ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
1The screen versions of these slides have full details of copyright and acknowledgements
β-lactamasesClinical Impact and Epidemiology
1
Professor Sebastian AmyesUniversity of Edinburgh
EdinburghScotland
β-lactamases in Gram-negative bacteria
>750 β-lactamases reported
…of clinical importance
Cephalosporins
2
Transferable class C β-lactamases Extended-spectrum β-lactamases (ESBLs)
CarbapenemsTransferable class B carbapenamsesTransferable class D carbapenamses
β-lactamase action
1. HO
H NH
N
SN
OO
2
N
S
H
3
Class & active site
Associatedsubstrate
ASerine
BMetal ion
CSerine
DSerine
Penicillin Carbapenem Cephalosporin Penicillin
COO-
β-lactamase
COO-H
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
2The screen versions of these slides have full details of copyright and acknowledgements
1. InductionInterference with repressor protein
2 De-repression
Enterobacter sppChromosomal β-lactamase expression
Chromosome
4
2. De repressionMutation in R gene
P Rβ-lactamase
Repressor
Emergence of the BIL-1 β-lactamaseMobilisation of chromosomal class C genes onto plasmids
ChromosomePlasmid
ResistantEnterobacteriaceae
ChromosomePlasmid
Klebsiella spp or Escherichia coli
5
P Rβ-lactamase
Dendrogram for AmpC β-lactamasesplasmid and chromsomal
E. coli K12
Ent. cloacaeACT-1
MIR-1
Ent. aerogenes
Citrobacter sppA. baumannii RYC
P. immobilis A5
M. morganii Y. enterocolitica IP97
DHA-2DHA-1 GN7471
1113
BIL-1 CMY-4 CMY-7CMY-3 CMY-6 LAT-4LAT-3 CMY-5 LAT-1
GN346
P99
6Data from: Philippon et al., (2002). Antimicrob. Agents Chemother. 46:1
Aeromonas spp
P. aeurginosa PAO1
O. anthropiP. stuartii VDG96
H. alvei
L. lactamgenus YK90
SLH62ACC-1
SLS73 SST-1 SRT-182116
2171
MOX-1MOX-2
CMY-1CMY-8CMY-9
CepS - A. sobria
CepH - A. hydrophila
AER14 - A. sobria
FOX-3FOX-4FOX-2FOX-5FOX-1
S. marcescens
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
3The screen versions of these slides have full details of copyright and acknowledgements
Transferable AmpC β-lactamasesCMY ACC ACT FOX MIR MOX Others CMY-1 ACC-1 ACT-1 FOX-1 MIR-1 MOX-1 CFE-1 CMY-2 ACC-2 ACT-2 FOX-2 MIR-2 MOX-2 CMY-3 ACC-3 ACT-3 FOX-3 MIR-3 MOX-3 DHA-1 CMY-4 ACC-4 ACT-4 FOX-4 MIR-4 MOX-4 DHA-2 CMY-5 ACT-5 FOX-5 MIR-5 MOX-5 CMY-6 ACT-6 FOX-6 MOX-6 LAT-1CMY-7 ACT-7 FOX-7 MOX-7CMY-8 CMY-9 CMY-10 CMY-11 CMY-12 CMY 13
7Total ~ 78
CMY-13 CMY-14 CMY-15 CMY-16 CMY-17 CMY-18 CMY-19 CMY-20 CMY-21 CMY-22
¦¦¦
CMY-44
~44 4 ~7 7 5 7 4
What are extended-spectrum β-lactamases?
“Extended-Spectrum β-lactamases (ESBLs) are enzymes that can be produced by bacteria making them resistant to cephalosporins”
8
making them resistant to cephalosporins
Health Protection Agency
http://www.hpa.org.uk/infections/topics_az/esbl/default.htm
OXA 1
TEM-2
SHV-1
Dominance of the TEM-1 β-lactamase
Accounts for 75% of all plasmid-encoded enzymes
9
OXA-1
PSE-1CARB-6
TEM-1OXA-2
SAR-2
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
4The screen versions of these slides have full details of copyright and acknowledgements
What happened in Liverpool in 1982?
