UPDATE ON ESBLS AND
CARBAPENEM RESISTANT
ENTEROBACTERIACEAE
Michael Costello, Ph.D.
Technical Director – Microbiology
ACL Laboratories
TOPICS TO COVER
• Extended spectrum β lactamases (ESBLs)
• Update on the recent changing patterns of different types of ESBLs in the
Chicago/Milwaukee area
• Implications
•
Healthcare associated infections (HAI) Vs. community acquired infections
• Carbapenemases – more than “just” KPC
• Summarize carbapenemases currently found in the Wisconsin/Illinois area
• Expand on how and why CREs have spread so rapidly throughout the
world.
• Define testing algorithms for rapid detection of CRE, faster the better
• Talk about new molecular based tests that are becoming available
• Molecular assays for identification of bacteria and resistance genes directly
from a positive blood culture bottle.
• Culture not required
ANTIBIOTIC RESISTANCE
• Gram Negatives
• Production of β-lactamases – Enzymatic destruction of antibiotic
• Switch from Tem and SHV to CTX-M
• Permeability alterations
• Porin mutations – antibiotic entry is limited
• Porins are barrel shaped proteins that cross cell membranes and act as a port
though which nutrients, toxins and antibiotics can diffuse
• Antibiotic extrusion by efflux pumps
• Rapidly pump out antibiotics before they are effective
• Rarely, PBP alterations
• PBP 7-8 in A. baumanii
• Combinations of the above
CHANGING ESBL PATTERNS OUT WITH THE
OLD (TEM, SHV) AND IN WITH THE NEW [ESBL
(CTX-M), CARBAPENEMASES (KPC, NDM-1)]
Target is still the same – β-lactam ring
Only difference between peniclliniases, cephalosporinases and carbapenemases
is the preferred substrate
CLASSIFICATION OF ß-LACTAMASES BUSH-JACOBYMEDERIOS
- FUNCTIONAL CLASSIFICATION
Group
Enzyme Type
Inhibition
by
Clavulanate
Molecular
Class
(Ambler)
# of
Enzymes
Characteristics
Example
1
Cephalosporinase
No
C
53
Mainly chromosomal located in gram negative
bacteria, but may be plasmid mediated.
Resistance to ß-lactams (except carbapenems)
E. Coli
2a
Penicillins
Yes
A
20
Narrow spectrum resistance to penicillins only
S. Aureus
2b
Broad spectrum
Yes
A
16
Broad spectrum penicillinases
TEM-1, SHV-1
2be
Extended
spectrum
Yes
A
38
ESBL conferring resistance to oxyiminocephalsporins and monobactams
TEM-3, SHV-2,
CTX-M
2br
Inhibitory
resistant
Partly
A
9
Inhibitor resistant ß-lactamases (mostly TEMtypes and to a lesser extent SHV derived ESBL
TEM-30, TRC-1
2c
Carbenicillinase
Yes
A
15
Carbenicillinases
BRO-1, CARB3, PSE-1
2d
Cloxacillinase
Variable
D or A
18
Oxacillinases, partly inhibited by clavulanate
OXA-1, PSE-2
2e
Cephalosporinase
Yes
A
19
Oxacillinases, inhibited by clavulanate
P. vulgaris,
Bacteroides
fragilis
2f
Carbapenemase
Yes
A
3
Serine active carbepemases, inhibited by
clavulanate.
E. cloacae,
3
Metalloenzyme
No
B
15
Metallo-ß-lactamases conferring resistance to
all ß-lactam drugs except monobactams aztreonam
S. maltophilia
4
Penicillins
No
7
Miscellaneous ß-lactamases that do not
conform to other groups
B. cepacia
ESBL Pandemics
Enterobacteriaceae
pan-resistance endemic
pAmpC
detected
KPC
detected
NDM
detected.
ESBL (EXTENDED SPECTRUM Β-LACTAMASE)
OUT WITH THE OLD AND IN WITH THE NEW!
• Old ESBLs - SHV (SulfHydryl Variable) and TEM (Temoneira)
• >120 variants
• TEM and SHV-1 (initially only hydrolyzed ampicillin) first described in 1960’s
•
First ESBLs
•
SHV-2 in 1983
•
TEM-3 in 1984
• TEM and SHV are primarily healthcare associated
•
Competitive disadvantage outside of a healthcare setting
•
Require administration of antibiotics to compete
• More reactive against ceftazidime than cefotaxime
• Rarely carbapenem resistant
• New ESBLs – CTX-M (CefoTaXime –Munich)
• First described in Japan in 1986 and named in Germany in 1989.
• Can show carbapenem resistance, especially in association with a porin mutation
CTX-M
• CTX-M -lactamases are extended-spectrum β-lactamases (ESBLs) that
mainly inactivate cefotaxime and cefriaxone and have less activity
against ceftazidime
• Sequencing evidence that gene mobilized from Kluyvera spp.
(environmental bacteria rarely associated with disease)
• Associated with community-acquired UTIs
• Highest incidence in E. coli
• Plasmid is stable and confers minimal competitive disadvantage
when β-lactams are not present
• Dramatic world-wide spread in the last decade
• Quickly replacing TEM- and SHV-type ESBLs
• Detected in both humans and animals (in the food chain)
• Present wherever β-lactam antibiotics are used
• Associated with other multidrug-resistant genes
• Found on plasmids that also include resistance genes to
aminoglycosides and fluoroquinolones
ANTIBIOGRAMS 2008 - NEW MORE AGGRESSIVE E. COLI STRAIN ESBL POSITIVE
ANTIBIOGRAMS
Ertapenem
Imipenem (%S)
Nitrofurantoin (%S)
Piperacillin/tazobactam (%S)
Tobramycin (%S)
Trimethoprim/sulfamethox. (%S)
100
100
80
88
40
37
100
100
88
94
39
39
97
72
77
40
46
100
100
78
96
36
68
51
100
100
89
74
25
32
52
100
100
83
90
30
57
Escherichia coli, ESBL (6%)
205
92
0
11
0
0
0
0
0
2
67
Bethany
Escherichia coli, ESBL (40%)
29
100
0
0
0
0
0
0
0
3
68
Good Sam
Escherichia coli, ESBL (2%)
43
100
0
12
0
0
0
0
0
14
92
GSH
Escherichia coli, ESBL (2%)
18
100
0
0
0
0
0
0
0
0
78
SSUB
Escherichia coli, ESBL (4%)
35
100
0
20
0
0
0
0
0
3
54
Trinity
Escherichia coli, ESBL (2%)
25
92
0
16
0
0
0
0
0
0
48
IMMC
Escherichia coli, ESBL (6%)
74
93
0
7
0
0
0
0
0
12
LGH
Escherichia coli, ESBL (8%)
190
96
0
1
0
0
0
0
0
6
Hospital
Gentamicin (%S)
46
Ciprofloxacin (%S)
21
Cefepime (%S)
66
Ceftriaxone (%S)
93
Ceftazidime (%S)
100
Cefazolin (%S)
53
Aztreonam (%S)
37
Ampicillin/sulbactam (%S)
85
Ampicillin (%S)
84
Amikacin (%S)
100
# Isolates
100
CMC
E. coli
ESBL
Isolates
Total = 619
Gram Negative
Unusual resistance pattern
1. ESBL
2. Aminoglycoside resistance
1. Tobramycin more resistant than Gentamicin
3. Flouroquinolone resistance Cipro = Levo
UROPATHOGENIC E. COLI ST131 MULTIPLE RESISTANCE GENES AND
VIRULENCE FACTORS - ALL COMMUNITY ACQUIRED
Multiple
genes
International Journal of Antimicrobial Agents, accepted for publication 201
CTX-M SUMMARY
Uropathogenic E. coli clone ST131 from phylogenetic group B2 that have
plasmids that produce multiple resistance factors
• CTX-M-15 or CTX-M-14
• CTX-M-15 is also resistant to Ceftazidime
• Different epidemiology – multidrug resistant community onset UTIs
• AAC (6’)-lb-cr aminoglycoside/fluoroquinolone acetyltransferase (ACC (6’)-Ib
responsible for resistance to kanamycin, tobramycin and amikacin. ACC (6’)-Ib-cr also
confers resistance to ciprofloxicin and norfloxicin)
• Aminoglycoside modifying enzyme that can also cause quinolone resistance, esp. in
norfloxicin and ciprofloxicin (also see resistance to levofloxicin)
Common cause of UTIs in the Chicago area by ESBL-producing E. coli.
Bacteria with multiple resistance genes becoming widespread
AMPC DETECTION –
DIFFERENTIATE FROM
CARBPENEMASE PRODUCERS
AMPC
• Chromosomal = MY SPACE bugs
• (Morgenella, Y. enterocolitica, Serratia, Providencia, Aeromonas, Citrobacter,
Enterobacter)
• Inducible = Any MYSPACE containing AmpC plasmid
• Organism may develop resistance during prolonged therapy with 3rd
generation cephalosporins.
• Identified in organisms exhibiting the following:
• Resistant to cephamycins
• Cefoxitin and Cefotetan
• Resistant to penicillin – β-lactam inhibitors
• Sensitive to cefepime and carbapenems
• Hyperproduction = Any Enterobacteriaceae
• Caused by a mutation in the AmpC regulator gene leading to permanent
(?) hyperproduction or derepression.
