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  1. Antibiotic Resistant Infections: Problems and Solutions George G. Zhanel Professor: Department of Medical Microbiology/Infectious Diseases Faculty of Medicine, University of Manitoba and Coordinator: Antibiotic Resistance Program, Departments of Clinical Microbiology and Medicine, Health Sciences Centre, Winnipeg, Canada Title of presentation umanitoba.ca

  2. Life Expectancy at Birth(US) Age (Yrs) Year

  3. History of Antibiotic Resistant Superbugs • 1928 Fleming discovers penicillin • 1946 Penicillin resistant Staphylococci • 1969 US Surgeon General “Its time to close the book on Infectious Diseases” • 2013 Superbugs winning the race Rubinstein and Zhanel. Lancet Infect Dis 2007. Gin and Zhanel. 1996.

  4. New systemic antibacterial agents approved by the US FDA Boucher et al. CID 2013;56(12):1685-1694.

  5. Today’s Anti-Infective Dilemma

  6. Leading Infectious Diseases Killers(World Health Organization-1998) Millions Deaths/yr WHO 2000.

  7. Why are Antibiotic Resistant Superbug Infections Important to You ? • Greater morbidity and mortality • Hospitalization and supportive care • Increased use of: • Laboratory and diagnostic tests • Infection control procedures • More expensive antimicrobials • Length of hospital stay and lost work days Rubinstein and Zhanel. Lancet Infect Dis 2007. Lynch and Zhanel. Sem Resp Crit Care Med 2005. Cohen. Science 1992.

  8. Urgent Clostridium difficile Carbapenem-resistant Enterobacteriaceae (CRE) Drug-resistant Neisseriagonorrhoeae Pathogens Representing a Threat(CDC 2013)

  9. Serious - Multidrug-resistant Acinetobacter - Drug-resistant Campylobacter - Fluconazole-resistant Candida (a fungus) - Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs) - Vancomycin-resistant Enterococcus (VRE) - Multidrug-resistant Pseudomonas aeruginosa - Drug-resistant Non-typhoidalSalmonella - Drug-resistant Salmonella Typhi - Drug-resistant Shigella - Methicillin-resistant Staphylococcus aureus(MRSA) - Drug-resistant Streptococcus pneumoniae - Drug-resistant tuberculosis Pathogens Representing a Threat(CDC 2013)

  10. Concerning Vancomycin-resistant Staphylococcus aureus(VRSA) Erythromycin-resistant Group A Streptococcus Clindamycin-resistant Group B Streptococcus CDC – Pathogens Representing a Threat CDC 2013

  11. CANWARD 2007-12 Study George Zhanel, Heather Adam, Mel Baxter, Melissa McCracken, Laura Mataseje, Michael R Mulvey, Barbara Weshnoweski, Ravi Vashisht, Nancy Laing, James Karlowsky, Kim Nichol, Andrew Denisuik, Alyssa Golden, Philippe Lagacé-Wiens, Andrew Walkty, Frank Schweizer, Jack Johnson, the Canadian Antimicrobial Resistance Alliance (CARA) and Daryl J Hoban University of Manitoba, Health Sciences Centre, National Microbiology Lab, Winnipeg, Canada and International Health Management Associates (IHMA), Chicago, USA Zhanel et al. JAC 2013. Zhanel et al. DMID symposium 2011. Zhanel et al. CANWARD supplement in CJIDMM 2009. www.can-r.ca 11/39

  12. Bacteriology of Top 10 Organisms in Canada CANWARD 2007-2012 (BLOOD n=11,929)

  13. Staphylococcus aureus • Leads to a wide range of infections • Virulence factors: skin and soft tissue, pneumonia, bacteremia • Toxin mediated: Food poisoning, toxic shock syndrome Lee and Bohach. 2004.

  14. Methicillin-Resistant Staphylococcus aureus(MRSA)

  15. History of Methicillin Resistant Staphylococcus aureus (MRSA) • Before penicillin S.aureus bacteremia had a very high mortality • 1940’s penicillin introduced 1946 PRSA • 1960 methicillin introduced late 1960’s MRSA • 1970’s - 1990’s MRSA (HA-MRSA) increases globally • 1970’s – 1990’s vancomycin last effective treatment • 1996 Japan first report of VISA • 1999 reports of CA-MRSA • 2002-present 9 isolates of VRSA Matzke, Zhanel and Guay. ClinPharmacokin 1986. GardamMA. CJID 2000. Nichol and Zhanel JAC 2013

  16. Antibiotic Resistance in MRSAIsolatesCANWARD 2007-2012 National (n=1266) % Resistant CTX-Ceftriaxone; PTZ-Piperacillin/Tazobactam; ERT-Ertapenem; CIP-Ciprofloxacin; CLA-Clarithromycin; CLI-Clindamycin; T/S-Trimethoprim/sulfamethoxazole; VAN-Vancomycin; LZD- Linezolid; DAP-Daptomycin; TIG-Tigecycline

  17. Prevalence of MRSA in Canadian HospitalsCANWARD 2007-2012 National Prevalence:MRSA 23.3% [1266/5442] Range: 6% – 43% Nichol et al. JAC 2013

  18. MRSA in Canadian HospitalsCANWARD 2007-2012 (n=1266) %-MRSA Nichol and Zhanel. JAC 2013.

  19. CA-MRSA in Canada(USA300; PVL+; SSCmecIVa) % CA-MRSA 2007 2008 2009 2010 2011 2012 Zhanel et al. AAC 2008. Nichol and Zhanel. JAC 2013.

  20. HA- and CA-MRSA Infection: Epidemiology MRSA prevalence increasing in US hospitals and community.1 1. McDonald LC. Clin Infect Dis. 2006;42:S65-71. 2. Naimi TS, et al. JAMA. 2003;290:2976-2984.

  21. Prevalence of CA/HA-MRSA in Canada by Region(2011)

  22. Community-associated MRSA • CA-MRSA may cause severe, life-threatening soft tissue infections in healthy adults N Engl J Med, April 7, 2005

  23. Community-associated MRSA • Injection drug addicts • Homeless shelters • Nursing homes

  24. Community-associated MRSA Epidemic outbreaks in: • Day-care centers • Prison inmates • Ships; military • Contact sports

  25. Community-associated MRSA • Epidemic of skin/soft tissue infections St. Louis Rams (2003) Kazakova, New Engl J Med Feb 3, 2005

  26. CA-MRSA: NFL Football Team • MRSA infections5 of 58 players (9%) • Identical strain New Engl J Med 2005:352;468

  27. CA-MRSA: NFL Football Team Risk factor • Lineman or linebacker: 10.6 • Antibiotics within 12 mos: 7.8 Kazakova, NEJM Feb. 3, 2005

  28. CA-MRSA: NFL Football Team Transmission of MRSA • During 2003 season, outbreak of abscesses in competing team after game with Rams Kazakova, NEJM 2005:352;468

  29. Severe Pneumonia in a Healthy Man (Community-Associated MRSA)

  30. SCCMEC in MRSA 30 Deurenberg RH. Infect Genet Evol 2008; Dec;8(6):747-63.

  31. Extended Spectrum β-lacatamse Producing Enterobacteriaceae(ESBL)

  32. B-Lactam Resistance Mechanisms http://www.Sitemaker.umich.edu/…/filesmedchemresistance.html

  33. Bradford, 2001. Clinical Microbiology reviews. 14(4):933-951.

  34. Ambler Classification • Four major classes based on amino acid sequence similarity • Class A; TEM, SHV, CTX-M ESBLs • Class B; Metallo-enzymes • Class C; AmpC • Class D; Miscellaneous enzymes • A,C and D have an active-site serine

  35. Bush Classification • Sufficiently differentiates Ambler class A enzymes • Based on four groups (1-4) and subgroups (a-f) • ESBLs are designated as group 2be