TEM-1
Extensive ceftazidime use
10
TEM-1 TEM-1
Gene duplication –small increase in MIC
TEM-1 TEM-12
Mutation at codon 164 –MIC increases to 4mg/L
ß-3ß-4
α-10α-2
α-9
Binding of amoxycillin
Active site of the TEM-1 β-lactamase
11
α-7
α-3
α-5
α-4
Ω-loop
Ser-70
Asp-179
Arg-164
Glu-171
ß-3ß-4
α-10α-2
α-9
Active site of the TEM-1 β-lactamaseFailure to bind cephalosporins
12
α-7
α-3
α-5
α-4 Ser-70
Arg-164
Asp-179
Glu-171 Ω-loop
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
5The screen versions of these slides have full details of copyright and acknowledgements
ß-3ß-4
α-10α -2
α-9
Serine for arginine substitution at 164 (TEM-12)
13
α-7
α-3
α-5
α-4 Ser-70
Ser-164
Asp-179
Glu-171
Amino acid substitutions in TEM ESBLs
Leu21
Gln39
Ala42
Leu51
Gly92
Glu104
His153
Arg164
Met182
Gly218
Ala237
Gly238
Glu240
Arg244
Thr265
Ser268
PheTEM-4TEM-9TEM-25TEM-48TEM-49TEM-53TEM-63
ValTEM-42
AspTEM-57TEM-66
ArgTEM-21TEM-56
ThrTEM-20TEM-43TEM-52TEM-63TEM-72
LysTEM-5TEM-10TEM-24TEM-27TEM-28 TEM-42TEM-46 TEM-47TEM-48
TEM-49TEM-61TEM-68TEM-72
SerTEM-50Thr
TEM-5TEM-24
GlyTEM-22
MetTEM-4TEM-9 TEM-13 TEM-25 TEM-27 TEM-42 TEM-47 TEM-48 TEM-49 TEM-68
TEM-1
14
LysTEM-3TEM-4TEM-6TEM-8TEM-9TEM-14TEM-15TEM-16TEM-17TEM-18TEM-21
TEM-22TEM-24TEM-26TEM-43TEM-46TEM-50TEM-52TEM-56TEM-60TEM-63TEM-66
LysTEM-2TEM-3TEM-7TEM-8TEM-11TEM-13TEM-16TEM-18TEM-21TEM-22TEM-42TEM-46TEM-56TEM-60TEM-61TEM-66TEM-72
ProTEM-60
GluTEM-55
SerTEM-5TEM-7TEM-8TEM-9TEM-10TEM-12TEM-22TEM-25TEM-26TEM-46TEM-53TEM-60 TEM-63
HisTEM-6TEM-11TEM-16 TEM-27 TEM-28 TEM-29 TEM-43 TEM-61
SerTEM-3TEM-4TEM-8TEM-14TEM-15TEM-18TEM-19TEM-20TEM-21TEM-22TEM-25TEM-42TEM-47TEM-48TEM-49TEM-52TEM-66TEM-68TEM-72
LeuTEM-54
SerTEM-58
GlyTEM-49
Data from: Bradford (2001). Clin. Microbiol. Rev. 14:933
Sequential mutation of ESBLsby cephalosporins
3rd generation cephalosporins
R164S E240K A237T
15
TEM-12 TEM-10 TEM-5TEM-1
MIC (mg/l)
Ceftazidime <0.1 4 64 64
Cefotaxime <0.1 <0.1 0.5 16
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
6The screen versions of these slides have full details of copyright and acknowledgements
Porin
Outside cell
Outer membrane
Interaction of cephalosporins with β-lactamases in Gram-negative bacteria
Ceftazidime
Porin
Ceftriaxone or Cefotaxime
16
Penicillin binding proteinsβ-lactamase
Periplasmicspace
Cytoplasm β-lactamase Penicillin binding proteins
Progression of TEM-1 to TEM-5 β-lactamaseEffect on hydrolysis rate and inhibitor sensitivity
0.01
0.1
1
10
100
s)
CeftazidimeCefotaximeAmpicillinClavulanic acid
17Data from Du Bois, Marriott & Amyes (1995). J. Antimicrob. Chemother. 35: 7
TEM-1 TEM-12 TEM-10 TEM-51
10
100
10000.001
1000
100
10
1
Kca
t(1
/s
Cla
vula
nic
acid
I 50(n
M)
ß-3ß-4
α-10α-2
α-9
Substitutions of the TEM-1 β-lactamase(ESBL formation)
18α-7
α-3
α-5
α-4
Ω-loop
Ser-70
Arg-164
Ala-237
Gly-238
Glu-240Glu-104
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
