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

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

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

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

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

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)

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

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

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)

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

New Video Conference Series The first IN-HASARD video conference will be held via WebEx on Friday, April 28th from 1-2 PM EST. Need an invite? Email Janae Meyers, ISDH Antibiotic Stewardship Epidemiologist, at jmeyers@isdh.in.gov IN-HASARD: Indiana Healthcare-associated infections, Antibiotic Stewardship, and Antibiotic Resistant Diseases

Contact Information DJ Shannon Multidrug-Resistant Organism Epidemiologist Infection Disease Epidemiology Epidemiology Resource Center Indiana State Department of Health Work: 317-233-1306 Email: dshannon1@isdh.in.gov