中国细菌耐药性现状（英文版）

Bacterial Resistance in China Minggui Wang, M.D. Institute of Antibiotics Huashan Hospital, Fudan University Outline Antimicrobial Resistance and Its Mechanisms n Gram-positive cocci Streptococcus pneumoniae Staphylococcus spp. n Gram-negative bacilli Enterobacteriaceae n Escherichia coli n Klebsiella spp. n Enterobacter spp., et al. Non-fermenting gram-negative bacilli (non-fermenters) Antimicrobial Resistance in Streptococcus pneumoniae History of studies on antimicrobial resistance on Streptococcus pneumoniae 1967 1970 1978 1980 1991 2001 Spread around the world First case of PRSP First case of MDR Mechanism of PRSP Regional problem Global problem -lactams (penicillin) Macrolides Fluoroquinolones Penicillin resistance in S. pneumoniae in China in late 1990 Year Region Population Source No. of Strains PNSSP (%) PISP (%) PRSP (%) 96-99 Shanghai Adults Clinical 68 3 3 0 Children Clinical 60 13 13 0 1998 Children Carriage 222 14 14 0 1998 Guangzhou Clinical 102 12 12 0 Children Carriage 151 15 15 0 1997* Bejing Clinical 79 14 11 2 Children Carriage 244 14 13 1 99-00 4 centers Clinical 553 14 12 2 PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae * AAC 1998; 42: 2633 Penicillin resistance in S. pneumoniae in China in early 2000 Year Region Population Source No. of Strains PNSSP(%) PISP(%) PRSP(%) 2001 Shanghai Children Clinical 100 55 49 6 01-02 BeijingShenyang Clinical 192 43 32 11 00-02 3 centers Children Clinical 887 40 34 6 00-01 4 centers Children Clinical 624 41 37 4 PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae Penicillin resistance in S. pneumoniae has been increasing markedly since 2000 Increasing trends of Penicillin resistance in S. pneumoniae in China Shanghai 100 strains each year Beijing More than 100 strains each year Clinical strains isolated from Childrens Hospital Reasons causing the rapid increasing of penicillin resistance n The increasing consumption of oral penicillins such as amoxicillin n The spead of resistant colonines Difference of penicillin resistance in S. pneumoniae isolated between adults and children Year Region Population Source No. of Strains PNSSP(%) PISP(%) PRSP(%) 96-99 Shanghai Adults Clinical 68 3 3 0 Children Clinical 60 13 13 0 2004 Shanghai Adults Clinical 34 9 9 0 Children Clinical 124 70 42 28 2004 Multiple centers Adults Clinical 69 20 17 3 PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae The penicillin resistance rates were much higher in children than that in adults Resistance of S. pneumoniae to macrolides 70%-90% of S. pneumoniae clinical isolates were resistant to erythromycin Antimicrobial resistance of S. pneumoniae isolated from children in Beijing, Shanghai, Guangzhou and Xian（ 2000 2001） Mechanism of bacterial resistance: Mosaic PBP Genes in PRSP n Penicillin resistance is due to alterations in endogenous PBPs DNA from related streptococci taken up and incorporated into S. pneumoniae genes Czechoslovakia (1987) USA (1983) South Africa (1978) S SXN pen-sensitive S. pneumoniae Streptococcus ? PBP 2b Mechanisms of resistance to macrolides (Wang M. Diagn Microbial Infect Dis 2001; 39:187) n Target modification Phenotype cMLS, 90% (159/176) Phenotype iMLS, 6% (10/176) n Active efflux Phenotype M 4% (7/176) Antimicrobial Resistance in Staphylococcus spp. Trends of methicillin resistant Staphylococcus spp. (MRS) in China 5%-24% 35%-60% 50%-70% Mechanism of MRSA n MRSA contain novel PBP2a, substitutes for native PBPs; low affinity for all -lactams n PBP2a is encoded by mecA gene; expression controlled by mecI, mecR1 and other factors Summary Antimicrobial resistance in gram-positive cocci n Penicillin resistance in S. pneumoniae has been increasing markedly since 2000 in China n The resistance rates of S. pneumoniae to macrolides such as erythromycin are very high n Methicillin-resistant staphylococci are highly prevalent Antimicrobial Resistance in Enterobacteriaceae Antimicrobial resistance rates of E. coli isolated in China in 2005 (n=3758) Wang F. Chin J Infect Chemother 2006; 6: 289 Antimicrobial resistance rates of K. pneumoniae in China in 2005 (n=2234) Wang F. Chin J Infect Chemother 2006; 6: 289 Extended-spectrum -lactamases (ESBLs) in Enterobacteriaceae in China n ESBL-producing strains Hospital-acquired infections1: n E. coli, 11-47% n K. pneumoniae, 14-51% Community-acquired infections2: n E. coli, 16% n K. pneumoniae, 17% n The main genotype of ESBLs is CTX-M1, typically provides resistance to ceftaxime but often not to ceftazidime or aztreonam3 1, Xiong Z. Diagn Microbiol Infect Dis 2002; 44: 195 2, Ling TK. AAC 2006; 50: 374 3, Jacoby GA. Chin J Infect Chemother 2006; 6: 361 Quinolone resistance rates in clinical isolates of E. coli in Shanghai Mechanisms involved in quinolone resistance n Alterations in drug target enzymes (DNA gyrase and/or topoisomerase IV) n Alterations in drug accumulation (active efflux system) Both result from chromosomal mutations Target modification Efflux Plasmid-mediated quinolone resistance: qnr determinats R S R R S R Conjugation Transformation R qnr qnrA: Lancet, 1998, the U.S. qnrB: AAC, 2006, the U. S. qnrS: AAC, 2005, Japan qnrC: 7th NCCM, 2007, China Plasmid-mediated quinolone resistance n qnr family: qnrA, qnrB, qnrS, qnrC Protection of quinolone targets n aac(6)-Ib-cr (2006) aminoglycoside acetyltransferase n qepA (2007) quinolone efflux pump Summary Antimicrobial resistance in gram-negative bacilli n ESBLs-producing strains of E. coli and K. pneumoniae are common, and spreading from hospital to community n Quinolone resistance rates in E. coli are especially high n New mechanisms of plasmid- mediated quinolone resistance emerged Antimicrobial Resistance in Non-fermenting gram- negative bacilli (non-fermenters) Importance of non-fermenters n Non-fermenting gram-negative bacilli (non- fermenters) include: Pseudomonas aeruginosa Acinetobacter spp. Stenotrophomonas maltophilia Alcaligenes spp. Burkholderia spp Flavobacterium (Chryseobaterium) spp. , et al n Non-fermenters are highly resistant to commonly used antimicrobials n The infections of non-fermenters are difficult to treat with high mortality Percentage of non-fermenters in gram- negative bacilli in Shanghai hospitals (Wang F, et al. Int J Antimicrob Agents 2003; 22: 444) 1460 1632 1215 1171 1369 1661 2028 3028 3275 3005 5242 5656 4818 5819 5665 Year No of strains High incidence of non-fermenters in Gram-negative bacilli n 45% (6686/15244) of GNB were non- fermenters in CHINET (Resistance surveillance network in China) surveillance program in China in 2005 (Wang F. Chin J Infect Chemother 2006; 6: 289) n Non-fermenters increased from 41% in 1999 to 48% in 2001 in ICU clinical isolates of GNB in NPRS (Nosocomial Pathogens