Extended spectrum Beta-lactamase (ESBL) and - PowerPoint Presentation

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Extended spectrum Beta-lactamase (ESBL) and carbapenamase producing E.coli and Klebsiella spp...the next multi-drug resistant catastrophe. 

Steven Weger

 

MMIC 7050

 

Dec. 10 2013

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β-lactam antibioticsNatural product application and discoveryExtremely important class of antimicrobial >50% of all systemically used antimicrobialsHigh efficacy

Safety profile

Several derivatives

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Transpeptidase and D-alanyl

carboxypeptidase

(

Penicillins Binding Proteins, PBP’s) contribute to "cross-linking,” a vital step in completing the cell wall.

The Beta-Lactam Ring binds at the active site of the

transpeptidase enzyme by mimicking the D-alanyl-D-alanine residues that would normally bind to this site

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β-lactam Resistance Mechanisms

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β-lactamasesHydrolyze amide bond of lactam ringPlasmid vs. ChromosomalInducible vs. constitutive

a

.a

. sequence

Substrate profile

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ESBLsHydrolyze penicillins, broad- and extended-spectrum cephalosporins, and

monobactams

Inhibited by

Clavulanic

acid

Spectrum of activity extanded by a.a. substitutions w/in enzymePlasmid mediatedMost commonly found in Enterobacteriaceae like E.coli and K. pneumoniae

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ESBLs3 main families:TEM-type -> Penicillin, ampicillin, 1st gen. cephalosporins

Over 200 variants

SHV-type ->

Penicillins

, ampicillin, 1

st gen. cephalosporinsOver150 variantsOther types (CTX-M, OXA, etc.)CTX-M have increased their spread due to ST131Frequently harbored in E. coli

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ESBL Treatment optionsβ-lactam/β-lactamase inhibitor combination (e.g. amoxicillin/clavulanate)

Clavulanic

acid

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ESBL Treatment optionsCarbapenemsPreferred agentLast line of defenseResist ESBL hydrolysis

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AmpC β-lactamasesHydrolyze penicillins, broad- and extended-spectrum cephalosporins

NOT inhibited β

-lactamase

inhibitor’s

Chromosomal or Plasmid encoded

Mutations in promoter can cause hyper-expression of chromosomal ampCCMY and DHA are most common plasmid-type in E. coli and K. pneumoniae

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CarbapenemasesSteadily increasing in prevalenceHydrolyze virtually all β-lactamsCRE =



morbidity,



mortality

Limited treatment options : aminoglycosides, polymyxins, tigecycline, fosfomycin, and temocillin

Limited by the side effect profiles, nephrotoxicity, administration issues, and efficacy Highly mobile

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Molecular epidemiology of extended-spectrum b-lactamase-, AmpC b-lactamase- and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae

isolated from Canadian hospitals over a 5 year period: CANWARD 2007–11

Andrew

J.

Denisuik1, Philippe R. S. Lagace´-Wiens, Johann D. Pitout, Michael

R.Mulvey, Patricia J. Simner, Franil Tailor,

James A. Karlowsky, Daryl J. Hoban, Heather J. Adam and George G. Zhanel on behalf of the Canadian Antimicrobial Resistance Alliance (CARA)†

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The StudyDetermine the proportion of Escherichia coli and Klebsiella pneumonia collected from Canadian hospitals

that produce ESBLs,

AmpC

β-lactamases, and

carbapenemases

. The molecular characteristics of these pathogens as well as the patterns of antibiotic resistance are also described.

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The study5451 E. coli and 1659 K. pneumonia isolates collected from 2007-2011

AST using broth micro-dilution method

MIC breakpoints using CLSI 2012 guidelines

MDR = Resistance to 3 antimicrobial classes

XDR = Resistance to 5 antimicrobial classes

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The StudyPutative ESBL-producer:ceftriaxone and/or ceftazadime MIC of ≥1mg/L

ESBL production confirmed by phenotypic disc test

Putative

AmpC

-

Producer:ceftriaxone and/or ceftazidime MIC of ≥1 mg/L cefoxitin MIC ≥32 mg/L that is ESBL negative by the CLSI confirmatory disc test Putative Carbapenemase

-Producer:ertapenem MIC ≥0.5 mg/L

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PCR for Resistance EnzymeESBL: blaSHV,

bla

TEM

,

bla

CTX-M and blaOXA AmpC:blaENT, blaDHA,

blaFOX, and blaCIT Promoter sequenced for all PCR Negative for above

Carbapenemase:blaKPC, blaIMP, blaVIM, blaIMI, blaNDM

,

bla

GES

, bla

OXA

-48

Genetic relatedness determined by PFGE

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AmpC E. coli CharacterizationOf 115 AmpC E. coli isolates:65 contained acquired

AmpC

β-lactamase

genes

64 produced CMY-2 1 produced FOX-5 50 contained mutations in the promoter of the chromosomal ampC gene

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Genetic Relatedness Among IsolatesNot related (<80% similarity) by PFGEST131 found in: 56% of

ESBL-producing

E. coli

29% of

AmpC-producing E. coliSteady  in ST131 over study period49%(2007)-72%(2011)102 of 153 CTX-M-15 Producers were ST131ST131 facilitating spread of CTX-M-15 in Canadian hospitals

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Antimicrobial Susceptibility/Treatment OptionsGreatest activity: amikacin,

meropenem

,

ertapenem

, and

colistin ESBL- and AmpC E. coli: highly susceptible (>93%) to piperacillin/tazobactamESBL-producing K. pneumonia susceptibility decreased to 67%

Tigecycline: ESBL- and AmpC- producing E. coli susceptibilities of 99.6% and 100% respectively

ESBL- producing K. pneumonia were less susceptible to this antibiotic with 83% susceptibility

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MDR:79% of ESBL-producing E. coli 69% of ESBL-producing K. pneumoniae

34% of

AmpC

-producing E. coli

MDR among the ESBL- producing E. coli increased from 77% in 2007 to 83% in 2011 2.6% of ESBL-producing E. coli and 10.4% of ESBL-producing K. pneumonia demonstrated an XDR phenotype 3 carbapenemase (all KPC) producing

isolates:Resistance to amoxicillin/clavulanate,

piperacillin/tazobactam, and ertapenemsusceptible to colistin and tigecycline. Only one of these isolates was resistant to meropenem.

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Diagnosis ESBL-producer = inadequate therapy until resistance determinedMortality doubles in bacteremiaMIC-based screening criteria and phenotypic methods of detection (disc test)

-Appropriate therapy determination

-Appropriate infection control -> Prevent clonal spread

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SummaryProportion of ESBL- and AmpC producing E. coli and K. pneumonia

demonstrated

significant

national increase

ESBL- producing E. coli = dominant group in Canada Rate of carbapenemase producers in Canadian hospitals will continue to increase Due to selection pressureForeign travel

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