- and fluoroquinolone-resistant Enterobacteriaceae has slowed (E. coli) or reversed (Klebsiella spp. and Enterobacter spp.) in the UK, though not in continental Europe (Fig 1). This shift may reflect the widespread reduction in UK of prescribing of cephalosporins and quinolones in the UK, predicated by concern about Clostridium difficile. Nevertheless, cephalosporin and quinolone resistances continues to be seen in 10-20% of UK bloodstream and urinary E. coli and K. pneumoniae isolates, with significant circulation in older patients who move between hospitals, nursing homes, and the community and who have frequent exposure to cross-infection and antibiotics . Carbapenem resistanceCarbapenem resistance was slow to emerge in Enterobacteriaceae, but is now a steadily expanding problem. It can occur through the production of an ESBL or AmpC combined with porin loss, or increasingly through acquired carbapenemases (typically KPC, VIM, IMP, NDM and OXA-48 types) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkd1cHRhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Canton et al. 2012;Gupta et al. 2011;Ho et al. 2010;Nordmann and Poirel 2013). Internationally there has been considerable spread of K. pneumoniae clonal complex (CC) 258 isolates with KPC carbapenemases. The rise of NDM and OXA-48 carbapenemases is more often associated with the spread of their encoding plasmids among bacterial strains. Carbapenem resistance due to ESBL or AmpC enzymes combined with porin loss may lead to treatment failure but is often unstable and may impose a fitness cost, meaning that spread among patients is rare, though it has been observed ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Gupta</Author><Year>2011</Year><RecNum>2820</RecNum><IDText>Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention</IDText><Prefix>Gupta et al.</Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2820</Ref_ID><Title_Primary>Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention</Title_Primary><Authors_Primary>Gupta,N.</Authors_Primary><Authors_Primary>Limbago,B.M.</Authors_Primary><Authors_Primary>Patel,J.B.</Authors_Primary><Authors_Primary>Kallen,A.J.</Authors_Primary><Date_Primary>2011/7/1</Date_Primary><Keywords>Bacterial Proteins</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Carbapenems</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Enzymes</Keywords><Keywords>enzymology</Keywords><Keywords>epidemiology</Keywords><Keywords>Genetic</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>metabolism</Keywords><Keywords>microbiology</Keywords><Keywords>mortality</Keywords><Keywords>pharmacology</Keywords><Keywords>Prevalence</Keywords><Keywords>prevention & control</Keywords><Keywords>Public Health</Keywords><Keywords>State</Keywords><Keywords>therapeutic use</Keywords><Keywords>transmission</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>60</Start_Page><End_Page>67</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>53</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gupta et al. 2011). Resistance conferred by acquired carbapenemases is the greater concern, and is generally associated with considerable resistance to other agents (HPR 2015).In the UK, rates of carbapenemase-production remain low for Enterobacteriaceae (<2%); nevertheless reference laboratory submissions are growing annually (fig 2), with many of the isolates coming from clinical rather than screening samples. These are pockets of local endemicity, especially of K. pneumoniae with KPC enzymes around Manchester or with VIM and OXA-48 in north Cheshire, that have persisted for 4-5 years. Many other sites, notably London teaching hospitals, are experiencing repeated challenge with a diversity of carbapenemase producers. Clonal complex 258 K. pneumoniae remains rare, despite repeated introduction, and the greater issue, particularly in NW England is dissemination of plasmids encoding KPC carbapenemases among different K. pneumoniae strains and other Enterobacteriaceae, some of them still susceptible to fluoroquinolones and aminoglycosides.Internationally, data from EARS-Net ADDIN REFMGR.CITE <Refman><Cite><Author>ECDC</Author><Year>2012</Year><RecNum>3161</RecNum><IDText> Ref_Type="Generic"><Ref_Type>Generic</Ref_Type><Ref_ID>3161</Ref_ID><Title_Primary> in File</Reprint><ZZ_WorkformID>33</ZZ_WorkformID></MDL></Cite></Refman>(ECDC 2012) suggests that the prevalence of carbapenem-resistant Enterobacteriaceae in bloodstream infections remains low in most parts of Europe, but with gradual year-on-year increases. Exceptions are Greece, Italy, Cyprus and Romania. In Greece, where the proportion of bloodstream K. pneumoniae isolates resistant to carbapenems increased from 27.8% in 2005 to 62.3% in 2014. VIM enzymes dominated early in this period but were replaced by KPC types, often carried by CC258. The rise of carbapenem-resistant K. pneumoniae in Italy has been dramatic and recent, from 1% of bloodstream infections in 2009,and 15% in 2010 to 32.3% in 2014. This increase again is mainly due to CC258 K. pneumoniae with KPC enzymes ADDIN REFMGR.CITE <Refman><Cite><Author>Giani</Author><Year>2013</Year><RecNum>2825</RecNum><IDText>Epidemic diffusion of KPC carbapenemase-producing Klebsiella pneumoniae in Italy: results of the first countrywide survey, 15 May to 30 June 2011</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2825</Ref_ID><Title_Primary>Epidemic diffusion of KPC carbapenemase-producing Klebsiella pneumoniae in Italy: results of the first countrywide survey, 15 May to 30 June 2011</Title_Primary><Authors_Primary>Giani,T.</Authors_Primary><Authors_Primary>Pini,B.</Authors_Primary><Authors_Primary>Arena,F.</Authors_Primary><Authors_Primary>Conte,V.</Authors_Primary><Authors_Primary>Bracco,S.</Authors_Primary><Authors_Primary>Migliavacca,R.</Authors_Primary><Authors_Primary>Pantosti,A.</Authors_Primary><Authors_Primary>Pagani,L.</Authors_Primary><Authors_Primary>Luzzaro,F.</Authors_Primary><Authors_Primary>Rossolini,G.M.</Authors_Primary><Date_Primary>2013/5/30</Date_Primary><Keywords>Biotechnology</Keywords><Keywords>Clinical</Keywords><Keywords>Diffusion</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enzymes</Keywords><Keywords>Health</Keywords><Keywords>Inpatients</Keywords><Keywords>Italy</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Laboratories</Keywords><Keywords>Medical</Keywords><Keywords>Outpatients</Keywords><Keywords>Public Health</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>20489</Start_Page><Periodical>Euro.Surveill.</Periodical><Volume>18</Volume><Issue>22</Issue><ZZ_JournalStdAbbrev><f name="System">Euro.Surveill.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Giani et al. 2013). 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ADDIN EN.CITE.DATA (Canton et al. 2012;Nordmann et al. 2011), where an aggressive, nationwide intervention was successful in bringing it under control ADDIN REFMGR.CITE <Refman><Cite><Author>Schwaber</Author><Year>2014</Year><RecNum>3223</RecNum><IDText>An ongoing national intervention to contain the spread of carbapenem-resistant enterobacteriaceae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3223</Ref_ID><Title_Primary>An ongoing national intervention to contain the spread of carbapenem-resistant enterobacteriaceae</Title_Primary><Authors_Primary>Schwaber,M.J.</Authors_Primary><Authors_Primary>Carmeli,Y.</Authors_Primary><Date_Primary>2014/3</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>beta-Lactam Resistance</Keywords><Keywords>Carbapenems</Keywords><Keywords>Carrier State</Keywords><Keywords>Communication</Keywords><Keywords>Contact Tracing</Keywords><Keywords>drug effects</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>Guideline Adherence</Keywords><Keywords>Guidelines</Keywords><Keywords>Guidelines as Topic</Keywords><Keywords>Health</Keywords><Keywords>Health Policy</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>Infection Control</Keywords><Keywords>isolation & purification</Keywords><Keywords>Israel</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Laboratories</Keywords><Keywords>Long-Term Care</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>organization & administration</Keywords><Keywords>pharmacology</Keywords><Keywords>prevention & control</Keywords><Reprint>Not in File</Reprint><Start_Page>697</Start_Page><End_Page>703</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>58</Volume><Issue>5</Issue><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Schwaber and Carmeli 2014) .Outbreaks of carbapenemase-producing Enterobacteriaceae have been reported in many other parts of the world, including almost all US states (CDC 2015) (where KPC enzymes dominate), South Asia (predominantly NDM enzymes), the Middle East (OXA-48), Brazil and Columbia (KPC) PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5DYW50b248L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA (Canton et al. 2012;Nordmann et al. 2011). The metallo-carbapenemase IMP-4 has spread widely in China and (often together with KPC-2) in Australia; further global spread is to be expected PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhhd2tleTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Hawkey 2015). Since prevalence is largely unknown, risk factors are difficult to derive, but seem to include travel to high prevalence area, notably including the Indian Subcontinent and exposure to healthcare and antimicrobials ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Gupta</Author><Year>2011</Year><RecNum>2820</RecNum><IDText>Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention</IDText><Prefix>Gupta et al.</Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2820</Ref_ID><Title_Primary>Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention</Title_Primary><Authors_Primary>Gupta,N.</Authors_Primary><Authors_Primary>Limbago,B.M.</Authors_Primary><Authors_Primary>Patel,J.B.</Authors_Primary><Authors_Primary>Kallen,A.J.</Authors_Primary><Date_Primary>2011/7/1</Date_Primary><Keywords>Bacterial Proteins</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Carbapenems</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Enzymes</Keywords><Keywords>enzymology</Keywords><Keywords>epidemiology</Keywords><Keywords>Genetic</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>metabolism</Keywords><Keywords>microbiology</Keywords><Keywords>mortality</Keywords><Keywords>pharmacology</Keywords><Keywords>Prevalence</Keywords><Keywords>prevention & control</Keywords><Keywords>Public Health</Keywords><Keywords>State</Keywords><Keywords>therapeutic use</Keywords><Keywords>transmission</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>60</Start_Page><End_Page>67</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>53</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gupta et al. 2011). Carbapenem resistance in Enterobacteriaceae has been associated with increased attributable mortality probably owing to the greater likelihood that initial empirical therapy proves inadequate PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5HdXB0YTwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Daikos et al. 2009;Gupta et al. 2011;Patel et al. 2008). 9.1.3How do Multi-Resistant Enterobacteriaceae differ from non-fermenters in terms of their prevalence and associated resistance genes?Carbapenem resistance is more common in non-glucose fermenting Gram-negative bacteria than in Enterobacteriaceae. In the case of Acinetobacter baumannii, it was common, even by the year 2000, to see isolates resistant to all treatment options except carbapenems, colistin and tigecycline. Subsequently, carbapenem resistance has proliferated, reaching c. 30% of bloodstream isolates. It is largely associated with acquired OXA-23, -40 or 58-like carbapenemases or with insertion-sequence mediated upregulation of the chromosomal OXA-51-like enzyme. The strain structure of A. baumannii is extremely clonal, making it difficult, without a history of patient transfers, to distinguish site-to-site spread from repeated independent selection of lineage variants that were previously circulating at low frequency. Multidrug resistant Acinetobacter largely cause outbreaks in ICU settings PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkthcmFnZW9yZ29wb3Vsb3M8L0F1dGhvcj48WWVhcj4yMDA4
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ADDIN EN.CITE.DATA (Coelho et al. 2006;Karageorgopoulos and Falagas 2008;Towner 2009), whereas carbapenem-resistant Enterobacteriaceae, principally E. coli and Klebsiella spp., cause infection in a wider group of patients, and have far greater potential to spread rapidly when introduced into wider patient populations PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNjaHdhYmVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA (Canton et al. 2012;Khan et al. 2012;Nordmann et al. 2011;Schwaber et al. 2011). Most UK P. aeruginosa remain susceptible to β-lactams, including ceftazidime, piperacillin-tazobactam and carbapenems, aminoglycosides and fluoroquinolones, with resistance rates of 5-10% for these agents. Nevertheless, single multidrug resistant lineages, some with carbapenemases, have persisted in a few UK hospitals for up to 9 years, causing multiple infections widely scattered over time and possibly reflecting colonisation of the hospital water systems. The most frequently encountered carbapenemase is VIM, which may be plasmid-mediated, with multiple gene copies conferring high level meropenem resistance PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5TYW48L0F1dGhvcj48WWVhcj4y
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ADDIN EN.CITE.DATA (San Millan et al. 2015). IMP-9 is also important, particularly in China, and has been shown to be derived (as probably are many carbapenemase genes) from environmental bacteria by horizontal gene transfer PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlhpb25nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Xiong et al. 2013). Multidrug resistance is also a major problem in P. aeruginosa from cystic fibrosis (CF), with resistance increasing over time in an individual patient’s lung microflora. Multidrug resistance profiles are extremely variable even within widely successful CF lineages, e.g. the Liverpool Epidemic Strain, which has been acquired by multiple CF patients and units. Rates of carbapenem-resistance in P. aeruginosa from bloodstream infections vary greatly across Europe, with high rates in Romania (58.5% ) and Greece (42.9% ). More generally, rates of resistance show a gradient, rising from NW to SE Europe, with extensive spread of carbapenemase-producing clones in Russia. In contrast to Enterobacteriacae rates of resistance to carbapenem are generally higher than those to ceftazidime, piperacillin/tazobactam or aminoglycosides.9.1.4 What impact have returning travellers made on UK epidemiology?Whilst mutational resistances often emerge locally, strains with acquired resistance genes are often imported to the UK from other countries. Examples include multidrug resistant K. pneumoniae with OXA-48 carbapenemases with Libyan conflict casualties and with patient transfers from elsewhere in the Middle East; K. pneumoniae with KPC carbapenemases from Greece, Israel and Curacao and, most significantly, Enterobacteriaceae with NDM-1 metallo-carbapenemase from south Asia PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkt1bWFyYXNhbXk8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA (Soraas et al. 2013). Previous travel to destinations where resistance is prevalent is a risk factor for acquired multidrug resistant bacteria and should be considered in respect of both empirical therapy and infection control. However many patients with multidrug resistant organisms lack any relevant travel and it is not known if this reflects spread from carriers who have a history of high risk travel or inter-hospital-transfer . The most significant impact that the movement of people can have on the problem of resistance in Gram-negative bacteria is the maintenance of higher levels of resistance in commensal bacteria after return from high incidence areas. One study in Birmingham showed that individuals of Middle Eastern or south Asian origin had a carriage rate of CTX-M ESBL E. coli of 22.2% versus 8.1% in those of European origin ADDIN REFMGR.CITE <Refman><Cite><Author>Wickramasinghe</Author><Year>2012</Year><RecNum>2653</RecNum><IDText>High community faecal carriage rates of CTX-M ESBL-producing Escherichia coli in a specific population group in Birmingham, UK</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2653</Ref_ID><Title_Primary>High community faecal carriage rates of CTX-M ESBL-producing Escherichia coli in a specific population group in Birmingham, UK</Title_Primary><Authors_Primary>Wickramasinghe,N.H.</Authors_Primary><Authors_Primary>Xu,L.</Authors_Primary><Authors_Primary>Eustace,A.</Authors_Primary><Authors_Primary>Shabir,S.</Authors_Primary><Authors_Primary>Saluja,T.</Authors_Primary><Authors_Primary>Hawkey,P.M.</Authors_Primary><Date_Primary>2012/3/8</Date_Primary><Keywords>Agar</Keywords><Keywords>Asia</Keywords><Keywords>Bacteria</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Dna</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Europe</Keywords><Keywords>Genotype</Keywords><Keywords>Guidelines</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>Patients</Keywords><Keywords>Prevalence</Keywords><Keywords>Software</Keywords><Keywords>therapy</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Periodical>J.Antimicrob.Chemother.</Periodical><Address>Department of Microbiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK</Address><Web_URL>PM:22403261</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Wickramasinghe et al. 2012). Empirical choice of antibiotics thus may need to therefore take into account recent travel history and cultural background.9.1.5 What is the clinical importance of carbapenemase versus Amp C and CTX-M producing strains? ESBL-producting Enterobateriaceae, multidrug-resistant P. aeruginosa and A. baumannii are associated with increased cost, mortality and length of stay in most but not all studies evaluating the impact of antibiotic resistance in Gram-negative bacteria PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdpc2tlPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Kwon et al. 2007;Lee et al. 2007;Shorr 2009;Sunenshine et al. 2007). More recently, studies have emerged evaluating the impact of carbapenem resistance in Enterobacteriaceae ADDIN REFMGR.CITE <Refman><Cite><Author>Falagas</Author><Year>2014</Year><RecNum>3347</RecNum><IDText>Deaths attributable to carbapenem-resistant Enterobacteriaceae infections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3347</Ref_ID><Title_Primary>Deaths attributable to carbapenem-resistant Enterobacteriaceae infections</Title_Primary><Authors_Primary>Falagas,M.E.</Authors_Primary><Authors_Primary>Tansarli,G.S.</Authors_Primary><Authors_Primary>Karageorgopoulos,D.E.</Authors_Primary><Authors_Primary>Vardakas,K.Z.</Authors_Primary><Date_Primary>2014/7</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteremia</Keywords><Keywords>Carbapenems</Keywords><Keywords>Case-Control Studies</Keywords><Keywords>Cohort Studies</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella Infections</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>mortality</Keywords><Keywords>pathogenicity</Keywords><Keywords>Patients</Keywords><Keywords>physiology</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Retrospective Studies</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>1170</Start_Page><End_Page>1175</End_Page><Periodical>Emerg.Infect.Dis.</Periodical><Volume>20</Volume><Issue>7</Issue><User_Def_5>PMC4073868</User_Def_5><Web_URL>PM:24959688</Web_URL><ZZ_JournalStdAbbrev><f name="System">Emerg.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Falagas et al. 2014b). Pooled analysis of nine studies comparing mortality in carbapenem-susceptible Enterobacteriaceae infections including bacteremia with CRE infections found that mortality was more than two fold higher in CRE infections. As colonization can precede infection invasive infection may develop in a patient following broad spectrum antibiotics other than carbapenem PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNlbGRlbjwvQXV0aG9yPjxZZWFyPjE5NzE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Corbella et al. 1996;Latibeaudiere et al. 2015;Schimpff et al. 1972;Selden et al. 1971;Thom et al. 2007;Wingard et al. 1986). 9.2 Treatment options for Multi resistant Gram-negative bacteria: What is the efficacy of carbapenems, mecillinam, temocillin, fosfomycin, colistin and other antibiotics against specific MRGNB and what are the recommended antibiotics for secondary/tertiary care?The evidence base (and grading) for all agents is generally weak, as most studies were retrospective case series, only rarely including a comparator agent. 9.2.1 Intravenous antibiotics for secondary and tertiary care9.2.1.1TemocillinTemocillin is a semi-synthetic 6-alpha-methoxy derivative of ticarcillin that is highly stable to most β-lactamases except metallo-carbapenemases (e.g. IMP, NDM, VIM) and OXA-48 like enzymes. It lacks activity against anaerobes, Gram positive bacteria and most Gram-negative non-fermenters such as Pseudomonas aeruginosa and Acinetobacter spp. It does, however, have in vitro activity against ESBL- and AmpC-producing Enterobacteriaceae PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxpdmVybW9yZTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+
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ADDIN EN.CITE.DATA (Livermore et al. 2006;Rodriguez-Villalobos et al. 2011), KPC-producing E. coli and Klebsiella pneumoniae ADDIN REFMGR.CITE <Refman><Cite><Author>Adams-Haduch</Author><Year>2009</Year><RecNum>3069</RecNum><IDText>Activity of temocillin against KPC-producing Klebsiella pneumoniae and Escherichia coli</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3069</Ref_ID><Title_Primary>Activity of temocillin against KPC-producing Klebsiella pneumoniae and Escherichia coli</Title_Primary><Authors_Primary>Adams-Haduch,J.M.</Authors_Primary><Authors_Primary>Potoski,B.A.</Authors_Primary><Authors_Primary>Sidjabat,H.E.</Authors_Primary><Authors_Primary>Paterson,D.L.</Authors_Primary><Authors_Primary>Doi,Y.</Authors_Primary><Date_Primary>2009/6</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacterial Proteins</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>biosynthesis</Keywords><Keywords>drug effects</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>Penicillins</Keywords><Keywords>pharmacology</Keywords><Reprint>Not in File</Reprint><Start_Page>2700</Start_Page><End_Page>2701</End_Page><Periodical>Antimicrob.Agents Chemother.</Periodical><Volume>53</Volume><Issue>6</Issue><ZZ_JournalStdAbbrev><f name="System">Antimicrob.Agents Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Adams-Haduch et al. 2009) and Burkholderia cepacia complex PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJvbmFjb3JzaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA (Balakrishnan et al. 2011). Urinary tract and bacteraemia (42 episodes each) were the most frequent indications followed by hospital acquired pneumonia. Optimal dosage (≥2g twice daily) was associated with improved outcome, whilst the presence of AmpC or ESBL did not affect outcome. Two studies of the use of temocillin in cystic fibrosis patients with B. cepacia complex have been published. Both were retrospective non-randomised audits the first showing equivalence of combinations with aminoglycoside of temocillin versus other agents against B. cenoepacia and in the second showing that 18/32 courses of temocillin resulted in improvement in the patient’s infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxla2thczwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Kent et al. 2008;Lekkas et al. 2006).EvidenceTemocillin is an effective and well tolerated drug within the limitations of its spectrum of activity3RecommendationsTemocillin can be used as a carbapenem-sparing agent against Enterobacteriaceae. Conditional9.2.1.2Ampicillin-sulbactamSulbactam has in vitro activity against some strains of Acinetobacter baumannii, including-against some carbapenem-resistant lineages. In an uncontrolled study, forty-two patients with carbapenem –resistant A.baumannii were treated with sulbactam; there were no major adverse events and 39 were improved or cured PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvcmJlbGxhPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48
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ADDIN EN.CITE.DATA (Kalin et al. 2014;Wood et al. 2002). Two small randomized controlled trials have tried to assess differences in dosing regimens and efficacy compared with colistin PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJldHJvc2lhbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA (Betrosian et al. 2007;Betrosian et al. 2008). Overall the evidence base is poor in context sulbactam MICs for most UK isolates of carbapenem-resistant A. baumanii are 16-32mg/L implying poor rates of susceptibility.EvidenceAmpicillin-sulbactam is effective in treating multiresistant Acinetobacter infections 3 RecommendationsAmpicillin-sulbactam can be used against multi-resistant Acinetobacter baumannii isolates based on susceptibility results. Conditional9.2.1.3 Amoxicillin- clavulanate?Co-amoxiclav has been successfully used to treat urinary tract infections due to ESBL-producers as described in case reports and an observational study PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJvZHJpZ3Vlei1CYW5vPC9BdXRob3I+PFllYXI+MjAwODwv
