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Treatment of Infections Caused by Multidrug-Resistant Gram-Negative

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Treatment of Infections Caused by Multidrug-Resistant Gram-Negative J Antimicrob Chemother 2018; 73 Suppl 3: iii2–iii78 doi:10.1093/jac/dky027 Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/ Healthcare Infection Society/British Infection Association Joint Working Party† Peter M. Hawkey1*, Roderic E. Warren2, David M. Livermore3, Cliodna A. M. McNulty4, David A. Enoch5, Jonathan A. Otter6 and A. Peter R. Wilson7 1Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK; 2Shrewsbury and Telford Hospital NHS Trust, Telford, UK; 3Norwich Medical School, University of East Anglia, Norwich, UK; 4Microbiology Department, Gloucestershire Royal Hospital, Great Western Road, Gloucester GL1 3NN, UK; 5Public Health England, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 6Imperial College London, UK; 7Department of Microbiology and Virology, University College London Hospitals, London, UK *Corresponding author. Institute of Microbiology and Infection, Biosciences Building, University of Birmingham, Birmingham, B15 2TT UK. Tel: !44 121 414 3113; E-mail: [email protected] The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new defini- tion of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibi- otic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publica- tions and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accord- ance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakehold- ers (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is crit- ically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments.Brothmicrodilutionmeth- ods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infec- tion by GNB should be improved. This guidance, with infectioncontroltoarrestincreasesinMDR,shouldbeusedto improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicro- bial pharmacy and paramedical staff where they can be adapted for local use. †NICE has accredited the process used by the Healthcare Infection Society to produce the ‘Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party’ guidelines. Accreditation is valid for 5 years from March 2015. More information on accreditation can be viewed at http://www.nice.org.uk/about/what-we-do/accreditation. VC The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: [email protected]. iii2 Downloaded from https://academic.oup.com/jac/article-abstract/73/suppl_3/iii2/4915406 by guest on 08 March 2018 Treatment of infections caused by MDR Gram-negative bacteria JAC Contents 7.3 Ceftazidime/avibactam 7.4 Ceftolozane/tazobactam Lay summary 7.5 Aztreonam 1. Introduction 7.6 Cefepime 2. Guideline development team 7.7 Cefoxitin 2.1 Guideline advisory group 7.8 Temocillin 2.2 Responsibility for guidelines 7.9 Ampicillin/sulbactam 3. The Working Party Report 7.10 Co-amoxiclav 3.1 What is The Working Party Report? 7.11 Piperacillin/tazobactam 3.2 Why do we need a Working Party Report for these 7.12 Aminoglycosides infections? 7.13 Polymyxins 3.3 What is the purpose of the Report’s 7.14 Fluoroquinolones recommendations? 7.15 Tigecycline and eravacycline 3.4 What is the scope of these guidelines? 7.16 Fosfomycin 3.5 What is the evidence for these guidelines? 7.17 Trimethoprim/sulfamethoxazole 3.6 Who developed these guidelines? 7.18 Intravenous combination therapy for infections due to 3.7 Who are these guidelines for? carbapenemase producers 3.8 How are the guidelines structured? 8. Oral agents for secondary/tertiary care treatment 3.9 How frequently are the guidelines reviewed and 8.1 Mecillinam and pivmecillinam updated? 8.2 Cefixime and oral cephalosporins 3.10 Aim 8.3 What are the recommended antibiotics for commun- 4. Summary of guidelines ity care, including care homes? 4.1 How can the guidelines be used to improve clinical 8.4 What are the risk factors for patients with urinary tract effectiveness? infections <!——>caused by MDR GNB in the UK? 4.2 How much will implementation of the guidelines cost? 9. Which oral antibiotics are preferred for use in treating uncom- 4.3 Summary of suggested audit measures plicated UTIs due to MDR GNB in the community? 4.4 E-learning tools 9.1 Trimethoprim 5. Methodology 9.2 Nitrofurantoin 5.1 Evidence appraisal 9.3 Fosfomycin trometamol 5.2 Data analysis and interpretation 9.4 Mecillinam and pivmecillinam 5.3 Consultation process 10. Managing urinary tract infection 6. Rationale for recommendations 10.1 Diagnosis and the need for treatment or prophylaxis 6.1 Usage 10.2 Choosing a suitable antibiotic 6.2 What is the definition of multidrug-resistant Gram- 10.3 Treatment of pyelonephritis and complicated UTI negative bacteria? caused by MDR GNB 6.3 What is the global epidemiology of MDR GNB? 10.4 What is the threshold level of resistance for changing 6.3.1 Origins and impact of multiresistance the choice of empirical treatment for UTIs? 6.3.2 Epidemiological trends among MDR 11. What effect does good antibiotic stewardship have on rates Enterobacteriaceae: cephalosporin and quino- of MDR GNB? lone resistance 11.1 The impact of good antibiotic stewardship in secon- 6.3.3 Carbapenem resistance dary/tertiary care facilities 6.3.4 Global resistance issues with oral drugs with 11.2 The national monitoring of good antibiotic steward- low resistance rates in the UK ship in secondary/tertiary care facilities 6.4 How do MDR Enterobacteriaceae differ from non-fer- 11.3 Antibiotic stewardship in the community and care menters in terms of their prevalence and associated homes to reduce MDR Gram-negative infections resistance genes? 12. Conclusions 6.5 Prevalence of antibiotic resistance in Gram-negative 13. Further research and development bacilli in the UK and relevant antibiotic prescribing 6.6 What impact have returning travellers made on UK epidemiology? Lay summary 6.7 What is the clinical importance of carbapenemase- Multidrug-resistant (MDR) Gram-negative bacteria (GNB) are bac- versus CTX-M- and AmpC-producing strains? teria (or germs) that remain susceptible to only one or two antibi- 7. Intravenous treatment options for MDR GNB: what is the effi- otics. Gram-negative bacteria usually live in the gut (or in the cacy of carbapenems, temocillin, fosfomycin, colistin and environment), where they do no harm, but can appear and cause other antibiotics against specific MDR GNB and what are the infection at other body sites that normally lack any bacteria, for recommended antibiotics for secondary/tertiary care? example in the bladder or blood. This especially occurs in patients 7.1 Carbapenems who are made vulnerable by underlying disease, injury or hospital- 7.2 Ceftazidime ization. MDR GNB may be acquired from other patients who have iii3 Downloaded from https://academic.oup.com/jac/article-abstract/73/suppl_3/iii2/4915406 by guest on 08 March 2018 Hawkey et al. received antibiotics. Infections caused by MDR GNB are difficult to addressed the questions raised in setting the Working Party’s treat and so may cause more prolonged symptoms in the site of remit. infection and can cause additional complications such as pneumo- nia or infection in the blood. This can prolong the length of stay in 3. The Working Party Report hospital, and in some cases can cause death. Some types of MDR GNB, Acinetobacter spp. for example, can be carried
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