Carbapenams

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Carbapenams, uses and drug reistance to carbapenams

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Carbapenams

  1. 1. Dr.T.V.Rao MD<br /> CARBAPENAMS<br />Uses and Resistance<br />1<br />Dr.T.V.Rao MD<br />
  2. 2. Conventional antibiotics<br />Penicillins<br />Cephalosporins<br />Carbapenems<br />Quinolones<br />Amino glycosides<br />Macrolides<br />Tetracyclines<br />Nitrofurantoin, metronidazole, clindamycin, vancomycin, teicoplanin, cotrimoxazole, fusidic acid, etc<br />Isoniazid, pyrazinamide, ethambutol, rifampin, cycloserine, etc<br />2<br />Dr.T.V.Rao MD<br />
  3. 3. Carbapenems xpenicillins<br />The carbapenems are structurally very similar to the penicillins, but the sulphur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenem<br />3<br />Dr.T.V.Rao MD<br />
  4. 4. Antibiotic formulation continue to growCONTINUE TO CONFUSE<br />50 penicillins<br />71 Cephalosporins<br />12 Tetracyclines<br />8 amino glycosides<br />1 monobactam<br />>3 carbapenems<br />9 macrolides<br />2 streptogramins<br />3 dihydrofolate reductase inhibitors<br />1 oxazolidinone<br />5.5 quinolones<br />4<br />Dr.T.V.Rao MD<br />
  5. 5. 18<br />16<br />14<br />12<br />10<br />Number of agents approved<br />8<br />6<br />4<br />0<br />2<br />0<br />A Changing Landscape forNumbers of Approved Antibacterial AgentsWe have more resistant Microbes<br />Resistance <br />1983-87<br />1988-92<br />1993-97<br />1998-02<br />2003-05<br />2008<br />Bars represent number of new antimicrobial agents approved by the FDA during the period listed.<br />Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;<br />New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912<br />5<br />Dr.T.V.Rao MD<br />
  6. 6. What are carbapenems<br />Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomycescattleya.<br />6<br />Dr.T.V.Rao MD<br />
  7. 7. Carbapenems common uses<br />Imipenem<br />Broad spectrum, covers Gram-positive, Gram-negative (including ESBL-producing strains), Pseudomonas and anaerobes<br />Meropenem<br />Less seizure-inducing potential, can be used to treat CNS infections<br />Ertapenem<br />Lacks activity vs. Acinetobacter and Pseudomonas<br />Has limited activity against penicillin-resistant pneumococci<br />7<br />Dr.T.V.Rao MD<br />
  8. 8. How are Carbapenems Used?<br />Uses by Clinical Syndrome<br />Bacterial meningitis<br />Hospital-associated sinusitis<br />Sepsis of unknown origin<br />Hospital-associated pneumonia<br />Use by Clinical Isolate<br /><ul><li>Acinetobacter spp.
  9. 9. Pseudomonas aeruginosa
  10. 10. Alcaligenesspp.
  11. 11. Enterobacteriaceae
  12. 12. Mogenella spp.
  13. 13. Serratia spp.
  14. 14. Enterobacter spp.
  15. 15. Citrobacter spp.
  16. 16. ESBL or AmpC + E. coli and Klebsiellaspp.</li></ul>Reference: Sanford Guide<br />8<br />Dr.T.V.Rao MD<br />
  17. 17. Enterobacteriaceae are real problamatic microbes<br />The rapid and disturbing spread of:<br />extended-spectrum ß-lactamases<br />AmpC enzymes<br />carbapenem resistance<br />metallo-β-lactamases <br />KPC and OXA-48 β-lactamases <br />Quinolones resistance<br />9<br />Dr.T.V.Rao MD<br />
  18. 18. Carbapenems effective on several common isolates<br />Staph (not MRSA), Strep (highly resistant), Neisseria, Haemophilus, Proteus, Pseudomonas, Klebseilla, Bacteroides, anaerobes (excluding C. dif)<br />.<br />10<br />Dr.T.V.Rao MD<br />
  19. 19. Carbapenems are broad spectrum antibiotic <br />These agents have the broadest antibacterial spectrum compared to other beta-lactam classes such as penicillins and cephalosporins. Additionally they are generally resistant to the typical bacterial beta-lactamase enzymes which are one of the principal resistance mechanisms of bacteria. They are active against both Gram positive and gram negative bacteria, with the exception of intracellular bacteria, such as the Chlamydia<br />11<br />Dr.T.V.Rao MD<br />
  20. 20. Drugs belong to the carbapenem class:<br />Imipenem<br />Meropenem Ertapenem Doripenem Panipenem/ betamipron Biapenem<br />12<br />Dr.T.V.Rao MD<br />
  21. 21. broadest antibacterial spectrum<br />These agents have the broadest antibacterial spectrum compared to other beta-lactam classes such as penicillins and cephalosporins. Additionally they are generally resistant to the typical bacterial beta-lactamase enzymes which are one of the principal resistance mechanisms of bacteria. They are active against both Gram positive and gram negative bacteria, with the exception of intracellular bacteria, such as the Chlamydia. <br />13<br />Dr.T.V.Rao MD<br />
  22. 22. Carbapenems<br />14<br />Dr.T.V.Rao MD<br />
  23. 23. Spectrum of Activity<br />15<br />Dr.T.V.Rao MD<br />
  24. 24. Carbapenemases<br />The most versatile family of -lactamases<br />Two major groups based on the hydrolytic mechanism at the active site<br />Serine at the active site: class A and D<br />Zinc at the active site: class B<br />All carbapenemases hydrolyze penicillins, extended spectrum cephalosporins, and carbapenems <br />16<br />Dr.T.V.Rao MD<br />
  25. 25. Mechanisms of Carbapenem Resistance<br />Carbapenemase hydrolyzing enzymes<br />Porin loss “OprD”<br />ESBL or AmpC + porin loss<br />17<br />Dr.T.V.Rao MD<br />
  26. 26. Carbapenamases<br />18<br />Dr.T.V.Rao MD<br />
  27. 27. Carbapenamases are complex in Mechanisims<br />Carbapenamases constitute the most versatile family of β-lactamases belonging to molecular classes A, B and D and are capable of hydrolyzing almost all β-lactams. Given their zinc dependent hydrolytic activity, Carbapenamases of class B is designated as metallo-ß-lactamases (MBL) that include, for example, IMP, GIM, SIM, SPM, and VIM carbapenemases, and these MBL enzymes have been reported in P.aeruginosa and other multidrug resistant pathogens<br />19<br />Dr.T.V.Rao MD<br />
  28. 28. Carbapenemases<br />Ability to hydrolyze penicillins,cephalosporins, monobactams, and carbapenems<br />Resilient against inhibition by all commercially viableß-lactamase inhibitors<br />Subgroup 2df: OXA (23 and 48) carbapenemases<br />Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC <br />Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems<br />IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae<br />20<br />Dr.T.V.Rao MD<br />
  29. 29. Carbapenamases are spreading faster<br />A new class of bacterial enzymes capable of inactivating Carbapenems, known as Klebsiella pneumoniae Carbapenamases (KPCs), has rapidly spread in the United States and continues to be extensively reported elsewhere in the world. KPCs are class A Carbapenamases that reside on transferable plasmids and can hydrolyze all pencillins, cephalosporins, and Carbapenems.<br />21<br />Dr.T.V.Rao MD<br />
