Rational use of antimicrobial

substances: Surveillance of
antimicrobial consumption

Hajo Grundmann

National Institute for Public Health and

the Environment, Bilthoven
Rijksuniversiteit Groningen, NL

1
Topics
‰ Why are antibiotics so popular ?

‰ Do we need surveillance of antimicrobial

consumption ?

‰ Is intensive livestock farming a threat to

antimicrobial effectiveness ?

‰ What explains the success of VRE ?

‰ Are there analogies with FQREC ?

‰ Conclusions

2
Medical anthropological
considerations (1)
‰ Health seeking behaviour

‰ Patients make rational choices

‰ Depending on the explanation for illness

‰ Illness is a social construct

‰ Disease is the anatomical/patho-

physiological manifestation frequently
underlying an illness

3
Medical anthropological
considerations (2)
‰ Patients expect and are expected to receive
treatment of their illness….

‰ …and not necessarily for their disease

‰ Health seeking behaviour is guided by the

prevailing illness paradigm (Explanatory
Model)

4
Medical anthropological
considerations: explanatory models
‰ The germ theory provides such an
Explanatory Model

‰ Since the early 20th century germ theory is

increasingly replacing competing EMs

‰ Germ theory is compelling, and …

‰ ….germs (microbial pathogens) are a

necessary cause but hardly ever the
sufficient cause for infectious diseases

5
Medical anthropological
considerations: the success of the
germ theory
‰ The latest advances of the germ theory as a
prevailing EM is found in Africa in the wake
of the HIV pandemic and its prevention and
treatment campaigns.

6
Medical anthropological
considerations (4)
‰ Medical interventions that are consistent with the
Explanatory Model of the patients, the healer, and
the society …

… and exert some desired physiological effects on

the disease are complete medicines.
medicines.
‰ Antimicrobial drugs are complete medicines.

7
Medical anthropological
considerations (4)
‰ Antimicrobial drugs fulfil many demands for 21st
century consumers:
‰ Give the right feeling of cleansing, sanitation, and
purging of nasty bugs

‰ Easy to take

‰ Work fast

‰ No need for long treatment

‰ Socially accepted

‰ Expected from a “good doctor”

doctor”

8
The LANCET
Volume 365, Number 9459 12 February 2005

Outpatient Antibiotic Use in Europe

and Association with Resistance.
Herman Goossens, M.D., Ph.D., Matus Ferech, Pharm.D., Robert Vander
Stichele, M.D., , Monique Elseviers, Ph.D, and the ESAC Project Group.

From the ESAC Management Team, Department of Microbiology, University of

Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

Address for correspondence:

Prof. Dr. H. Goossens
Department of Microbiology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
Tel (+) 32 3 821 3789
Fax (+) 32 3 825 4281
E-mail: Herman.Goossens@uza.be

9
 Figure 1 Total Outpatient antibiotic use in 26
European countries in 2002

Others
35 J01B+J01G+J01X

Sulfonamides and
30
trimethoprim
J01E
DDD per 1000 inh. per day

25 Quinolones
J01M

20 Macrolides, Lincosam.,
Streptogramins
J01F
15 Tetracyclines
J01A

10 Cephalosporins
J01D

5
Penicillins
J01C

0
FR GR LU PT IT BE SK HR PL IS IE ES FI BG CZ SI SE HU NO UK DK DE LV AT EE NL

10
Figure 2 Seasonal variation of total outpatient antibiotic
use in 10 European countries

35
BE

DK
30
FI
DDD per 1000 inh. per day

25 GR

NL
20
PL

15 PT

SE
10
SI

5 UK

0
1997 1998 1999 2000 2001 2002

11
Antimicrobial consumption in
human ambulant care in 2004
40

35

30

25
DID

20

15

10

0
GR FR LU PT HR BE SK IS IE ES HU FI SI BG CZ UK SE DK AT DE NL
Country code

Penicillins (J01C) Other B-lactams (mostly Cephalosporins, J01D)

Macrolides, Lincosamides & Streptogramins (J01F) Fluoroquinolones (J01MA)
Aminoglycosides (J01GB) Other

