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Taiwan Surveillance of Antimicrobial
Resistance (TSAR)
Tsai-Ling Yang Lauderdale ( )
Microbial Infections Reference Laboratory (MIRL)
Division of Infectious Diseases, National Health Research Institutes
2009 MIRL Symposium
July 17, 2009
Mission of MIRL*
* MIRL, Microbial Infections Reference Laboratory
Division of Infectious Diseases
§ Surveillance : monitor important clinical pathogens and their antimicrobial susceptibility trends
§ Research : study the epidemiology, mechanisms of resistance, pathogenesis and virulence of important resistant pathogens
§ Service : assist in national effort in controlling antibiotic resistance
§ Advocacy : promote discriminatory antibiotic use
* Population:
22.4 mil
*Area: 142 x
394 km
N
M
S
E
North:
Middle:
South:
East: Medical center
Regional Hosp.
TSAR Collection timeNo. of
Hospitals
I Oct-Dec 1998 44
II Mar-May 2000 21
III Jul-Sep 2002 26
IV Jul-Sep 2004 26
V Jul-Sep 2006 25
VI Jul-Sep 2008 26
TSAR III VI Hospitals – Thank You
TSAR Progress
Antimicrobial Susceptibility Testing
§ Primary: broth microdilution (MIC)
§ Additional testing as needed:
- Disk diffusion & Etest
- Agar dilution
- ESBL Confirmatory testing
- Modified Hodge Test
M100-S19
M02-A10
M07-A8
TSAR III VI Collection ProcessClinically significant non-duplicate bacterial isolates
Outpatients Inpatients
*OPD/ER(50) Adult Pediatric
*ICU(30) *NON-ICU(100) *PED(20)
(After above)
*Blood isolates 20 more isolates
S. pneumoniae, Gr. A Streptococci, H. influenzae - All
Campylobacter spp. - All
Salmonella spp. & Enterococcus spp. 10 more isolates each
* = Isolate category (# of isolates)*S
pec
ial (50 Blood and SBS in TSAR VI)
Highlights of TSAR VI
v Extended spectrum ß-lactam reduced susceptible and
resistant E. coli and K. pneumoniae:
- ESBL and AmpC ß-lactamases
v Carbapenem-resistant Acinetobacter baumannii
v Haemophilus influenzae
v Streptococcus pneumoniae
v Staphylococcus aureus (methicillin-resistant S. aureus)
v Enterococci
Antimicrobials Prescribed for Outpatients in Taiwan
Based on Ho & Hsiung et al., IJAA
2004;23:438-45
All Outpatients
Aminopenicillins
1st-gen. Cepha
Tetracycline
Macrolides
Trimethoprim
and/or-Sulfa
Quinolones
Others
2nd-gen. Cepha
For UTI
Based on Jan et al., JMMI 2007;40:532-6
Aminopenicillins
1st-gen.
Cepha
Trimethoprim
and/or Sulfa.
