Taiwan Surveillance of Antimicrobial Resistance (TSAR)

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1 Taiwan Surveillance of Antimicrobial Resistance (TSAR) 2009 MIRL Symposium July 17, 2009 Tsai-Ling Yang Lauderdale ( ) Microbial Infections Reference Laboratory (MIRL) Division of Infectious Diseases, National Health Research Institutes

2 Mission of MIRL* 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 * MIRL, Microbial Infections Reference Laboratory Division of Infectious Diseases

3 North: Middle: South: East: S M TSAR Progress TSAR III VI Hospitals Thank You N E * Population: 22.4 mil *Area: 142 x 394 km Medical center Regional Hosp. TSAR Collection time No. of Hospitals I Oct-Dec II Mar-May III Jul-Sep IV Jul-Sep V Jul-Sep VI Jul-Sep

4 Antimicrobial Susceptibility Testing Primary: broth microdilution (MIC) M100-S19 Additional testing as needed: - Disk diffusion & Etest - Agar dilution - ESBL Confirmatory testing - Modified Hodge Test M02-A10 M07-A8

5 TSAR III VI Collection Process Clinically significant non-duplicate bacterial isolates * = Isolate category (# of isolates) Outpatients Inpatients *OPD/ER(50) Adult Pediatric *ICU(30) *NON-ICU(100) *PED(20) (After above) *Special *Blood isolates 20 more isolates (50 Blood and SBS in TSAR VI) S. pneumoniae, Gr. A Streptococci, H. influenzae - All Campylobacter spp. - All Salmonella spp. & Enterococcus spp. 10 more isolates each

6 Highlights of TSAR VI Extended spectrum ß-lactam reduced susceptible and resistant E. coli and K. pneumoniae: - ESBL and AmpC ß-lactamases Carbapenem-resistant Acinetobacter baumannii Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus (methicillin-resistant S. aureus) Enterococci

7 Antimicrobials Prescribed for Outpatients in Taiwan All Outpatients For UTI Others Non-guideline drugs Trimethoprim and/or Sulfa. 2nd-gen. Cepha Quinolones Trimethoprim and/or-sulfa Aminopenicillins 2nd-gen. Cepha Nitrofurantoin Aminopenicillins 1 st -gen. Cepha Macrolides Tetracycline 1 st -gen. Cepha Quinolones Based on Ho & Hsiung et al., IJAA 2004;23: Based on Jan et al., JMMI 2007;40:532-6 UTI, Urinary tract infections (uncomplicated cystitis)

8 Outpatient Urine E. coli Resistance - Taiwan (TSAR IV-2004) vs. USA ( ) %R Ampicillin SXT AMP+SXT Ciprofloxacin Taiwan SXT+CIP USA AMP+SXT+CIP Nitrofurantoin USA data from: Zhanel et al., Int J Antimicrob Agent 2006;27:468-75

9 Increasing Resistance in OPD Urine E. coli * Cephalothin Ciprofloxacin Cefazolin % Resistant Cefuroxime ESBL Suspects 10 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) *Cephalothin was not tested in 2008

10 Resistance in E. coli - TSAR VI (2008 data) OPD/ER (N=614) Non-ICU(N=263) ICU (N=127) HAI (N=116) % Resistant Ampicillin SXT Ciprofloxacin Gentamicin Cefazolin Ceftazidime and/or cefotaxime Cefepime

11 Resistance in K. pneumoniae - TSAR VI (2008) OPD/ER (N=187) Non-ICU (N= 400) ICU (N=140) HAI (N=84) % Resistant SXT Ciprofloxacin Gentamicin Cefazolin Cefotaxime and/or Ceftazidime Cefepime

12 Extended Spectrum ß-Lactamase (ESBL) Suspects (ESBL Screen Test Positive = reduced susceptibility and resistance to extended spectrum ß-lactams) 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 From : CLSI M100-S18 Appendix A

13 ESBL and AmpC β-lactamases in GNB (ESBL, extended spectrum ß-lactamase; AmpC, cephalosporinase) β-lactamase Examples Substrates Broadspectrum Expanded (extended) spectrum TEM-1, TEM-2, SHV-1 OXA-family TEM- & SHV- family CTX-M family Penicillins, narrow-spectrum cephalosporin Above plus cloxacillin, oxacillin and methicillin Above plus 3 rd -generation cephalosporins & monobactam Above plus for some enzymes, cefepime Inhibition by Clavulanate 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:

Cefotaxime CTL, Cefotaxime+clavulanic acid - The use of more than one.

14 ESBL Confirmatory Tests Disk Diffusion Etest 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 - 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

15 Increasing Problem with ESBL Suspects Plasmid-mediated AmpC Co-carriage of AmpC 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: 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

16 K. pneumoniae NK29 For all confirmed ESBL-producing strains, the test interpretation should be reported as resistant for all penicillins, cephalosporins, and aztreonam. - CLSI M100-S18 Interpretation based on β-lactams MIC (ug/ml) ESBL Confirmatory Test ESBL Confirmatory Test: Negative Positive Amoxicillin/Clavulanate CAZ/CAZ+CA Etest: 16/> ug/ml; DD: R 17 vs. 17 mm R Ampicillin CTX/CTX+CA Etest: >16/>1.0 ug/ml; RDD: 13 vs. 15 Rmm Aztreonam Cefazolin Cefepime Cefotaxime Cefoxitin Ceftazidime Ceftriaxone Cefuroxime 4 > > >16 S R S I R I I R R R R R R R R R Imipenem 0.25 S S

17 Co-carriage of AmpC and ESBL Co-Carriage of ESBL and AmpC ß-Lactamases on the Same Plasmid (pk29) Chen et al., AAC 2007;51:3004-7

18 ESBL Suspects in E. coli & K. pneumoniae E. coli K. pneumoniae Strata TSAR IV (2004) TSAR V (2006) TSAR VI (2008) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) HAI Patient Location: ICU Non-ICU OPD Specimen: Blood Resp. ND ND ND Urine

aminophenylboronic acid hemisulfate ATCC25922 E.

19 AmpC Phenotypic Detection Double disk synergy test (DDST) Modified Hodge Test CAZ APB CTX FOX FOX Disk Potentiation test (DPT) CAZ CAZ+APB APB, aminophenylboronic acid hemisulfate ATCC25922 E. coli & 4 test strains (81, 82, 84-pos, 83-neg) CAZ, Ceftazidime; CTX, cefotaxime; FOX, cefoxitin

20 ESBL and AmpC Positive Isolates in TSAR VI (2008) % of ESBL and AmpC phenotypic test positives in ESBL-suspects E. coli (n=225) K. pneumoniae (n=173) ESBL+ ESBL+ AmpC + ESBL & AmpC + AmpC + ESBL & AmpC + Species Phenotypic test N Genotypic test (PCR & sequencing) (HAI Isolates) ESBL AmpC bla ESBL bla AmpC E. coli K. pneumoniae

21 CLSI M100-S19 Appendix G. Screening and confirmatory test for suspected carbapenemase production in Enterobacteriaceae Modified Hodge Test using etrapenem* Screening test Test Method Disk Diffusion Broth Microdilution Medium MHA CAMHB Antimicrobial Concentration Inoculum/ Incubation Initial Screen Positive Results Ertapenem 10 µg or Meropenem 10 µg (Imipenem Poor) Standard, 35+2 o C; Ambient air; h Ertapenem mm Meropenem mm Ertapenem 1 µg/ml or Imipenem 1 µg/ml or Meropenem 1 µg/ml Standard, 35+2 o C; Ambient air; 16-20h Ertapenem 2 µg/ml Imipenem 2-4 µg/ml Meropenem 2-4 µg/ml QC ATCC ATCC Performed on isolates resistant to one or more agents in cephalosporin subclass III and positive screen test.

22 Resistance to Other Agents: ESBL Suspects vs. Not-ESBL Suspects* Antimicrobial Agent ESBL suspect E. coli K. pneumoniae Not ESBL suspect ESBL suspect Not ESBL suspect Amikacin Amoxicillin/CA Cefoxitin Ciprofloxacin Gentamicin Imipenem *TSAR IV-VI data combined

23 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:

24 Escalating Carbapenem Resistance in Acinetobacter baumannii 80 % Resistant Ciprofloxacin Amikacin Ceftazidime Imipenem 10 0 TSAR I (1998) TSAR II (2000) TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

25 CRAB Increased in A. baumannii from Different Sources ICU Non-ICU OPD/ER Respiratory Urine Blood %CRAB TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

26 CRAB vs. CSAB Susceptibility a -1 Antimicrobial agent % Susceptible CRAB CSAB (n = 178) (n = 188) Amikacin Ampicillin/sulbactam Cefepime Ceftazidime FQ (Ciprofloxacin and/or levofloxacin) Piperacillin/tazobactam a CRAB, carbapenem-resistant A. baumannii; CSAB, Carbapenem-susceptible A. baumannii (TSAR VI isolates)

27 P. aeruginosa Resistance Resistance % Gentamicin Pip/Tazo Ciprofloxacin Ceftazidime Imipenem TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) No. of isolates: Around 600 for each round of TSAR

28 Resistance in H. influenzae %R Ampicillin Trimeth./Sulfa. Levofloxacin 10 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

29 Resistance in S. pneumoniae TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) % Resistant Erythromycin Tetracycline Trimeth/Sulfa. (SXT) * Over half (54%) of TSAR S. pneumoniae isolates ( are resistant to these 3 antimicrobial agents

30 Penicillin MIC Distribution in S. pneumoniae Penicillin Interpretive Criteria Changed in 2008 S I R Parenteral (nonmeningitis) < 2 4 > 8 MIC >=8.0 Parenteral (meningitis) < > 0.12 Oral (penicillin V) & Before 2008 < > 2 <=0.03 MIC 4.0 MIC 0.06 MIC 0.12 MIC 0.25 MIC 0.5 MIC 1.0 MIC 2.0 TSAR III VI (n 1260)

31 Resistance in S. pneumoniae by Penicillin MIC Penicillin MIC <= 1 ug/ml Penicillin MIC 2 ug/ml Penicillin MIC >=4 ug/ml 80 %R Erythromycin TMP/SMX (SXT) Tetracycline Cefepime Ceftriaxone Levofloxacin

32 Nosocomial MRSA Rates: USA vs. Taiwan % Taiwan USA Year Data source. - USA: NNIS System on ICU patients, data was for 2003 (incomplete) - Taiwan: TSAR, data was for 2004

33 Proportions of Invasive S. aureus Resistant to Methicillin in Europe Taiwan: 52% (TSAR V, 2006) of S. aureus blood isolates were MRSA EARSS,

34 100 Resistance in S. aureus TSAR VI (2008) OPD/ER (N=257) Non-ICU (N= 425) ICU (N=113) HAI (N=95) % Resistant Ciprofloxacin Erythromycin Gentamicin Oxacillin SXT Tetracycline

35 MRSA% in S. aureus from Inpatients & Outpatients HAI ICU Non-ICU OPD/ER 70 % MRSA TSAR I (1998) TSAR II (2000) TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

36 Molecular Epidemiology of Taiwan MRSA - TSAR III data (EID, 2005) Pulsotype (no.) MLST SCCmec PVL CIP/GEN/SXT ICU non-icu OPD B1 ( 2 ) ST59 IVnot a-d - S/R/S B2 ND IVnot a-d - S/R/S B4 ND IVnot a-d - S/R/S B3 ND IVnot a-d - S/R/S B5 ST59 IVnot a-d - S/R/S ST59 IVnot a-d - S/R/S C2 ( 4 ) ST59 V + S/S/S C3 ST59 V + S/S/S C5 ( 2 ) ST59 V + S/S/S C6 ST59 V + S/S/S C7 ND V + S/S/S C4 ST59 IVa + S/S/S C1 ( 8 ) ST59 (2) V + S/S/S ST59 IVc - S/R/S ST1 IVa - S/S/S ND IVa - S/S/S ST6 V - S/S/S A7 ST239 III - R/R/R A6 ( 4 ) ND III - R/R/R A4 ND III - R/R/R A3 ND III - R/R/R A1 (21) ST239 III - R/R/R A5 ND III - R/R/R A9 ND III - R/R/R A10 ND III - R/R/R A2 ( 3 ) ST239 III - R/R/R A11 ( 3 ) ND III - R/R/R A13 ND III - R/R/R A12 ( 3 ) ST239 III - R/R/R A8 ND III - R/R/R A17 ND III - R/R/R A16 ND III - R/R/R A14 ( 2 ) ND III - R/R/R A15 ND III - R/R/R ND IIa - R/R/S ST5 IIa - R/R/S ND IIa - R/R/S ST573 IVc - S/R/S 0 0 1

37 Resistance in MRSA - TSAR III VI 100 % Resistant Erythromycin Tetracycline Ciprofloxacin Gentamicin SXT TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

38 Resistance in E. faecalis and E. faecium 100 E. faecalis E. faecium %R %VRE Vancomycin-resistant E. faecium Vancomycin-resistant E. faecalis 0 Ampicllin Ciproflocacin Erythromycin Gentamicin-High level (TSAR II IV Combined) Tetracycline 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)

39 Summary 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 Changing epidemiology of MRSA?

40 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?

41 July 9, 2009 NEJM 361:2, 120-1

42 TSAR Hospitals Acknowledgements 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:

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