Source : ESAC 2005

12
Antimicrobial use for veterinary
purposes in the Netherlands

Source : MARAN report 2005

13
Antimicrobial consumption in the
Netherlands
‰ 16.5 million people consume 40.000 kg per year

‰ 15.0 million cattle and pigs and 100 million

poultry consume 500.000 kg per year

‰ 12 times more antibiotics are used veterinary

than human medicinal purposes in the
Netherlands

14
Factors facilitating the selection of AMR
by mass husbandry
metaphylaxis

15
Factors facilitating the selection of AMR
by mass husbandry
crowding

16
Historical note
‰ In 1994, total human consumption of
vancomycin in Denmark was 24 kg.

‰ In the same year 24,000 kg of avoparcin

was used as food additives for farm
animals.

Wegener et al. (1999)

Emerg Infect Dis 5:329-
5:329-335

17
Differential expansion of VRE in the
USA vs. Europe (1)

‰ VRE was first described by Leclerq in France in 1988

‰ Between 1992 and 1997 the proportion of VRE among all

enterococci isolated in US hospitals increased from 2-
2-
15%

‰ In ICUs that proportion rose to 30%

‰ Currently VRE is the third most frequent pathogen

isolated in US ICUs.

‰ Glycopeptides (Avoparcin
(Avoparcin)) were never used in the US

18
In Europe
‰ Vancomycin-resistant enterococci were
frequently isolated from healthy individuals

‰ Nosocomial VRE outbreaks have only recently

emerged.

Endtz HP, et al. (1997)

J Clin Microbiol 35:3026-
35:3026-3031

EARSS annual report 2006

19
VRE in Europe

20
Expansion of VRE

Fridkin SK, et al (2001)

Annals Int Med 135:175-
135:175-183

21
Differential expansion of VRE in the
USA vs. Europe (2)

‰ Vancomycin consumption in 130 US

hospitals in 2002: 45 DDD/1000 pds

‰ Vancomycin consumption in 27 French

hospitals in 2001: 12.4 DDD/1000 pds

‰ In the US, vancomycin consumption is 3.7x

higher than in Europe Polk RE et al (2007)
Clin Infect Dis 44:665--670
Clin Infect Dis 44:665 670

Alfandari S et al (2007)
Med Mal Infect 37:103-
37:103-107

22
 Population structure of E. faecium

CC-17

DI

BI

CI

EI

100%
AI

50% Other
CL-17

0% Outbreak Clin_isol Hosp_surv Comm_surv Non-human

Other 3 61 48 38 119
CL-17 29 95 17 3 1

23
 Population structure of E. faecium

CC-17

DI

BI

CI

EI

AI
100%

50%
Other
CL-17
0%
AmpR AmpS GlycoR GycoS

Other 20 226 115 146

CL-17 128 2 66 75

24
 Population structure of E. faecium

CC-17

DI

BI

CI

EI

100%
AI

50%
Other
CL-17
0%
Esp+ Esp-

Other 4 243

CL-17 78 63

25
 Genomic Capitalism

purK1+ E. faecium

esp+
esp+
esp
Amp R
Amp R

van A+
van A

26
Logistic regression model: contribution of
mobile genetic elements to the abundance of
VRE at different levels of hospitalism

log odds = b0 + b1x1 + b2x2 + b3x3 + … + bixi . (1)

whereby, b i denotes the parameter estimated by maximum

likelihood methods and x i the level of exposures e.g. 0 and 1 for
amp an the other genetic markers and 0-0-4 for the degree of
hospitalisation.

Willems R, et al (2005)
Emerg Infect Dis 11:821-
11:821-828.

27
 Relative abundance of E. faecium in
Environments with increasing degree of
hospitalization
7

0
0 1 2 3 4
CC17

28
 Relative abundance of E. faecium in
Environments with increasing degree of
hospitalization
7

0
0 1 2 3 4
CC17 effect of amp

29
 Relative abundance of E. faecium in
Environments with increasing degree of
hospitalization
7

0
0 1 2 3 4
CC17 effect of amp effect of amp+esp

30
 Relative abundance of E. faecium in
Environments with increasing degree of
hospitalization
7

0
0 1 2 3 4
CC17 effect of amp effect of amp+esp effect of amp+esp+glyc

31
What’s missing ?

Using shotgun genome hybridisation assays

an additional 146 clade-specific sequencies
were found

Mainly associated with IS elements

indicating an extraordinary amount of
horizontal gene transfer
Leavis HL. Et al (2007)
PLoS Pathogens 3:75-
3:75-95

