DRUG RESISTANT GRAM-NEGATIVE                BACTERIA                 Dr.T.V.Rao MDDR.T.V.RAO MD                    12/8/20...
NO ESKAPE ? FROM PATHOGENSBugs, No Drugs: No ESKAPE   – Enterococcus faecium (E), Staphylococcus aureus (S), Klebsiella   ...
EXTENDED-SPECTRUM Β-LACTAMASES (ESBLS):THE FORGOTTEN (AND UNDERRATED) MDR GNB• Most commonly identified in enterobacteriac...
WHAT ARE ESBL• ESBLs are enzymes  capable of  hydrolysing  penicillins, broad-  spectrum  cephalosporins and  Monobactams,...
ALEXANDER FLEMINGNOBEL LECTURE, DECEMBER 11, 1945                “It arose simply from a fortunate occurrence which happen...
WHAT IS A BETA-LACTAM?• Abx      • Penicillin      • Cephalosporin      • Monobactam      • Carbapenem• Bactericidal      ...
ESBLS• Enterobacteriaceae• Resistance to  oxyimino-  cephalosporins and  monobactams but  not cephamycins and  carbamenems...
GENES• SHV• TEM• CTX-M• OXA• AmpCDR.T.V.RAO MD           12/8/2012   8
CLASSIFICATION• Ambler Classification   • Molecular class A – D         •A• Bush-Jacoby-Medeiros Classification   • Functi...
ESBL EVOLUTION• Mid 1980s• Variants of TEM and  SHV• Breakdown 3rd  generation  cephalosporins• Mainly in hospital  Klebsi...
WHERE ESBL ARE LOCATED                • ESBLs are often                  located on                  plasmids that are    ...
CTX-M: ESBL EPIDEMIC•Common ESBL worldwide, often produced by Escherichia coli•Often causes UTI•Now reported in US • Healt...
WHY WE NEED ESBL DETECTION• ESBL-producing Enterobacteriaceae have been  responsible for numerous outbreaks of infection  ...
ESBL PRODUCING BACTERIA ARE MORE                 COMPLEX ?• Antibacterial choice is often complicated by  multi-resistance...
DYNAMICS OF ANTIBIOTIC                     RESISTANCEDR.T.V.RAO MD                      12/8/2012   15
PENICILLINS• 1st generation• Extended-  spectrum      • With or w/o        beta-lactamase        inhibitor• Broad spectrum...
CEPHALOSPORINS                      4th                      3rd                      2nd                      1st        ...
ESBL DYNAMICS• Although in in vitro tests  ESBLs are inhibited by  â-lactamase inhibitors such  as clavulanic acid, the  a...
THE FIGHT• Beta-lactam• Beta-lactamase• Beta-lactamase  inhibitor• ESBL                                  Google ImagesDR.T...
THE FIGHT                        BETA-LACTAM                                                    PG                    N   ...
THE FIGHT                    BETA-LACTAMASE                                                 PG                            ...
THE FIGHT                BETA-LACTAMASE                                             PG                O        NH         ...
THE FIGHT                    BETA-LACTAMASE INHIBITOR                                                   PG                ...
THE FIGHT                BETA-LACTAMASE INHIBITOR                                                        PG               ...
WHAT ARE EXTENDED-SPECTRUM               Β-LACTAMASES?• ESBLs are enzymes that mediate  resistance to extended-spectrum (t...
WHY SHOULD CLINICAL LABORATORY PERSONNEL BE       CONCERNED ABOUT DETECTING THESE ENZYMES?• The presence of an ESBL-produc...
HOW CAN CLINICAL LABORATORY  PERSONNEL CONFIRM ESBL PRODUCTION?• NCCLS recommends performing phenotypic confirmation of  p...
CLINICAL STRATEGY TO DETECT            ESBL       CTX/CLA         CAZ/CLA CTX             CAZ
HOW SHOULD LABORATORY PERSONNEL TEST FOR    CEFOTAXIME AND CEFTAZIDIME IN COMBINATION WITH                  CLAVULANIC ACI...
CTX-M: ESBL EPIDEMIC•Common ESBL worldwide, often produced by Escherichia coli•Often causes UTI•Now reported in US  • Heal...
CARBAPENEM RESISTANCE• Emerging problem in Pseudomonas  aeruginosa, Acinetobacter  baumannii, Enterobacteriaceae (CRE)• Ri...
KLEBSIELLA PNEUMONIAE CARBAPENEMASES (KPCS)                     • Plasmid-mediated carbapenemases• KPC-producing strains o...
KPCS (CONT)• Might appear susceptible to imipenem or  meropenem, but with borderline MICs per 2009 CLSI  breakpoints     •...
DO ISOLATES OTHER THAN K.       PNEUMONIAE, K. OXYTOCA, OR E. COLI               PRODUCE ESBL’S?•     Other isolates of   ...
HOW SHOULD CEPHALOSPORIN AND    PENICILLIN RESULTS BE REPORTED?• If an isolate is confirmed as an ESBL-producer by the  NC...
BACTERIA NOT TO TEST FOR                ESBLS• Acinetobacter• Often S to clavulanate  alone• S. maltophila +ve result  by ...
NEW DELHI METALLO-BETA-LACTAMASE-1                         (NDM-1)• Carbapenemases mediating broad spectrum  resistance   ...
MDR GNB IN LONG TERM CARE• Quinolone resistance increasingly common in  hospitals, long-term care and in some community  s...
STRATEGIES TO CONTROL THE           SPREAD OF MDR GNB• Contact  precautions/hand  hygiene• Environment and  source control...
ROLE OF THE ENVIRONMENT• Environmental sources of contamination/infection  • Increasingly recognized as sources of infecti...
ENVIRONMENTAL CLEANING• Adequacy of cleaning of patients’ rooms  suboptimal• Improve monitoring and feedback of efficacy o...
SUPPLEMENTS TO ROUTINE ENVIRONMENTAL                  CLEANING • Disinfection units that decontaminate   environmental sur...
CHLORHEXIDINE GLUCONATE (CHG)• Broad-spectrum  antimicrobial disinfectant• Preferred agent for skin  preparation prior to ...
ENHANCED INFECTION CONTROL PROCESSES                         • Active Surveillance     • Use of “screening” cultures to id...
ANTIMICROBIAL STEWARDSHIP - GOALS    • Optimize appropriate use of antimicrobials         • The right agent, dose, timing,...
BUNDLES• A bundle is a structured  way of improving the  processes of care and  patient outcomes: a  small, straightforwar...
CONCLUSIONS• MDR GNB are growing in prevalence in multiple  geographic locales• Occur in a variety of healthcare associate...
NEW DELHI METALLO-BETA-LACTAMASE-1                         (NDM-1)• Carbapenemases mediating broad spectrum  resistance   ...
STILL THE BEST WAY TO PREVENT SPREAD OF      INFECTIONS AND DRUG RESISTANCE IS ……DR.T.V.RAO MD                      12/8/2...
VISIT ME FOR MORE ARTICLES OF INTEREST        ON INFECTIOUS DISEASES ……DR.T.V.RAO MD                 12/8/2012   50
• Programme Created by Dr.T.V.Rao MD     for Microbiologists in the Developing                    World                   ...
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Drug resistant gram - ve bacteria

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Drug resistant gram-negative bacteria

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Drug resistant gram - ve bacteria

  1. 1. DRUG RESISTANT GRAM-NEGATIVE BACTERIA Dr.T.V.Rao MDDR.T.V.RAO MD 12/8/2012 1
  2. 2. NO ESKAPE ? FROM PATHOGENSBugs, No Drugs: No ESKAPE – Enterococcus faecium (E), Staphylococcus aureus (S), Klebsiella pneumoniae (K), Acinetobacter baumannii (A), Pseudomonas aeruginosa (P), and Enterobacter spp. (E)ate-stage clinical development pipeline remains unacceptably lean – Some important molecules for problematic pathogens such as MRSA – Few novel molecules for other ESKAPE pathogens – No new drugs for infection due to multidrug-resistant Gram-negative bacilli (eg, A. baumannii and P. aeruginosa) – None represent more than an incremental advance over currently available therapies DR.T.V.RAO MD 12/8/2012 2
  3. 3. EXTENDED-SPECTRUM Β-LACTAMASES (ESBLS):THE FORGOTTEN (AND UNDERRATED) MDR GNB• Most commonly identified in enterobacteriaceae• Plasmid-mediated• Impart decreased susceptibility to β-lactam antimicrobials • Often co-resistance to aminoglycosides, fluoroquinolones• Carbapenems are drugs of choice for invasive infections due to ESBL-producers DR.T.V.RAO MD 12/8/2012 3
  4. 4. WHAT ARE ESBL• ESBLs are enzymes capable of hydrolysing penicillins, broad- spectrum cephalosporins and Monobactams, and are generally derived from TEM and SHV- type enzymesDR.T.V.RAO MD 12/8/2012 4
  5. 5. ALEXANDER FLEMINGNOBEL LECTURE, DECEMBER 11, 1945 “It arose simply from a fortunate occurrence which happened when I was working on a purely academic bacteriological problem which had nothing to do with antagonism, or moulds, or antiseptics, or antibiotics.” www.nobelprize.org Google imagesDR.T.V.RAO MD 12/8/2012 5
  6. 6. WHAT IS A BETA-LACTAM?• Abx • Penicillin • Cephalosporin • Monobactam • Carbapenem• Bactericidal Google ImagesDR.T.V.RAO MD 12/8/2012 6
  7. 7. ESBLS• Enterobacteriaceae• Resistance to oxyimino- cephalosporins and monobactams but not cephamycins and carbamenems • Susceptible to beta-lactamase inhibitors Oteo, et al., 2010DR.T.V.RAO MD 12/8/2012 7
  8. 8. GENES• SHV• TEM• CTX-M• OXA• AmpCDR.T.V.RAO MD 12/8/2012 8
  9. 9. CLASSIFICATION• Ambler Classification • Molecular class A – D •A• Bush-Jacoby-Medeiros Classification • Functional group 1 – 4 •2 • 2b • 2be Paterson and Bonomo, 2005 DR.T.V.RAO MD 12/8/2012 9
  10. 10. ESBL EVOLUTION• Mid 1980s• Variants of TEM and SHV• Breakdown 3rd generation cephalosporins• Mainly in hospital Klebsiella• Spread world wideDR.T.V.RAO MD 12/8/2012 10
  11. 11. WHERE ESBL ARE LOCATED • ESBLs are often located on plasmids that are transferable from strain to strain and between bacterial species.DR.T.V.RAO MD 12/8/2012 11
  12. 12. CTX-M: ESBL EPIDEMIC•Common ESBL worldwide, often produced by Escherichia coli•Often causes UTI•Now reported in US • Healthcare associated • Some community•Community-based ESBL infection raise concern for continued increases in carbapenem useDR.T.V.RAO MD 12/8/2012 12
  13. 13. WHY WE NEED ESBL DETECTION• ESBL-producing Enterobacteriaceae have been responsible for numerous outbreaks of infection throughout the world and pose challenging infection control issues. Clinical outcomes data indicate that ESBLs are clinically significant and, when detected, indicate the need for the use of appropriate antibacterial agents.• Unfortunately, the laboratory detection of ESBLs can be complex and, at times, misleading.DR.T.V.RAO MD 12/8/2012 13
  14. 14. ESBL PRODUCING BACTERIA ARE MORE COMPLEX ?• Antibacterial choice is often complicated by multi-resistance. Many ESBLproducing organisms also expressAmpC â- lactamases and may be co-transferredwith plasmids mediating aminoglycoside resistance. In addition, there is an increasing association between ESBL production and fluoroquinolone resistanceDR.T.V.RAO MD 12/8/2012 14
