1. Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae
DJ Shannon
Multidrug-Resistant Organism Epidemiologist
Infectious Disease Epidemiology
Epidemiology Resource Center
Indiana State Department of Health

2. Overview Definitions Antibiotic resistance CRE and CP-CRE
Spread
Mechanisms of action
CRE and CP-CRE
MDRO Reporting
Laboratory aspects
Infection control and prevention
IP Video Conference Series

3. Definitions
Multidrug-resistant organism (MDRO): an organism that is resistant to one or more agent in at least three classes of antibiotics – or that exhibits a classification of resistance that is of epidemiological concern (e.g. MRSA, VRE, ESBL, CRE)
Extensively drug-resistant organism (XDRO): microorganisms that are resistant to nearly all antimicrobial agents that would be considered for treatment

4. Definitions
Pan-resistant organism: microorganisms that are resistant to all antimicrobial agents that would be considered for treatment

6. Mechanisms of Antibiotic Resistance
Penicillin-binding protein modifications
Porin mutations
Efflux pumps
Antibiotic target changes
Enzymatic inhibition

7. Enzymatic Inhibition ß-lactamases AmpC cephalosporinases
Confers resistance to cephalosporins (and many penicillins)
Extended-spectrum ß-lactamases (ESBL)
Confers resistance to penicillins and cephalosporins
Can also exhibit coresistance to tetracyclines, sulfonamides, and aminoglycoside
Some ESBLs confer resistance to fluoroquinolones
Carbapenemases
Capable of inactivating all ß-lactam antibiotics (except Aztreonam)
Enzymatic inhibition tends to be more of a problem in Gram-negative bacteria than in Gram-positive bacteria
Carbapenemases are divided in to three classes
Class A
Serine carbapenemase
Klebsiella pneumoniae carbapenemase (KPC)
Class B
Metallo-beta-lactamase
New Delhi Metallo-beta-lactamase (NDM)
Imipenemase (IMP) *********************** check
Verona Integron-mediated Metallo-beta-lactamase (VIM)
Class D
Oxacillinase-48 (OXA-48)

8. Carbapenemases Class A Carbapenemases
Klebsiella pneumoniae carbapenemase (KPC)
Confers resistance to all ß-lactams
Susceptible to ß-lactamase inhibitors
ß-lactamase inhibitors are use in conjunction with ß-lactams to inhibit ß-lactamase production from the bacteria so the antibiotic can act
SME: Serratia marcescens enzyme
IMI: Imipenemase
NMC: Non-metallo-carbapenemase

9. Carbapenemases Class B Carbapenemases Metallo-ß-lactamases (MBLs)
MBLs break down all ß-lactams, except aztreonam
High mobility poses an infection control threat
Examples:
New Delhi Metallo-ß-lactamase (NDM)
Imipenemase (IMP)
Verona Integron-mediated Metallo-ß lactamase (VIM)
MBLs require zinc for enzymatic activity and are not inhibited by serine ß-lactamase inhibitors
Can be inhibited by EDTA or other chelators of divalent cations

10. Carbapenemases Class D Carbapenemases
Confers low-level resistance to carbapenems unless in the presence of other ß-lactamases
Not very efficient at breaking down 3rd generation cephalosporins
Example:
Oxacillinase-48 (OXA-48)

11. Mobility of Carbapenemases
Carbapenemase genes are found on plasmids
Horizontal gene transfer
This occurs when a gene conferring resistance moves from one bacterial cell to another
Methods:
Conjugation
Transduction
Transformation
Horizontal gene transfer:
This occurs when a gene conferring resistance moves from one bacterial cell to another
Methods:
Conjugation
Bacterial conjugation of DNA (plasmid or chromosomal) from cell to cell
More frequently plasmid DNA
Plasmids can acquire many resistance genes and are capable of conferring multidrug-resistance
Transduction
As a result of bacteriophage activity
Bacteriophage engulfs plasmid and released plasmid in next bacterial “target”
Transformation
From free DNA
Uptake of free DNA (usually from nearby dead bacterial cell) can be utilized in DNA transformation

12. CRE: A Public Health Threat
CP-CRE in the United States are an urgent threat
CP-CRE infections are associated with high mortality rates
CP-CRE confer high levels of resistance
CP-CRE have very mobile resistance genes that can easily be shared with other organisms (CP-CROs)
Invasive infections caused by CRE have been associated with 40-50% mortality
CRE and CP-CRE leave few options for antibiotic therapy. Many times, an available antibiotic (e.g. Colistin) has significant side effects
CP-CRO: carbapenemase-producing carbapenem-resistant organism