Resistance Surveillance) study program in China (Wang H, Chen MJ. Natl Med J China 2003; 83:385) Resistance profile of 6123 strains of non-fermenters against 8 antimicrobials in CHINET in 2005 (Wang F. Chin J Infect Chemother 2006; 6:289 ) Antimicrobial agents Resistance rate (%) Susceptibility rate (%) Ceftazidime 41 52 Cefepime 45 46 Piperacillin-tazobactam 44 49 Cefoperazone-sulbactam 23 52 Imipenem 43 54 Meropenem 43 55 Ciprofloxacin 41 48 Amikacin 46 48 Trends in antimicrobial resistance rates among strains of P. aeruginosa isolated from Shanghai hospitals(%) Antimicrobial agents 1993* (232) 2000 (1790) 2001 (2302) 2002 (2457) 2003 (2123) 2004 (2287) 2005 (2520) Piperacillin 24 31 33 30 33 33 34 Ceftazidime 8 17 21 20 20 24 19 Cefoperazone 20 26 30 29 30 31 28 Cefepime - - 17 16 17 17 15 Piperacillin-tazobactam - - 29 27 26 26 24 Ticarcillin-clavulanic acid - 37 47 47 37 43 38 Cefoperazone-sulbactam - 15 15 14 15 15 13 Imipenem 6 17 24 26 25 21 21 Meropenem - 14 21 - 17 24 23 Gentamicin 36 33 34 35 38 33 32 Amikacin 8 20 23 21 20 20 17 Ciprofloxacin 13 28 27 19 25 21 24 * Testing year, number of isolates in the parentheses Mechanisms of resistance to imipenem in P. aeruginosa n Producing of -lactamases: carbapenemases n IMP, VIM, OXA, KPC, GIM, SPM families ESBLs AmpC n Decreased permeability: lost of porin D2 n Active efflux XEfflux Inactivation Decreased permeability Trends in antimicrobial resistance rates among strains of Acinetobacter spp. isolated from Shanghai hospitals(%) Antimicrobial agents 1999* (1199) 2000 (1365) 2001 (1851) 2002 (2056) 2003 (1686) 2004 (2191) 2005 (2418) Piperacillin 41 51 44 42 49 52 57 Ceftazidime 40 46 30 38 43 45 50 Cefoperazone 64 - 57 59 65 79 - Cefepime - 33 29 29 35 37 43 Piperacillin-tazobactam 19 - 20 27 30 32 37 Ampicillin-sulbactam 11 16 19 21 19 22 30 Cefoperazone-sulbactam - - 5 6 8 9 14 Imipenem 4 3 3 2 4 4 10 Meropenem - 4 3 - 5 6 11 Gentamicin 42 49 42 41 46 50 54 Amikacin 31 33 31 31 33 36 41 Ciprofloxacin 37 45 37 38 42 46 50 * Testing year, number of isolates in the parentheses Antimicrobial resistance rates among ICU strains of Acinetobacter spp. in China between 2003 and 2004(%) (Wang H, et al. Chin J Lab Med 2005; 28: 1295) Antimicrobial agents 2003 2004 Ceftazidime 47 50 Cefepime 51 52 Piperacillin-tazobactam 27 30 Cefoperazone-sulbactam 11 13 Imipenem 4.5 18 Meropenem 4.5 17 Amikacin 41 52 Ciprofloxacin 53 59 Outbreak of carbapenem-resistant A. baumannii in Beijing and Guangzhou (Wang H, et al. Chin J Lab Med 2005; 28: 636) n MDR-AB, resistant to 3 of the following 5 drugs: Pip/TAZ, CAZ, Sul/CFP, Gen, Cip, Imi 5% in 1995 67% in 2002 in BJ 20% in 1998 57% in 2002 in GZ n 90%(35/39) strains produced OXA-23 carbapenemase n PFGE results indicated resistance colonies spread in each of 4 hospitals, mainly in patients with VAP and surgical infections Lane 1-3, 5, 8, 11-16 PFGE type A, indicating same colony Outbreak of COS-AB in Shanghai (Yang L, et al. Natl Med J China 2006; 86: 592) n Outbreak of COS- AB (colistin-only- sensitive A. baumannii) in some hospitals PFGE type B strains caused outbreak of COS -AB in burn ward in a Shanghai hospital PFGE type A strains of COS-AB spread in surgical wards Lane 5-10, 13-14, PFGE type A Lane 3-4, 12, PFGE type B Trends in antimicrobial resistance rates among strains of S. maltophilia isolated from Shanghai hospit