  15. 15. DYNAMICS OF ANTIBIOTIC RESISTANCEDR.T.V.RAO MD 12/8/2012 15
  16. 16. PENICILLINS• 1st generation• Extended- spectrum • With or w/o beta-lactamase inhibitor• Broad spectrumDR.T.V.RAO MD 12/8/2012 16
  17. 17. CEPHALOSPORINS 4th 3rd 2nd 1st Willey, et al., 2008DR.T.V.RAO MD 12/8/2012 17
  18. 18. ESBL DYNAMICS• Although in in vitro tests ESBLs are inhibited by â-lactamase inhibitors such as clavulanic acid, the activity of â-lactam/â- lactamase inhibitor combination agents is influenced by the bacterial inoculum, dose administration regimen and specific type of ESBL presentDR.T.V.RAO MD 12/8/2012 18
  19. 19. THE FIGHT• Beta-lactam• Beta-lactamase• Beta-lactamase inhibitor• ESBL Google ImagesDR.T.V.RAO MD 12/8/2012 19
  20. 20. THE FIGHT BETA-LACTAM PG N cell ODR.T.V.RAO MD 12/8/2012 LYSIS 20
  21. 21. THE FIGHT BETA-LACTAMASE PG beta-lactamase N cell ODR.T.V.RAO MD 12/8/2012 21
  22. 22. THE FIGHT BETA-LACTAMASE PG O NH OH cellDR.T.V.RAO MD 12/8/2012 22
  23. 23. THE FIGHT BETA-LACTAMASE INHIBITOR PG beta-lactamase N Inhibitor cell ODR.T.V.RAO MD 12/8/2012 23
  24. 24. THE FIGHT BETA-LACTAMASE INHIBITOR PG beta-lactamase Inhibitor N cell ODR.T.V.RAO MD 12/8/2012 LYSIS 24
  25. 25. WHAT ARE EXTENDED-SPECTRUM Β-LACTAMASES?• ESBLs are enzymes that mediate resistance to extended-spectrum (third generation) cephalosporins (e.g., ceftazidime, cefotaxime, and ceftriaxone) and monobactams (e.g., aztreonam) but do not affect cephamycins (e.g., cefoxitin and cefotetan) or Carbapenems (e.g., meropenem or imipenemDR.T.V.RAO MD 12/8/2012 25
  26. 26. WHY SHOULD CLINICAL LABORATORY PERSONNEL BE CONCERNED ABOUT DETECTING THESE ENZYMES?• The presence of an ESBL-producing organism in a clinical infection can result in treatment failure if one of the above classes of drugs is used. ESBLs can be difficult to detect because they have different levels of activity against various cephalosporins. Thus, the choice of which antimicrobial agents to test is critical. For example, one enzyme may actively hydrolyze ceftazidime, resulting in ceftazidime minimum inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on cefotaxime, producing MICs of only 4 µg/ml. If an ESBL is detected, all penicillins, cephalosporins, and aztreonam should be reported as resistant, even if in vitro test results indicate DR.T.V.RAO MD 12/8/2012 26 susceptibility
  27. 27. HOW CAN CLINICAL LABORATORY PERSONNEL CONFIRM ESBL PRODUCTION?• NCCLS recommends performing phenotypic confirmation of potential ESBL-producing isolates of K. pneumoniae, K. oxytoca, or E. coli by testing both cefotaxime and ceftazidime, alone and in combination with clavulanic acid . Testing can be performed by the broth micro dilution method or by disk diffusion. For MIC testing, a decrease of > 3 doubling dilutions in an MIC for either cefotaxime or ceftazidime tested in combination with 4 µg/ml clavulanic acid, versus its MIC when tested alone, confirms an ESBL-producing organism. For disk diffusion testing, a > 5 mm increase in a zone diameter for either antimicrobial agent tested in combination with clavulanic acid versus its zone when tested alone confirms an ESBL-producing organism.DR.T.V.RAO MD 12/8/2012 27
  28. 28. CLINICAL STRATEGY TO DETECT ESBL CTX/CLA CAZ/CLA CTX CAZ
  29. 29. HOW SHOULD LABORATORY PERSONNEL TEST FOR CEFOTAXIME AND CEFTAZIDIME IN COMBINATION WITH CLAVULANIC ACID?• NCCLS suggests making disks by adding 10 µl of a 1000 µg/ml stock solution of clavulanic acid to cefotaxime and ceftazidime disks each day of testing . In the future, commercial manufacturers of antimicrobial disks may produce disks containing cefotaxime and ceftazidime with clavulanic acid.DR.T.V.RAO MD 12/8/2012 29