  36. β-lactamase substrate profiles:

  37. Extended-Spectrum -Lactamases (ESBL) • Confers resistance to penicillins and 1st, 2nd and 3rd generation cephalosporins • Inhibited by -Lactamase inhibitors • Most common CTX-M, TEM and SHV • >300 have been identified • Plasmid-mediated, highly mobile • Often associated with resistance genes to aminoglycoside, TMP/SMX and tetracycline • Associated with fluoroquinolone resistance phenotype Paterson and Bonomo, Clin Micro Rev 2005. Bonnet, AAC 2004.

  38. The prevalence of ESBL-producing E. coli from Canadian hospitals: CANWARD 2007-2012

  39. The regional prevalence of ESBL-E. coli: CANWARD 2012 AmpC-EC  6.6%* (6.0%) 3.4% (2.9%) AmpC-EC  6.7%* (2.2%) ESBL-KPN  ≥10% 11.6%* (7.1%) <10 – ≥5% 5.6% (3.9%) <5 – ≥2% <2% (Nova Scotia/New Brunswick) No Data

  40. Patterns of multi-drug resistance: ESBL-E. coli ESBL-E. coli: XDR (n=8, 3.0%): CEF. FQ. AG. BL/I. TMP-SMX

  41. A Patient With a Multi-Drug Resistant (MDR) Urinary Infection • 78y M with prostatic hypertrophy and urinary infection symptoms • Already taking ciprofloxacin without any benefit x 10 days • Recent travel to India, no prior history of urinary infection • Urine culture from one week ago grew E. coli • Pelvic, rectal and kidney ultrasound normal Lagacé-Wiens and Zhanel. JAC 2006; 57:1262-3.

  42. Ampicillin ..….R TMP/SMX .....R Ciprofloxacin .....R Gentamicin …...R Tobramycin ...…R Amikacin …...R Cefazolin ...…R Cefuroxime .…..R Cefotaxime …...R Ceftazidime .…..R Meropenem .…..S This MDR E. coli is a Superbug! Lagacé-Wiens and Zhanel. JAC 2006; 57:1262-3.

  43. How Should We Treat This Patient ? • Amoxicillin-Clavulanate 500mg/125mg po TID and his symptoms resolve in 4 days • Repeat cultures at 8 weeks were negative • We got lucky !!! Lagacé-Wiens and Zhanel. JAC 2006; 57:1262-3.

  44. Causes of Antibiotic Resistance • Overuse/abuse of antibiotics in humans • Overuse/abuse of antibiotics in non-humans • developing countries • world travel • critically ill patients • industry advertising/promoting Zhanel. Treat Resp Med 2005. Gin and Zhanel. Annals Pharmacother 1996. Gin and Zhanel. Can Pharm J 2001.

  45. Antibiotic Use For Adults With (Viral) Coughs, Colds and Bronchitis by Family Physicians • 21% of all prescriptions were for coughs, sore throats, colds, and bronchitis • patients were treated with antibiotics in • 51% colds • 52% sore throat • 66% bronchitis Gonzales et al. JAMA 1997.

  46. How do Antibiotics Promote Resistance • Selection of resistant bacteria • Societal effects • Global spread Zhanel. Treat Resp Med 2005. Levy SB. Scient Amer 1998.

  47. Outpatient Antibiotic Use Compared to Europe*2003 *selected countries European data from the www.esac.ua.ac.be/ DDD=defined daily dose (WHO ATC) Antibiotic use derived from data from IMS Health Canada www.can-r.ca

  48. Mechanisms of Antibiotic Resistance • Alteration in target site (eg. MRSA, VRE, PRSP) • inactivation/alteration of antibiotic (eg. B-Lactamases) • decreased uptake (eg. P. aeruginosa) • efflux (eg. S.aureus and fluoroquinolones) Murray B. 1998; Gin and Zhanel 1996.