32
 % fluoroquinolone resistance

0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
NO (1117)

EE (116)

2006
2005
2004
2003
2002
SE (2904) 2001

FI (1543)

IS (99)

NL (2140)

FR (4610)

GR (950)

SI (526)

HR (527)

BE (1118)

LU (191)

UK (1879)

PL (153)

IE (1184)

AT (1336)

CZ (1809)

BG (155)

HU (723)

Country code (average number of isolates reported per year) IT (826)

IL (862)

PT (754)

ES (2816)

DE (1040)

MT (84)
Fluoroquinolone-resistant E. coli

CY (57)

RO (47)

TR (782)
33
Fluoroquinolone-resistance and
outpatient use in Europe
0

-0,5

-1 PT 25%
DE ES
SK BG

HU
-1,5 LU
CZ AT
BE
Logodds of FQRE

-2 SI
GR 12%

% FQRE
HR
-2,5 FI SE
NL

-3 5%

-3,5

-4 IS 2%

-4,5
0,5 1 1,5 2 2,5 3 3,5
Fluoroquinolone consumption in DID (2004)
r=0.6, p=0.02

34
Resistance in E. coli: Mutations

Fluoroquinolone resistance (FQR)

‰ stepwise mutational alteration of gyrA gene

‰ occasionally gyrB, parC or parE gene

‰ each step diminishes quinolone-susceptibility

4-8 fold

35
Mutation rate and FQ resistance

36
E. coli: major phylogenetic
groups

A commensal strains in animals and

B1 humans, intestinal infections

B2 ExPEC

D ExPEC, intestinal infections

37
 E. coli population structure ... ...
...
... ...

...

... ...

... ...
...
... ...
...
...

ST Complex 23
...
... ...

... ...
... ... ... ... ...
... ...
... ...
...
... 21
23
... ... ...
... ...
29
... 155 ...
... ...
88
...
... 141
... 73
... ... 127
...
...
...
... ...
...

ST Complex 73
...
... ...
... ...

ST Complex 69
...
... ...
... ... ... ... ...
...
...
...
...
394 ... 12
...
...
95 ...
69 ...
...
... ...
... ... ...
... ...

38 ... ... ... ...

... ... ...

ST Complex 95
31
... ... 62
20 ...
... ... ...
...

17
48
117 ... ...
... ... ...
3
...
...
...
...
...
... ...
10

... ...
... ...

...
...
...
...

... UPEC (UTI/pyelonephritis/cystitis)

NMEC
...
11 ...
...
...
... ...
...

...
...
306

...
Septicemia (Human)
Septicemia (Poultry, APEC)
6

...

Lothar H. Wieler ...

...

38
Host specificity of extraintestinal
pathogenic E.coli

‰ No single subtraction fragment could

discriminate between avian and human strains

‰ Avian and human ExPECs may share a

common genetic pool

‰ Poultry could be a reservoir for human ExPECs

and vice versa

39
Antimicrobial use in poultry

‰ No reliable data available

‰ Frequent water medication for prevention of

colibacillosis (Enrofloxacin)

‰ Resistance rates in broiler chicken between 28-

54% in Europe

40
Conclusions
‰ Antimicrobials have become the most successful drugs
in human medicine
‰ Most of the problems with AMR in human medicine can
be sufficiently explained by antibiotic use in humans
‰ Surveillance of antimicrobial consumption is vitals to
support necessary changes in consumer choices
‰ The evolution of adaptive variants is linked to bacterial
sex
‰ Adaptive variants can readily exploit nosocomial niches
‰ Intensive animal rearing practices provide important
reservoirs of genetic elements conferring AMR in
human medicine

41
Thanks to,
The EARSS MT, Bilthoven

Herrman Goossens, Antwerp The Dutch Ministry for Health and

Sport
Lothar Wieler, Berlin The European Commission
Rob Willems, Utrecht The European Centres for Disease
Prevention and Control
Dick Mevius, Lelystad

All EARSS National

Representatives & Network of
National Reference
Laboratories

42