11

22

Extended-Extended-Spectrum-Spectrum-ββ LactamaseLactamase

(ESBLs)(ESBLs)

33

44

HistoryHistory

Pul Ehrlis 1910 Salvarsan Pul Ehrlis 1910 Salvarsan Gerhard Domagk 1935 Sulfanilamid Gerhard Domagk 1935 Sulfanilamid Alexander Fleming 1929 Penicillin Alexander Fleming 1929 Penicillin Ernest Chain and Howard Florey 1941 Ernest Chain and Howard Florey 1941 the drug was testedthe drug was tested

55

Classes of antibacterial agentsClasses of antibacterial agents

Basis of the mechanism of action: Basis of the mechanism of action: 1-Inhibitors of cell wall synthesis 1-Inhibitors of cell wall synthesis 2-Inhibitors of cytoplasmic membrane 2-Inhibitors of cytoplasmic membrane function function 3-Inhibitors of protein synthesis 3-Inhibitors of protein synthesis 4-Inhibitors of nucleic acid 4-Inhibitors of nucleic acid synthesis 5-antimetabolitessynthesis 5-antimetabolites

66

77

Inhibitors of cell wall synthesisInhibitors of cell wall synthesis

11--Beta- lactams Beta- lactams Penicillins,Cephalosporins,Carbapenems, Penicillins,Cephalosporins,Carbapenems, Monobactams Monobactams 2-Glycopeptides: 2-Glycopeptides: Vancomycin,teicoplani (active only Vancomycin,teicoplani (active only against G-P)against G-P)

88

-Lactams: Classification (1)-Lactams: Classification (1)PenicillinsPenicillins

Narrow-spectrum penicillinsNarrow-spectrum penicillinsBroad-spectrum penicillinsBroad-spectrum penicillins

ββ-lactamase inhibitor combinations-lactamase inhibitor combinationsOxacillin derivativesOxacillin derivatives

Cephalosporins (ATC/WHO 2005 classification)Cephalosporins (ATC/WHO 2005 classification)1st generation: Gram-positive cocci (GPCs), some 1st generation: Gram-positive cocci (GPCs), some

Gram-negative bacilli (GNBs)Gram-negative bacilli (GNBs)2nd generation: some GNBs, anaerobes2nd generation: some GNBs, anaerobes

3rd generation: many GNBs, GPCs3rd generation: many GNBs, GPCs 4th generation: many GNBs resistant to 3rd 4th generation: many GNBs resistant to 3rd

generation, GPCsgeneration, GPCs

99

-Lactams: Classification (2)-Lactams: Classification (2)

CarbapenemsCarbapenemsImipenem, meropenem, ertapenemImipenem, meropenem, ertapenem

MonobactamsMonobactamsAztreonamAztreonam

1010

1111

1212

The β-lactam family of antibioticsThe β-lactam family of antibiotics

Ceftriaxone 3Ceftriaxone 3rdrdTicarcillinTicarcillin

Ceftazidime Ceftazidime 33rdrd

MezlocillinMezlocillin

Cefotaxime Cefotaxime 33rdrd

CarbenicillinCarbenicillin

ErtapenemErtapenemCefmetazolCefmetazolee

Cefuroxime Cefuroxime 22ndndAmpicillinAmpicillin

MeropenemMeropenemCefotetanCefotetanCefamandole Cefamandole

22ndndMethicillinMethicillin

AztreonamAztreonamImipenemImipenemCefoxitinCefoxitinCephalothin Cephalothin 11stst

Benzyl-Benzyl-penicillinpenicillin

MonobactaMonobactamsms

CarbapenemCarbapenemss

CephamycinCephamycinss

CephalosporinCephalosporinss

PenicillinsPenicillins

Cefepime 4Cefepime 4thth

DefinitionsDefinitions

Narrow-spectrum Narrow-spectrum -lactam agents-lactam agentsActive against G- or G+ bacteria only; e.g., Active against G- or G+ bacteria only; e.g.,

penicillinpenicillin

Broad-spectrum Broad-spectrum -lactam agents-lactam agentsActive against G- and G+ bacteria; e.g., Active against G- and G+ bacteria; e.g.,

ampicillin, 1ampicillin, 1stst generation cephalosporins generation cephalosporins

1313

Definitions (con’t)Definitions (con’t)

Extended-spectrum ß-lactam agentsExtended-spectrum ß-lactam agentsEnhanced activity against G- and some G+ Enhanced activity against G- and some G+

bacteria; e.g., 3bacteria; e.g., 3rdrd and 4 and 4thth generation generation cephalosporins, carboxy- and cephalosporins, carboxy- and ureidopenicillinsureidopenicillins

Extended-spectrum ß-lactamases Extended-spectrum ß-lactamases (ESBLs)(ESBLs)

Enzymes produced by GNR that destroy Enzymes produced by GNR that destroy certain extended-spectrum ß-lactam agents, certain extended-spectrum ß-lactam agents, including including 33rdrd generation cephalosporins generation cephalosporins

1414

1515

1616

Mechanism of actionMechanism of action

Binding to penicillin Binding Protein(P B P) Binding to penicillin Binding Protein(P B P) this protein are this protein are carboxypeptidase ,aminopeptidase and carboxypeptidase ,aminopeptidase and transpeptidase enzymes transpeptidase enzymes Inhibition of one or more of this Inhibition of one or more of this enzymes accumulation of precursor cell enzymes accumulation of precursor cell wall unit cell's autolytic system to be wall unit cell's autolytic system to be activated and results finally cell lysesactivated and results finally cell lyses

1717

Resistance to Resistance to -Lactams-Lactams

1818

ResistanceResistance

11--Alteration in target site Alteration in target site 2-Production of beta- lactamases2-Production of beta- lactamases Genes encoding are found on the Genes encoding are found on the chromosome (generally G-N) and on the chromosome (generally G-N) and on the plasmid (generally G-P )plasmid (generally G-P )

1919

Beta-lactamase inhibitorsBeta-lactamase inhibitors

Resemble β-lactam antibiotic structureResemble β-lactam antibiotic structureBind to β-lactamase and protect the Bind to β-lactamase and protect the

antibiotic from destructionantibiotic from destructionMost successful when they bind the β-Most successful when they bind the β-

lactamase irreversiblylactamase irreversiblyThree important in medicineThree important in medicine

Clavulanic acidClavulanic acidSulbactamSulbactam

TazobactamTazobactam

2020

ββ-lactamase inhibitors-lactamase inhibitors

Clavulonic acid: derived from Clavulonic acid: derived from Streptomyces clavuligerusStreptomyces clavuligerusLittle antibiotic effect in itselfLittle antibiotic effect in itself

Given in combination with a Given in combination with a ββ -lactam Ab -lactam AbFunction: by binding the Function: by binding the ββ -lactamase enzyme more -lactamase enzyme more

efficiently than the actual efficiently than the actual ββ -lactam -lactamThus protect the Thus protect the ββ -lactam Ab from hydrolysis -lactam Ab from hydrolysis

Not efficient against cephalosporinasesNot efficient against cephalosporinases

2121

Plasmid-mediated TEM and SHV -lactamases

Ampicillin

1965

TEM-1E.coliS.paratyphi

1970s

TEM-1Reported in 28 Gm(-) sp

1983

ESBL in Europe

1988

ESBL in USA

2000

> 130 ESBLsWorldwide

Extended-spectrumCephalosporins

1963

Evolution of -Lactamases

2222

2323

History of GNR resistanceHistory of GNR resistance

1928

Fleming

1941

Penicillin use

1940 Penicillinase detected in E.

coli

1959

β -lactamase resistant penicillins: Methicillin

1960s

Broad spectrum/ extended spectrum

penicillins

1964

Cefalotin use

1965

Broad spectrum β –lactamases (TEM-1 in E. coli) 1983 Extended

spectrum β-lactamases

1950 1960 1970 1980 1990 2000

1985

Carbapenem (Imipenem)

Early 1980s

3rd generation ceph.

Carbapenemases

TEM-1 widespread

2005

Tigecycline

ESBL outbreaks in

France

1976

β –lactamases inhibitors

2424

Ambler Ambler Classification of Classification of ββ--LactamasesLactamases

Active site

Nucleotide sequence

Four evolutionarily distinct molecular classes

A C D

Serine-enzymes

B

Zinc-enzymes

β-lactamases

2525

Modified Modified Bush–Jacoby–Medeiros Bush–Jacoby–Medeiros CClassification of lassification of –Lactamases–Lactamases

Functional Substrate profile Group

Molecular Class

Inhibitor

Example

1 Cephalosporinase C Oxa AmpC, MIR-1

2a Penicillinase A Clav. S.aureus

2b Broad spectrum A Clav. TEM-1/2, SHV-1

2be Extended spectrum A Clav. TEM 3-29, TEM46-104 SHV2-28, CTX-M types

2br Inhibition resistant A - TEM 30-41 (IRT1-12)

2c Carbenicillinase A Clav. PSE-1

2d Oxacillinase D (Clav.) OXA-1 (OXA-2 &-10 derived ESBL)

2e Cephalosporinase A Clav. FPM-1 P. vulgaris, CepA B. fragilis.

2f Carbapenemase A Clav. IMI-1, NmcA, Sme 1-3

3 Metallo-enzyme B - S.maltophilia

4 Penicillinase - - B.cepacia

2626

Extended-Spectrum Extended-Spectrum -Lactamases (ESBL)-Lactamases (ESBL)

Confers resistance to penicillins andConfers resistance to penicillins and 11stst, 2, 2ndnd and 3 and 3rdrd generation cephalosporins generation cephalosporins

Inhibited by Inhibited by -Lactamase inhibitors-Lactamase inhibitorsMost common CTX-M, TEM and SHVMost common CTX-M, TEM and SHV

>>300300 have been identifiedhave been identifiedPlasmid-mediated, highly mobilePlasmid-mediated, highly mobile

Often associated with resistance genes to Often associated with resistance genes to aminoglycoside, TMP/SMX and tetracyclineaminoglycoside, TMP/SMX and tetracycline

Associated with fluoroquinolone resistance Associated with fluoroquinolone resistance phenotypephenotype

2727

Types of ESBLsTypes of ESBLs

TEMTEMSHVSHV

CTX-MCTX-MOXAOXA

Mutations

ESBL PhenotypePlasmid-mediated

2828

Evolution of TEM EnzymesEvolution of TEM EnzymesMIC (MIC (g/mL) ceftazidimeg/mL) ceftazidime

102102162162

TEM-1 TEM-1 0.250.25

glutamineglutamineargininearginine

TEM-12TEM-12

2.02.0

glutamineglutamineserineserine

TEM-26TEM-26

128128

lysinelysineserineserine

Fresno 11/00Fresno 11/00

EnzymeEnzyme Ceftaz Ceftaz Amino Acid PositionAmino Acid Position

MICMIC 104104 164164 240240

TEM-1TEM-1 0.12 0.12 GluGlu ArgArg GluGlu

TEM-10TEM-10 > 256 > 256 GluGlu SerSer LysLys

TEM-12TEM-12 16 16 GluGlu SerSer GluGlu

TEM-26TEM-26 256 256 LysLys SerSer GluGlu

from: Jacoby, IDCNA 11:875, 1997from: Jacoby, IDCNA 11:875, 1997

Molecular Basis of ESBLsMolecular Basis of ESBLs

3030

Other ESBLs

CTX-M preferentially hydrolyze CTX-M preferentially hydrolyze cefotaximecefotaxime.. - -found in strains of found in strains of Salmonella enterricaSalmonella enterrica

- -E.coli and other species ofE.coli and other species of EnterobacteriaceaeEnterobacteriaceae OXAOXA

Mainly inMainly in P.aeroginosa P.aeroginosa

66

3131

Other ESBls (cont,n)Other ESBls (cont,n)

PER-1 :Discovered in PER-1 :Discovered in P.aeruginosa P.aeruginosa (turkey)(turkey)PER-2 In south AmericaPER-2 In south America

VEB-1 VEB-1 E.coli E.coli (Vietnam) (Vietnam)CME-1 CME-1 Chrysobacterium Chrysobacterium

meningosepticummeningosepticum( Thailand)( Thailand)TLA-1 TLA-1 E.colE.coli ( Mexico )i ( Mexico )

Patrica A Cli Microbiol Rev 14; 2001Patrica A Cli Microbiol Rev 14; 2001

3232

ESBls are clinically ESBls are clinically importantimportant

They destroy cephalosporinsThey destroy cephalosporinsDelayed recognition and inappropriate Delayed recognition and inappropriate

treatment of sever infectiontreatment of sever infection ESBls –mediated resistance is not always ESBls –mediated resistance is not always

obvious to all cephalosporinsobvious to all cephalosporinsMany ESBL produce multi-resistant to non- Many ESBL produce multi-resistant to non- -

lactam antibiotics such as quinolons .aminoglycosides and trimethoprime

1313

Why is important to do special tests and Why is important to do special tests and follow complex reporting rules for ESBLsfollow complex reporting rules for ESBLs??

Why is important to do special tests and Why is important to do special tests andfollow complex reporting rules for ESBLsfollow complex reporting rules for ESBLs??

In vitro tests may be In vitro tests may be misleadingmisleading (e.g., may see (e.g., may see “S” in vitro but drug may not work!)“S” in vitro but drug may not work!)

Many types of ESBLs with varying susceptibility Many types of ESBLs with varying susceptibility profiles profiles (TEM (TEM 130; SHV 130; SHV 50; CTX-M 50; CTX-M 30) 30)

Treatment failuresTreatment failures (esp. bacteremia) when (esp. bacteremia) when patient treated with 3rd generation patient treated with 3rd generation cephalosporinscephalosporins

ESBL-producing isolates can cause ESBL-producing isolates can cause nosocomial nosocomial outbreaksoutbreaks

3333

3434

Which microorganisms are ESBls Which microorganisms are ESBls positivepositive

K.pneumoniae K.pneumoniae andand K.oxytoca K.oxytocaE.coliE.coli

Enterobacter sppEnterobacter sppSalmonella sppSalmonella spp

Morganell morganii,Proteus mirabilisMorganell morganii,Proteus mirabilisSerratia marcescensSerratia marcescens

Pseudomonas aeruginosaPseudomonas aeruginosa

1616

ESBL TestingESBL TestingOrganisms Organisms

E. E. coli, Klebsiellacoli, Klebsiella spp., spp., Proteus mirabilisProteus mirabilis

Screen test: Screen test: Decreased Decreased

susceptibility to extended-spectrum ß-lactamssusceptibility to extended-spectrum ß-lactams

Phenotypic confirmatory test: Phenotypic confirmatory test: ß-lactam activity restored by ß-lactamase inhibitor ß-lactam activity restored by ß-lactamase inhibitor (i.e. clavulanic acid) (i.e. clavulanic acid)

3535

ESBLESBL Screening TestScreening Test

ESBLESBL Screening TestScreening Test

Disk zone (mm) MIC (µg/ml)Disk zone (mm) MIC (µg/ml)

**Cefpodoxime Cefpodoxime 17 17 >4 >4****

**CeftazidimeCeftazidime 22 22 >1 >1**CefotaximeCefotaxime 27 27 >1 >1 CeftriaxoneCeftriaxone 25 25 >1 >1 AztreonamAztreonam 27 27 >1 >1

* only these drugs appropriate for * only these drugs appropriate for P. mirabilisP. mirabilis**>1 **>1 g/ml for g/ml for P. mirabilisP. mirabilis

ESBL ESBL Phenotypic Confirmatory TestPhenotypic Confirmatory Test

TestTest::cefotaximecefotaxime

cefotaxime/clavulanic acidcefotaxime/clavulanic acidceftazidimeceftazidime

ceftazidime/clavulanic acidceftazidime/clavulanic acid ResultsResults::

clavulanic acid restores activity of cefotaxime or clavulanic acid restores activity of cefotaxime or ceftazidime or bothceftazidime or both

QCQC E. coliE. coli ATCC 25922; ATCC 25922; K. pneumoniaeK. pneumoniae ATCC 700603 ATCC 700603

3838

MIC TestMIC Testcefotaxime and ceftazidime +/- 4 μg/ml cefotaxime and ceftazidime +/- 4 μg/ml

clavulanateclavulanate::>> 33 doubling dilution decrease with either drugdoubling dilution decrease with either drug

Disk TestDisk Testcefotaxime and ceftazidime +/- 10 μg clavulanatecefotaxime and ceftazidime +/- 10 μg clavulanate

>> 55 mm zone increasemm zone increase

e.g. ceftazidime 8 μg/ml

ceftazidime + clavulanate 1 μg/ml

CLSI Confirmatory Test – CLSI Confirmatory Test – Klebsiella, E. coli, P. mirabilisKlebsiella, E. coli, P. mirabilis

