Current status of -lactamases-producing

gram-negative bacilli isolated in Korea

Kyungwon Lee, MD, PhDKyungwon Lee, MD, PhDDepartment of Laboratory Medicine and Department of Laboratory Medicine and

Research Institute of Bacterial ResistanceResearch Institute of Bacterial Resistance

Yonsei University College of Medicine, Seoul, KoreaYonsei University College of Medicine, Seoul, Korea

Antimicrobial Resistance of Bacteria

29

47

71

76

84 84 84

77

46

54 55

7072

7074 75

0 1

15

33

46

15

20

33

46

1518

2723

11

2319

26

39

34

28

43

28

0

20

40

60

80

100

1988 1990 1992 1994 1996 1998 2000 2002

% RPRSPMRSAVREFMIMPRPAECTXRKPNFUQRECO

Serious problemsSerious problems in in

many countriesmany countries

In KoreaIn Korea, ,

- relatively more - relatively more

prevalent prevalent

- has worsened during- has worsened during

past several yearspast several years

Major clinical problems with antibiotic-resistant bacteria

Gram-negative bacilli : 59%Gram-negative bacilli : 59%

- 3- 3rdrd-gen cepha.-resistant-gen cepha.-resistant E. coliE. coli 3,6813,681 K. pneumoniaeK. pneumoniae 1,728 1,728 E. cloacaeE. cloacae 756 756 S. marcescensS. marcescens 454 454 C. freundiiC. freundii 271271

- Carbapenem-resistant- Carbapenem-resistant P. aeruginosa P. aeruginosa 3,4763,476 A. baumanniiA. baumannii 1,894 1,894

Gram-positive cocci: 41%Gram-positive cocci: 41%

- Methicillin-resistant- Methicillin-resistant Staphylococcus Staphylococcus aureusaureus 4,0084,008

- Vancomycin-resistant- Vancomycin-resistant Enterococcus Enterococcus faeciumfaecium 1,8701,870

- Penicillin-nonsusceptible- Penicillin-nonsusceptible Streptococcus Streptococcus pneumoniae pneumoniae 236 236

Antimicrobial resistance newsletter, 2003Antimicrobial resistance newsletter, 2003

Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR)

WHO, organized in 1997WHO, organized in 1997 To monitor To monitor

the nationwide the nationwide

antimicrobial resistance antimicrobial resistance 72 university or general 72 university or general

hospitalshospitals WHONET programWHONET program

KONSAR 2003KONSAR 2003

262

1

β-lactam resistance in gram-negative rodβ-lactam resistance in gram-negative rodss

ImpermeabilityImpermeability Alteration of PBPAlteration of PBP β-lactamase production: β-lactam hydrolysisβ-lactamase production: β-lactam hydrolysis - 1995, 170; 2000, 350- 1995, 170; 2000, 350 - Novel β-lactamase - Novel β-lactamase Most important groups of enzymesMost important groups of enzymes - Extended spectrum β-lactamase (ESBL)- Extended spectrum β-lactamase (ESBL) - AmpC β-lactamase- AmpC β-lactamase - Carbapenemase- Carbapenemase

(Bush CID, 2001)(Bush CID, 2001)

Classification of β-lactamasesClassification of β-lactamases

Ambler Bush Activity CAAmbler Bush Activity CA class group PEN CAR OXA CEP CTX AZT IMP Inh Enzymesclass group PEN CAR OXA CEP CTX AZT IMP Inh Enzymes SerineSerine

A 2a +++ + A 2a +++ + - +/- - +/- - - - - - - ++ GPC pen-nase ++ GPC pen-nase 2b +++ + + ++ 2b +++ + + ++ -- - -- - ++ TEM-1, 2, SHV-1 ++ TEM-1, 2, SHV-1 2be +++ + +2be +++ + + ++ ++ ++ ++ ++ ++ -- ++ TEM-3, SHV-2 ++ TEM-3, SHV-2 2br 2br +++ + + +++ + + + + -- -- -- - - TEM-30TEM-30 2c ++ +++ +2c ++ +++ + + + - - -- -- + PSE-1 + PSE-1 2e ++ ++ 2e ++ ++ -- ++ ++ ++ ++ ++ ++ -- ++ Induc. ceph-nase ++ Induc. ceph-nase