7The screen versions of these slides have full details of copyright and acknowledgements
Lys SerLys Pro GluSer His Leu Gly
Amino acid substitutions in TEM ESBLs
Leu21
Gln39
Ala42
Leu51
Gly92
Glu104
His153
Arg164
Met182
Gly218
Ala237
Gly238
Glu240
Arg244
Thr265
Ser268
PheTEM-4TEM-9TEM-25TEM-48TEM-49TEM-53TEM-63
ValTEM-42
AspTEM-57TEM-66
ArgTEM-21TEM-56
ThrTEM-20TEM-43TEM-52TEM-63TEM-72
LysTEM-5TEM-10TEM-24TEM-27TEM-28 TEM-42TEM-46 TEM-47TEM-48
TEM-49TEM-61TEM-68TEM-72
SerTEM-50Thr
TEM-5TEM-24
GlyTEM-22
MetTEM-4TEM-9 TEM-13 TEM-25 TEM-27 TEM-42 TEM-47 TEM-48 TEM-49 TEM-68
TEM-1
19
LysTEM-3TEM-4TEM-6TEM-8TEM-9TEM-14TEM-15TEM-16TEM-17TEM-18TEM-21
TEM-22TEM-24TEM-26TEM-43TEM-46TEM-50TEM-52TEM-56TEM-60TEM-63TEM-66
SerTEM-3TEM-4TEM-8TEM-14TEM-15TEM-18TEM-19TEM-20TEM-21TEM-22TEM-25TEM-42TEM-47TEM-48TEM-49TEM-52TEM-66TEM-68TEM-72
LysTEM-2TEM-3TEM-7TEM-8TEM-11TEM-13TEM-16TEM-18TEM-21TEM-22TEM-42TEM-46TEM-56TEM-60TEM-61TEM-66TEM-72
ProTEM-60
GluTEM-55
SerTEM-5TEM-7TEM-8TEM-9TEM-10TEM-12TEM-22TEM-25TEM-26TEM-46TEM-53TEM-60 TEM-63
HisTEM-6TEM-11TEM-16 TEM-27 TEM-28 TEM-29 TEM-43 TEM-61
LeuTEM-54
SerTEM-58
GlyTEM-49
Data from: Bradford (2001). Clin. Microbiol. Rev. 14:933
ß-3ß-4
α-10α-2
α-9
Substitution of the SHV-1 β-lactamase
Leu-205
20
α-7
α-3
α-5
α-4 Ser-70
Arg-164
Gly-238Glu-240
Interaction of the extended-spectrumSHV β-lactamases
SHV-2
SHV-1
G238S
SHV ?
21
SHV-4
SHV-5
R205L
SHV-3
R205L
E240K
E240K
SHV-?
SHV-?
SHV-7
I8F
I8FR43S
R43S
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
8The screen versions of these slides have full details of copyright and acknowledgements
Group A
Dendrogram of PFGE patterns in Klebsiella pneumoniae
22
Group BGroup C
Group D
Group E
ESBLs in Klebsiella pneumoniaeRoyal Infirmary Edinburgh 1999 - 2000
Group A 25 SHV-2 (21)SHV-2 + SHV-5 (4)
TEM-1 70 + 141
No ESBLs Other blas Plasmids (kb)
23
Group BGroup C
Group D
Group E
12
4
10
5
SHV-2
SHV-2
SHV-2
SHV-2
-
TEM-1
-
TEM-1
141
70 + 141
141
70 + 141
Extended-spectrum β-lactamasesTEM SHV CTX OXA
TEM-4 SHV-2 CTX-M-1 OXA-10 TEM-5 SHV-2a CTX-M-2 OXA-11 TEM-6 SHV-3 CTX-M-3 OXA-13 TEM-9 SHV-4 CTX-M-4 OXA-14 TEM-10 SHV-5 CTX-M-5 OXA-15 TEM-12 SHV-6 CTX-M-6 OXA-16 TEM-14 SHV-7 CTX-M-7 OXA-17 TEM-15 SHV-8 CTX-M-8 OXA-19 TEM-17 SHV-9 CTX-M-9 OXA-28 TEM-19 SHV-12 CTX-M-10 OXA-32 TEM-20 SHV-13 Toho-1 OXA-35 TEM-24 SHV-14 ¦ TEM-25 SHV-18 ¦ TEM-26 SHV-19 ¦ TEM-27 SHV-20 CTX-M-89 TEM-28 SHV-21 TEM 29 SHV 22
Original enzyme
24
TEM-29 SHV-22 TEM-43 SHV-24 TEM-47 ¦ TEM-48 ¦ TEM-49 ¦ TEM-50 SHV-127
¦ ¦ ¦
TEM-174
~160 ~127 ~89 11
Total ~ 360SlowFast FastSlowType of cephalosporin
Ceftazidime CeftazidimeCefotaxime/Ceftriaxone
Cefotaxime/Ceftriaxone
Example
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
9The screen versions of these slides have full details of copyright and acknowledgements
Emergence of CTX-M β-lactamases in Ramón y Cajal Hospital, Madrid
30
40
50
CTX-M-32CTX-M-15CTX-M-1/3of
Clo
nes 1st CTX-M-14, CTX-M-1/3
CTX-M-15
1st CTX-M-32
25
0
10
20
1988
198919
90199
1199
21993
1994199
51996
1997
199819
9920
00200
1200
2
CTX-M-14CTX-M-9CTX-M-10SHVTEM
Data from: Canton et al., (2006); Current Op Microbiol. 9: 466
Year
Num
ber
1st CTX-M-91st CTX-M(CTX-M-10)
European spread of CTX-M β-lactamases
CTX-M-2
CTX-M-1, -3, -32
CTX M 9 14 18 19 20 21
CTX-M-1, -3, -32CTX-M-9, -14
CTX-M-1, -3, -10, -15
CTX-M-40
26CTX-M-1, -3, -32
CTX-M-4
CTX-M-15
CTX-M-9, -14, -18, -19, -20, -21
CTX-M-1, -3, -15
CTX-M-2,5
EndemicSporadicNo dataCTX-M-1CTX-M-2CTX-M-8CTX-M-9
Data from: Canton et al., (2006); Current Op Microbiol. 9: 466
CTX-M-1, -10, -15, -32
CTX-M-2
CTX-M-9, -14
Origins of CTX-M β-lactamases
CTX-M-31
CTX-M-6
CTX-M-5Toho-1
CTX-M-20
CTX-M-7CTX-M-4
CTX-M-2 CTX-M-2
CTX-M-27CTX-M-24
CTX M 19
CTX-M-16CTX-M-9
CTX-M-14CTX-M-18
CTX-M-9
27
Toho-2
CTX-M-3
CTX-M-28CTX-M-22
CTX-M-10CTX-M-11
CTX-M-12CTX-M-29
CTX-M-30CTX-M-15CTX-M-33
CTX-M-23CTX-M-1
CTX-M-1
CTX-M-19
CTX-M-13CTX-M-17
CTX-M-21
CTX-M-26CTX-M-25 CTX-M-25
CTX-M-8
CTX-M-8CTX-M-1 CTX-M-2 CTX-M-9 CTX-M-25 CTX-M-8
Year 1989 1986 1996 1994 2000
Country Germany Japan Brazil Spain Canada
Origin K. ascobata K. ascobata K. georgiana K. georgiana
www.lahey.org
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
10The screen versions of these slides have full details of copyright and acknowledgements
ESBL activity
Vitek 2 tests for extended-spectrum β-lactamases
28
1684 3224126321.51.0.75.5 TZ4 1 .
5
.758 6 3 1 .5 .38
.25
.19
.125
TZ
L testESBL
ε-test for extended-spectrum β-lactamases
Why should we measure ESBL activity?
Many ESBLs are a combination of sequential mutations
Early detection of the initial mutations is essential
S d thi d t ti i id i i MIC
29
Second or third mutations may give very rapid rises in MIC
Ceftazidime and cefotaxime breakpoints are set for clinical efficacy and are too high to detect early ESBL mutations
ESBL-producing Klebsiella pneumoniaeAntibiotic time kill
56789
10
ount
(CFU
/ml) Growth controlPiperacillin-tazobactam
Cefepime
30Data from Burgess & Hall (2004); Diagnostic Microbiology and Infectious Disease 49: 41–46
012345
0 4 8 12 16 20 24
Log
Col
ony
co
Time (hours)
Meropenem
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
11The screen versions of these slides have full details of copyright and acknowledgements
Carbapenem resistance emerging in a CTX-M containing K. pneumoniae
Outbreak of ESBL producing Klebsiella pneumoniaein a hospital in Mallorca, Spain in 200551 patients infected with single clone –determined by PFGE
31
ESBL identified as CTX-M-1All but 1 strain resistant to ciprofloxacin, gentamicin, co-trimoxazole and tetracyclineIn 2 patients strains resistant to imipenem, meropenem and ertapenemTwo outer membrane proteins lost, Omp35 and Omp36Treatment unspecified!
