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
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
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 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
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
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
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
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;23:438-45 Based on Jan et al., JMMI 2007;40:532-6 UTI, Urinary tract infections (uncomplicated cystitis)
Outpatient Urine E. coli Resistance - Taiwan (TSAR IV-2004) vs. USA (2003-2004) %R 100 90 80 70 60 50 40 30 20 10 0 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
Increasing Resistance in OPD Urine E. coli 50 40 * Cephalothin Ciprofloxacin Cefazolin % Resistant 30 20 Cefuroxime ESBL Suspects 10 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) *Cephalothin was not tested in 2008
Resistance in E. coli - TSAR VI (2008 data) 100 90 80 70 OPD/ER (N=614) Non-ICU(N=263) ICU (N=127) HAI (N=116) % Resistant 60 50 40 30 20 10 0 Ampicillin SXT Ciprofloxacin Gentamicin Cefazolin Ceftazidime and/or cefotaxime Cefepime
Resistance in K. pneumoniae - TSAR VI (2008) 100 90 80 70 OPD/ER (N=187) Non-ICU (N= 400) ICU (N=140) HAI (N=84) % Resistant 60 50 40 30 20 10 0 SXT Ciprofloxacin Gentamicin Cefazolin Cefotaxime and/or Ceftazidime Cefepime
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
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;352:380-91.
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
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;50:1861-4. - 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 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/>4.0 32 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 2 32 >256 16 32 >16 S R S I R I I R R R R R R R R R Imipenem 0.25 S S
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
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 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 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
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 - + 48 14 47 K. pneumoniae - + 10 3 10
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; 16-18 h Ertapenem 19-21 mm Meropenem 16-21 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 25922 ATCC 25922 - Performed on isolates resistant to one or more agents in cephalosporin subclass III and positive screen test.
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 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 *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
Escalating Carbapenem Resistance in Acinetobacter baumannii 80 % Resistant 70 60 50 40 30 20 Ciprofloxacin Amikacin Ceftazidime Imipenem 10 0 TSAR I (1998) TSAR II (2000) TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
CRAB Increased in A. baumannii from Different Sources 70 60 50 ICU Non-ICU OPD/ER 70 60 50 Respiratory Urine Blood %CRAB 40 30 40 30 20 20 10 10 0 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)
CRAB vs. CSAB Susceptibility a -1 Antimicrobial agent % Susceptible CRAB CSAB (n = 178) (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 a CRAB, carbapenem-resistant A. baumannii; CSAB, Carbapenem-susceptible A. baumannii (TSAR VI isolates)
P. aeruginosa Resistance Resistance % 50 45 40 35 30 25 20 Gentamicin Pip/Tazo Ciprofloxacin Ceftazidime Imipenem 15 10 5 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) No. of isolates: Around 600 for each round of TSAR
Resistance in H. influenzae 80 70 60 %R 50 40 30 20 Ampicillin Trimeth./Sulfa. Levofloxacin 10 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
Resistance in S. pneumoniae 100 90 80 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008) % Resistant 70 60 50 40 30 20 10 0 Erythromycin Tetracycline Trimeth/Sulfa. (SXT) * Over half (54%) of TSAR S. pneumoniae isolates ( are resistant to these 3 antimicrobial agents
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) < 0.06 - > 0.12 Oral (penicillin V) & Before 2008 < 0.06 0.12-1 > 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)
Resistance in S. pneumoniae by Penicillin MIC 100 90 Penicillin MIC <= 1 ug/ml Penicillin MIC 2 ug/ml Penicillin MIC >=4 ug/ml 80 %R 70 60 50 20 18 16 14 40 12 10 30 20 10 0 Erythromycin TMP/SMX (SXT) Tetracycline 8 6 4 2 0 Cefepime Ceftriaxone Levofloxacin
Nosocomial MRSA Rates: USA vs. Taiwan % 90 80 70 60 50 40 30 20 10 0 Taiwan USA 1998 2000 2002 2003-2004 Year 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 Taiwan: 52% (TSAR V, 2006) of S. aureus blood isolates were MRSA EARSS, http://www.rivm.nl/earss/database/2006
100 Resistance in S. aureus TSAR VI (2008) 90 80 70 OPD/ER (N=257) Non-ICU (N= 425) ICU (N=113) HAI (N=95) % Resistant 60 50 40 30 20 10 0 Ciprofloxacin Erythromycin Gentamicin Oxacillin SXT Tetracycline
MRSA% in S. aureus from Inpatients & Outpatients 100 90 80 HAI ICU Non-ICU OPD/ER 70 % MRSA 60 50 40 30 20 10 0 TSAR I (1998) TSAR II (2000) TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
Molecular Epidemiology of Taiwan MRSA - TSAR III data (EID, 2005) 40 50 60 70 80 90 100 Pulsotype (no.) MLST SCCmec PVL CIP/GEN/SXT ICU non-icu OPD B1 ( 2 ) ST59 IVnot a-d - S/R/S 0 2 0 B2 ND 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 B5 ST59 IVnot a-d - S/R/S 0 1 0 ST59 IVnot a-d - S/R/S 0 1 0 C2 ( 4 ) ST59 V + S/S/S 0 3 1 C3 ST59 V + S/S/S 0 0 1 C5 ( 2 ) ST59 V + S/S/S 0 1 1 C6 ST59 V + S/S/S 0 1 0 C7 ND V + S/S/S 0 1 0 C4 ST59 IVa + S/S/S 0 1 0 C1 ( 8 ) ST59 (2) V + S/S/S 1 3 4 ST59 IVc - S/R/S 1 0 0 ST1 IVa - S/S/S 0 1 0 ND IVa - S/S/S 0 0 1 ST6 V - S/S/S 0 1 0 A7 ST239 III - R/R/R 0 1 0 A6 ( 4 ) ND III - R/R/R 0 4 0 A4 ND III - R/R/R 1 0 0 A3 ND III - R/R/R 0 1 0 A1 (21) ST239 III - R/R/R 7 12 2 A5 ND III - R/R/R 0 0 1 A9 ND III - R/R/R 0 1 0 A10 ND III - R/R/R 0 1 0 A2 ( 3 ) ST239 III - R/R/R 0 3 0 A11 ( 3 ) ND III - R/R/R 0 3 0 A13 ND III - R/R/R 0 1 0 A12 ( 3 ) ST239 III - R/R/R 2 1 0 A8 ND III - R/R/R 0 1 0 A17 ND III - R/R/R 0 1 0 A16 ND III - R/R/R 1 0 0 A14 ( 2 ) ND III - R/R/R 1 1 0 A15 ND III - R/R/R 0 1 0 ND IIa - R/R/S 1 0 0 ST5 IIa - R/R/S 0 1 0 ND IIa - R/R/S 0 1 0 ST573 IVc - S/R/S 0 0 1
Resistance in MRSA - TSAR III VI 100 % Resistant 90 80 70 60 50 40 Erythromycin Tetracycline Ciprofloxacin Gentamicin SXT 30 20 10 0 TSAR III (2002) TSAR IV (2004) TSAR V (2006) TSAR VI (2008)
Resistance in E. faecalis and E. faecium 100 E. faecalis E. faecium %R 90 80 70 60 50 40 30 20 10 %VRE 30 25 20 15 10 5 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)
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?
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
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: