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: