current status of -lactamases-producing gram-negative bacilli isolated in korea kyungwon lee, md,...
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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