Bacterial Resistance in China Minggui Wang, M.D. Institute of Antibiotics Huashan Hospital, Fudan University

Antimicrobial Resistance and It’s Mechanisms Outline Antimicrobial Resistance and It’s Mechanisms Gram-positive cocci Streptococcus pneumoniae Staphylococcus spp. Gram-negative bacilli Enterobacteriaceae Escherichia coli Klebsiella spp. Enterobacter spp., et al. Non-fermenting gram-negative bacilli (non-fermenters)

Antimicrobial Resistance Streptococcus pneumoniae in Streptococcus pneumoniae

β-lactams (penicillin) 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 We can summarize the evolution of pneumococcal resistance by several historical events. About 30 years ago, Dr. Hansman and Dr. Bullen first reported the isolation of penicillin-nonsusceptible strain in clinical specimen. 10 years later, Dr. Michael Jacobs in South Africa first reported the emergence of multidrug-resistance. But, pneumococcal resistance had been regarded as one of the regional problems in 1980s. In 1991, Dr. Munoz in Spain first documented the intercontinental spread of serotype 23f resistant clone from Spain to Ohio, United States. In 1990s, many countries reported the increasing prevalence of pneumococcal resistance. And pneumococcal resistance became a global issue in 1990s. Pneumococcal resistance will remain a major issue in the 21st century. β-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 Children 60 13 1998 Carriage 222 14 Guangzhou 102 12 151 15 1997* Bejing 79 11 2 244 1 99-00 4 centers 553 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’ Penicillin resistance in S. pneumoniae has been increasing markedly since 2000 Year Region Population Source No. of Strains PNSSP (%) PISP PRSP 2001 Shanghai Children Clinical 100 55 49 6 01-02 Beijing Shenyang 192 43 32 11 00-02 3 centers 887 40 34 00-01 4 centers 624 41 37 4 PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae

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 Children’s Hospital

Reasons causing the rapid increasing of penicillin resistance The increasing consumption of oral penicillins such as amoxicillin The spead of resistant colonines

The penicillin resistance rates were much higher in children Difference of penicillin resistance in S. pneumoniae isolated between adults and children The penicillin resistance rates were much higher in children than that in adults Year Region Population Source No. of Strains PNSSP (%) PISP PRSP 96-99 Shanghai Adults Clinical 68 3 Children 60 13 2004 34 9 124 70 42 28 Multiple centers 69 20 17 PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae

Resistance of S. pneumoniae to macrolides 70%-90% of S. pneumoniae clinical isolates were resistant to erythromycin

Antimicrobial resistance of S Antimicrobial resistance of S. pneumoniae isolated from children in Beijing, Shanghai, Guangzhou and Xi’an（2000－2001）

Mechanism of bacterial resistance: Mosaic PBP Genes in PRSP 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 Mechanisms of resistance to macrolides (Wang M. Diagn Microbial Infect Dis 2001; 39:187) Target modification Phenotype cMLS, 90% (159/176) Phenotype iMLS, 6% (10/176) Active efflux Phenotype M 4% (7/176)

Antimicrobial Resistance in Staphylococcus spp.

Trends of methicillin resistant Staphylococcus spp. (MRS) in China 50%-70% 35%-60% 5%-24%

Mechanism of MRSA MRSA contain novel PBP2a, substitutes for native PBPs; low affinity for all -lactams PBP2a is encoded by mecA gene; expression controlled by mecI, mecR1 and other factors

Summary Antimicrobial resistance in gram-positive cocci Penicillin resistance in S. pneumoniae has been increasing markedly since 2000 in China The resistance rates of S. pneumoniae to macrolides such as erythromycin are very high Methicillin-resistant staphylococci are highly prevalent

Antimicrobial Resistance in Enterobacteriaceae

Antimicrobial resistance rates of E 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 Antimicrobial resistance rates of K. pneumoniae in China in 2005 (n=2234) Wang F. Chin J Infect Chemother 2006; 6: 289

Extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae in China ESBL-producing strains Hospital-acquired infections1: E. coli, 11-47% K. pneumoniae, 14-51% Community-acquired infections2: E. coli, 16% K. pneumoniae, 17% 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 Alterations in drug target enzymes (DNA gyrase and/or topoisomerase IV) Alterations in drug accumulation (active efflux system) Both result from chromosomal mutations Efflux Target modification