13. Carbapenem-Resistant Enterobacteriaceae
Definition: Any Enterobacteriaceae that are not susceptible (i.e. intermediate or resistant) to a carbapenem antibiotic
Enterobacteriaceae can be resistant to carbapenems through several resistance mechanisms
Carbapenemase production is currently the most concerning
Carbapenem antibiotics: Doripenem, ertapenem, imipenem, meropenem

14. Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae
Enterobacteriaceae that are not susceptible (i.e. intermediate or resistant) to at least one carbapenem antibiotics
AND one of the following:
Positive for carbapenemase production by a phenotypic test
Not susceptible to at least three carbapenem antibiotics
OR:
Positive for a carbapenemase gene marker
Phenotypic test examples: Modified Hodge, Carba NP, modified Carbapenemase Inhibition method (mCIM)
Carbapenemase gene marker examples: KPC, VIM, IMP, NDM, OXA
Carbapenem antibiotics:
Doripenem
Ertapenem
Imipenem
Meropenem
Note: Proteus species, Providencia species, and Morganella species may have elevated MICs to imipenem by mechanisms other than a carbapenemase

15. Carbapenem-Resistant Enterobacteriaceae
CRE vs. CP-CRE
Carbapenem-Resistant Enterobacteriaceae
Non-Carbapenemases
PBP mutation
Efflux Pumps
Porin Mutations
Carbapenemases
KPC
NDM, VIM, IMP
OXA
CP-CRE !!!
Essentially, All CP-CRE are CRE, but not all CRE are CP-CRE
Non-carbapenemases are CRE that have different mechanisms of antibiotic resistance
PBP mutation
Overactive efflux pumps
Porin mutations
Examples of carbapenemases, an enzymes that break down carbapenem antibiotics, is shown on the diagram as reportable
Microbiologists can identify these enzymes through PCR testing
Reportable

16. Risk Factors of CRE Recent healthcare exposure
ACH, LTC, LTACH
Recent medical procedures
Recent invasive device use
Mechanical ventilator, PICC line, Foley catheter
Recent antibiotic use
Prior history of MDRO colonization or infection

17. Laboratory Aspects Culture Antibiotic Susceptibility Phenotypic Tests
Minimum Inhibitory Concentration (MIC)
Phenotypic Tests
Modified Hodge test, CarbaNP, Carbapenemase Inhibition method (CIM), modified CIM (mCIM)
Molecular Tests
PCR

18. Infection Prevention Implications for CRE
Facility-Level Prevention Strategies
Hand Hygiene
Contact Precautions
Healthcare Personnel Education
Use of Devices
Laboratory Notification
Inter-facility Communication
Antibiotic Stewardship
Environmental Cleaning
Patient and Staff Cohorting
Screening Contacts of CRE Patients
Active Surveillance Testing
Chlorhexidine Bathing

19. Indiana CP-CRE 2016 Data 354 CP-CRE cases 281 Klebsiella pneumoniae
22 Serratia marcescens
21 Escherichia coli
20 Enterobacter cloacae complex
5 Citrobacter freundii
3 Proteus mirabilis
1 Citrobacter amalonaticus
1 Enterobacter aerogenes
334 KPC
4 NDM
4 VIM
2 OXA-48
1 SME
9 unknown
Unknown means case was classified by methods other than a molecular PCR test
i.e. not susceptible to three carbapenems, positive for carbapenemase production by a phenotypic test (MHT, CarbaNP)

21. 2016 CP-CRE Counts by District
State: 354
District 1: 153
District 2: 13
District 3: 38
District 4: 8
District 5: 79
District 6: 42
District 7: 5
District 8: 11
District 9: 5
District 10: 0

23. I-NEDSS CDR Submission
Please attach the following:
History and physical
Associated antibiotic susceptibility labs
Medication history
Additional information:
Start date of contact precautions
Healthcare exposure history
Travel history

24. Resources
Facility Guidance for Control of CRE
Google: CDC CRE Toolkit

25. Resources
Guidance for a Health Response to Contain Novel or Targeted MDROs
Google: CDC contain novel MDRO

26. New Video Conference Series
The ISDH Epidemiology Resource Center is launching a video conference series for infection preventionists in Indiana
Video conference will focus on HAIs, MDROs, antibiotic stewardship, and feature hot topics from other subject matter experts
IN-HASARD: Indiana Healthcare-associated infections, Antibiotic Stewardship, and Antibiotic Resistant Diseases

27. New Video Conference Series
The first IN-HASARD video conference will be held via WebEx on Friday, April 28th from PM EST.
Need an invite? Janae Meyers, ISDH Antibiotic Stewardship Epidemiologist, at
IN-HASARD: Indiana Healthcare-associated infections, Antibiotic Stewardship, and Antibiotic Resistant Diseases

28. Contact Information
DJ Shannon Multidrug-Resistant Organism Epidemiologist Infection Disease Epidemiology Epidemiology Resource Center Indiana State Department of Health Work: