Carbapenamases Facts and Detecction
Carbapenamases Facts and Detecction
Carbapenamases Facts and Detecction
Dr.T.V.Rao MD
A Changing Landscape for
Numbers of Approved Antibacterial Agents
We have more resistant Microbes
18
16
Number of agents approved
14
12
Resistance
10
2
0
0
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 Dr.T.V.Rao MD 2
Carbapenems x Penicillin
• 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
Dr.T.V.Rao MD 3
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 Streptomyces cattleya.
Dr.T.V.Rao MD 4
Spectrum of activity
• Broad spectrum activity
– GPC & GNB
– Aerobic & Anaerobic bacteria
– Active against MDR isolates
– Active against ESBL +ve GNB
– Active against Ps aeruginosa & Acinetobacter spp.
• Not active against
– MRSA
– Enterococcus spp.
– Stenotrophomonas maltophilia
Carbapenems in Common Use
• 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
Dr.T.V.Rao MD 6
Carbapenems effective on several
common isolates
– Staph (not MRSA),
Strep (highly
resistant),
Neisseria,
Haemophilus,
Proteus,
Pseudomonas,
Klebseilla,
Bacteroides,
anaerobes
(excluding C. dif)
–. Dr.T.V.Rao MD 7
Spectrum of Activity
Strep spp. & Entero- Non-
Drug Anaerobes
MSSA bacteriaeae fermentors
Imipenem + + + +
Meropenem + + + +
Limited
Ertapenem + + activity +
Doripenem + + + +
Dr.T.V.Rao MD 8
Carbapenems
Route of
Drug FDA Status
Administration
Imipenem IV Cleared
Meropenem IV Cleared
Doripenem IV Application
Submitted
Dr.T.V.Rao MD 9
Enterobacteriaceae are real
problamatic microbes
• The rapid and disturbing
spread of:
– ESBL extended-spectrum
ß-lactamases
– AmpC enzymes
– carbapenem
resistance
• metallo-β-lactamases
• KPC and OXA-48 β-
lactamases
– Quinolones resistance
Dr.T.V.Rao MD 10
Bush 2010 : Distribution of β lactamases according to function
Dr.T.V.Rao MD 15
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 16
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 to
meropenem or Imipenem.
• Modified Hodge test is confirmatory..
PCR is gold standard.
Dr.T.V.Rao MD 17
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 includes
cephalosporins and
carbapenems
Dr.T.V.Rao MD 18
KPC’s in Enterobacteriaceae
Species Comments
Klebsiella spp. K. pneumoniae-cause of outbreaks
K. oxytoca-sporadic occurrence
Enterobacter spp.
Escherichia coli
Salmonella spp. Sporadic occurrence
Citrobacter freundii
Serratia spp.
Dr.T.V.Rao MD 19
Mechanism of Resistance to Carbapenems
1. Cephalosporinase : Amp C & CTX- M
+ Porin mutation = low level resistance
2. Carbapenemase: β lactamases that can hydrolyze
carbapenems
Amber Class A: 9 families
KPC, SME, NMC-A, IMI, PER, GES, SFO, SFC,
IBC
Amber Class B: 6 families
VIM, GIM, SIM, NDM, IMP, SPM
Amber Class D: 2 families
OXA, PSE
Pseudomonas aeruginosa Carbapenamases
Cefazolin ≤8 16 ≥32 ≤1 2 ≥4
Dr.T.V.Rao MD 27
Laboratory Detection
Clinical and Laboratory Standards Institute breakpoints: 2009 & 2010
Revised Break Points 2010
S MHT I R S MHT I R
Dr.T.V.Rao MD 32
Modified Hodge Test for
Carbapenemase Detection
in Enterobacteriaceae
Laboratory Detection of KPC-Producers
Problems:
1) Some isolates demonstrate low-level
carbapenem resistance
– 100% specificity
Procedure described by Lee et al. CMI, 7, 88-102. 2001.
The Modified Hodge Test (MHT)
Susceptible
E. coli
Carbapenem Disk
Test Isolate
Modified Hodge Test
Test isolates
Imipenem disk
• An international
organization dedicated to
curbing antibiotic
resistance
• Chapters exist currently in
several Asian countries:
Australia, China, India,
Nepal, Pakistan,
Philippines, South Korea,
Taiwan, Vietnam
Dr.T.V.Rao MD 66
Hand Washing Can Reduce the
Spread of Microbes
Created by Dr.T.V.Rao MD for ‘ e ‘ learning
resources for the Medical Professionals in
the Developing World
email.
doctortvrao@gmail.com