2f 2f ++ + ?++ + ? + + + ++ ++ + ++ ++ + NMC-A, Sme-1 + NMC-A, Sme-1 C C 1 ++ +/- 1 ++ +/- 저해 저해 +++ + +++ + 저해저해 -- - GNR- GNR 의 의 AmpCAmpC D 2d D 2d ++ + +++ + ++ + +++ + -- -- -- +/- +/- OXA-1OXA-1 - - 4 4 ++ ++ ++ v ++ ++ ++ v v v -- -- - - B. cepaciaB. cepacia

penicillinasepenicillinase Zinc Zinc

B 3 B 3 ++ ++ ++ ++ ++ - ++ - ++ ++ ++ ++ ++ - ++ - S. maltophiliaS. maltophilia L1 L1

Extended-spectrum TEM and SHV Extended-spectrum TEM and SHV β-lactamases-lactamases

Class A, Bush group 2be, plasmid-mediatedClass A, Bush group 2be, plasmid-mediated Europe, 1983Europe, 1983 MutationMutation - Ampicillin, 1-Gen cepha: TEM-1, 2, SHV-1- Ampicillin, 1-Gen cepha: TEM-1, 2, SHV-1 Penicillin, 1-Gen cepha (R)Penicillin, 1-Gen cepha (R) - Extended-spectrum cepha: TEM, SHV derivatives- Extended-spectrum cepha: TEM, SHV derivatives 3-Gen cepha, monobactam (R)3-Gen cepha, monobactam (R) Carbapenem, cephamycin (S)Carbapenem, cephamycin (S) Inhibited by Inhibited by β-lactamase inhibitors-lactamase inhibitors

Extended spectrum β-lactamases

TEM and SHV derivativesTEM and SHV derivatives

Non-TEM and Non-SHVNon-TEM and Non-SHV

- CTX-M family, TOHO-1, TOHO-2- CTX-M family, TOHO-1, TOHO-2 - OXA type- OXA type - Other ESBLs: PER-1, PER-2, VEB-1, etc- Other ESBLs: PER-1, PER-2, VEB-1, etc

Estimated No.: 1995, 36; 2000, 119Estimated No.: 1995, 36; 2000, 119

Bradford PA: CMR 14:933, 2001; Bush K: CID 32:1085, 2001Bradford PA: CMR 14:933, 2001; Bush K: CID 32:1085, 2001

Extended-spectrum TEM and SHV Extended-spectrum TEM and SHV β-lactamases-lactamases

Enzyme Amino acidEnzyme Amino acid 39 104 164 205 237 238 240 26539 104 164 205 237 238 240 265

TEM-1TEM-1 Gln Glu Arg Arg Ala Gly Glu Thr Gln Glu Arg Arg Ala Gly Glu ThrTEM-2TEM-2 Lys Lys TEM-13TEM-13 Lys Lys Met Met

TEM-3 Lys LysTEM-3 Lys Lys Ser Ser TEM-4TEM-4 Lys Lys Ser Ser Met MetTEM-5TEM-5 Ser Ser Thr Thr Lys Lys ::SHV-1SHV-1 Gln Asp Arg Arg Ala Gly Glu Leu Gln Asp Arg Arg Ala Gly Glu LeuSHV-2 SHV-2 Ser SerSHV-3SHV-3 Leu Leu Ser Ser ::

TEM-type ESBLs

Parent enzymeParent enzyme: TEM-1, 2: TEM-1, 2 Isoelectric pointIsoelectric point: 5.4-6.5: 5.4-6.5 TEM-type enzymesTEM-type enzymes: > 90, ESBL, IRT, BS: > 90, ESBL, IRT, BS TEM-type ESBLsTEM-type ESBLs

- - E. coli, K. pneumoniaeE. coli, K. pneumoniae: common: common

- Other gram-negative bacilli- Other gram-negative bacilli

EnterobacteriaceaeEnterobacteriaceae - EAE, MMO, PMI, SAL - EAE, MMO, PMI, SAL

Pseudomonas aeruginosaPseudomonas aeruginosa - TEM-42 - TEM-42

Capnocytophaga ochraceaCapnocytophaga ochracea - TEM-17 - TEM-17

SHV-type ESBLs Parent enzymeParent enzyme: SHV-1; : SHV-1; Isoelectric pointIsoelectric point: 7.0-8.2: 7.0-8.2 SHV-type enzymesSHV-type enzymes: > 25, ESBL, IR, BS: > 25, ESBL, IR, BS SHV-type ESBLsSHV-type ESBLs K. pneumoniae K. pneumoniae >> C. diversus, E. coli, C. diversus, E. coli, P. aeruginosaP. aeruginosa

pI Enzymes TypepI Enzymes Type

7.0 3, 14 ESBL7.0 3, 14 ESBL

7.5-7.8 1, 11 BS7.5-7.8 1, 11 BS

2, 2a, 4, 6, 7, 8, 13, 18-22, 24 ESBL2, 2a, 4, 6, 7, 8, 13, 18-22, 24 ESBL

8.2 5, 9, 12 ESBL8.2 5, 9, 12 ESBL

10 IR10 IR

CTX-M-type ESBLs

Preferentially hydrolyzePreferentially hydrolyze cefotaxime cefotaxime Inhibited better by Inhibited better by TZBTZB than by SUB and CA than by SUB and CA Salmonella enterica Salmonella enterica serovar Typhimuriumserovar Typhimurium, E. coli, E. coli > other spp. of > other spp. of EnterobacteriaceaeEnterobacteriaceae

Enzymes pI Country Bacterial spp.Enzymes pI Country Bacterial spp. CTX-M-1 8.9 Germany, Italy CTX-M-1 8.9 Germany, Italy E. coliE. coli CTX-M-2 7.9 Argentina CTX-M-2 7.9 Argentina S. entericaS. enterica : : : : : : : : CTX-M-10 8.1 Spain CTX-M-10 8.1 Spain E. coliE. coli

Toho-1, 2 7.8, 7.7 Japan Toho-1, 2 7.8, 7.7 Japan E. coliE. coli

CTX-M-type ESBLs

Phylogenetic studyPhylogenetic study:: 4 major groups 4 major groups

1) CTX-M-1 related: CTX-M-1, 3, 10, 11, 12, 221) CTX-M-1 related: CTX-M-1, 3, 10, 11, 12, 22

2) CTX-M-2 related: CTX-M-2, 4, 5, 6, 7, 20, Toho-12) CTX-M-2 related: CTX-M-2, 4, 5, 6, 7, 20, Toho-1

3) Toho-2 related: Toho-2, 3) Toho-2 related: Toho-2,

CTX-M-9,13, 14, 15, 16, 18, 19, 21CTX-M-9,13, 14, 15, 16, 18, 19, 21

4) CTX-M-8 4) CTX-M-8

OXA-type ESBLs

Molecular Molecular class Dclass D, functional , functional group 2dgroup 2d Hydrolytic activity against Hydrolytic activity against oxacillin & cloxacilllinoxacillin & cloxacilllin Poorly inhibited by CAPoorly inhibited by CA Mainly Mainly Pseudomonas aeruginosaPseudomonas aeruginosa OXA-type ESBLsOXA-type ESBLs

- OXA-10:- OXA-10: OXA-11, 14, 16, 17 (pI 6.1-6.4) OXA-11, 14, 16, 17 (pI 6.1-6.4)

OXA-13, 19, 28 (pI 7.6-8.0) OXA-13, 19, 28 (pI 7.6-8.0)

- OXA-2: - OXA-2: OXA-15 (pI 8.7, 8.9)OXA-15 (pI 8.7, 8.9)

- OXA-9?: - OXA-9?: OXA-18 (pI 5.5)OXA-18 (pI 5.5)

Other novel, unrelated ESBLs

Enzymes pI Substrate Country Bacterial spp.Enzymes pI Substrate Country Bacterial spp.

PER-1PER-1 5.4 5.4 CAZ CAZ France France P. aeruginosaP. aeruginosa PER-2 PER-2 5.4 5.4 CAZ Argentina CAZ Argentina S.S. Typhimurium Typhimurium VEB-1VEB-1 5.35 CAZ, ATM Vietnam 5.35 CAZ, ATM Vietnam E. coliE. coli CME-1CME-1 >9.0 >9.0 CAZ CAZ C. meninosepC. meninosep.. TLA-1 TLA-1 9.0 CAZ, CTX, ATM Mexico 9.0 CAZ, CTX, ATM Mexico E. coliE. coli SFO-1 SFO-1 7.3 CTX Japan 7.3 CTX Japan E. cloacaeE. cloacae GES-1 GES-1 5.8 CAZ Guiana 5.8 CAZ Guiana K. pneumoniae K. pneumoniae

Bradford PA: CMR 14, 2001Bradford PA: CMR 14, 2001

Treatment for infections caused by ESBL-producersTreatment for infections caused by ESBL-producers

MICMIC 101044 10 1066 Clinical usefulness Clinical usefulness

3 gen cepha. Usu. high High None 3 gen cepha. Usu. high High None 4 gen cepha. Usu. low 4 gen cepha. Usu. low High Low, high dosage High Low, high dosage w/ aminoglycoside w/ aminoglycoside -lactam--lactam- -lactamase inh. High or low High Clin. data, limited-lactamase inh. High or low High Clin. data, limited Cephamycin Low Low Clin. data, limited Cephamycin Low Low Clin. data, limited attractive, 2nd-lineattractive, 2nd-line Carbapenem Carbapenem Low Low 1st-lineLow Low 1st-line

Paterson (CMI, 2000)Paterson (CMI, 2000)

Prevalence of ESBLs

Varies depending on country or institution Varies depending on country or institution USA: 3% (0-25%)USA: 3% (0-25%) Netherlands (1999): <1% of Netherlands (1999): <1% of E. coliE. coli and and K. pneumoniae K. pneumoniae strainsstrains France (1998): 40% of France (1998): 40% of K. pneumoniae, K. pneumoniae, CAZ (R) CAZ (R) Japan (2000):Japan (2000): <0.1%<0.1% of of E. coli E. coli 0.3%0.3% of of K. pneumoniaeK. pneumoniae Taiwan (2000): 8.5% of Taiwan (2000): 8.5% of K. pneumoniaeK. pneumoniae

Bradford PA (2001)Bradford PA (2001)

Cefotaxime susceptibility of E. coli(Severance Hospital)

9998

95 94 92 9288 88 88

80

7577

7578

9085

73

0

20

40

60

80

100

'86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02

Cefotaxime susceptibility of K. pneumoniae(Severance Hospital)

94

86

7875

7267

7369

55

46 46

54 5558

67

58 57

0

20

40

60

80

100

'86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02

Prevalence of ESBL-producing E. coli and K. pneumoniae in Korea (1999)

19.6

10

41.3

3.5

0

5

10

15

20

25

30

35

40

45%

E. coli K. pneumoniae

ESBL types

Germany: SHV-2, SHV-5Germany: SHV-2, SHV-5 France: TEM-3, SHV-3, SHV-4France: TEM-3, SHV-3, SHV-4 U.S.A.: TEM-10, TEM-12, TEM-26U.S.A.: TEM-10, TEM-12, TEM-26 Japan: TOHO-1, TOHO-2Japan: TOHO-1, TOHO-2 Korea: TEM-52, SHV-12, SHV-2aKorea: TEM-52, SHV-12, SHV-2a SHV-2, 5: widespread internationallySHV-2, 5: widespread internationally China, Denmark, France, Spain, South AfricaChina, Denmark, France, Spain, South Africa Switzerland, Tunisia, UKSwitzerland, Tunisia, UK

Nordmann P (1998); Bradford PA (2001); Pai (1997)Nordmann P (1998); Bradford PA (2001); Pai (1997)

Evolution of TEM-type ESBLs in Korea

Blood isolates of ESBL-producing Blood isolates of ESBL-producing E. coliE. coli and and K. pneumoniae K. pneumoniae in 1994-1999in 1994-1999 TEM-type ESBLsTEM-type ESBLs: : E. coli E. coli (12),(12), K. pneumoniae K. pneumoniae (18)(18)

amino acid at: amino acid at:

TEM No 104 182 196 238TEM No 104 182 196 238 1 Glu (GAG) Met (ATG) Gly (GGC) Gly (GGT) 1 Glu (GAG) Met (ATG) Gly (GGC) Gly (GGT) 15 2 Lys (AAG) Ser (AGT)15 2 Lys (AAG) Ser (AGT) 52 25 Lys (AAG) Thr (ACG) Ser (AGT)52 25 Lys (AAG) Thr (ACG) Ser (AGT) 88 3 Lys (AAG) Thr (ACG) Asp (GAC) Ser (AGT)88 3 Lys (AAG) Thr (ACG) Asp (GAC) Ser (AGT)

Pai et al (AAC, 2001)Pai et al (AAC, 2001)

Evolution of TEM-type ESBLs in Korea

Nationwide study (1999-2000)Nationwide study (1999-2000) ESBL-producing ESBL-producing E. coliE. coli (202) and (202) and

K. pneumoniae K. pneumoniae (329)(329) Novel TEM type ESBLs: TEM-106, 107Novel TEM type ESBLs: TEM-106, 107

TEM-15 TEM-88TEM-15 TEM-88

TEM-1 TEM-20 TEM-52 TEM-107 TEM-1 TEM-20 TEM-52 TEM-107

TEM-106 TEM-43TEM-106 TEM-43

TEM-52 ESBL-producing non-typhoidal Salmonella isolates in Korea

S. enterica S. enterica AgeAge

serovar (Year) Present illnessserovar (Year) Present illness

Saintpaul 0.4 Loose stoolSaintpaul 0.4 Loose stool

Stanley Stanley 1 Diarrhea1 Diarrhea

Agona 1 Diarrhea Agona 1 Diarrhea

Enteritidis 25 Enteritidis 25 Diarrhea 1 mon. after adm.Diarrhea 1 mon. after adm.

Enteritidis 51 Enteritidis 51 Diarrhea 1 mon. after adm.Diarrhea 1 mon. after adm.

CTX-M-type ESBLs in Korea

Pai et al (JCM, 2001):Pai et al (JCM, 2001): CTX-M-14 CTX-M-14 vs. CTX-M-9 (1 aa), Toho-2 (1 aa)vs. CTX-M-9 (1 aa), Toho-2 (1 aa) E. coliE. coli 1, 1, K. pneumoniaeK. pneumoniae 2 in 1995-96 2 in 1995-96 Shigella sonneiShigella sonnei 1 in 2000 1 in 2000

Nationwide study (1999-2000)Nationwide study (1999-2000) ESBL-producingESBL-producing E. coliE. coli and and K. pneumoniaeK. pneumoniae CTX-M-type: 27 (18.8%) of 144CTX-M-type: 27 (18.8%) of 144 CTX-M-1 related (15): CTX-M-12 CTX-M-1 related (15): CTX-M-12 Toho-2 related (12): CTX-M-14 Toho-2 related (12): CTX-M-14

PER-1 ESBL

Reported only in European countriesReported only in European countries

- First report (1991): - First report (1991): P. aeruginosa,P. aeruginosa, France France

- - AcinetobacterAcinetobacter spp., spp., P. aeruginosa, P. aeruginosa, Turkey, ItalyTurkey, Italy