Quinolones
2nd-gen. Cepha
Non-guideline
drugs
Nitrofurantoin
UTI, Urinary tract infections
(uncomplicated cystitis)
0
10
20
30
40
50
60
70
80
90
100
Am
picillin
SXT
AM
P+SXT
Ciprofloxacin
SXT+C
IP
AM
P+SXT+C
IPN
itrofurantoin
Taiwan USA
Outpatient Urine E. coli Resistance
- Taiwan (TSAR IV-2004) vs. USA (2003-2004)
%R
USA data from: Zhanel et al., Int J Antimicrob Agent 2006;27:468-75
% R
esis
tan
t
Increasing Resistance in OPD Urine E. coli
0
10
20
30
40
50
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
Cephalothin
Ciprofloxacin
Cefazolin
Cefuroxime
ESBL Suspects
*Cephalothin was not tested in 2008
*
0
10
20
30
40
50
60
70
80
90
100
Ampicillin SXT Ciprofloxacin Gentamicin Cefazolin Ceftazidime
and/or
cefotaxime
Cefepime
OPD/ER (N=614)Non-ICU(N=263)
ICU (N=127)HAI (N=116)
% R
esis
tan
t
Resistance in E. coli - TSAR VI (2008 data)
0
10
20
30
40
50
60
70
80
90
100
SXT Ciprofloxacin Gentamicin Cefazolin Cefotaxime
and/or
Ceftazidime
Cefepime
OPD/ER (N=187)Non-ICU (N= 400)
ICU (N=140)HAI (N=84)
% R
esis
tan
t
Resistance in K. pneumoniae - TSAR VI (2008)
From : CLSI M100-S18 Appendix A
Antimicrobial
agent
Disk Zone
(mm)
MIC
(μg/mL)
Aztreonam < 27 > 2
Ceftazidime < 22 > 2
Cefotaxime < 27 > 2
Ceftriaxone < 25 > 2
Cefpodoxime < 17 > 8
For E. coli, K. pneumoniae, and K. oxytoca
Extended Spectrum ß-Lactamase (ESBL) Suspects
(ESBL Screen Test Positive = reduced susceptibility and
resistance to extended spectrum ß-lactams)
ESBL and AmpC β-Lactamases in GNB
β-Lactamase Examples SubstratesInhibition by
Clavulanate
Broad-
spectrum
TEM-1, TEM-2, SHV-1 Penicillins, narrow-spectrum
cephalosporin
+++
OXA-family Above plus cloxacillin, oxacillin
and methicillin
+
Expanded
(extended)–
spectrum
TEM- & SHV- family Above plus 3rd-generation
cephalosporins & monobactam
++++
CTX-M family Above plus for some enzymes,
cefepime
++++
OXA family Same as CTX-M family +
Others (PER-, VEB, etc.) Same as TEM & SHV family ++++
AmpC CMY family, DHA-1 & 2,
FOX family & others
Above plus cephamycins
(cefotetan, cefoxitin)
0
Modified from Jacoby & Munoz-Price NEJM 2005;352:380-91.
(ESBL, extended spectrum ß-lactamase; AmpC, cephalosporinase)
CAZ, Ceftazidime
CAZ CLA, Ceftazidime+clavulanic acid
CTX, Cefotaxime
CTX CLA, Cefotaxime+clavulanic acid
TZ, Ceftazidime
TZL, Ceftazidime+clavulanic acid
CT, Cefotaxime
CTL, Cefotaxime+clavulanic acid
Disk Diffusion Etest
- The use of more than one….. agent for screening improves the sensitivity …….
- Confirmatory testing requires use of both cefotaxime and ceftazidime…
CLSI M100-S18 Appendix A
ESBL Confirmatory Tests
Increasing Problem with ESBL Suspects
v Plasmid-mediated AmpC
v Co-carriage of AmpC
v False negative ESBL
- Treatment
- Infection control
Yan et al., ESBL and AmpC in E.
coli and K. pneumoniae from 7
medical centers in Taiwan. AAC
2006;50:1861-4.
- Most common ESBL: CTX-M-type
and SHV-Type; Most common
AmpC: CMY-2-like and DHA-1 like
- Among 10 ESBL-confirmatory test
negative isolates, 5 E. coli coproduced
CMY-2-like and SHV5-related
enzymes, and 5 K. pneumoniae
coproduced DHA-1-related and SHV-
5-related enzymes
K. pneumoniae NK29
Negative
R
R
S
R
S
I
R
I
I
R
S
Positive
R
R
R
R
R
R
R
R
R
R
S
Amoxicillin/Clavulanate 32
Ampicillin >16
Aztreonam 4
Cefazolin >16
Cefepime 2
Cefotaxime 32
Cefoxitin >256
Ceftazidime 16
Ceftriaxone 32
Cefuroxime >16
Imipenem 0.25
Interpretation based on
ESBL Confirmatory TestMIC (ug/ml)β-Lactams
For all confirmed ESBL-producing strains, the test interpretation should be reported
