Carbapenemase 2011


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Problem of emergence of carbapenemase and how to control its spread

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  • Imipenem and cilastatin shows color change usually pink after its reconstitution in 2-3 days whereas Meropenem does not show any color change for 5-6 days after its reconstitution. That is why Imipenem could not be due to its much wastage as the Total cost of therapy will be more for the patient receiving Imipenem than Meropeam. Could you please share me how the Imipenem gets colored in 2-3 days. My email id:
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Carbapenemase 2011

  1. 1. The emerging threat posed by carbapenemase producing enterobacteria & how to address it Dr. Ashok Rattan Fortis Clinical Research Ltd.
  2. 2. Thienamycin Streptomyces cattleya Imipenem cilastatin Meropenem Ertapenem Doripenem + In 1 : 1 ratio
  3. 3. Spectrum of activity <ul><li>Broad spectrum activity </li></ul><ul><ul><li>GPC & GNB </li></ul></ul><ul><ul><li>Aerobic & Anaerobic bacteria </li></ul></ul><ul><ul><li>Active against MDR isolates </li></ul></ul><ul><ul><li>Active against ESBL +ve GNB </li></ul></ul><ul><ul><li>Active against DRSP </li></ul></ul><ul><ul><li>Active against Ps aeruginosa & Acinetobacter spp. </li></ul></ul><ul><li>Not active against </li></ul><ul><ul><li>MRSA </li></ul></ul><ul><ul><li>Entrococcus spp. </li></ul></ul><ul><ul><li>Stenotrophomonas maltophilia </li></ul></ul>
  4. 4. <ul><ul><li>Pramod M. Shah & Robin D. Isaacs Classification </li></ul></ul><ul><ul><li>Group 1: Broad spectrum for Community acquired infections </li></ul></ul><ul><ul><ul><li>Ertapenem </li></ul></ul></ul><ul><ul><li>Group 2: Broad spectrum for hospital acquired infections </li></ul></ul><ul><ul><ul><li>Imipenem </li></ul></ul></ul><ul><ul><ul><li>Meropenem </li></ul></ul></ul><ul><ul><ul><li>Doripenem </li></ul></ul></ul><ul><ul><li>Group 3: MRSA active </li></ul></ul><ul><ul><ul><li>Nil at present </li></ul></ul></ul><ul><ul><li>Journal of Antimicrobial Chemotherapy (2003) 52 , 538–542 </li></ul></ul>
  5. 5. Clinical Uses <ul><li>Imipenem </li></ul><ul><ul><li>Lower Respiratory Tract infection </li></ul></ul><ul><ul><li>Urinary Tract Infection (uncomplicated or complicated) </li></ul></ul><ul><ul><li>Intra abdominal infection </li></ul></ul><ul><ul><li>Gynaecological infection </li></ul></ul><ul><ul><li>Bacterial septicemia </li></ul></ul><ul><ul><li>Bone & joint infection </li></ul></ul><ul><ul><li>Skin & soft tissue infection </li></ul></ul><ul><ul><li>Endocarditis </li></ul></ul><ul><ul><li>Polymicrobial infections </li></ul></ul><ul><li>Meropenem </li></ul><ul><ul><li>Skin & soft tissue infection </li></ul></ul><ul><ul><li>Intra abdominal infection </li></ul></ul><ul><ul><li>Bacterial meningitis </li></ul></ul><ul><li>Ertapenem </li></ul><ul><ul><li>Community acquired pneumonia requiring hospitalization </li></ul></ul>
  6. 6. Carabpenemases: a problem in waiting ? David M Livermore & Neil Woodford Current Opinion in Microbiology 2000; 3: 489 - 495 Natural resistance Acquired resistance
  7. 7. Bush 2010 : Distribution of β lactamases according to function Most Carbapenemases can Hydrolyze ALL Beta lactam antibiotics
  8. 8. Carbapenemases <ul><li>The most versatile family of  -lactamases </li></ul><ul><li>Two major groups based on the hydrolytic mechanism at the active site </li></ul><ul><ul><li>Serine at the active site: class A and D </li></ul></ul><ul><ul><li>Zinc at the active site : class B </li></ul></ul><ul><li>All carbapenemases hydrolyze penicillins, extended spectrum cephalosporins, and carbapenems </li></ul>
  9. 9. Classification 2d 3 2f Functional Group - - + APBA Inhibition - + - EDTA Inhibition - - + Aztreonam Hydrolysis Serine Zn ++ Serine Active site D B A Molecular Class
