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
To Review ESBL
background……
 Extended Spectrum Beta-
Lactamases
 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
 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 MICs
Ceftaz Cefotax Aztreo
TEM-1 0.12 0.06 0.12
TEM-10 > 256 1 128
TEM-12 16 0.12 1
TEM-26 256 0.5 64
from: Jacoby, IDCNA 11:875, 1997
 Inoculum Effect with ESBLs - MICs
with SHV-3 producing C. freundii
Inoculum
105 107
Cefotaxime 2 256
Ceftazidime 1 32
Cefepime 0.5 >128
Meropenem 0.06 0.06
Thomson, AAC45:3548, 2001
Clinical Significance of ESBLs
 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
 Test “indicator” drugs with special
“screening” breakpoints
- cefpodoxime or look for elevated MICs of
ceph 3s
 Must confirm with clavulanate combos
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
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
 AmpC Beta-Lactamase
 ampC gene is present in all Enterobacter,
Citrobacter freundii, Morganella morganii, P.
aeruginosa
 Selection of resistant mutants with “up-
regulated” production of ampC during therapy
- Resistance to all cephs except cefepime
 ampC can be plasmid-mediated in some E.
coli and K. pneumoniae
– Jacoby and Munoz-Price, NEJM 352:380, 2005
 ESBL vs. AmpC
ESBL
 Spectrum “extended”
from parent enzyme
 Susceptible to cefotetan
 Inhibited by clavulanate
 Can hydrolyze cefepime
at high inoculum
 Carbapenem
susceptible
ampC
 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
 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.?
 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
70
60
# of ESBLs per year

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”

 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
 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
 Have emerged as predominant ESBL over
last 3 years
- %CTX-M in 2000-2002: 0-25%
- %CTX-M in 2003-2006: 60-89%
 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
40% CTX-M

20%

0%
2000 2001 2002 2003 2004 2005 2006

From Lewis, et al, AAC 51:4015, 2007

 ESBL Producers in 2007
 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
 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
pneumoniae (4)
K. oxytoca (9) 16.8mm 9.2mm
 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
 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?
 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
Modified Hodge Test
 Other Carbapenemases -
Metallo-Beta-Lactamases
 Mostly found in P. aeruginosa
- IMP, VIM, SIM, GIM, and SPM
- Europe, Asia, S. America, N. America (IMP, VIM)
- Plasmid, chromosomal, or integrons
 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