Update on ESBLS and Carbapenem Resistant Enterobacteriaceae - PowerPoint Presentation

1. Update on ESBLS and Carbapenem Resistant EnterobacteriaceaeMichael Costello, Ph.D.Technical Director – MicrobiologyACL Laboratories

2. Topics To CoverExtended spectrum β lactamases (ESBLs)Update on the recent changing patterns of different types of ESBLs in the Chicago/Milwaukee areaImplicationsHealthcare associated infections (HAI) Vs. community acquired infections Carbapenemases – more than “just” KPCSummarize carbapenemases currently found in the Wisconsin/Illinois areaExpand on how and why CREs have spread so rapidly throughout the world.Define testing algorithms for rapid detection of CRE, faster the betterTalk about new molecular based tests that are becoming availableMolecular assays for identification of bacteria and resistance genes directly from a positive blood culture bottle.Culture not required

3. Antibiotic ResistanceGram NegativesProduction of β-lactamases – Enzymatic destruction of antibioticSwitch from Tem and SHV to CTX-MPermeability alterationsPorin mutations – antibiotic entry is limitedPorins are barrel shaped proteins that cross cell membranes and act as a port though which nutrients, toxins and antibiotics can diffuseAntibiotic extrusion by efflux pumps Rapidly pump out antibiotics before they are effectiveRarely, PBP alterationsPBP 7-8 in A. baumaniiCombinations of the above

4. 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 ringOnly difference between peniclliniases, cephalosporinases and carbapenemasesis the preferred substrate

5. Classification of ß-Lactamases Bush-Jacoby-Mederios- Functional ClassificationGroupEnzyme TypeInhibition by ClavulanateMolecular Class (Ambler)# of EnzymesCharacteristicsExample1CephalosporinaseNoC 53Mainly chromosomal located in gram negative bacteria, but may be plasmid mediated. Resistance to ß-lactams (except carbapenems)E. Coli2aPenicillinsYesA 20Narrow spectrum resistance to penicillins onlyS. Aureus2bBroad spectrumYesA16Broad spectrum penicillinasesTEM-1, SHV-1 2beExtended spectrumYesA38ESBL conferring resistance to oxyimino-cephalsporins and monobactamsTEM-3, SHV-2, CTX-M2brInhibitory resistantPartlyA9Inhibitor resistant ß-lactamases (mostly TEM-types and to a lesser extent SHV derived ESBLTEM-30, TRC-12cCarbenicillinaseYesA15CarbenicillinasesBRO-1, CARB-3, PSE-12dCloxacillinaseVariableD or A18Oxacillinases, partly inhibited by clavulanateOXA-1, PSE-22eCephalosporinaseYesA19Oxacillinases, inhibited by clavulanateP. vulgaris, Bacteroides fragilis2fCarbapenemaseYesA3Serine active carbepemases, inhibited by clavulanate. E. cloacae,3MetalloenzymeNoB15Metallo-ß-lactamases conferring resistance to all ß-lactam drugs except monobactams - aztreonamS. maltophilia4PenicillinsNo7Miscellaneous ß-lactamases that do not conform to other groupsB. cepacia

6. ESBL PandemicspAmpC detectedKPCdetectedNDMdetected.Enterobacteriaceae pan-resistance endemic

7. 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 ESBLsSHV-2 in 1983TEM-3 in 1984TEM and SHV are primarily healthcare associatedCompetitive disadvantage outside of a healthcare settingRequire administration of antibiotics to competeMore reactive against ceftazidime than cefotaximeRarely carbapenem resistantNew 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

8. CTX-MCTX-M -lactamases are extended-spectrum β-lactamases (ESBLs) that mainly inactivate cefotaxime and cefriaxone and have less activity against ceftazidimeSequencing evidence that gene mobilized from Kluyvera spp. (environmental bacteria rarely associated with disease)Associated with community-acquired UTIsHighest incidence in E. coliPlasmid is stable and confers minimal competitive disadvantage when β-lactams are not presentDramatic world-wide spread in the last decadeQuickly replacing TEM- and SHV-type ESBLsDetected in both humans and animals (in the food chain)Present wherever β-lactam antibiotics are usedAssociated with other multidrug-resistant genes Found on plasmids that also include resistance genes to aminoglycosides and fluoroquinolones

