1. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Antimicrobial resistance – Biological basis and public health consequences John Stelling, MD, MPH WHO Collaborating Centre for Surveillance of Antimicrobial Resistance Boston, USA

2. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA What is antimicrobial resistance? If a drug has no effect on a bacteria, the bacteria is Resistant to the compound Some resistance is ancient – intrinsic –E. coli and vancomycin –M. tuberculosis and penicillin A lot of it is new since 1930 – acquired –S. aureus and oxacillin –N. gonorrhoeae and penicillin

3. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Our universe – an overview Big BangThe SunEarth Bacteria Humans 12 Billion10 Billion 6 Billion 4 Billion  Organisms have been producing “antibiotics” for billions of years – on a tiny scale!  Humans have been using antibiotics on massive scales for the past seven decades Present ASM, © David Phillips/Visuals Unlimited Dinosaurs “Antibiotics” Antibiotic use

4. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA pABADHF THF Folate Synthesis PLASMID CHROMOSOME Protein Synthesis Gram Positive Bacteria Gram Negative Bacteria Cell Wall Synthesis RNA Synthesis DNA Synthesis CELL WALL CELL MEMBRANE BIOFILM RIBOSOMES OUTER MEMBRANE

5. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA How do susceptible bacteria become resistant? Mutation Acquisition of resistance genes S R S R R R In most bacteria, these events are rare* – but critical! * But there are important exceptions – M. tuberculosis, Pseudomonas, Enterobacter

6. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Why are resistant bacteria so common? Selection Spread

7. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Leading bacterial pathogens in 1900 Streptococcus pneumoniaeCorynebacterium diphtheriae Streptococcus pyogenesMycobacterium tuberculosis Staphylococcus aureusHaemophilus influenzae Escherichia coliNeisseria meningitidis Vibrio choleraeNeisseria gonorrhoeae Shigella speciesTreponema pallidum Salmonella typhi

8. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Initial appearance Vancomycin-intermediate Staphylococcus aureus Responses: confirmation, molecular characterization, diagnostic tools, active surveillance, notification of health care providers and general public, review of treatment guidelines, development of new agents

9. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Spread Strep. pneumoniae: multi-resistant, virulent clones Source: WHO Report WHO/CDS/BVI/95.7

10. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Emergence in hospitals Vancomycin-Resistant Enterococci, USA Source: National Nosocomial Infections Surveillance System, CDC, USA

11. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Emergence in the community Resistant E. coli in Healthy Children Source: Lester, NEJM 323:285-289

12. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Emergence in outbreaks Shigella sp. in Rwanda, Amp+TMP Resistant Resistance in S. dysenteriae type 1 has been high for many years. Resistance in other species has been increasing in recent years.

13. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Pig isolates Emergence in animals and humans Resistant Salmonella Typhimurium, Netherlands Human isolates

14. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA The impact of 7 decades of antibiotic use and misuse on bacterial populations Same pathogens as in 1930 –BUT NOW WITH ACQUIRED RESISTANCE!! Plus many new species –Staph. epidermidis, Enterococcus, Pseudomonas, Klebsiella, Acinetobacter, fungi, etc. –features: take advantage of changing societal demographics take advantage of changes in health-care practice intrinsic resistance to commonly used antimicrobials!!  The use of antibiotics has radically altered the microbial populations of the world and the epidemiology of infection

15. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA The impact of Antimicrobial resistance Consequences – morbidity and mortality – direct and indirect costs – transmission Antimicrobials are “societal” drugs. Antimicrobial use in one person affects us all

16. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Antimicrobial resistance as an unusual public health threat A problem created by medical innovation – antimicrobial use by patients, health-care providers, food- producers, industry drives resistance trends A problem of dependence – Antimicrobial resistance is NOT a disease. It’s a characteristic of many organisms which cause a wide variety diseases. – If we can prevent or treat disease in other ways, resistance would cease to be a public health menace.

17. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Strategies for Containment of Antimicrobial resistance John Stelling, MD, MPH WHO Collaborating Centre for Surveillance of Antimicrobial Resistance Boston, USA

18. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Target areas –Disease prevention and infection control –Access to antimicrobials –Appropriate use –Legislation and regulation –Surveillance –Focused research Target groups –patients and general community –hospitals, prescribers and dispensers –food animal industry –governments and health systems –international organizations –pharmaceutical and diagnostic industries –researchers

19. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA In using antimicrobials, we must seek a balance: Increase appropriate use of antimicrobials –Ensure the provision of good quality therapy to infected patients who needs antimicrobials: standard treatment guidelines, drug access, drug quality Decrease inappropriate use of antimicrobials –Through education, policy, and regulation, decrease the use of antimicrobials where there is no benefit to patients

20. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Resistance emergence – Critical steps New resistance Selection Spread Mutations

21. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Factors promoting resistance Selection pressure – antibiotic use – intensive use: intensive care units, new antibiotics –indiscriminate use: for nonbacterial diseases –incorrect use: inappropriate agent, dosing, compliance –use in animals and food production Spread – poor sanitation and overcrowding in the community – inadequate control of infections in health care facilities – international travel

22. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA  -lactam consumption and TEM  -lactamase resistance in M. (B.) catarrhalis from Finnish children Nissinen et al. (1995), Clinical Infectious Diseases, 21: 1193-6

23. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA AMR Containment Interventions: Approaches General –Disease prevention: improved hygiene, water quality, nutrition –Disease therapy: decreasing inappropriate use of antibiotics, development of new agents Disease-specific –Disease prevention: vaccination –Disease therapy: improved disease diagnosis, standard treatment guidelines

24. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Strategy 1: Reduce the need for antibiotics Disease prevention – use existing vaccines and develop new ones – improve nutrition, hygiene, and general health status New approaches for disease therapy – immune modulators, bacteriophages Evaluate the use of antibiotics in food production – decrease the use of antimicrobial growth promoters

25. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Strategy 2: Improve the use of antibiotics Do not use antibiotics when they do not benefit the patient – Educate health workers and patients Ensure quality of drug supply – Regulation and control of the quality of antimicrobials available on the market Use standard treatment guidelines adapted for local resistance issues – use narrow-spectrum where appropriate – reserve highly effective drugs – regulate and monitor antimicrobial prescription – do susceptibility testing when possible – optimize surgical prophylaxis – improve patient compliance

26. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Total Outpatient antibiotic use in 26 European countries in 2002

27. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Consumption of the Fourth Generation Cephalosporins in Ambulatory Care in 26 European Countries in 2002

28. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Factors Influencing Drug Use DRUG USE Cultural Beliefs Knowledge Deficits Unbiased Information Relation With Peers Authority & Supervision Influence of Industry Workload & Staffing Infra- structure Acquired Habits Patient Demand Interpersonal Workplace Workgroup Personal Informational

29. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Penicillin consumption (1991-1996) and penicillin resistance (1988-2000) in S. pneumoniae from Icelandic children

30. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Strategy 3: Decrease transmission Communities – improve sanitation and hygiene Health-care facilities – strengthen hospital infection control: hand- washing, sterilization techniques, quality control, use of face masks

31. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA New Drug Development – 1995 -2005 80 FDA Drug Approvals for Anti-Infectives – 17 Antibacterials – 27 Anti-HIV – 23 Other antivirals – 7 Antifungals – 6 Antiparasitics

32. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA FDA Approved Antibacterials – 1995-2006 17 Antibacterials – 10 “New” Compounds – but no novel drug classes Ceftibuten, cefditoren Moxifloxacin, trovafloxacin, gatifloxacin Telithromycin, dirithromycin Ticarcillin+clavulanic acid Quinupristin/dalfopristin Rifaximin – 7 Reformulations of existing compounds Clarithromycin, azithromycin Metronidazole Clindamycin Cefazolin Two removed from market because of toxicity concerns – Trovafloxacin, gatifloxacin

33. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Disincentives to New Drug Development Because of resistance, anti-infectives lose efficacy over time Short courses of patient therapy Tight restrictions on the use of new agents Many competitors with very good safety profiles For “me too” drugs, resistance can emerge rapidly

34. WHO Collaborating Center for Surveillance of Antimicrobial Resistance Boston, USA Conclusion Resistance is an unavoidable consequence of the use of anti-infective agents on diverse microbial populations Prudent antimicrobial use must thus aim to balance –the necessity of treating infected patients today with –the need for efficacious treatment options in the future