Data from: Mena et al., (2006); J Clin Microbiol. 44: 2831
The original transferable carbapenemases
Sme-1
Sme-2
NMC-A
IMI-1
Class AS. marcescens
E. cloacae
UK, USA
France, USA
32
IMP
VIM
Class B
Data from Livermore et al., (2000) Curr. Opin. Microbiol 3: 489
24
23
OXA-23 β-lactamase
MIC = 16mg/L
Imipenem resistance in Acinetobacter baumannii from Scotland
33Paton et al., (1993); Int. J. Antimicrob. Agents. 2: 81Scaife et al., (1995); J. Antimicrob. Chemother. 36:585
MIC 16mg/Lβ-lactamase not induced− pI of β-lactamase is 6.65
Gene located on 40kB plasmid & is transferable to A. juniiDNA sequence shows close similarity with OXA β-lactamasesIst plasmid-mediated class D carbapenemaseStrain is sensitive to sulbactam
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
12The screen versions of these slides have full details of copyright and acknowledgements
Pairwise (OG:100%,UG:0%) (FAST:2,10) Gapcost:3%
100
9590858075706560 EuropeS. AmericaAsia
Dendrogram of OXA β-lactamases in Acinetobacter baumannii
OXA-23
34Brown et al., (2006); J. Antimicrob. Chemother. 57:1-3Rasmussen et al., (2006); J. Antimicrob. Chemother. 57:373-383
EuropeAsiaAfricaS. AmericaN. America
EuropeAsiaS America
OXA-51
EuropeOXA-40
OXA-58
1 OXA-23 MN--KYFTCYVVASLFLSGCTVQHNLIN-ETPSQIVQG--HNQVIHQYFDEKNTSGVLVI 552 OXA-40 MKKFILPIFSISILVSLSACSSIKTKSEDNFHIS-SQQ--HEKAIKSYFDEAQTQGVIII 573 OXA-51 MN--IKTLLLITSAIFISACSPYIVTANPNHSASKSDE--KAEKIKNLFNEVHTTGVLVI 564 OXA-58 MK-LLKILSLVCLSISIGACAEHSMSRAKTSTIPQVNNSIIDQNVQALFNEISADAVFVT 59
1 OXA-23 QTDKKINLYGNALSRANTEYVPASTFKMLNALIGLENQKTDINEIFKWKGEKRSFTAWEK 1152 OXA-40 KEGKNLSTYGNALARANKEYVPASTFKMLNALIGLENHKATTNEIFKWDGKKRTYPMWEK 1173 OXA-51 QQGQTQQSYGNDLARASTEYVPASTFKMLNALIGLEHHKATTTEVFKWDGQKRLFPEWEK 1164 OXA-58 YDGQNIKKYGTHLDRAKTAYIPASTFKIANALIGLENHKATSTEIFKWDGKPRFFKAWDK 119
OXA β-lactamase subgroupsSequence similarities
Subgroup
35
1 OXA-23 DMTLGEAMKLSAVPVYQELARRIGLDLMQKEVKRIGFGNAEIGQQVDNFWLVGPLKVTPI 1752 OXA-40 DMTLGEAMALSAVPVYQELARRTGLELMQKEVKRVNFGNTNIGTQVDNFWLVGPLKITPV 1773 OXA-51 DMTLGDAMKASAIPVYQDLARRIGLELMSKEVKRVGYGNADIGTQVDNFWLVGPLKITPQ 1764 OXA-58 DFTLGEAMQASTVPVYQELARRIGPSLMQSELQRIGYGNMQIGTEVDQFWLKGPLTITPI 179
1 OXA-23 QEVEFVSQLAHTQLPFSEKVQANVKNMLLLEESNGYKIFGKTGWAMDIKPQVGWLTGWVE 2352 OXA-40 QEVNFADDLAHNRLPFKLETQEEVKKMLLIKEVNGSKIYAKSGWGMGVTPQVGWLTGWVE 2373 OXA-51 QEAQFAYKLANKTLPFSPKVQDEVQSMLFIEEKNGNKIYAKSGWGWDVDPQVGWLTGWVV 2364 OXA-58 QEVKFVYDLAQGQLPFKPEVQQQVKEMLYVERRGENRLYAKSGWGMAVDPQVGWYVGFVE 239
1 OXA-23 QPDGKIVAFALNMEMRSEMPASIRNELLMKSLKQLNII--- 2732 OXA-40 QANGKKIPFSLNLEMKEGMSGSIRNEITYKSLENLGII--- 2753 OXA-51 QPQGNIVAFSLNLEMKKGIPSSVRKEITYKSLEQLGIL--- 2744 OXA-58 KADGQVVAFALNMQMKAGDDIALRKQLSLDVLDKLGVFHYL 280
40
50
60
ffici
ency
Carbapenemase efficiency (kcat/Km)related to benzylpenicillin
360
10
20
30
OXA-23 OXA-40 OXA-51 OXA-58Subgroup 1 2 3 4
Perc
enta
ge e
f
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
13The screen versions of these slides have full details of copyright and acknowledgements
Carbapenem-hydrolysing β-lactamasesClass B metallo β-lactamase Class A serine β-lactamase Class D OXA serine β-lactamase
IMP VIM IND GES KPC SME OXA-23-
like OXA-40-
like OXA-51-
like OXA-58-
like IMP-1 VIM-1 IND-1 GES-1 KPC-1 SME-1 OXA-23 OXA-40 OXA-51 OXA-58IMP-2 VIM-2 IND-2 GES-2 KPC-2 SME-2 OXA-27 (OXA-24) OXA-64 OXA-96IMP-3 VIM-3 IND-2a GES-3 KPC-3 SME-3 OXA-49 OXA-25 OXA-65 OXA-97IMP-4 VIM-4 IND-3 GES-4 KPC-4 OXA-102 OXA-26 OXA-66IMP-5 VIM-5 IND-4 GES-5 KPC-5 OXA-103 OXA-72 OXA-67IMP-6 VIM-6 IND-5 GES-6 KPC-6 OXA-105 OXA-68IMP-7 VIM-7 IND-6 GES-7) KPC-7 OXA-133 OXA-69IMP-8 VIM-8 IND-7 GES-8 KPC-8 OXA-134 OXA-70IMP-9 VIM-9 GES-9 KPC-9 OXA-71IMP-10 VIM-10 GES-10 KPC-10 OXA-73IMP-11 VIM-11 GES-11 OXA-74
37
IMP-11 VIM-11 GES-11 OXA-74IMP-12 VIM-12 GES-12 OXA-75 IMP-13 VIM-13 OXA-76IMP-14 VIM-14 OXA-77IMP-15 VIM-15 OXA-78IMP-16 VIM-16 OXA-79IMP-17 VIM-17 OXA-80IMP-18 VIM-18 OXA-82IMP-19 VIM-19 ¦ IMP-20 VIM-20 ¦ IMP-21 VIM-21 ¦ IMP-22 VIM-22 ¦ IMP-23 VIM-23 ¦ IMP-24 OXA-132 24 23 8 12 10 3 8 4 56 3
55 25 ~ 71
Total > 150
OXA 71
Q194POXA-64
OXA-99
A5TA48V
Q57RK209M
OXA-87 OXA-86 OXA-67A5T
Q194L
V196A T74I
A31TV101I
A12T
T24SOXA-111 K109M
K146N D117N
A12T
OXA-93
G90S
OXA-75
P256SH29Y
K4Q
S267GK266R V151I
OXA-89
P20HA5T
A182T
OXA-78I255TE100AT24S
K
N225D
K
The OXA-51-like β-lactamases
OXA-98
OXA 113 L167V
OXA-51
38
K107EQ57H
OXA-71K107Q
OXA-91 OXA-68
195E
OXA-77
K146N
E36KD105NOXA-106OXA-70
D198H
OXA-94
OXA-80
OXA-83
OXA-84
E36V
Q239H K4Q
P130S
E36K
OXA-109OXA-82
P130Q
OXA-65 OXA-88
OXA-92OXA-69E36D W234S
L167V
OXA-110 OXA-107 OXA-112
A25TOXA-108 A156T
OXA-95
OXA-104 K146ND117N
OXA-79
OXA-76Q270K
OXA-113
OXA-80 P130L
Data from: Evans, Hamouda, Towner & Amyes (2008); Clin Microbiol Infect 14: 268–275
OXA-66
Dice (Opt:1.30%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]Apa1
100
806040
Apa1
A1
A384
A388
A230
A387
A25
A4
Nottingham, United Kingdom
Oslo, Norway
Ioannina, Greece
Nottingham, United Kingdom
Ioannina, Greece
Nottingham, United Kingdom
Nottingham, United Kingdom
0.25
4
1
0.25
4
0.25
0.5
0.5
2
2
1
4
0.5
0.5
8
128
>256
>256
>256
32
32
OXA-69
OXA-69
OXA-92
OXA-66
OXA-66
