Antibiotic Resistancein Belgium :

Current Situation 2005

Marc StruelensService de microbiologie

Hopital Erasme

PEN ERY CLI DOT

GEN KAN SXT CIP

MIN RIF FUC MUP

OXA

The Clinical Challenge ofAntimicrobial Resistance

• Inapropriate antimicrobial therapyincreases the mortality in severe infection

• Infection with antibiotic resistant bacteriaincreases the risk of inappropriate therapy

• Drug spectrum escalation drives excessmedication costs & selective pressure

Impact of antimicrobial treatment appropriateness on patient outcome

(904 cases of microbiologically documented severe sepsis)

0 10 20 300

25

50

75

100Appropriate treatment

Inappropriate treatment

Prob

abili

ty o

f sur

viva

l (%

)

Log-rank test, P < 0.001Adjusted OR = 1.8 (CI95, 1.2-2.6)

Harbarth et al. Am J Med 2003

Microbial etiology and treatment appropriateness in severe sepsis

(904 cases of microbiologically documented severe sepsis)

Inappropriate Antimicrobial

Therapy (n = 211)

Appropriate Antimicrobial

Therapy(n = 693)

- Adequately treated bacteriaStreptococcus pneumoniaeEscherichia coliMethicillin-sensitive S. aureus

- Inadequately treated bacteriaMRSAPseudomonas aeruginosaEnterobacter sppAcinetobacter or Stenotrophomonas

74736

12402428

130176105

8423211

Harbarth et al. Am J Med 2003

The Public Health Challengeof Resistance

• Alert for transmissible resistance– Clonal spread– Gene epidemics

• Early detection enhances efficacy ofinfection control

• Reducing the antibiotic selective pressure by streamlining therapy

MRSA in the UK Press

The Challenging PathogensHealthcare Community

• MDR- Strep. pneumoniae• CA- MRSA• Salmonella (ESBL, FQ)• Campylobacter (FQ,

Macrolides)• Helicobacter pylori• MDR-Tuberculosis

• Staphylococcus aureus(MRSA, GISA, GRSA)

• Enterococci (GRE)• Enterobacteriaceae

(ESBL, carbapenemase, FQ)

• MDR-Pseudomonasaeruginosa

• MDR-Acinetobacterbaumannii

MRSA Proportion in S.aureusBacteremia, EARSS 2003

No data

<1%

1-5%

5-10%

10–25%

25-50%

http://www.earss.nivm.nl.

No data

<1%

1-5%

5-10%

10–25%

25-50%

http://www.earss.nivm.nl.

Trends in MRSA bacteraemia, EARSS, 1999-2004

05

101520253035404550

Neth Den Fin Swe Aus Ger Bel UK Italy Ire

% S

. aur

eus

199920002001200220032004

http://www.earss.rivm.nl

Incidence of Nosocomial MRSABelgium, 1994-2004

3 ,5

3 ,03 ,3

2 ,6

2 ,2

2 ,8

2 ,52 ,6

1 ,8 1 ,8

2 ,42 ,2

1 ,9

2 ,5 2 ,6

3 ,23 ,1

3 ,5

3 ,2

3 ,5

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

Périodes de surveillance

Inci

denc

e m

oyen

ne g

loba

le/1

000

adm

issi

ons

Jans ISP NSIH MRSA Report 2004

Decrease in nosocomial vs imported MRSA,

Belgium, 1994-2004

0102030405060708090

100

n-M

RSA

/MR

SA g

loba

l (%

)

94/2

95/2

96/2

97/2

98/2

99/2

00/2

01/2

02/2

03/2

Période de surveillance

MRSA nosocomial (échant. clin)

Evolution of geographic distribution of epidemic MRSA PFGE types A1, A20, B2

1995 2001

Denis AAC 2004;48:3625

1995 2001

•♦

♦

♦

♦

♦

♦

••

•

•

•

♦ ••

•• Type B2, ST45-IV• TypeA1, ST247-I♦ Types A20 et A21, ST8-IV• Type G10, ST5-II♦ Type C3, ST5-IV• Type L1, ST22-IV

•

••

•

•

♦ •

Enright et al. PNAS 2002 99:7687Aires de Sousa et al. JCM 2003:3806Melter et al. JCM 2003:4998Denis et al. AAC 2004:3625

••

•

•

• •

•

•

•

•

••

MRSA Co-resistance to non β-lactamsHospitalised patients, Belgium 1995-2003

0%

10%

20%

30%

40%

1 2 3 4 5 6 7 8 9 10 11

Number of drug resistance

% o

f st

rain

s

1995 2003

MRSA resistance to aminoglycosides, Belgium, 1995-2003

0

25

50

75

100

Genta Tobra Amika

% o

f str

ains

resi

stan

t to

1995199720012003

Denis O. et al. Microb Drug Resist. 2003;9:61Denis O. et al. Antimicrob. Agents Chemother. 2004;48:3625Denis O. et al. 15th ECCMID P1570; Copenhagen, Denmark