  30. 30. CTX-M: ESBL EPIDEMIC•Common ESBL worldwide, often produced by Escherichia coli•Often causes UTI•Now reported in US • Healthcare associated • Some community•Community-based ESBL infection raise concern for continued increases in carbapenem useUrban, Diag Micro Infect Dis, 2010; Sjölund-Karlsson, EID, 2011DR.T.V.RAO MD 12/8/2012 30
  31. 31. CARBAPENEM RESISTANCE• Emerging problem in Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae (CRE)• Risk factors include ICU stay, prolonged exposures to healthcare, indwelling devices, antibiotic exposures • Long-term acute care centers (LTACs)• Severely limits treatment options • Increased use of older, toxic agents such as colistinDR.T.V.RAO MD 12/8/2012 31
  32. 32. KLEBSIELLA PNEUMONIAE CARBAPENEMASES (KPCS) • Plasmid-mediated carbapenemases• KPC-producing strains of Klebsiella pneumonia and other enterobacteriaceae • KPC-2, KPC-3• Endemicity in many locales in the US • Hyperendemicity in NYC • 24% of K. pneumoniae infections were due to KPCs in 2 hospitals• Country-wide outbreak ongoing in Israel, Greece, Columbia and others 32* DR.T.V.RAO MD 12/8/2012
  33. 33. KPCS (CONT)• Might appear susceptible to imipenem or meropenem, but with borderline MICs per 2009 CLSI breakpoints • Usually Ertapenem resistant • Modified Hodge test• Usually only susceptible to colistin, Tigecycline and select aminoglycosides• Easily spread in hospitals (often requires Cohorting of staff and patients to control) DR.T.V.RAO MD 12/8/2012 33
  34. 34. DO ISOLATES OTHER THAN K. PNEUMONIAE, K. OXYTOCA, OR E. COLI PRODUCE ESBL’S?• Other isolates of Enterobacteriaceae, such as Salmonella species and Proteus mirabilis, and isolates of Pseudomonas aeruginosa produce ESBLs. However, at this time, methods for screening and phenotypic confirmatory testing of these isolates have not been determined by NCCLS.DR.T.V.RAO MD 12/8/2012 34
  35. 35. HOW SHOULD CEPHALOSPORIN AND PENICILLIN RESULTS BE REPORTED?• If an isolate is confirmed as an ESBL-producer by the NCCLS-recommended phenotypic confirmatory test procedure, all penicillins, cephalosporins, and aztreonam should be reported as resistant. This list does not include the Cephamycins (cefotetan and cefoxitin), which should be reported according to their routine test results. If an isolate is not confirmed as an ESBL-producer, current recommendations suggest reporting results as for routine testing. Do not change interpretations of penicillins, cephalosporins, and aztreonam for isolates not confirmed as ESBLDR.T.V.RAO MD 12/8/2012 35
  36. 36. BACTERIA NOT TO TEST FOR ESBLS• Acinetobacter• Often S to clavulanate alone• S. maltophila +ve result by inhibition of L-2 chromosomal b- lactamase, ubiquitous in the speciesDR.T.V.RAO MD 12/8/2012 36
  37. 37. NEW DELHI METALLO-BETA-LACTAMASE-1 (NDM-1)• Carbapenemases mediating broad spectrum resistance • Usually found in Klebsiella pneumonia, E. coli• Initially identified in India, Pakistan, Bangladesh• Recovered in Australia, France, Japan, Kenya, North America, Singapore, Taiwan, and the United Kingdom, Australia, Canada• Recovered in the US (Massachussetts, Illinois and California) DR.T.V.RAO MD 12/8/2012 37
  38. 38. MDR GNB IN LONG TERM CARE• Quinolone resistance increasingly common in hospitals, long-term care and in some community settings• B-lactam resistance established in hospitals, many long-term care settings• Risk factors in long-term care for resistant Gram- negative bacilli • Indwelling devices • Poor functional status • Pressure ulcers/wounds • Antimicrobial/quinolone exposure • Prior hospitalization DR.T.V.RAO MD 12/8/2012 38
  39. 39. STRATEGIES TO CONTROL THE SPREAD OF MDR GNB• Contact precautions/hand hygiene• Environment and source control• Antibiotic stewardship• Enhanced infection control measures• BundlesDR.T.V.RAO MD 12/8/2012 39
  40. 40. ROLE OF THE ENVIRONMENT• Environmental sources of contamination/infection • Increasingly recognized as sources of infection• Particularly important with pathogens such as Clostridium difficile, Norovirus, Acinetobacter spp.• Bleach preparations are more effective for some pathogens (still need cleaning)• Latest technology being tested: UV light, hydrogen peroxide vapor DR.T.V.RAO MD 12/8/2012 40
  41. 41. ENVIRONMENTAL CLEANING• Adequacy of cleaning of patients’ rooms suboptimal• Improve monitoring and feedback of efficacy of cleaning • Direct observation and culturing not efficient, time- consuming and expensive• Other options: ATP bioluminescence and fluorescent dyes • Monitor process, efficacy of cleaningDR.T.V.RAO MD 12/8/2012 41
  42. 42. SUPPLEMENTS TO ROUTINE ENVIRONMENTAL CLEANING • Disinfection units that decontaminate environmental surfaces • Must remove debris and dirt in order for these units to be effective • Two most common methods • UV light • Hydrogen peroxide (HP) DR.T.V.RAO MD 12/8/2012 42
  43. 43. CHLORHEXIDINE GLUCONATE (CHG)• Broad-spectrum antimicrobial disinfectant• Preferred agent for skin preparation prior to insertion of vascular catheter and prior to surgery• Studied for “source control”, decrease in degree of contamination of patients by problem hospital pathogensDR.T.V.RAO MD 12/8/2012 43
  44. 44. ENHANCED INFECTION CONTROL PROCESSES • Active Surveillance • Use of “screening” cultures to identify patients colonized with pathogens (usually MDR) of interest • Goal is to prevent spread in the hospital by identifying patients who are colonized and intervening to prevent spread • Most experience is with Gram positive pathogens • Limited use for some pathogens (due to low sensitivity)• Cohorting of patients• Dedicated staff DR.T.V.RAO MD 12/8/2012 44
  45. 45. ANTIMICROBIAL STEWARDSHIP - GOALS • Optimize appropriate use of antimicrobials • The right agent, dose, timing, duration, route • Optimize clinical outcomes • Reduce emergence of resistance • Limit drug-related adverse events • Minimize risk of unintentional consequences • Help reduce antimicrobial resistance • The combination of effective antimicrobial stewardship and infection control has been shown to limit the emergence and transmission of antimicrobial-resistant bacteriaDellit TH et al. Clin Infect Dis. 2007;44(2):159–177; . Drew RH. J Manag Care Pharm.2009;15(2 Suppl):S18–S23; Drew RH et al. Pharmacotherapy. 2009;29(5):593–607. DR.T.V.RAO MD 12/8/2012 45
  46. 46. BUNDLES• A bundle is a structured way of improving the processes of care and patient outcomes: a small, straightforward set of evidence-based practices that, when performed collectively and reliably, have been proven to improve patient outcomes. Resar R, Joint Commission JournalDR.T.V.RAO MD 12/8/2012 46 on Quality and Patient Safety.
  47. 47. CONCLUSIONS• MDR GNB are growing in prevalence in multiple geographic locales• Occur in a variety of healthcare associated settings • Even in the community• Antimicrobial stewardship is here to stay• Problem is compounded by dry pharmaceutical pipeline• Novel methods to control spread of MDROs are attractive but not clearly effective/cost-effective DR.T.V.RAO MD 12/8/2012 47
  48. 48. NEW DELHI METALLO-BETA-LACTAMASE-1 (NDM-1)• Carbapenemases mediating broad spectrum resistance • Usually found in Klebsiella pneumonia, E. coli• Initially identified in India, Pakistan, Bangladesh• Recovered in Australia, France, Japan, Kenya, North America, Singapore, Taiwan, and the United Kingdom, Australia, Canada• Recovered in the US (Massachussetts, Illinois and California) DR.T.V.RAO MD 12/8/2012 48
  49. 49. STILL THE BEST WAY TO PREVENT SPREAD OF INFECTIONS AND DRUG RESISTANCE IS ……DR.T.V.RAO MD 12/8/2012 49
  50. 50. VISIT ME FOR MORE ARTICLES OF INTEREST ON INFECTIOUS DISEASES ……DR.T.V.RAO MD 12/8/2012 50
  51. 51. • Programme Created by Dr.T.V.Rao MD for Microbiologists in the Developing World • Email • doctortvrao@gmail.comDR.T.V.RAO MD 12/8/2012 51
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