as resistant for all penicillins, cephalosporins, and aztreonam. - CLSI M100-S18
ESBL Confirmatory Test:
CAZ/CAZ+CA Etest: 16/>4.0 ug/ml; DD: 17 vs. 17 mm
CTX/CTX+CA Etest: >16/>1.0 ug/ml; DD: 13 vs. 15 mm
Co-carriage of AmpC and ESBLCo-Carriage of ESBL and AmpC ß-Lactamases on the
Same Plasmid (pK29)
Chen et al., AAC 2007;51:3004-7
ESBL Suspects in E. coli & K. pneumoniae
Strata
E. coli K. pneumoniae
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
HAI 44.7 45.5 48.0 42.6 50.7 44.2
Patient Location:
ICU 30.1 23.5 41.9 33.0 31.1 26.8
Non-ICU 22.5 22.9 26.9 22.6 24.7 25.1
OPD 10.1 10.8 16.4 6.7 11.0 12.3
Specimen:
Blood 19.6 11.4 20.5 14.8 17.3 18.3
Resp. ND ND ND 15.6 23.8 23.3
Urine 14.8 18.8 24.2 36.6 30.5 39.0
AmpC Phenotypic Detection
Modified Hodge Test
ATCC25922 E. coli & 4 test strains
(81, 82, 84-pos, 83-neg)
Double disk synergy test (DDST)
Disk Potentiation test (DPT)
APB, aminophenylboronic acid hemisulfate
CAZ, Ceftazidime; CTX, cefotaxime; FOX, cefoxitin
CAZ+APBCAZ
APBCAZ CTX
FOX
FOX
ESBL+
ESBL & AmpC +
AmpC +
E. coli (n=225)
ESBL and AmpC Positive Isolates in TSAR VI (2008)
% of ESBL and AmpC phenotypic test positives in ESBL-suspects
ESBL+
ESBL & AmpC +
AmpC +
K. pneumoniae (n=173)
Species Phenotypic test NGenotypic test
(PCR & sequencing)
(HAI Isolates) ESBL AmpC blaESBL blaAmpC
E. coli - + 48 14 47
K. pneumoniae - + 10 3 10
Phen c test N
CLSI M100-S19 Appendix G.
Screening and confirmatory test for suspected
carbapenemase production in Enterobacteriaceae
Modified Hodge Test
using etrapenem*
- Performed on isolates resistant to one or more agents in
cephalosporin subclass III and positive screen test.
Test Method Disk Diffusion Broth Microdilution
Medium MHA CAMHB
Antimicrobial
Concentration
Ertapenem 10 µg or
Meropenem 10 µg
(Imipenem – Poor)
Ertapenem 1 µg/mL or
Imipenem 1 µg/mL or
Meropenem 1 µg/mL
Inoculum/
Incubation
Standard, 35+2oC;
Ambient air; 16-18 h
Standard, 35+2oC;
Ambient air; 16-20h
Initial Screen
Positive
Results
Ertapenem 19-21 mm
Meropenem 16-21 mm
Ertapenem 2 µg/mL
Imipenem 2-4 µg/mL
Meropenem 2-4 µg/mL
QC ATCC 25922 ATCC 25922
Screening test
Antimicrobial
Agent
E. coli K. pneumoniae
ESBL
suspect
Not
ESBL
suspect
ESBL
suspect
Not
ESBL
suspect
Amikacin 10.1 0.1 43.4 0
Amoxicillin/CA 78.2 2.9 70.3 1.1
Cefoxitin 74.3 1.3 60.4 2.4
Ciprofloxacin 64.6 13.9 66.5 4.3
Gentamicin 62.9 19.8 73.8 3.6
Imipenem 0.5 0 1.4 0
Resistance to Other Agents:
ESBL Suspects vs. Not-ESBL Suspects*
*TSAR IV-VI data combined
In their ongoing war against antibiotics,
the bacteria seem to be winning, and the drug pipeline is verging on empty
Taubes G. Science 2008;321:356-360
0
10
20
30
40
50
60
70
80
TSAR I
(1998)
TSAR II
(2000)
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
Ciprofloxacin
Amikacin
Ceftazidime
Imipenem
% R
esis
tan
t
Escalating Carbapenem Resistance
in Acinetobacter baumannii
CRAB Increased in A. baumannii
from Different Sources
0
10
20
30
40
50
60
70
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
ICU
Non-ICU
OPD/ER
%C
RA
B
0
10
20
30
40
50
60
70
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
Respiratory
Urine
Blood
Antimicrobial agent
% Susceptible
CRAB
(n = 178)
CSAB
(n = 188)
Amikacin 7.3 63.8
Ampicillin/sulbactam 11.2 70.2
Cefepime 3.4 57.4
Ceftazidime 1.1 52.1
FQ (Ciprofloxacin and/or levofloxacin) 2.2 52.1
Piperacillin/tazobactam 0.5 53.7
CRAB vs. CSAB Susceptibilitya -1
aCRAB, carbapenem-resistant A. baumannii; CSAB, Carbapenem-susceptible A.
