Carbapenemase 2011
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  • 1. The emerging threat posed by carbapenemase producing enterobacteria & how to address it Dr. Ashok Rattan Fortis Clinical Research Ltd.
  • 2. Thienamycin Streptomyces cattleya Imipenem cilastatin Meropenem Ertapenem Doripenem + In 1 : 1 ratio
  • 3. Spectrum of activity
    • Broad spectrum activity
      • GPC & GNB
      • Aerobic & Anaerobic bacteria
      • Active against MDR isolates
      • Active against ESBL +ve GNB
      • Active against DRSP
      • Active against Ps aeruginosa & Acinetobacter spp.
    • Not active against
      • MRSA
      • Entrococcus spp.
      • Stenotrophomonas maltophilia
  • 4.
      • Pramod M. Shah & Robin D. Isaacs Classification
      • Group 1: Broad spectrum for Community acquired infections
        • Ertapenem
      • Group 2: Broad spectrum for hospital acquired infections
        • Imipenem
        • Meropenem
        • Doripenem
      • Group 3: MRSA active
        • Nil at present
      • Journal of Antimicrobial Chemotherapy (2003) 52 , 538–542
  • 5. Clinical Uses
    • Imipenem
      • Lower Respiratory Tract infection
      • Urinary Tract Infection (uncomplicated or complicated)
      • Intra abdominal infection
      • Gynaecological infection
      • Bacterial septicemia
      • Bone & joint infection
      • Skin & soft tissue infection
      • Endocarditis
      • Polymicrobial infections
    • Meropenem
      • Skin & soft tissue infection
      • Intra abdominal infection
      • Bacterial meningitis
    • Ertapenem
      • Community acquired pneumonia requiring hospitalization
  • 6. Carabpenemases: a problem in waiting ? David M Livermore & Neil Woodford Current Opinion in Microbiology 2000; 3: 489 - 495 Natural resistance Acquired resistance
  • 7. Bush 2010 : Distribution of β lactamases according to function Most Carbapenemases can Hydrolyze ALL Beta lactam antibiotics
  • 8. Carbapenemases
    • The most versatile family of  -lactamases
    • Two major groups based on the hydrolytic mechanism at the active site
      • Serine at the active site: class A and D
      • Zinc at the active site : class B
    • All carbapenemases hydrolyze penicillins, extended spectrum cephalosporins, and carbapenems
  • 9. Classification 2d 3 2f Functional Group - - + APBA Inhibition - + - EDTA Inhibition - - + Aztreonam Hydrolysis Serine Zn ++ Serine Active site D B A Molecular Class
  • 10. Mechanism of Resistance to Carbapenem
    • 1. Cephalosporinase : Amp C & CTX- M
    • + Porin mutation = low level resistance
    • 2. Carbapenemase : β lactamases that can hydrolyze carbapenem
    • Amber Class A : 9 families
    • KPC, SME, NMC-A, IMI, PER, GES, SFO, SFC, IBC
    • Amber Class B : 6 families
    • VIM, GIM, SIM, NDM, IMP, SPM
    • Amber Class D : 2 families
    • OXA, PSE
  • 11. Serine β lactamases: Kleb. pneumoniae All β lactams USA A KPC Kleb pn. carbapenamase Ps. Imipenem & extended spectrum cephalosporins French Guiana A GES Guiana Extended spectrum Scotland Europe USA Country Acinetobacter, Ps. Carbapenems (weak) D OXA Oxacillin hydrolysing Enterobacter spp Carbapenem, aztreonam but not 3 rd gen cephalosporins A NMC – A, IMI Non metallo carbapenamse Serratia marcescens Carbapenem, aztreonam but not 3 rd gen cephalosporins A SME Serratia marcesance enzyme Organisms Spectrum of activity Ambler Class Enzyme
  • 12. Metallo β lactamases (Zn at active site) Kleb pneu, E. coli Pan R India, UK B NDM New Delhi South Korea Germany Brazil Italy Japan Country Acinetobacter, Ps. Pan R B SIM Souel Ps. Pan R B GIM German Ps Pan R B SPM Sao Paulo Ps. , Acinetobacter Pan R, may be S to aztreonam B VIM (12) Verona Ps., Acinetobacter All β lactams B IMP (18) Imipenem Japan Organisms Spectrum of activity Ambler Class Enzyme
  • 13. March of Carbapenemases Lancet Infect Dis 2010; 10: 597–602 Published Online August 11, 2010 1985 1986 1990 1995 2000 2008 2010 Imipenem launched Chromosomal R in Ps IMP in Japan VIM in Verona KPC in USA NDM 1 Clinical Microbiology and Infection, Volume 16 Number 12, December 2010 Castanheira M et al: Anti Agents Chem 2010 SENTRY Program Out of 39 strains collected from India in 2006 15 strains had NDM 1 10 strains carried OXA 48 variant 2 strains carried VIM 6 Multiple PFGE patterns
  • 14.  
  • 15.  
  • 16.  
  • 17. Location of Bla KPC gene
  • 18. Why is CRE a public health emergency ?
    • Significantly limits treatment options for life threatening infections
    • No new drug for GNB in the pipeline
    • Resistant mechanism easily transferable as it in now on a transposon
    • Rapid Detection & effective infection control measures essential to control spread
  • 19. Why is CRE spreading ?
    • Resistance mechanism of a transposon
    • Suboptimal methods of laboratory detection of isolates, large reservoir
    • Continued antibiotic selection pressure
    • Inadequate or incomplete institution of infection control measures
  • 20. Who is infected with CRE ?
    • Hospitalized patients with
      • Increased number of co morbid conditions
      • Frequent & prolonged hospitalization
      • Invasive devises
      • Antimicrobial selective pressure
        • Previous Carbapenem use
        • Previous Metronidazole use
      • CRE most frequently isolated in surgical wards from surgical drainage, bile , blood or urine
  • 21. Recommendations for control
    • Surveillance
    • Infection control
    • Laboratory detection
  • 22. Surveillance
    • Is CRE present in your facility ?
      • Review microbiology data for 6 to 12 months
      • If no,
        • Conduct a point prevalence survey
          • Single round of AST in high risk patients
      • If yes
        • Conduct AST on patients with epidemiological link to CRE case
    • Goal:
      • Identify undetected carriers of CRE
  • 23. Infection Control CDC’s recommendations
    • Goal : Institute contact precautions to prevent patient to patient transmission
    • Contact isolation
      • Disposable gloves & gowns available at each bedside
      • Alcohol based hand rub available & used
      • Environmental surfaces cleaned daily with aerosolized foam quaternary ammonium compound
      • Disposable antibacterial wipes containing isopropanol & quaternary ammonium compound for cleaning patient related items at least once a day
    • Infection control team participated in daily round
    • Rectal swabs on admission & weekly
  • 24. Infection control: add ons Kochar S et al. Infect control & Hosp Epidemiol 2009; 30: 447 - 452
    • ICU extensively cleaned: environment & pt care items
    • For All pts. culture positive for CRE,
      • a copy of antibiogram placed in bedside records
      • Moved & gathered at one end of ICU
      • Nursing personnel also grouped
    • Free standing dispensers for alcohol based hand rub available at bedside
    • Disposable antibacterial wipes to clean environment at beginning of 12 hour shift and SOS
  • 25. Laboratory Detection Clinical and Laboratory Standards Institute breakpoints: 2009 & 2010 Revised Break Points 2010 < 15 < 19 16-18 20-22 19-21 > 22 > 23 > 8 > 1 4 0.5 2 < 1 < 0.25 ERT < 13 < 19 14-15 20-22 16-21 > 22 > 23 > 16 > 4 8 2 2-4 < 1 < 1 MEM < 13 < 19 14-15 20-22 NA > 16 > 23 > 16 > 4 8 2 2-4 < 1 < 1 IPM R I MHT S R I MHT S DD breakpoints (mm) MIC breakpoint (ug/ml) Agent
  • 26.  
  • 27.  
  • 28. Screening for CRE
  • 29. Screening for CRE carriage Sample Select Differentiate TSB + carbapenem disk
  • 30. CHROMagar ESBL & KPC Panagea T et al : Evaluation of CHROMagar TM KPC for the detection of carbapenemase-producing Enterobacteriaceae in rectal surveillance cultures. International JournalofAntimicrobialAgents xxx (2010) xxx–xxx Randall LP et al: Evaluation of CHROMagar CTX, a novel medium for isolating CTX-M-ESBL-positive Enterobacteriaceae while inhibiting AmpC-producing strains. Journal of Antimicrobial Chemotherapy (2009) 63, 302–308
  • 31. Test for Carbapenemase Detection Anderson KF et al. Evaluation of methods to identify KPC in enterobacteriaceae. JCM 2007; 45: 2723 – 2725.
    • Modified Hodge Test (MHT)
    • Carbapenem Inactivation Assay
    Carbapenem Disk Susceptible E. coli Test Isolate
  • 32. Double Disk Picao RC et al: MBL detection: Double Disk Synergy vs Combined Disk. JCM 2008; 46: 2028 - 2037
  • 33. Combined Disk Doi Y et al. Single disk method for detecting KPC by use of a Boronic acid compound. JCM 2008; 46: 4083 - 4086
  • 34. E test Walsh T et al. Evaluation of a new Etest for detecting MLB in routine clinical testing. JCM 2002; 40: 2755 - 2759
  • 35. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
  • 36. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
  • 37. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332 False Positive
  • 38. MASUDA ASSAY
  • 39. Phenotypic Detection N N N OXA Y N N MBL N Y N KPC N Y Y Amp C N N N ESBL Inhibited by Cloxacillin Boronic acid EDTA/DPA Enzyme
  • 40. Sensitivity & specificity of phenotypic methods 77 100 Carbapenemase Modified Hodge 80 100 MBL EDTA 100 100 MBL DPA 100 80 Amp C APBA+ CLX 98 100 KPC APBA Specificity Sensitivity β lactamase Test
  • 41. Genotypic detection of CRE Mendes RE et al: RT PCR for MBL JCM 2007; 45: 544 - 547
  • 42. Naaz T et al: Evaluation of a DNA Microarray, the Check-Points ESBL/KPC Array, for Rapid Detection of TEM, SHV, and CTX-M Extended-Spectrum β-Lactamases and KPC Carbapenemases. Anti Agents Chemother 2010; 54: 3086 - 3092
  • 43. Detecting CRE
    • Clinical CRE is tip of iceberg
    • Asymptomatic carriage is common (faecal)
    • Active Surveillance Test would help identify carriage
    • Institution of contact precautions & monitoring of pt to pt transmission within ICU
    • AST: When pt is transferred in from other hospitals
    • AST: ? On discharge (medical tourism)
  • 44. Guideline for phenotypic screening and confirmation of carbapenemases in Enterobacteriaceae 2010 Dutch Working Party on the Detection of Highly Resistant Microorganisms Clinical isolates
  • 45. Algorithm for disk diffusion synergy tests to detect C arbapenem N on S usceptible E nterobacteriaceae APBA = aminophenyl boronic acid ( β lactamase inhibitor) DPA = dipicolinic acid (metal chelating agent)
  • 46. Epidemiological scale & stage of nationwide expansion of CNSE Areas of Improvement
    • Ad hoc care ascertainment with existing laboratory capacity
    • Standardization of detection & reporting
    • Need for consistent capacity building of reference diagnostics
    • Need for structured surveys to determine sensitivity & specificity of break points
    • Need for harmonized typing tool/initiative
    • Need for control data collection on dissemination & introduction of strains
    • of public health importance
    • 7. Need for guidelines for graded approaches to infection control
    • 8. Antibiotic policy
    • 9. Treatment and clinical research
    • 10. Political commitment
  • 47. Carry Home messages
    • Carbapenemases in Enterobacteriaceae compromise our ability to effectively treat life threatening infections
    • Pt to pt transmission can be halted by application of strict infection control measures
    • Laboratory identification of infection or carriage must be paired with rapid implementation of Infection control interventions
    • Ongoing Surveillance is essential
  • 48.
    • Laboratory can help preserve Carbapenem antibiotics as very important resource for life threatening infections
    • Susceptibility to Carbapenem must be determined accurately in the laboratory:
      • Wild type
      • ESBL producers
      • ESBL + omp mutation
      • CRE
    Would respond to treatment with A carbapenem
  • 49. We may not be able to stop the emergence of Super bugs but we CAN