  10. 10. Mechanism of Resistance to Carbapenem <ul><li>1. Cephalosporinase : Amp C & CTX- M </li></ul><ul><li>+ Porin mutation = low level resistance </li></ul><ul><li>2. Carbapenemase : β lactamases that can hydrolyze carbapenem </li></ul><ul><li>Amber Class A : 9 families </li></ul><ul><li>KPC, SME, NMC-A, IMI, PER, GES, SFO, SFC, IBC </li></ul><ul><li>Amber Class B : 6 families </li></ul><ul><li> VIM, GIM, SIM, NDM, IMP, SPM </li></ul><ul><li>Amber Class D : 2 families </li></ul><ul><li> OXA, PSE </li></ul>
  11. 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. 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. 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. 17. Location of Bla KPC gene
  15. 18. Why is CRE a public health emergency ? <ul><li>Significantly limits treatment options for life threatening infections </li></ul><ul><li>No new drug for GNB in the pipeline </li></ul><ul><li>Resistant mechanism easily transferable as it in now on a transposon </li></ul><ul><li>Rapid Detection & effective infection control measures essential to control spread </li></ul>
  16. 19. Why is CRE spreading ? <ul><li>Resistance mechanism of a transposon </li></ul><ul><li>Suboptimal methods of laboratory detection of isolates, large reservoir </li></ul><ul><li>Continued antibiotic selection pressure </li></ul><ul><li>Inadequate or incomplete institution of infection control measures </li></ul>
  17. 20. Who is infected with CRE ? <ul><li>Hospitalized patients with </li></ul><ul><ul><li>Increased number of co morbid conditions </li></ul></ul><ul><ul><li>Frequent & prolonged hospitalization </li></ul></ul><ul><ul><li>Invasive devises </li></ul></ul><ul><ul><li>Antimicrobial selective pressure </li></ul></ul><ul><ul><ul><li>Previous Carbapenem use </li></ul></ul></ul><ul><ul><ul><li>Previous Metronidazole use </li></ul></ul></ul><ul><ul><li>CRE most frequently isolated in surgical wards from surgical drainage, bile , blood or urine </li></ul></ul>
  18. 21. Recommendations for control <ul><li>Surveillance </li></ul><ul><li>Infection control </li></ul><ul><li>Laboratory detection </li></ul>
  19. 22. Surveillance <ul><li>Is CRE present in your facility ? </li></ul><ul><ul><li>Review microbiology data for 6 to 12 months </li></ul></ul><ul><ul><li>If no, </li></ul></ul><ul><ul><ul><li>Conduct a point prevalence survey </li></ul></ul></ul><ul><ul><ul><ul><li>Single round of AST in high risk patients </li></ul></ul></ul></ul><ul><ul><li>If yes </li></ul></ul><ul><ul><ul><li>Conduct AST on patients with epidemiological link to CRE case </li></ul></ul></ul><ul><li>Goal: </li></ul><ul><ul><li>Identify undetected carriers of CRE </li></ul></ul>
  20. 23. Infection Control CDC’s recommendations <ul><li>Goal : Institute contact precautions to prevent patient to patient transmission </li></ul><ul><li>Contact isolation </li></ul><ul><ul><li>Disposable gloves & gowns available at each bedside </li></ul></ul><ul><ul><li>Alcohol based hand rub available & used </li></ul></ul><ul><ul><li>Environmental surfaces cleaned daily with aerosolized foam quaternary ammonium compound </li></ul></ul><ul><ul><li>Disposable antibacterial wipes containing isopropanol & quaternary ammonium compound for cleaning patient related items at least once a day </li></ul></ul><ul><li>Infection control team participated in daily round </li></ul><ul><li>Rectal swabs on admission & weekly </li></ul>
  21. 24. Infection control: add ons Kochar S et al. Infect control & Hosp Epidemiol 2009; 30: 447 - 452 <ul><li>ICU extensively cleaned: environment & pt care items </li></ul><ul><li>For All pts. culture positive for CRE, </li></ul><ul><ul><li>a copy of antibiogram placed in bedside records </li></ul></ul><ul><ul><li>Moved & gathered at one end of ICU </li></ul></ul><ul><ul><li>Nursing personnel also grouped </li></ul></ul><ul><li>Free standing dispensers for alcohol based hand rub available at bedside </li></ul><ul><li>Disposable antibacterial wipes to clean environment at beginning of 12 hour shift and SOS </li></ul>
  22. 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
  23. 28. Screening for CRE
  24. 29. Screening for CRE carriage Sample Select Differentiate TSB + carbapenem disk
  25. 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
  26. 31. Test for Carbapenemase Detection Anderson KF et al. Evaluation of methods to identify KPC in enterobacteriaceae. JCM 2007; 45: 2723 – 2725. <ul><li>Modified Hodge Test (MHT) </li></ul><ul><li>Carbapenem Inactivation Assay </li></ul>Carbapenem Disk Susceptible E. coli Test Isolate
  27. 32. Double Disk Picao RC et al: MBL detection: Double Disk Synergy vs Combined Disk. JCM 2008; 46: 2028 - 2037
  28. 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
  29. 34. E test Walsh T et al. Evaluation of a new Etest for detecting MLB in routine clinical testing. JCM 2002; 40: 2755 - 2759
  30. 35. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
  31. 36. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332
  32. 37. Pasteran F et al. Controlling false positive results in MHT.. JCM 2010; 48: 1323 - 1332 False Positive
  33. 38. MASUDA ASSAY
  34. 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
  35. 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
  36. 41. Genotypic detection of CRE Mendes RE et al: RT PCR for MBL JCM 2007; 45: 544 - 547
  37. 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
  38. 43. Detecting CRE <ul><li>Clinical CRE is tip of iceberg </li></ul><ul><li>Asymptomatic carriage is common (faecal) </li></ul><ul><li>Active Surveillance Test would help identify carriage </li></ul><ul><li>Institution of contact precautions & monitoring of pt to pt transmission within ICU </li></ul><ul><li>AST: When pt is transferred in from other hospitals </li></ul><ul><li>AST: ? On discharge (medical tourism) </li></ul>
  39. 44. Guideline for phenotypic screening and confirmation of carbapenemases in Enterobacteriaceae 2010 Dutch Working Party on the Detection of Highly Resistant Microorganisms Clinical isolates
  40. 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)
  41. 46. Epidemiological scale & stage of nationwide expansion of CNSE Areas of Improvement <ul><li>Ad hoc care ascertainment with existing laboratory capacity </li></ul><ul><li>Standardization of detection & reporting </li></ul><ul><li>Need for consistent capacity building of reference diagnostics </li></ul><ul><li>Need for structured surveys to determine sensitivity & specificity of break points </li></ul><ul><li>Need for harmonized typing tool/initiative </li></ul><ul><li>Need for control data collection on dissemination & introduction of strains </li></ul><ul><li>of public health importance </li></ul><ul><li>7. Need for guidelines for graded approaches to infection control </li></ul><ul><li>8. Antibiotic policy </li></ul><ul><li>9. Treatment and clinical research </li></ul><ul><li>10. Political commitment </li></ul>
  42. 47. Carry Home messages <ul><li>Carbapenemases in Enterobacteriaceae compromise our ability to effectively treat life threatening infections </li></ul><ul><li>Pt to pt transmission can be halted by application of strict infection control measures </li></ul><ul><li>Laboratory identification of infection or carriage must be paired with rapid implementation of Infection control interventions </li></ul><ul><li>Ongoing Surveillance is essential </li></ul>
  43. 48. <ul><li>Laboratory can help preserve Carbapenem antibiotics as very important resource for life threatening infections </li></ul><ul><li>Susceptibility to Carbapenem must be determined accurately in the laboratory: </li></ul><ul><ul><li>Wild type </li></ul></ul><ul><ul><li>ESBL producers </li></ul></ul><ul><ul><li>ESBL + omp mutation </li></ul></ul><ul><ul><li>CRE </li></ul></ul>Would respond to treatment with A carbapenem
  44. 49. We may not be able to stop the emergence of Super bugs but we CAN