  30. 30. Carbapenemases within the Enterobacteriaceae<br />KPC carbapenemase<br />Difficult to detect using current MIC breakpoints.<br />Isolates that have an MIC of 2 mg/ml to ertapenem or an MIC of 2-4 mg/ml tomeropenem or Imipenem.<br /> Modified Hodge test is confirmatory. Discussed in manual. PCR is gold standard. <br />22<br />Dr.T.V.Rao MD<br />
  31. 31. KPC (K. pneumoniae carbapenemase)<br />KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K.pneumoniae<br />Substrate hydrolysis spectrum includescephalosporins and carbapenems<br />23<br />Dr.T.V.Rao MD<br />
  32. 32. KPC’s in Enterobacteriaceae<br />Pseudomonas aeruginosa – Columbia & Puerto Rico<br />24<br />Dr.T.V.Rao MD<br />
  33. 33. Pseudomonas aeruginosaCarbapenamases<br />KPC resistance has been reported in inherently resistant organisms such as Pseudomonasfrom Trinidad, an isolate of multidrug-resistant Pseudomonas aeruginosa that harboured a novel KPC-6 gene was detected.<br />25<br />Dr.T.V.Rao MD<br />
  34. 34. Emerging Carbapenem Resistance in Gram-Negative Bacilli<br />Significantly limits treatment options for life-threatening infections<br />No new drugs for gram-negative bacilli <br />Emerging resistance mechanisms, carbapenemases are mobile, <br />Detection of carbapenemases and implementation of infection control practices are necessary to limit spread<br />26<br />Dr.T.V.Rao MD<br />
  35. 35. Enterobacteriaceae: Breakpoints revised so need for other newer drugs, may be carbapenms?<br />27<br />Dr.T.V.Rao MD<br />
  36. 36. 28<br />Carbapenems = ertapenem, imipenem, meropenem <br />Intrinsically less susceptibleorganisms – Acinetobacter, P. aeruginosa<br />Other organisms may acquire resistance – K. pneumoniae, other Enterobacteriaceae<br />Know mechanisms of carbapenem resistance:<br />Class A carbapenemases (KPC, SME,…)<br />Class B metallo-β-lactamases (IMP, VIM, SPM…)<br />Class D oxa 23, -40, -51, -58<br />Organisms that acquire these resistance mechanisms will be resistant to all carbapenems but may test susceptible to imipenem<br />Resistance to Carbapenems<br />Dr.T.V.Rao MD<br />
  37. 37. Carbapenemase Classification<br />29<br />Dr.T.V.Rao MD<br />
  38. 38. Emerging Metallo-β-Lactamaseswith Mobile Genetics(SENTRY Program 2001-2005)<br />30<br />Dr.T.V.Rao MD<br />
  39. 39. Resistance to Carbapenems<br />Can also have carbapenem resistance due to <br />Class A ESBL’s (CTX-M) + reduced permeability<br />Class C High AmpC + reduced permeability<br />These hydrolyze ertapenem more than meropenem or imipenem<br />31<br />Dr.T.V.Rao MD<br />
  40. 40. Carbapenemase Class A<br />First identified 1982 in UK<br />Four major families<br />Chromosomally encoded<br />Serratia marcescens enzyme (SME)<br />Not metalloenzyme carbapenemases (NMC)<br />Imipenem-hydrolyzing -lactamases (IMI)<br />Plasmid encoded<br />Klebsiella pneumoniae carabapenemases (KPC)<br />Guiana Extended-Spectrum (GES) <br />32<br />Dr.T.V.Rao MD<br />
  41. 41. 33<br />Class A Carbapenemases<br />K. pneumoniae carbapenemase (KPC-type) possess carbapenem-hydrolyzing enzymes most common on East Coast of U.S. <br />Enzymes are capable of efficiently hydrolyzing penicillins, Cephalosporins, aztreonam, and carbapenems and are inhibited by clavulanic acid and tazobactam<br />To date 4 KPC enzymes have been identified: KPC-1, KPC-2, KPC-3, KPC-4 – E. coli, K. pneumoniae, K. oxytoca, E. cloacae<br />Dr.T.V.Rao MD<br />
  42. 42. 34<br />Carbapenemase-Producing Klebseilla pneumonia (KPC)<br />KPC-3 is the most recently reported enzyme in that group<br />KPC-3 is closely related to its predecessors, differing by only 1 amino acid from KPC-2 and by 2 amino acids from KPC-1<br />It has been recovered from isolates of K. pneumoniae, E. coli, and E. cloacae<br />Dr.T.V.Rao MD<br />
  43. 43. Carbapenem Resistance: Mechanisms<br />35<br />Dr.T.V.Rao MD<br />
  44. 44. Carbapenemases<br />36<br />Dr.T.V.Rao MD<br />
