1. Multidrug Resistant Bacteria P. Stogsdill, MD, FIDSA Sept 2013

2. Bad bugs, No drugs NO ESKAPE Enterococcus faecium Staphylococcus aureus Klebsiella pneumoniae Clostridium difficile Acinetobacter spp Pseudomonas aeruginosa Enterbacter spp Enterbacteriaceae

3. New Resistance Patterns ESBL: extended spectrum β-lactamases (1978) AmpC β-lactamases (1981) CRE: Carbapenem-resistant Enterobacteriaceae KPC: Klebsiella pneumoniae Enterobacteriaceae (2001) NDM: New Delhi Metallo β-lactamases (2012)

4. KPC in the US 9/9/13

5. CRE infections CRE 2001: 1.2%  4.2% in 2011 Klebsiella 1.6% 10.4% Urine (89%), blood (10%) Risk factors: Health care exposure, recent hospitalization Very high mortality rates

6. β-lactamases Chromosomal-Mediated (intrinsic) Inducible enzymes (CTX/Enterobacter) Intrinsic changes in DNA Sequence Structural changes, target site alteration Plasmid-mediated (acquired) Transferable/acquired (always “on”) Associated with other resistant genes

7. AmpC resistance Chromosomally-inducible Beta-lactamases CTX for Enterobacter Produced by Enterobacteriaceae sp Asso w/ “SPICE/SPACE” bacteria Serratia spp Pseudomonas aeruginosa Acinetobacter/Indole positive Proteae ( Proteus, Morganella, Providencia spp) Citrobacter spp Enterobacter cloacae

8. ● AmpC mutants 1 in 10 4-7 organisms Impaired Immune System Intact Immune System 3GC Ceftazidime Ceftriaxone Cefotaxime Serratia spp. P. aeruginosa Acinetobacter Citrobacter Enterobacter Induction of AmpC

9. AmpC Resistant to all β-lactams, β -lactamase inhibitors and aztreonam Exception: cefepime MIC “creep” over time Inducible in the presence of 3 rd gen ceph

10. ESBL E coli

11. Plasmid-mediated Resistance in ESBLs Typically confers resistance to Multiple classes of ABXs TMP-SMX Tetracyclines Fluoroquinolones Aminoglycosides

12. ESBLs Plasmid mediated, transmissable, always “on” Found in all Enterobacteriae (usu E coli or Klebsiella) Decr susceptibility to cephalosporins and aztreonam usu suscept to cefoxitin, but avoid Likely ok to use cefepime if MIC ≤ 2 Best Rx option: carbapenems or pip/tazo

14. ESBL Rx options Carbapenems --no RCT Tigecycline-- limited clinical data, not for UTI, concern for bacteremia β-lactam/β-Lactamase Inhibitor Combinations Variable inhibitory activity Tazobactam>>sulbactam & clavulanate Pip/tazo—ok for UTI (high urinary concentrations) Cephalosporins—not recommended (? Cefepime) Fosfomycin—uncomplicated UTI only

15. ESBL Rx options (cont) AG, FQ, Bactrim: Avoid—high risk of developing resistance Colistin: No CLSI breakpoints, consider E-test Fosfomycin Inhibits bacterial cell wall synthesis ’cidal vs GP and GN Uncomplicated UTI

16. CRE

17. Carbapenem-Resistant Enterobacteriaceae Enterobacteriaceae GNR, GI tract CA- and HCA-infections 70 genera, but mostly E coli, Klebsiella, Enterobacter sp Uncommon in US before 2000 Complex, multiple resistant mechanisms Carbapenemases (KPC, NDM—India/Pakistan) Mortality rates 40-50%

18. Risk factors for CRE Exposure to health care and antimicrobials Carbapenems, cephalosporins, FQ, vanco Recent organ or stem-cell transplants Mechanical ventilation Longer LOS

19. CRE Resistant to most β-lactams K pneumoniae plasmid-borne (KPC) Most prevalent and widely distributed carbapenamases Difficult to detect in the lab Previously Ertapenem was “canary in the coal mine” New carbapenem MIC breakpoints

20. Definition of CRE “conservative definition”: nonsusceptibility to Imipenem, Meropeneum or Doripenem using the revised 2010 CLSI breakpoints. Elevated MICs to carbapenems Similar to ESBL-producing organisms Also resistant to AG and FQ

21. CRE breakpoints

22. CRE diagnosis CDC: Resistant to all 3 rd generation cephalosporins AND Resistant to Imipenem/Meropenem/Doripenem Ertapenem not included New breakpoints No modified Hodge test necessary

23. CRE isolate

24. CRE Rx Options Tigecycline Limited clinical experience Avoid in UTI and primary BSI Colistin Emerging resistance Fosfomycin Looks great in vitro

25. Infection Control and CRE Contact precautions Pt cohorting? Use of dedicated staff? Miami: 1:1 nursing/RT care Surveillance: Peri-rectal swabs and wound cx Urinary catheters CDC workbook

26. Cipro +TMP/SMX at MMC

27. Questions?

28. Jan-June 2012 3918 hospitals (CAUTI or CLABSI surveillance) 181 (4.6%) with ≥ 1 CRE infxn 145 (3.9%) short-term hosp, 36 (17.8%) LTACH Highest in large, Northeast teaching hospitals

29. By MICHELLE CASTILLO / CBS NEWS/ September 16, 2013, 2:41 PM CDC: Hospitals major source of antibiotic- resistant infections

30. More than two million people in the U.S. get drug- resistant infections annually. About 23,000 die from these diseases that are becoming increasingly resistant to antibiotics in doctors' arsenals. CDC director Dr. Tom Frieden said to CBSNews.com during a press conference. "If we're not careful, the medicine chest will be empty when we go there to look for a lifesaving antibiotic for someone with a deadly infection. If we act now, we can preserve these medications while we continue to work on lifesaving medications."

31. World Health Organization (WHO) Director- General Dr. Margaret Chan said in March 2012 that the overuse of antibiotics was becoming so common that she feared we may come to a day where any normal infection could become deadly because bacteria have evolved to survive our treatments.any normal infection could become deadly because bacteria have evolved to survive our treatments.

32. antibiotic resistance costs $20 billion in excess health care costs in the U.S. each year, with costs to society for lost productivity reaching as much as an additional $35 billion. CDC estimated in April that enough antibiotics are prescribed each year for four out of five Americans to be taking them. Doctors and other health care providers prescribed 258 million courses of antibiotics in 2010 for a population a little less than 309 million. They also estimated in this current report that up to 50 percent of antibiotics are prescribed incorrectly or to people who do not need them.four out of five Americans to be taking them. Doctors and other health care providers prescribed 258 million courses of antibiotics in 2010 for a population a little less than 309 million. They also estimated in this current report that up to 50 percent of antibiotics are prescribed incorrectly or to people who do not need them.

33. CRE infections are caused by a family of 70 bacteria that normally live in the digestive system. They are extremely resistant to even the strongest kinds of antibiotics, and can kill one out of every two patients who develop bloodstream infections caused by them. Thirty- eight states reported at least one case of CRE last year, up from just one state a decade ago. can kill one out of every two patients who develop bloodstream infections caused by them. Thirty- eight states reported at least one case of CRE last year, up from just one state a decade ago.

34. Antimicrobial stewardship programs, which measure and promote the correct use of antibiotics, have been shown to lower antibiotic-resistant infections in different facilities by as much as 80 percent.

35. CDC sets threat levels for drug-resistant 'superbugs' By Miriam Falco, CNN updated 5:48 PM EDT, Tue September 17, 2013 Briefing speakers, report: antibiotic resistant infections “pose a catastrophic threat to people in every country” BY RABITA AZIZ ON SEPTEMBER 18, 2013.RABITA AZIZ ON SEPTEMBER 18, 2013. But fighting antimicrobial resistance isn’t possible without committed resources, IDSA President Dr. David Relman said. The CDC’s current budget is the lowest it’s been in a decade, risking a future that may resemble the days before “miracle” drugs were developed, when people died of common infections, Dr. Relman said. On superbugs, the CDC sounds an alarm. (Washington Post Editorial Board)

36. CDC director: A disease outbreak anywhere is a risk everywhere By Dr. Tom Frieden, Special to CNN updated 7:23 AM EDT, Fri September 20, 2013