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

2. 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)

3. Antimicrobial Resistance Streptococcus pneumoniaein
Streptococcus pneumoniae

4. β-lactams (penicillin)
History of studies on antimicrobial resistance on Streptococcus pneumoniae
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

5. 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

6. 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

7. 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

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

9. 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

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

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

12. 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

13. 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)

14. Antimicrobial Resistancein
Staphylococcus spp.

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

16. 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

17. 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

18. Antimicrobial Resistancein
Enterobacteriaceae

19. 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

20. 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

21. 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

22. Quinolone resistance rates in clinical isolates of E. coli in Shanghai

23. 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

24. 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

25. 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

26. 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

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

28. 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

29. 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

30. 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)

31. Susceptibility rate (%)
Resistance profile of 6123 strains of non-fermenters against 8 antimicrobials in CHINET in (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

32. 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

33. 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

34. 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

35. 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

36. 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, PFGE type A, indicating same colony

37. 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

38. 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

39. 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

40. 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

41. Huashan Hospital, Bird View
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