• Increased AmpC production and proin mutation can result in carbapenem
resistance
PAMPC
• AmpC enzymes in the midwest
• C. freundii cluster
• CMY-2
• Enterobacter cluster
• MIR-1, ACT-1
• M. morganii cluster**
• DHA-1
• plasmid-encoded inducible cephalosporinase , other plasmid-encoded
AmpC enzymes are almost always expressed constitutively
• H. alvei cluster
• ACC-1
• Aeromonas cluster
• CMY-1 and FOX-1
DETECTION OF AMPC
HYPERPRODUCER
Cephamycin – inducible AmpC
Inducible AmpC
Cefotetan
+ cloxacillin
Cefotetan
Hyperproduction of AmpC
> 3 mm difference
Hyperpoduction associated with a mutation
Of the AmpC regulator gene. Cephalosporinase
not regulated and AmpC produced at higher levels
Meropenem
+ Cloxacillin
Meropenem
+ Boronic acid
Meropenem
AMPC + PORIN LOSS = CARBAPENEM RESISTANCE
Porins - Protein channels through bacterial membrane allow for exchange of water, ions, glucos
and other nutrients as well as waste products
AMPC SUMMARY
• Gene can be found on plasmids
• No longer restricted to MYSPACE bacteria
• Morgenella, Y. enterocolitica, Serratia, Providencia, Aeromonas,
Citrobacter, Enterobacter
• Different AmpC genes with differing ranges
• DHA-1 can hydrolyze carbapenems
• Carbapenem resistance usually requires
overexpression of AmpC (mutation in the regulator
gene) and the presence of a porin mutation,
restricting migration of antibiotic into the bacteria
Carbapenem-Resistant Enterobacteriaceae
(CRE)
Meropenem
Imipenem
Doripenem
Ertapenem
CARBAPENEMASES
THE RISE OF CARBAPENEMASES
WHY ARE PLASMID CRE’S A
PUBLIC HEALTH EMERGENCY
• Limited treatment options for life threatening
infections
• Co-migrate with other resistance genes
• Resistant mechanisms have transferred to plasmids
• Plasmids easily spread to other bacterial species
• No/few new drugs/drug classes
• Rapid detection and effective infection control
measures are essential to control spread
IPDH NEW RULE - REPORTING
CARBAPENEMASES
• Major points:
• This establishes the mechanism by which carbapenem-resistant Enterobacteriaceae
(CRE) are reported to IDPH, starting Sept 1, 2013, for all Illinois healthcare facilities
• Beginning September 1, 2013, reporting facilities shall report carbapenem-resistant
enterobacteriaceae (e.g., E. coli, Klebsiella species, Enterobacter species, Proteus species,
Citrobacter species, Serratia species, Morganella species, or Providentia species) based
on laboratory test results
•
Laboratory tests
•
Molecular tests (PCR specific for carbapeneamse)
•
•
KPC PCR currently offered at Rosemont
Phenotypic test (Modified Hodge Test) specific for carbapeneamse production
•
Rosemont offers modified Hodge Test and ROSCO Disks – identification of KPC, MBL, hyper AmpC, and Oxa-48
carbapenemases
•
•
E . coli and Klebsiella species only: nonsusceptible to one of the following carbapenems:
doripenem, meropenem, or imipenem and resistant to the following 3rd generation cephalosporins:
ceftriaxone, cefotaxime, and ceftazidime
•
•
Phenotypic tests are too slow!
We use this definition for all Enterobacteriaceae
The rationale to use a registry mechanism for reporting, versus the traditional INEDSS, is to allow
the database to serve as an inter-facility information exchange for patient-related CRE status.
For example, a hospital IP can query the database to see if a newly admitted patient has a history of
CRE. Querying is restricted to IDPH-registered personnel with login access to the XDRO
registry .
WHY ARE CRES SO IMPORTANT?
•
Invasive infections (e.g., bloodstream infections) with CRE are
associated with mortality rates exceeding 40%
•
Carbapenem-resistant strains frequently possess additional
resistance mechanisms that render them resistant to most available
antimicrobials
•
CRE can spread rapidly in health-care settings
•
Enterobacteriaceae are a common cause of community infections,
and CRE have the potential to move from their current niche among
health-care–exposed patients into the community
MMWR March 8, 2013 / 62(09);165-170
Number of Subjects
100
80
60
*
*
CRKP
*
*
CSKP
* p <0.001
40
20
0
From: CDC webcast 3/19/09
IDENTIFICATION OF CARBAPENEMASES FOUND IN THE CHICAGO/MILWAUKEE
AREA Carbapenemase
Hydrolysis Profilea
Inhibition Profileb
Molecular
Class
Functional
Group
Enzyme
A
2f
NMC-A
Penicillins
Early
Cephalosporins
Extended
Spectrum
Cephalosporins
Aztreonam
EDTA/
DPA
Clavulanic
Acid
Boronic Acid
Cloxacillin
Temocilin
+
+
-/+
+
-
+
-
-
+/-
+
+
-/+
+
-
+
-
-
+/-
+
+
+
+
-
+/-
+
-
+/-
IMI#
+
+
+/-
+
-
+
-
-
-
GES^
+
+
+
-
-
+
-
+
+
+
-
+
-
-
-
+/-
+
+
-/+
-
-
-/+
-
-
+
(chromosomal)
SME
(chromosomal)
KPC
(plasmid)
(chromosomal)
(plasmid, low
carbapenemase
-
activity)
B1
3
NDM, IMP,
VIM, GIM,
SPM
(most plasmid)
D
#
2d
OXA-48
(plasmid)?
Selective increased resistance to imipenem
Sensitive to AZT; clavulanic Acid +, Boronic Acid and EDTA –
a Hydrolysis Symbols: - +, strong hydrolysis; +/-, weak hydrolysis; -, no measureable hydrolysis
b Inhibition Symbols: +, inhibition; +/-, variable inhibition among β-lactam family members; -, no inhibition
NMC-A = Not MetalloCarbapenease A; SME = Serratia marcescens Enzyme; KPC = Klebsiella pneumoniae carbapenemase;
IMI = imipenem hydrolyzing β-lactamase; GES = Guiana Extended Spectrum β-lactamase; NDM = New Delhi Metallo carbapenemase; IMP =
active on imipenem ;
VIM = Verona Integron-encoded Metallo-β-lactamase; GIM = German Imipenemase; SPM = Sao Paulo Metallo-β-lactamase;
DPA = dipicolinic acid (Metallo β-lactamase inhibitor); Boronic Acid (KPC and AmpC inhibitor); Cloxacillin (AmpC inhibitor)
^
CRES DETECTED IN
CHICAGO/MILWAUKEE AREA
CRE Type
Year Detected
Chromosomal or
Plasmid
Bacteria
SME
2005
Chromosomal
Serratia marcescens
NMC-A
2004
Chromosomal
Enterobacter spp.
KPC
2009
Plasmid
Enterobacteriaceae
NDM-1
2010
Plasmid
K. pneumoniae, E. coli
OXA-48
2012?
Plasmid
Screening started 2013
VIM, IMP
2010?
Chromosomal/plasmid
Screening started 2009
Carbapenem Breakpoints Lowered 9/2012
EFFECTS OF LOWERING CARBAPENEM
BREAKPOINTS
• Detect chromosomal carbapenemases that
are not considered an infection control
emergency
• More SME (Serratia Marcescens Enzyme)
• Carbapenems resistant and 3rd and 4th generation cephalosporins
sensitive
• More NMC-A (Not Metallo Carbapenemase, in
Enterobacter sp.)
• Carbapenems resistant and 3rd and 4th generation cephalosporins
sensitive
Acute care
hospital
Long term
Care facilities
Need to break
the cycle!
ADVOCATE HOSPITALS –
K. PNEUMONIAE
IMIPENEM (% SENSITIVE)
Hosp.
2007
2008
2009
2010
2011
2012
100
96
94
92
93
92
Condell
-
-
-
99
99
99
G. Sam
100
100
99
98
95
96
G. Shep
100
100
100
96
98
97
IMMC
100
98
92
91
92
92
LGH
100
98
95
91
92
92
SSUB
100
97
94
94
90
90
Trinity
100
97
94
94
93
92
CMC
VITAL SIGNS: CARBAPENEMRESISTANT
ENTEROBACTERIACEAE
• Enterobacteriaceae are gram-negative bacteria that can cause
invasive disease but generally have been susceptible to a
variety of antibiotics.
• Carbapenem-Resistant Enterobacteriaceae (CRE) are
Enterobacteriaceae that have become highly resistant to most
or all antibiotics through several mechanisms. Carbapenem
resistance, while relatively uncommon among
Enterobacteriaceae (4% of Enterobacteriaceae in this
study), has increased from about 1% during the past decade.
CRE bloodstream infections are associated with mortality
rates approaching 50%.
MMWR March 8, 2013 / 62(09);165-170
VITAL SIGNS: CARBAPENEMRESISTANT ENTEROBACTERIACEAE
• CRE has now spread throughout the United States but in most areas
they remain relatively uncommon; about 4% of acute-care
hospitals and 18% of long-term acute-care hospitals reported
at least one CRE to the National Healthcare Safety Network in the
first 6 months of 2012. Nearly all patients with CRE were currently
or recently treated in a health-care setting. However, CRE could
spread into the community among otherwise healthy persons
MMWR March 8, 2013 / 62(09);165-17
VITAL SIGNS: CARBAPENEMRESISTANT ENTEROBACTERIACEAE
• Preventing spread is important before CRE gains a
foothold in more hospitals or in the community. This
requires active (rapid) case detection and contact
precautions for colonized or infected patients as
well as cohorting of patients and staff; appropriate
antibiotic use in all settings; and communication
about infections when patients transfer. Regional and
state-based approaches have been shown to be
effective in reducing incidence.
• Additional information is available
atMarch 8, 2013 / 62(09);165-17
MMWR
http://www.cdc.gov/vitalsigns
MECHANISMS OF CARBAPENEM
RESISTANCE
• Non enzymatic
• Modifications of outer membrane permeability
• Porin loss
•
Allow passage molecules include water, ions, glucose, and other nutrients as well as
waste products
• Up regulation of efflux systems
• Enzymatic
• Production of carbapenem hydrolyzing β-lactamases
• hyperproduction of AmpC β-lactamases
• Certain ESBLs with increased capacity to hydrolyze carbapenems
•
CTX-M
• Production of carbapenemases
• KPC, NDM-1, others
• Combinations of all of the above
NEED TO DISTINGUISH MECHANISMS OF
CARBAPENEM RESISTANCE – WHY?
• KPC (increasing numbers)
• Make all penicillins, cephalosporins, inhibitor combinations,
aztreonam, and carbapenems resistant
• Hyper AmpC (most common)
• Make all penicillins, cephalosporins, inhibitor combinations,
and aztreonam Resistant
• Cefepime may still be effective
• Do not change carbapenem interpretations
• Metallo β-lactamases (rare, but increasing)
• Same as KPC, except do not change aztreonam interpretation
• Other carbapenemases
• Antibiotic profiles not clear
•
1st described in 1998, 2001 in NYC
• Now endemic in the Northeastern/Mid-Atlantic region of the United
States
• surveillance cultures of hospitals in the New York City area reporting rates of
carbapenem resistance in K. pneumoniae isolates ranging up to 40%
• Reported in Europe, China, Central America, South America –
Since 1998
• Also reported in Pseudomonas aeruginosa (Columbia)
• KPC is a class A b-lactamase (serine residue at the active site)
• Confers resistance to all b-lactams including extendedspectrum cephalosporins and carbapenems
•
Occurs in other Enterobacteriaceae
• Most commonly seen in Kliebsiella pneumoniae
• Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter
spp., Escherichia coli, Salmonella spp., Serratia spp.,
CARBAPENEM RESISTANT ENTEROBACTERIACEAE:
INCIDENCE AND RISK FACTORS IN A COMMUNITY-TEACHING HOSPITAL
A. Makarem, MD; P. Alvarez, MD; M. Kulkarni, MD; M. Costello, PhD; T. Chou, MPH; J. Kerridge, RN; K. Wickman, RN; J. Malow, MD
BACKGROUND
METHODS
Carbapenems are the treatment of choice for
multidrug resistant Enterobacteriaceae. However,
there have been increasing reports of
carbapenem resistant Enterobacteriaceae (CRE),
and their prevalence has increased since they
were first described in 2001.
The study population included adults who were
hospitalized in our institution (level 1 trauma
community-teaching Hospital, with 551 licensed
beds, 2 adult intensive care units and a neonatal
intensive care unit) from July 2008 through
March 2010 and had positive cultures for CRE.
CRE are resistant to almost all available
antimicrobial agents. Infections with CRE have
been associated with high rates of morbidity and
mortality, even when treated appropriately,
particularly among individuals with prolonged
hospitalization and those who are critically ill and
exposed to invasive devices.
CRE detection: all bacteria with MIC > 1mcg/ml for
any carbapenem and resistance to any 3rd
generation cephalosporin are considered screen
positive. These are then confirmed as CRE by
modified Hodge test and Etest.
Outbreaks have been reported in many countries,
predominately Asia and South America. In the
U.S., CRE were first reported in North Carolina,
with the first reported healthcare-related
outbreak in New York. Since then, CRE have
been reported in at least 32 states.
Patient records were reviewed for the following:
type and location of residence, presence of
indwelling devices (ventilator, central line,
urinary catheter, and gastrostomy tubes), recent
antibiotic exposure, signs and symptoms of
infection, sites of positive cultures, co-morbidities,
and mortality.
RESULTS
• There were a total of 20 patients with 32 CRE
positive cultures in our institution during the study
period.
• 19/20 (95%) were infected, only 1 (5%) was
colonized.
FIGURES
DISCUSSION
All CRE isolates obtained are multidrug resistant
with very limited therapeutic options, and are
widespread throughout the extended care
facilities (ECF) in the Chicago metropolitan area.
With a mortality rate of 40%, CRE may pose a
real challenge unless appropriately addressed.
RESIDENCE OF PATIENTS WITH
CRE POSITIVE CULTURES
30%
55%
Horizontal dissemination appears to have an
important role in the emergence of CRE infections.
This is supported by the fact that most patients
resided in an ECF prior to admission. Furthermore,
only one patient had previous exposure to a
carbapenem, and all infections were acquired
prior to admission except for one.
10%
NURSING HOME
5%
LONG TERM ACUTE CARE FACILITY
PRIVATE RESIDENCE
Chronic illnesses and indwelling supportive devices
also appear to increase the risk of acquiring CRE
infections. This might be related to a decreased
functional status, or possibly some degree of
immunosupression, both of which have been
reported as risk factors for CRE infections.
REHABILITATION INSTITUTION
ANTIBIOTIC SUSCEPTIBILITIES
OF CRE ISOLATES
A larger sample size is needed for more accurate
calculations.
100%
80%
60%
40%
20%
0%
CONCLUSIONS
• Patients in extended care facilities are at risk for
acquiring CRE.
• Use of contact precautions, hand hygiene, and
other infection control measures may limit the
spread of CRE.
• Only one patient (5%) had previous carbapenem
exposure.
• 40% had two sites of infection with CRE.
SUSCEPTIBLE
INTERMEDIATE
• Screening for CRE should be considered in areas
of high CRE endemicity.
RESISTANT
• Development of new antimicrobial agents is
needed.
• Infection sites included urine (60%), blood (25%),
wounds (15%), sputum (15%), and PEG tubes (5%).
• 2/5 of bacteremic patients died (40%).
• 95% had at least one type of chronic indwelling
supportive device (PEG tube, urinary catheter,
tracheostomy, PICC line).
SITES OF THE 32 CRE POSITIVE
ISOLATES
REFERENCES
1. Rapid Spread of Carbapenem-Resistant K pneumoniae in New York City. S Bratu, MD et al. Arch Intern Med.
2005;165:1430-1435.
18%
2. Carbapenemase-producing Enterobacteriaceae, U.S. rivers. Aubron, C., L. Poirel, R. J. Ash, and P. Nordmann. 2005.
Emerg. Infect. Dis. 11: 260-264.
• 90% had at least one chronic co-morbidity.
• 80% of patients with chronic indwelling urinary
catheter presented with CRE in the urine.
• 30/32 CRE cultures (93.7%) were identified as K.
pneumoniae while the other two isolates were E.
coli and P. mirabilis.
Represents the location of our institution
Represents the residence locations of CRE positive cases
3. Carbapenem resistance in Klebsiella pneumoniae not detected by automated susceptibility testing. Tenover FC. Kalsi
RK. Williams PP. Carey RB. Stocker S. Lonsw ay D. Rasheed JK. Biddle JW. McGow an JE Jr. Hanna B. Emerging
Infectious Diseases. 12(8):1209-13, 2006 Aug.
15%
52%
4. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA 300:2911-3 2008
5. Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from
microbiological and clinical studies. Journal of Antimicrobial Chemotherapy 62:895-904 2008
11%
6. Guidance for control of infections w ith carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in
acute care facilities. Centers for Disease Control and Prevention (CDC). Morbidity & Mortality Weekly Report.
58(10):256-60, 2009 Mar 20.
URINE
BLOOD
SPUTUM
PEG TUBE
7. Ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae carrying multiple metallobeta-lactamase genes. Dw ivedi M. Mishra A. Azim A. Singh RK. Baronia AK. Prasad KN. Dhole TN. Dw ivedi UN.
Indian Journal of Pathology & Microbiology. 52(3):339-42, 2009 Jul-Sep.
WOUND
8. Potential role of active surveillance in the control of a hospital-w ide outbreak of carbapenem-resistant Klebsiella
pneumoniae infection. Infection Control & Hospital Epidemiology 31:620-6 2010
4%
9. Risk Factors and Outcomes Associated w ith Acquisition of Colistin-Resistant KPC-Producing K pneumoniae: a
Matched Case-Control Study. Zarkotou et al. J. Clin. Microbiol. 2010;48:2271-2274
160
140
120
100
150/3206 = 4.7%
KPC Positive
Patients
ACL
148/3534 = 4.3%
- 6 NDM PATIENTS WITH LAST 6 MONTHS
- OXA-48 PATIENTS, PROBABLY (CARBAPENEM R, 3RD/4TH
GENERATION CEPHALOSPORIN S, PIP/TAZO R)
Chicago
area
80
60
Milwaukee
Southeast
Wisconsin
53/3040 = 1.7%
36/2365 = 1.6%
40
36/2448 = 1.5%
20
2/2408=0.08%
0
2008
2009
2011
2012
Advocate
0
53
150
148
Aurora
0
2
39
36
KPC positive defined by modified Hodge positive or boronic acid positive /cloxacillin negative. Based on K. pneumoniae isolates.
Figure 1. A) Worldwide geographic distribution of Klebsiella pneumoniae
carbapenemase (KPC) producers. Gray shading indicates regions shown
separately: B) distribution in the United States; C) distribution in Europe; D)
EID, Oct. 2011
CURRENT TESTS FOR CARBAPENEMASE PRODUCERS
• AST patterns (ACL - all carbapenems in Gram negative panels)
• Gram negative panels must include doripenem, ertapenem, imipenem, and
meropenem for optimal sensitivity
• Modified Hodge test ( ACL - Screen if carbapenems are NS)
• Lacks sensitivity (does not detect all NDM, VIM, IMI producers) and specificity (hyper
AmpC producers)
• Takes too long, an additional 24-48 hours
• E Tests
• MBL for verification of a metallo-lactamase - carbapenem +EDTA/carbapenem
• Cefotetan/Cefotetan+ cloxacillin for AmpC expression
• Takes too long
• Rosco Disks (ACL - Classify carbapenemases)
• Differentiates MBLs, from KPCs, from hyper AmpC
• Low sensitivity for Oxa-48
• Takes too long
• Amplified molecular methods (ACL – KPC only, so far)
• Rapid
• Sensitivity dependent on variation of sequences of carbapenem resistance genes
• Costly?
POSITIVE FOR KPC
Modified
Hodge test
ROSCO
Disks
CLASS B CARBAPENEMASE
• VIM, IMP, and NDM most common
• NDM more common in E. coli than KPC
• Require zinc at active site for hydrolysis of the beta-lactam ring
• Resistant to all beta-lactams except for aztreonam
• May not be modified Hodge Test positive
CLASS B CARBAPENEMASE
RECENT CASE - PATIENT HISTORY
• 70 year old male. Visiting relatives.
• History – diabetes and chronic kidney failure, on dialysis
• Admitted 9/23/2012 to CMC for shortness of breath.
• Cardiac surgery - Triple bypass
• Complicated recovery, discharged 10/22 to Long Term Acute
Care Hospital (LTACH)
LABORATORY DATA
Treated with Pip/tazo and fluconazole
LABORATORY DATA
Repeat urine culture on 10/3 was negative
Fosfomycin = S
Colistin
Sample is MHT +
Tigecycline
AmpC
MBL
IMI
+
EDTA
IMI
NDM
10/8/2012
K. Pneumoniae
MHT positive
2/17/2013
K. Pneumoniae
MHT negative
Meropenem +
cloxacillin
Meropenem +
Boronic acid
Meropenem
Temocillin
Positive =
> 5 mm difference
Meropenem +
Dipicolinic acid
CASE REVIEW
• Patient not isolated prior to MBL report on 10/8
• Did treatment (Pip-tazo) select for MBL?
• Rectal swabs taken on all patients in Adult Surgical Heart Unit.
All were negative for MBL
• Rectal swabs preincubated in 2 μg/ml ertapenem in TSB for 18
hours and then plated on gram negative selective media with
meropenem disks.
• Gown and glove precautions on entire unit.
• Patient discharged to Kindred (LTACH)
CURRENT METALLO Β-LACTAMASE OUTBREAK
Pt.SQ. 70M 9/2012 CMC
Indian national
Urine - K. Pneumoniae x 2
NDM-1 confirmed by CDC
Pt. In LTACH
Pt. CK 68F 1/2013
LGH
Urine – E. coli NDM-1 (CDC
Confirmed) x 2
Undermined acquisition
LGH - Seen in ER and admitted
Risk factors: close relative
Recent Travel to Asia/Canada
Pt. MM. 68F 4/2013.
LGH
Abd. Wound- E. coli,
NDM (CDC Confirmed)
Present on admission
to LGH
Risk factors:
unknown, new pt.
At LTACH at
same time
Pt. FR. 85M 4/2013
Nursing Home
Rectal swab – E. coli NDM
(CDC Confirmed)
Risk factors: Ventilator
dependent, roommate to
Pt. KK at nursing home B,
multiple MDRs
Pt. KK. 73M 3/2013 LGH
Sputum - E. coli NDM-1 (CDC
Confirmed)
Present on admission to LGH
Risk factors: ventilator
dependent , feeding tube,
LTACH and Nursing home
stays
Pt. expired 3/28/13
Pt. MR. 88F 3/2013 LGH
Urine – E. coli NDM (CDC
Confirmed)
Present on admission to
LGH
Risk factors: multiple AB
for frequent UTIs, recent
nursing home stay (G),
Dementia
PFGE Results
= highly related
= pending
Follow-up Actions
•
Each case reported to CCPH and IDPH by LGH Infection Prevention
•
Communicated to LGH and Advocate Senior leadership
•
Education provided to physicians and associates
•
There are no relationships among these cases with locations and time at LGH
•
CCDP and IDPH conducting active surveillance of CRE in LTACH and 2 Nursing Homes
•
LTACH screen 25% KPC+
•
Active surveillance for CRE on LGH Rehab Unit negative
•
Beginning 4/29 all admits to LGH Rehab Unit will be screened for CRE
•
~20% KPC+
•
55% P. aeruginosa carbapenem resistant
NATIONAL RESISTANCE ALERT 3 ADDENDUM
CARBAPENEMASE-PRODUCING ENTEROBACTERIACEAE IN THE
UK:
NDM (NEW DELHI METALLO-) Β-LACTAMASE: REPEATED
IMPORTATION FROM INDIAN SUBCONTINENT
•
Numbers of carbapenemase-producing Enterobacteriaceae continue to increase sharply
•
Many recently referred carbapenemase producers have NDM (New Delhi Metallo)-β-lactamase
•
•
Most producers are resistant to ALL antibiotics except polymyxins and tigecycline and may pose a serious treatment challenge in severe
infections
· Vigilance and good infection control are essential to minimize transmission and accumulation in the
UK
NDM-1 +
• E. coli
• K. pneumoniae
Medical
Tourism
Detection of Enterobacteriaceae Isolates Carrying Metallo-Beta-Lactamase —
United States, 2010 – MMWR. June 25, 2010
• K. oxytoca
• Enterobacter spp.
• Proteus spp.
• C. freundii
• M. morganii
• Providencia spp.
Metallo β-Lactamases, Next Wave
NDM, Current Wave
IMP = imipenem hydrolyzing metallo β-lactamase
NDM = New Delhi Metallo carbapenemase
VIM = Verona Integron-encoded Metallo-β-lactamase
Emerging Infectious Disease, Oct. 2011
THE CARBAPENEMASE THREAT
CLASS D - OXACILLIN HYDROLYZING ΒLACTAMASE
• First identified in Turkey in 2003,
• Originated from Shewanella spp.
• Confers resistance or reduced susceptibility to carbapenems
and penicillin-inhibitor combinations, but producers only show
slight resistance to oxyiminocephalosporins (Ceftriaxone,
Ceftazidime) unless they have co-resident mechanisms such as
ESBLs or AmpC.
• High-level resistance to both piperacillin-tazobactam and
temocillin may be useful indicators of OXA-48 production
in enterobacteriae
• Found in Acinetobacter baumanii, Pseudomonas aeruginosa, and
Enterobacteriaceae.
• Not confirmed in Midwest???
OXA-48
EID,
Oct. 2011
WHY CARE ABOUT MECHANISMS OF
RESISTANCE?
• Carbapenemases
• Chromosomal Vs. plasmid based
• Chromosomal – Not an Infection Control Emergency
• SME, NMC
•
See more with lower carbapenem breakpoints
• Plasmid – Infection Control Emergency!
• KPC, NDM, GES, VIM, Oxa-48
• Need to isolate all patients??
• A commercially available, standardized, and reproducible
amplified molecular assay will make CRE
detection/identification faster, more sensitive, and consistent
NANOSPHERE - GRAM NEGATIVE
BLOOD CULTURE ID
• Pathogens detected
• Escherichia coli/Shigella spp., Klebsiella pneumonaie,
Klebsiella oxytoca, Serratia marcescens, Pseudomonas
aeruginosa, Citrobacter spp., Enterobacter Spp., Proteus
spp., Acinetobacter spp.
• Resistance genes
• KPC
• NDM
• CTX-M
• VIM
• IMP
• Oxa-48
IN SUMMARY
Clinical Cases
• New resistance mechanisms, new challenges
• Lines blurring between HAI and community acquired infections
•
MRSA, CREs, ESBLs, etc.
•
ESBLs are not just HAI’s anymore
Asymptomatic
Carriage
• Team approach absolutely required
• Lab, Pharmacy, and ICPs
•
Antibiotic stewardship
•
Lab needs to be more responsive and less conservative
•
Do you need to double check your results prior to reporting?
• Patient to patient transmission can be limited by strict infection control measures
• Laboratory identification of infection or carriage must be paired with rapid implementation of
infection control measures
•
Group effort required
•
Screening – who pays?
• Ongoing surveillance is essential
• Surveillance must include extended care facilities and cooperation between healthcare systems
• Moving target
• Rapid detection and reporting essential