  45. 45. KlebsiellaPneumoniae and Carbapenemase <br />KPC is a class A b-lactamase<br />Confers resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems<br />Occurs in Enterobacteriaceae<br />Most commonly in Klebsiella pneumoniae<br />Also reported in: K. oxytoca, Citrobacterfreundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp., <br />Also reported in Pseudomonas aeruginosa (Columbia)<br />37<br />Dr.T.V.Rao MD<br />
  46. 46. KPC Enzymes<br />Located on plasmids; conjugative and nonconjugative<br />blaKPC is usually flanked by transposon sequences<br />blaKPC reported on plasmids with:<br />Normal spectrum b-lactamases<br />Extended spectrum b-lactamases<br />Aminoglycoside resistance<br />38<br />Dr.T.V.Rao MD<br />
  47. 47. KPC Enzymes<br />Molecular class A and functional group 2f<br />Inhibited by clavulanic acid but not by EDTA<br />Confers resistance to ALL -LACTAM antibiotics<br />Plasmid-encoded<br />Associated with other resistant genes (aminoglycosides, fluoroquinolones)<br />Transferable <br />39<br />Dr.T.V.Rao MD<br />
  48. 48. KPC Epidemiology<br />Predominantly in K. pneumoniae (KP)<br />Reported in Enterobacter spp., Salmonella spp., E. coli, P. aeruginosa, and Citrobacter spp.<br />First identified in KP clinical isolate from North Carolina in 1996 (KPC-1)<br />KPC-2, -3, and -4 have been reported.<br />Mostly identified on the East cost<br />40<br />Dr.T.V.Rao MD<br />
  49. 49. KPC Epidemiology<br />KPC producers have been identified outside USA<br />France<br />Brazil<br />Columbia<br />China<br />Not detected at the University of Nebraska Medical Center<br />45 ESBL-like isolates collected-6 had elevated carbapenem MICs-none contained KPC<br />41<br />Dr.T.V.Rao MD<br />
  50. 50. K. Pneumoniae with carbapenemase-producing clones<br />Norman P et al. LID 2009<br />42<br />Dr.T.V.Rao MD<br />
  51. 51. Carbapenemases within the Enterobacteriaceae<br />KPC carbapenemase<br />Difficult to detect using current MIC breakpoints.<br />Isolates that have an MIC of 2 mg/ml to ertapenem or an MIC of 2-4 mg/ml tomeropenem or Imipenem.<br /> Modified Hodge test is confirmatory. Discussed in manual. PCR is gold standard. <br />43<br />Dr.T.V.Rao MD<br />
  52. 52. Major families of β-lactamases of clinical importance<br />Bush K and Jacboy G AAC 2010<br />44<br />Dr.T.V.Rao MD<br />
  53. 53. When to Suspect a KPC-Producer<br />Enterobacteriaceae – especially Klebsiella pneumoniae that are resistant to extended-spectrum cephalosporins:<br />MIC range for 151 KPC-producing isolates<br />Ceftazidime 32 to >64 mg/ml<br />Ceftriaxone ≥ 64 mg/ml<br />Cefotaxime ≥ 64 mg/ml<br />Variable susceptibility to cefoxitin and cefepime <br />45<br />Dr.T.V.Rao MD<br />
  54. 54. Newer Carbapenemases <br />As of June 2010, there were three reported cases of Enterobacteriaceae isolates bearing this newly described resistance mechanism in the US, the CDC stated that "All three U.S. isolates were from patients who received recent medical care in India."<br />
  55. 55.
  56. 56. CDC reports the new genetic mechanisms<br />The isolate, Klebseilla pneumoniae 05-506, was shown to possess a metallo-beta-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained bla(CMY-4) flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7<br />
  57. 57. Genetic origin of the NDM-1<br />An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated bla(NDM-1), flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. <br />
  58. 58. Molecular configuration of NDM-1<br />NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all beta-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most Cephalosporins.<br />
  59. 59. NDM genetic coding differs from other recent isolates<br />Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, bla(NDM-1) was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation<br />
  60. 60. blaNDM-1 is expressed in...<br />Isolates, which include an Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, carry blaNDM-1, which confers resistance to all beta-lactam agents except aztreonam (a monobactam antimicrobial) ; all three isolates were aztreonam resistant, presumably by a different mechanisms.<br />