baumannii (TSAR VI isolates)
P. aeruginosa Resistance
No. of isolates: Around 600 for each round of TSAR
Res
ista
nce
%
0
5
10
15
20
25
30
35
40
45
50
TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
GentamicinPip/TazoCiprofloxacinCeftazidimeImipenem
0
10
20
30
40
50
60
70
80
TSAR III
(2002)
TSAR IV
(2004)
TSAR V (2006) TSAR VI
(2008)
Ampicillin
Trimeth./Sulfa.
Levofloxacin
%R
Resistance in H. influenzae
0
10
20
30
40
50
60
70
80
90
100
Erythromycin Tetracycline Trimeth/Sulfa. (SXT)
TSAR III (2002) TSAR IV (2004)
TSAR V (2006) TSAR VI (2008)
% R
esis
tan
t
* Over half (54%) of TSAR S. pneumoniae isolates (
are resistant to these 3 antimicrobial agents
Resistance in S. pneumoniae
Penicillin MIC Distribution in S. pneumoniae
TSAR III – VI (n 1260)
Penicillin Interpretive Criteria Changed in 2008 S I R
Parenteral (nonmeningitis) < 2 4 > 8
Parenteral (meningitis) < 0.06 - > 0.12
Oral (penicillin V) & Before 2008 < 0.06 0.12-1 > 2
<=0.03
MIC 0.06
MIC 0.12
MIC 0.25
MIC 0.5
MIC 1.0
MIC 2.0
MIC 4.0
MIC >=8.0
Resistance in S. pneumoniae by Penicillin MIC
0
10
20
30
40
50
60
70
80
90
100
Erythromycin TMP/SMX
(SXT)
Tetracycline
Penicillin MIC <= 1 ug/ml
Penicillin MIC 2 ug/ml
Penicillin MIC >=4 ug/ml
0
2
4
6
8
10
12
14
16
18
20
Cefepime Ceftriaxone Levofloxacin
%R
0
10
20
30
40
50
60
70
80
90
1998 2000 2002 2003-2004
Year
%
Taiwan
USA
Nosocomial MRSA Rates: USA vs. Taiwan
Data source.- USA: NNIS System on ICU patients, 2003-2004 data was for 2003 (incomplete)- Taiwan: TSAR, 2003-2004 data was for 2004
Proportions of Invasive S. aureus
Resistant to Methicillin in Europe
EARSS, http://www.rivm.nl/earss/database/2006
Taiwan: 52% (TSAR V, 2006) of S. aureus blood isolates were MRSA
0
10
20
30
40
50
60
70
80
90
100
Ciprofloxacin Erythromycin Gentamicin Oxacillin SXT Tetracycline
OPD/ER (N=257)Non-ICU (N= 425)
ICU (N=113)HAI (N=95)
% R
esis
tan
t
Resistance in S. aureus – TSAR VI (2008)
MRSA% in S. aureus from Inpatients & Outpatients
0
10
20
30
40
50
60
70
80
90
100
TSAR I
(1998)
TSAR II
(2000)
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
HAI
ICU
Non-ICU
OPD/ER
% M
RS
A
Molecular Epidemiology of Taiwan MRSA- TSAR III data (EID, 2005)
100908070605040Pulsotype (no.) MLST SCCmec PVL CIP/GEN/SXT ICU non-ICU OPD
ST59 IVc - S/R/S 1 0 0
C1 ( 8 ) ST59 (2) V + S/S/S 1 3 4
C2 ( 4 ) ST59 V + S/S/S 0 3 1
C3 ST59 V + S/S/S 0 0 1
C4 ST59 IVa + S/S/S 0 1 0
C6 ST59 V + S/S/S 0 1 0
C5 ( 2 ) ST59 V + S/S/S 0 1 1
