1. Multidrug resistant organisms: What are we up against? Hans Jørn Kolmos MD DMSc Professor, consultant Department of Clinical Microbiology Odense University Hopsital hans.joern.kolmos@ouh.regionsyddanmark.dk Progress in Studies in the Reversal of Drug Resistance SDU 4 June 2012

2. Antibiotics: Miracle drugs, it started out so well, but ….

3. The antibiotic crisis: accelerating resistance & little new drug development Clatworthy. Nature Biochem Biol 2007; 3: 541-8

4. Staph aureus (MRSA) Pneumococci Enterococci Gonococci Clostridium difficile Corynebactera E. Coli (ESBL) Klebsiella (ESBL+CPE) Salmonella Pseudomonas Acinetobacter Stenotrophomonas Helicobacter …plus many others Multi-drug resistant bacteria: a rough overview MDR- & XDR-TB

5. http://www.salute.gov.it/imgs/C_17_pubblicazioni_1404_allegato.pdf MRSA in Europe 2009

6. ESBL producing E. coli & Klebsiella pneumoniae http://www.salute.gov.it/imgs/C_17_pubblicazioni_1404_allegato.pdf

7. Beyond ESBL: carbapenem resistance - the ultimate horror scenario Resistance to ESBL producing Enterobacteriaceae Penicillins Cephalosporins Carbapenem resistant Enterobacteriaceae (VIM,NDM-1, KPC-2,oxa-48) Penicillins Cephalosporins Carbapenems + others

8. The ecology of resistance: Selection and transmission Selection with antibiotics

9. ESBL: The steps from contamination to infection Healthy individual Intestinal colonization (low conc) Acquisition of ESBL by human contact & food Selection of ESBL (high conc) Destruction of normal intestinal flora by antibiotics Breach of natural barriers (surgery, catheters, chemotherapy etc) Patient with invasive infection ManySomeFew

10. Bugs fighting back: Antibiotic resistance mechanisms

11. A direct relationship between antibiotic consumption and antibiotic resistance Bronzwaer et al. Emerg Infect Dis 2002; 8: 278-82

12. Coupling of resistance on plasmids or gene cassettes: the genetic background for co-selection R tetra R ampi R ceph R genta R copper R zinc Virulence factors factors

13. Co-selection with tetracyclines: a driving force behind MRSA & ESBL in food animals DANMAP 2010 ESBL E. coli (broilers & pigs) 89-97 % MRSA CC398 (pigs) 95 % Costa et al. Vet Microbiol 2009; 138: 339-44 Ho et al. JAC 2011; 66: 765-8 DANMAP 2008 Tetracycline resistance MRSA, ESBL

14. Why worry? n MDRO are dangerous n More difficult to treat n May be more virulent n Increase mortality n Increase morbidity n Resource-intensive n More expensive antibiotics n Increase length of hospitalization n Increase demand for isolation-facilities n Derived problems n Drug toxicity n Poorer quality of care due to single room isolation

15. End of antibiotics - the ultimate consequence

16. Measures against multidrug resistance 1.Stop selection n Antibiotic restriction 2.Stop transmission n Hygiene n Food animal management 3. Develop new drugs n antibiotics n helper compounds to antibiotics