  61. 61. Phenotypic Tests for Carbapenemase Activity<br />Modified Hodge Test <br />100% sensitivity in detecting KPC; also positive when other carbapenemases are present<br />100% specificity<br />Procedure described by Lee et al. CMI, 7, 88-102. 2001.<br />53<br />Dr.T.V.Rao MD<br />
  62. 62. CLSI guidelines for Carbapenamases detection<br /> CLSI has published guidelines for detection of isolates producing carbapenemases (CLSI document M100) . For isolates that test susceptible to a carbapenem but demonstrate reduced susceptibility either by disk diffusion or MIC testing, performing a phenotypic test for carbapenemase activity, the Modified Hodge Test (MHT), is recommended<br />54<br />Dr.T.V.Rao MD<br />
  63. 63. Modified Hodge Test<br />Lawn of E. coli ATCC 25922<br /> 1:10 dilution of a<br /> 0.5 McFarland suspension<br />Test isolates<br />Imipenem disk<br />Described by Lee et al. CMI, 7, 88-102. 2001.<br />55<br />Dr.T.V.Rao MD<br />
  64. 64. Modified Hodge Test<br />Preliminary results suggest that any of the three carbapenem disks work in the Modified Hodge Test<br />56<br />Dr.T.V.Rao MD<br />
  65. 65. 57<br />Dr.T.V.Rao MD<br />
  66. 66. Indian data on Carbapenem resistance<br />Incidence of Meropenem resistance higher than that of Imipenem/cilastatin across clinically significant nosocomial pathogens<br />Gupta E et al, Indian J Med Res 2006 July; 124: 95-98<br />58<br />Dr.T.V.Rao MD<br />
  67. 67. Indian data on Carbapenem resistance<br />Overall Imipenem/cilastatin showed better activity than Meropenem<br />Gupta E et al, Indian J Med Res 2006 July; 124: 95-98<br />59<br />Dr.T.V.Rao MD<br />
  68. 68. Mechanisms of Carbapenem Resistance<br />Carbapenemase hydrolyzing enzymes<br />Porin loss “OprD”<br />ESBL or AmpC + porin loss<br />60<br />Dr.T.V.Rao MD<br />
  69. 69. What Labs Should Do Now<br />Look for isolates of Enterobacteriaceae (especially K. pneumoniae), with carbapenem MIC ≥ 2 mg/ml or nonsusceptible to ertapenem by disk diffusion<br />Consider confirmation by Modified Hodge Test<br />Can submit initial isolate to CDC via NJ State Lab for confirmation by blaKPC PCR if KPC-producers not previously identified in hospital’s isolate population<br />Alert clinician and infection control practitioner to possibility of mobile carbapenemase in isolate<br />61<br />Dr.T.V.Rao MD<br />
  70. 70. Carbapenemases Class A<br />First identified 1982 in UK<br />Four major families<br />Chromosomally encoded<br />Serratia marcescens enzyme (SME)<br />Not metalloenzyme carbapenemases (NMC)<br />Imipenem-hydrolyzing -lactamases (IMI)<br />Plasmid encoded<br />Klebsiella pneumoniae carabapenemases (KPC)<br />Guiana Extended-Spectrum (GES) <br />62<br />Dr.T.V.Rao MD<br />
  71. 71. KPC Epidemiology<br />Predominantly in K. pneumoniae (KP)<br />Reported in Enterobacter spp., Salmonella spp., E. coli, P. aeruginosa, and Citrobacter spp.<br />First identified in KP clinical isolate from North Carolina in 1996 (KPC-1)<br />KPC-2, -3, and -4 have been reported.<br />Mostly identified on the East cost<br />63<br />Dr.T.V.Rao MD<br />
  72. 72. When to Suspect a KPC Producer<br />Enterobacteriaceae<br />Resistance to extended spectrum Cephalosporins (cefotaxime, ceftazidime, and ceftriaxone)<br />Variable susceptibility to cephamycins (cefoxitin, cefotetan)<br />Carbapenem MICs  2 g/ml<br />64<br />Dr.T.V.Rao MD<br />
  73. 73. How to Detect a KPC Producer<br />Antimicrobial susceptibility tests (ASTs)<br />MIC<br />Carbapenem MIC  2 g/ml<br />Disk diffusion<br />Carbapenem: “I” or “R”<br />Among carbapenems, ertapenem: <br />Most sensitive<br />less specific<br />Anderson et al. 2007. JCM 45 (8): 2723 <br />65<br />Dr.T.V.Rao MD<br />
  74. 74. Definitive Identification of a KPC Producer<br />Modified Hodge test<br />100% sensitivity to detect KPC<br />Swab E. coli ATCC 25922 onto plate to create lawn Place imipenem disk in center.<br />Streak test isolates from edge of disk to end of plate.<br />Incubate overnight.<br />Look for growth of E. coli around test isolate streak - indicates carbapenem-hydrolyzing enzyme.<br />pos<br />pos<br />pos<br />neg<br />neg<br />neg<br />meropenem<br />ertapenem<br />imipenem<br />Janet Hindler, What’s New in the 2008 CLSI Standards for (AST)?<br />66<br />Dr.T.V.Rao MD<br />
  75. 75. 67<br />K. Pneumoniae with KPC-2<br />Dr.T.V.Rao MD<br />
  76. 76. Tris/EDTA Disk Test<br />Tris/EDTA disks used in combination with a carbapenem disk provides a sensitive test for class A carbapenem-hydrolyzing enzymes<br />Imipenem disks most sensitive carbapenem disks to use with this method, but ertapenem and meropenem also work well <br />Dr.T.V.Rao MD<br />68<br />
  77. 77. 69<br />KPC-2 producing K. pneumoniae is both the lawn culture and inoculated onto Tris/EDTA disk placed beside imipenem disk. <br />Indentation indicates production of carbapenem-hydrolyzing enzyme (positive test). <br />Second Tris/EDTA disk (not inoculated with test organism) is placed further away from imipenem disk to test for metallo-β-lactamase production (negative test).<br />Tris/EDTA Disk Test<br />Procedure described by Ellen Molan and Ken Thompson, Creighton University<br />Dr.T.V.Rao MD<br />
  78. 78. Imipenem resistant K. pneumoniae expressing Class A carbapenemase and Imipenem resistant S. maltophilia expressing Class B carbapenemase<br />70<br />Dr.T.V.Rao MD<br />
  79. 79. 71<br />Modified Hodge Test<br />Inoculate MH agar with a 1:10 dilution of a 0.5 McFarland suspension of E. coli ATCC 25922 and streak for confluent growth using a swab. <br />Place 10-µg imipenem disk in center<br />Streak each test isolate from disk to edge of plate<br />Isolate A is a KPC producer and positive by the modified Hodge test.<br />Anderson KF et al. JCM 2007 Aug;45(8):2723-5. <br />Dr.T.V.Rao MD<br />
  80. 80. KPC Producer - Example<br />meropenem <br />≤4 µg/ml*<br />imipenem <br />≤4 µg/ml*<br />ertapenem <br />≤2 µg/ml*<br />*CLSI breakpoint for “S”;<br /> marked w/ arrow<br />Courtesy of J. Patel, PhD., CDC<br />72<br />Dr.T.V.Rao MD<br />
  81. 81. 73<br />E. cloacae: ertapenem resistance, meropenem susceptible<br />Dr.T.V.Rao MD<br />
  82. 82. 74<br />E. cloacae derepressed mutant expressing AmpC and porin mutation<br />KPC positive Control<br />Patient Isolate<br />Dr.T.V.Rao MD<br />
  83. 83. Activity against Acinetobacter spp.<br />Carbapenems are considered the drugs of choice for treating serious infections caused by Acinetobacter baumanii<br />Progressive antimicrobial resistance in Acinetobacter is a cause of concern<br />Imipenem/cilastatin demonstrates lower MICs and lower resistance rates than Meropenem against Acinetobacter baumanii<br />Canduela MJ et al, J AntimocrobChemother 2006; 57: 1220-1222<br />75<br />Dr.T.V.Rao MD<br />
  84. 84. Alternative Treatment for a KPC Producer<br />Tigecycline (100.0% effective)<br />Colistin (88.1% effective)<br />SENTRY report. AAC. 2008. Feb;52(2):570-3<br />Minocycline <br />A strategy for susceptibility testing is needed <br />76<br />Dr.T.V.Rao MD<br />
  85. 85. 77<br />Carbapenemase-Producing Klebseilla pneumonia (KPC)<br />Conclusions:<br />Correct inoculum's of any organism undergoing identification and susceptibility testing should be assured<br />K. pneumoniae intermediate or resistant to ertapenem or meropenem should be considered resistant to all carbapenems, regardless of the other susceptibility results<br />Inoculum effect with imipenem has also been observed in KPC-possessing Enterobacter spp. <br />Bratu, S. et al AAC 49:3018-3020, 2005<br />Dr.T.V.Rao MD<br />
  86. 86. Clsi guidelines to be followed in detection<br />ESBL detection—CLSI guidelines present<br />Need to have guidelines to detect ESBLs present in other species besides E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis. <br />AmpC detection-No guidelines available<br />KPC detection-Not widespread, need to have lower concentrations of carbapenems on panels. <br />78<br />Dr.T.V.Rao MD<br />