3939

ESBL Confirmatory TestESBL Confirmatory TestPositivePositive for ESBL for ESBL

Ceftaz/CACefotax/CA

Ceftaz Cefotax

4040

4141

ESBL Confirmatory Test ESBL Confirmatory Test NegativeNegative for ESBL for ESBL

Ceftaz/CA Cefotax/CA

Ceftaz Cefotax

4141

4242

E-test for detection of ESBLsE-test for detection of ESBLs

AB Biodisk (Solna,Sweden) has introduced AB Biodisk (Solna,Sweden) has introduced a two sided ESBL E-test strip that contain a two sided ESBL E-test strip that contain either a combination of ceftazidime and either a combination of ceftazidime and ceftazidime/clavulani acid or cefotaxime ceftazidime/clavulani acid or cefotaxime and cefotaxime /clavulanic acidand cefotaxime /clavulanic acid

4343

E-test for detection ESBlsE-test for detection ESBls

Both strips have a decreasing gradient of Both strips have a decreasing gradient of ceftazidime or cefotaxime alone on one end and ceftazidime or cefotaxime alone on one end and a decreasing gradient of ceftazidime or a decreasing gradient of ceftazidime or cefotaxime plus a fixed gradient of clavulanic cefotaxime plus a fixed gradient of clavulanic acid on the other end .A>3log reduction in the acid on the other end .A>3log reduction in the MIC of cefotaxime or ceftazidime in the MIC of cefotaxime or ceftazidime in the presence of the clavulanicis considered a presence of the clavulanicis considered a

positivepositive . .

ESBL Confirmatory TestESBL Confirmatory Test

Ceftaz/CA CeftazEtest

MicroScan – ESBL panel

Vitek – confirmatory test

Vitek 2 - Advanced Expert4444

Proteus mirabilisProteus mirabilis and ESBLs and ESBLs

Not necessary to test routinelyNot necessary to test routinely

Uncommon in USAUncommon in USA

Significant problems in some locations Significant problems in some locations (e.g., Europe, South America)(e.g., Europe, South America)

4545

4646

Proteus mirabilisProteus mirabilis ESBL testing ESBL testing

Routine screening not recommendedRoutine screening not recommended Perform ESBL test when clinically relevant (e.g. Perform ESBL test when clinically relevant (e.g.

bcteremiabcteremia))

--consult with medical staff to determine to testconsult with medical staff to determine to test--Practical approach ,test sterile body site isolatePractical approach ,test sterile body site isolate

Use Standard ESBLs screen test with slight Use Standard ESBLs screen test with slight modificationmodification

4747

Proteus mirablisProteus mirablis ESBL ESBLScreen TestScreen Test

DrugDrug Disk ScreenDisk Screen

( ( mmmm))

MIC ScreenMIC Screen

((µ g/mlµ g/ml))

CefpodoximeCefpodoxime 1717 ≥ ≥ 22**

CeftazidimCeftazidim ≤ ≤ 2222 ≥ ≥ 22

AztreonamAztreonam NANA NANA

CefotaximeCefotaxime ≤ ≤ 2727 ≥ ≥ 22

CeftriaxoneCeftriaxone NANA NANA

4848

Proteus mirabilisProteus mirabilis ESBLs Testing ESBLs Testing (con’t)(con’t)

Use standard disk diffusion or MIC ESBL Use standard disk diffusion or MIC ESBL phenotype confirmatory test without phenotype confirmatory test without modificationmodification

3939

ESBL Reporting RuleESBL Reporting RuleThe rule The rule (CLSI =NCCLS) M100-S15(CLSI =NCCLS) M100-S15…)…)

““Strains of Strains of KlebsiellaKlebsiella spp. spp. E. coli, E. coli, andand Proteus Proteus mirabilismirabilis that produce ESBLs may be clinically that produce ESBLs may be clinically resistant to therapy with penicillins, resistant to therapy with penicillins, cephalosporins, or aztreonam, despite apparent cephalosporins, or aztreonam, despite apparent

in vitro susceptibility to some of these agentsin vitro susceptibility to some of these agents”.”.The messageThe message……

Report “confirmed” ESBL-producing strains as R Report “confirmed” ESBL-producing strains as R to all to all penicillins, cephalosporins, penicillins, cephalosporins, andand aztreonam aztreonam

4949

If ESBL screen test is positive, must we do If ESBL screen test is positive, must we do the confirmatory test prior to reporting the confirmatory test prior to reporting

isolate as an ESBLisolate as an ESBL??

YesYes - unless you are confident that the - unless you are confident that the isolate isolate is / is not an ESBLis / is not an ESBL producer based producer based onon::

A previous isolate from the patientA previous isolate from the patient An endemic strain in your institutionAn endemic strain in your institution

5050

What about testing / reporting for ESBLs on What about testing / reporting for ESBLs on urine isolatesurine isolates??

The suggestion The suggestion (CLSI M100-S15)(CLSI M100-S15)……““The decision to perform ESBL screening tests on The decision to perform ESBL screening tests on all all

urine isolatesurine isolates should be made on an institutional should be made on an institutional basisbasis”.”.

RationaleRationale……-lactam concentration in bladder is very high and -lactam concentration in bladder is very high and

overcomes hydrolysis by ESBL enzymesovercomes hydrolysis by ESBL enzymesThe concernsThe concerns……

Identifying urine from acute cystitis vs. otherIdentifying urine from acute cystitis vs. other Patient with isolate from urine + other sitesPatient with isolate from urine + other sites

Infection control issuesInfection control issues5151

Will CLSI confirmatory test detect ALL ESBL-Will CLSI confirmatory test detect ALL ESBL-producing GNRproducing GNR??

No No - some isolates have - some isolates have ESBLs plusESBLs plus other resistance other resistance mechanismsmechanisms that mask ESBL detection in the that mask ESBL detection in the

confirmatory test, e.gconfirmatory test, e.g ,. ,. > >11 ESBLESBL

ESBL + ampCESBL + ampCESBL + porin mutationESBL + porin mutation

ESBLs occur in ESBLs occur in speciesspecies other than other than E. coli, KlebsiellaE. coli, Klebsiella spp., and spp., and Proteus mirabilisProteus mirabilis which CLSI does not which CLSI does not currently addresscurrently address

5252

5353

ESBLs Test QC frequency Disk ESBLs Test QC frequency Disk Diffusion and MIC MethodsDiffusion and MIC Methods

Screen TestScreen Test Phenotypic ConfirmatoryPhenotypic Confirmatory

TestTest

Daily/weekly QCDaily/weekly QC

K.PneumoniaeK.Pneumoniae ATCC700603 ATCC700603

OROR

E.ColiE.Coli ATCC 25922 ATCC 25922

Daily/Weekly QCDaily/Weekly QC

K.pneumoniae ATCC 700603K.pneumoniae ATCC 700603

ANDAND

E.Coli E.Coli ATCC 25922ATCC 25922

ESBLs gene on plasmid; must store QC strain at-60ESBLs gene on plasmid; must store QC strain at-60°°C or lowerC or lower

5454

Microbiology Laboratories and Microbiology Laboratories and ESBLsESBLs

Unfortunately ,many clinical laboratories lack Unfortunately ,many clinical laboratories lack of understanding regarding ESBLs and Ampc ß-of understanding regarding ESBLs and Ampc ß-lactamase and their detection .This has been lactamase and their detection .This has been documented in a study in Connecticut USA, documented in a study in Connecticut USA, where it was found that 21% of laboratories where it was found that 21% of laboratories failed to detect extended –spectrum failed to detect extended –spectrum cephalosporins and Aztreonam in ESBLs and cephalosporins and Aztreonam in ESBLs and

AmpcAmpc . .

5555

Prevalence of ESBLsPrevalence of ESBLs

The true prevalence of ESBLs is not The true prevalence of ESBLs is not known and is probably underestimated known and is probably underestimated because of difficulties encounter in their because of difficulties encounter in their detection. However ,it is clear that ESBLs detection. However ,it is clear that ESBLs –producing organisms are distributed –producing organisms are distributed worldwide and their prevalence is worldwide and their prevalence is increasingincreasing..

5656

ESBls in EuropeESBls in Europe

ESBLs were first described in 1983 from ESBLs were first described in 1983 from Germany and EnglandGermany and England..In Netherlands less than 1% of In Netherlands less than 1% of E.coliE.coli and and K.pneumoniaeK.pneumoniae were ESBLs In France were ESBLs In France and Italy more than 40% strains of and Italy more than 40% strains of K.pneumoniaeK.pneumoniae resistant to Ceftazidime resistant to Ceftazidime..It is not known why the prevalence varies It is not known why the prevalence varies

so widely in closely related regionsso widely in closely related regions . .

5757

North AmericaNorth America

The first ESBLs –producing organisms The first ESBLs –producing organisms reported in 1988..reported in 1988..The prevalence of ESBLs production The prevalence of ESBLs production among Enterobacteriaceae in the USA among Enterobacteriaceae in the USA ranges from 0 to 25 % with the national ranges from 0 to 25 % with the national average being 3%average being 3%

5858

Prevalence of ESBLs USA (cont, )Prevalence of ESBLs USA (cont, )

CDC Report from ICUs(1999)CDC Report from ICUs(1999)

--E.coli E.coli 48%48%

--K.pneumoniae K.pneumoniae 10.4%10.4%

5959

Latin AmericaLatin America

ESBLs appear common in many Latin ESBLs appear common in many Latin Americans countriesAmericans countries..

The SENETRY study surveillance program The SENETRY study surveillance program among 10,000 bacterial from ten centers among 10,000 bacterial from ten centers showedshowed::

- - 45%45% K.pneumoniaeK.pneumoniae ESBLs positive ESBLs positive

- - 8.5%8.5% E.coliE.coli ESBLs positive ESBLs positive

6060

Asia and AustraliaAsia and Australia

The prevalence of ESBL –producing strains of The prevalence of ESBL –producing strains of Enterobacteriaceae varies fro country to country and Enterobacteriaceae varies fro country to country and from species to speciesfrom species to species.'.'

- - E.coliE.coli 5% in Korea and 23.3% in Indonesia5% in Korea and 23.3% in Indonesia .. - - Klebsiella sppKlebsiella spp 48.8% in Korea and 20-40% 48.8% in Korea and 20-40%

Southeast Asia , China and Japan .Outbreaks of Southeast Asia , China and Japan .Outbreaks of infections due to ESBls –producing organisms have been infections due to ESBls –producing organisms have been described widely in Australiadescribed widely in Australia

6161

Africa and Middle EastAfrica and Middle East

Although national surveillance are not Although national surveillance are not lacking ,outbreaks of infections due to lacking ,outbreaks of infections due to ESBL-producing organism have bee noted ESBL-producing organism have bee noted in some African nationsin some African nations,,

6262

Infection Control caused by ESBLsInfection Control caused by ESBLs

Isolation measureIsolation measure

- - private room, Private bathroomprivate room, Private bathroom

- - Contact isolation (gloves .gownContact isolation (gloves .gown..

- - Hand hygiene complianceHand hygiene compliance

- - Dedicated equipment Dedicated equipment (Thermometer, Stethoscope)(Thermometer, Stethoscope)

6363

Infection control(cont,)Infection control(cont,)

Identification of patientsIdentification of patients

--patients charts should be” flagged so that contact patients charts should be” flagged so that contact isolation for ESBL-colonization can be isolation for ESBL-colonization can be considered on subsequent admissions thorough considered on subsequent admissions thorough decontamination for environmental –of –care decontamination for environmental –of –care with routine low-level disinfectant (Quaternary with routine low-level disinfectant (Quaternary ammonium ,phenol)ammonium ,phenol)

6464

Infection Control(cont,)Infection Control(cont,)

Antibiotic UseAntibiotic Use

Antibiotic use protocol should be institute Antibiotic use protocol should be institute eliminate indiscriminate use of eliminate indiscriminate use of antibacterials and decrease selective antibacterials and decrease selective pressure for ESBLs producing strains of pressure for ESBLs producing strains of bacteriabacteria

6565

Increasing Numbers of ESBLsIncreasing Numbers of ESBLs

0

10

20

30

40

50

60

70

80

2000 2001 2002 2003 2004 2005 2006 2007

# o

f E

SBLs per year

Lewis, et al. AAC 51:4015, 2007

6666

Current ESBL Detection Current ESBL Detection Methods FailMethods Fail Routine tests are not designed for ESBL detectionRoutine tests are not designed for ESBL detection

Low level ESBL expression will not be detected by Low level ESBL expression will not be detected by current tests using low inoculumcurrent tests using low inoculum

MIC values and zone sizes of ESBL producers MIC values and zone sizes of ESBL producers overlap those of susceptible non-ESBL producersoverlap those of susceptible non-ESBL producers

ESBL double disk test may be inaccurate if ESBL double disk test may be inaccurate if positioning is suboptimalpositioning is suboptimal

ESBL breakpoint methods are limited since MICs ESBL breakpoint methods are limited since MICs for different strains can range over 7 dilutionsfor different strains can range over 7 dilutions

6767

Rapidly Rapidly IIncreasing ncreasing AAntibiotic ntibiotic RResistance esistance CConstitutes onstitutes OOne of the ne of the MMost ost IImportant mportant CClinical, linical, EEpidemiological and pidemiological and MMicrobiological icrobiological PProblems of roblems of TTodayoday

6868

6969