Carbapenem Resistance

an update on
essential learning
Dr.T.V.Rao MD

Definition of Carbapenems
4:5 fused
ring lactam of penicillin's with a double
bond between C-2 and C-3 but with the
substitution of carbon for sulfur at C-1 . The

The term carbapenem is defined as the

hydroxyethyl side chain of thienamycin is a radical

departure from the structure of conventional
penicillin's and cephalosporins, all of which have an
acylamino substituent on the -lactam ring; the
stereochemistry of this hydroxyethyl side chain is a key
attribute of carbapenems and is important for activity.

We have more stable Carbapenems

Along the journey to
the discovery of
more-stable
carbapenems with a
broader spectrum,
the other currently
available
compounds,

Meropenem,
biapenem,
ertapenem, and

Synthetic journey of
Carbapenems

A major advance in this synthetic journey was the

addition of a methyl group to the 1- position . This
modification was found to be protective against DHP-I
hydrolysis . Several carbapenems were identified with
this modification in the subsequent 2 decades; many
were similar to the currently available carbapenems,
having a 1--methyl and a pyrrolidine ring at C-2

Newer use of Carbapenems

These novel
carbapenems included
antipseudomonal
carbapenems, antimethicillin-resistant S.
aureus (MRSA)
carbapenems (i.e.,
cationic and
dithiocarbamate
carbapenems), orally
available carbapenems,
trinem carbapenems, a
dual quinolonyl-

Mechanism of action of
Carbapenams

Mechanism of action. As a class of lactams, carbapenems are not easily

diffusible through the bacterial cell wall .
Generally speaking, carbapenems enter
Gram-negative bacteria through outer
membrane proteins (OMPs), also known as
porins. After transversing the periplasmic
space, carbapenems permanently acylate
the PBPs (for the mechanism, . PBPs are
enzymes (i.e., transglycolases,

What are Current Insights

Current insights into this
process suggest that the
glycan backbone forms a
right-handed helix with a
periodicity of three per
turn of the helix .
Carbapenems act as
mechanism-based
inhibitors of the
peptidase domain of
PBPs and can inhibit
peptide cross-linking as

What are Current Insights

A key factor of the efficacy of carbapenems is their ability to

bind to multiple different PBPs . Since cell wall formation is a
dynamic three-dimensional process with formation and
autolysis occurring at the same time, when PBPs are
inhibited, autolysis continues . Eventually the
peptidoglycan weakens, and the cell bursts due to
osmotic pressure.

Microbiological activity
Carbapenems
demonstrate an overall
broader antimicrobial
spectrum in vitro than
the available penicillin's,
cephalosporins, and lactam/-lactamase
inhibitor combinations .
In general, imipenem,
panipenem, and
doripenem are potent

Every Carbapenem
has
Meropenem, biapenem,
ertapenem, and doripenem
Different potentials
are slightly more effective
against Gram-negative
organisms . Important
considerations here are the
following:
(i) ertapenem has a
more limited spectrum,
because it is not as active
as imipenem or
Meropenem against P.
aeruginosa ;
(ii)
Meropenem is not as
potent as imipenem or

Meropenem in Resistant
Mycobacterial Infections
A unique application of
Meropenem is that when
combined with clavulanic
acid, it is potent at killing
MDR Mycobacterium
tuberculosis, a bacterium
that typically is not
susceptible to -lactams
due to a chromosomally
expressed -lactamase .
This ability to inhibit or
kill M. tuberculosis is
likely to be a property of

Carbapenems can be
Combined with
other
Carbapenems can also
be combined with
Antimicrobials
other antimicrobials
to treat serious
infections.
Combination therapy
is a subject of intense
interest, since the
emergence of MDR
pathogens often
requires us to treat

Safety and Tolerability

Nephrotoxicity,
neurotoxicity, and
immunomodulation have
been reported with the
use of carbapenems, and
thus predisposing factors
should be considered
when administering any
carbapenem . In
addition, the use of
carbapenems can alter

Carbapenems are Important

Antibiotics in clinical care
Carbapenems play a
critically important role
in our antibiotic
armamentarium. Of
the many hundreds of
different -lactams,
carbapenems possess
the broadest spectrum
of activity and greatest
potency against Grampositive and Gram-

Used as last line life saving Drugs

They are often used as last-line agents or antibiotics of last

resort when patients with infections become gravely ill or are
suspected of harbouring resistant bacteria . Unfortunately,
the recent emergence of multidrug-resistant (MDR) pathogens
seriously threatens this class of lifesaving drugs

Recent studies show

Several recent studies
clearly show that
resistance to
carbapenems is increasing
throughout the world .
Despite this menacing
trend, our understanding
of how to best use these
agents is undergoing a
renaissance, especially
concerning their role with
regard to -lactamase
inhibition

Major Mechanism of Drug

Resistance in Bacteria

Spectrum of Activity
Strep spp. &
MSSA

Enterobacteriaeae

Nonfermentors

Anaerobes

Imipenem

Meropenem

Ertapenem

Limited
activity

Doripenem

Drug

MECHANISMS OF
RESISTANCE AGAINST
CARBAPENEMS
Many nonterminating Gram-negative

bacteria (e.g., Pseudomonas spp.,

Acinetobacter spp., and Stenotrophomonas
spp.), as well as the Enterobacteriaceae
(e.g., Klebsiella spp., Escherichia coli, and
Enterobacter spp.) and Gram-positive
bacteria (e.g., Staphylococcus spp.,
Streptococcus spp., Enterococcus spp., and
Nocardia spp.), are or are becoming
resistant to most clinically available

MECHANISMS OF RESISTANCE
AGAINST CARBAPENEMS
Mechanisms of resistance
to carbapenems include
production of lactamases, efflux pumps,
and mutations that alter
the expression and/or
function of porins and
PBPs . Combinations of
these mechanisms can
cause high levels of
resistance to
carbapenems in certain
bacterial species, such as

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.
Pseudomonas aeruginosa
Alcaligenes spp.
Enterobacteriaceae

Reference: Sanford Guide

Mogenella spp.
Serratia spp.
Enterobacter spp.
Citrobacter spp.
ESBL or AmpC + E. coli
and Klebsiella spp.

Emerging Carbapenem
Resistance in Gram-Negative
Bacilli
Significantly limits treatment options for lifethreatening 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

Carbapenem Resistance: Mechanisms

Enterobacteriaceae

Cephalosporinase + porin loss

Carbapenemase

P. aeruginosa

Porin loss
Up-regulated efflux
Carbapenemase

Acinetobacter spp.

Cephalosporinase + porin loss

Carbapenemase

Carbapenemases
Classification

Enzyme

Most Common Bacteria

Class A

KPC, SME,
IMI, NMC,
GES

Enterobacteriaceae
(rare reports in P. aeruginosa)

Class B
IMP, VIM,
(metallo--lactamse) GIM, SPM

P. aeruginosa
Enterobacteriacea
Acinetobacter spp.

Class D

Acinetobacter spp.

OXA

Klebsiella Pneumoniae Carbapenemase

KPC is a class A -lactamase
Confers resistance to all -lactams including
extended-spectrum cephalosporins and carbapenems

Occurs in Enterobacteriaceae
Most commonly in Klebsiella pneumoniae
Also reported in: K. oxytoca, Citrobacter freundii,
Enterobacter spp., Escherichia coli, Salmonella spp.,
Serratia spp.,

Also reported in Pseudomonas aeruginosa (Columbia)

Susceptibility Profile of KPCProducing K. pneumoniae

(Antimicrobial
Learn Interpretation
from Antibiograms
)
Antimicrobial
Interpretation
Amikacin

Chloramphenicol R

Amox/clav

Ciprofloxacin

Ampicillin

Ertapenem

Aztreonam

Gentamicin

Cefazolin

Imipenem

Cefpodoxime

Meropenem

Cefotaxime

Pipercillin/Tazo

Cetotetan

Tobramycin

Cefoxitin

Trimeth/Sulfa

Ceftazidime

Polymyxin B

MIC >4g/ml

Ceftriaxone

Colistin

MIC >4g/ml

Cefepime

Tigecycline

KPC Enzymes
Located on plasmids;
conjugative and nonconjugative
blaKPC is usually flanked by
transposon sequences
blaKPC reported on plasmids
with:
Normal spectrum -lactamases
Extended spectrum -lactamases
Aminoglycoside resistance

KPCs 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.
Pseudomonas aeruginosa Columbia & Puerto Rico

Laboratory Detection of
KPCProducers
Problems:
1) Some isolates
demonstrate lowlevel carbapenem
resistance
2) Some automated
systems fail to
detect low-level
resistance

Can Carbapenem
Susceptibility of I or R Detect
KPC-Producers?
Sens/Spec (%) for Detection of KPC-mediated R*
Method

Imipenem

Meropenem

Ertapenem

Ref BMD

94/93

94/98

97/89

Disk Diffusion

42/96

71/96

97/82

Etest

55/96

58/96

90/84

Vitek Legacy

55/96

52/98

N/A

Vitek 2

71/98

48/96

94/93

MicroScan

74/96

84/98

100/89

Phoenix

81/96

61/98

N/A

*N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

CAP Results (D-05)

KPC-producing Klebsiella
pneumoniae
Susceptible Results
MIC Method

Disk Method

Imipenem

63

57

Meropenem

63

18

Ertapenem

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, 88102. 2001.

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.

Modified Hodge Test

Preliminary results suggest that

any of the three carbapenem disks
work in the Modified Hodge Test

What Labs Should Do Now

Look for isolates of Enterobacteriaceae (especially
K. pneumoniae), with carbapenem MIC 2 g/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 hospitals isolate, or any
other reference laboratories experienced with
genomic methods Alert clinician and infection
control practitioner to possibility of mobile
carbapenems in isolate

We have no Appropriate
Documentation on Carbapenem
resistance
Outbreaks of
carbapenem-resistant
Escherichia coli and
Klebsiella pose
significant public
health threats, but
there is currently no
surveillance network
that alerts public
health officials when
outbreaks occur or
provides easilyaccessible information

Antibiograms is Highly
essential to reduce
Antibiotic Resistance

Scientific Documentation is
highly Essential
The Weissman Lab and
collaborators created
CaseFinder.org, which tracks
Carbapenem-resistant
Enterobacteriaceae (CRE)
infections in the continental
United States.
Hope India urgently needs
one to forecast trends in our
own country

Why Carbapenems cannot

be Misused
The discovery of a -lactam (e.g.,
carbapenem) with PBP and -lactamase
inhibitory properties was a major
breakthrough in infectious disease
therapeutics. The carbapenems are often
agents of last resort for many complicated
bacterial infections. As MDR pathogens
continue to emerge, the sustained study of
the development of novel carbapenems is an
essential undertaking.

References and Adopted from

Carbapenem Resistance in Enterobacteriaceae Jean B.
Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance
Team Division of Healthcare Quality Promotion CDC

Carbapenems: Past, Present, and Future Krisztina

M. Papp-Wallace1,2, Andrea Endimiani1,2,3,
Magdalena A. Taracila2 and Robert A. Bonomo
American Society for Microbiology
Antimicrobial Agents and Chemotherapy

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