ST5 IIa - R/R/S 0 1 0
ST1 IVa - S/S/S 0 1 0
ST6 V - S/S/S 0 1 0
ND IIa - R/R/S 1 0 0
ND IIa - R/R/S 0 1 0
ND IVa - S/S/S 0 0 1
ST573 IVc - S/R/S 0 0 1
C7 ND V + S/S/S 0 1 0
B1 ( 2 ) ST59 IVnot a-d - S/R/S 0 2 0
B5 ST59 IVnot a-d - S/R/S 0 1 0
B4 ND IVnot a-d - S/R/S 0 1 0
B3 ND IVnot a-d - S/R/S 0 1 0
B2 ND IVnot a-d - S/R/S 0 1 0
ST59 IVnot a-d - S/R/S 0 1 0
A2 ( 3 ) ST239 III - R/R/R 0 3 0
A1 (21) ST239 III - R/R/R 7 12 2
A7 ST239 III - R/R/R 0 1 0
A12 ( 3 ) ST239 III - R/R/R 2 1 0
A14 ( 2 ) ND III - R/R/R 1 1 0
A15 ND III - R/R/R 0 1 0
A9 ND III - R/R/R 0 1 0
A6 ( 4 ) ND III - R/R/R 0 4 0
A3 ND III - R/R/R 0 1 0
A5 ND III - R/R/R 0 0 1
A4 ND III - R/R/R 1 0 0
A13 ND III - R/R/R 0 1 0
A11 ( 3 ) ND III - R/R/R 0 3 0
A10 ND III - R/R/R 0 1 0
A16 ND III - R/R/R 1 0 0
A8 ND III - R/R/R 0 1 0
A17 ND III - R/R/R 0 1 0
% R
esis
tan
tResistance in MRSA - TSAR III VI
0
10
20
30
40
50
60
70
80
90
100
TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
Erythromycin
Tetracycline
Ciprofloxacin
Gentamicin
SXT
Resistance in E. faecalis and E. faecium
0
10
20
30
40
50
60
70
80
90
100
Ampicllin Ciproflocacin Erythromycin Gentamicin-High
level
Tetracycline
E. faecalis E. faecium
%R
(TSAR II IV Combined)
0
5
10
15
20
25
30
TSAR III
(2002)
TSAR IV
(2004)
TSAR V
(2006)
TSAR VI
(2008)
Vancomycin-resistant E. faecium
Vancomycin-resistant E. faecalis
%V
RE
Summary
v Problematic and emerging resistance
- Reduced susceptibility and resistance to extended spectrum
ß-lactams
- Emerging carbapenem resistance in E. coli and K. pneumoniae
- Escalating carbapenem-resistance in Acinetobacter baumannii
- Increasing fluoroquinolone resistance in both GN and GP
pathogens
- Increasing vancomycin resistant E. faecium
v Changing epidemiology of MRSA?
Containment of Antimicrobial Resistance
§ Judicious antimicrobial use in hospitals and community: Antimicrobial stewardship
§ Increase public awareness
§ Practice good hygiene
§ Enforce infection control measures
§ Active and passive surveillance
§ Correlate antimicrobial resistance with use
§ Identify reservoirs of resistant bacteria
§ Develop new drugs (antimicrobials, other compounds) and vaccines
§ Other approaches: antimicrobial cycling?
July 9, 2009 NEJM 361:2, 120-1
Acknowledgements
§ TSAR Hospitals
§ Division Directors (past and present)
- Dr. , Dr. , Dr. ,
- Dr. , Dr.
§ MIRL Steering Committee Members (past and present)- Dr. , Dr. , Dr.
- Dr. , Dr. , Dr.
- Dr.
MIRL Staff: