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Carbapenams

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Carbapenams, uses and drug reistance to carbapenams

Carbapenams, uses and drug reistance to carbapenams

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