1. Antimicrobial Stewardship The Welsh Perspective Using antibiotics prudently Insert name of presenter

2. Contents of this presentation Antibiotic resistance – a patient safety issue –Situation in Europe –Drivers of antibiotic resistance –Consequences of antibiotic resistance Why inappropriate use of antibiotics contributes to antibiotic resistance How prudent use of antibiotics can be promoted in hospitals European Antibiotic Awareness Day – a campaign to promote prudent use of antibiotics

3. Antibiotic resistance – a patient safety and public health issue

4. Antibiotic resistance – a problem in the present and the future Antibiotic resistance is an increasingly serious patient safety and public health problem: resistant bacteria have become an everyday concern in hospitals across Europe (figure 1) The pipeline for new antibiotics is discouraging Figure 1: European E. coli bacteraemia resistance rates 2009 hhttp://www.ecdc.europa.eu/en /activities/ surveillance/ EARS- Net/database/Pages/map_reports.aspx

5. Use selects resistance Acquired resistance absent from bacteria collected pre-1940 Resistance repeatedly followed introduction of new antibiotics Resistance greatest where use heaviest (figure 2) Resistant mutants selected in therapy

6. 1. Bronzwaer et al Emerg Infect Dis. 2002; 8:278-82 Figure 2: Β-lactam use & resistance in S. pneumoniae across countries in Europe 1 Low rates of antibiotic use = Low resistance rates

7. Antibiotic resistance – a patient safety issue for all hospitals The emergence, selection and spread of resistant bacteria in hospitals is a major patient safety and public health issue. o Infections with antibiotic-resistant bacteria can result in increased patient morbidity and mortality, as well as increased hospital length of stay and cost of care. 2-3 o Antibiotic resistance frequently leads to a delay in appropriate antibiotic therapy. 4 o Inappropriate or delayed antibiotic therapy in patients with severe infections is associated with worse patient outcomes and sometimes death. 5-7 2. Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis. 2003 Jun 1;36(11):1433-7. 3. Roberts RR, Hota B, Ahmad I, Scott RD, 2nd, Foster SD, Abbasi F, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009 Oct 15;49(8):1175-84. 4. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999 Feb;115(2):462-74. 5. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000 Jul;118(1):146-55. 6. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003 Jun 1;36(11):1418-23. 7. Alvarez-Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired pneumonia Study Group. Intensive Care Med. 1996 May;22(5):387-94.

8. Antibiotics remain an invaluable but finite resource Current evidence clearly demonstrates that the inappropriate use of broad-spectrum antibiotics is associated with the selection of antibiotic resistant bacteria such as Extended-Spectrum Beta-Lactamase (ESBL)-producing Gram-negative bacteria 8 It is important to preserve antibiotics In particular carbapenems (imipenem, meropenem, ertapenem and doripenem) which are invaluable for the treatment of infections due to multi-resistant gram- negative bacteria, including those with extended- spectrum b-lactamases. Carbapenem-resistant Enterobacteriaceae remain rare but are emerging (Figure 3) 8. Livermore DM and Hawkey PM. CTX-M: changing the face of ESBLs in the UK. Journal of Antimicrobial Chemotherapy, 2005; 56:451-454

9. http:// www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1294740725984 Figure 3: Carbapenemase-producing Enterobacteriaceae referred to Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency, England Carbapenemase-producing Enterobacteriaceae in England

10. Carbapenemases ClassificationEnzymeMost Common Bacteria Class AKPC, SME, IMIK. pneumoniae Enterobacteriaceae (rare reports in P. aeruginosa) Class B (metallo-  - lactamase) NDM, IMP, VIMP. aeruginosa Enterobacteriaceae Acinetobacter spp. Class DOXAAcinetobacter spp.

11. Emerging Carbapenem Resistance in Gram-Negative Bacilli Significantly limits treatment options for life-threatening infections There are currently no new drugs for gram-negative bacilli Emerging resistance mechanisms, carbapenemases are mobile Prudent antimicrobial stewardship is essential Detection of carbapenemases and implementation of infection prevention & control practices are also necessary to limit acquisition and spread of resistance

12. Antibiotic resistance – a daily occurrence in our hospital and community In Wales the most frequent infections where resistance is an issue are o E. coli bacteraemias (secondary care) o Coliform UTIs (primary care)

13. All-Wales resistance rates for E. coli bacteraemias Figure 4: All-Wales E. coli bacteremia resistance rates 2005-2010 http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457&pid=20787 Key: 3GC: Third generation cephalosporins AMO: Amoxicillin COA: Co-amoxiclav CARB: Carbapenems CXM: Cefuroxime FQ: Fluoroquinolones GEN: Gentamicin PTZ: Piperacillin/tazobactam

14. Hospital-level resistance rates for E. coli bacteraemias http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457&pid=20787 Table 1: Hospital-level E. coli bacteremia resistance rates 2010

15. All-Wales resistance rates for Community urinary coliforms Figure 5: All-Wales E. coli bacteremia resistance rates 2005-2010 http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457&pid=20787 Key: 1GC: First generation cephalosporins AMO: Amoxicillin AMO/TRI: Combined resistance to both agents AMO/TRI/FQ: Combined resistance to all 3 agents COA: Co-amoxiclav FQ: Fluoroquinolones NIT: Nitrofurantoin TRI: Trimethoprim

16. Laboratory-level resistance rates for community urinary coliforms http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457&pid=20787 Table 2: Laboratory-level community urinary coliform resistance rates 2010

17. Why inappropriate use of antibiotics contributes to antibiotic resistance –“why” this should be important to you 17

18. In-patients are at high risk of antibiotic- resistant infections Studies show that misuse of antibiotics in hospitals is one of the main factors that drive development of antibiotic resistance. 9-10 Patients in hospitals have a high probability of receiving an antibiotic 11 and up to 50% of all antibiotic use in hospitals can be inappropriate. 12-13 References: 9. Lesch CA, Itokazu GS, Danziger LH, Weinstein RA. Multi-hospital analysis of antimicrobial usage and resistance trends. Diagn Microbiol Infect Dis. 2001 Nov;41(3):149-54. 10. Lepper PM, Grusa E, Reichl H, Hogel J, Trautmann M. Consumption of imipenem correlates with beta-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2002 Sep;46(9):2920-5. 11. Ansari F, Erntell M, Goossens H, Davey P. The European surveillance of antimicrobial consumption (ESAC) point-prevalence survey of antibacterial use in 20 European hospitals in 2006. Clin Infect Dis. 2009 Nov 15;49(10):1496-504. 12. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543. 13. Willemsen I, Groenhuijzen A, Bogaers D, Stuurman A, van Keulen P, Kluytmans J. Appropriateness of antimicrobial therapy measured by repeated prevalence surveys. Antimicrob Agents Chemother. 2007 Mar;51(3):864-7.

19. Misuse of antibiotics drives antibiotic resistance Studies prove that misuse of antibiotics may cause patients to become colonised or infected with antibiotic- resistant bacteria, such as meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and highly-resistant Gram-negative bacilli. 14-15 Misuse of antibiotics is also associated with an increased incidence of Clostridium difficile infections. 16-18 References: 14. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. 2002 Jun 4;136(11):834-44. 15. Tacconelli E, De Angelis G, Cataldo MA, Mantengoli E, Spanu T, Pan A, et al. Antibiotic usage and risk of colonization and infection with antibiotic-resistant bacteria: a hospital population-based study. Antimicrob Agents Chemother. 2009 Oct;53(10):4264-9. 16. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 15. 2005(4):CD003543. 17. Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 18. Fowler S, Webber A, Cooper BS, Phimister A, Price K, Carter Y, et al. Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series. J Antimicrob Chemother. 2007 May;59(5):990-5.