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ADDIN EN.CITE.DATA (Lagace-Wiens et al. 2006;Rodriguez-Bano et al. 2008). The cure rate among 37 patients with cystitis treated with co-amoxiclav was 93% for those with susceptible isolates (minimum inhibitory concentration ≤8 μg/mL) and 56% for those with intermediate or resistant isolates (minimum inhibitory concentration ≥16 μg/mL) (P=0.02)(Rodriguez-Bano et al. 2008). The study was performed in Spain, where many ESBL producers have CTX-M-14 enzyme; in the UK more have CTX-M-15 and many of these co-produce OXA-1, an inhibitor-resistant penicillinase, raising co-amoxiclav MICs to the intermediate or resistant range. Furthermore the β-lactam:β-lactamase inhibitor ratio was 2:1 which would result in higher apparent susceptibility than using a fixed clavulante concentration of 2 mg/L. The outcomes for bloodstream infections treated with co-amoxiclav have been reviewed and the findings are discussed in the section on piperacillin-tazobactam ADDIN REFMGR.CITE <Refman><Cite><Author>Rodriguez-Bano</Author><Year>2012</Year><RecNum>2631</RecNum><IDText>beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2631</Ref_ID><Title_Primary>beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts</Title_Primary><Authors_Primary>Rodriguez-Bano,J.</Authors_Primary><Authors_Primary>Navarro,M.D.</Authors_Primary><Authors_Primary>Retamar,P.</Authors_Primary><Authors_Primary>Picon,E.</Authors_Primary><Authors_Primary>Pascual,A.</Authors_Primary><Date_Primary>2012/1/15</Date_Primary><Keywords>analysis</Keywords><Keywords>Bacteremia</Keywords><Keywords>Carbapenems</Keywords><Keywords>Combination</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Hospital</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>methods</Keywords><Keywords>mortality</Keywords><Keywords>Multivariate Analysis</Keywords><Keywords>Patients</Keywords><Keywords>Research</Keywords><Keywords>Spain</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>167</Start_Page><End_Page>174</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>54</Volume><Issue>2</Issue><Address>Unidad Clinica de Enfermedades Infecciosas y Microbiologia, Hospital Universitario Virgen Macarena, Spain. jesusrb@us.es</Address><Web_URL>PM:22057701</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Rodriguez-Bano et al. 2012).EvidenceAmoxicillin-clavulanate is effective in urinary infections caused by ESBL-producing bacteria that appear susceptible in vitro 3RecommendationsAmoxicillin-clavulanate should not be used to treat infection with known ESBL-producing organism unless sensitivity known Conditional9.2.1.4 Piperacillin-tazobactamThe use of piperacillin-tazobactam for treating ESBL bacteraemias remains contentious. One recent study suggested carbapenems were superior to piperacillin-tazobactam in a study of 331 patients with ESBL bacteraemia PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbW1hPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Tamma et al. 2015). One hundred three (48%) patients received piptazobactam empirically and 110 (52%) received carbapenems empirically. The adjusted risk of death was 1.92 times higher for patients receiving empiric PTZ compared with empiric carbapenem therapy.An analysis of patients with bloodstream infections due to ESBL-producing E. coli was performed to assess the efficacy of combinations of β-lactam: β-lactamase inhibitor combinations (BLBLI) compared with carbapenems ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Rodriguez-Bano</Author><Year>2012</Year><RecNum>2631</RecNum><IDText>beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts</IDText><Prefix>Rodriguez-Bano et al.</Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2631</Ref_ID><Title_Primary>beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts</Title_Primary><Authors_Primary>Rodriguez-Bano,J.</Authors_Primary><Authors_Primary>Navarro,M.D.</Authors_Primary><Authors_Primary>Retamar,P.</Authors_Primary><Authors_Primary>Picon,E.</Authors_Primary><Authors_Primary>Pascual,A.</Authors_Primary><Date_Primary>2012/1/15</Date_Primary><Keywords>analysis</Keywords><Keywords>Bacteremia</Keywords><Keywords>Carbapenems</Keywords><Keywords>Combination</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Hospital</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>methods</Keywords><Keywords>mortality</Keywords><Keywords>Multivariate Analysis</Keywords><Keywords>Patients</Keywords><Keywords>Research</Keywords><Keywords>Spain</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>167</Start_Page><End_Page>174</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>54</Volume><Issue>2</Issue><Address>Unidad Clinica de Enfermedades Infecciosas y Microbiologia, Hospital Universitario Virgen Macarena, Spain. jesusrb@us.es</Address><Web_URL>PM:22057701</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Rodriguez-Bano et al. 2012). Mortality in patients treated with an active combination (coamoxiclav or piperacillin-tazobactam) or carbapenem were compared in two cohorts: empirical therapy and definitive therapy. Mortality rates at day 30 for those treated with BLBLI versus carbapenems were 9.7% versus 19.4% for empirical therapy and 9.3% versus 16.7% for definitive therapy respectively. After adjustment for confounders, no association was found between either empirical therapy or definitive therapy and increased mortality. The study suggested that co-amoxiclav and piperacillin-tazobactam may be suitable alternatives to carbapenems for treating patients with bloodstream infections due to ESBL-E coli but only in the minority that were active in vitro. It was non-randomized, and confounding due to unmeasured variables may have occurred. A retrospective case review of ESBL-producing E. coli bacteraemia suggested similar mortality rate following treatment with piperacillin-tazobactam (n=50) was as a carbapenem (n=70) if the organism appeared susceptible in vitro PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBlcmFsdGE8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Tsai et al. 2014). Forty-seven patients with available clinical data were included. The overall 30-day mortality rate was 29.8%. The 30-day (14.3% versus 23.1%, P = 0.65) or in-hospital (19.1% versus 30.8%, P = 0.68) mortality rate of 21 patients treated by a carbapenem was lower than that of 13 treated by piperacillin /tazobactam. However, among those treated by piperacillin/tazobactam, the mortality rate of those infected by the isolates with lower piperacillin/tazobactam MICs (≤0.5/4 mg/L) was lower than that of the isolates with MICs of ≥1/4 mg/L (0%, 0/7 versus 60%, 3/5; P = 0.045). Piperacillin-tazobactam is commonly used to treat infections caused by Pseudomonas aeruginosa. A retrospective cohort study of bacteremic patients showed that in 34 episodes of bacteraemia caused by strains with a MIC of 32 or 64 mg/L piperacillin-tazobactam (i.e. resistant by EUCAST/BSAC criteria), the 30 day mortality was significantly greater than controls given other appropriate therapy PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Tam et al. 2008). A similar study of 39 bacteremic episodes from Spain found a statistically significant reduction in 30 day mortality if the MIC ≤ 2 mg/L than with those with higher MIC. Although the EUCAST breakpoint is 8 mg/L PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJldGFtYXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Retamar et al. 2013).EvidencePiperacillin-tazobactam is effective in blood stream infections due to ESBL-producing bacteria that appear susceptible in vitro. 3RecommendationsPiperacillin-tazobactam can be considered for use in mild-moderate infections (i.e. not severe sepsis) due to ESBL-producing Enterobacteriaceae if supported by susceptibility results.ConditionalPiperacillin-tazobactam can be considered for use in treating infections caused by Pseudomonas aeruginosa of all types of severity based on susceptibility results. However combination with an aminoglycoside is advisable for severe infections. Conditional9.2.1.5 CarbapenemsCarbapenems should be regarded as the drugs of choice for serious infections with ESBL-producing Enterobacteriaceae ADDIN REFMGR.CITE <Refman><Cite><Author>Hawkey</Author><Year>2012</Year><RecNum>3163</RecNum><IDText>Carbapenem antibiotics for serious infections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3163</Ref_ID><Title_Primary>Carbapenem antibiotics for serious infections</Title_Primary><Authors_Primary>Hawkey,P.M.</Authors_Primary><Authors_Primary>Livermore,D.M.</Authors_Primary><Date_Primary>2012/5/31</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>beta-Lactam Resistance</Keywords><Keywords>Carbapenems</Keywords><Keywords>Cephalosporins</Keywords><Keywords>Cost-Benefit Analysis</Keywords><Keywords>drug therapy</Keywords><Keywords>economics</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Medical</Keywords><Keywords>therapeutic use</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>e3236</Start_Page><Periodical>BMJ.</Periodical><Volume>344:e3236. doi: 10.1136/bmj.e3236.</Volume><ZZ_JournalStdAbbrev><f name="System">BMJ.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Hawkey and Livermore 2012). This is based on susceptibility data and increasingly extensive clinical experience.Meropenem was found to be narrowly superior to imipenem-cilastatin in both clinical and bacteriological outcomes in one meta-analysis of 27 randomised controlled trials ADDIN REFMGR.CITE <Refman><Cite><Author>Edwards</Author><Year>2005</Year><RecNum>2544</RecNum><IDText>Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2544</Ref_ID><Title_Primary>Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections</Title_Primary><Authors_Primary>Edwards,S.J.</Authors_Primary><Authors_Primary>Emmas,C.E.</Authors_Primary><Authors_Primary>Campbell,H.E.</Authors_Primary><Date_Primary>2005/5</Date_Primary><Keywords>Adult</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>Cilastatin</Keywords><Keywords>Clinical</Keywords><Keywords>Comparative Study</Keywords><Keywords>drug therapy</Keywords><Keywords>Drug Therapy,Combination</Keywords><Keywords>Humans</Keywords><Keywords>Imipenem</Keywords><Keywords>Infection</Keywords><Keywords>mortality</Keywords><Keywords>Patients</Keywords><Keywords>Protease Inhibitors</Keywords><Keywords>Randomized Controlled Trials</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Research</Keywords><Keywords>Risk</Keywords><Keywords>Selection</Keywords><Keywords>therapeutic use</Keywords><Keywords>Thienamycins</Keywords><Reprint>Not in File</Reprint><Start_Page>785</Start_Page><End_Page>794</End_Page><Periodical>Curr.Med.Res.Opin.</Periodical><Volume>21</Volume><Issue>5</Issue><Address>Outcomes Research Department, AstraZeneca UK Ltd, Luton, Bedfordshire, UK. steven.j.edwards@</Address><Web_URL>PM:15969878</Web_URL><ZZ_JournalStdAbbrev><f name="System">Curr.Med.Res.Opin.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Edwards et al. 2005). The clinical response rates (complete remission or improvement in signs and symptoms of sepsis) for meropenem and imipenem were 91.4% and 87.2%, whereas bacteriological response rates were 85.1% and 82.8% respectively. There was no significant difference in mortality in the nine trials reporting data (7.4% for meropenem, 9.7% for imipenem).Meropenem and imipenem (sometimes referred to as ‘Group 2’ carbapenems, based upon activity against Gram-negative non-formentative bacteria) are typically preferred for the treatment of bloodstream infections (often arising from the urinary tract) because of the broader spectrum than ertapenem (see below). The use of imipenem/meropenem selects for carbapenem-resistant Gram-negative organisms including Acinetobacter baumannii and Pseudomonas aeruginosa PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkt1bzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Kuo et al. 2012) ADDIN REFMGR.CITE <Refman><Cite><Author>McDougall</Author><Year>2013</Year><RecNum>3164</RecNum><IDText>Association of ertapenem and antipseudomonal carbapenem usage and carbapenem resistance in Pseudomonas aeruginosa among 12 hospitals in Queensland, Australia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3164</Ref_ID><Title_Primary>Association of ertapenem and antipseudomonal carbapenem usage and carbapenem resistance in Pseudomonas aeruginosa among 12 hospitals in Queensland, Australia</Title_Primary><Authors_Primary>McDougall,D.A.</Authors_Primary><Authors_Primary>Morton,A.P.</Authors_Primary><Authors_Primary>Playford,E.G.</Authors_Primary><Date_Primary>2013/2</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Australia</Keywords><Keywords>beta-Lactam Resistance</Keywords><Keywords>beta-Lactams</Keywords><Keywords>Carbapenems</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Utilization</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>Humans</Keywords><Keywords>Information Systems</Keywords><Keywords>isolation & purification</Keywords><Keywords>Laboratories</Keywords><Keywords>methods</Keywords><Keywords>Models</Keywords><Keywords>Pharmacies</Keywords><Keywords>Prevalence</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>Queensland</Keywords><Keywords>Software</Keywords><Keywords>statistics & numerical data</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>457</Start_Page><End_Page>460</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>68</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(McDougall et al. 2013). Whilst both imipenem and meropenem have a similar spectra of activity, use of imipenem has declined and meropenem is the most widely prescribed carbapenem in the UK (Hawkey & Livermore, 2012). They are the drugs of choice for the empirical therapy of patients with serious sepsis caused by Gram-negative bacteria, depending on local resistance rates. Widespread usage particularly internationally, has driven the emergence of resistance and considered usage is essential. Emergence of resistance during treatment of infections caused by P. aeruginosa with imipenem is well recognizedand this species is now more commonly resistant to carbapenems than to ceftazidime. .Ertapenem is licensed in Europe for the treatment of intra-abdominal and gynaecological infections and community-acquired pneumonia. In the rest of the world, including in the USA, it is also licensed for skin and skin structure infections and for complicated urinary tract infections (for which it is widely used ‘off-label’ in the UK). Ertapenem shares the broad spectrum of imipenem and meropenem against Enterobacteriaceae, Gram-positive species and anaerobes, but is less active against non-fermenters ADDIN REFMGR.CITE <Refman><Cite><Author>Livermore</Author><Year>2003</Year><RecNum>2217</RecNum><IDText>Properties and potential of ertapenem</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2217</Ref_ID><Title_Primary>Properties and potential of ertapenem</Title_Primary><Authors_Primary>Livermore,D.M.</Authors_Primary><Authors_Primary>Sefton,A.M.</Authors_Primary><Authors_Primary>Scott,G.M.</Authors_Primary><Date_Primary>2003/9</Date_Primary><Keywords>Bacteria</Keywords><Keywords>Bacterial</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>beta-Lactams</Keywords><Keywords>Carbapenems</Keywords><Keywords>Ceftriaxone</Keywords><Keywords>Cephalosporinase</Keywords><Keywords>Clinical Trials as Topic</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance</Keywords><Keywords>drug therapy</Keywords><Keywords>Ecology</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enzymes</Keywords><Keywords>Half-Life</Keywords><Keywords>Humans</Keywords><Keywords>Imipenem</Keywords><Keywords>Infection</Keywords><Keywords>Laboratories</Keywords><Keywords>Lactams</Keywords><Keywords>London</Keywords><Keywords>pharmacokinetics</Keywords><Keywords>pharmacology</Keywords><Keywords>Pneumonia</Keywords><Keywords>Public Health</Keywords><Keywords>Skin</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>331</Start_Page><End_Page>344</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>52</Volume><Address>Antibiotic Resistance Monitoring & Reference Laboratory, Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT. david.livermore@.ukFAU - Livermore, David M</Address><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Livermore et al. 2003) and is sometimes called a Group 1 carbapenem on this basis. 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ADDIN EN.CITE.DATA (Collins et al. 2012). A retrospective study in Taiwan evaluated 251 patients with bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates treated by a carbapenem PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Lee et al. 2012). Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MIC ≤0.5 mg/L EUCAST) were 83.8% and 76.4%, respectively and those to meropenem were 100% and 99.3%. Sepsis-related mortality was 5.3% in those patients infected with an ertapenem-susceptible isolate versus 33% for an ertapenem non-susceptible isolate. A recently published multinational retrospective cohort study of 195 patients given empirical carbapenem and 509 given targeted therapy for bloodstream infections with ESBL producing Enterobacteriaceae found ertapenem to be equivalent to other carbapenems PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkd1dGllcnJlei1HdXRpZXJyZXo8L0F1dGhvcj48WWVhcj4y
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ADDIN EN.CITE.DATA (Gutierrez-Gutierrez et al. 2016). The authors recognized that as in other similar studies ertapenem was more frequently used in lower risk patients and that more studies are needed in the severely ill patient populations.Resistance (MIC>1mg/L EUCAST) and high-level resistant (MIC>16mg/L) to ertapenem in Klebsiella spp. and Enterobacter spp. has been well recognised in Klebsiella spp. and Enterobacter spp. PFJlZm1hbj48Q2l0ZT48QXV0aG9yPldvb2Rmb3JkPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA (Woodford et al. 2007). Imipenem and meropenem were active (geometric mean MICs <2 mg/L) against most isolates with low-level ertapenem resistance but were less active against highly ertapenem-resistant isolates. Most of this resistance which precedes the spread of carbapenemases is thought to be due to combinations of a β-lactamase (often a CTX-M ESBL in Klebsiella spp.) or an AmpC enzyme in Enterobacter spp. plus impermeability and/or increased efflux. This view is supported by an in vitro study showing the frequent emergence of this type of resistance in ESBL E. coli in a pharmacokinetic model PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbmdkZW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Tangden et al. 2013). In a survey of UK isolates in 2007 only one of 95 ertapenem-resistant isolates of Klebsiella pneumoniae produced a defined carbapenemase, namely IMP-1 (Woodford et al. 2007). However, this situation has changed radically with KPC, OXA-48 and NDM are enzymes now regularly encountered in the UK PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkphaW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Jain et al. 2014;Thomas et al. 2013;Woodford et al. 2007) . A retrospective case-control study from the Eastern USA found that risk factors for infection caused by ertapenem-resistant Enterobacteriaceae included exposure to any antibiotic (not just β-lactams and carbapenems) during the 30 days before a positive culture result, PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkh5bGU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Teo et al. 2012).The use of ertapenem usually appears to have no detrimental effect on selecting for Pseudomonas aeruginosa ADDIN REFMGR.CITE <Refman><Cite><Author>Nicolau</Author><Year>2012</Year><RecNum>3094</RecNum><IDText>Carbapenem stewardship: does ertapenem affect Pseudomonas susceptibility to other carbapenems? A review of the evidence</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3094</Ref_ID><Title_Primary>Carbapenem stewardship: does ertapenem affect Pseudomonas susceptibility to other carbapenems? A review of the evidence</Title_Primary><Authors_Primary>Nicolau,D.P.</Authors_Primary><Authors_Primary>Carmeli,Y.</Authors_Primary><Authors_Primary>Crank,C.W.</Authors_Primary><Authors_Primary>Goff,D.A.</Authors_Primary><Authors_Primary>Graber,C.J.</Authors_Primary><Authors_Primary>Lima,A.L.</Authors_Primary><Authors_Primary>Goldstein,E.J.</Authors_Primary><Date_Primary>2012/1</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>beta-Lactams</Keywords><Keywords>Carbapenems</Keywords><Keywords>Clinical</Keywords><Keywords>Clinical Trials as Topic</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Interactions</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Imipenem</Keywords><Keywords>Infection</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>Patients</Keywords><Keywords>pharmacology</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>Pseudomonas Infections</Keywords><Keywords>Research</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>11</Start_Page><End_Page>15</End_Page><Periodical>Int.J.Antimicrob.Agents.</Periodical><Volume>39</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Int.J.Antimicrob.Agents.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Nicolau et al. 2012). Results from ten clinical studies showed that use of ertapenem did not result in decreased susceptibility to carbapenems in Pseudomonas. A further study found that use of ertapenem was directly associated with less use of imipenem and ciprofloxacin, which may have contributed to improve the susceptibility of P. aeruginosa to imipenem. However increasing consumption of ertapenem was associated with a rising incidence density of carbapenem-resistant P. aeruginosa in Singapore (Lim 2013). Interestingly, ertapenem use had no impact on the susceptibility of A. baumannii to imipenem PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNvdXNhPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Sousa et al. 2013).EvidenceCarbapenems are drug of choice for treatment of serious ESBL infection 1+Ertapenem treatment is associated with emergence of resistance when treating infections due to Klebsiella spp and Enterobacter spp. 3RecommendationsCarbapenems should be used to treat serious ESBL-producing Gram-negative infections subject to antibiotic stewardship to minimize the risk of developing resistance StrongErtapenem is effective in treatment of infections with multi-resistant Enterobacteriaceae apart from carbapenemase producers. StrongIn view of the once daily dosing regimen, ertapenem should be preferred for outpatient antibiotic treatment (OPAT) Conditional9.2.1.6Ceftazidime and CefepimeCeftazidimeObservational studies of ceftazidime-susceptible ESBL-producing E. coli and Klebsiella spp. infections treated with ceftazidime frequently show treatment failure, mainly during bacteraemias PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkthbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Kang et al. 2014). Ceftazidime retains activity against many isolates of Pseudomonas aeruginosa.EvidenceCeftazidime is usually ineffective in treating multiresistant Gram-negative infections except Pseudomonas aeruginosa 3RecommendationsAlthough it retains good efficacy against infections with Pseudomonas aeruginosa, ceftazidime is not recommended for the treatment of other serious infections due to ESBL / AmpC producing Enterobacteriaceae, even if in vitro tests suggest the isolate is susceptible. ConditionalCefepime Cefepime may appear to be active in vitro against ESBL-producing Enterobacteriaceae. However, a failure rate of 83% was noted in a prospective trial to determine the outcome of cephalosporin treatment for serious infections due to ESBL-producing Klebsiella spp. and E. coli PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhdGVyc29uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA (Paterson et al. 2001). A retrospective, case-controlled study compared the clinical and microbiologic responses of patients receiving cefepime for infections due to ESBL-producing Klebsiella spp. and E. coli from a non-urine source with matched controls receiving cefepime for non-ESBL strains. Identification of ESBL production was by Etest, specific ESBL genes were not identified. Ten patients receiving cefepime for ESBLs were matched to 20 controls. Four had strains that were reistant to cefepime by broth microdilution MIC, one of which responded . The remaining six patients had susceptible strains and treatment failed in three (NCCLS breakpoint MIC ≤8mg/L). Patients receiving cefepime for an ESBL infection were 9.7 times as likely to have an unsuccessful clinical and microbiological response compared with those with a non-ESBL infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPktvdGFwYXRpPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (Kotapati et al. 2005). A randomised evaluator-controlled trial of ICU patients compared cefepime with imipenem for the treatment of hospital acquired pneumonia. The failure rate was 31% in the cefepime group compared to 0% in the imipenem group ADDIN REFMGR.CITE <Refman><Cite><Author>Zanetti</Author><Year>2003</Year><RecNum>407</RecNum><IDText>Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>407</Ref_ID><Title_Primary>Cefepime versus imipenem-cilastatin for treatment of nosocomial pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective, randomized study</Title_Primary><Authors_Primary>Zanetti,G.</Authors_Primary><Authors_Primary>Bally,F.</Authors_Primary><Authors_Primary>Greub,G.</Authors_Primary><Authors_Primary>Garbino,J.</Authors_Primary><Authors_Primary>Kinge,T.</Authors_Primary><Authors_Primary>Lew,D.</Authors_Primary><Authors_Primary>Romand,J.A.</Authors_Primary><Authors_Primary>Bille,J.</Authors_Primary><Authors_Primary>Aymon,D.</Authors_Primary><Authors_Primary>Stratchounski,L.</Authors_Primary><Authors_Primary>Krawczyk,L.</Authors_Primary><Authors_Primary>Rubinstein,E.</Authors_Primary><Authors_Primary>Schaller,M.D.</Authors_Primary><Authors_Primary>Chiolero,R.</Authors_Primary><Authors_Primary>Glauser,M.P.</Authors_Primary><Authors_Primary>Cometta,A.</Authors_Primary><Date_Primary>2003/11</Date_Primary><Keywords>analysis</Keywords><Keywords>Imipenem</Keywords><Keywords>Intensive Care</Keywords><Keywords>microbiology</Keywords><Keywords>mortality</Keywords><Keywords>Multivariate Analysis</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Pneumonia</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>3442</Start_Page><End_Page>3447</End_Page><Periodical>Antimicrob.Agents Chemother.</Periodical><Volume>47</Volume><Issue>11</Issue><ZZ_JournalStdAbbrev><f name="System">Antimicrob.Agents Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Zanetti et al. 2003). One hundred and forty-five patients with bacteraemia due to ESBL-producing pathogens were retrospectively studied. Sixty-nine received cefepime-containing regimens and 44 received carbapenem-containing regimens. Receipt of empirical cefepime alone (n=43) was associated with increased mortality, although this association did not reach statistical significance PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNob3ByYTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Chopra et al. 2012). Another retrospective case-control study of cefepime-susceptible bacteraemia caused by ESBL producers compared 30 day mortality amongst 17 patients treated with cefepime versus 161 cases treated with a carbapenem PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Lee et al. 2013). Mortality in the cefepime group was 58.8% versus 16.8% of carbapenem treatment and, in multi variate analysis cefepime was strongly associated with mortality (OR, 9.9; 95% CI, 2.8-319; p 0.001). In order to maximise cefepime use and spare carbapenems the concept of susceptible dose dependent isolates of Enterobacteriaceae has been suggested by CLSI. A recent systematic review did not support the use of cefepime in empirical therapy of critically-ill patients when ESBL E coli or ESBL Klebsiella infection is suspected. Evenin patients with ESBL strains. Susceptible to cefepime (≤2mg/l CLSI; < 1mg/L EUCAST), treatment failure can be seen ADDIN REFMGR.CITE <Refman><Cite><Author>Nguyen</Author><Year>2014</Year><RecNum>3359</RecNum><IDText>Determining a clinical framework for use of cefepime and beta-lactam/beta-lactamase inhibitors in the treatment of infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3359</Ref_ID><Title_Primary>Determining a clinical framework for use of cefepime and beta-lactam/beta-lactamase inhibitors in the treatment of infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae</Title_Primary><Authors_Primary>Nguyen,H.M.</Authors_Primary><Authors_Primary>Shier,K.L.</Authors_Primary><Authors_Primary>Graber,C.J.</Authors_Primary><Date_Primary>2014/4</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteria</Keywords><Keywords>beta-Lactamase Inhibitors</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Cephalosporins</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>drug therapy</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Enzyme Inhibitors</Keywords><Keywords>enzymology</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Laboratories</Keywords><Keywords>microbiology</Keywords><Keywords>secretion</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Treatment Outcome</Keywords><Reprint>Not in File</Reprint><Start_Page>871</Start_Page><End_Page>880</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>69</Volume><Issue>4</Issue><Address>Northwest Permanente, Portland, OR, USA</Address><Web_URL>PM:24265230</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Nguyen et al. 2014). However, in a retrospective study of 305 adults with monomicrobial Enterobacter cloacae infections, those infected with cefepime susceptible dose-dependent isolates (MIC 4-8 mg/L) and treated with cefepime had significantly higher mortality than those treated with carbapenem 71.4% v 18.2% (= 0.045) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Lee et al. 2015). Mortality was not reduced even when high dose regimens (2g 8h iv) had been used EvidenceCefepime has a higher failure rate in treatment of infections due to ESBL and Amp C producing Gram -egative bacteria than carbapenems 2+RecommendationsCefepime should not be used for treating infection caused by ESBL, Amp C and carbapenemase-producing Enterobacteriaceae. Strong negative 9.2.1.7 Ceftazidime/avibactamCeftazidime has recently been combined with the β-lactamase inhibitor avibactam. This combination has broad Gram-negative activity including Enterobacteriaceae and P. aeruginosa, including the entire spectrum of ceftazidime, but avibactam protecting against class A (TEM, SHV, CTX-M, KPC) class C (AmpC) and some class D (OXA) β-lactamases PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNoYWxob3ViPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA (Chalhoub et al. 2015;Coleman et al. 2014;Crandon et al. 2012;Flamm et al. 2014;Sader et al. 2015). Avibactam has no inhibitory activity against the metallo-β-lactamases (NDM-1, IMP and VIM) but it is the first β-lactam/β-lactamase inhibitor to retain activity against KPC carbapenemase-producing isolates. It has minimal activity against Acinetobacter spp. anaerobic or Gram-positive organisms PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5TYWRlcjwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Citron et al. 2011;Sader et al. 2014a;Sader et al. 2015). A recent susceptibility study that included 120 KPC-producing Enterobacteriaceae collected from US hospitals demonstrated that ceftazidime/avibactam retained its activity with MIC50/90 values of 0.5/2mg/L PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNhc3RhbmhlaXJhPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh
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ADDIN EN.CITE.DATA (Wang et al. 2014)In phase II double-blind randomized trials , efficacy (combined with metronidazole) was similar to meropenem in treatment of intra-abdominal infection, 91.2% (62/68) and 93.4% (71/76) of patients (Vazquez 2012). Efficacy was similar to imipenem in treating complicated urinary infection (Lucasti 2013). It is not yet available in UK. EvidenceCeftazidime-avibactam has similar efficacy to carbapenems in abdominal and urinary infection 1+RecommendationWith the exception of infections with metallo-β-lactamase strains, ceftazidime-avibactam, when available, should be used as alternative treatment to carbapenems. Strong 9.2.1.8 Ceftolozane/tazobactamCeftolozane is an oxyimino cephalosporin that has been combined with tazobactam. Ceftolozane/tazobactam is licensed for complicated intra-abdominal infection and complicated urinary tract infection. Ceftolozane / tazobactam is active against many Gram-negative organisms, including Enterobacteriaceae and P. aeruginosa PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5GYXJyZWxsPC9BdXRob3I+PFll
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ADDIN EN.CITE.DATA (Farrell et al. 2013 2013) Sader et al. 2012; Sader et al. 2014). It has shown activity against P. aeruginosa isolates resistant to standard agents. Ceftolozane/tazobactam was active against 310 multidrug resistant isolates of Pseudomonas aeruginosa with MIC50/90 values of 2/8mg/L (Farrell et al. 2013). Activity against Acinetobacter spp. is variable PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5TYWRlcjwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Sader et al. 2014a). Tazobactam protects ceftolozane against most ESBL PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNhZGVyPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Solomkin et al. 2015). Non-inferiority was demonstrated overall and MIC was not related to outcome. However, only 50 patients had an ESBL identified. In these patients, the clinical cure rate was 95.8% (23/24) in the ceftolozane/tazobactam plus metronidazole group and 88.5% (23/26) in the meropenem group. In patients with CTX-M-14/15 ESBL-producing Enterobacteriaceae, clinical cure was observed in 13 of 13 (100%) and 8 of 11 (72.7%) patients, respectively.Another study compared ceftolozane/tazobactam against levofloxacin in 1083 patients with complicated urinary infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPldhZ2VubGVobmVyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh
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ADDIN EN.CITE.DATA (Wagenlehner et al. 2015). Patients were randomised to receive ceftolozane /tazobactam (1.5g iv 8h) or levofloxacin (750mg od iv). The majority of participants (82%) had pyelonephritis. Overall, ceftolozane/tazobactam was found to be non-inferior in clinical and superior in microbiological outcome to levofloxacin therapy ADDIN REFMGR.CITE <Refman><Cite><Author>Scott</Author><Year>2016</Year><RecNum>3475</RecNum><IDText>Ceftolozane/Tazobactam: A Review in Complicated Intra-Abdominal and Urinary Tract Infections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3475</Ref_ID><Title_Primary>Ceftolozane/Tazobactam: A Review in Complicated Intra-Abdominal and Urinary Tract Infections</Title_Primary><Authors_Primary>Scott,L.J.</Authors_Primary><Date_Primary>2016/2</Date_Primary><Keywords>Adult</Keywords><Keywords>analysis</Keywords><Keywords>beta-Lactams</Keywords><Keywords>Clinical</Keywords><Keywords>Combination</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>Intraabdominal Infections</Keywords><Keywords>Levofloxacin</Keywords><Keywords>Metronidazole</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>New Zealand</Keywords><Keywords>Patients</Keywords><Keywords>Prevalence</Keywords><Keywords>Private</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>Pyelonephritis</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>231</Start_Page><End_Page>242</End_Page><Periodical>Drugs</Periodical><Volume>76</Volume><Issue>2</Issue><Address>Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand. demail@</Address><Web_URL>PM:26746849</Web_URL><ZZ_JournalStdAbbrev><f name="System">Drugs</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Scott 2016). Baseline susceptibility testing to study drugs showed that in the microbiological intention to treat population, 20 (2·7%) of 731 Gram-negative pathogens at baseline were resistant to ceftolozane-tazobactam, whereas 195 (26·7%) of 731 were resistant to levofloxacin. Two (0·3%) of 594 of E. coli isolates were resistant to ceftolozane-tazobactam and 144 (24·2%) of 594 were resistant to levofloxacin. Clinical cure was seen in 90 (90·0%) of 100 patients in the ceftolozane-tazobactam group compared with 86 (76·8%) of 112 in the levofloxacin group with levofloxacin-resistant uropathogens, and in 55 (90·2%) of 61 compared with 42 (73·7%) of 57 for patients with ESBL-producing uropathogens (95% CI 2·6–30·2).EvidenceCeftolozane/tazobactam is not active against carbapenemase-producing strains but otherwise is non-inferior to meropenem in intra abdominal infection and levofloxacin in complicated urinary infection. 1+Ceftolozane/tazobactam is the most active β-lactam against Pseudomonas aeruginosa 3RecommendationsCeftolozane-tazobactam should be used as alternative treatment to carbapenems in treating ESBL-producing Gram negative pathogens (but not carbapenemase producers). Strong 9.2.1.9 PolymyxinsThe polymyxins are a group of five chemically different bactericidal antibiotics (polymyxins A to E). Only polymyxin B and polymyxin E (colistin) have been used in clinical practice. Intravenously administered colistin methane sulphonate is most widely used, and requires conversion in the body to the native molecule. Polymyxins have a wide spectrum of activity against Gram-negative organisms, including most Enterobacteriaceae, A. baumannii, P. aeruginosa and S. maltophilia, but are inactive against B. cepacia, Proteus spp., Providencia spp., Morganella spp. and Serratia marcescens. Resistance to colistin in P. aeruginosa isolates has been reported from the USA and elsewhere ADDIN REFMGR.CITE <Refman><Cite><Author>Landman</Author><Year>2005</Year><RecNum>3129</RecNum><IDText>Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3129</Ref_ID><Title_Primary>Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B</Title_Primary><Authors_Primary>Landman,D.</Authors_Primary><Authors_Primary>Bratu,S.</Authors_Primary><Authors_Primary>Alam,M.</Authors_Primary><Authors_Primary>Quale,J.</Authors_Primary><Date_Primary>2005/6</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>Bacteria</Keywords><Keywords>Clinical</Keywords><Keywords>Combination</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>Humans</Keywords><Keywords>Imipenem</Keywords><Keywords>In Vitro</Keywords><Keywords>Medical</Keywords><Keywords>methods</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>Multiple</Keywords><Keywords>pharmacology</Keywords><Keywords>Polymyxin B</Keywords><Keywords>Prevalence</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>Ribotyping</Keywords><Reprint>Not in File</Reprint><Start_Page>954</Start_Page><End_Page>957</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>55</Volume><Issue>6</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Landman et al. 2005)but remains rare and almost exclusive to cystic fibrosis isolates. 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ADDIN EN.CITE.DATA (Li et al. 2006). This may be related to exposure to suboptimal polymyxin concentrations. Detection can be difficult and requires obtaining an MIC either by broth microdilution or Etest?; disc diffusion and VITEK2 are unreliable ADDIN REFMGR.CITE <Refman><Cite><Author>Maalej</Author><Year>2011</Year><RecNum>3356</RecNum><IDText>Comparison of disc diffusion, Etest and agar dilution for susceptibility testing of colistin against Enterobacteriaceae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3356</Ref_ID><Title_Primary>Comparison of disc diffusion, Etest and agar dilution for susceptibility testing of colistin against Enterobacteriaceae</Title_Primary><Authors_Primary>Maalej,S.M.</Authors_Primary><Authors_Primary>Meziou,M.R.</Authors_Primary><Authors_Primary>Rhimi,F.M.</Authors_Primary><Authors_Primary>Hammami,A.</Authors_Primary><Date_Primary>2011/11</Date_Primary><Keywords>Agar</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>chemistry</Keywords><Keywords>Clinical</Keywords><Keywords>Colistin</Keywords><Keywords>Comparative Study</Keywords><Keywords>Diffusion</Keywords><Keywords>Disk Diffusion Antimicrobial Tests</Keywords><Keywords>drug effects</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>growth & development</Keywords><Keywords>Humans</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Laboratories</Keywords><Keywords>methods</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>pharmacology</Keywords><Keywords>standards</Keywords><Keywords>Tunisia</Keywords><Reprint>Not in File</Reprint><Start_Page>546</Start_Page><End_Page>551</End_Page><Periodical>Lett.Appl.Microbiol.</Periodical><Volume>53</Volume><Issue>5</Issue><Address>Laboratoire de Microbiologie CHU Habib Bourguiba, Sfax, Tunisia</Address><Web_URL>PM:21895730</Web_URL><ZZ_JournalStdAbbrev><f name="System">Lett.Appl.Microbiol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Maalej et al. 2011). Multiple potential resistance mechanisms exist and are typically chromosomally mediated, involving modulation of two component regulatory systems (e.g. pmrAB, phoPQ and its negative regulator mgrB in the case of K. pneumoniae), leading to modification of lipid A with moieties such as phosphoethanolamine or 4-amino-4-arabinose, or in rare instances total loss of the lipopolysaccharide PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNhbm5hdGVsbGk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy
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ADDIN EN.CITE.DATA (Liu et al. 2015). It is now being detected elsewhere, including in the UK and Europe; it remains much rarer than mutational resistance.Pharmacokinetic and pharmacodynamic data are limited, particularly in critically ill patients. The agents were developed before the advent of contemporary drug development procedures and knowledge of the variation in metabolism of colistin methan sulphonate to active drug. Colistin can be given parenterally, via the aerosol route (typically in patients with CF; either alone or combined with IV administration) or intrathecally.Clinical reports and reviews of experience with colistin are encouraging, with side effects observed less often than expected from historical data PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdhcm5hY2hvLU1vbnRlcm88L0F1dGhvcj48WWVhcj4yMDAz
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ADDIN EN.CITE.DATA (Garnacho-Montero et al. 2003;Levin et al. 1999;Linden et al. 2003;Markou et al. 2003;Michalopoulos et al. 2005;Reina et al. 2005)(Table 3). A high quality randomized trial of treatment of ESBL carriage with oral colistin and neomycin sulphate vs. placebo showed a higher rate of eradfication during treatment (day 6, RR 0.40, 95% CI 0.23-0.70) but not during the follow up period PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkh1dHRuZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Kofteridis et al. 2010). Both had methodological flaws. A recent retrospective cohort study compared 45 patients with P. aeruginosa bacteraemia treated appropriately with polymyxin B versus 88 patients treated with a comparator (typically a β-lactam). The in-hospital mortality was 66% in the arm treated with polymyxin B versus 28% for those treated with a comparator, suggesting polymyxin B is inferior to the comparators usedPFJlZm1hbj48Q2l0ZT48QXV0aG9yPkt2aXRrbzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Kvitko et al. 2011). This was regardless of dosing regimens. A higher dose (≥200mg/day) of polymyxin B was found to be associated with reduced mortality but increased renal impairment in another retrospective cohort study PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkVsaWFzPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Lee and Burgess 2012;Tumbarello et al. 2015). Nephrotoxicity and neurotoxicity are the principal side effects associated with parenteral administration of polymyxins. The toxicity demonstrated in earlier studies was almost certainly related to lack of understanding of its PK/PD and the use of inappropriate doses ADDIN REFMGR.CITE <Refman><Cite><Author>Li</Author><Year>2005</Year><RecNum>3131</RecNum><IDText>Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3131</Ref_ID><Title_Primary>Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria</Title_Primary><Authors_Primary>Li,J.</Authors_Primary><Authors_Primary>Nation,R.L.</Authors_Primary><Authors_Primary>Milne,R.W.</Authors_Primary><Authors_Primary>Turnidge,J.D.</Authors_Primary><Authors_Primary>Coulthard,K.</Authors_Primary><Date_Primary>2005/1</Date_Primary><Keywords>Acinetobacter</Keywords><Keywords>Acinetobacter baumannii</Keywords><Keywords>Aminoglycosides</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Australia</Keywords><Keywords>Bacteria</Keywords><Keywords>chemistry</Keywords><Keywords>Clinical</Keywords><Keywords>Colistin</Keywords><Keywords>Cystic Fibrosis</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Multiple,Bacterial</Keywords><Keywords>Fibrosis</Keywords><Keywords>Gram-Negative Bacteria</Keywords><Keywords>Gram-Negative Bacterial Infections</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>Patients</Keywords><Keywords>Pharmacies</Keywords><Keywords>pharmacokinetics</Keywords><Keywords>pharmacology</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>therapeutic use</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>11</Start_Page><End_Page>25</End_Page><Periodical>Int.J.Antimicrob.Agents.</Periodical><Volume>25</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Int.J.Antimicrob.Agents.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Li et al. 2005). Studies suggest that age, high doses, prolonged courses, concomitant vancomycin, hypoalbuminaemia and non-steroidal anti-inflammatory drugs, were independent risk factors for nephrotoxicity PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkZhbGFnYXM8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Deryke et al. 2010;Falagas et al. 2010;Kim et al. 2009;Rattanaumpawan et al. 2010). Monitoring renal function closely is essential for patients receiving colistin. Recent expert opinon suggests the risk benefit ratio should be carefully considered with strategies applied to reduce toxicity ADDIN REFMGR.CITE <Refman><Cite><Author>Kelesidis</Author><Year>2015</Year><RecNum>3421</RecNum><IDText>The safety of polymyxin antibiotics</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3421</Ref_ID><Title_Primary>The safety of polymyxin antibiotics</Title_Primary><Authors_Primary>Kelesidis,T.</Authors_Primary><Authors_Primary>Falagas,M.E.</Authors_Primary><Date_Primary>2015/11</Date_Primary><Keywords>Antibiotics</Keywords><Keywords>Bacteria</Keywords><Keywords>Boston</Keywords><Keywords>Clinical</Keywords><Keywords>Clinical Trials</Keywords><Keywords>Colistin</Keywords><Keywords>Critical Care</Keywords><Keywords>Drug Monitoring</Keywords><Keywords>Gram-Negative Bacteria</Keywords><Keywords>Greece</Keywords><Keywords>Infectious</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>Polymyxin B</Keywords><Keywords>Polymyxins</Keywords><Keywords>Risk</Keywords><Keywords>Safety</Keywords><Keywords>therapy</Keywords><Keywords>toxicity</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>1687</Start_Page><End_Page>1701</End_Page><Periodical>Expert.Opin.Drug Saf</Periodical><Volume>14</Volume><Issue>11</Issue><Address>a 1 University of California, David Geffen School of Medicine, Division of Infectious Diseases, Department of Medicine , Los Angeles, CA 90095, USA
b 2 Alfa Institute of Biomedical Sciences (AIBS) , 9 Neapoleos Street, 151 23 Marousi, Athens, Greece +30 69 46 11 00 00 ; +30 21 06 83 96 05 ; m.falagas@aibs.gr
c 3 Tufts University School of Medicine, Department of Medicine , Boston, MA, USA</Address><Web_URL>PM:26365594</Web_URL><ZZ_JournalStdAbbrev><f name="System">Expert.Opin.Drug Saf</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Kelesidis and Falagas 2015). There are gaps in our knowledge about these agents. Although they were developed many years ago (1947), they have only been used extensively recently. Much of the current knowledge is summarised in the Prato consensus report PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk5hdGlvbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Dalfino et al. 2012). Further clinical and PK/PD studies are required to determine appropriate dosing regimens including a loading dose, combination therapy and monitoring.EvidenceColistin is effective in treatment of multiresistant gram-negative infections with reduced mortality at high dosage (i.e. 9 MU 12h) 3 Nephrotoxicity is the major adverse effect of the use of colistin 3RecommendationsPolymyxins should be reserved for infections due to multiresistant strains guided by susceptibility testing and preferably used in combination with other agents. ConditionalRenal function must be closely monitored especially in the elderly, for those receiving high doses for prolonged periods and those on concomitant nephrotoxic agents. Strong9.2.1.10 FluoroquinolonesFluoroquinolones (intravenous and oral) may be suitable for complicated urinary tract infections due to ESBL-producing Enterobacteriaceae if there is no resistance in vitro to them, however most ESBL producing strains are resistant to fluoroquinolones. In general, the newer quinolones are unlikely to provide substantial additional benefits over ciprofloxacin. Three observational clinical studies have assessed the relative merits of quinolones and carbapenems for serious infections due to ESBL-producing organisms PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkthbmc8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Endimiani et al. 2004;Kang, Kim, Park, Lee, Kim, Kim, Oh, & Choe 2004). Two of these studies found that carbapenems were superior to quinolones , although susceptible, whereas one of the studies found that they were equivalent in effectiveness PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5FbmRpbWlhbmk8L0F1dGhvcj48
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ADDIN EN.CITE.DATA (Endimiani et al. 2004;Kang et al. 2004). There was no significant difference in cure rate in serious ICU pneumonia between pefloxacin and imipenem given for 12 days PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdpYW1hcmVsbG91PC9BdXRob3I+PFllYXI+MTk5MDwvWWVh
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ADDIN EN.CITE.DATA (Giamarellou et al. 1990). The fluoroquinolones have variable in vitro activity against S. maltophilia, and newer fluoroquinolones, such as moxifloxacin, are more active than older ones, such as ciprofloxacin (MIC90 4mg/L v 16mg/L) ADDIN REFMGR.CITE <Refman><Cite><Author>Weiss</Author><Year>2000</Year><RecNum>3141</RecNum><IDText>Comparative activity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3141</Ref_ID><Title_Primary>Comparative activity of new quinolones against 326 clinical isolates of Stenotrophomonas maltophilia</Title_Primary><Authors_Primary>Weiss,K.</Authors_Primary><Authors_Primary>Restieri,C.</Authors_Primary><Authors_Primary>De,Carolis E.</Authors_Primary><Authors_Primary>Laverdiere,M.</Authors_Primary><Authors_Primary>Guay,H.</Authors_Primary><Date_Primary>2000/3</Date_Primary><Keywords>4-Quinolones</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>Canada</Keywords><Keywords>Ciprofloxacin</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Microbial</Keywords><Keywords>Gram-Negative Bacterial Infections</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>Patients</Keywords><Keywords>pharmacology</Keywords><Keywords>Quebec</Keywords><Keywords>Quinolones</Keywords><Keywords>Respiratory Tract Infections</Keywords><Keywords>Stenotrophomonas maltophilia</Keywords><Keywords>Trimethoprim-Sulfamethoxazole Combination</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>363</Start_Page><End_Page>365</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>45</Volume><Issue>3</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Weiss et al. 2000). Fluoroquinolones have been used to treat infections caused by S. maltophilia; however resistance is not uncommon so combination with one or more of: co-trimoxazole, ceftazidime, and tigecycline have been proposed PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNoYW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Chang et al. 2015). A wide range of resistance mechanisms exist: mutational resistance from to the target-site in of DNA gyrase (GyrA and/or ParC) is almost always involved in high-level resistance, but reduced susceptibility can arise from plasmid acquired genes eg. aac(6’)-1b-cr, qnrA, etc. or via derepression of outer-membrane efflux pumps/porin loss ADDIN REFMGR.CITE <Refman><Cite><Author>Fabrega</Author><Year>2009</Year><RecNum>3295</RecNum><IDText>Mechanism of action of and resistance to quinolones</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3295</Ref_ID><Title_Primary>Mechanism of action of and resistance to quinolones</Title_Primary><Authors_Primary>Fabrega,A.</Authors_Primary><Authors_Primary>Madurga,S.</Authors_Primary><Authors_Primary>Giralt,E.</Authors_Primary><Authors_Primary>Vila,J.</Authors_Primary><Date_Primary>2009/1</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteria</Keywords><Keywords>Bacterial</Keywords><Keywords>Bacterial Proteins</Keywords><Keywords>Dna</Keywords><Keywords>DNA Gyrase</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Enzymes</Keywords><Keywords>Evolution</Keywords><Keywords>Fluoroquinolones</Keywords><Keywords>Gene Expression Regulation,Bacterial</Keywords><Keywords>Genes</Keywords><Keywords>genetics</Keywords><Keywords>Hospital</Keywords><Keywords>metabolism</Keywords><Keywords>microbiology</Keywords><Keywords>Mutation</Keywords><Keywords>Nalidixic Acid</Keywords><Keywords>pharmacology</Keywords><Keywords>Plasmids</Keywords><Keywords>Protein Binding</Keywords><Keywords>Proteins</Keywords><Keywords>Quinolones</Keywords><Keywords>Research</Keywords><Keywords>Selection</Keywords><Keywords>Spain</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>40</Start_Page><End_Page>61</End_Page><Periodical>Microb.Biotechnol.</Periodical><Volume>2</Volume><Issue>1</Issue><User_Def_5>PMC3815421</User_Def_5><Address>Department of Microbiology, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain</Address><Web_URL>PM:21261881</Web_URL><ZZ_JournalStdAbbrev><f name="System">Microb.Biotechnol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Fabrega et al. 2009). EvidenceQuinolones are effective in treatment of complicated urinary tract infection caused by susceptible ESBL- Gram-negative bacteria 3RecommendationFluoroquinolones can be used to treat urinary infection due to multidrug resistant Gram-negative bacteria based on susceptibility results Conditional9.2.1.11 TigecyclineTigecycline is a glycylcycline, a semisynthetic derivative of minocycline and like other tetracyclines, is bacteriostatic. ADDIN REFMGR.CITE <Refman><Cite><Author>Livermore</Author><Year>2005</Year><RecNum>3150</RecNum><IDText>Tigecycline: what is it, and where should it be used?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3150</Ref_ID><Title_Primary>Tigecycline: what is it, and where should it be used?</Title_Primary><Authors_Primary>Livermore,D.M.</Authors_Primary><Date_Primary>2005/10</Date_Primary><Keywords>Acinetobacter</Keywords><Keywords>analogs & derivatives</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Aztreonam</Keywords><Keywords>Bacteria</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>chemistry</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>Gram-Negative Bacteria</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Laboratories</Keywords><Keywords>London</Keywords><Keywords>Minocycline</Keywords><Keywords>Molecular Structure</Keywords><Keywords>pharmacology</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Skin</Keywords><Keywords>Surgical Wound Infection</Keywords><Keywords>Tetracycline</Keywords><Keywords>Tetracyclines</Keywords><Keywords>therapeutic use</Keywords><Keywords>Vancomycin</Keywords><Keywords>Wound Infection</Keywords><Reprint>Not in File</Reprint><Start_Page>611</Start_Page><End_Page>614</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>56</Volume><Issue>4</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Livermore 2005). The main determinants of acquired resistance to older tetracyclines, namely active efflux and ribosomal protection, are overcome by steric hindrance from the large R-group at position 9. Use of tigecycline is an independent predictor of emergence of tigecycline resistance when treating multiresistant Klebsiella pneumoniae infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk5pZ288L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Dean et al. 2003;Visalli et al. 2003). Upregluation of analoguos pumps in other Enterobacteriaceae and A. baumannii can confer resistance in these ordinarily-susceptible groups.Tigecycline is given via the IV route. It is licensed for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJhYmluY2hhazwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA (Babinchak et al. 2005;Ellis-Grosse et al. 2005). However, the US FDA issued a warning describing an increased mortality risk with its use when compared with other drugs (FDA 2010). The highest risk was in patients treated for ventilator-associatied pneumonia which was not a licensed indication. However even in FDSA approved uses there was a higher risk of death among patients given tigecycline compaed with other antibacterial drugs PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbmFzZWFudTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA (Freire et al. 2010;Tanaseanu et al. 2008). One concern expressed is that no randomized controlled trials exist addressing the treatment of Multidrug Resistant Gram-negative pathogens with polymyxins, fosfomycin, sulbactam and other antibiotics, alone or in combinations, and the comparative performance of these antibiotics relative to tigecycline is unclear ADDIN REFMGR.CITE <Refman><Cite><Author>Curcio</Author><Year>2011</Year><RecNum>3143</RecNum><IDText>Tigecycline for severe infections: the gap between the warning and the necessity</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3143</Ref_ID><Title_Primary>Tigecycline for severe infections: the gap between the warning and the necessity</Title_Primary><Authors_Primary>Curcio,D.</Authors_Primary><Date_Primary>2011/2</Date_Primary><Keywords>adverse effects</Keywords><Keywords>analogs & derivatives</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>drug therapy</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Minocycline</Keywords><Keywords>therapeutic use</Keywords><Keywords>United States</Keywords><Keywords>United States Food and Drug Administration</Keywords><Reprint>Not in File</Reprint><Start_Page>454</Start_Page><End_Page>456</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>66</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Curcio 2011). There have been a number of meta-analyses of the efficacy and safety of tigecycline (not confined to MDR Gram negative bacilli) which have reported conflicting findings. A very recent analysis reviews the earlier studies and includes a number of new trials. Clinical success rates were lower than comparator for hospital-acquired pneumonia and diabetic foot infection with increased gastrointestinal adverse events and higher all cause mortality probably due to reduced efficacy PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNoZW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Shen et al. 2015). Further work on tigecycline is needed as its efficacy in ventilator associated pneumonia using higher doses (i.e. 200 mg initial and then 100 mg twice daily) may be improved if an increase in adverse events is not seen. Tigecycline in combination with other antibiotics (e.g. carbapenems and polymyxins) is a potentially valuable approach, as shown by Tumbarello et al. with better outcomes when combined with colistin rather than monotherapy PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlR1bWJhcmVsbG88L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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ADDIN EN.CITE.DATA (Tumbarello et al. 2012). Tigecycline has a propensity to select resistant mutants (e.g. of Acinetobacter spp.) and to favour superinfections by Pseudomonas aeruginosa or Proteeae; these aspects require further investigation. Most tigecycline use for the treatment of infections due to A. baumannii and multidrug resistant Enterobacteriaciae is not a licensed indication. Whilst the in vitro data supports its use, there is poor correlation between this and clinical outcome PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkthcmFnZW9yZ29wb3Vsb3M8L0F1dGhvcj48WWVhcj4yMDA4
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ADDIN EN.CITE.DATA (Gordon and Wareham 2009;Karageorgopoulos et al. 2008;Kelesidis et al. 2008). Whilst tigecycline resistance has been described in treatment na?ve patients, another potential problem concerns the development of resistance during treatment, but the frequency is unclear particularly when used in combination PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBlbGVnPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Gordon & Wareham 2009;Hornsey et al. 2011;Navon-Venezia et al. 2007;Peleg et al. 2007). Further studies are required, possibly including different dosing regimens and in combination with other agents. Tigecycline has in vitro activity against S. maltophilia, and susceptibility rates of >87% to tigecycline have been reported PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNhZmRhcjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Safdar and Rolston 2007). However there is little clinical experience with this agent.EvidenceThe role of tigecycline remains uncertain in the treatment of infections due to Multidrug Resistant Gram-negative organisms1-RecommendationsTigecycline can be used in combination in the treatment of multiresistant soft tissue, intra abdominal, respiratory and bacteremic infections Conditional9.2.1.12Co-trimoxazoleTrimethoprim-sulfamethoxazole (TMP-SMX) (available as intravenous and oral formulations) has the most potent and reliable in vitro activity against S. maltophilia (Safdar and Rolston 2007) and some other non-fermenting Gram-negative bacilli (e.g. members of the genera Achromobacter, Alcaligenes, Burkholderia and Elizabethkingia)PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkplYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Jean et al. 2014). Trimethoprim is not active against the organism but sulphamethoxazole is synergistic. Problems occur with disc susceptibility testing due to trailing endpoints. The mechanism(s) of occasional resistance to TMP-SMX is not well understood in these non-fermenters. Plasmid-mediated resistance due to the presence of the sulI gene has been described for 3 clones of Stenotrophomonas maltophilia that had elevated MICs for TMP-SMX PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJhcmJvbGxhPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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bj4A
ADDIN EN.CITE.DATA (Barbolla et al. 2004). Several β-lactam antibiotics have been reported to have variable activity : against S. maltophilia, including the cephalosporins, ceftazidime and cefepime, and β-lactam /β-lactamase inhibitor combination agents, such as ticarcillin-clavulanate and piperacillin-tazobactam; a complicating factor is that MICs typically are higher on Mueller-Hinton agar than IsoSensitest and it is unclear which better reflects the patient.A recent systematic review suggested that some strains of Acinetobacter spp are susceptible to co-trimoxazole and can be used successfully guided by in vitro testing PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkZhbGFnYXM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Livermore et al. 2014).EvidenceCo-trimoxazole has in vitro activity against Stenotrophomonas maltophilia Achromobacter, Alcaligenes, Burkholderia and Elizabethkingia 3RecommendationCo-trimoxazole should be used in treatment of infections due to Stenotrophomonas maltophilia Conditional9.2.1.13 FosfomycinFosfomycin is used as an oral treatment for patients with urinary infection due to susceptible organisms that are resistant to first line agents. However experience with IV fosfomycin is limited in the UK; however it is more widely used in Europe. It exhibits excellent penetration into tissue after an intravenous dose as it is a small (138 Da), highly hydrophilic phosphonic acid with negligible protein binding; it also has a long half life of between 4 – 8 hours PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhcmtlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Parker et al. 2013). A prospective study of 11 ICU patients with serious infections caused by carbapenem-resistant K. pneumoniae reported a mortality of 18.2%, although 6 patients were also treated with colistin and 3 with gentamicin PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1pY2hhbG9wb3Vsb3M8L0F1dGhvcj48WWVhcj4yMDEwPC9Z
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ADDIN EN.CITE.DATA (Michalopoulos et al. 2010). A larger outcome study of 48 similar patients (mainly VAP) infected with K. pneumoniae and P. aeruginosa reported clinical success in 54.2% patients and 28-day all-cause mortality of 37.5% PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBvbnRpa2lzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA (Pontikis et al. 2014). The use of intravenous fosfomycin has been reviewed extensively by Falagas et al. Clinical cure was described in 1242 of 1529 (81.2%) of patients overall (for both Gram-positive and -negative infections) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkZhbGFnYXM8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Falagas et al. 2008). Most of the Gram-negative infections in this series were due to P. aeruginosa (which is resistant) but also included infections due to Enterobacter spp., Klebsiella spp., E. coli, Proteus spp. and S. typhi; most patients also received concomitant antibiotics. A wide variety of infections were treated and fosfomycin was well tolerated. Despite in vitro resistance to fosfomycin, most patients with infections caused by P. aeruginosa improved. The most frequently encountered side effect is hypokalaemia (26% patients) ADDIN REFMGR.CITE <Refman><Cite><Author>Florent</Author><Year>2011</Year><RecNum>3169</RecNum><IDText>Adverse events associated with intravenous fosfomycin</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3169</Ref_ID><Title_Primary>Adverse events associated with intravenous fosfomycin</Title_Primary><Authors_Primary>Florent,A.</Authors_Primary><Authors_Primary>Chichmanian,R.M.</Authors_Primary><Authors_Primary>Cua,E.</Authors_Primary><Authors_Primary>Pulcini,C.</Authors_Primary><Date_Primary>2011/1</Date_Primary><Keywords>administration & dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Drug-Related Side Effects and Adverse Reactions</Keywords><Keywords>epidemiology</Keywords><Keywords>Fosfomycin</Keywords><Keywords>France</Keywords><Keywords>Humans</Keywords><Keywords>Injections,Intravenous</Keywords><Keywords>Middle Aged</Keywords><Keywords>Prevalence</Keywords><Reprint>Not in File</Reprint><Start_Page>82</Start_Page><End_Page>83</End_Page><Periodical>Int.J.Antimicrob.Agents.</Periodical><Volume>37</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Int.J.Antimicrob.Agents.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Florent et al. 2011). Further detailed studies are required regarding its use for infections outside the urinary tract, especially respiratory tract, in cystic fibrosis and in combination therapyEvidenceFosfomycin is effective and well tolerated in treatment of urinary infection but the oral form can only be used in lower urinary tract infection 3RecommendationFosfomycin should be used in treatment of urinary infection due to multiresistant Gram-negative bacteria (oral administration only suitable for lower urinary infection)Conditional9.2.1.14 AztreonamAztreonam is labile to AmpC and ESBL enzymes; it is stable to metallo-β-lactamases and OXA-48 but most Enterobacteriaceae with these enzymes also express ESBLs or AmpC (PHE 2015). Isolates with MBLs or OXA 48 and no ESBL production may be susceptible (those with OXA-48 alone are likely also to be susceptible to ceftazidime). With EUCAST breakpoints most P. aeruginosa will count as intermediate. In treatment of complicated skin and soft tissue infections, pooled results of double-blind studies suggested aztreonam with vancomycin was non inferior to tigecycline or to ceftaroline. However the majority of pathogens were Gram-positive and therefore susceptible only to the vancomycin component of therapy. There was no separate analysis for MDR Gram negative pathogens PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvcmV5PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Corey et al. 2010;Ellis-Grosse et al. 2005).EvidenceAztreonam is not active against Gram-negative bacteria producing ESBL or AmpC; it is only moderately active against P. aeruginosa.3RecommendationAztreonam should only be used in combination with other agents if resistance or Gram-positive pathogens are suspected ???Conditional9.2.2 Oral agents for secondary/tertiary care treatment9.2.2.1MecillinamPivmecillinam (the oral form of mecillianam) can be considered as oral therapy for lower urinary infection caused by multiresistant Enterobacteriaceae. Patients should be carefully monitored both clinically and microbiologically as the stability of mecillinam to many β-lactamases is poor and treatment failure might be encountered. Mecillinam is described below.9.2.2.2Cefixime Cefixime is an oral third-generation cephalosporin which has been used an oral switch for patients with pyelonephitis. Among uropathogenic enterobacteriaceae, it has less activity than ciprofloxacin against ESBL E.coli but resistance to both was common PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpc3Rpa2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Rezai et al. 2015) EvidenceCefixime does not have reliable activity against multiresistant Gram-negative bacteria 3RecommendationsCefixime should not be used for treating infections caused by ESBL-, Amp-C- or CPE producing Enterobacteriaceae. Conditional9.2.3Treatment of carbapenemase-producers with combination therapyAlthough randomised controlled trials are anticipated, most of the evidence for efficacy of combination therapy for carbapenem-resistant infections derives from observational studies and reports have favoured use in severely-ill patients or those where the pathogen has reduced sensitivity to colistin ADDIN REFMGR.CITE <Refman><Cite><Author>Doi</Author><Year>2015</Year><RecNum>3250</RecNum><IDText>Carbapenemase-producing Enterobacteriaceae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3250</Ref_ID><Title_Primary>Carbapenemase-producing Enterobacteriaceae</Title_Primary><Authors_Primary>Doi,Y.</Authors_Primary><Authors_Primary>Paterson,D.L.</Authors_Primary><Date_Primary>2015/2</Date_Primary><Keywords>Africa</Keywords><Keywords>Asia</Keywords><Keywords>Australia</Keywords><Keywords>beta-Lactams</Keywords><Keywords>Carbapenems</Keywords><Keywords>Clinical</Keywords><Keywords>Colistin</Keywords><Keywords>Combination</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Greece</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Israel</Keywords><Keywords>Italy</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>mortality</Keywords><Keywords>Multiple</Keywords><Keywords>Patients</Keywords><Keywords>Queensland</Keywords><Keywords>Research</Keywords><Keywords>State</Keywords><Keywords>therapy</Keywords><Keywords>United States</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>74</Start_Page><End_Page>84</End_Page><Periodical>Semin.Respir.Crit Care Med.</Periodical><Volume>36</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Semin.Respir.Crit Care Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Doi and Paterson 2015). An international working group report recommended combination including a carbapenem as optimal treatment in settings but only where NDM carbapenemase was infrequent PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxldnk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Levy et al. 2013). However, retrospective studies are liable to bias in that investigators have no control over antibiotic use. Different studies and reviews of combination therapy have reached contradictory conclusions. One systematic review identified that evidence for combination treatment was poor quality, being based on small observational studies with heterogeneity of antibiotic dosage and severity of illness PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhdWw8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Falagas et al. 2014a). In contrast a third systematic review of treatment found mortality at 30 days was lower in patients given combination treatment including polymyxin than with polymyxins alone ADDIN REFMGR.CITE <Refman><Cite><Author>Ni</Author><Year>2015</Year><RecNum>3258</RecNum><IDText>Efficacy of polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3258</Ref_ID><Title_Primary>Efficacy of polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis</Title_Primary><Authors_Primary>Ni,W.</Authors_Primary><Authors_Primary>Cai,X.</Authors_Primary><Authors_Primary>Wei,C.</Authors_Primary><Authors_Primary>Di,X.</Authors_Primary><Authors_Primary>Cui,J.</Authors_Primary><Authors_Primary>Wang,R.</Authors_Primary><Authors_Primary>Liu,Y.</Authors_Primary><Date_Primary>2015/3</Date_Primary><Keywords>China</Keywords><Keywords>Clinical</Keywords><Keywords>Cohort Studies</Keywords><Keywords>Combination</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>Hospital</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>mortality</Keywords><Keywords>Patients</Keywords><Keywords>pharmacology</Keywords><Keywords>Polymyxins</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>170</Start_Page><End_Page>180</End_Page><Periodical>Braz.J.Infect.Dis.</Periodical><Volume>19</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">Braz.J.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Ni et al. 2015). Conclusions from other studies must be interpreted with caution, given methodological limitations. A retrospective cohort study of 661 infections caused by to carbapenemase-producing strains of Klebsiella pneumoniae reported improved survival in patients treated with two or more active drugs versus those given monotherapy ADDIN REFMGR.CITE <Refman><Cite><Author>Tumbarello</Author><Year>2015</Year><RecNum>3264</RecNum><IDText>Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study-authors' response</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3264</Ref_ID><Title_Primary>Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study-authors' response</Title_Primary><Authors_Primary>Tumbarello,M.</Authors_Primary><Authors_Primary>Viale,P.</Authors_Primary><Authors_Primary>Bassetti,M.</Authors_Primary><Authors_Primary>De Rosa,F.G.</Authors_Primary><Authors_Primary>Spanu,T.</Authors_Primary><Authors_Primary>Viscoli,C.</Authors_Primary><Date_Primary>2015/7/13</Date_Primary><Keywords>Hospital</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Italy</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Medical</Keywords><Keywords>microbiology</Keywords><Keywords>mortality</Keywords><Keywords>therapy</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>dkv200</Start_Page><Periodical>J.Antimicrob.Chemother.</Periodical><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Tumbarello, Viale, Bassetti, De Rosa, Spanu, & Viscoli 2015). Mortality was 54.3% with monotherapy and 34.1% with combination. Combinations including tigecycline, colistin and meropenem were associated with the lowest mortality (12.5% OR 0.11 95%CI 0.02-0.69). Use of meropenem was associated with lower mortality if MIC ≤8 mg/l. A review of 20 studies of treatment of carbapenemase-producing Enterobacteriaceae suggested superiority of combination over mono therapy with mortality rates of 27.4% vs 38.7% respectively. Carbapenem-containing regimens had the lowest mortality (18.8%) ADDIN REFMGR.CITE <Refman><Cite><Author>Tzouvelekis</Author><Year>2014</Year><RecNum>3266</RecNum><IDText>Treating infections caused by carbapenemase-producing Enterobacteriaceae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3266</Ref_ID><Title_Primary>Treating infections caused by carbapenemase-producing Enterobacteriaceae</Title_Primary><Authors_Primary>Tzouvelekis,L.S.</Authors_Primary><Authors_Primary>Markogiannakis,A.</Authors_Primary><Authors_Primary>Piperaki,E.</Authors_Primary><Authors_Primary>Souli,M.</Authors_Primary><Authors_Primary>Daikos,G.L.</Authors_Primary><Date_Primary>2014/9</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>Bacterial Proteins</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Clinical</Keywords><Keywords>Combination</Keywords><Keywords>drug therapy</Keywords><Keywords>Drug Therapy,Combination</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Enterobacteriaceae Infections</Keywords><Keywords>enzymology</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>isolation & purification</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>mortality</Keywords><Keywords>Patients</Keywords><Keywords>secretion</Keywords><Keywords>Survival Analysis</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Treatment Outcome</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Reprint>Not in File</Reprint><Start_Page>862</Start_Page><End_Page>872</End_Page><Periodical>Clin.Microbiol.Infect.</Periodical><Volume>20</Volume><Issue>9</Issue><ZZ_JournalStdAbbrev><f name="System">Clin.Microbiol.Infect.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Tzouvelekis et al. 2014). 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ADDIN EN.CITE.DATA (Daikos et al. 2014). Combination therapy was associated with a lower mortality rate of 27% compared with 44% for monotherapy, most marked in the more severe cases. Furthermore, mortality with a carbapenem combination was 19.3% compared to 30.6% without a carbapenem. Anecdotal reports suggest double carbapenem combinations can be effective as last resort treatment with Klebsiella pneumoniae carbapenemase but not withNDM carbapenemase present PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNlY2NhcmVsbGk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy
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ADDIN EN.CITE.DATA (Ceccarelli et al. 2013;Oliva et al. 2014). In cases where the Klebsiella strain was resistant to colistin and carbapenems, use of gentamicin in a combination was independently associated with reduced mortality in a retrospective cohort study ADDIN REFMGR.CITE <Refman><Cite><Author>Gonzalez-Padilla</Author><Year>2015</Year><RecNum>3254</RecNum><IDText>Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3254</Ref_ID><Title_Primary>Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae</Title_Primary><Authors_Primary>Gonzalez-Padilla,M.</Authors_Primary><Authors_Primary>Torre-Cisneros,J.</Authors_Primary><Authors_Primary>Rivera-Espinar,F.</Authors_Primary><Authors_Primary>Pontes-Moreno,A.</Authors_Primary><Authors_Primary>Lopez-Cerero,L.</Authors_Primary><Authors_Primary>Pascual,A.</Authors_Primary><Authors_Primary>Natera,C.</Authors_Primary><Authors_Primary>Rodriguez,M.</Authors_Primary><Authors_Primary>Salcedo,I.</Authors_Primary><Authors_Primary>Rodriguez-Lopez,F.</Authors_Primary><Authors_Primary>Rivero,A.</Authors_Primary><Authors_Primary>Rodriguez-Bano,J.</Authors_Primary><Date_Primary>2015/3</Date_Primary><Keywords>Cohort Studies</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitalization</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Intensive Care</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>Models</Keywords><Keywords>mortality</Keywords><Keywords>Research</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Sepsis</Keywords><Keywords>Spain</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>905</Start_Page><End_Page>913</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>70</Volume><Issue>3</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gonzalez-Padilla et al. 2015). However this was a clonal K. pneumoniae ST512 (CC258) with a KPC enzyme, a lineage that commonly has the gentamicin-sparing AAC(6’)-1b enzyme; it is unlikely to be true for isolates with NDM carbapenemases, which mostly have ribosomal methyltransferases, with resistance to all standard aminoglycosides, including gentamicin Evidence for efficacy of tigecycline in combination largely derives from observational studies but microbiological cure rates are lower than clinical cure rates and mortality rates may be higher ADDIN REFMGR.CITE <Refman><Cite><Author>Tasina</Author><Year>2011</Year><RecNum>3263</RecNum><IDText>Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3263</Ref_ID><Title_Primary>Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis</Title_Primary><Authors_Primary>Tasina,E.</Authors_Primary><Authors_Primary>Haidich,A.B.</Authors_Primary><Authors_Primary>Kokkali,S.</Authors_Primary><Authors_Primary>Arvanitidou,M.</Authors_Primary><Date_Primary>2011/11</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>analogs & derivatives</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteria</Keywords><Keywords>Bacterial</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>Clinical</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>Middle Aged</Keywords><Keywords>Minocycline</Keywords><Keywords>Models</Keywords><Keywords>mortality</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Patients</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Registries</Keywords><Keywords>Safety</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>834</Start_Page><End_Page>844</End_Page><Periodical>Lancet Infect.Dis.</Periodical><Volume>11</Volume><Issue>11</Issue><ZZ_JournalStdAbbrev><f name="System">Lancet Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Tasina et al. 2011). Pooled results from 5 observational studies suggested a clinical response rate of 77% (567/733) for all patients and 81% (329/408) for tigecycline monotherapy in the treatment of complicated intra-abdominal infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkVja21hbm48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Durante-Mangoni et al. 2013). A retrospective study reached a similar conclusion PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJhdGlyZWw8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Batirel et al. 2014). An observational study of 101 patients with multidrug resistant Acinetobacter infections did not show any improvement in mortality rates for combination therapy (e.g. colistin plus tigecycline or carbapenem plus tigecycline) over a single agent (usually colistin) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxvcGV6LUNvcnRlczwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll
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ADDIN EN.CITE.DATA (Lopez-Cortes et al. 2014). In the case of multidrug-resistant Pseudomonas infections a prospective cohort study showed no outcome advantage in combination vs monotherapy PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBlbmE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBlbmE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Pena et al. 2013). Combination therapy did not reduce the development of resistance PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhdWw8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Pontikis et al. 2014). EvidenceThe majority of systematic reviews do not show a benefit of combination therapy over monotherapy. 2++Observational studies suggest combination of meropenem with other agents is associated with a lower mortality than monotherapy. 3In treatment of carbapenem-resistant Enterobacteriaceae infection, polymyxin used in combination with other agents is associated with a lower mortality than polymyxin alone. 1+In treatment of multidrug resistant Acinetobacter infections, addition of rifampicin to colistin does not affect 30 day mortality. 1+ RecommendationWhen a combination of agents is used in the treatment of carbapenem-resistant Enterobacteriacae infections e.g. Klebsiella pneumoniae carbapenemase, a carbapenem should be included with the active agents unless NDM carbapenemase is presentConditionalPolymyxins should be given in combination with other agents if they are used in treating carbapenem-resistant Enterobacteriaceae. Strong9.3What are the recommended antibiotics for community care, including care homes?The majority of infections encountered in the community caused by MDRGNB are urinary tract infections. As described earlier in this report, ESBL-producing Enterobacteriaceae are a significant and growing problem whilst there are much smaller numbers of carbapenemase-producing Enterobacteriaceae. There are no published randomized controlled trials of antibiotic treatment of urinary infections due to ESBL-producing organisms in the community or care homes. Recommendations must rely on observational studies of ESBL-producing Gram-negative organisms, or randomized controlled trials of effectiveness of antibiotics against urinary infections caused by ESBL non -producing Gram-negative organisms in other health settings. In order to help in the assessment of patients we review risk factors for MDRGNB and suitable oral agents for use in acute uncomplicated and complicated UTI.9.3.1 What are the risk factors for patients with urinary infections caused by MDRGNB in the UK?Generally antibiotic resistance in the community is still quite uncommon. A 2008 pan-European study of community-acquired, acute, uncomplicated, non-recurrent urinary infection in unselected women aged 18-65 years involved 12 GP practices in the UK andenrolled 200 patients. Resistance in E coli were low to mecillinam (1%), nitrofurantoin (0%), fosfomycin (0.5%) amoxicillin/clavulanic acid (2.0%) and ciprofloxacin (0.5%), but much higher to amoxicillin (32%), sulfamethoxazole (26%), trimethoprim (15%) and trimethoprim/sulfamethoxazole (14%) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkthaGxtZXRlcjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA (Kahlmeter and Poulsen 2012). Prospective and retrospective epidemiological studies identify a number of risk factors for carriage risk of ESBL E. coli PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJlbi1BbWk8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJlbi1BbWk8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Ben-Ami et al. 2009) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJvb25leTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Anon 10 A.D.;Johnson et al. 2013; 2009; 2010). Patients are at increased risk if they have: ?recurrent urinary infection ?persistent urinary symptoms after initial antibiotic, ?over 7 days hospital admission in the last 6 months, ?residence in a care home?recent travel and especially healthcare in a country with increased antimicrobial resistance (outside North America, Northern Europe and Australasia) ?previous known urinary infection resistant to co-amoxiclav, cephalosporins or quinolones or recent treatment with these agentsEvidenceEmpirical antibiotic choice for lower urinary tract infection can be determined by the presence of established risk factors for a multiresistant organism; 2+ RecommendationMultiresistant organisms do not need to be considered in the empirical treatment of acute uncomplicated urinary infection in younger women without risk factors or recent foreign travelStrong9.3.2 Which oral antibiotics are preferred for use in treating uncomplicated UTIs in the community due to MDRGNB?9.3.2.1TrimethoprimThe combination of trimethoprim with sulfamethoxazole was introduced in 1968; sulphamethoxazole was thought to suppress the development of resistance to trimethoprim. This was shown to be fallacious ADDIN REFMGR.CITE <Refman><Cite><Author>Lacey</Author><Year>1980</Year><RecNum>3241</RecNum><IDText>Comparison of trimethoprim alone with trimethoprim sulphamethoxazole in the treatment of respiratory and urinary infections with particular reference to selection of trimethoprim resistance</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3241</Ref_ID><Title_Primary>Comparison of trimethoprim alone with trimethoprim sulphamethoxazole in the treatment of respiratory and urinary infections with particular reference to selection of trimethoprim resistance</Title_Primary><Authors_Primary>Lacey,R.W.</Authors_Primary><Authors_Primary>Lord,V.L.</Authors_Primary><Authors_Primary>Gunasekera,H.K.</Authors_Primary><Authors_Primary>Leiberman,P.J.</Authors_Primary><Authors_Primary>Luxton,D.E.</Authors_Primary><Date_Primary>1980/6/14</Date_Primary><Keywords>administration & dosage</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Drug Resistance,Microbial</Keywords><Keywords>drug therapy</Keywords><Keywords>Drug Therapy,Combination</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Patients</Keywords><Keywords>Respiratory Tract Infections</Keywords><Keywords>Selection</Keywords><Keywords>Skin</Keywords><Keywords>Sputum</Keywords><Keywords>Sulfamethoxazole</Keywords><Keywords>Trimethoprim</Keywords><Keywords>Trimethoprim Resistance</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>1270</Start_Page><End_Page>1273</End_Page><Periodical>Lancet.</Periodical><Volume>1</Volume><Issue>8181</Issue><ZZ_JournalStdAbbrev><f name="System">Lancet.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Lacey et al. 1980) and the much higher rate of adverse events seen with co-trimoxazole ADDIN REFMGR.CITE <Refman><Cite><Author>Ho</Author><Year>2011</Year><RecNum>3240</RecNum><IDText>Considerations when prescribing trimethoprim-sulfamethoxazole</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3240</Ref_ID><Title_Primary>Considerations when prescribing trimethoprim-sulfamethoxazole</Title_Primary><Authors_Primary>Ho,J.M.</Authors_Primary><Authors_Primary>Juurlink,D.N.</Authors_Primary><Date_Primary>2011/11/8</Date_Primary><Keywords>Abnormalities,Drug-Induced</Keywords><Keywords>adverse effects</Keywords><Keywords>Anti-Infective Agents</Keywords><Keywords>Anticoagulants</Keywords><Keywords>Biomedical Research</Keywords><Keywords>chemically induced</Keywords><Keywords>Clinical</Keywords><Keywords>Cytochrome P-450 Enzyme System</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Eruptions</Keywords><Keywords>Drug Interactions</Keywords><Keywords>Female</Keywords><Keywords>Folic Acid Deficiency</Keywords><Keywords>Hematologic Diseases</Keywords><Keywords>Hemolysis</Keywords><Keywords>Humans</Keywords><Keywords>Hyperkalemia</Keywords><Keywords>Hypoglycemia</Keywords><Keywords>Hypoglycemic Agents</Keywords><Keywords>Immunocompromised Host</Keywords><Keywords>Infant,Small for Gestational Age</Keywords><Keywords>Infant,Newborn</Keywords><Keywords>Kidney</Keywords><Keywords>Nervous System Diseases</Keywords><Keywords>pharmacology</Keywords><Keywords>Pregnancy</Keywords><Keywords>Trimethoprim-Sulfamethoxazole Combination</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Warfarin</Keywords><Reprint>Not in File</Reprint><Start_Page>1851</Start_Page><End_Page>1858</End_Page><Periodical>CMAJ.</Periodical><Volume>183</Volume><Issue>16</Issue><ZZ_JournalStdAbbrev><f name="System">CMAJ.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Ho and Juurlink 2011) was associated with the sulfamethoxazole component. Trimethoprim alone is therefore favoured for treatment except for special situations (e.g. Pneumocystis jiroveci, Toxoplasma gondii and Stenotrophomonas maltophilia). An audit of urine samples taken at presentation from primary and secondary care in South London found that 43.3% of isolates were resistant to amoxicillin, 22.6% were resistant to trimethoprim, and 10.3% were resistant to nitrofurantoin ADDIN REFMGR.CITE <Refman><Cite><Author>Newell</Author><Year>2005</Year><RecNum>3244</RecNum><IDText>Multicentre audit of the treatment of uncomplicated urinary tract infection in South Thames</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3244</Ref_ID><Title_Primary>Multicentre audit of the treatment of uncomplicated urinary tract infection in South Thames</Title_Primary><Authors_Primary>Newell,A.</Authors_Primary><Authors_Primary>Bunting,P.</Authors_Primary><Authors_Primary>Anson,K.</Authors_Primary><Authors_Primary>Fox,E.</Authors_Primary><Date_Primary>2005/1</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteria</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>Cephalexin</Keywords><Keywords>chemistry</Keywords><Keywords>classification</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Great Britain</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>isolation & purification</Keywords><Keywords>London</Keywords><Keywords>Male</Keywords><Keywords>Medical Audit</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>pharmacology</Keywords><Keywords>therapeutic use</Keywords><Keywords>Trimethoprim</Keywords><Keywords>Trimethoprim Resistance</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>74</Start_Page><End_Page>77</End_Page><Periodical>Int.J.STD AIDS.</Periodical><Volume>16</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">Int.J.STD AIDS.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Newell et al. 2005). Since this audit resistance to trimethoprim has slowly risen across the UK, and is significantly higher in patients over 65 years ADDIN REFMGR.CITE <Refman><Cite><Author>Heginbothom</Author><Year>2015</Year><RecNum>3501</RecNum><IDText>A Report from Public Health Wales Antimicrobial Reistance Programme Surveillance Unit: Antibacterial Resistance In Wales 2005-2014.</IDText><MDL Ref_Type="Online Source"><Ref_Type>Online Source</Ref_Type><Ref_ID>3501</Ref_ID><Title_Primary>A Report from Public Health Wales Antimicrobial Reistance Programme Surveillance Unit: Antibacterial Resistance In Wales 2005-2014.</Title_Primary><Authors_Primary>Heginbothom,M</Authors_Primary><Authors_Primary>Howe,R</Authors_Primary><Date_Primary>2015/4/7</Date_Primary><Keywords>Public Health</Keywords><Keywords>Health</Keywords><Keywords>Wales</Keywords><Reprint>Not in File</Reprint><Publisher>GIG CYMRU NHS Wales, lechyd Cyhoeddus Cymru, Public Health Wales</Publisher><Web_URL><u>;(Heginbothom and Howe 2015). 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ADDIN EN.CITE.DATA (Heginbothom et al. 2004). In Wales trimethoprim remains the suggested first-line empirical therapy for most of these patients. Trimethoprim should not be used as empirical treatment for urinary infection if there are risk factors for an antibiotic resistant organism unless susceptibility to trimethoprim has been confirmed in the previous month and there have been no new risk factors for resistance. In the absence of resistance, trimethoprim attains excellent bacteriological cure, two-weeks after completion of treatment, 94% of women using a 3-day course of trimethoprim achieved bacteriological cure compared with 97% of those using a 10-day course of trimethoprim (n =135) ADDIN REFMGR.CITE <Refman><Cite><Author>Gossius</Author><Year>1985</Year><RecNum>3317</RecNum><IDText>The treatment of acute dysuria-frequency syndrome in adult women: Double-blind, randomized comparison of three-day vs ten-day trimethoprim therapy</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3317</Ref_ID><Title_Primary><f name="Cambria">The treatment of acute dysuria-frequency syndrome in adult women: Double-blind, randomized comparison of three-day vs ten-day trimethoprim therapy</f></Title_Primary><Authors_Primary>Gossius,G</Authors_Primary><Authors_Primary>Vorland,L</Authors_Primary><Date_Primary>1985</Date_Primary><Keywords>Adult</Keywords><Keywords>Trimethoprim</Keywords><Reprint>Not in File</Reprint><Start_Page>34</Start_Page><End_Page>42</End_Page><Periodical>Current Therapeutic Research, Clinical & Experimental</Periodical><Volume>37</Volume><ZZ_JournalFull><f name="System">Current Therapeutic Research, Clinical & Experimental</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gossius and Vorland 1985). An open randomised controlled trial in general practice (n = 538) found that 7 days of trimethoprim had equivalent clinical cure rates to co-trimoxazole and nitrofurantoin . The rate of gastrointestinal adverse effects was similar between groups (7-8%) ADDIN REFMGR.CITE <Refman><Cite><Author>Spencer</Author><Year>1994</Year><RecNum>3243</RecNum><IDText>Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3243</Ref_ID><Title_Primary>Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice</Title_Primary><Authors_Primary>Spencer,R.C.</Authors_Primary><Authors_Primary>Moseley,D.J.</Authors_Primary><Authors_Primary>Greensmith,M.J.</Authors_Primary><Date_Primary>1994/5</Date_Primary><Keywords>administration & dosage</Keywords><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>Bacteriology</Keywords><Keywords>Clinical</Keywords><Keywords>Delayed-Action Preparations</Keywords><Keywords>drug therapy</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Family Practice</Keywords><Keywords>Female</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>Patients</Keywords><Keywords>therapeutic use</Keywords><Keywords>Treatment Outcome</Keywords><Keywords>Trimethoprim</Keywords><Keywords>Trimethoprim-Sulfamethoxazole Combination</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>121</Start_Page><End_Page>129</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>33 Suppl A:121-9.</Volume><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Spencer et al. 1994).9.3.2.2NitrofurantoinNitrofurantoin is widely used in the community but attains only low concentrations in renal tissue and the blood stream. It should not be used if pyelonephritis or bacteraemia is suspected and treatment may fail if used for ascending infection ADDIN REFMGR.CITE <Refman><Cite><Author>Oplinger</Author><Year>2013</Year><RecNum>3361</RecNum><IDText>Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3361</Ref_ID><Title_Primary>Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence</Title_Primary><Authors_Primary>Oplinger,M.</Authors_Primary><Authors_Primary>Andrews,C.O.</Authors_Primary><Date_Primary>2013/1</Date_Primary><Keywords>adverse effects</Keywords><Keywords>Anti-Infective Agents</Keywords><Keywords>Anti-Infective Agents,Urinary</Keywords><Keywords>Blood</Keywords><Keywords>Clinical</Keywords><Keywords>Clinical Trials</Keywords><Keywords>complications</Keywords><Keywords>contraindications</Keywords><Keywords>Creatinine</Keywords><Keywords>drug therapy</Keywords><Keywords>Genetic</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Kidney</Keywords><Keywords>Kidney Diseases</Keywords><Keywords>Kidney Function Tests</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>Patients</Keywords><Keywords>Pharmacies</Keywords><Keywords>pharmacokinetics</Keywords><Keywords>pharmacology</Keywords><Keywords>physiopathology</Keywords><Keywords>Risk</Keywords><Keywords>Safety</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>106</Start_Page><End_Page>111</End_Page><Periodical>Ann.Pharmacother.</Periodical><Volume>47</Volume><Issue>1</Issue><Address>Wegmans School of Pharmacy, St. John Fisher College, Rochester, NY, USA</Address><Web_URL>PM:23341159</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann.Pharmacother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Oplinger and Andrews 2013). Furthermore, if a patient has a reduced glomerular filtration rate, urinary concentrations may be inadequate of nitrofurantoin. The 1988 nitrofurantoin modified release product information indicated a creatinine clearance lower limit of 40 mL/min (Norwich Eaton Pharmaceuticals New York USA) but the 2003 information raised the lower threshold to 60 mL/min (Procter & Gamble Co, Ohio, USA). eGFR frequently declines with age, on average by between 6 and 9ml/min/1.73m2 per decade. Around half of women over 75 years and men over 85 years will have an eGFR under 60mL/min/1.73m2. A recent systematic review of the literature (Oplinger and Andrews 2013) considered patients with reduced renal function, and suggested that nitrofurantoin could be used in patients with eGFR of 40mL/min. 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ADDIN EN.CITE.DATA (Geerts et al. 2013). Long term and/or repeated courses of nitrofurantoin are associated with severe pulmonary fibrosis which can be fatal ADDIN REFMGR.CITE <Refman><Cite><Author>Goemaere</Author><Year>2008</Year><RecNum>3414</RecNum><IDText>Nitrofurantoin-induced pulmonary fibrosis: a case report</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3414</Ref_ID><Title_Primary>Nitrofurantoin-induced pulmonary fibrosis: a case report</Title_Primary><Authors_Primary>Goemaere,N.N.</Authors_Primary><Authors_Primary>Grijm,K.</Authors_Primary><Authors_Primary>van Hal,P.T.</Authors_Primary><Authors_Primary>den Bakker,M.A.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>adverse effects</Keywords><Keywords>Autopsy</Keywords><Keywords>Bladder</Keywords><Keywords>Case Report</Keywords><Keywords>Clinical</Keywords><Keywords>Dyspnea</Keywords><Keywords>etiology</Keywords><Keywords>Fibrosis</Keywords><Keywords>history</Keywords><Keywords>Hospital</Keywords><Keywords>Infection</Keywords><Keywords>Lung</Keywords><Keywords>Lung Transplantation</Keywords><Keywords>Medical</Keywords><Keywords>Netherlands</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>pathology</Keywords><Keywords>Patients</Keywords><Keywords>Respiratory Insufficiency</Keywords><Keywords>toxicity</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>169</Start_Page><Periodical>J.Med.Case.Rep.</Periodical><Volume>2</Volume><User_Def_5>PMC2408600</User_Def_5><Address>Departmentof Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, CA, Rotterdam, The Netherlands. n.goemaere@pathan.nl</Address><Web_URL>PM:18495029</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Med.Case.Rep.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Goemaere et al. 2008) Nitrofurantoin is poorly tolerated by some patients, but the modified release form has fewer side effects (Spencer et al. 1994). When used as a modified release format an open randomised controlled trial (n = 538) found that nitrofurantoin had equivalent clinical cure rates to co-trimoxazole and trimethoprim in a group of patients with acute uncomplicated lower UTI (Spencer et al. 1994). The rate of gastrointestinal adverse effects was similar between groups (7-8%). A review and meta-analysis suggested a clinical cure rate almost equivalent to comparators but with a 5 day rather than 3 day course (Huttner et al. 2015). Toxicity was mainly gastrointestinal effects and no pulmonary adverse events were reported though this may be a reflection of short follow up periods PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkh1dHRuZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Huttner et al. 2015). There are no specific studies of nitrofurantoin in urinary infection caused by ESBL producing organisms, but UTIs that are susceptible to nitrofurantoin have a similar response rate irrespective of ESBL production if the patient has an adequate GFR. However ESBL-producing members of the E coli ST131 clone which are common in the UK often have urinary virulence factors that are associated with recurrence and upper UTI and bacteremia PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNoYTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Giske 2015;Karageorgopoulos et al. 2012). Fosfomycin is predominantly eliminated renally and therefore is licensed for the treatment of uncomplicated UTI. After an oral dose, the urinary concentrations of fosfomycin obtained in elderly patients with a mean GFR of 40mL/min exceeded the MIC for the common pathogens of uncomplicated cystitis (E. coli) for at least 48 h. After 24 h concentrations exceeded those reported for healthy young subjects PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkphbmtuZWd0PC9BdXRob3I+PFllYXI+MTk5NDwvWWVhcj48
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ADDIN EN.CITE.DATA (Janknegt et al. 1994). Treatment with fosfomycin trometamol was associated with a clinical success rate (defined as the resolution of symptoms after treatment) between 77.8% and 94.2% in three observational studies of treatment of lower UTI due to multiresistant bacteria. (NICE 2013). A single open study of 38 patients with acute pyelonephritis showed fosfomycin similar efficacy to ampicillin in a 7 day course ADDIN REFMGR.CITE <Refman><Cite><Author>Ode</Author><Year>1988</Year><RecNum>3494</RecNum><IDText>Fosfomycin versus ampicillin in the treatment of acute pyelonephritis</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3494</Ref_ID><Title_Primary>Fosfomycin versus ampicillin in the treatment of acute pyelonephritis</Title_Primary><Authors_Primary>Ode,B.</Authors_Primary><Authors_Primary>Haidl,S.</Authors_Primary><Authors_Primary>Hoffstedt,B.</Authors_Primary><Authors_Primary>Walder,M.</Authors_Primary><Authors_Primary>Ursing,J.</Authors_Primary><Date_Primary>1988/4</Date_Primary><Keywords>Acute Disease</Keywords><Keywords>adverse effects</Keywords><Keywords>Ampicillin</Keywords><Keywords>Clinical</Keywords><Keywords>Comparative Study</Keywords><Keywords>drug therapy</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Infectious</Keywords><Keywords>Patients</Keywords><Keywords>pharmacokinetics</Keywords><Keywords>Pyelonephritis</Keywords><Keywords>Random Allocation</Keywords><Keywords>Research</Keywords><Keywords>Serum</Keywords><Keywords>Sweden</Keywords><Keywords>therapeutic use</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>96</Start_Page><End_Page>100</End_Page><Periodical>Chemioterapia.</Periodical><Volume>7</Volume><Issue>2</Issue><Address>Department of Infectious Diseases, University of Lund, Malmo General Hospital, Sweden</Address><Web_URL>PM:3396118</Web_URL><ZZ_JournalStdAbbrev><f name="System">Chemioterapia.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Ode et al. 1988). Fosfomycin should be administered while fasting or 2 or 3 hours before meals, as food can slow its absorption, leading to lower concentrations in the urine ADDIN REFMGR.CITE <Refman><Cite><Author>Borgia</Author><Year>1989</Year><RecNum>3369</RecNum><IDText>Relative bioavailability of fosfomycin and of trometamol after administration of single dose by oral route of fosfomycin trometamol in fasting conditions and after a meal</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3369</Ref_ID><Title_Primary>Relative bioavailability of fosfomycin and of trometamol after administration of single dose by oral route of fosfomycin trometamol in fasting conditions and after a meal</Title_Primary><Authors_Primary>Borgia,M.</Authors_Primary><Authors_Primary>Longo,A.</Authors_Primary><Authors_Primary>Lodola,E.</Authors_Primary><Date_Primary>1989/8</Date_Primary><Keywords>Administration</Keywords><Keywords>Administration,Oral</Keywords><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>Biological Availability</Keywords><Keywords>Blood</Keywords><Keywords>Food</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Half-Life</Keywords><Keywords>Humans</Keywords><Keywords>Italy</Keywords><Keywords>Middle Aged</Keywords><Keywords>Oral</Keywords><Keywords>pharmacokinetics</Keywords><Keywords>Serum</Keywords><Keywords>Tromethamine</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>411</Start_Page><End_Page>417</End_Page><Periodical>Int.J.Clin.Pharmacol.Ther.Toxicol.</Periodical><Volume>27</Volume><Issue>8</Issue><Address>Ospedale M.O.A. Locatelli, Piario-Bergamo, Italy</Address><Web_URL>PM:2793277</Web_URL><ZZ_JournalStdAbbrev><f name="System">Int.J.Clin.Pharmacol.Ther.Toxicol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Borgia et al. 1989). The emergence of resistance developing during therapy by selection of mutants can occur so monitoring is advisable ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Karageorgopoulos</Author><Year>2012</Year><RecNum>3119</RecNum><IDText>Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens</IDText><Prefix>Karageorgopoulos et al.</Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3119</Ref_ID><Title_Primary>Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens</Title_Primary><Authors_Primary>Karageorgopoulos,D.E.</Authors_Primary><Authors_Primary>Wang,R.</Authors_Primary><Authors_Primary>Yu,X.H.</Authors_Primary><Authors_Primary>Falagas,M.E.</Authors_Primary><Date_Primary>2012/2</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Environment</Keywords><Keywords>Epithelial Cells</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Evolution</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Gram-Negative Bacterial Infections</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>microbiology</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>Mutation</Keywords><Keywords>pharmacology</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Urinary Tract</Keywords><Reprint>Not in File</Reprint><Start_Page>255</Start_Page><End_Page>268</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>67</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Karageorgopoulos et al. 2012). Clinical and in vitro studies suggest resistance is less likely to emerge in urinary tract infections and with infections due to E. coli (rather than P. aeruginosa). In addition to the selection of a variety of mutations in genes encoding the hexose phosphate transport and glycerol permase pathways imparing drug uptake, the acquired fosA gene encodes metalloglutathione transferase resulting in drug inactivation ADDIN REFMGR.CITE <Refman><Cite ExcludeAuth="1"><Author>Karageorgopoulos</Author><Year>2012</Year><RecNum>3119</RecNum><IDText>Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens</IDText><Prefix>Karageorgopoulos et al.</Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3119</Ref_ID><Title_Primary>Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens</Title_Primary><Authors_Primary>Karageorgopoulos,D.E.</Authors_Primary><Authors_Primary>Wang,R.</Authors_Primary><Authors_Primary>Yu,X.H.</Authors_Primary><Authors_Primary>Falagas,M.E.</Authors_Primary><Date_Primary>2012/2</Date_Primary><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Environment</Keywords><Keywords>Epithelial Cells</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Evolution</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Gram-Negative Bacterial Infections</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>microbiology</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>Mutation</Keywords><Keywords>pharmacology</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>Urinary Tract</Keywords><Reprint>Not in File</Reprint><Start_Page>255</Start_Page><End_Page>268</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>67</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Karageorgopoulos et al. 2012). 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ADDIN EN.CITE.DATA (Ho et al. 2013). Oral fosfomycin trometamol was available in the UK between Feb 1994 and 1996 then withdrawn. Nevertheless a survey of resistance in Leeds detected the fosA gene in 2 urinary tract isolates despite it not being used in the study hospital ADDIN REFMGR.CITE <Refman><Cite><Author>Gray</Author><Year>2001</Year><RecNum>15</RecNum><IDText>Transmissible fosfomycin resistance markers in urinary isolates and imported foodstuffs in the UK during 1994 and 1995</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>15</Ref_ID><Title_Primary>Transmissible fosfomycin resistance markers in urinary isolates and imported foodstuffs in the UK during 1994 and 1995</Title_Primary><Authors_Primary>Gray,K.J.</Authors_Primary><Authors_Primary>Gascoyne-Binzi,D.M.</Authors_Primary><Authors_Primary>Nicholson,P.</Authors_Primary><Authors_Primary>Heritage,J.</Authors_Primary><Authors_Primary>Hawkey,P.M.</Authors_Primary><Date_Primary>2001/11</Date_Primary><Keywords>Conjugation,Genetic</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Food Microbiology</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Genetic Markers</Keywords><Keywords>genetics</Keywords><Keywords>Glutathione Transferase</Keywords><Keywords>Gram-Negative Bacteria</Keywords><Keywords>Great Britain</Keywords><Keywords>Human</Keywords><Keywords>isolation & purification</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>744</Start_Page><End_Page>745</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>48</Volume><Issue>5</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gray et al. 2001) and a study of foods in Leeds in 1995 identified 2 isolates of enterobacteriaceae carrying fosA . 9.3.2.4 MecillinamMecillinam is a β-lactam antibiotic that retains activity at breakpoint against some Enterobacteriaceae (including many ESBL and AmpC producers), but innate resistance occurs in Proteus, Morganella, Providencia, some Serratia and Acinetobacter: moreover many SHV ESBLs confer resistance ADDIN REFMGR.CITE <Refman><Cite><Author>Thomas</Author><Year>2006</Year><RecNum>1378</RecNum><IDText>Activity of mecillinam against ESBL producers in vitro</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1378</Ref_ID><Title_Primary>Activity of mecillinam against ESBL producers in vitro</Title_Primary><Authors_Primary>Thomas,K.</Authors_Primary><Authors_Primary>Weinbren,M.J.</Authors_Primary><Authors_Primary>Warner,M.</Authors_Primary><Authors_Primary>Woodford,N.</Authors_Primary><Authors_Primary>Livermore,D.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Amdinocillin</Keywords><Keywords>antagonists & inhibitors</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>Clavulanic Acid</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>Drug Synergism</Keywords><Keywords>Enzyme Inhibitors</Keywords><Keywords>enzymology</Keywords><Keywords>Gram-Negative Bacteria</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>metabolism</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>Penicillins</Keywords><Keywords>pharmacology</Keywords><Reprint>Not in File</Reprint><Start_Page>367</Start_Page><End_Page>368</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>57</Volume><Issue>2</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Thomas et al. 2006). In vitro activity against ESBL-producing Enterobacteriaceae has been demonstrated in a study which showed only 6.2% of cefpodoxime resistant E coli being resistant ADDIN REFMGR.CITE <Refman><Cite><Author>Wootton</Author><Year>2010</Year><RecNum>3104</RecNum><IDText>Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3104</Ref_ID><Title_Primary>Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins</Title_Primary><Authors_Primary>Wootton,M.</Authors_Primary><Authors_Primary>Walsh,T.R.</Authors_Primary><Authors_Primary>Macfarlane,L.</Authors_Primary><Authors_Primary>Howe,R.A.</Authors_Primary><Date_Primary>2010/1</Date_Primary><Keywords>Agar</Keywords><Keywords>Amdinocillin</Keywords><Keywords>Amoxicillin</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>beta-Lactamases</Keywords><Keywords>biosynthesis</Keywords><Keywords>Cefotaxime</Keywords><Keywords>Cephalosporins</Keywords><Keywords>Ciprofloxacin</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>enzymology</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Escherichia coli Infections</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>isolation & purification</Keywords><Keywords>methods</Keywords><Keywords>Microbial Sensitivity Tests</Keywords><Keywords>microbiology</Keywords><Keywords>Multiple</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>pharmacology</Keywords><Keywords>Selection</Keywords><Keywords>Trimethoprim</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Wales</Keywords><Reprint>Not in File</Reprint><Start_Page>79</Start_Page><End_Page>81</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>65</Volume><Issue>1</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Wootton et al. 2010). Susceptibility is generally good with 4.8% of E coli from uncomplicated UTI resistant , although gradually rising ADDIN REFMGR.CITE <Refman><Cite><Author>Kahlmeter</Author><Year>2015</Year><RecNum>3397</RecNum><IDText>Antimicrobial Resistance of Escherichia coli Causing Uncomplicated Urinary Tract Infections: A European Update for 2014 and Comparison with 2000 and 2008</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3397</Ref_ID><Title_Primary>Antimicrobial Resistance of Escherichia coli Causing Uncomplicated Urinary Tract Infections: A European Update for 2014 and Comparison with 2000 and 2008</Title_Primary><Authors_Primary>Kahlmeter,G.</Authors_Primary><Authors_Primary>Ahman,J.</Authors_Primary><Authors_Primary>Matuschek,E.</Authors_Primary><Date_Primary>2015/12</Date_Primary><Keywords>Ciprofloxacin</Keywords><Keywords>Clinical</Keywords><Keywords>Diffusion</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>France</Keywords><Keywords>Germany</Keywords><Keywords>Hospital</Keywords><Keywords>Infection</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>Spain</Keywords><Keywords>State</Keywords><Keywords>Statistical</Keywords><Keywords>Sweden</Keywords><Keywords>Trimethoprim</Keywords><Keywords>United States</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>417</Start_Page><End_Page>423</End_Page><Periodical>Infect.Dis.Ther.</Periodical><Volume>4</Volume><Issue>4</Issue><User_Def_5>PMC4675763</User_Def_5><Address>Department of Clinical Microbiology, Central Hospital, Vaxjo, Sweden. gunnar.kahlmeter@kronoberg.se
Department of Clinical Microbiology, Central Hospital, Vaxjo, Sweden
Department of Clinical Microbiology, Central Hospital, Vaxjo, Sweden</Address><Web_URL>PM:26507395</Web_URL><ZZ_JournalStdAbbrev><f name="System">Infect.Dis.Ther.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Kahlmeter et al. 2015). Similar rises have been seen in Spain (1% in 2000 to 6.5% in 2014) in the same study. It has no activity against enterococci. Co-amoxiclav can be added, to prevent hydrolysis by those ESBLs that can attack the molecule; the amoxicillin component also may synergise with mecillinam, reflecting attack on different PBPs. Pivmecillinam (the oral formulation of mecillinam) is frequently inactive against carbapenemase and KPC- β-lactamase producing organisms, although published data have suggested, at least in vitro, activity against OXA-48 producing bacteria PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxpdmVybW9yZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