  87. 87. Purchase QC strains<br />ATCC BAA-1708- mupA S. aureus isolate, ATCC BAA-1705 and BAA-1706. Positive and Negative modified Hodge test isolates, respectively.<br />New ampicillin, piperacillin and ticarcillin QC tests for E. coli ATCC35218. <br />Dr.T.V.Rao MD<br />79<br />
  88. 88. Definitive Identification of a KPC Producer<br />PCR<br />The method of choice to confirm KPC<br />80<br />Dr.T.V.Rao MD<br />
  89. 89. 81<br />Automated Systems cannot detect all types of antibiotic resistance <br />Limitations of Automated Systems in detecting emerging resistance in Gram-Negative Bacilli<br />Unable to detect ESBLs in organisms other than E. coli and Klebsiella<br />Unable to detect Inducible AmpC<br />Unable to detect ESBLs in AmpC positive strains<br />Unable to detect imipenem resistance in strains producing KPC carbapenemases<br />Dr.T.V.Rao MD<br />
  90. 90. Carbapenems: Myths and Reality<br />Inspite of expensiveness of Carbapenems, pharmacoeconomic studies have demonstrated the advantages of these drugs over a number of cheaper conventional antibiotics<br />Since inadequate empirical antimicrobial therapy is associated with significantly higher mortality in serious infections, Carbapenems are no longer considered second-line antimicrobials<br />The main ways to improve use of Carbapenems is:<br /> - De escalation therapy<br /> - Optimal dosing of Carbapenems<br />Bereznyakov IG, Kharkov Medical Academy of Post Graduate Education, Kharkov, Ukraine<br />82<br />Dr.T.V.Rao MD<br />
  91. 91. Testing Other Drugs for clinical use in carbapenem resistant strains<br />Polymixin B or Colistin<br />Could test either, but colistin used clinically<br />Disk diffusion test does not work – don’t use!<br />Etest – works well, but not FDA cleared <br />Broth microdilution – reference labs<br />Breakpoints - none<br />MIC ≤ 2 mg/ml, normal MIC range<br />MIC ≥ 4 mg/ml indicates increased resistance<br />83<br />Dr.T.V.Rao MD<br />
  92. 92. Testing Other Drugs to treat patients with resistant carbapenem isolates<br />Tigecycline:<br />Test by Etest if possible – disk diffusion tends to overcall resistance<br />No CLSI breakpoint, but there are FDA breakpoint<br />Susceptible ≤ 2 mg/ml<br />Intermediate = 4 mg/ml<br />Resistant ≥ 8 mg/ml<br />84<br />Dr.T.V.Rao MD<br />
  93. 93. How to improve our microbiology departments<br />Each laboratory should have a staff member with the time, interest, and expertise to provide leadership in antibiotic testing and resistance. This person would read relevant publications, network with other laboratories, and evaluate potentially useful tests to detect new forms of resistance before new CLSI-recommended tests become available”<br />Ken Thomson, Emerging Infect. Dis., 2001<br />85<br />Dr.T.V.Rao MD<br />
  94. 94. Interpretation/ResultsConveyed to Infection Control Departments<br />Report all cultures that are positive for CRE or carbapenemase-producing Enterobacteriaceae to the appropriate infection control personnel. <br />86<br />Dr.T.V.Rao MD<br />
  95. 95. INSPITE OF SEVERAL ADVANCES SIMEPLE hand WASH CAN SAVE SEVERAL LIVES<br />87<br />Dr.T.V.Rao MD<br />
  96. 96. The programme designed with references<br />Livermore et. al. 2001. Interpretive reading: recognizing the unusual and inferring resistance mechanisms from resistance phenotypes. J AntimicrobChemother. 48:S1, 87-102.<br />Paul C. Schreckenberger, Ph.D., D(ABMM) Professor of Pathology<br /> Director, Clinical Microbiology Laboratory Loyola University Medical Center<br /> Ken Thomson, Emerging Infect. Dis., 2001<br />Gupta E et al, Indian J Med Res 2006 July; 124: 95-98<br />Bratu S et al AAC 49:776-778; Schreckenberger, P personal observation<br />Canduela MJ et al, J AntimocrobChemother 2006; 57: 1220-1222<br /> Lee et al. CMI, 7, 88-102. 2001.<br />88<br />Dr.T.V.Rao MD<br />
  97. 97. Programme created by Dr.T.V.Rao.MD for ‘e’ learning by Medical Professionals<br />Email <br /> doctortvrao@gmail.com <br />Dr.T.V.Rao MD<br />89<br />
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