Plasmid-mediated quinolone resistance: qnr determinats Conjugation Transformation 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 qnr family: qnrA, qnrB, qnrS, qnrC Protection of quinolone targets aac(6’)-Ib-cr (2006) aminoglycoside acetyltransferase qepA (2007) quinolone efflux pump

Summary Antimicrobial resistance in gram-negative bacilli ESBLs-producing strains of E. coli and K. pneumoniae are common, and spreading from hospital to community Quinolone resistance rates in E. coli are especially high New mechanisms of plasmid-mediated quinolone resistance emerged

Antimicrobial Resistance Non-fermenting gram-negative bacilli (non-fermenters)

Importance of non-fermenters Non-fermenting gram-negative bacilli (non-fermenters) include: Pseudomonas aeruginosa Acinetobacter spp. Stenotrophomonas maltophilia Alcaligenes spp. Burkholderia spp Flavobacterium (Chryseobaterium) spp. , et al Non-fermenters are highly resistant to commonly used antimicrobials 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) Year No of strains 1460 1632 1215 1171 1369 1661 2028 3028 3275 3005 5242 5656 4818 5819 5665

High incidence of non-fermenters in Gram-negative bacilli 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) 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)

Susceptibility rate (%) 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 Imipenem 43 54 Meropenem 55 Ciprofloxacin 48 Amikacin

Trends in antimicrobial resistance rates among strains of P 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 34 Ceftazidime 8 17 21 20 19 Cefoperazone 26 29 28 Cefepime - 16 15 Piperacillin-tazobactam 27 Ticarcillin-clavulanic acid 37 47 43 38 Cefoperazone-sulbactam 14 13 Imipenem 6 25 Meropenem 23 Gentamicin 36 35 32 Amikacin Ciprofloxacin * Testing year, number of isolates in the parentheses

Mechanisms of resistance to imipenem in P. aeruginosa Producing of β-lactamases: carbapenemases IMP, VIM, OXA, KPC, GIM, SPM families ESBLs AmpC Decreased permeability: lost of porin D2 Active efflux X Efflux 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 - 59 65 79 Cefepime 33 29 35 37 Piperacillin-tazobactam 19 20 27 32 Ampicillin-sulbactam 11 16 21 22 Cefoperazone-sulbactam 5 6 8 9 14 Imipenem 4 3 2 10 Meropenem Gentamicin 54 Amikacin 31 36 Ciprofloxacin * Testing year, number of isolates in the parentheses

Antimicrobial resistance rates among ICU strains of Acinetobacter spp 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 17 Amikacin 41 Ciprofloxacin 53 59

Outbreak of carbapenem-resistant A Outbreak of carbapenem-resistant A. baumannii in Beijing and Guangzhou (Wang H, et al. Chin J Lab Med 2005; 28: 636) 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 90%(35/39) strains produced OXA-23 carbapenemase 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 Outbreak of COS-AB in Shanghai (Yang L, et al. Natl Med J China 2006; 86: 592) 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 Trends in antimicrobial resistance rates among strains of S. maltophilia isolated from Shanghai hospitals(%) Antimicrobial agents 1999* (271) 2000 (323) 2001 (581) 2002 (573) 2003 (448) 2004 (583) 2005 (751) Piperacillin 69 77 59 65 68 74 73 Ceftazidime 53 37 33 40 38 Cefoperazone 27 22 44 42 Cefepime - 36 49 46 48 Piperacillin-tazobactam 51 56 57 Ticarcillin-clavulanic acid 23 13 26 30 35 Cefoperazone-sulbactam 14 9 18 17 Imipenem 91 96 98 97 Meropenem 89 50 79 85 83 Gentamicin 70 75 78 76 Amikacin 71 Ciprofloxacin 12 19 Trimethoprim-sulfamethoxazole 31 24 15 21 20

Summary Antimicrobial resistance in non-fermenters The isolation of non-fermenters has been increasing in recent years The resistance rates of non-fermenters have been increasing More than 20% strains of P. aeruginosa are resistant to imipenem There were reports of outbreak of carbapenem-resistant A. baumannii

Conclusions Antimicrobial resistance becomes a big problem in the field of Infectious Diseases in China Rational use of antimicrobials is the most important way to decrease or hinder antimicrobial resistance

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