OXA-66
OXA-66
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
+
-
+
-
-
-
+
+
-
+
+
+
-
-
+
-
+
-
-
-
+
+
-
+
-
-
Linkage of specific blaOXA-51-like genes to common multi-resistant clones
39
A6
A24
A13
A20
A478
A37
A397
A47
A320
A297
A392
A60
A377
Nottingham, United Kingdom
Nottingham, United Kingdom
Rotterdam, The Netherlands
Paris, France
LUH 5875 European clone III
Singapore
Thessaloniki, Greece
Berlin, Germany
RUH 134 European clone II
RUH 875 European clone I
Freiburg, Germany
Buenos Aires, Argentina
Regensburg, Germany
0.25
0.12
1
0.25
0.25
0.25
4
0.5
0.12
0.25
8
0.25
4
0.5
0.25
2
1
2
0.25
4
1
0.5
0.5
8
1
2
32
16
>256
32
64
128
>256
16
8
8
32
32
64
OXA-66
OXA-66
OXA-71
OXA-71
OXA-71
OXA-64
OXA-66
OXA-66
OXA-66
OXA-69
OXA-66
OXA-65
OXA-71
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
-
-
-
+
-
+
+
+
-
-
-
+
-
+
+
+
+
+
-
-
-
-
-
-
-
+
-
-
-
+
-
+
-
-
-
-
-
-
+
-
-
-
+
-
+
Data from: Evans, Hamouda, Towner & Amyes.(2007) ICAAC, Chicago
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
14The screen versions of these slides have full details of copyright and acknowledgements
OXA-66
ISAba1
Insertion of ISAba1 OXA-51-like β-lactamases now confer carbapenem resistance
40
OXA-69OXA-71blaOXA-51-like
Promoter
7 bases from start codon
Summary of OXA β-lactamases in Acinetobacter baumannii
Class D carbapenemases are now the major mechanism of carbapenem resistance in Acinetobacter baumanniiOXA-23 now found in 2 clones in 50 hospitals in and around London, EnglandOXA-58 found to be the predominant carbapenemase in parts of Asia
41
OXA-51-like is the largest group of OXA-β-lactamases in this genus; Can causes carbapenem resistance if ISAba1 is presentThe carriage of OXA-51-like β-lactamases in all Acinetobacter baumanniistrains worldwide has serious implications for the treatment of A. baumannii infections Pan-drug resistant Acinetobacter baumannii are prevalent in some hospitals
Acknowlegements
University of DundeeDr Hilary-Kay YoungDr Wendy ScaifeHelen Donald
University of EdinburghDr Susan BrownDr Sarah DaviesBen EvansDr Ahmed HamoudaDr Paul Higgins South Africa
ArgentinaDr Carlos Bantar
EnglandDr Neil WoodfordHPA Colindale
42
ggDr Stephen Du BoisDr Ali DashtiDr Rachel WalkerDr Fiona WalshDr Alexandra RolfeDr John HoodDr Robert PatonDr Rex MilesDr Ian Laurenson
South AfricaProf Heather Crewe-BrowneUSADr Fred TenoverCDC, Atlanta
ß-lactamasesClinical Impact and Epidemiology
Professor Sebastian Amyes
15The screen versions of these slides have full details of copyright and acknowledgements
43