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

Bacterial Resistance in China Bacterial Resistance in China

Minggui Wang, M.D.Minggui Wang, M.D.

Institute of AntibioticsInstitute of AntibioticsHuashan Hospital, Fudan UniversityHuashan Hospital, Fudan University

OutlineOutline

Antimicrobial Resistance and It’s MechanismsAntimicrobial Resistance and It’s Mechanisms Gram-positive cocciGram-positive cocci

• Streptococcus pneumoniaeStreptococcus pneumoniae• Staphylococcus spp.Staphylococcus spp.

Gram-negative bacilliGram-negative bacilli• EnterobacteriaceaeEnterobacteriaceae

Escherichia coliEscherichia coli Klebsiella spp.Klebsiella spp. Enterobacter sppEnterobacter spp., et al.., et al.

• Non-fermenting gram-negative bacilli Non-fermenting gram-negative bacilli (non-fermenters)(non-fermenters)

Antimicrobial Resistance Antimicrobial Resistance

inin

Streptococcus pneumoniaeStreptococcus 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

β-lactams (penicillin)

Macrolides

Fluoroquinolones

Penicillin resistance in Penicillin resistance in S. pneumoniaeS. pneumoniae in China in late 1990’in China in late 1990’

YearYear RegionRegion PopulatiPopulationon SourceSource No. of No. of

StrainsStrainsPNSSPPNSSP

(%)(%)PISPPISP

(%)(%)PRSPPRSP

(%)(%)

96-9996-99 ShanghaiShanghai

AdultsAdults ClinicalClinical 6868 33 33 00ChildrenChildren ClinicalClinical 6060 1313 1313 00

19981998 ChildrenChildren CarriageCarriage 222222 1414 1414 00

19981998 GuangzhouGuangzhouClinicalClinical 102102 1212 1212 00

ChildrenChildren CarriageCarriage 151151 1515 1515 00

1997*1997* BejingBejingClinicalClinical 7979 1414 1111 22

ChildrenChildren Carriage Carriage 244244 1414 1313 1199-0099-00 4 centers4 centers ClinicalClinical 553553 1414 1212 22PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae

* AAC 1998; 42: 2633

Penicillin resistance in Penicillin resistance in S. pneumoniaeS. pneumoniae in China in early 2000’in China in early 2000’



(%)(%)PISPPISP

(%)(%)PRSPPRSP

(%)(%)

20012001 ShanghaiShanghai ChildrenChildren Clinical Clinical 100100 5555 4949 66

01-0201-02BeijingBeijingShenyangShenyang ClinicalClinical 192192 4343 3232 1111

00-0200-02 3 centers3 centers ChildrenChildren ClinicalClinical 887887 4040 3434 66

00-0100-01 4 centers4 centers ChildrenChildren Clinical Clinical 624624 4141 3737 44

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 ofIncreasing trends of Penicillin Penicillin resistance in resistance in S. pneumoniaeS. pneumoniae in China in China

34.7

49 50

1

611

0

10

20

30

40

50

60

70

2000 2001 2002

R

I

23 2531

2 0

5

0

10

20

30

40

50

60

70

2002 2003 2004

R

I

Shanghai100 strains each year

BeijingMore than 100 strains each year

Clinical strains isolated from Children’s Hospital

Reasons causing the rapid Reasons causing the rapid increasing of penicillin resistanceincreasing of penicillin resistance

The increasing consumption of oral peThe increasing consumption of oral penicillins such as amoxicillinnicillins such as amoxicillin

The spead of The spead of resistant resistant coloninescolonines

Difference of penicillin resistance in Difference of penicillin resistance in S. pneumoniaeS. pneumoniae isolated between adults and children isolated between adults and children



(%)(%)PISPPISP

(%)(%)PRSPPRSP

(%)(%)

96-9996-99 ShanghaiShanghaiAdultsAdults ClinicalClinical 6868 33 33 00

ChildrenChildren ClinicalClinical 6060 1313 1313 00

20042004 ShanghaiShanghaiAdultsAdults ClinicalClinical 3434 99 99 00

ChildrenChildren Clinical Clinical 124124 7070 4242 2828

20042004 Multiple Multiple centerscenters AdultsAdults ClinicalClinical 6969 2020 1717 33

PNSSP, penicillin non-susceptible S. pneumoniae; PISP, penicillin intermediate S. pneumoniae; PRSP, penicillin resistant S. pneumoniae

The penicillin resistance rates were much higher in childrenThe penicillin resistance rates were much higher in children

than that in adultsthan that in adults

Resistance of Resistance of S. pneumoniaeS. pneumoniae to to macrolidesmacrolides

70%-90%70%-90% of of S. pneumoniaeS. pneumoniae clinical isolates were resistant clinical isolates were resistant to erythromycinto erythromycin

4 07 11 7 10 7 7

0

4937

0.061

14 15

8482 76

40

0

0

10

20

30

40

50

60

70

80

90

100

RI

Antimicrobial resistance ofAntimicrobial resistance of S. pneumoniaeS. pneumoniae isolated from children in Beijing, isolated from children in Beijing, Shanghai, Guangzhou and Xi’anShanghai, Guangzhou and Xi’an （（ 20002000 －－ 20012001 ））

Mechanism of bacterial resistance:Mechanism of bacterial resistance:Mosaic PBP Genes in PRSPMosaic PBP Genes in PRSP

Penicillin resistance is due to alteratioPenicillin resistance is due to alterations in endogenous PBPsns in endogenous PBPs• DNA from related streptococci taken up anDNA from related streptococci taken up an

d incorporated into d incorporated into S. pneumoniae S. pneumoniae genesgenes

Czechoslovakia (1987)

USA (1983)

South Africa (1978)

S SXN

pen-sensitive S. pneumoniae Streptococcus ?

PBP 2b

Mechanisms of resistance to macrolidesMechanisms of resistance to macrolides(Wang M. Diagn Microbial Infect Dis 2001; 39:187)(Wang M. Diagn Microbial Infect Dis 2001; 39:187)

Target modificationTarget modification• Phenotype cMLS, 90%Phenotype cMLS, 90% (159/176)(159/176)• Phenotype iMLS, 6%Phenotype iMLS, 6% (10/176)(10/176)

Active effluxActive efflux• Phenotype M Phenotype M 4% 4% (7/176)(7/176)


inin

Staphylococcus spp.Staphylococcus spp.

Trends of methicillin resistant Trends of methicillin resistant StaphylococcusStaphylococcus spp. (MRS) in China spp. (MRS) in China

0

10

20

30

40

50

60

1980' s 1990' s 2000'

5%-24%

35%-60%

50%-70%

Mechanism of MRSAMechanism of MRSA MRSA contain novel MRSA contain novel PBP2aPBP2a, substit, substit

utes for native PBPs; low affinity futes for native PBPs; low affinity for all or all -lactams-lactams

PBP2a is encoded by PBP2a is encoded by mecAmecA gene; egene; expression controlled by mecI, mecxpression controlled by mecI, mecR1 and other factorsR1 and other factors

SummarySummaryAntimicrobial resistance in gram-positive cocciAntimicrobial 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


inin

EnterobacteriaceaeEnterobacteriaceae

Antimicrobial resistance rates of Antimicrobial resistance rates of E. coliE. coli isolated in China in 2005 (n=3758)isolated in China in 2005 (n=3758)

0

10

20

30

40

50

60

70

80

90

Ampi

cil l

i n

Pipe

raci

l li n

Cefo

taxi

me

Ceft

azi d

i me

Cefe

pime

Amp/

Sul

CFP/

Sul

Pip/

Taz

Imi p

enem

Mero

pene

m

Cipr

oflox

aci n

Ami k

aci n

SMZ-

TMP

Wang F. Chin J Infect Chemother 2006; 6: 289Wang F. Chin J Infect Chemother 2006; 6: 289

Antimicrobial resistance rates of Antimicrobial resistance rates of K. K. pneumoniaepneumoniae in China in 2005 (n=2234) in China in 2005 (n=2234)

0102030405060708090

100

Ampi

cil l

i n

Pipe

raci

l li n

Cefo

taxi

me

Ceft

azi d

i me

Cefe

pime

Amp/

Sul

CFP/

Sul

Pip/

Taz

Imi p

enem

Mero

pene

m

Cipr

oflox

aci n

Ami k

aci n

SMZ-

TMP

Wang F. Chin J Infect Chemother 2006; 6: 289Wang F. Chin J Infect Chemother 2006; 6: 289

Extended-spectrum Extended-spectrum ββ-lactamases (ESBLs)-lactamases (ESBLs) iin Enterobacteriaceae in Chinan Enterobacteriaceae in China

ESBL-producing strains ESBL-producing strains • Hospital-acquired infectionsHospital-acquired infections11::

E. coliE. coli, 11-47%, 11-47% K. pneumoniaeK. pneumoniae, 14-51%, 14-51%

• Community-acquired infectionsCommunity-acquired infections22:: E. coliE. coli, 16%, 16% K. pneumoniaeK. pneumoniae, 17%, 17%

The main genotype of ESBLs is The main genotype of ESBLs is CTX-MCTX-M11, typically pr, typically provides resistance to ceftaxime but often not to ceftovides resistance to ceftaxime but often not to ceftazidime or aztreonamazidime or aztreonam33

1, Xiong Z. Diagn Microbiol Infect Dis 2002; 44: 1952, Ling TK. AAC 2006; 50: 3743, Jacoby GA. Chin J Infect Chemother 2006; 6: 361

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

16

14

21

41

54 55 5653 53

57 5653

5558 56 55

61

0

10

20

30

40

50

60

70

Year

Res

ista

nce

rat

e (%

)

Mechanisms involved in quinolone resistanceMechanisms involved in quinolone resistance

Alterations in drug target enzymes Alterations in drug target enzymes (DNA gyrase and/or topoisomerase IV) (DNA gyrase and/or topoisomerase IV)

Alterations in drug accumulation (active Alterations in drug accumulation (active efflux system)efflux system)

Both result from chromosomal Both result from chromosomal mutations mutations

Target modification

Efflux

Plasmid-mediated quinolone resistance: Plasmid-mediated quinolone resistance: qnrqnr determinats 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 resistancePlasmid-mediated quinolone resistance

qnrqnr family: family: qnrA, qnrBqnrA, qnrB,, qnrS qnrS,, qnrC qnrC Protection of quinolone targetsProtection of quinolone targets aac(6’)-Ib-cr aac(6’)-Ib-cr (2006)(2006) aminoglycoside acetyltransferaseaminoglycoside acetyltransferase qepA qepA (2007)(2007) qquinolone uinolone eefflux fflux ppump ump

SummarySummaryAntimicrobial resistance in gram-negative bacilliAntimicrobial resistance in gram-negative bacilli

ESBLs-producing strains of ESBLs-producing strains of E. coliE. coli and and K. K. pneumoniaepneumoniae are common, and spreadin are common, and spreading from hospital to communityg from hospital to community

Quinolone resistance rates in Quinolone resistance rates in E. coliE. coli are are especially highespecially high

New mechanisms of plasmid-mediated New mechanisms of plasmid-mediated quinolone resistance emergedquinolone resistance emerged


inin

Non-fermenting gram-Non-fermenting gram-negative bacilli negative bacilli

(non-fermenters)(non-fermenters)

Importance of non-fermentersImportance of non-fermenters Non-fermenting gram-negative bacilli (non-fermentNon-fermenting gram-negative bacilli (non-ferment

ers) include:ers) include:• Pseudomonas aeruginosaPseudomonas aeruginosa• AcinetobacterAcinetobacter spp. spp.• Stenotrophomonas maltophiliaStenotrophomonas maltophilia• AlcaligenesAlcaligenes spp. spp.• BurkholderiaBurkholderia spp spp• FlavobacteriumFlavobacterium ( (ChryseobateriumChryseobaterium) spp. , et al) spp. , et al

Non-fermenters are highly resistant to commonly usNon-fermenters are highly resistant to commonly used antimicrobialsed antimicrobials

The infections of non-fermenters are difficult to treaThe infections of non-fermenters are difficult to treat with high mortalityt with high mortality

Percentage of non-fermenters in gram-negatPercentage of non-fermenters in gram-negative bacilli in Shanghai hospitalsive bacilli in Shanghai hospitals

((Wang F, et al. Int J Antimicrob Agents 2003; 22: 444)Wang F, et al. Int J Antimicrob Agents 2003; 22: 444)

2625

26

23

28

30

26

32

34 3435 35

3334

35

20

22

24

26

28

30

32

34

36

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Perc

enta

ge (

%)

14601460 16321632 12151215 11711171 13691369 16611661 20282028 30283028 32753275 30053005 52425242 56565656 48184818 58195819 56655665

YearYear

No of strainsNo of strains

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

Resistance profile of 6123 strains of non-fermenters Resistance profile of 6123 strains of non-fermenters against 8 antimicrobials in CHINET in 2005against 8 antimicrobials in CHINET in 2005

(Wang F. Chin J Infect Chemother 2006; 6:289 ) (Wang F. Chin J Infect Chemother 2006; 6:289 )

Antimicrobial agentsAntimicrobial agents Resistance Resistance rate (%)rate (%)

Susceptibility Susceptibility rate (%)rate (%)

CeftazidimeCeftazidime 4141 5252CefepimeCefepime 4545 4646Piperacillin-tazobactamPiperacillin-tazobactam 4444 4949Cefoperazone-sulbactamCefoperazone-sulbactam 2323 5252Imipenem Imipenem 4343 5454MeropenemMeropenem 4343 5555CiprofloxacinCiprofloxacin 4141 4848AmikacinAmikacin 4646 4848

Trends in antimicrobial resistance rates among strains Trends in antimicrobial resistance rates among strains of of P. aeruginosaP. aeruginosa isolated from Shanghai hospitals(%) isolated from Shanghai hospitals(%)

Antimicrobial agentsAntimicrobial agents 1993*1993*

(232)(232)20002000(1790(1790

))

20012001(2302(2302

))

20022002(2457)(2457)

20032003(2123)(2123)

20042004(2287(2287

))

20052005(2520)(2520)

PiperacillinPiperacillin 2424 3131 3333 3030 3333 3333 3434

CeftazidimeCeftazidime 88 1717 2121 2020 2020 2424 1919

Cefoperazone Cefoperazone 2020 2626 3030 2929 3030 3131 2828

CefepimeCefepime -- -- 1717 1616 1717 1717 1515

Piperacillin-tazobactamPiperacillin-tazobactam -- -- 2929 2727 2626 2626 2424

Ticarcillin-clavulanic acidTicarcillin-clavulanic acid -- 3737 4747 4747 3737 4343 3838

Cefoperazone-sulbactamCefoperazone-sulbactam -- 1515 1515 1414 1515 1515 1313

Imipenem Imipenem 66 1717 2424 2626 2525 2121 2121

Meropenem Meropenem -- 1414 2121 -- 1717 2424 2323

Gentamicin Gentamicin 3636 3333 3434 3535 3838 3333 3232

Amikacin Amikacin 88 2020 2323 2121 2020 2020 1717

Ciprofloxacin Ciprofloxacin 1313 2828 2727 1919 2525 2121 2424* Testing year, number of isolates in the parentheses

Mechanisms of resistance to Mechanisms of resistance to imipenem in imipenem in P. aeruginosaP. aeruginosa

Producing of Producing of ββ-lactamases:-lactamases:• carbapenemasescarbapenemases

IMP, VIM, OXA, KPC, GIM, SPM familiesIMP, VIM, OXA, KPC, GIM, SPM families• ESBLsESBLs• AmpCAmpC

Decreased permeability: lost of porin D2 lost of porin D2 Active effluxActive efflux

XEfflux

Inactivation

Decreasedpermeability

Trends in antimicrobial resistance rates among strains of Trends in antimicrobial resistance rates among strains of Acinetobacter spp.Acinetobacter spp. isolated from Shanghai hospitals(%) isolated from Shanghai hospitals(%)

Antimicrobial agentsAntimicrobial agents 1999*1999*(1199)(1199)

20002000(1365(1365

))

20012001(1851(1851

))

20022002(2056)(2056)

20032003(1686)(1686)

20042004(2191)(2191)

20052005(2418)(2418)



Cefoperazone Cefoperazone 6464 -- 5757 5959 6565 7979 --

CefepimeCefepime -- 3333 2929 2929 3535 3737 4343

Piperacillin-tazobactamPiperacillin-tazobactam 1919 -- 2020 2727 3030 3232 3737

Ampicillin-sulbactamAmpicillin-sulbactam 1111 1616 1919 2121 1919 2222 3030

Cefoperazone-sulbactamCefoperazone-sulbactam -- -- 55 66 88 99 1414


Meropenem Meropenem -- 44 33 -- 55 66 1111



Ciprofloxacin Ciprofloxacin 3737 4545 3737 3838 4242 4646 5050

* Testing year, number of isolates in the parentheses

Antimicrobial resistance rates among ICU strains of Antimicrobial resistance rates among ICU strains of AcinetobacterAcinetobacter spp. in China between 2003 and spp. in China between 2003 and

2004(%)2004(%) ( (Wang H, et al. Chin J Lab Med 2005; 28: 1295)

Antimicrobial agentsAntimicrobial agents 20032003 20042004

CeftazidimeCeftazidime 4747 5050

CefepimeCefepime 5151 5252

Piperacillin-tazobactamPiperacillin-tazobactam 2727 3030

Cefoperazone-sulbactamCefoperazone-sulbactam 1111 1313

Imipenem Imipenem 4.54.5 1818

MeropenemMeropenem 4.54.5 1717

Amikacin Amikacin 4141 5252

Ciprofloxacin Ciprofloxacin 5353 5959

Outbreak of carbapenem-resistant Outbreak of carbapenem-resistant A. baumanA. baumanniinii in Beijing and Guangzhou in Beijing and Guangzhou(Wang H, et al. Chin J Lab Med 2005; 28: 636)(Wang H, et al. Chin J Lab Med 2005; 28: 636)

MDR-AB, resistant to 3 of the follMDR-AB, resistant to 3 of the following 5 drugs: Pip/TAZ, CAZ, Sul/owing 5 drugs: Pip/TAZ, CAZ, Sul/CFP, Gen, Cip, ImiCFP, Gen, Cip, Imi

5% in 1995 → 67% in 2002 in BJ5% in 1995 → 67% in 2002 in BJ 20% in 1998 → 57% in 2002 in GZ20% in 1998 → 57% in 2002 in GZ 90%(35/39) strains produced 90%(35/39) strains produced OXOX

A-23A-23 carbapenemase carbapenemase PFGE results indicated resistance PFGE results indicated resistance

colonies spread in each of 4 hospcolonies spread in each of 4 hospitals, mainly in patients with VAP itals, mainly in patients with VAP and surgical infectionsand surgical infections

Lane 1-3, 5, 8, 11-16 PFGE type A, indicating same colony

Outbreak of COS-AB in ShanghaiOutbreak of COS-AB in Shanghai(Yang L, et al. Natl Med J China 2006; 86: 592)(Yang L, et al. Natl Med J China 2006; 86: 592)

Outbreak of COS-AB Outbreak of COS-AB (colistin-only-sensiti(colistin-only-sensitive ve A. baumanniiA. baumannii) in s) in some hospitalsome hospitals• PFGE type B strains causePFGE type B strains cause

d outbreak of COS-AB in bd outbreak of COS-AB in burn ward in a Shanghai hourn ward in a Shanghai hospitalspital

• PFGE type A strains of COPFGE type A strains of COS-AB spread in surgical waS-AB spread in surgical wardsrds

Lane 5-10, 13-14, PFGE type A

Lane 3-4, 12, PFGE type B

Trends in antimicrobial resistance rates among strains Trends in antimicrobial resistance rates among strains of of S. maltophiliaS. maltophilia isolated from Shanghai hospitals(%) isolated from Shanghai hospitals(%)

Antimicrobial agentsAntimicrobial agents 1999*1999*

(271)(271)20002000(323)(323)

20012001(581)(581)

20022002(573)(573)

20032003(448)(448)

20042004(583)(583)

20052005(751)(751)



Cefoperazone Cefoperazone 3838 2727 2222 3333 3333 4444 4242

CefepimeCefepime -- -- 3636 4949 3838 4646 4848

Piperacillin-tazobactamPiperacillin-tazobactam -- -- 4040 5151 5656 5757 5353

Ticarcillin-clavulanic acidTicarcillin-clavulanic acid 3636 2323 1313 3333 2626 3030 3535

Cefoperazone-sulbactamCefoperazone-sulbactam -- 1414 99 1818 1717 1818 2222


Meropenem Meropenem -- 8989 6565 5050 7979 8585 8383



CiprofloxacinCiprofloxacin 1313 1818 1717 1212 1313 1919 2222Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole 3131 2424 1515 1313 3131 2121 2020

SummarySummaryAntimicrobial resistance in non-fermentersAntimicrobial resistance in non-fermenters

The isolation of non-fermenters has beeThe isolation of non-fermenters has been increasing in recent yearsn increasing in recent years

The resistance rates of non-fermenters hThe resistance rates of non-fermenters have been increasingave been increasing

More than 20% strains of More than 20% strains of P. aeruginosaP. aeruginosa a are resistant to imipenemre resistant to imipenem

There were reports of outbreak of carbaThere were reports of outbreak of carbapenem-resistant penem-resistant A. baumanniiA. baumannii

ConclusionsConclusions

Antimicrobial resistance becomes a Antimicrobial resistance becomes a big problem in the field of Infectious big problem in the field of Infectious Diseases in ChinaDiseases in China

Rational use of antimicrobials is the Rational use of antimicrobials is the most important way to decrease or most important way to decrease or hinder antimicrobial resistance hinder antimicrobial resistance

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