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carbapenams uses and reistance
Dr.T.V.Rao MD

CARBAPENAMS

Uses and Reistance

Dr.T.V.Rao MD

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

Dr.T.V.Rao MD

Conventional antibiotics
carbapenems x penicillins
Dr.T.V.Rao MDCarbapenems 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
antibiotic formulation continue to grow continue 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

Dr.T.V.Rao MD

Antibiotic formulation continue to growCONTINUE TO CONFUSE
a changing landscape for numbers of approved antibacterial agents we have more resistant microbes
A Changing Landscape forNumbers of Approved Antibacterial AgentsWe have more resistant Microbes

18

16

14

12

10

Number of agents approved

8

6

4

0

2

0

Dr.T.V.Rao MD

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

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.

Dr.T.V.Rao MD

What are carbapenems
carbapenems common uses
Dr.T.V.Rao MDCarbapenems 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
how are carbapenems used
Dr.T.V.Rao MDHow 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.
  • Pseudomonas aeruginosa
  • Alcaligenesspp.
  • Enterobacteriaceae
    • Mogenella spp.
    • Serratia spp.
    • Enterobacter spp.
    • Citrobacter spp.
    • ESBL or AmpC + E. coli and Klebsiellaspp.

Reference: Sanford Guide

enterobacteriaceae are real problamatic microbes
Dr.T.V.Rao MDEnterobacteriaceae 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
carbapenems effective on several common isolates
Dr.T.V.Rao MDCarbapenems effective on several common isolates
  • Staph (not MRSA), Strep (highly resistant), Neisseria, Haemophilus, Proteus, Pseudomonas, Klebseilla, Bacteroides, anaerobes (excluding C. dif)
  • .
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

Dr.T.V.Rao MD

Carbapenems are broad spectrum antibiotic
drugs belong to the carbapenem class
Dr.T.V.Rao MDDrugs belong to the carbapenem class:
  • Imipenem
  • Meropenem Ertapenem Doripenem Panipenem/ betamipron Biapenem
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.

Dr.T.V.Rao MD

broadest antibacterial spectrum
carbapenems
Carbapenems

Dr.T.V.Rao MD

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

Dr.T.V.Rao MD

Carbapenemases
mechanisms of carbapenem resistance

Carbapenemase hydrolyzing enzymes

  • Porin loss “OprD”
  • ESBL or AmpC + porin loss

Dr.T.V.Rao MD

Mechanisms of Carbapenem Resistance
carbapenamases
Carbapenamases

Dr.T.V.Rao MD

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

Dr.T.V.Rao MD

Carbapenamases are complex in Mechanisims
carbapenemases20
Dr.T.V.Rao MDCarbapenemases
  • 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
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.

Dr.T.V.Rao MD

Carbapenamases are spreading faster
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.

Dr.T.V.Rao MD

Carbapenemases within the Enterobacteriaceae
kpc k pneumoniae c arbapenemase
Dr.T.V.Rao MDKPC (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
kpc s in enterobacteriaceae
KPC’s in Enterobacteriaceae

Pseudomonas aeruginosa – Columbia & Puerto Rico

Dr.T.V.Rao MD

pseudomonas aeruginosa carbapenamases
Dr.T.V.Rao MDPseudomonas 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.
emerging carbapenem resistance in gram negative bacilli
Dr.T.V.Rao MDEmerging 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
enterobacteriaceae breakpoints revised so need for other newer drugs may be carbapenms
Enterobacteriaceae: Breakpoints revised so need for other newer drugs, may be carbapenms?

Dr.T.V.Rao MD

resistance to carbapenems
Dr.T.V.Rao MDResistance to Carbapenems
  • 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 carbapenems31
Dr.T.V.Rao MDResistance 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
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)

Dr.T.V.Rao MD

Carbapenemase Class A
class a carbapenemases
Dr.T.V.Rao MDClass 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
carbapenemase producing klebseilla pneumonia kpc
Dr.T.V.Rao MDCarbapenemase-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
carbapenemases36
Carbapenemases

Dr.T.V.Rao MD

k lebsiella p neumoniae and c arbapenemase
Dr.T.V.Rao MDKlebsiellaPneumoniae 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)
kpc enzymes
Dr.T.V.Rao MDKPC 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
kpc enzymes39

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

Dr.T.V.Rao MD

KPC Enzymes
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

Dr.T.V.Rao MD

KPC Epidemiology
kpc epidemiology41

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

Dr.T.V.Rao MD

KPC Epidemiology
k pneumoniae with carbapenemase producing clones
K. Pneumoniae with carbapenemase-producing clones

Dr.T.V.Rao MD

Norman P et al. LID 2009

carbapenemases within the enterobacteriaceae43

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.

Dr.T.V.Rao MD

Carbapenemases within the Enterobacteriaceae
slide44

Major families of β-lactamases of clinical importance

Dr.T.V.Rao MD

Bush K and Jacboy G AAC 2010

when to suspect a kpc producer
Dr.T.V.Rao MDWhen 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
newer carbapenemases
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."
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

CDC reports the new genetic mechanisms
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.

Genetic origin of the NDM-1
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.

Molecular configuration of NDM-1
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

NDM genetic coding differs from other recent isolates
bla ndm 1 is expressed in
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.
phenotypic tests for carbapenemase activity
Dr.T.V.Rao MDPhenotypic 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.

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

Dr.T.V.Rao MD

CLSI guidelines for Carbapenamases detection
modified hodge test
Dr.T.V.Rao MDModified 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.

modified hodge test56
Dr.T.V.Rao MDModified Hodge Test
  • Preliminary results suggest that any of the three carbapenem disks work in the Modified Hodge Test
indian data on carbapenem resistance
Dr.T.V.Rao MDIndian 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

indian data on carbapenem resistance59
Dr.T.V.Rao MDIndian 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

mechanisms of carbapenem resistance60

Carbapenemase hydrolyzing enzymes

  • Porin loss “OprD”
  • ESBL or AmpC + porin loss

Dr.T.V.Rao MD

Mechanisms of Carbapenem Resistance
what labs should do now
Dr.T.V.Rao MDWhat 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
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)

Dr.T.V.Rao MD

Carbapenemases Class A
kpc epidemiology63

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

Dr.T.V.Rao MD

KPC Epidemiology
when to suspect a kpc producer64

Enterobacteriaceae

Resistance to extended spectrum Cephalosporins (cefotaxime, ceftazidime, and ceftriaxone)

Variable susceptibility to cephamycins (cefoxitin, cefotetan)

Carbapenem MICs  2 g/ml

Dr.T.V.Rao MD

When to Suspect a KPC Producer
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

Dr.T.V.Rao MD

How to Detect a KPC Producer
  • Anderson et al. 2007. JCM 45 (8): 2723
definitive identification of a kpc producer
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

Dr.T.V.Rao MD

Janet Hindler, What’s New in the 2008 CLSI Standards for (AST)?

tris edta disk test
Dr.T.V.Rao MDTris/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
tris edta disk test69
Dr.T.V.Rao MDTris/EDTA Disk Test
  • 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).

Procedure described by Ellen Molan and Ken Thompson, Creighton University

slide70
Dr.T.V.Rao MD

Imipenem resistant K. pneumoniae expressing Class A carbapenemase and Imipenem resistant S. maltophilia expressing Class B carbapenemase

modified hodge test71
Dr.T.V.Rao MDModified 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.

kpc producer example
Dr.T.V.Rao MDKPC Producer - Example

imipenem

≤4 µg/ml*

meropenem

≤4 µg/ml*

ertapenem

≤2 µg/ml*

*CLSI breakpoint for “S”;

marked w/ arrow

Courtesy of J. Patel, PhD., CDC

slide74

E. cloacae derepressed mutant expressing AmpC and porin mutation

Dr.T.V.Rao MD

KPC positive Control

Patient Isolate

activity against acinetobacter spp
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

Dr.T.V.Rao MD

Canduela MJ et al, J AntimocrobChemother 2006; 57: 1220-1222

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

Dr.T.V.Rao MD

Alternative Treatment for a KPC Producer
carbapenemase producing klebseilla pneumonia kpc77
Dr.T.V.Rao MDCarbapenemase-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

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.

Dr.T.V.Rao MD

Clsi guidelines to be followed in detection
purchase qc strains
Dr.T.V.Rao MDPurchase 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.
definitive identification of a kpc producer80
Dr.T.V.Rao MDDefinitive Identification of a KPC Producer
  • PCR
    • The method of choice to confirm KPC
automated systems cannot detect all types of antibiotic resistance
Dr.T.V.Rao MDAutomated 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
carbapenems myths and reality
Dr.T.V.Rao MDCarbapenems: 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

testing other drugs for clinical use in carbapenem resistant strains
Dr.T.V.Rao MDTesting 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
testing other drugs to treat patients with resistant carbapenem isolates
Dr.T.V.Rao MDTesting 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
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

Dr.T.V.Rao MD

How to improve our microbiology departments
interpretation results conveyed to infection control departments
Dr.T.V.Rao MDInterpretation/ResultsConveyed to Infection Control Departments
  • Report all cultures that are positive for CRE or carbapenemase-producing Enterobacteriaceae to the appropriate infection control personnel.
inspite of several advances simeple hand wash can save several lives
Dr.T.V.Rao MDINSPITE OF SEVERAL ADVANCES SIMEPLE hand WASH CAN SAVE SEVERAL LIVES
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.

Dr.T.V.Rao MD

The programme designed with references
slide89

Programme created by Dr.T.V.Rao.MD for ‘e’ learning by Medical Professionals

Email

doctortvrao@gmail.com

Dr.T.V.Rao MD