The Emergence of Carbapenem Resistance in Canada and Globally. CNISP Annual Meeting Delta Ottawa January 19, 2012

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1 The Emergence of Carbapenem Resistance in Canada and Globally CNISP Annual Meeting Delta Ottawa January 19, 2012

2 2 Overview Carbapenem-resistance in Enterobacteriaceae Klebsiella pneumoniae Carbapenemases (KPC) New Delhi Metallo-beta-lactamases (NDM-1) OXA-48 Why is NDM-1 going to be a major issue? Can we predict what is going to happen? CNISP CRGNB Studies

3 3 Ambler Molecular Designation of Beta-Lactamases Molecular Class A B C Types TEM, SHV, CTX-M KPC, GES, SMC, IMI, PER, NMC-A, SFO, SFC, BIC, IBC NDM-1, IMP, VIM, GIM, SPM, SIM, DIM, AIM, KHM CMY, ACT, FOX, MOX D OXA, PSE OXA-48

4 Mulvey and Simor (2009) CMAJ 180:

5 Global Dissemination of KPC United States KPC first reported in North Carolina in 2001-subsequent outbreaks and transmission of KPC-producing organisms reported in northeastern U.S December 2010 KPCs in 36 states (CDC) Dominant clone ST258 accounts for 70% of KPC isolates sent to CDC National USA surveillance MEM-R among clinical K. pneumoniae increased from 0.6% in 2004 to 5.6% in Israel Increased reports of KPC cases started in hospitals and 5 chronic care centers with similar PFGE fingerprints Genetic relation to U.S strains suggested strain exchange Gupta, N et al CID.53:60-67.

6 Global Distribution of KPCs 6 26 countries Nordmann et al EID 17:

7 KPCs in Canada 7 1 st report KPC in Ottawa (3 cases), cases had travel history to USA possible transmission between 2 cases Goldfarb et al. (2009) JCM 47: case from Toronto in 2008, no travel history Pillai et al, (2009) EID 15: Similar plasmids and clones (ST238) from Toronto isolates and NYC Mataseje et al, (2011) JAC. 66:

8 8 KPC Outbreaks Montreal Outbreak 1 ICU 9 cases (3 pneumonia, 1 UTI, I SSI) E. coli (5), K. oxytoca (2), S. marcescens (2), and C. freundii (1) 4 deaths none attributed entirely to infection 2011 Leung et al, Can J Med Micro Infect Dis. In press. Outbreak 2 5 months 27 patients colonized with KPC-Kp and one patient with a KPC-positive E. cloacae 7 infections pneumonia, urinary tract and wound infections Isolation ward with dedicated nursing staff seems to have decreased transmission 2011 Leung et al, ICAAC K-824

9 9 NDM-1 first identified 2007 from a Swedish individual initially hospitalized in India K. pneumoniae UTI colonization and E. coli from a fecal sample Susceptible only colistin

10 10 Distribution of NDM Isolates: Indian Subcontinent & UK India - Most Ec and Kp - Suscep. Tig and colistin - 1 Kp pan-resistant - Many from community UK (n=37) - 1 st NDM travel to India/Pakistan - 14 hospitalized (including elective surgery) Kumarasamy et al Lancet Infect Dis. 10:

11 11 Global Distribution NDM-1 u u u u u u u u u u u u u u u u u u u u u u u u 26 countries u u u u u

12 12 Organisms Harbouring NDM-1 E. coli (ST131), K. pneumoniae, K. oxytoca, C. freundii, E. cloacae, E. aerogenes, M. morganii, Proteus spp., Providencia spp., and Salmonella Seftenberg Achromobacter spp Aeromonas caviae Acinetobacter baumannii Kingella denitrificans Pseudomonas aeruginosa, P. putida, P. pseudoalcaligenes, P. oryzihabitans Stenotrophomonas maltophilia Sutonella indologenes Vibrio cholerae Shigella boydii

13 NDM-1 Canada 13 Feb yo female (E. coli, K. pneumonia UTI) was hospitalized in India. Mulvey et al EID 17: yo male hospitalized in India E. coli UTI. Successfully treated with fosfomycin/ert. Peirano et al EID 17: Aug yo female Brampton, Ontario, Kp urine isolate, not treated,hospitalized in India Tijet et al EID 17: cases Ontario. UTI colonizations, M. morganella, P. retgerri. Liberation therapy (MS) India, one had no travel history. Kus et al CMAJ. May 30 epub.

