Transcript ESBL

Emerging Antimicrobial
Resistance in Texas
The new ESBLs
Most Important Emerging
Resistance
MRSA in the community
 Resistance to alternative drugs for
MRSA, including vancomycin
 Re-emergence of DRSP
 ESBL in various gram-negative species
 Carbapenemases in various GNs
 Multi-drug resistance in Pseudomonas,
enterics, Acinetobacter, S. maltophilia
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To Review ESBL
background……
Extended Spectrum BetaLactamases
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Most ESBL - mutations of TEM or SHV
plasmid-mediated enzymes normally
found in E. coli and Klebsiella
Now TEM-1 to 161, SHV-1 to 105 (as of
3-20-08) - Source: www.lahey.org/studies/webt.asp
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Differences in substrate specificity especially ceftaz vs. cefotax
Hydrolyze 3rd and 4th gen cephs and
aztreonam at high bacterial inoculum
Molecular Basis of ESBLs
Enzyme
Ceftaz
Amino Acid Position
MIC
104
164
240
TEM-1
0.12
Glu
Arg
Glu
TEM-10
> 256
Glu
Ser
Lys
TEM-12
16
Glu
Ser
Glu
TEM-26
256
Lys
Ser
Glu
from: Jacoby, IDCNA 11:875, 1997
Different Substrate Affinities of ESBL
Enzyme
TEM-1
TEM-10
TEM-12
TEM-26
MICs
Ceftaz Cefotax
0.12
0.06
> 256
1
16
0.12
256
0.5
from: Jacoby, IDCNA 11:875, 1997
Aztreo
0.12
128
1
64
Inoculum Effect with ESBLs - MICs
with SHV-3 producing C. freundii
Cefotaxime
Ceftazidime
Cefepime
Meropenem
Inoculum
105
107
2
256
1
32
0.5
>128
0.06
0.06
Thomson, AAC45:3548, 2001
Clinical Significance of ESBLs
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Global bacteremia study in ‘96 and ‘97
- 455 K. pneumoniae
- 18.7% (85) produced ESBLs
- 9 treated with a cephalosporin that was
CLSI Susceptible or Intermediate
- 3 died, 5 required Rx change
Overall, 32 pts. Rx with a ceph (S or I)
- 4/4 I’s failed; 15/28 S’s failed
- 4/5 treated with cefepime failed
D. Paterson, JCM 2001
Two Step Process of Detection
and Confirmation of ESBLs
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Test “indicator” drugs with special
“screening” breakpoints
- cefpodoxime or look for elevated MICs of
ceph 3s
 Must confirm with clavulanate combos
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of cefotaxime and ceftazidime by MIC or
disk
Report as ESBL if either clavulanate
combo is positive
Laboratory Reporting of
ESBL-Producing Isolates
“Expertize” results to resistant for
all penicillins, aztreonam, and “true
cephalosporins” irrespective of
individual test results and/or
 Provide a warning comment that
ESBL-producers should be
considered clinically resistant to all
penicillins, cephalosporins, and
aztreonam
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Gram-Negative Species
Known to Harbor ESBL
Klebsiella pneumoniae
 Klebsiella oxytoca
 E. coli
 Proteus mirabilis
 Salmonella spp.
 Also in Citrobacter, Enterobacter,
Serratia, Morganella, P.
aeruginosa, Acinetobacter
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AmpC Beta-Lactamase
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ampC gene is present in all Enterobacter,
Citrobacter freundii, Morganella morganii, P.
aeruginosa
Selection of resistant mutants with “upregulated” production of ampC during therapy
- Resistance to all cephs except cefepime
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ampC can be plasmid-mediated in some E.
coli and K. pneumoniae
– Jacoby and Munoz-Price, NEJM 352:380, 2005
ESBL vs. AmpC
ESBL
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Spectrum “extended”
from parent enzyme
Susceptible to cefotetan
Inhibited by clavulanate
Can hydrolyze cefepime
at high inoculum
Carbapenem
susceptible
ampC
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Spectrum not
“extended,” although
may be basal or
hyperproducing level
Resistant to cefotetan
Not inhibited by clav
Hydrolyzes cefepime
poorly
Carbapenem suscept
ESBL That Are Not Derived
From TEM or SHV
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CTX-M-1 thru 69 - hydrolyze
cefotaxime better than ceftazidime
- Derived from Kluyvera ascorbata
- Most common ESBL in Latin America,
Japan, Eastern Europe, and U.S.?
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OXA-1 thru 119 (~11 ESBL)
- Mostly in Eastern Europe
- Usually in P. aeruginosa or Acinetobacter
E. coli with “Cefotaximase”
P. mirabilis with CTX-M15
E. cloacae with CTX-M15:
Use of cefepime + clavulanate
Increasing Numbers of ESBLs
80
# of ESBLs per year
70
60
50
40
30
20
10
0
2000
2001
2002
2003
2004
2005
2006
2007
Lewis, et al. AAC 51:4015, 2007
“First Report of the Emergence of CTX-M
Type ESBLs as the Predominant ESBL
Isolated in a U.S. Healthcare System”
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Retrieved all frozen ESBL isolates from
2000 - mid 2006
- Standard CLSI ESBL screening and
confirmatory tests used throughout period
- Screening by cefpodoxime disk and Vitek 2
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PCR and sequencing for TEM, SHV,
CTX-M (and OXA in some)
Lewis, et al, AAC, November, 2007
Emergence of CTX-M ESBLs
in San Antonio
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Have emerged as predominant ESBL over
last 3 years
- %CTX-M in 2000-2002: 0-25%
- %CTX-M in 2003-2006: 60-89%
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CTX-M in E. coli, K. pneumoniae, K. oxytoca,
P. mirabilis, Enterobacter spp., M. morganii
Now predominantly CTX-M15 in E. coli, often
outpatient urines - 8% with 2nd ESBL
86% fluoroquinolone resistant; 66% to SXT
• Lewis, et al, AAC 2007
Evolution of CTX-M ESBLs
100%
80%
60%
TEM
SHV
CTX-M
40%
20%
0%
2000 2001 2002 2003 2004 2005 2006
From Lewis, et al, AAC 51:4015, 2007
ESBL Producers in 2007
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64% (48) of ESBL in E. coli; 15% (11) in K.
pneumoniae, 9.3% (7) K. oxytoca, 6.7% (5)
Enterobacter, 2 Serratia, 1 P. mirabilis, 1C.
koseri
53% from urine; 22% from blood or BF
What are risk factors for OP E coli CTX-M
UTI?
When is a urine culture needed?
What agents are available for therapy of OP
E. coli ESBL?
ESBL Producers in 2007
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64% (48) of ESBL in E. coli; 15% (11) in K.
pneumoniae, 9.3% (7) K. oxytoca, 6.7% (5)
Enterobacter, 2 Serratia, 1 P. mirabilis, 1C.
koseri
53% from urine; 22% from blood or BF
What are risk factors for OP E coli CTX-M
UTI?
When is a urine culture needed?
What agents are available for therapy of OP
E. coli ESBL?
Cefotaxime and Ceftazidime Zones
with Different Species Producing
CTX-M ESBLs
Mean Cefotaxime
Mean Ceftazidime
E. coli (30)
8.8mm
15.9mm
Klebsiella
10.8mm
9.8mm
16.8mm
9.2mm
pneumoniae (4)
K. oxytoca (9)
The Newest Mechanisms of
Concern - Carbapenemases
 The
alphabet soup of rapidly
emerging carbapenemases
-
KPCs 1-4
IMP 1-23
VIM 1-18
PER, SME, VEB
Some OXA enzymes
Source: www.lahey.org/studies/webt.asp
KPC Carbapenemases
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Plasmid-mediated - KPCs 1-4
- Klebsiella pneumoniae carbapenemase
- Can hydrolyze all beta-lactams, including
carbapenems
- Often also resistant to FQs, SXT, aminoglycosides
- Suscept to colistin, tigecycline
- Have rapidly spread in the Eastern U.S.
- Difficult to detect by commercial or ref. methods
- Are they in Texas??
How Do Labs Perform in
Detection of KPCs?
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CAP sample DA-05, 2007 illustrated
problems of detection
- Partial or inconsistent clavulanate effect - like
ESBL
- Some commercial systems (and disks) had a high
false susceptible rate with imipenem
- Meropenem also problematic
- Best detection by testing ertapenem
- Ertapenem > meropenem > imipenem
Detection of KPCs
Look for resistance to all penicillins and
cephalosporins
 Look for carbapenem MICs > 1
 Perform “modified Hodge test”
 PCR using primers for all KPC, and
sequence product
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Modified Hodge Test
Other Carbapenemases Metallo-Beta-Lactamases
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Mostly found in P. aeruginosa
- IMP, VIM, SIM, GIM, and SPM
- Europe, Asia, S. America, N. America (IMP, VIM)
- Plasmid, chromosomal, or integrons
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P. aeruginosa with VIM-2 in CAP DA-01, 2007
- Resistant to all carbapenems, cephs, pens
- Suscept. to aztreonam, pip-tazo
- Colistin suceptible
Newer Beta-Lactamases are
emerging in Texas
• Labs must look for them
• Physicians must be aware of
their existence