PER-2PER-2: : Salmonella typhimuriumSalmonella typhimurium in Argentina in Argentina

Yong et al (Korea, 2002)Yong et al (Korea, 2002)

- PER-1: - PER-1: AcinetobacterAcinetobacter spp., 53 of 97 spp., 53 of 97

P. aeruginosaP. aeruginosa: none of 282 : none of 282

Amp C type β-lactamases

Class C, chromosomalClass C, chromosomal Ubiquitous in GNB, species-specificUbiquitous in GNB, species-specific

- Uninducible : - Uninducible : E. coliE. coli etc, insignificant amount etc, insignificant amount

- Inducible : - Inducible : C. freundii, E. cloacae, S. marcescensC. freundii, E. cloacae, S. marcescens

Absence ofAbsence of β-lactam: trace amount - AMP, CEP (r)

Present of β-lactam

Induction: 100-fold - FOX (R), CTX (S)

Mutation: permanent hyperproduction, derepression

FOX, CTX (R), 4-Gen Cepha (S)

Plasmid-mediated class C β-lactamases

CephamycinCephamycin - Second-line therapy for infections caused by ESBL-producers - Resistance is mainly due to chromosomal -lactamases - Chromosomal ampC gene: plasmid

Plasmid-mediated class C Plasmid-mediated class C -lactamases - CMY-1 - CMY-1 K. pneumoniae Korea 1989 Korea 1989 - MIR-1MIR-1 K. pneumoniae U.S.A. 1990 U.S.A. 1990 - Subsequently, over 20 types have been discovered - CMY, FOX, MOX, LAT, ACT, ACC; MIR-1, DHA, BIL

Philippon (AAC, 2002)

Cefoxitin-resistant E. coli and K. pneumoniae

KONSAR survey (1997 vs. 2000)KONSAR survey (1997 vs. 2000)

- Cefoxitin resistance- Cefoxitin resistance

E. coliE. coli 12% vs. 9%, 12% vs. 9%, K. pneumoniaeK. pneumoniae 16% vs.16% 16% vs.16%

Yong et al (1999): Yong et al (1999): CMY-1 CMY-1 -lactamase-lactamase

FOX (I,R) CMY-1 DHA-1FOX (I,R) CMY-1 DHA-1

E. coliE. coli (97) 33 24 (24.7%) 0 (97) 33 24 (24.7%) 0

K. pneumoniaeK. pneumoniae (48) 10 5 (10.4%) 2 (4.2%) (48) 10 5 (10.4%) 2 (4.2%)

DHA-1, inducible AmpC -lactamase

In 2002In 2002, 3109 clinical isolates in a Korean hospital , 3109 clinical isolates in a Korean hospital

Antagonistic zone between cefoxitin and Antagonistic zone between cefoxitin and

aztreonam disksaztreonam disks

- - E. coliE. coli: 8 (0.4%) of 1937: 8 (0.4%) of 1937

- - K. pneumoniaeK. pneumoniae: 55 (6.1%) of 899: 55 (6.1%) of 899

- - K. oxytocaK. oxytoca: 8 (5.4%) of 149: 8 (5.4%) of 149

- - P. mirabilisP. mirabilis: 1 (0.8%) of 124: 1 (0.8%) of 124

blablaDHA-1DHA-1 alleles were detected in all of them alleles were detected in all of them In 2003In 2003, DHA-1, , DHA-1, 29 (10.5%) of 275 29 (10.5%) of 275 K. pneumoniaeK. pneumoniae

Imipenem resistance of P. aeruginosa and Acinetobacter spp. at Severance hospital

0

5

10

15

20

25

30

35

1994 1995 1996 1997 1998 1999 2000 2001 2002

A, baumanniiP. aeruginosa

% r

es

ista

nce

Antimicrobial resistance in P. aeruginosa

LargeLarge Seoul Non-Seoul Mean An Seoul Non-Seoul Mean Antimicrobials timicrobials >1000>1000 <1000 <1000 <1000 <1000

(5,414)(5,414) (4,050) (4,050) (7,740) (17,204) (7,740) (17,204)

PiperacillinPiperacillin 38% 37% 38% 37% 42% 42% 39% 39% Pip/tazobactam 25 Pip/tazobactam 25 24 24 36 36 2828CeftazidimeCeftazidime 18 18 19 19 19 19 1919AztreonamAztreonam 22 22 18 18 18 18 1919ImipenemImipenem 21 21 20 20 19 19 2020AmikacinAmikacin 26 26 35 35 36 36 3232GentamicinGentamicin 41 41 44 44 47 47 4444FluoroquinoloneFluoroquinolone 39 39 44 44 42 42 4242

(KONSAR 2000)(KONSAR 2000)

Antimicrobial resistance in P. aeruginosa

Asia-Asia- Europe Latin North Antimicro Europe Latin North Antimicrobials Pacificbials Pacific America America America America

(894)(894) (1,702) (1,702) (1,103) (3,270) (1,103) (3,270)

PiperacillinPiperacillin 14 (39) 20 14 (39) 20 32 32 13 13 Pip/tazobactam 11 (28) 14Pip/tazobactam 11 (28) 14 24 24 1010CeftazidimeCeftazidime 14 (19) 15 14 (19) 15 28 28 1414AztreonamAztreonam 19 (19) 15 19 (19) 15 33 33 2020ImipenemImipenem 9 (20) 12 9 (20) 12 18 18 9 9AmikacinAmikacin 5 (32) 14 5 (32) 14 27 27 5 5GentamicinGentamicin 16 (44) 28 16 (44) 28 38 38 1616FluoroquinoloneFluoroquinolone 12 (42) 25 12 (42) 25 33 33 1616

SENTRY 1997-2000; ( ), KONSAR, 2000SENTRY 1997-2000; ( ), KONSAR, 2000

Carbapenem resistance mechanism

-lactamase-lactamase

- Serine - Serine -lactamase: Bush group 1, 2f, 2d-lactamase: Bush group 1, 2f, 2d

- Metallo-- Metallo--lactamase: IMP, VIM, SPM-1-lactamase: IMP, VIM, SPM-1

Outer membrane impermeability or effluxOuter membrane impermeability or efflux

- OprD porin, MexAB-OprM overexpression - OprD porin, MexAB-OprM overexpression

Penicillin binding proteinPenicillin binding protein

Metallo--lactamase

IMP typeIMP type - IMP-1: Japan (1990s): - IMP-1: Japan (1990s): P. aeruginosa, S. marcesens, P. aeruginosa, S. marcesens,

A. baumannii, K. pneumoniaeA. baumannii, K. pneumoniae

Korea (2000): Korea (2000): AcinetobacterAcinetobacter genomospecies 3 genomospecies 3

A. baumanniiA. baumannii

- IMP-2: Italy (2000), - IMP-2: Italy (2000), A. baumanniiA. baumannii

- IMP-3: Japan (2000), - IMP-3: Japan (2000), S. flexneriS. flexneri

- IMP-4: Hong Kong, China (2001), - IMP-4: Hong Kong, China (2001),

Acinetobacter, CitrobacterAcinetobacter, Citrobacter

- IMP-5, 6, 7,….12: gram-negative rods in several countries- IMP-5, 6, 7,….12: gram-negative rods in several countries

Metallo--lactamase

VIM typeVIM type

- VIM-1: Italy (1999), - VIM-1: Italy (1999), P. aeruginosa; P. aeruginosa; (2001),(2001), Achromobacter xylosoxydans Achromobacter xylosoxydans - VIM-2: France (2001), - VIM-2: France (2001), P. aeruginosaP. aeruginosa Greece (2000), Greece (2000), P. aeruginosaP. aeruginosa - VIM-3: Taiwan (2001), - VIM-3: Taiwan (2001), P. aeruginosaP. aeruginosa - VIM-4: Greece (2002), - VIM-4: Greece (2002), P. aeruginosaP. aeruginosa - Korea- Korea VIM-2: VIM-2: P. aeruginosa, P. putida, A. baumanniiP. aeruginosa, P. putida, A. baumannii S. marcescens,S. marcescens, AcinetobacterAcinetobacter genomospecies 3 genomospecies 3 E. cloacae, Achromobacter xylosoxydansE. cloacae, Achromobacter xylosoxydans