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ADDIN EN.CITE.DATA (Giske 2015;Livermore et al. 2011). Clinical trials of mecillinam against ESBL-producing Enterobacteriaceae are limited to case series. The bacteriological cure rate was 79% (31/39) in one small trial, but five relapsed; clinical cure was attained in 16 of 19(84%) patients ADDIN REFMGR.CITE <Refman><Cite><Author>Jansaker</Author><Year>2014</Year><RecNum>3100</RecNum><IDText>Clinical and bacteriological effects of pivmecillinam for ESBL-producing Escherichia coli or Klebsiella pneumoniae in urinary tract infections</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3100</Ref_ID><Title_Primary>Clinical and bacteriological effects of pivmecillinam for ESBL-producing Escherichia coli or Klebsiella pneumoniae in urinary tract infections</Title_Primary><Authors_Primary>Jansaker,F.</Authors_Primary><Authors_Primary>Frimodt-Moller,N.</Authors_Primary><Authors_Primary>Sjogren,I.</Authors_Primary><Authors_Primary>Dahl,Knudsen J.</Authors_Primary><Date_Primary>2014/3</Date_Primary><Keywords>Bacteria</Keywords><Keywords>Clinical</Keywords><Keywords>Denmark</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Escherichia</Keywords><Keywords>Escherichia coli</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>methods</Keywords><Keywords>microbiology</Keywords><Keywords>Patients</Keywords><Keywords>Prevalence</Keywords><Keywords>Questionnaires</Keywords><Keywords>Sweden</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>769</Start_Page><End_Page>772</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>69</Volume><Issue>3</Issue><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Jansaker et al. 2014). A population-based study was performed to investigate the efficacy of mecillinam treatment of community-acquired urinary tract infections caused by ESBL-producing E. coli. Treatment failure, defined as a new antibiotic prescription appropriate for urinary infection prescribed within two weeks after the initial antimicrobial therapy. A total of 343 patients were included, of which 158 (46%) were treated with mecillinam. Eighty-one patients had infections caused by ESBL producing E. coli, and 41 of these patients (51%) received mecillinam as the primary treatment. Mecillinam treatment failure was observed in 18 (44%) of patients infected by ESBL-producing strains and in 16 (14%) of patients with a urinary infection caused by ESBL non-producing strains. Multivariable analysis showed that ESBL status (odds ratio (OR) 3.2, 95% confidence interval (CI) 1.3-7.8, p = 0.009) and increased MIC of mecillinam (OR 2.0 for each doubling value of MIC, CI 1.4-3.0, p<0.001) were independently associated with mecillinam treatment failure PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNvcmFhczwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Dewar et al. 2014). In an in vitro human gut model, mecillinam did not elicit C. difficile germination, proliferation or toxin production; therefore, mecillinam appears to be a low-risk agent for the induction of C. difficile infection ADDIN REFMGR.CITE <Refman><Cite><Author>Baines</Author><Year>2009</Year><RecNum>3321</RecNum><IDText>Mecillinam: a low-risk antimicrobial agent for induction of Clostridium difficile infection in an in vitro human gut model</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3321</Ref_ID><Title_Primary>Mecillinam: a low-risk antimicrobial agent for induction of Clostridium difficile infection in an in vitro human gut model</Title_Primary><Authors_Primary>Baines,S.D.</Authors_Primary><Authors_Primary>O'Connor,R.</Authors_Primary><Authors_Primary>Huscroft,G.</Authors_Primary><Authors_Primary>Saxton,K.</Authors_Primary><Authors_Primary>Freeman,J.</Authors_Primary><Authors_Primary>Wilcox,M.H.</Authors_Primary><Date_Primary>2009/4</Date_Primary><Keywords>Aged</Keywords><Keywords>Amdinocillin</Keywords><Keywords>Anti-Infective Agents</Keywords><Keywords>Clostridium</Keywords><Keywords>Clostridium difficile</Keywords><Keywords>drug effects</Keywords><Keywords>Gastrointestinal Tract</Keywords><Keywords>growth & development</Keywords><Keywords>Human</Keywords><Keywords>Humans</Keywords><Keywords>In Vitro</Keywords><Keywords>Infection</Keywords><Keywords>microbiology</Keywords><Keywords>Models,Theoretical</Keywords><Keywords>Research</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>838</Start_Page><End_Page>839</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>63</Volume><Issue>4</Issue><Web_URL>PM:19211576</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Baines et al. 2009). Further clinical studies are required with outcome data, with and without clavulanate to determine the role of this antibiotic regimen. Resistance to mecillinam can be readily obtained in the laboratory by selection of mutations in many different cellular functions but remains at low levels in the clinic 4-7% in ESBL E coli in Sweden ADDIN REFMGR.CITE <Refman><Cite><Author>Giske</Author><Year>2015</Year><RecNum>3398</RecNum><IDText>Contemporary resistance trends and mechanisms for the old antibiotics colistin, temocillin, fosfomycin, mecillinam and nitrofurantoin</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3398</Ref_ID><Title_Primary>Contemporary resistance trends and mechanisms for the old antibiotics colistin, temocillin, fosfomycin, mecillinam and nitrofurantoin</Title_Primary><Authors_Primary>Giske,C.G.</Authors_Primary><Date_Primary>2015/10</Date_Primary><Keywords>Acinetobacter</Keywords><Keywords>Antibiotics</Keywords><Keywords>Clinical</Keywords><Keywords>Colistin</Keywords><Keywords>Enterobacteriaceae</Keywords><Keywords>Fosfomycin</Keywords><Keywords>Hospital</Keywords><Keywords>Infection</Keywords><Keywords>Klebsiella</Keywords><Keywords>Klebsiella pneumoniae</Keywords><Keywords>Laboratories</Keywords><Keywords>microbiology</Keywords><Keywords>Multidrug-Resistant</Keywords><Keywords>Nitrofurantoin</Keywords><Keywords>Oral</Keywords><Keywords>Pseudomonas</Keywords><Keywords>Pseudomonas aeruginosa</Keywords><Keywords>Sweden</Keywords><Keywords>trends</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinary Tract</Keywords><Reprint>Not in File</Reprint><Start_Page>899</Start_Page><End_Page>905</End_Page><Periodical>Clin.Microbiol.Infect.</Periodical><Volume>21</Volume><Issue>10</Issue><Address>Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: christian.giske@karolinska.se</Address><Web_URL>PM:26027916</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Microbiol.Infect.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Giske 2015). However, a recent study examined clinical isolates and found all have mutations leading to inactivation of the cysB gene. Reduced cysteine biosynthesis results in accumulation of ppGpp so that the mecillinam targetted PBP2 becomes non-essential PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRodWxpbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Schito et al. 2009). Local community antibiotic guidance should be informed by local surveillance data. Choosing between fosfomycin, mecillinam and nitrofurantoin is difficult as there are no direct comparisons of these three antibiotics in infections due to ESBL-producing organisms. In urinary infections due to non-ESBL-producing organisms nitrofurantoin for 7 days and a single dose of fosfomycin have similar efficacy PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlZhbjwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Stein 1999;Van et al. 1993). In a systematic review of the length of antibiotic treatment for acute uncomplicated urinary infection, therapy for 3 days was similarly effective to prolonged therapy in achieving symptomatic cure for cystitis, but prolonged treatment was more effective in obtaining bacteriological cure. (Gai 2005) Eight reviewed studies included pivmecillinam, but none included nitrofurantoin. After a single dose of fosfomycin high concentrations are maintained in the urine for 2 days. A single dose is usually sufficient in uncomplicated UTI in women, but for confirmed ESBL a second dose at 3 days is needed to promote bacteriological cure (Brayfield 2014)EvidenceIn lower uncomplicated UTI where risk factors for multidrug resistance are present these four treatment options can be used rather than trimethoprim:a.fosfomycin 2- b.nitrofurantoin (unless patients Glomerular Filtration Rate is less than 60), 2+c.Pivmecillinam 3d.Another antibiotic if causative organism confirmed as susceptible. 4RecommendationsAlways send a urine specimen for culture and susceptibility if an antibiotic-resistant organism is suspected AND the patient is symptomatic StrongThe following antibiotics should be used (guided where possible by sensitivity testing) against suspected antibiotic resistant strains: nitrofurantoin, fosfomycin, pivmecillinam. StrongIn uncomplicated UTI due to a proven ESBL-producing organism, treatment is recommended for 7 days to improve bacteriological clearance. Conditional9.4Treatment of pyelonephritis and complicated UTI caused by MDR Gram-negative bacteriaWhenever resistant pathogens are anticipated. culture of a urine specimen is essential before empircial treatment. As nitrofurantoin, mecillinam and oral fosfomycin are not appropriate for the treatment of suspected or confirmed pyelonephritis, and oral β-lactams are less efficacious, intravenous ertapenem is recommended above to treat patients with confirmed or suspected ESBL producing pathogens that are resistant to trimethoprim and quinolones PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvbGxpbnM8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Collins, Marchaim, Pogue, Moshos, Bheemreddy, Sunkara, Shallal, Chugh, Eiseler, Bhargava, Blunden, Lephart, Memon, Hayakawa, Abreu-Lanfranco, Chopra, Munoz-Price, Carmeli, & Kaye 2012;Lee et al. 2012). If a patient has penicillin hypersensitivity intravenous amikacin should be used in hospital or alternatively the patient treated in line with the hospital antibiotic guidance until antibiotic susceptibilities are known and a less toxic agent can be considered. Trimethoprim, ciprofloxacin or co-amoxiclav can be used in pyelonephritis if the causative organism is known to be susceptible (or a susceptible organism has been isolated in the last month). A retrospective cohort study of patients with community onset acute pyelonephritis due to ESBL- producing E. coli compared 85 patients receiving carbapenems with 67 receiving other agents to which the infecting bacterium was susceptible in vitro. There was no difference in the rate of clinical or microbiological failure PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhcms8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Park et al. 2014) A randomized double-blind controlled trial showed that 7 days of ciprofloxacin 500 mg bd was as effective as 14 days co-trimoxazole against susceptible organisms but quinolone resistance is now more common PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbGFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj
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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRhbGFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Talan et al. 2000). The addition of clavulanate to mecillinam has been studied in vitro PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxhbXByaTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Lampri et al. 2012). Among 48 ESBL producers, 47 (97.9%) were susceptible to mecillinam. CTX-M-type enzymes were produced by 87.2%, Synergy with clavulanate was detected in 40 - 60.4% of isolates (depending on the method used). When a high inoculum was used, 60.4% (29/48) were resistant to mecillinam, but 97.9% (47/48) were susceptible in the presence of clavulanate. Further clinical studies are required, with outcome data, with and without clavulanate to determine the role of this mecillinam-based regimen.EvidencePending antibiotic susceptibility testing, patients at increased risk of MDR Gram-negative bacteria and suspected of pyelonephritis or complicated UTI (indwelling catheter, renal stones, prostatic obstruction, diabetes, urological abnormality) can be treated empirically with: a. outpatient intravenous therapy with ertapenem. 2+b. admission for intravenous aminoglycoside therapyi. if hypersensitivity to penicillin treat with gentamicin (if no past evidence of resistance) or amikacin 3ii. meropenem 2+c. Trimethoprim, ciprofloxacin or co-amoxiclav if urine testing shows UTI susceptible in the last month and no previous clinical failure. 1RecommendationPatients should have a urine sample collected and started on empirical intravenous therapy with ertapenem or meropenem. If known to have sensitive organisms in last month and well enough for oral therapy then use best choice active agent. If a carbapenem-resistant bacterium is present treatment, is then guided by susceptibility testing and other recent isolates.Strong9.5What is the threshold level of resistance for changing the choice of empirical treatment for urinary tract infections?Most patients with urinary infection are treated with empirical therapy, particularly if it is a first episode of lower UTI. Failure of empirical therapy particularly in complicated UTI (e.g., pyelonephritis) is a common cause of Gram-negative bacteremia where an increase in 30-day mortality is associated with ineffective empirical therapy PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5SZXRhbWFyPC9BdXRob3I+PFll
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ADDIN EN.CITE.DATA (Morata et al. 2012;Retamar et al. 2013). On the other hand in order to slow the emergence of resistance older narrower spectrum antibiotics may be recommended for empirical use. One group of authors concludedthat the right of future patients to come to less harm outweighs the right of the present patient to share in decisions on antibiotic treatment ADDIN REFMGR.CITE <Refman><Cite><Author>Leibovici</Author><Year>2012</Year><RecNum>3329</RecNum><IDText>Ethical dilemmas in antibiotic treatment</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3329</Ref_ID><Title_Primary>Ethical dilemmas in antibiotic treatment</Title_Primary><Authors_Primary>Leibovici,L.</Authors_Primary><Authors_Primary>Paul,M.</Authors_Primary><Authors_Primary>Ezra,O.</Authors_Primary><Date_Primary>2012/1</Date_Primary><Keywords>administration & dosage</Keywords><Keywords>analysis</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteria</Keywords><Keywords>Bacterial Infections</Keywords><Keywords>Decision Support Systems</Keywords><Keywords>drug effects</Keywords><Keywords>Drug Resistance,Bacterial</Keywords><Keywords>drug therapy</Keywords><Keywords>ethics</Keywords><Keywords>Guidelines</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Israel</Keywords><Keywords>Medical</Keywords><Keywords>methods</Keywords><Keywords>Patients</Keywords><Reprint>Not in File</Reprint><Start_Page>12</Start_Page><End_Page>16</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>67</Volume><Issue>1</Issue><Address>Department of Medicine E, Beilinson Hospital, Rabin Medical Center, Petah-Tiqva, Israel. leibovic@post.tau.ac.il</Address><Web_URL>PM:21980065</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Leibovici et al. 2012). Allowing for routine laboratory testing data on submitted samples overestimating the “true” resistance rates for community isolates then a 20% resistance rate to trimethoprim for the treatment of lower UTI would be acceptable. When the probability of bacteraemia associated with the urinary infection rises, a lower threshold is needed because of the greater risk to the individual patient. A probability of inadequate coverage of <5% is often used and is for instance achieved with co-amoxiclav plus gentamicin or carbapenem monotherapy in Netherlands PFJlZm1hbj48Q2l0ZT48QXV0aG9yPktvbmluZ3N0ZWluPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA (Niranjan and Malini 2014). EvidenceA threshold of 20% expected resistance is accepted in the treatment of lower urinary infection, falling to 5% when there is an increased risk of bacteraemia.4RecommendationThe threshold for changing empirical therapy in the face of rising resistance should be determined locally based on the risk of bacteremia and rates of resistance Conditional 9.6 What effect does good antibiotic stewardship have on rates of MRGNB?9.6.1 The impact of good antibiotic stewardship in secondary/tertiary care facilitiesAntibiotic therapy differs from other treatment in being directed against diverse and frequently unknown organisms and in exercising selection for resistant organisms, which may then cause infection either in the same or other patients. Treatment options for multi-resistant organisms are restricted and failure to deploy appropriate treatment in these infections may be associated with a poor outcome whereas excessive use of a single agent is more likely to select for superinfection caused by resistant organisms. The clinical governance of antibiotic policies is therefore is a balance between treatment of the individual and treatment of the community. The evidence base and practice of antibiotic stewardship has been recently promulgated in both the UK Public Health England guidelines for antimicrobial prescribing and stewardship competencies ADDIN REFMGR.CITE <Refman><Cite><Author>Public Health England (PHE)</Author><Year>2013</Year><RecNum>3216</RecNum><IDText>Antimicrobial prescribing and stewardship competencies</IDText><MDL Ref_Type="Electronic Citation"><Ref_Type>Electronic Citation</Ref_Type><Ref_ID>3216</Ref_ID><Title_Primary>Antimicrobial prescribing and stewardship competencies</Title_Primary><Authors_Primary>Public Health England (PHE)</Authors_Primary><Date_Primary>2013/9/1</Date_Primary><Reprint>Not in File</Reprint><Periodical> name="System">;(Public Health England (PHE) 2013) and the NICE guidance on Antibiotic Stewardship (NICE 2015). This report will focus on aspects of stewardship that pertain to MDR Gram-negative bacteria, the more general aspects can be found in the above sources. Monitoring antibiotic use and prevalence of MDR Gram-negative bacilli are possible but (i) the former do not indicate whether use was appropriate , and (ii) the latter is no guide to the incidence of new cases is caused by MDR Gram-negative bacilli. Root cause analysis of individual cases is burdensome and very complex if it is intended to relate to outcome, and runs the risk of bias with regard to outcome unless the proportion of resistant or susceptible organisms examined match the overall population. It does not produce reliable statistically comparable data between institutions . Clinical trials early in a product’s availability offer guidance on efficacy against susceptible organisms and for narrower spectrum agents, an indication of potential for selection for resistance. However, antibiotic efficacy is not sustained and becomes less relevant once resistance becomes more prevalent. , Anticipating when empirical therapy active against multi-resistant organisms should be used is very difficult and accounts for recommendations that limit use of drugs such as carbapenems, or which reserve agents for multi-resistant organisms to those patients whose infections with a potential high mortality. The Cochrane systematic review showed that interventions to reduce excessive antibiotic prescribing to hospital inpatients can reduce antimicrobial resistance and interventions to increase effective prescribing can improve clinical outcome PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRhdmV5PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Davey et al. 2013). Of the 89 studies cited to 2009 (reporting 95 interventions), 56 were interrupted time series (ITS), 25 were randomised controlled trials (RCT), 5 were controlled before-after studies (CBA) and three were controlled clinical trials (CCT). The reporting of outcomes was very variable (only 13/25 RCTs reported on mortality and only 5 on readmissions) making comparison between studies difficult. Interventions that enhanced the quality of prescribing in patients with any infection had no effect on mortality whereas interventions to increase compliance with evidence-based guidelines in community acquired pneumonia were associated with reduced mortality. Reducing excessive prescribing, as determined by evidence-based guidelines, was associated with increased re-admission but not with increased mortality or length of stay. Restrictive and persuasive interventions were associated with improved prescribing outcomes based on median outcome effect (proportion of subjects with an improvement or change antibiotic selection, dose, route or duration versus control). Multifaceted interventions were common but not necessarily more effective than simple interactions. Most (80/95, 84%) of the interventions targeted the antibiotic prescribed (choice of antibiotic, timing of first dose and route of administration). The remaining 15 interventions aimed to change exposure of patients to antibiotics by targeting the decision to treat or the duration of treatment. Nine studies evaluated interventions reporting the effect on colonization or infection with antibiotic-resistant Gram-negative bacteria. Seven of these were interrupted time series studies (ITS), with a median effect size of 47% PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxhbmRtYW48L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Calil et al. 2001;Carling et al. 2003;de Man et al. 1994;Gerding and Larson 1985;Landman et al. 1999;Leverstein-van Hall et al. 2001;Meyer et al. 1993). One controlled clinical trial (CCT), showed a reduction in colonization/infection of 68% PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5kZTwvQXV0aG9yPjxZZWFyPjIw
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ADDIN EN.CITE.DATA (de Man et al. 2000) while another showed an increase of39% PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlRvbHR6aXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Gerding & Larson 1985;Landman et al. 1999;Toltzis et al. 1998).Kaki et al. produced another systematic review of antibiotic stewardship programmes studies, limited to the critical care unit PFJlZm1hbj48Q2l0ZT48QXV0aG9yPktha2k8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Kaki et al. 2011). These included three randomised controlled trials , three interrupted time series, and 18 uncontrolled before-and-after studies. Among these studies, introduction of various antibiotic stewardship interventions led to reductions in antimicrobial utilization of 11% to 38% defined daily doses/1000 patient-days (except a single study increase of 6%), lower total antimicrobial costs, shorter average duration of antibiotic therapy, less inappropriate use and fewer antibiotic adverse events. They also found reductions in antimicrobial resistance rates beyond six months. Meta-analysis of 52 interrupted time series studies was used to compare restrictive versus persuasive interventions PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5EYXZleTwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Davey et al. 2013). Restrictive interventions had significantly greater impact on prescribing outcomes at one month (32%), 95% CI 2-61%, P=0.03) and on microbial outcomes at 6 months (53%, 95% CI 31-75%, P=0.001) but there were no significant differences at 12 or 24 months.In the USA the Department of Veterans Affairs recently commissioned a systematic review of antimicrobial stewardship programmes (ASP) ADDIN REFMGR.CITE <Refman><Cite><Author>Filice</Author><Year>2013</Year><RecNum>3416</RecNum><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3416</Ref_ID><Authors_Primary>Filice,G.</Authors_Primary><Authors_Primary>Drekonja,D.</Authors_Primary><Authors_Primary>Greer,N.</Authors_Primary><Authors_Primary>Butler,M.</Authors_Primary><Authors_Primary>Wagner,B.</Authors_Primary><Authors_Primary>MacDonald,R.</Authors_Primary><Authors_Primary>Carlyle,M.</Authors_Primary><Authors_Primary>Rutks,I.</Authors_Primary><Authors_Primary>Wilt,T.J.</Authors_Primary><Date_Primary>2013/9</Date_Primary><Keywords>Clinical</Keywords><Keywords>Clostridium</Keywords><Keywords>Clostridium difficile</Keywords><Keywords>Feedback</Keywords><Keywords>Formularies</Keywords><Keywords>Guidelines</Keywords><Keywords>Health</Keywords><Keywords>Hospital</Keywords><Keywords>Human</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Intensive Care</Keywords><Keywords>Laboratories</Keywords><Keywords>Patients</Keywords><Keywords>Prescriptions</Keywords><Keywords>Selection</Keywords><Keywords>State</Keywords><Keywords>therapy</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Web_URL>PM:25411666</Web_URL><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Filice et al. 2013a) ADDIN REFMGR.CITE <Refman><Cite><Author>Filice</Author><Year>2013</Year><RecNum>3335</RecNum><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3335</Ref_ID><Authors_Primary>Filice,G.</Authors_Primary><Authors_Primary>Drekonja,D.</Authors_Primary><Authors_Primary>Greer,N.</Authors_Primary><Authors_Primary>Butler,M.</Authors_Primary><Authors_Primary>Wagner,B.</Authors_Primary><Authors_Primary>MacDonald,R.</Authors_Primary><Authors_Primary>Carlyle,M.</Authors_Primary><Authors_Primary>Rutks,I.</Authors_Primary><Authors_Primary>Wilt,T.J.</Authors_Primary><Date_Primary>2013/9</Date_Primary><Keywords>Clinical</Keywords><Keywords>Clostridium</Keywords><Keywords>Clostridium difficile</Keywords><Keywords>Feedback</Keywords><Keywords>Formularies</Keywords><Keywords>Guidelines</Keywords><Keywords>Health</Keywords><Keywords>Hospital</Keywords><Keywords>Human</Keywords><Keywords>Incidence</Keywords><Keywords>Infection</Keywords><Keywords>Infectious</Keywords><Keywords>Intensive Care</Keywords><Keywords>Laboratories</Keywords><Keywords>Patients</Keywords><Keywords>Prescriptions</Keywords><Keywords>Selection</Keywords><Keywords>State</Keywords><Keywords>therapy</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Web_URL>PM:25411666</Web_URL><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Filice et al. 2013b). The key findings have been published and the reader is referred to those publications for detail findings PFJlZm1hbj48Q2l0ZT48QXV0aG9yPldhZ25lcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Wagner et al. 2014). To avoid duplication, the VA systematic review only included papers meeting their eligibility criteria but not included in the most recent Cochrane review. The review reported mixed results for clinical/microbial outcomes and overall improvement in prescribing. Because (i) few studies of different interventions reported each outcome, (ii) inconsistency across studies and (iii) medium/high risk of bias, the strength of evidence for all clinical outcomes was low. No single antimicrobial stewardship programme was shown to be superior but amongst studies since 2000 the greatest body of evidence of effectiveness was for decreasing inappropriate or increasing appropriate antibiotic use. Effects were seen across all species of Gram-negative bacteria and broad-spectrum antimicrobials.There were some individual studies of high quality. Introduction of a stewardship program in one US hospital reduced the use of broad spectrum agents and was associated with a reduction in hospital-acquired infections caused by MDR Gram-negative pathogens from 37% to 8% over 6 years PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRvcnRjaDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Dortch et al. 2011). Similarly carbapenem-resistant E coli and Klebsiella declined when national guidelines on stewardship were implemented PFJlZm1hbj48Q2l0ZT48QXV0aG9yPllvbmc8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Yong et al. 2010). A carbapenem-restriction policy as part of an infection control strategy was effective in controlling an outbreak of carbapenem-resistant Klebsiella pneumonia. However, although there was a significant reduction in meropenem use, prescription of colistin rose PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJvcmVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Chastre et al. 2003). Early rapid and automated diagnostic tests for the organisms and the antimicrobial susceptibility together with promptly administered and appropriate antibiotics is likely to improve prognosis. As a performance measure, overall time to active treatment can and should be initially and repeatedly audited against what could best be achieved. Objectively countable disseminated infections such as bacteraemia may reflect failed initial diagnosis or treatment and are associated with a poor outcome iif septic shock develops. As such, bacteraemias are suitable for outcome audit.Annual publication of audit data is probably adequate since antibiotic resistance emerges slowly and antibiotic policy is seldom changed more frequently. Gram-negative bacteraemias should be assigned as being of community or hospital onset al.though this frequently does not reflect the acquisition point, which may reflect hospitalisation within the preceding year. Dates of collection of blood cultures, as recorded in computer systems, may be distorted by weekends so an interval of less than 3 days since admission is recommended for defining ‘community onset’. Residence in a nursing home is a marker of healthcare, not general community acquisition, and these patients should be separately categorised. At the local level, bacteraemia data require more analysis to explain and address unsatisfactory outcomes and improvements in informatics are now needed in all hospitals with the rise in multi-resistant organisms. Routine national reporting systems on bacteraemia should be linked to public health mortality data and fed back annually to individual hospitals. Early Warning Scores are frequently now available on computerised systems for monitoring vital signs. Patient-based prescribing systems record the date of prescription and antibiotics are individually identifiable. Laboratory system data on (i) the date of the first positive blood culture from a patient, and (ii) the organism and its antimicrobial susceptibilities, should be linked electronically with (i) data on admission date and place of residence from hospital patient administration systems, (ii) Early Warning Score and (iii) antibiotics administered. Early Warning Scores of 6 or more indicate a poorer prognosis in bacteraemia. Batch processing by year should be adequate in most hospitals for governance monitoring as this would address (1) the diversity of organisms to be scrutinised and the match to antibiotics prescribed, (2) the usually slow progression of antibiotic resistance in the presence of good infection control and absence of a common-source outbreak, (3) the need to feedback and organise changes to prescribing policy and ward action to all staff with document control. The most difficult area to address is usually the unequivocal measurement of outcome. Mortality is associated with poor functional state and co-morbidities, which may link to age. Defining mortality at a point less than 30 days after bacteraemia could tighten linkage to resistance and inappropriate prescribing, and should be studied. Acute renal injury is also a useful outcome measure as is subsequent development of C. difficile infection within 28 days. Quality and commissioning organisations should ensure hospitals are collecting and analysing data and that they and communities are showing improvement in hospital and community-onset bacteraemia if they were previously in the bottom quartile of outcomes.The deployment of antibiotic stewardship programmes is variable, as shown by a survey of 660 hospitals in 67 countries PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhvd2FyZDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Howard et al. 2015). This study included the first data from sites in Asia, Africa and South America with considerable MDR Gram-negative bacterial problems. There is an urgent need for the adoption of an international antibiotic stewardship timetable.Evidence1.Establishment of an antimicrobial resistance surveillance based feedback stewardship programme is associated with lower and more appropriate prescribing and may reduce the emergence of MDR Gram negative bacilli in the hospital.2++2.Key components of an effective antimicrobial stewardship programme are consistent effort from specialists with good communication and support for electronic prescribing/records and computerised decision support systems.2++3.Interventions intended to decrease excessive antibiotic prescribing are associated with reductions in both colonisation and infections caused by aminoglycoside or cephalosporin-resistant bacteria.2++4.Restrictive rather than persuasive prescribing interventions have a significant short term effect on prescribing and microbial outcomes of MDR Gram-negative bacilli.2++Recommendations1.All hospitals should have an antimicrobial stewardship programmme based on both surveillance and active feedback to prescribers, with monitoring of clinical and prescribing outcomes.Strong2.Outcomes of bacteraemia in relation to antibiotic treatment should be collected for each hospital and made publicly available as a tabulated comparison by public health authorities, as a measure of the adequacy of treatment of infection.missioning and quality organisations should review outcome data linked to antibiotic prescribing to improve quality of care in both hospitals and the communityConditional4.Restrictive prescribing policies should be used to reduce the likelihood of new occurrences of MDR Gram-negative infection.Strong5.Hospitals should ensure that new antimicrobials that may be required to treat MDR Gram-negative infections are readily identified through horizon scanning and available/monitored through existing formulary groups and other similar bodies.Conditional 9.6.2Antibiotic stewardship in the community and care homes to reduce MDR Gram-negative infectionsSeveral RCTs in the UK community setting have shown that multifaceted interventions that included general practice staff education and education of the patient through improving communication during the doctor-patient consultation have improved prescribing. PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJ1dGxlcjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Butler et al. 2012;Francis et al. 2009). There have also been several Cochrane reviews that include studies in the hospital setting, but the findings should be transferable to the community and care home setting. In a Cochrane review of different interventions in the hospital setting aimed at improving antibiotic prescribing, restrictive interventions (selective reporting of laboratory susceptibilities, formulary restriction, and antibiotic policy change strategies) had a greater effect in the short term in reducing broad spectrum antibiotics than persuasive interventions (distribution of educational materials; educational meetings; local consensus processes; educational outreach visits; local opinion leaders; reminders provided verbally, on paper or on computer; audit and feedback). However they were both equally effective in controlling antibiotic use and antimicrobial resistance after 6 months PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5EYXZleTwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Davey et al. 2013). In a separate Cochrane review, printed educational materials alone had an effect on the practice of healthcare professionals and patient health outcomes PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdpZ3VlcmU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdpZ3VlcmU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Giguere et al. 2012). Based on seven RCTs and 54 outcomes, the median absolute risk difference in categorical practice outcomes was 0.02 when printed educational materials were compared to no intervention (range from 0 to +0.11) PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5HaWd1ZXJlPC9BdXRob3I+PFll
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ADDIN EN.CITE.DATA (Giguere et al. 2012). Other Cochrane reviews show multifaceted interventions are more effective and moreover those that are based on cognitive theories and consider personal attitudes, subjective norms and perceived behavioural controls (confidence and other barriers) are more likely to be successful, e.g., posters raise awareness and change subjective norms but alone are ineffective. In an audit and feedback process, an individual’s professional practice or performance is measured and then compared to professional standards or targets. The results of this comparison are then fed back to the individual. In general practices this will probably be via the medicine manager, local GP prescribing champions or microbiologists in collaboration with the former. The aim of this process is to encourage the individual to follow professional standards PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5JdmVyczwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Ivers et al. 2012). In a Cochrane review, a total of 82 comparisons from 49 studies compared any health care intervention in which audit and feedback was a core, essential component to usual care and evaluated effects on professional practice. PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5JdmVyczwvQXV0aG9yPjxZZWFy
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ADDIN EN.CITE.DATA (Ivers et al. 2012). Multivariable meta-regression indicated that feedback may be more effective when baseline performance is low, the source is a supervisor or colleague, it is provided more than once, it is delivered in both verbal and written formats, and when it includes both explicit targets and an action plan. In addition, the effect size varied based on the clinical behaviour targeted by the intervention PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkl2ZXJzPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Ivers et al. 2012). An RCT evaluating a multifaceted intervention in English general practice aimed at improving antibiotic prescribing included feedback of practice level data on antibiotic dispensing and resistance and led to a 4.2% fall in total antibiotic use. PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5CdXRsZXI8L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA (Butler et al. 2012). In the UK audit with action plans, and intense infection control measures, have been associated with falls in quinolones and cephalosporin use and resistance ADDIN REFMGR.CITE <Refman><Cite><Author>Dancer</Author><Year>2008</Year><RecNum>3385</RecNum><IDText>The effect of antibiotics on methicillin-resistant Staphylococcus aureus</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3385</Ref_ID><Title_Primary>The effect of antibiotics on methicillin-resistant Staphylococcus aureus</Title_Primary><Authors_Primary>Dancer,S.J.</Authors_Primary><Date_Primary>2008/2</Date_Primary><Keywords>Animals</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Antibiotics</Keywords><Keywords>Clinical</Keywords><Keywords>drug effects</Keywords><Keywords>drug therapy</Keywords><Keywords>Hospital</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Methicillin Resistance</Keywords><Keywords>Methicillin-Resistant Staphylococcus aureus</Keywords><Keywords>microbiology</Keywords><Keywords>Molecular</Keywords><Keywords>mortality</Keywords><Keywords>pathogenicity</Keywords><Keywords>Patients</Keywords><Keywords>pharmacology</Keywords><Keywords>physiology</Keywords><Keywords>Quinolones</Keywords><Keywords>Risk</Keywords><Keywords>Scotland</Keywords><Keywords>Skin</Keywords><Keywords>Staphylococcal Infections</Keywords><Keywords>Staphylococcus</Keywords><Keywords>Staphylococcus aureus</Keywords><Keywords>therapeutic use</Keywords><Keywords>therapy</Keywords><Keywords>transmission</Keywords><Keywords>Virulence</Keywords><Reprint>Not in File</Reprint><Start_Page>246</Start_Page><End_Page>253</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>61</Volume><Issue>2</Issue><Address>Department of Microbiology, Southern General Hospital, Glasgow G51 4TF, Scotland, UK. stephanie.dancer@sgh.scot.nhs.uk</Address><Web_URL>PM:18057071</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Dancer 2008). Incentives attached to action plans can also be very effective but without personal attitude changes, when removed change may reverse ADDIN REFMGR.CITE <Refman><Cite><Author>Ashiru-Oredope</Author><Year>2012</Year><RecNum>2751</RecNum><IDText>Improving the quality of antibiotic prescribing in the NHS by developing a new Antimicrobial Stewardship Programme: Start Smart--Then Focus</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2751</Ref_ID><Title_Primary>Improving the quality of antibiotic prescribing in the NHS by developing a new Antimicrobial Stewardship Programme: Start Smart--Then Focus</Title_Primary><Authors_Primary>Ashiru-Oredope,D.</Authors_Primary><Authors_Primary>Sharland,M.</Authors_Primary><Authors_Primary>Charani,E.</Authors_Primary><Authors_Primary>McNulty,C.</Authors_Primary><Authors_Primary>Cooke,J.</Authors_Primary><Date_Primary>2012/7</Date_Primary><Keywords>Antibiotics</Keywords><Keywords>Carbapenems</Keywords><Keywords>Cephalosporins</Keywords><Keywords>Clostridium</Keywords><Keywords>Clostridium difficile</Keywords><Keywords>England</Keywords><Keywords>Health</Keywords><Keywords>Hospital</Keywords><Keywords>Hospitals</Keywords><Keywords>Infection</Keywords><Keywords>London</Keywords><Keywords>Oral</Keywords><Keywords>Patients</Keywords><Keywords>Public Health</Keywords><Keywords>Quinolones</Keywords><Keywords>therapy</Keywords><Reprint>Not in File</Reprint><Start_Page>i51</Start_Page><End_Page>i63</End_Page><Periodical>J.Antimicrob.Chemother.</Periodical><Volume>67 Suppl 1:i51-63.</Volume><ZZ_JournalStdAbbrev><f name="System">J.Antimicrob.Chemother.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Ashiru-Oredope et al. 2012). Any audit indicators need to be well monitored as implementation of an already proven effective multiple intervention strategy at a larger scale in general practice showed no reduction of antibiotic prescription rates and the authors attributed the failure to a less tight monitoring of the intervention and audit PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNtZWV0czwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Smeets et al. 2009).Choosing an antibiotic to which the bacterium causing an UTI is susceptible is important as UTI symptoms resolve more slowly when an inappropriate antibiotic is givenPFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5TbWVldHM8L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA (McNulty et al. 2006;Smeets et al. 2009). Bacteraemias due Escherichia coli have increased over the last ten years in England and Wales, and receipt of antibiotics in the 4 weeks preceding bacteraemia was the most important risk factor. Age over 65 years, summer months and urinary catheterisation were also important (Kiernan 2014). Therefore all patients should be given advice on when to seek further medical advice, if their symptoms worsen (even if the same day) or do not improve after several days. Good practice in differentiating urinary infections from other infections and asymptomatic bacteriuria is vital to reducing unnecessary use of antibiotics. A systematic review of diagnostic studies found that the presence of vaginal discharge or vaginal irritation reduced the probability of urinary infection to 20-30% ADDIN REFMGR.CITE <Refman><Cite><Author>Bent</Author><Year>2002</Year><RecNum>3489</RecNum><IDText>Does this woman have an acute uncomplicated urinary tract infection?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3489</Ref_ID><Title_Primary>Does this woman have an acute uncomplicated urinary tract infection?</Title_Primary><Authors_Primary>Bent,S.</Authors_Primary><Authors_Primary>Nallamothu,B.K.</Authors_Primary><Authors_Primary>Simel,D.L.</Authors_Primary><Authors_Primary>Fihn,S.D.</Authors_Primary><Authors_Primary>Saint,S.</Authors_Primary><Date_Primary>2002/5/22</Date_Primary><Keywords>Acute Disease</Keywords><Keywords>Adult</Keywords><Keywords>Algorithms</Keywords><Keywords>Bacteriuria</Keywords><Keywords>Clinical</Keywords><Keywords>Combination</Keywords><Keywords>Consensus</Keywords><Keywords>diagnosis</Keywords><Keywords>Diagnosis,Differential</Keywords><Keywords>Female</Keywords><Keywords>Hematuria</Keywords><Keywords>history</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Medical History Taking</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Keywords>Physical Examination</Keywords><Keywords>Probability</Keywords><Keywords>Selection</Keywords><Keywords>Sexually Transmitted Diseases</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinalysis</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Keywords>Vaginal Diseases</Keywords><Reprint>Not in File</Reprint><Start_Page>2701</Start_Page><End_Page>2710</End_Page><Periodical>JAMA</Periodical><Volume>287</Volume><Issue>20</Issue><Address>University of California, San Francisco, San Francisco VAMC, 94121, USA. bent@itsa.ucsf.edu</Address><Web_URL>PM:12020306</Web_URL><ZZ_JournalFull><f name="System">JAMA</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Bent et al. 2002). When clinical variables were examined in a Health Technology Assessment predictive rules validation study, the positive predictive value for urinary infection was 82% for women with all three of cloudy urine, dysuria, and nocturia. The negative predictive value was 67% for none of these three features. When individual clinical features were considered alone, cloudy urine or dysuria were predictive of UTI, but nocturia or smelly urine were not (Little 2009)in women with uncomplicated UTI, the negative predictive value when nitrite, leucocytes, and blood are ALL negative was 76%. The positive predictive value for having nitrite and EITHER blood or leucocytes was 92%. Several different studies have shown the prevalence of asymptomatic bacteriuria is about 6% in men and 16% of women aged over 65 years (SIGN 2012). In a cohort study, 1173 elderly female residents without catheters in care homes were followed for 9 years with urine cultures every six months (Abrutyn 1994). No relation was found between ever having had asymptomatic bacteriuria and death after adjusting for covariates (hazard ratio, 1.10; CI, 0.78 to 1.55). The death rate in those who never had asymptomatic bacteriuria group was similar to those who had bacteriuria but either received no treatment or were treated (P > 0.2) ADDIN REFMGR.CITE <Refman><Cite><Author>Abrutyn</Author><Year>1994</Year><RecNum>3390</RecNum><IDText>Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3390</Ref_ID><Title_Primary>Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?</Title_Primary><Authors_Primary>Abrutyn,E.</Authors_Primary><Authors_Primary>Mossey,J.</Authors_Primary><Authors_Primary>Berlin,J.A.</Authors_Primary><Authors_Primary>Boscia,J.</Authors_Primary><Authors_Primary>Levison,M.</Authors_Primary><Authors_Primary>Pitsakis,P.</Authors_Primary><Authors_Primary>Kaye,D.</Authors_Primary><Date_Primary>1994/5/15</Date_Primary><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>analysis</Keywords><Keywords>Anti-Infective Agents</Keywords><Keywords>Bacteriuria</Keywords><Keywords>Catheters</Keywords><Keywords>Clinical</Keywords><Keywords>Cohort Studies</Keywords><Keywords>Comorbidity</Keywords><Keywords>Double-Blind Method</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Longitudinal Studies</Keywords><Keywords>Medical</Keywords><Keywords>mortality</Keywords><Keywords>Pennsylvania</Keywords><Keywords>Proportional Hazards Models</Keywords><Keywords>Research</Keywords><Keywords>Risk</Keywords><Keywords>therapeutic use</Keywords><Keywords>Urinary Tract</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>827</Start_Page><End_Page>833</End_Page><Periodical>Ann.Intern.Med.</Periodical><Volume>120</Volume><Issue>10</Issue><Address>Medical College of Pennsylvania, Philadelphia Department of Veterans Affairs Medical Center</Address><Web_URL>PM:7818631</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann.Intern.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Abrutyn et al. 1994). The lack of benefit in treating asymptomatic bacteriuria was confirmed in a study in another smaller study, neither mortality nor the frequency of symptomatic episodes was reduced, but for every three women with asymptomatic bacteriuria in a care home given antibiotics (the type was not specified in this study), one experienced adverse effects (such as rash or GI symptoms) ADDIN REFMGR.CITE <Refman><Cite><Author>Nicolle</Author><Year>2005</Year><RecNum>3490</RecNum><IDText>Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3490</Ref_ID><Title_Primary>Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults</Title_Primary><Authors_Primary>Nicolle,L.E.</Authors_Primary><Authors_Primary>Bradley,S.</Authors_Primary><Authors_Primary>Colgan,R.</Authors_Primary><Authors_Primary>Rice,J.C.</Authors_Primary><Authors_Primary>Schaeffer,A.</Authors_Primary><Authors_Primary>Hooton,T.M.</Authors_Primary><Date_Primary>2005/3/1</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Aging</Keywords><Keywords>Anti-Bacterial Agents</Keywords><Keywords>Bacteriuria</Keywords><Keywords>Canada</Keywords><Keywords>diagnosis</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Guidelines</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infectious</Keywords><Keywords>Male</Keywords><Keywords>Manitoba</Keywords><Keywords>Risk Factors</Keywords><Keywords>Societies</Keywords><Keywords>Spinal Cord Injuries</Keywords><Keywords>therapeutic use</Keywords><Keywords>Universities</Keywords><Keywords>University</Keywords><Keywords>Urinary Catheterization</Keywords><Reprint>Not in File</Reprint><Start_Page>643</Start_Page><End_Page>654</End_Page><Periodical>Clin.Infect.Dis.</Periodical><Volume>40</Volume><Issue>5</Issue><Address>University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba, Canada. lnicolle@hsc.mb.ca</Address><Web_URL>PM:15714408</Web_URL><ZZ_JournalStdAbbrev><f name="System">Clin.Infect.Dis.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Nicolle et al. 2005). 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ADDIN EN.CITE.DATA ( 1984). Intermittent catheterisation is associated with a lower incidence of asymptomatic bacteriuria than long-term catheterization ADDIN REFMGR.CITE <Refman><Cite><Author>Shekelle</Author><Year>1999</Year><RecNum>3491</RecNum><IDText>Systematic review of risk factors for urinary tract infection in adults with spinal cord dysfunction</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3491</Ref_ID><Title_Primary>Systematic review of risk factors for urinary tract infection in adults with spinal cord dysfunction</Title_Primary><Authors_Primary>Shekelle,P.G.</Authors_Primary><Authors_Primary>Morton,S.C.</Authors_Primary><Authors_Primary>Clark,K.A.</Authors_Primary><Authors_Primary>Pathak,M.</Authors_Primary><Authors_Primary>Vickrey,B.G.</Authors_Primary><Date_Primary>1999</Date_Primary><Keywords>Adult</Keywords><Keywords>Bacteriuria</Keywords><Keywords>Bladder</Keywords><Keywords>Catheterization</Keywords><Keywords>Catheters</Keywords><Keywords>Clinical</Keywords><Keywords>Clinical Trials</Keywords><Keywords>Clinical Trials as Topic</Keywords><Keywords>Cohort Studies</Keywords><Keywords>complications</Keywords><Keywords>Cross-Sectional Studies</Keywords><Keywords>deficiency</Keywords><Keywords>Drainage</Keywords><Keywords>etiology</Keywords><Keywords>Evidence-Based Practice</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Hygiene</Keywords><Keywords>Indwelling</Keywords><Keywords>Infection</Keywords><Keywords>Morbidity</Keywords><Keywords>Research</Keywords><Keywords>Risk</Keywords><Keywords>Risk Factors</Keywords><Keywords>Spinal Cord Injuries</Keywords><Keywords>Urinary Bladder,Neurogenic</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>258</Start_Page><End_Page>272</End_Page><Periodical>J.Spinal Cord.Med.</Periodical><Volume>22</Volume><Issue>4</Issue><Address>RAND Health Division, Southern California Evidence-Based Practice Center, Santa Monica, USA</Address><Web_URL>PM:10751130</Web_URL><ZZ_JournalStdAbbrev><f name="System">J.Spinal Cord.Med.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Shekelle et al. 1999). Catheterised patients should only receive antibiotic treatment when they are symptomatic to reduce the risk of colonisation by antibiotic resistant bacteria PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNoYXBpcm88L0F1dGhvcj48WWVhcj4xOTg0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Shapiro et al. 1984;Warren et al. 1978).Differentiating urinary tract infection from asymptomatic bacteriuria can be particularly challenging in elderly patients with dementia as they cannot always describe their symptoms. A positive urine culture or dipstick test will not differentiate between UTI or ASB PFJlZm1hbj48Q2l0ZSBFeGNsdWRlQXV0aD0iMSI+PEF1dGhvcj5BYnJ1dHluPC9BdXRob3I+PFll
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ADDIN EN.CITE.DATA (Loeb et al. 2005). Patients were considered for antibiotic treatment based on presence of fever greater than 37.9?C or 1.5?C increase above baseline on at least two occasions over last 12 hours and one or more signs of UTI Figure 3 (Loeb 2005). Fewer courses of antibiotics for suspected urinary tract infections per 1000 resident days were prescribed in the intervention nursing homes than in control care homes (1.17 v 1.59 courses per 1000 resident days). Antimicrobials for suspected UTI represented 28.4% of all courses of drugs prescribed in the intervention nursing homes compared with 38.6% prescribed in the control care homes (weighted mean difference – 9.6%, ? 16.9% to –2.4%). No significant difference was found in admissions to hospital or mortality between the study arms.β Stop antibiotics if urine culture is negative or no pyuria is presentDeciding whether to give prophylaxis is a balance between the benefits of reducing symptomatic relapse and pyelonephritis versus side effects and the risks of selecting antibiotic resistance . Guidance is based on a systematic review of 19 trials. Nightly prophylaxis in non-pregnant women with recurrent urinary infection showed that prophylaxis reduced the relative risk of having one microbiological recurrence by five- fold (0.21) (95% CI 0.13 to 0.34), giving number needed to treat of 1.85, over 6–12?months (Albert 2004). However, adverse effects occurred, particularly following nitrofurantoin, and 30% of women did not adhere to treatment. Any benefit was lost as soon as the prophylaxis stopped. Post-coital antibiotics were equally effective to nightly prophylaxis ADDIN REFMGR.CITE <Refman><Cite><Author>Albert</Author><Year>2004</Year><RecNum>3493</RecNum><IDText>Antibiotics for preventing recurrent urinary tract infection in non-pregnant women</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3493</Ref_ID><Title_Primary>Antibiotics for preventing recurrent urinary tract infection in non-pregnant women</Title_Primary><Authors_Primary>Albert,X.</Authors_Primary><Authors_Primary>Huertas,I.</Authors_Primary><Authors_Primary>Pereiro,I.I.</Authors_Primary><Authors_Primary>Sanfelix,J.</Authors_Primary><Authors_Primary>Gosalbes,V.</Authors_Primary><Authors_Primary>Perrota,C.</Authors_Primary><Date_Primary>2004</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>analysis</Keywords><Keywords>Antibiotic Prophylaxis</Keywords><Keywords>Antibiotics</Keywords><Keywords>Candidiasis</Keywords><Keywords>Ciprofloxacin</Keywords><Keywords>Clinical</Keywords><Keywords>Confidence Intervals</Keywords><Keywords>Data Collection</Keywords><Keywords>Female</Keywords><Keywords>Health</Keywords><Keywords>Humans</Keywords><Keywords>Infection</Keywords><Keywords>Oral</Keywords><Keywords>Pefloxacin</Keywords><Keywords>prevention & control</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Recurrence</Keywords><Keywords>Risk</Keywords><Keywords>Safety</Keywords><Keywords>Secondary Prevention</Keywords><Keywords>Selection</Keywords><Keywords>Spain</Keywords><Keywords>Statistical</Keywords><Keywords>therapy</Keywords><Keywords>Urinary Tract</Keywords><Keywords>Urinary Tract Infections</Keywords><Reprint>Not in File</Reprint><Start_Page>CD001209</Start_Page><Periodical>Cochrane.Database.Syst.Rev.</Periodical><Issue>3</Issue><Address>Health Center of Marco Merenciano, Conselleria de Sanidad, Marco Merenciano no 26, Valencia, Spain, 46025. albert_xav@gva.es</Address><Web_URL>PM:15266443</Web_URL><ZZ_JournalStdAbbrev><f name="System">Cochrane.Database.Syst.Rev.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Albert et al. 2004). If recurrence is not too frequent it may be better to provide the patient with standby nitrofurantoin or fosfomycin to take post-coitally or as soon as symptoms occur; this approach was shown to result in less use of antibiotics and intuitively should result in less antibiotic resistance. Prophylactic antibiotics given at catheter change do not reduce infections (NICE 2012) and contribute to pressure on emergence of resistance . This recommendation was based on consensus of the NICE group. NICE recommends that clinicians should consider antibiotic prophylaxis at change of catheter for patients who: ihave a history of symptomatic urinary tract infection after catheter change or ii. experience trauma during catheterisation (frank haematuria after catheterisation or two or more attempts of catheterisation). EvidenceRestrictive and persuasive interventions are equally effective in controlling antibiotic use and antimicrobial resistance1+ Audit and feedback interventions result in a increase in healthcare professionals compliance with desired practice 1++In women with uncomplicated urinary infection the highest positive predictive value for urinalysis was for having nitrite and EITHER blood or leucocytes 1+Bacteraemias due to Escherichia coli have increased in the last 10 years4 There is no patient benefit in treating asymptomatic bacteruria 1+Treatment of catheterised patients with antibiotics increases colonisation by antibiotic resistant strains1+Using an algorithm based on fever and at least one sign of urinary infection reduces the number of antibiotic prescriptions in nursing homes 3Daily (1++) or post coital (1+) antibiotic prophylaxis is very effective in reducing recurrent urinary infection but, to reduce emergence of resistance, standby antibiotics are preferable . 4Prophylactic antibiotics given at catheter change do not reduce infections and prophylaxis may lead to an increase in resistance to that drug 4. Local surveillance data is needed to determine appropriate empirical antibiotic regimens 4RecommendationsUse persuasive and restrictive interventions to reduce the total antibiotic consumption, particularly broad-spectrum antibiotics in the, community and care home setting. StrongUse audit and feedback to reduce antimicrobial use in the community and care home setting.ConditionalFollow local guidance for advice on what antibiotics to prescribe, basing decision on when to prescribe (whatever the age) primarily on symptoms and using dipstick tests only to confirm the diagnosis of urinary infection, especially when symptoms are mild. StrongCommunity onset E. coli bacteraemias are increasing so ALWAYS inform patients what to look out for, how to seek further help and what to expect over time, so that the patient or their carers knows when to reconsult if their symptoms worsen or do not improve. StrongDo not prescribe antibiotics in asymptomatic bacteriuria in older people or those with indwelling catheters. StrongOnly start empirical antibiotics and send urine for culture in an elderly patient if they have two or more signs of infection, especially dysuria, fever > 38 o C or new incontinence ConditionalAlthough daily or post-coital antibiotic prophylaxis is very effective in reducing recurrent UTI, use standby antibiotics as the default.ConditionalDo not give antibiotic prophylaxis for urinary catheter insertion or changes unless previous history of symptomatic urinary infections associated with a catheter change or there is trauma during the catheter insertion. ConditionalLocal surveillance data should be used to inform empirical antibiotic advice for UTI in the community setting. Conditional Further ResearchDiagnostic tests and or serum markers should be assessed for safety and efficacy as aids in deciding to stop antimicrobial treatment, particularly in critically ill and patients with haematological malignancies. Randomized controlled studies of antimicrobial agents (both new and old) in the treatment of Gram-negative infection in areas where multiresistance likely e.g. critical care and urology.To develop new models of licensing and funding of antimicrobials for treating multiresistant Gram-negative infections. Undertake surveillance in both the hospital and community populations for incidence of known mechanisms of resistance and the emergence of novel resistance mechanisms to currently used antimicrobials.Develop non-microbial therapies for MRGNB (e.g. phage, antibacterial peptides, etc.).Table 1 Levels of evidence for intervention studies(SIGN 2014, Cochrane 2013) 1++High-quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias1 +Well-conducted meta-analyses, systematic reviews or RCTs with a low risk of bias1 -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 andthree data points after the intervention2+ Well-conducted case–control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal.Controlled before–after studies with two or more intervention and control sites2-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 site3Non-analytic studies (e.g. uncontrolled before–after studies, case reports, case series)4Expert 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.Table 2 Recommendation grading(SIGN 2014)RecommendationUndesirable consequences clearly outweighdesirable consequencesStrong recommendation againstUndesirable consequences probably outweighdesirable consequencesConditional recommendation againstBalance between desirable and undesirableconsequences is closely balanced or uncertain.Recommendation for research and possiblyconditional recommendation for use restricted totrialsDesirable consequences probably outweighundesirable consequencesConditional recommendation forDesirable consequences clearly outweighundesirable consequencesStrong recommendation for Table 3 Studies of the efficacy of ColistinStudy No of patientsConditions treatedPathogensDuration (mean)OutcomeLevin 199959VAP 33%UTI 20%BSI 15%CNS 8%A. baumannii 65%P. aeruginosa 35% 12 days58% success overallWorst in pneumonia group (25%)Garnacho-Montero et al. 200321VAP 100%A. baumannii 100%14 days57% successLinden et al. 200323VAP 78%BSI 35%Intra-abdominal 26%P. aeruginosa 100%17 days61% favourableMarkou et al. 200324VAP 63%Catheter related 12%Meningitis 4%A. baumannii 24%P. aeruginosa 76% 13.5 days73% successMichalopoulos et al. 2005 43VAP 73%BSI 33%A. baumannii 19%P. aeruginosa 81%18.6 days69% clinical cureReina et al. 2005 55VAP 53%UTI 18%BSI 16%A. baumannii 65%P. aeruginosa 35% 13 days15%Koomanachai et al. 2007 78VAP 58%BSI 10%A. baumannii 91%P. aeruginosa 9%12 days81% clinical responseVAP ventilator associated pneumoniaUTI urinary tract infection#BSI bloodstream infectionCNS central nervous system Figure 1. Flow chart of systematic review12592051621155Records identified through database searchingN = 239800Records identified through database searchingN = 2398-800103634740Screening00Screening-800106835140Included00Included-800105234940Eligibility00Eligibility25139642411730004799964241173000-800102034540Identification00Identification38296851621155Additional records identified through other sourcesN = 100Additional records identified through other sourcesN = 122713952868930Records after duplicates removedN = 238500Records after duplicates removedN = 238528225753897630Records screenedN = 238500Records screenedN = 238551435003897630Records excludedN = 190200Records excludedN = 190228035254813300Full-text articles assessed for eligibilityN = 252300Full-text articles assessed for eligibilityN = 252351409604813300Full-text articles excluded, with reasonsN = 440Full-text articles not retrievedN = 600Full-text articles excluded, with reasonsN = 440Full-text articles not retrievedN = 628035255839460Studies included in qualitative synthesisN = 4900Studies included in qualitative synthesisN = 4928003506869430Studies included in quantitative synthesis (meta-analysis)N = 000Studies included in quantitative synthesis (meta-analysis)N = 03656964344043000365696444691300036569645497830003656964652653000449262541827440045148505154294009144004598035Full-text articles assessed for eligibility in September 2014N = 11400Full-text articles assessed for eligibility in September 2014N = 11426289005142864009144005831205Studies included in qualitative synthesis in September 2014N = 1600Studies included in qualitative synthesis in September 2014N = 162628900617156400Figure 2 – Carbapenemase-producing Enterobacteriaceae confirmed by PHE-AMRHAI-Colindale from Laboratories in England (Prof. D.A. 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High-level expression confers resistance to penicillins (except temocillin), cephalosporins (except cefepime), aztreonam and penicillin- β-lactamase inhibitor combinations.Antimicrobial: A substance that kills or inhibits the growth of microorganismsBacteraemia: The presence of micro-organisms in the blood streamβ-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 meropenem; most also attack and confer resistance to penicillins and cephalosporins Colonization: Situation whereby microorganisms establish themselves in a particular environment, such as a body surface, without producing diseaseCommunity-acquired: infection or colonization that is acquired outside of hospitals. Community-associated: usually defined as infection or colonization detected in an outpatient or within 48 hours of hospital admission.ESBL (extended-spectrum β-lactamase): β-Lactamases that attack cephalosporins with an oxyimino side chain, for example, cefotaxime, ceftriaxone, and ceftazidime, as well as the oxyimino-monobactam aztreonam. Unlike AmpC -lactamases (q.v.) they are inhibited by clavulanic acid and tazobactam and unlike carbapenemases (q.v.) they do not attack carbapenemsHealthcare – associated (acquired): infection or colonization detected in an inpatient more than 48 hours after hospital admission.Infection: Invasion by and multiplication of pathogenic microorganisms in the body, producing tissue injury and disease, requiring treatment.KPC Klebsiella pneumoniae carbapenemase-producing bacteria are drug-resistant Gram negative bacilli which spread rapidly and cause significant morbidity and mortality. They are the most prevalent carbapenemase producers encoded by the blaKPC gene, which can be found in other Gram negative species.Metallo β-lactamase (MBL) producing gram negative bacteria use a Zn2+ ion in expressing resistance to carbapenemsMulti-drug resistant Gram-negative bacteria are bacteria resistant to at least three different antibiotics. NDM New Delhi metallo β-lactamase is located on a mobile genetic element blaNDM-1 and is found on plasmids of various sizes. It is found in various species making outbreaks more difficult to identify. OXA-48 carbapenemases hydrolyze penicillins at a high level but carbapenems at a low level sparing broad spectrum cephalosporins and are no susceptible to β-lactamase inhibitors. Recogniition in the laboratory can be difficult. The gene blaOXA-48 is carried on a plasmid.Outbreak: at least two similar (i.e. not distinct) cases related in time and place Porins: These are proteins that span the outer membrane of Gram-negative bacteria and mycobacteria forming pores that allow the entry of small water-soluble molecules, including antibiotics.VIM metallo-β-carbapenemases are predominantly found in Pseudomonas aeruginosa. The genes blaVIM are located on mobile integrons. They can degrade virtually all β-lactams exept monobactams.Appendix 2: Working Party ScopeJoint BSAC/HIS Working Party on Multi-resistant Gram-negative bacteriaA proposal for the Councils to considerGuideline titlePrevention and Control of MDR Gram-negative bacteria – recommendations from a Joint Working PartyShort title Multi-resistant Gram-negative bacteriaThe remitTo examine and make recommendations both for treatment and prevention of transmission of multi-resistant-Gram-negative infections, resulting in the publication of guidelines on:ACurrent epidemiology and infection control issues.BTherapeutic issues and antibiotic guidance for treating infections caused by multi-resistant Gram-negatives.Clinical need for the guidelineEpidemiologyThere 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. Current practiceMembers 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.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.PopulationGroups that will be coveredAdultsChildren over 1 month oldParticular 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 settingsGroups that will not be coveredCystic fibrosisCommunity outbreaksHealthcare settingAll settings in which NHS care is receivedClinical managementKey clinical issues that will be coveredConsideration 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. The use of antibiotic combinations in the therapy of infections will be considered, particularly oral combinations that can be used in the outpatient setting. 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.Clinical issues that will not be coveredChildren younger than 1 month (neonates). This group has physiologically different needs and care is very specialised. people with cystic fibrosis, who need specialised carepeople , who receive community health care in nursing homesMain outcomesOutputs 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:Current epidemiology and infection control issues – Journal of Hospital InfectionTherapeutic issues and antibiotic guidance for treating infections caused by multi-resistant Gram-negatives – Journal of Antimicrobial ChemotherapyIn 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.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. Economic aspectsDevelopers will take into account both clinical and cost effectiveness when making recommendations involving a choice between alternative interventions.StatusScopeFinal scopeTimingThe work will start in October 2011.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.Appendix 3Guideline DevelopmentThe 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 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.Conflict of InterestsConflicts 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. Infection Control -Systematic Review ProcessPICO: 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 recommendationsComparisons: comparisons between intervention and standard management were used; Outcomes were objective referring to length of hospital stay, mortality, rate of acquisition or infection. Systematic Review QuestionsWhat is the definition of Multidrug Resistant Gram-negative bacilli? What Gram-negative bacilli cause infection control problems?What are the relative contributions of community and hospital acquisition?What is the evidence for reservoir and spread of mulitresistant Gram-negatives in Care Homes and secondary care?What is the role of agricultural use of sewage and antibiotic treatment in veterinary practice in spreading ESBL?What insights has national E. coli bacteraemia surveillance provided?What is the role for screening in patients and staff?What organisms should screening include?Who, how and when to screen patients for Multidrug Resistant Gram-negative bacilli?What can be done concerning patients unable to consent to a rectal swab?How frequently does screening need to be performed?Is there evidence for effective interventions on positive patients i.e. can carriage be cleared? Selective decontamination: Why is it not used? Is there a role?When should the environment be sampled?What is the evidence that respiratory equipment contributes to transmission?What national surveillance is performed and how should it be developed?What is the evidence that sensor taps contribute to transmission?Is there any cleaning method more effective than others at removing the Multidrug Resistant Gram-negative bacilli from the environment?What is the evidence that infection control precautions prevent transmission? Are standard infection control measures sufficient to stop transmission? What are the minimum standards to stop spread in public areas, primary care or care homes? Is there evidence for high/low risk areas within a healthcare facility?Are there any organisational structures within a healthcare facility that play a role in the successful control of multi-resistant Gram-negative bacilli?How should we undertake local screening, why is it important and how should it be interpreted?At what point should passive surveillance switch to active surveillance i.e. screening?What is the role of isolation in the care home/hospital settings?Is there evidence of differences between organisms in respect of transmission, morbidity and mortality: Antimicrobial Chemotherapy -Systematic Review ProcessSystematic Review QuestionsWhat is the clinical importance of carbapenemases versus Amp C and CTX-M strains? What impact have returning travellers made on UK epidemiology?What is the global epidemiology of MDR-GNR?How do Multidrug Resistant Enterobacteriaceae differ from the non-fermenters in terms of their prevalence and associated resistance genes?What is the efficacy of carbapenems, mecillinam, temocillin, fosfomycin and colistin against specific pathogens?What are the recommended antibiotics for community/secondary/tertiary care?What is the threshold level of resistance for changing choice of empirical treatment for urinary infection? Databases and Search terms Used 23/5/14DatabasesThe Cochrane Library; MEDLINE; EMBASE; CINAHLMeSH Terms see Appendix 1Free text terms. See Appendix 1Search Date: Medline 1946-2014; Embase 1980-2012; CINAHL (1984-2012)Search Results (Figure 2)Total number of articles located after duplicates removed = 2523Sift 1 CriteriaAbstract screening: Systematic review, primary research, infection relates to MDR Gram-negative infection, informs one or more review questionArticles RetrievedTotal number of studies selected = 597Sift 2 CriteriaFull 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 = 49Critical appraisalArticles 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 discussionAccepted and Rejected EvidenceNo meta analyses were availableAccepted after critical appraisal 49Rejected after critical appraisal 0 Appendix 4. Search StrategyCINAHL (January 1984-December 2012)# Query Results S83 S48 AND S82 275S82 S55 OR S56 OR S81 515,966S81 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 471,263S80 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’) ) 1,527S79 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) ) 45,564S78 TI ( multicentre or multicenter or multi-centre or multi-center ) or AB random* 101,899S77 TI random* OR controlled 94,669S76 TI ( trial or (study n3 aim) or ‘our study’ ) or AB ( (study n3 aim) or ‘our study’ ) 87,121S75 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) ) 283S74 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* ) 1,290S73 (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) 23,198S72 TI ( collaborativ* or collaboration* or tailored or personalised or personalized ) or AB ( collaborativ* or collaboration* or tailored or personalised or personalized ) 38,021S71 TI pilot 13,958S70 (MH ‘Pilot Studies’) 36,433S69 AB ‘before-and-after’ 17,437S68 AB time series 1,670S67 TI time series 359S66 AB ( before* n10 during or before n10 after ) or AU ( before* n10 during or before n10 after ) 32,982S65 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*) ) 51,050S64 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* ) ) 12,758S63 TI pre w7 post or AB pre w7 post 9,367S62 MH ‘Multiple Time Series’ or MH ‘Time Series’ 1,312S61 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 ) 11,680S60 MH Experimental Studies or Community Trials or Community Trials or Pretest-Posttest Design + or Quasi-Experimental Studies + Pilot Studies or Policy Studies + Multicenter Studies 34,567S59 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* ) 6,868S58 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* ) 151,748S57 (MH ‘Quasi-Experimental Studies’) 5,747S56 (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*)) 59,817S55 S49 OR S50 OR S51 OR S52 OR S53 OR S54 158,596S54 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*’ ) 1S53 TI controlled or AB controlled 68,638S52 TI random* or AB random* 117,418S51 TI ( ‘clinical study’ or ‘clinical studies’ ) or AB ( ‘clinical study’ or ‘clinical studies’ ) 7,969S50 (MM ‘Clinical Trials+’) 10,670S49 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*) ) 8,917S48 S18 AND S21 AND S47 917S47 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 16,726S46 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) ) 171S45 (MH ‘Colistin’) 134S44 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) ) 13S43 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) ) 1,569S42 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) ) 171S41 (MH ‘Cephalosporins+’) 2,105S40 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) ) 325S39 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) ) 96S38 (MH ‘Aztreonam’) 54S37 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) ) 57S36 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) ) 342S35 (MH ‘Amikacin’) 140S34 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) ) 993S33 (MH ‘Gentamicins’) 808S32 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) ) 1,269S31 (MH ‘Aminoglycosides+’) 6,215S30 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) ) 834S29 (MH ‘Quinolines+’) OR (MH ‘Antiinfective Agents, Quinolone+’) 4,842S28 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*)) ) 208S27 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) ) 10S26 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’)) ) 805S25 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) ) 247S24 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) ) 296S23 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*) ) 974S22 (MH ‘Carbapenems+’) 559S21 S19 OR S20 14,473S20 (MH ‘Drug Resistance, Microbial+’) 14,182S19 TI ( (multiresistant or (multi n1 resistan*)) ) OR AB ( (multiresistant or (multi n1 resistan*)) ) 604S18 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 7,706S17 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)) ) 20S16 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)) ) 32S15 (MH ‘Citrobacter’) 40S14 TI Serratia OR AB Serratia 238S13 (MH ‘Serratia’) OR (MH ‘Serratia Infections’) 174S12 TI Proteus OR AB Proteus 257S11 (MH ‘Proteus’) OR (MH ‘Proteus Infections’) 118S10 TI ( (Acinetobacter or mima or mimae or herellea or acinetobacterium) ) OR AB ( (Acinetobacter or mima or mimae or herellea or acinetobacterium) ) 889S9 (MH ‘Acinetobacter Infections’) 581S8 TI ‘p. aeruginosa’ OR AB ‘p. aeruginosa’ 610S7 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))) ) 1,855S6 TI ( (enterobacter or aerobacter) ) OR AB ( (enterobacter or aerobacter) ) 370S5 TI ( (‘k. pneumoniae’ or ‘b. friedlander’) ) OR AB ( (‘k. pneumoniae’ or ‘b. friedlander’) ) 200S4 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) ) 1,039S3 (MH ‘Klebsiella’) OR (MH ‘Klebsiella Infections’) 835S2 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)) ) 2,914S1 (MH ‘Escherichia Coli’) OR (MH ‘Escherichia Coli Infections’) 2,983Cochrane Library (Issue 11, 2012)IDSearch#1MeSH 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)#3MeSH descriptor: [Klebsiella] explode all trees#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)#5k. pneumoniae or b. friedlander:ti,ab,kw (Word variations have been searched)#6MeSH descriptor: [Enterobacter] explode all trees#7(enterobacter or aerobacter):ti,ab,kw (Word variations have been searched)#8MeSH 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)#10p. aeruginosa:ti,ab,kw (Word variations have been searched)#11MeSH descriptor: [Acinetobacter] explode all trees#12(Acinetobacter or mima or mimae or herellea or acinetobacterium):ti,ab,kw (Word variations have been searched)#13MeSH descriptor: [Proteus] explode all trees#14Proteus:ti,ab,kw (Word variations have been searched)#15MeSH descriptor: [Serratia] explode all trees#16Serratia:ti,ab,kw (Word variations have been searched)#17MeSH 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)#19MeSH 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)#23MeSH descriptor: [Drug Resistance, Multiple] explode all trees#24#22 or #23 #25MeSH 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)#27MeSH descriptor: [Carbapenems] explode all trees#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$):ti,ab,kw (Word variations have been searched)#29MeSH descriptor: [Piperacillin] explode all trees#30(acopex or avocin or cl 227,193 or Cl 227193 or cl 227193 or cl 227193 or cl227,193 or Cl227193 or cl227193 or cl227193 or Cl-227193 or cl-227193 or cypercil or hishiyaclorin or ivacin or pentcillin or pentocillin or picillin$ 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)#32MeSH 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)#36MeSH 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)#38MeSH 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)#40MeSH descriptor: [Gentamicins] explode all trees#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)#42MeSH 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)#44MeSH 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)#46MeSH 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)#48MeSH 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)#50MeSH descriptor: [Cephalosporins] explode all trees#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)#52MeSH 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)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 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)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)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)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)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$))).ti,ab. (105122)134 or/120-133 (3341084)135 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ (18985259)136 human/ or normal human/ or human cell/ (14037258)137 135 and 136 (14004971)138 135 not 137 (4980288)139 (‘time series’ adj2 interrupt$).ti,ab. (922)140 134 not (138 or 139) (2996658)141 108 or 119 or 140 (5157863)142 60 and 141 (1860)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)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$) or clarin-duo or clavamox or clavar or clavinex or clavodar or clavoxil or (clavoxilin adj plus) or clavubactin or clavudale or clavulanate-amoxicillin or clavulin or (clavulox adj duo) or clavumox or (co adj amoxiclav) or (co adj amoxyclav) or coamoxiclav or co-amoxiclav or coamoxyclav or (cramon adj duo) or (croanan adj duo) or curam or danoclav or (darzitil adj plus) or e-moxclav or enhancin or fleming or fugentin or (fullicilina adj plus) or gumentin or hibiotic or inciclav or klamonex or kmoxilin or lactamox or lansiclav or moxiclav or moxicle or moxyclav or natravox or nufaclav or palentin or quali-mentin or ranclav or spektramox or stacillin or suplentin or synermox or synulox or (velamox adj cl) or vestaclav or viaclav or vulamox or xiclav or (zami adj ‘8503’)).ti,ab. (9184)34 ((brl adj ‘17421’) or brl17421 or (thiophenemalonamic adj acid) or negaban or temocillin or temopen).ti,ab. (179)35 (tigecycline or (tbg adj mino) or tygacil or gar 936 or gar936 or (tert adj butylglycinamido$)).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)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$)).mp. (150717)71 or/57-70 (968331)72 (review or review,tutorial or review, academic).pt. (1758734)73 (systematic$ 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$.tw. (5290)96 critical review.tw. (9227)97 quantitative review.tw. (382)98 structured review.tw. (376)99 realist review.tw. (24)100 realist synthesis.tw. (11)101 review.ti. (212126)102 (review$ 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)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)Appendix 5: CPD material1. Which of the following are appropriate meropenem-sparing agents:a) Temocillinb) Cefiximec) Ceftolozane-tazobactamd) Fosfomycine) Ceftazidime-avibactamAnswer a, c, d, e2. Which of the following are true:a) Polymyxins do not require monitoring renal function in the elderly.b) Fluoroquinolones can be used to treat urinary infection due to multidrug resistant Gram-negative bacteria c) Oral fosfomycin can be used in the treatment of upper urinary infectiond) Polymyxins should be given in combination with other agents if they are used in treating carbapenem-resistant Enterobacteriaceae. e) Co-trimoxazole should be used in treatment of infections due to Stenotrophomonas maltophilia Answer b, d, e3. Which of the following are true:a) In uncomplicated urinary infection due to a proven ESBL-producing organism, treatment is recommended for 7 days to improve bacteriological clearance. b) If MDR Gram negative infection is suspected, treat asymptomatic bacteriuria c) Give antibiotic prophylaxis for urinary catheter insertion if previous historyof symptomatic urinary infections associated with a catheter change or there is trauma during the catheter insertion d) Daily antibiotic prophyalxis is preferable to standby antibiotics in recurrent urinary infectione) Always send a urine specimen for culture if an antibiotic-resistant organism is suspected AND the patient is asymptomatic Answer a, c,Appendix 6: Consultation stakeholdersAntimicrobial Resistance and Hospital Acquired Infection Advisory Committee (ARHAI) British Medical Association British Society of Antimicrobial Chemotherapy British Infection Association C. Diff SupportEuropean Society of Clinical Microbiology and Infectious DiseasesFaculty of Intensive Care MedicineFoundation Trust NetworkHand Hygiene AllianceHealthcare Infection Society Infection Prevention Society Lee Spark FoundationMRSA Action UKNHS ConfederationNHS EnglandNHS Trust Development AuthorityPatient’s AssociationPublic Health England/ Wales/ Scotland/ Northern Ireland Royal College of Pathologists Royal College of General PractitionersRoyal College of Nursing Royal College of Physicians Royal College of Surgeons Service User Research Forum Healthcare acquired Infections UK Clinical Pharmacists AssociationUnison ................
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