20. What is misuse of antibiotics? Misuse of antibiotics include: 19 Prescribing antibiotics unnecessarily Delaying antibiotic treatment in critically ill patients; Using broad-spectrum antibiotics too generously, or narrow-spectrum antibiotics incorrectly; Using lower or higher antibiotic dose than appropriate for the specific patient; Inappropriate duration of antibiotic treatment - too short or too long; Not streamlining antibiotic treatment according to microbiological culture data results. Omitting or delaying doses of prescribed antibiotics 19. Gyssens IC, van den Broek PJ, Kullberg BJ, Hekster Y, van der Meer JW. Optimizing antimicrobial therapy. A method for antimicrobial drug use evaluation. J Antimicrob Chemother. 1992 Nov;30(5):724-7.

21. Benefits of prudent use of antibiotics 1 Prudent use of antibiotics can prevent the emergence and selection of antibiotic-resistant bacteria. 20-24 Figure 6: Rates of Vancomycin-resistant Enterococci in hospital before and after implementation of the antibiotic management program compared with rates in National Nosocomial Infections Surveillance (NNIS) System* hospitals of similar size 28. *NNIS is now the National Healthcare Safety Network (NHSN). References: 20. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543. 21. Lepper PM, Grusa E, Reichl H, Hogel J, Trautmann M. Consumption of imipenem correlates with beta-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2002 Sep;46(9):2920-5. 22 & 28. Carling P, Fung T, Killion A, Terrin N, Barza M. Favourable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 23. Bradley SJ, Wilson AL, Allen MC, Sher HA, Goldstone AH, Scott GM. The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage. J Antimicrob Chemother. 24. De Man P, Verhoeven BAN, Verbrugh HA, Vos MC, Van Den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli. Lancet. 2000;355(9208):973-8.

22. Benefits of prudent use of antibiotics 2 Decreasing antibiotic use have also been shown to result in lower incidence of Clostridium difficile infections. 25-27 Figure 7: Rates of nosocomial Clostridium difficile, expressed per 1,000 patient-days, before and after implementation of the antibiotic management program. 29 References: 25. Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis. 1999 Jul;29(1):60-6; discussion 7-8. 26, 27, 29. Carling P, Fung T, Killion A, Terrin N, Barza M. Favourable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706.

23. How prudent use of antibiotics can be promoted in hospitals And How we are trying to make it easier for you

24. Multifaceted strategies can address and decrease antibiotic resistance in hospitals A ntibiotic prescribing practices and decreasing antibiotic resistance can be addressed through multifaceted strategies (Antimicrobial Stewardship) including: 30-32 o Use of ongoing education o Use of evidence-based hospital antibiotic guidelines and policies o Restrictive measures and consultations from infectious disease physicians, microbiologists and pharmacists Rerefernces: 30. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543. 31. Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 32. Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis. 1999 Jul;29(1):60-6; discussion 7-8.

25. Measures that can decrease antibiotic resistance Pr escribing Measures likely to decrease antibiotic resistance in hospitals are described in the Start Smart – then Focus guidance by the DH’s Advisory Committee on Antimicrobial Resistance and Health Care Associated Infections (ARHAI) 33-35 START SMART: Start prompt effective treatment in patients with life-threatening infection Collect appropriate and early cultures before starting antibiotic therapy 36. Prescribe in accordance with local antibiotic policies/guidelines and resistance patterns 37 Document indication (s), route, dose and duration for antibiotic prescription on prescription chart and in clinical notes and For most surgical procedures, only single dose prophylaxis is recommended Consult infection expert (s) and/or pharmacists if appropriate 33-35 References: 33, Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543 34, Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 35 Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis. 1999 Jul;29(1):60-6; discussion 7-8. 36. Rello J, Gallego M, Mariscal D, Sonora R, Valles J. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med. 1997 Jul;156(1):196-200. 37. Beardsley JR, Williamson JC, Johnson JW, Ohl CA, Karchmer TB, Bowton DL. Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest. 2006 Sep;130(3):787-93.

26. Measures that can decrease antibiotic resistance THEN FOCUS: At 48 hours; review the patient and make a clinical decision “the Antimicrobial Stewardship Decision” on the need for on-going antibiotic therapy. Does patient’s condition and/or culture results) necessitate: 1.Stop of antibiotic therapy (if no evidence of infection) 2.Switch from intravenous to oral therapy 3.Change: De-escalation/substitution/addition of agents 4.Continuation - review again at 72 hours OR 5.Outpatient Parenteral Antibiotic Therapy (OPAT). Document Decision References: 33, Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543 34, Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 35 Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis. 1999 Jul;29(1):60-6; discussion 7-8.

27. DH-ARHAI Antimicrobial Stewardship Guidance – Launch date: 18 November 2011

29. Our hospital tools for prudent antibiotic prescribing [Hospital antibiogram if available] [Hospital guidelines if available] [Antibiotic stewardship committee if it exists] [Names of infectious diseases / antibiotic experts]

30. Antibiotics – handle with care Misuse of antibiotics leads to resistance 38-40 All hospital practitioners can play an active role in reversing the trend of antibiotic-resistant bacteria: –Take cultures before starting antibiotic therapy 41 –Consult the hospital antibiotic expert 42-44, [hospital antibiotic guidelines and local antibiogram] –Streamline antibiotic therapy based on culture results 45 30 References: 38. Singh N, Yu VL. Rational empiric antibiotic prescription in the ICU. Chest. 2000 May;117(5):1496-9. 39. Lesch CA, Itokazu GS, Danziger LH, Weinstein RA. Multi-hospital analysis of antimicrobial usage and resistance trends. Diagn Microbiol Infect Dis. 2001 Nov;41(3):149-54. 40. Lepper PM, Grusa E, Reichl H, Hogel J, Trautmann M. Consumption of imipenem correlates with beta-lactam resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2002 Sep;46(9):2920-5. 41 & 45. Rello J, Gallego M, Mariscal D, Sonora R, Valles J. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med. 1997 Jul;156(1):196-200. 42. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005(4):CD003543 43. Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699-706. 44.Byl B, Clevenbergh P, Jacobs F, Struelens MJ, Zech F, Kentos A, et al. Impact of infectious diseases specialists and microbiological data on the appropriateness of antimicrobial therapy for bacteremia. Clin Infect Dis. 1999 Jul;29(1):60-6; discussion 7-8.

31. European Antibiotic Awareness Day – a campaign to promote prudent use of antibiotics

32. About European Antibiotic Awareness Day European Antibiotic Awareness Day is marked across Europe around 18 November. European Antibiotic Awareness Day provides a platform and support to national campaigns about prudent antibiotic use in the community and in hospitals.

33. E uropean Antibiotics Awareness Day: Planned local activities [Insert planned local activities, highlighting where involvement by the audience of this presentation would be welcome]

34. Acknowledgements Dr Robin Howe & Dr Maggie Heginbothom – Antimicrobial Resistance Programme, Public Health Wales European Centre for Disease Prevention & Control (ECDC) Professor Brian Duerden – Previously Inspector of Microbiology and Infection Control, Department of Health Dr Cliodna McNulty – Head Primary Care Unit, Health Protection Agency (HPA) & Chair Public Education, DH Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections (ARHAI) Dr Diane Ashiru-Oredope – Pharmacist Lead, DH ARHAI ARHAI EAAD 2011 Planning Group

35. THANK YOU! For more information on data sources and references, please visit: o http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457 &pid=20618 http://howis.wales.nhs.uk/sites3/page.cfm?orgid=457 &pid=20618 o http://www.dh.gov.uk/en/Publichealth/Antibioticresist ance/index.htm http://www.dh.gov.uk/en/Publichealth/Antibioticresist ance/index.htm o http://antibiotic.ecdc.europa.eu http://antibiotic.ecdc.europa.eu