P. aeruginosaP. aeruginosa P. putidaP. putida Acinetobacter Acinetobacter spp.spp.

Year No. Year No. blablaVIM VIM + No. + No. blablaVIM VIM + No. + No. blablaVIM VIM + + blablaIMP IMP ++

1994 1 0 NT NT 1994 1 0 NT NT 1995 20 5 NT NT1995 20 5 NT NT 1996-7 138 15 1 1 1996-7 138 15 1 1 NT NT 1998-9 324 23 8 8 28 13 11998-9 324 23 8 8 28 13 1 2000-1 325 46 6 6 42 6 282000-1 325 46 6 6 42 6 28 2002 454 38 15 15 195 34 392002 454 38 15 15 195 34 39 Total (%) 1262 127 (10) Total (%) 1262 127 (10) 30 30 265 53 (20)30 30 265 53 (20) 68 (26)68 (26)

Lee et al. (AAC, 2002; JAC, 2002)Lee et al. (AAC, 2002; JAC, 2002)

Prevalence of Prevalence of blablaVIM-2 or VIM-2 or blablaIMP-1 IMP-1 -positive strains -positive strains

among imipenem-resistant isolatesamong imipenem-resistant isolates

Prevalence of MBL-producing gram-negative bacilli in Korean Hospitals

Organism No. (%) hospital No. (%) of isolatesOrganism No. (%) hospital No. (%) of isolates Tested MBL+ Tested VIM-2+ IMP-1+ TotalTested MBL+ Tested VIM-2+ IMP-1+ Total

Pseudo-Pseudo- monasmonas spp. 21 11 (52.4) 387 44 0 44 (11.4) spp. 21 11 (52.4) 387 44 0 44 (11.4)Acineto-Acineto- bacter bacter spp. spp. 24 10 (41.7) 267 27 11 38 (14.2) 24 10 (41.7) 267 27 11 38 (14.2)

Total Total 28 17 (60.7) 654 71 11 82 (12.5) 28 17 (60.7) 654 71 11 82 (12.5)

Lee et al (ICAAC, 2002)Lee et al (ICAAC, 2002)

A. baumannii YMC 98-7-R363 (3 kb; AF324464)

IntI1 blaVIM-2 aacA7 aadA1 qacE1

Acinetobacter genomospecies 3 YMC 99-11-U160 (5 kb; AF369871)

IntI1 blaVIM-2 aacA4 aadA1 “orfII” “orfIII” qacE1

P. aeruginosa YMC 95-1-704 (5.6 kb; AY029772)

IntI1 aacA4 blaVIM-2 “orfI” aadA1 “orfII” “orfIII” qacE1

S. marcescens YMC 00-4-1591 (4 kb; AY030343)

IntI1 qacblaVIM-2 “orfII” “orfIII” qacE1

P. putida YMC 97-8-322 (3 kb; AF327064)

IntI1 blaVIM-2 aacA7 aadA1 qacE1

Structure of integrons found

Conclusions

ESBL- or plasmid-mediated AmpC-produciESBL- or plasmid-mediated AmpC-producing gram-negative bacilling gram-negative bacilli

- More prevalent in Korea- More prevalent in Korea

- High levels of antimicrobial selective pressure- High levels of antimicrobial selective pressure

- Nosocomial spread- Nosocomial spread Carbapenem-resistant Carbapenem-resistant P. aeruginosa P. aeruginosa andand A A

cinetobacter cinetobacter spp.spp.

- New threats in Korea- New threats in Korea