14 OXA First described in Turkey Poirel et al AAC. 48:15 22 Focused around Mediterranean countries Found in 2/4 puddles sampled Morocco Potron et al AAC epub August Most difficult to detect of the carbapenemases Low MICs to carb and cephalosporins No inhibitors (ie. clav, EDTA) Under reporting? Canada: 10 cases (1 West; 9 Ont/Que)

15 OXA-48 Global Distribution 15 Nordmann et al EID 17:

16 Enterobacteriaceae Producing Carbapenemases in Canada (n=205) ss of Jan, 2011 WEST (n=40) 21 NDM 6 KPC 1 OXA Other East (n=1) 1 NDM 0 KPC 0 OXA-48 0 Other Central (n=164) 34 NDM 113 KPC 10 OXA-48 7 Other

17 Effect of National Infection Control Interventions in Israel on KPC hospitals Direct correlation between compliance of isolation guidelines and success of containment transmission (P=0.02) Schwaber et al CID. Feb 11.

18 18 Why is NDM-1 Getting so much Attention? The Perfect Storm? Overuse of antimicrobials in endemic regions India has 1.3 B people, overcrowding issues Diarrhea common, poor sanitation, overuse leads to community spread NDM-1 found on promiscuous MDR plasmids with addiction systems Most susceptible only to colstin or Tigecycline but pan-resistance also reported No new drugs in the pipeline

19 Silver Clin Micro Rev. 24:

20 20 How big of a problem is NDM-1? Tim Walsh, Cardiff University we estimate that the carriage rate of NDM-1 in India is between 100 and 200 million The Times of India, Oct. 9, 2011

21 21 NDM-1 New Delhi Water 51/171 (30%) waste water seepage 2/50 (4%) communal drinking water samples Shigella boydii Vibrio cholerae Aeromonas caviae P. aeruginosa P. putida P. pseudoalcaligenes P. oryzihabitans Sutonella indologenes S. maltophilia Achromobacter spp. Kingella denitrificans Walsh et al. TLID, 2011, 11:

22 22 Pharmaceutical Manufacturing, India Sampled water near Hyderabad, India which receives effluent from 90 drug manufacturers Identified antimicrobials, antifungals, antihistamines, and antidepressants in water Ciprofloxacin: Well water 1 µg/l Effluent from plant 14 mg/l Two lakes 6.5 mg/l Fluoroquinolones are not degraded in the environment Fick et al. Environ Toxicol Chem :

23 23 Why use ESBL/AmpC as a predictor NDM-1 spread? ESBLs rates very high in India similar to what seems to be emerging for NDM-1 NDM-1 is carried on similar plasmids along with CTX-M-15, CMY and OXA genes Epidemic E. coli ST131 now harbours NDM-1 plasmids

24 ESBL+ve isolates, Asia-Pacific 2007; intra-abdominal infection 24 Hawser et al., AAC 2009; 53: 3280

25 Meta-analysis of ESBL vs non- ESBL Risk for Bacteremia 25 Mortality ~2X more likely to die with an ESBL bacteremia Inappropriate Therapy ~6X more likely to receive the wrong antibiotic Schwaber and Carmeli JAC :

26 26 Risk Factors and Mortality Associated with CARB-R K. pneumoniae Bacteremia Cases (n=32) carb-r K. pneumoniae bacteremia matched with other bacterial infections Crude mortality cases 72% vs 22% other bacterial infections Attributable mortality cases was 50% (highest reported for any bacterema caused by other bacteria) 3.3X (95% CI, ) more likely to die Cases significantly more likely: Require care in ICU (37.5% vs 9.4%) Ventilator support (53% vs 25%) Central venous catheters (59% vs 28%) Urinary catheter (84% vs 41%) None of the case subjects received appropriate empiric antibiotic therapy Borer et al, Infect Contr Hosp Epi. 30:972-6.

27 Predicted Trends MRSA/E. coli ESBL Bloodstream Infections in Europe 27 1,293 hospitals from 31 European countries 2007: 9.3% BSI E. coli 3GC resistant De Kraker et al PLOS Med 8:e

28 CNISP ESBL Studies 28 ESBLs 116/34,479 (0.34%) Mulvey et al. (2004) AAC. 48:

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31 31 CANWARD ESBL E. coli Rates 50% CTX-M-15 E. coli ST131 % ESBL E. coli Simner et al. (2011) DMID 69: Year

32 32 ESBL in Community: Calgary Health Region ESBLs incidence 5.5 cases per 100,000 population per year 71% community onset Females >65 years old CTX-M-14 and CTX-M-15 Pitout et al. CID (2004) 38: AmpC rates cases per 100,000 population per year 5X more likely to be female 83% community onset 34% CMY-2 Pitout et al. (2007)EID 13:443-8

33 33 CTX-M-15 E. coli ST131 Clone Infections Pitout et al. AAC (2009) 53:

34 CTX-M-15 Animals and 34 Environment Environment and Birds Seawater in Algerian Beaches Microbes Environ. 2011; doi: Seagulls and beaches in Portugal. Emerg Infect Dis. 2010; 16: River water in the UK. J Antimicrob Chemother 2011; 66: Food Producing Animals Chicken and pig farms in Spain. Appl Environ Microbiol 2010;76: Poultry meat in Canada. Emerg Infect Dis 2010;16: Piglets in Germany. Environ. Microbiol. 2008; 10: Companion Animals Dogs visiting healthcare facilities in Ontario (ESBLs). Lefebvre J Hosp Infect. 2006; 62: Companion animals in Spain, Denmark, the Netherlands, France and Germany. J Antimicrob Chemother 2010;65: Dogs and cats (single household) in USA. J Clin Microbiol 2009;47: Companion animals in Australia. J. Antimicrob. Chemother. 2010; 65:

35 35 Prospective ESBL Colonization Study - 24% of 100 travelers came back with ESBL - ESBL pos carriers more likely to have gastroenteritis during the trip (P = 0.003) - 13/24 were CTX-M-15 all from India - 2/24 carried ESBL after 6 months Tangden et al. AAC :

36 Canadian Travelers and ESBLs 36 Diarrheal stool samples from travelers (2009) 14% travelers positive for E. coli ESBL Travelers 5.2X (95% CI ) more likely than nontravelers to have ESBL-E. coli No Mer or Ert res detected Peirano et al J Trav Med. 18:

37 Novel Agents for Treatment 37 Avibactam (NXL104) beta-lactamase inhibitor In combination cephalosporins has activity against Enterobacteriaceae KPC and OXA-48 (Class A and D) Aztreonam + NXL104 has activity against metallobetalactamases Plazoicin (ACHN-490) aminoglycoside Activity against both Gram-pos and Gram-neg Good activity against MDR CARB-R (NDM, KPC, OXA) Apramycin Aminoglycoside approved in veterinary medicine for poultry NAB739 and NAB7061 experimental polymyxin derivatives that are potentially less nephrotoxic than commercially available polymyxins.

38 38 CNISP-Carbapenemases 1 Year Pilot Study Enterobacteriaceae: 10 isolates identified from 9 cases (~50,000 isolates screened) blakpc-3 (n=7; Klebsiella pneumoniae, K. oxytoca, Serratia, and E. coli) blandm-1 (n=2; K. pneumoniae, E. coli) blasme (n=1; Serratia spp.) Manuscript submitted JAC Public Health Agency of Canada Agence de la santé publique du Canada

39 CRGNB surveillance Year 2 Number of cases 141 (EPI +LAB merged) 9 CHEC sites reported at least one case Epidemiological case definition identified 129: 78 infections 32 colonizations 19 with unknown infection status

40 CRGNB surveillance Year 2 40 Colonization (n=32) Infection (n=78) Min Age 1 1 Max Age Mean Age Paediatric cases 2 (both < 1yr) 3 (ages 1, 6, 9 yrs) Female Male Travel History (yes=10; no=118; unknown=37) - India: K. pneumo and Providencia (both NDM & sought medical attention in India) - Philippines: (no isolate), - Afghanistan/Germany: Acinetobacter (no isolate) - Greece: K. pneumo (KPC/VIM) - Greenland: Enterobacter (non-carbapenemase) - Ecuador: Enterobacter (KPC) - 2 unknown; 1 blank

41 CRGNB surveillance Year 2 Site of isolation Infection Colonization Frequency % Frequency % Urinary tract infection Skin/soft tissue infection Sputum Blood NA - Surgical site infection Peritonitis Device-related Perirectal Other

42 Carbapenemases Identified Pathogen GES KPC NDM OXA TOTAL Enterobacter spp Klebsiella spp Escherichia coli Raoutella terigena Serratia spp Morganella morganii Acinetobacter TOTAL Year 1* *Other carbapenemases included 1 SME and 1 VIM, smaller sample size

43 CRGNB surveillance deaths registered during the surveillance year CRGNB Infections CRGNB Colonizations Non-classified CRGNB 10 cases 7 cases 2 cases Carbapenamase-producing organisms 1 Serratia marcescens (GES-5) 1 Raoutella terrigena (KPC-3) 1 Klebsiella pneumoniae (NDM-1) 1 Raoutella terrigena (KPC-3) 1 Enterobacter cloacae (KPC) 1 Acinetobacter baumanii (OXA-51) 1 Escherichia coli (GES-5) 1 Klebsiella pneumoniae (KPC)) NON Carbapenamase-producing organisms 1 Raoutella terrigena 2 Escherichia coli 3 Enterobacter cloacae 1 Enterobacter aerogenes 1 Citrobacter freundii 1 Acinetobacter baumanii 1 Raoutella terrigena 2 Serratia marcescens

44 Dice (Opt:1.00%) (Tol 1.0%-1.0%) (H>0.0% S>0.0%) [0.0%-100.0%] PFGE - XbaI PFGE - XbaI CRGN No. Organism Province BL CARB 11ACRGNY ACRGNY ACRGNY ACRGNY CCRGNY ACRGNY2002 K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae. QC. QC. ON. QC. ON. ON. SHV. SHV. SHV,TEM. SHV. SHV,CTX-M,OXA-1. SHV,OXA-1. KPC-3. KPC-3. KPC-3. KPC-2. NDM-1. NDM-1 11ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY2075 R. terrigena R. terrigena R. terrigena R. terrigena R. terrigena K. pneumoniae R. terrigena R. terrigena R. terrigena R. terrigena. QC. QC. QC. QC. QC. QC. QC. QC. QC. QC. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3. KPC-3 Clusters with ST258* 09ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY ACRGNY2004 K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae K. pneumoniae. ON. ON. ON. ON. ON. ON. ON. ON. ON. ON. SHV,TEM. SHV,TEM. SHV,TEM. SHV,TEM. SHV,CTX-M,OXA. SHV,CTX-M,OXA. SHV,CTX-M,OXA. SHV,CTX-M,OXA. SHV,CTX-M,OXA. SHV,CTX-M,OXA-1. KPC-3. KPC-3. KPC-3. KPC-3. NDM-1. NDM-1. NDM-1. NDM-1. NDM-1. NDM-1 Clusters with ST147* 01ACRGNY ACRGNY2104 K. pneumoniae K. pneumoniae. BC. QC. SHV,TEM. SHV,TEM. KPC-2 VIM-1. KPC-2 07CCRGNY ACRGNY2103 K. pneumoniae K. pneumoniae. ON. QC. SHV,TEM. SHV,TEM. KPC-2. KPC-type *Although sequence typing has not been completed these patterns cluster (>80% similarity) with ST types already in database.

45 Enterobacter Fingerprints Dice (Opt:1.00%) (Tol 1.0%-1.0%) (H>0.0% S>0.0%) [0.0%-100.0%] PFGE - XbaI 1-35s PFGE - XbaI 1-35s CRGN No. Organism Province BL a CARB a 09ACRGNY Enterobacter cloacae. ON. SHV,TEM. KPC-3 11ACRGNY2107 Enterobacter cloacae. QC. NEG. KPC-2 11ACRGNY2014 Enterobacter cloacae. QC. SHV. KPC-3 04ACRGNY2016 Enterobacter cloacae. AB. NEG. KPC-2 a BL-Additional beta-lactamases, CARB-carbapenemases

46 46 Future Work Susceptibility testing and finalize characterization of isolates AMMI/CACMID Abstract for Year 2? Manuscript for year 2 study? Monitoring for carb-r in Salmonella Canadian Integrated Program on Antimicrobial Resistance Surveillance (CIPARS) Meeting at AMMI/CACMID with provinces 2 yr funding to sequence genomes and plasmids of carb-r

47 47 Acknowledgements E. Bryce (chair) J. Embree K. Katz P. Kibsey M. Kuhn A. Simor G. Taylor E. Thomas N. Turgeon PHAC A. Mounchili D. Gravel K. Cassidy J. Shurgold M. Mulvey L. Mataseje D. Boyd K. Fakharuddin