Proportion of MRSA strains carrying AME genes

Belgium, National Survey 2001

aac(6’)-aph(2“)

ant(4’)

aph(3’)

2% 4%

35%

0.4%

06%

None53%

0

Denis Antimicrob. Agents Chemother. 2004;48:3625

MLSb constitutive resistance phenotype

PEN ERY CLI DOX

GEN KAN SXT CIP

MIN RIF FUC MUP

OXA

MLSb inducible resistance phenotype

PEN ERY CLI DOX

GENKAN SXT CIP

MIN RIF FUCMUP

OXA

Proportion of MRSA strains withMLS resistance genes, Belgium 2001

ermAermCermA + ermCNone

35

30

34

Denis Antimicrob. Agents Chemother. 2004;48:3625

Macrolide-Lincosamide-StreptograminResistance in MRSA and MSSA isolates

Belgium National Survey, 2003

63

43

0

22

4 00

25

50

75

100

Erythro Clinda Q-D

% o

f str

ains

resi

stan

t to

MRSA (n=512)MSSA (n=102)

70 % inducible MLSb

The Shadow Mutant:Vancomycin Intermediate S.aureus / VISA

Denis JAC 2002;50:383

Electron microscopy X 60.000

VISA strain - P1V44 Vancomycin MIC 8 mg/l

S.aureus ATCC 29213

S.aureus Glycopeptide Resistance• Definitions

– GISA : MIC > 4 µg/m for vancomycin or > 8 µg/ml for teicoplanin– Hetero-GISA : sub-population (10-6) able to grow at ≥ 4 µg/ml

vancomycin or at ≥ 8 µg/ml teicoplanin

• National surveys in Belgium• (Denis Microb Drug Resist. 2003;9:61;Nonhoff CMI 2005;11:214)

– Hetero-VISA : from 1.7H% in 1997 to 0.7% in 2001– Hetero-TISA : 2.7% in 2001– PFGE group A (69%) and group D (31%)

• Local surveys in Belgium– Van Eldere (37th ICAAC 1997) : Outbreak of TISA in ICU– Denis (JAC 2002; 50:755) : First Belgian VISA infection– Pierard (Pathol Biol 2004;52:486): 0.6 % hVISA– Glupczynski (ECCMID 2005 P870): 1.5 % hGISA

Population analysis of MRSA isolates with decreased teicoplanin susceptibility,

Belgium, 2001

0

2

4

6

8

10

0 2 4 6 8 10 12 14 16

Teicoplanin (mg/l)

CFU

/ml (

log)

HIP5827ATCC29213Mu3105124151202209242245254412421469632703

Nonhoff Clin. Microbiol. Infect. 2005

Community-Acquired PVL (+)-MRSA :Furonculosis & Necrotizing Pneumonia

Emergence since 1990s Australia, USA, Asia, Europe

Healthy children & young adultsNew disease

Demographic characteristics of 16 patientswith PVL positive MRSA strains, Belgium

Median age (range) 24 (1-70) yrs

Previous beta-lactam therapy 5Familial transmission 1

SexMale 7Female 9

AcquisitionCommunity 15Hospital 1

Travel abroad (Tunisia, Egypt, Ecuador) 3

Denis ECCMID 2005

Clinical origin of 16 PVL positive MRSA strains from Belgium

Community-acquired infections (n = 15)Skin and soft tissue abscesses 8Furonculosis 3

Wound infection 1Cellulitis with bacteremia 1

Hospital-acquired infection (n = 1)

Post-surgical peritonitis 1

Colonization 2

• CA-MRSA PFGE Group X-ST80-IV

• CA-MRSA PFGE Group J-ST30-IV

• CA-MRSA PFGE Group A-ST8-IV

• CA-MRSA PFGE Group Y-ST88-IV

•

•

•

•

•

•••

•

••••

••

Antimicrobial resistance ofPVL-positive MRSA strains

0

25

50

75

100

Tetra Fusi Kana Erythro

% o

f str

ains

resi

stan

t to

96

9

1

Molecular characteristics ofPVL-positive MRSA strains,

Belgium 2002-04

PFGEGroup

MLST SCCmec agr spa No of strains

t044 8

1

1

3

2

Y ST88 IV 3 t186 1

* 1 repeat deletion from t044 , ** single allele variant of ST80

t131*

t044

t008

t019

X ST80 IV 3

X ST80 IV 3

X ST153** IV 3

A ST8 IV 1

J ST30 IV 3

Epidemiology of ESBL-producingEnterobacteria

• Clonal outbreaksinter-hospital epidemic spread by transfer of colonised

patients (France, USA, Belgium,…)

• Plasmid epidemics

• ESBL-producing strains often co-resistant to fluoroquinolones, SXT and aminoglycosides

lens 18/06/03

Geographic distribution of E. aerogenes isolates(n=260)

BE 1

BE 2

?

TEM-24

TEM-3(de Champs. ICAAC,

SFO,1999)

Enterobacter aerogenesPersistence of multi resistant E. aerogenes in Belgium

• Second multicentric survey403 strains from 87 centres– Proportion of MREA: 60%– Incidence of MREA: 3.2/1000

admissions

• stable proportion of ESBL-producing strains– 61% in 2000, 54% in 2003– Co-resistance CAZ and CIP in

99%

14

45

9185

23

70

99 9992

99

15

0

10

20

30

40

50

60

70

80

90

100

CAZ

CTX

FEPIM

I_MEM AK GM CIP

2000-01 2003

% of susceptible strains

De Gheldre, ECCMID 2004, P1122

Escherichia coliEARSS surveillance in Belgium 2002

48.5

6

13.3

3.1 1.9

0

10

20

30

40

50

60

% Resist

Ampi Genta/Tobra FQ C3 ESBL

% ESBL

• n=1185 from blood or CSF

• Prevalence of ESBL: 1.9%

Hendrickx, ECCMID 2004, P1123

ESBL-producing EnterobacteriaceaeHôpital Erasme-ULB 2000-2004

E. aerogenes29%

E. cloacae23%

C. amalonaticus0%

Autres5%

K. pneumoniae10%

E. coli29%

K. oxytoca3%

M. morganii1%

S. marcescens1%

K. ornithinolitica0%

P. stuartii1%

P. mirabilis1%

C. freundii2%

N= 847 ESBL-producing strains from 725 patients

Rodriguez, ECCMID 2005, P429

ESBL-producing EnterobacteriaceaeHôpital Mont-Godinne-UCL 2003-2004

N=80 isolates (7% Enterobacteriaceae)

E. aerogenes64%

E. coli20%

K. pneumoniae5%

K. oxytoca3%

C. freundii6%

P. mirabilis1% E. cloacae

1%

De Gheldre ECCMID 2005, P432

•Diversity of ESBL types

•Emergence of CTX-M group

ESBL-producing E. cloacae in ICU pts by cloneHôpital Erasme, 2000-03

0

2

4

6

8

10

12

aoûtoctdécfév avriljuinaoûtoctdécfév avriljuinaoûtoctdécfév avriljuinaoûtoct

Type PFGE A Type PFGE K Type PFGE LType PFGE Q Other type

No. patient

G P

2000 2001 2002 2003

3 major clones and 10 sporadic clonesSHV+CTX-M ESBL (80% of ESBL)

Frankard, ECCMID 2004

ESBL-producing EnterobacteriaceaePrevalence by species, Hôpital Erasme-ULB, 2000-2004

0

10

20

30

40

50

60

70

80

2000 2001 2002 2003 2004year

n° o

f iso

late

s

E. aerogenesE. cloacaeE. coliK. pneumoniaeLinéaire (E. coli)

p<0.001

0.92 % 1.25 % 1.85 % 2.34 % 3.40 %

Percentage of ESBL producing E. coli

ESBL gene families by speciesErasme Hospital-ULB 2000-2003

0%10%20%30%40%50%60%70%80%90%

100%

E.aerogenes E. cloacae E. coli K.pneumoniae

TEM SHV CTX-M

TEM+CTX-M TEM+SHV CTX-M+SHV

TEM+SHV+CTX-M

N=201 N=58N=103N=272

Increase of CTX-M enzymes among ESBL producing E.coli

Erasme Hospital – ULB, 2000-04

year

0

10

20

30

40

50

60

70

2000 2001 2002 2003 2004

Num

ber o

f cas

es

CTX-M

TEM

SHV

H. Rodriguez. Eurosurveillance Vol 10 .2005

Community-associated emergence of CTX-M/TEM ESBL-producing E.coli

H. Rodriguez. Eurosurveillance Vol 10 .2005

Nosocomial59%

Community associated

24%

Prior hospitalization

17%

Antibiotic resistance in P.aeruginosa:reduced outer membrane

permeability

Antibiotic resistance in P.aeruginosa:

Active efflux systems

MexB/D/F/Y Inner membrane

Outer membraneOprM/J/N

pump

MexA/C/E/X

porin

bridge Periplasmic space

Belgian national survey 2002:b-lactam resistance in

P.aeruginosaVan Eldere JAC 2003

Drug S I R

Pip-tazo 82,5% 17,5%

Cefta 59,0% 12,5% 28,5%

Cefep 50,5% 20% 29,5%

Mero 81,5% 9% 9,5%

J Clin Microbiol 2005;43:1198

Antibiotic Resistance BelgiumCurrent Situation 2005

• Major challenges:– MRSA, ESBL-Enterobacteriaceae,

P.aeruginosa… & others!

• Blurring frontier between community andhospital reservoirs requires new studies

• Need for consolidation of initiatives by BAPCOC & federal platform for hygiene

• Need for concerted international action