9. ANTIBIOGRAMS 2008 - NEW MORE AGGRESSIVE E. COLI STRAIN ESBL POSITIVE ANTIBIOGRAMSHospital# IsolatesAmikacin (%S)Ampicillin (%S)Ampicillin/sulbactam (%S)Aztreonam (%S)Cefazolin (%S)Ceftazidime (%S)Ceftriaxone (%S)Cefepime (%S)Ciprofloxacin (%S)Gentamicin (%S)ErtapenemImipenem (%S)Nitrofurantoin (%S)Piperacillin/tazobactam (%S)Tobramycin (%S)Trimethoprim/sulfamethox. (%S) Gram Negative                 CMCEscherichia coli, ESBL (6%)205920110000026710010084853753BethanyEscherichia coli, ESBL (40%)291000000000368 10093662146Good SamEscherichia coli, ESBL (2%)4310001200000149210010080884037GSHEscherichia coli, ESBL (2%)18100000000007810010088943939SSUBEscherichia coli, ESBL (4%)3510002000000354 9772774046TrinityEscherichia coli, ESBL (2%)25920160000004810010078963668IMMCEscherichia coli, ESBL (6%)74930700000125110010089742532LGHEscherichia coli, ESBL (8%)19096010000065210010083903057Unusual resistance patternESBLAminoglycoside resistanceTobramycin more resistant than GentamicinFlouroquinolone resistance Cipro = LevoE. coliESBL IsolatesTotal = 619

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11. International Journal of Antimicrobial Agents, accepted for publication 2010.UROPATHOGENIC E. COLI ST131 MULTIPLE RESISTANCE GENES AND VIRULENCE FACTORS - ALL COMMUNITY ACQUIREDMultiple genes

12. CTX-M SummaryUropathogenic E. coli clone ST131 from phylogenetic group B2 that have plasmids that produce multiple resistance factors CTX-M-15 or CTX-M-14CTX-M-15 is also resistant to CeftazidimeDifferent 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

13. AmpC detection – differentiate from carbpenemase producers

14. AmpCChromosomal = MY SPACE bugs(Morgenella, Y. enterocolitica, Serratia, Providencia, Aeromonas, Citrobacter, Enterobacter)Inducible = Any MYSPACE containing AmpC plasmidOrganism may develop resistance during prolonged therapy with 3rd generation cephalosporins.Identified in organisms exhibiting the following:Resistant to cephamycinsCefoxitin and CefotetanResistant to penicillin – β-lactam inhibitorsSensitive to cefepime and carbapenemsHyperproduction = Any EnterobacteriaceaeCaused 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

15. pAmpCAmpC enzymes in the midwestC. freundii cluster CMY-2Enterobacter clusterMIR-1, ACT-1M. morganii cluster**DHA-1plasmid-encoded inducible cephalosporinase , other plasmid-encoded AmpC enzymes are almost always expressed constitutively H. alvei clusterACC-1Aeromonas clusterCMY-1 and FOX-1

16. Detection of AmpC HyperproducerMeropenemMeropenem+ Boronic acidMeropenem+ Cloxacillin> 3 mm differenceHyperpoduction associated with a mutationOf the AmpC regulator gene. Cephalosporinasenot regulated and AmpC produced at higher levelsCephamycin – inducible AmpC Hyperproduction of AmpCInducible AmpCCefotetan+ cloxacillinCefotetan

17. AmpC + Porin Loss = Carbapenem ResistancePorins - Protein channels through bacterial membrane allow for exchange of water, ions, glucose, and other nutrients as well as waste products

18. AmpC SummaryGene can be found on plasmidsNo longer restricted to MYSPACE bacteriaMorgenella, Y. enterocolitica, Serratia, Providencia, Aeromonas, Citrobacter, EnterobacterDifferent AmpC genes with differing rangesDHA-1 can hydrolyze carbapenemsCarbapenem 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

19. Carbapenem-Resistant Enterobacteriaceae (CRE)

20. CarbapenemasesImipenemErtapenemMeropenemDoripenem

21. The Rise of Carbapenemases

22. Why are Plasmid CRE’s a Public Health EmergencyLimited treatment options for life threatening infectionsCo-migrate with other resistance genesResistant mechanisms have transferred to plasmidsPlasmids easily spread to other bacterial speciesNo/few new drugs/drug classes Rapid detection and effective infection control measures are essential to control spread

23. IPDH New Rule - Reporting CarbapenemasesMajor points:This establishes the mechanism by which carbapenem-resistant Enterobacteriaceae (CRE) are reported to IDPH, starting Sept 1, 2013, for all Illinois healthcare facilitiesBeginning 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 resultsLaboratory testsMolecular tests (PCR specific for carbapeneamse) KPC PCR currently offered at RosemontPhenotypic test (Modified Hodge Test) specific for carbapeneamse productionRosemont offers modified Hodge Test and ROSCO Disks – identification of KPC, MBL, hyper AmpC, and Oxa-48 carbapenemases Phenotypic tests are too slow!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 ceftazidimeWe use this definition for all EnterobacteriaceaeThe 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    .  

24. 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 antimicrobialsCRE can spread rapidly in health-care settingsEnterobacteriaceae 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 communityMMWR March 8, 2013 / 62(09);165-170

25. Healthcare-Associated Factors * * * ** p <0.001From: CDC webcast 3/19/09

26. CarbapenemaseHydrolysis Profilea Inhibition ProfilebMolecular ClassFunctional GroupEnzymePenicillinsEarly CephalosporinsExtended Spectrum CephalosporinsAztreonamEDTA/DPAClavulanic AcidBoronic AcidCloxacillinTemocilinA2fNMC-A (chromosomal)++-/++-+--+/-SME(chromosomal)++-/++-+--+/-KPC(plasmid)++++-+/-+-+/-IMI#(chromosomal)+++/-+-+---GES^(plasmid, low carbapenemase activity)+++--+--B13NDM, IMP, VIM, GIM, SPM(most plasmid)+++-+---+/-D2dOXA-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 hydrolysisb Inhibition Symbols: +, inhibition; +/-, variable inhibition among β-lactam family members; -, no inhibitionNMC-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)IDENTIFICATION OF CARBAPENEMASES FOUND IN THE CHICAGO/MILWAUKEE AREA

27. CREs Detected in Chicago/Milwaukee AreaCRE TypeYear DetectedChromosomal or PlasmidBacteriaSME2005ChromosomalSerratia marcescens NMC-A2004ChromosomalEnterobacter spp.KPC2009PlasmidEnterobacteriaceaeNDM-12010PlasmidK. pneumoniae, E. coliOXA-482012?PlasmidScreening started 2013VIM, IMP2010?Chromosomal/plasmidScreening started 2009

28. Carbapenem Breakpoints Lowered 9/2012

29. Effects of Lowering Carbapenem BreakpointsDetect chromosomal carbapenemases that are not considered an infection control emergencyMore SME (Serratia Marcescens Enzyme)Carbapenems resistant and 3rd and 4th generation cephalosporins sensitiveMore NMC-A (Not Metallo Carbapenemase, in Enterobacter sp.)Carbapenems resistant and 3rd and 4th generation cephalosporins sensitive

30. Acute care hospitalLong termCare facilitiesNeed to break the cycle!

31. Advocate hospitals –k. pneumoniae Imipenem (% sensitive)Hosp.200720082009201020112012CMC1009694929392Condell---999999G. Sam10010099989596G. Shep100100100969897IMMC1009892919292LGH1009895919292SSUB1009794949090Trinity1009794949392

32. Vital Signs: Carbapenem-Resistant EnterobacteriaceaeEnterobacteriaceae 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

33. Vital Signs: Carbapenem-Resistant EnterobacteriaceaeCRE 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 personsMMWR March 8, 2013 / 62(09);165-170

34. Vital Signs: Carbapenem-Resistant EnterobacteriaceaePreventing 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 at http://www.cdc.gov/vitalsignsMMWR March 8, 2013 / 62(09);165-170

35. Mechanisms of Carbapenem ResistanceNon enzymaticModifications of outer membrane permeabilityPorin lossAllow passage molecules include water, ions, glucose, and other nutrients as well as waste products Up regulation of efflux systemsEnzymaticProduction of carbapenem hydrolyzing β-lactamaseshyperproduction of AmpC β-lactamasesCertain ESBLs with increased capacity to hydrolyze carbapenemsCTX-MProduction of carbapenemasesKPC, NDM-1, othersCombinations of all of the above

36. NEED TO DISTINGUISH MECHANISMS OF CARBAPENEM RESISTANCE – WHY?KPC (increasing numbers)Make all penicillins, cephalosporins, inhibitor combinations, aztreonam, and carbapenems resistantHyper AmpC (most common)Make all penicillins, cephalosporins, inhibitor combinations, and aztreonam Resistant Cefepime may still be effectiveDo not change carbapenem interpretationsMetallo β-lactamases (rare, but increasing)Same as KPC, except do not change aztreonam interpretationOther carbapenemasesAntibiotic profiles not clear

37. Class a - Klebsiella Pneumoniae Carbapenemase (kpc) 1st described in 1998, 2001 in NYCNow endemic in the Northeastern/Mid-Atlantic region of the United Statessurveillance 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 1998Also 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 extended-spectrum cephalosporins and carbapenemsOccurs in other EnterobacteriaceaeMost commonly seen in Kliebsiella pneumoniaeAlso reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp.,

38. Carbapenem Resistant Enterobacteriaceae: Incidence and Risk Factors in a Community-Teaching HospitalA. Makarem, MD; P. Alvarez, MD; M. Kulkarni, MD; M. Costello, PhD; T. Chou, MPH; J. Kerridge, RN; K. Wickman, RN; J. Malow, MD BACKGROUNDRESULTSDISCUSSIONCarbapenems 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.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.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.METHODSCONCLUSIONSREFERENCES1. Rapid Spread of Carbapenem-Resistant K pneumoniae in New York City. S Bratu, MD et al. Arch Intern Med. 2005;165:1430-1435. 2. Carbapenemase-producing Enterobacteriaceae, U.S. rivers. Aubron, C., L. Poirel, R. J. Ash, and P. Nordmann. 2005. Emerg. Infect. Dis. 11: 260-264.3. Carbapenem resistance in Klebsiella pneumoniae not detected by automated susceptibility testing. Tenover FC. Kalsi RK. Williams PP. Carey RB. Stocker S. Lonsway D. Rasheed JK. Biddle JW. McGowan JE Jr. Hanna B. Emerging Infectious Diseases. 12(8):1209-13, 2006 Aug. 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 20086. Guidance for control of infections with 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. 7. Ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae carrying multiple metallo-beta-lactamase genes. Dwivedi M. Mishra A. Azim A. Singh RK. Baronia AK. Prasad KN. Dhole TN. Dwivedi UN. Indian Journal of Pathology & Microbiology. 52(3):339-42, 2009 Jul-Sep.8. Potential role of active surveillance in the control of a hospital-wide outbreak of carbapenem-resistant Klebsiella pneumoniae infection. Infection Control & Hospital Epidemiology 31:620-6 20109. Risk Factors and Outcomes Associated with Acquisition of Colistin-Resistant KPC-Producing K pneumoniae: a Matched Case-Control Study. Zarkotou et al. J. Clin. Microbiol. 2010;48:2271-2274 Represents the location of our institution Represents the residence locations of CRE positive cases FIGURES 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. Only one patient (5%) had previous carbapenem exposure. 40% had two sites of infection with CRE. 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). 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.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 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.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.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. 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. 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.A larger sample size is needed for more accurate calculations. 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. Screening for CRE should be considered in areas of high CRE endemicity. Development of new antimicrobial agents is needed.

39. Chicagoarea53/3040 = 1.7%2/2408=0.08%150/3206 = 4.7%

40. EID, Oct. 2011Figure 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) distribution in China.

41. Current tests for carbapenemase producersAST patterns (ACL - all carbapenems in Gram negative panels)Gram negative panels must include doripenem, ertapenem, imipenem, and meropenem for optimal sensitivityModified 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 hoursE TestsMBL for verification of a metallo-lactamase - carbapenem +EDTA/carbapenemCefotetan/Cefotetan+ cloxacillin for AmpC expressionTakes too longRosco Disks (ACL - Classify carbapenemases)Differentiates MBLs, from KPCs, from hyper AmpCLow sensitivity for Oxa-48Takes too longAmplified molecular methods (ACL – KPC only, so far)RapidSensitivity dependent on variation of sequences of carbapenem resistance genesCostly?

42. Positive for KPCModified Hodge testROSCO Disks

43. Class b carbapenemaseVIM, IMP, and NDM most common NDM more common in E. coli than KPCRequire zinc at active site for hydrolysis of the beta-lactam ringResistant to all beta-lactams except for aztreonamMay not be modified Hodge Test positive

44. Class b carbapenemaseRecent Case - Patient History 70 year old male. Visiting relatives.History – diabetes and chronic kidney failure, on dialysisAdmitted 9/23/2012 to CMC for shortness of breath.Cardiac surgery - Triple bypassComplicated recovery, discharged 10/22 to Long Term Acute Care Hospital (LTACH)

45. Laboratory DataTreated with Pip/tazo and fluconazole

46. Laboratory DataRepeat urine culture on 10/3 was negative

47. Fosfomycin = S

48.

49.

50. ColistinTigecyclineMBLAmpCIMI+EDTAIMISample is MHT +

51. 2/17/2013K. PneumoniaeMHT negative10/8/2012K. PneumoniaeMHT positiveMeropenemMeropenem +Dipicolinic acidTemocillinMeropenem + Boronic acidMeropenem + cloxacillinPositive = > 5 mm differenceNDM

52. Case ReviewPatient not isolated prior to MBL report on 10/8Did treatment (Pip-tazo) select for MBL?Rectal swabs taken on all patients in Adult Surgical Heart Unit. All were negative for MBLRectal 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)

53. Current Metallo β-Lactamase OutbreakPt.SQ. 70M 9/2012 CMCIndian national Urine - K. Pneumoniae x 2NDM-1 confirmed by CDCPt. In LTACH Pt. CK 68F 1/2013 LGHUrine – E. coli NDM-1 (CDCConfirmed) x 2Undermined acquisitionLGH - Seen in ER and admittedRisk factors: close relativeRecent Travel to Asia/CanadaPt. MR. 88F 3/2013 LGHUrine – E. coli NDM (CDCConfirmed)Present on admission to LGHRisk factors: multiple AB for frequent UTIs, recent nursing home stay (G), DementiaPt. KK. 73M 3/2013 LGHSputum - E. coli NDM-1 (CDC Confirmed)Present on admission to LGHRisk factors: ventilator dependent , feeding tube, LTACH and Nursing home staysPt. expired 3/28/13Pt. FR. 85M 4/2013 Nursing HomeRectal swab – E. coli NDM (CDC Confirmed)Risk factors: Ventilator dependent, roommate to Pt. KK at nursing home B, multiple MDRsPt. MM. 68F 4/2013. LGHAbd. Wound- E. coli, NDM (CDC Confirmed)Present on admission to LGHRisk factors: unknown, new pt.At LTACH at same timeFollow-up ActionsEach case reported to CCPH and IDPH by LGH Infection PreventionCommunicated to LGH and Advocate Senior leadershipEducation provided to physicians and associatesThere are no relationships among these cases with locations and time at LGHCCDP and IDPH conducting active surveillance of CRE in LTACH and 2 Nursing HomesLTACH screen 25% KPC+Active surveillance for CRE on LGH Rehab Unit negativeBeginning 4/29 all admits to LGH Rehab Unit will be screened for CRE~20% KPC+55% P. aeruginosa carbapenem resistant= highly related= pendingPFGE Results

54. National Resistance Alert 3 ADDENDUMCarbapenemase-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 UKDetection of Enterobacteriaceae Isolates Carrying Metallo-Beta-Lactamase — United States, 2010 – MMWR. June 25, 2010NDM-1 + E. coli K. pneumoniae K. oxytoca Enterobacter spp. Proteus spp. C. freundii M. morganii Providencia spp.Medical Tourism

55. Emerging Infectious Disease, Oct. 2011NDM, Current WaveMetallo β-Lactamases, Next WaveIMP = imipenem hydrolyzing metallo β-lactamaseVIM = Verona Integron-encoded Metallo-β-lactamaseNDM = New Delhi Metallo carbapenemase

56. The Carbapenemase Threat Class D - Oxacillin hydrolyzing β-lactamaseFirst 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 enterobacteriaeFound in Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae.Not confirmed in Midwest???

57. Oxa-48EID, Oct. 2011

58. Why Care About Mechanisms of Resistance?CarbapenemasesChromosomal Vs. plasmid basedChromosomal – Not an Infection Control Emergency SME, NMCSee more with lower carbapenem breakpointsPlasmid – Infection Control Emergency!KPC, NDM, GES, VIM, Oxa-48Need to isolate all patients??A commercially available, standardized, and reproducible amplified molecular assay will make CRE detection/identification faster, more sensitive, and consistent

59. Nanosphere - Gram Negative Blood Culture IDPathogens detectedEscherichia coli/Shigella spp., Klebsiella pneumonaie, Klebsiella oxytoca, Serratia marcescens, Pseudomonas aeruginosa, Citrobacter spp., Enterobacter Spp., Proteus spp., Acinetobacter spp.Resistance genesKPCNDMCTX-MVIMIMPOxa-48

60. In SummaryNew resistance mechanisms, new challengesLines blurring between HAI and community acquired infectionsMRSA, CREs, ESBLs, etc.ESBLs are not just HAI’s anymoreTeam approach absolutely requiredLab, Pharmacy, and ICPsAntibiotic stewardshipLab needs to be more responsive and less conservativeDo you need to double check your results prior to reporting?Patient to patient transmission can be limited by strict infection control measuresLaboratory identification of infection or carriage must be paired with rapid implementation of infection control measuresGroup effort requiredScreening – who pays?Ongoing surveillance is essentialSurveillance must include extended care facilities and cooperation between healthcare systemsMoving target Rapid detection and reporting essentialClinical CasesAsymptomaticCarriage