The Relationship Between Antibiotic Use and Resistance:: The Not So Obvious Evidence

The Relationship between Antibiotic
Use and Resistance:

the not so obvious evidence
Herman Goossens, MD, PhD
ESAC Coordinator
VAXINFECTIO
University of Antwerp
Belgium
Antibiotic Use and Resistance

Proving the obvious
As in all similar Darwinian selection systems, it is
obvious that antibiotics generate resistance. It is

also obvious to most that if more antibiotics are
used, resistance will be more prevalent. So why
do investigators such as Herman Goossens and
colleagues wish to prove the obvious: that there is
a correlation between use and resistance?
Turnidge and Christiansen. Lancet Feb 2007: 548 - 549.
Objectives of my Talk
Analyze the consumption of

antibiotics in the community and in
hospitals
Discuss the link with resistance

and review the evidence
Outline
Hospital:
Measuring antibiotic use:
Conclusions
Community:
which numerator?
Link between macrolide use and resistance
which numerator and which denominator?
from ecological data to individual data and back to ecological data
Systematic Review and Meta-analysis
Conclusions
Conclusions and recommendations
Hospital
% Gentamicin-resisitant
Gram-negative Bacilli
Correlation between Aggregate Gentamicin Use and Resistance among

Gram-negatieve Bacilli Isolates, St Pieters Hospital, Brussels, 1979-1986
Gentamicin use
same year (g/year)
Gentamicin use
previous year (g/year)
Goossens H, et al. Lancet 1986;2: 804.
How to Measure Antibiotic Use in Hospitals?
Numerator:
Weight (g or kg or units of treatment)

Vials
Agent days
Courses
Treatment periods
Percentage of patients exposed to antimicrobials
Antibiotic days or Days of Treatment (DOT)
DDD (Defined Daily Dose)
PDD (Presribed Daily Dose)
Denominator:
Per month or year

Per 1000 inhabitants-days
Per 100 or 1,000 patient-days
Per 100 or 1,000 administrative bed-days
Per 100 or 1,000 occupied bed-days
Per 100 or 1,000 admissions
Per 100 or 1,000 discharges
Per month/occupied bed
Per Thousand Finished Consultant Episodes
Numerator: DDDs or DOT?
5 patients admitted to ward X
Treated with antibiotic Y (DDD = 1 g)
Situation A:
1/5 patients treated with 3 g/daily/10 days
Aggregated number of DDD: 30
Aggregated number of DOT: 10
Situation B:
3/5 patients treated with 1 g/daily/10 days
Aggregated number of DDD: 30
Aggregated number of DOT: 30
Denominator: OBD or AD?
Objectives:
Duration:
6 years (Jan 2000- Jan 2006

as a monthly basis)
Numerator:
Longitudinal survey
validating two denominators
Drug consumption for J01

antibacterials, converted to
WHO (DDDs)
Denominator:
- Occupied Bed-days (OBD)
- Admissions (AD)
Statistical method:
Times Series Analysis
Ansari et al., J Antimicrob Chemother, 2010
Time Series Regression Model
A = admissions
B = occupied bed days
R = discharges
L = estimated length of stay

are the coefficients which capture the impact of these variables
with s lags
t = time
Dmi = seasonal dummies with coefficients i s that capture the shift in

month i relative to month 1
DDD Change: Total
c
c
DDD, DBD & DAD
Time Trends of Antibiotic Use in Hospital 4

in DDD with Two Denominators
Fig. 2-Time Trends in Antibiotic Use with Two
Denominators and DDDs, Hospital 4
14000
DDD
DDD
100
800
75
600
50
400
25
200
DDD/100 Bed days
DDD/ 100 Admissions
12
24
36
48
60
DDD/100 Admissions
DDD/100 Bed-days
Conclusions
Primary analysis should be done on DDD
without adjustment for clinical activity
Adjustment for clinical activity should be done
with both admissions and occupied bed
days
These results have relevance to
microbiological surveillance as well as to
prescribing surveillance:
e.g. change in antibiotic exposure very likely
if statistically significant change in the same
direction of DDDs, DBDs and DADs and
change in DDDs independent of clinical
activity
Outline
Hospital:
Conclusions
Community:
which numerator?
Link between macrolide use and resistance
which numerator and which denominator?
from ecological data to individual data and back to ecological data
Systematic Review and Meta-analysis
Conclusions
Conclusions and recommendations
Total Outpatient Antibiotic Use in 27

European Countries and the US in 2004
DDD per 1000 inhabitants and per day
35
30
25
Other (J01 classes)

Sulfonamides and trimethoprim (J01E)
Quinolones (J01M)
Macrolides, lincosamides, and streptogramins (J01F)
Tetracyclines (J01A)
Cephalosporins and other beta-lactams (J01D)
Penicillins (J01C)
20
15
10
5
0
GR USA LU
HR SK
IE
PL
HU SI
CZ
UK DK AT
EE
RU
FR
IT
PT
BE
IS
IL
ES
FI
BG NO SE
DE
LV
NL
CH
Goossens H, et al. Clin Infect Dis. 2007;44:1091-1095.
Volume of Antibiotic Use: DID

Defined Daily Dose (DDD) per 1,000 inhabitants per day
Numerator: Defined Daily Dose
It is the assumed average maintenance dose per

day for a drug used for its main indication in adults.
The DDD is a unit of measurement and does not
necessarily reflect the recommended or prescribed
daily dose.
Denominator: 1,000 inhabitants per day
It is a method to express exposure, to a given drug

or a given class of drugs, for a given area and a
given period, independent of the population size of
the catchment's area.
Outpatient Antibiotic Use in Belgium

DDD per 1,000 Inhabitants per day; 1997 2006, July to June
30
DDD p er 1 0 0 0 in h . p er d ay
25
Ot h er J0 1 classes
Su lfon am id es an d
t rim et h op rim (J0 1 E)
Qu in olon es (J0 1 M)
Macrolid es, lincosam id es an d
st rep t og ram in s
(J0 1racy
F) clin es (J0 1 A)
Tet
Cep h alosp orin s an d
ot h er b et a-lact am s
(J0 1 D)
Pen icillin s (J0 1 C)
20
15
10
0
97-98
98-99
99-00
00-01
01-02
02-03
03-04
04-05
05-06
Antibiotic Resistance of S. pneumoniae in Belgium.

1985 2008
40
peniG
tetra
erythro
ofloxacine
35
percentage
30
25
20
15
10
5
0
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 1
year
National Reference Centre S. pneumoniae (University Leuven)
Outpatient Antibiotic Use in Belgium
Packages per 1,000 inhabitants per day; 1997 2007, July to June
4
-1.0%
-3.4%
-36%
3.5
-6.4%
-9.1%
inh./dayper dag
Packages/1000
per 1,000 inwoners
Verpakkingen
-6.9%
-7.5%
-3.8%
2.5
-3.6%
-5.3%
1.5
Other J01 classes

Sulfonamides and
trimethoprim (J01E)
Quinolones (J01M)
Macrolides, lincosamides
and streptogramins (J01F)
Tetracyclines (J01A)
Cephalosporins and other
beta-lactams (J01D)
Penicillins (J01C)
0.5
0
97-98
98-99
99-00
00-01
01-02
02-03
03-04
04-05
05-06
06-07
Goossens H. et al. Eurosurveillance 2008; 13:10 -13
Outpatient Penicillins Use in Belgium

1997-2003, DID vs. PID
J01CR +32% DID
J01CR -6% PID
Link between Use and Resistance and How to

Measure the Impact of Awareness Campaigns
Antibiotic consumption
DDD
Campaigns
persons
packages
DID
PID
Person
sID
PrID
Prescriptions
Antibiotic resistance
T
i
m
e
Sweden
Bulgaria
Latvia
Netherlands
Estonia
Israel
Germany
Norway
Finland
Iceland
Croatia
Belgium
Denmark
Poland
Luxembourg
UK
Czech Rep.
Spain
Ireland
Slovenia
Europe
France
Austria
Slovakia
USA
Portugal
Hungary
Italy
Greece
DDD/1000 inhabitants/day
Total Outpatient MLS Use in 27 European Countries

and the US in 2004
Others
Telithromycin
Spiramycin
Clindamycin
Roxithromycin
Erythromycin
Clarithromycin
Azithromycin
Relative Outpatient MLS Use in 27 European

Countries and the US in 2004
100%
Others
Telithromycin
Spiramycin
Clindamycin
Roxithromycin
Erythromycin
Clarithromycin
Azithromycin
60%
40%
20%
UK
Ireland
Sweden
Greece
Hungary
Latvia
Israel
Austria
Germany
Poland
Norway
Europe
Denmark
Czech Rep.
Belgium
Slovakia
France
Estonia
Italy
Netherlands
Luxembourg
Iceland
Spain
Finland
Portugal
Bulgaria
Slovenia
USA
0%
Croatia
Relative proportion
80%
Outpatient MLS Use in the US and Europe in 2004

(DID: DDD/1000 inhabitants/day)
Antibiotic
Azithromycin
Clarithromycin
Erythromycin
Clindamycin
US
Europe
Range in Europe
DID (%)
DID (%)
Highest DID
(country)
Lowest DID
(country)
1.68 (6.7)
1.10 (4.4)
0.43 (1.7)
0.25 (1.0)
0.52 (2.7)
1.23 (6.5)
0.34 (1.8)
0.14 (0.8)
1.34 (Croatia)
7.16 (Greece)
1.72 (UK)
0.70 (Hungary)
0.04 (Sweden)
0.06 (Sweden)
0.01 (Bulgaria)
<0.01 (Italy)
Erythromycin-resistant S. pneumoniae (%)
Correlation Between Macrolides Use and Prevalence of

Erythromycin-resistant S. pneumoniae
60
FR
50
ESBE
40
GR
IT
30
LU
DE
20
FI
10
IE
UK
PT
AT
SE
NL NO
DK
Consumption of Macrolides (J01FA) in DID, AC 1998

Organism year of
isolation [source of
information]
Antibiotic
resistance
Antibiotic use ATC group

(year of data)
No. of
countries
Spearman
correlation (r)
(confidence interval)
P-value
S. pneumoniae
1999-2000
[8]
Erythromycin
Macrolides J01FA
(1998)
16
0.83
(0.67-0.94)
<0.001
Goossens H, et al. Lancet. 2005; 365:579-587.
Distribution of Resistance Genes Among Macrolide-resistant

S. pneumoniae (n=618) Collected During the Pneumoworld Europe Study
(2001-2003)
Country
No. of
strains
No. (%) of isolates with the following resistance

erm(B)
mef(A)
erm(B)/mef(A)
negative
Belgium
33
27 (82)
5 (15)
1 (3)
Austria
12
7 (58)
5 (42)
0 (0)
France
202
199 (98)
3 (2)
0 (0)
Germany
56
28 (50)
26 (46)
2 (4)
Italy
160
119 (74)
40 (25)
1 (1)
Portugal
18
16 (89)
2 (11)
0 (0)
Spain
129
119 (92)
8 (6)
2 (2)
6 (75)
2 (25)
0 (0)
618
521 (84)
91 (15)
6 (1)
Switzerland
Total
Reinert R, et al. Antimicrob Agents Chemother. 2005; 49:2903-2913.
Distribution of Resistance Genes Among Macrolide-resistant

S. pneumoniae (n=9103) Collected During the PROTEKT US Study
(2000-2003)
100%
9.7
12.1
16.4
12.7
% of isolates
80%
60%
68.8
67.3
63.9
66.6
16.9
16.5
16.5
16.6
Year 1
(n=3133)
Year 2
(n=2793)
Year 3
(n=3177)
Total
(n=9103)
40%
Other*
Ribosomal mutation
erm(B)+mef(A)
mef(A)
erm(B)
20%
0%
*Includes
isolates not viable for further testing and isolates expressing erm(TR).
Jenkins S, et al. J Infection. 2005; 51:355-363.
Oropharyngeal Carriage of Macrolide-resistant

Viridans Streptococci
A
large majority (71%) of the healthy Belgian population

studied (n=154) carried macrolide-resistant Viridans
Streptococci
cMLS
was the predominant phenotype
Predominant
macrolide-resistant species was S. mitis
Resistance phenotypes
Constitutive (cMLS)
Inducible (iMLS)
Macrolide (M)
Total
Isolates
105 (66%)
7 (4%)
45 (28%)
157
Macrolide-resistance
Tetracycline-resistance
Genes
Genes
erm (B)
tet (M)
erm (B) mef (A)
tet (M) tet (O)
+mef (A)
+tet (O)
76
0
26
90
2
1
5
0
2
7
0
0
0
45
0
14
0
0
81
0
28
111
2
1
Malhotra-Kumar S, et al. J Antimicrob Chemother. 2004;53:271-276.
Aims of the Study

To
investigate the abilities of azithromycin and

clarithromycin to promote carriage of macrolide-resistant
oral streptococci and the temporal persistence of the
selected resistant commensals in healthy volunteers
To
study the temporal changes in prevalence of macrolideresistance genes following administration of azithromycin
and clarithromycin
Effect of Macrolide Therapy on Carriage of Macrolideresistant Streptococci in Healthy Volunteers

347 volunteers
123 ineligible
224 eligible volunteers
randomized
Azithromycin 500 mg
(3 days, once daily)
Placebo-1
(3 days, once daily)
74 volunteers at Day 0
(pre-antibiotic sample)
6 withdrew
- 1 diagnosed with leptospirosis
- 1 diagnosed with herpes
- 1 had diarrhea
- 1 complained of headaches
- 2 not known
5 withdrew
- 1 rejoined at Day 8
- 4 not known
Clarithromycin 500 mg
(7 days, twice daily)
6 withdrew
- 1 had an infection
- 5 not known
Placebo-2
(7 days, twice daily)
4 withdrew
- 4 not known
(end of treatment)
(end of treatment)
1 rejoined
(end of treatment)
(end of treatment)
1 withdrew
1 withdrew
1 rejoined
1 rejoined
29 withdrew
19 withdrew
40 withdrew
17 withdrew
Malhotra-Kumar S, et al. Lancet. 2007;369:482-490.
Temporal Changes in Proportion of Macrolideresistant Oral Streptococci

% Macrolide resistant
100
Azithromycin
Clarithromycin
Placebo-1
Placebo-2
80
60
40
20
0
0 4 8 14
28
42
180
Days
MAIN FINDINGS
Mean
pre-antibiotic (Day 0) carriage of macrolide-resistant streptococci

was 28%
Use
of both macrolides resulted in a huge increase in resistant

streptococci, which persisted for at least 6 months (P0.01)
In
the azithromycin group, resistance remained at a higher level than in

the clarithromycin group during mid-time points (P0.001)
Temporal Changes in Proportion of Macrolideresistant Genes in Oral Streptococci

MAIN FINDINGS
Mef (~85%) was predominant among
the pre-antibiotic (Day 0) macrolideresistant streptococci
In the clarithromycin group,

proportions of erm(B) and tet(M)
were higher and of mef lower than
pre-antibiotic levels at Month 6
Placebo
tet(M)
tet(O)
80
60
40
Proportion of macrolide resistance
Use of clarithromycin resulted in a

decrease in mef and an increase in
erm(B)-carrying isolates
100
mef
erm(B)
erm(B)+mef
20
0
100
Clarithromycin
80
60
40
20
0
100
Azithromycin
80
60
40
20
0
0 8
42
Time (days)
180
Conclusions
Macrolide
use is the single most important driver for the

emergence of macrolide resistance that can persist for
>6 months posttherapy
Azithromycin
selected quantitatively more resistant

organisms in the early posttherapy phases
Correlates to persistence of azithromycin 3-4 weeks

posttherapy
Clarithromycin
qualitatively selected for the higher

resistance-conferring erm(B) gene
Active against mef-carrying S. pneumoniae with MICs

of 8 g/mL
Implications of increased erm(B) carriage: resistance

to macrolides, lincosamides, and streptogramins B,
and also to tetracyclines (co-carriage with tet(M) on
one genetic element)
Conclusions (contd)
Higher
consumption of clarithromycin in Europe correlates

to predominance of erm(B)-carrying S. pneumoniae
Higher
consumption of azithromycin in the US and Canada

correlates to predominance of mef-carrying S. pneumoniae
Systematic Review and Meta-analysis on Effect of Antibiotic

Prescribing in Outpatients on Resistance in Individual Patients
Costelloe et al. BMJ 2010: 340: 2096
Only One Study Met All Criteria...
Forest Plot Showing Individual Analytic and Pooled ORs for

Resistance and Previous Antibiotic Prescribing in Strept.
Antibiotic Use and Resistance

Proving the obvious
As in all similar Darwinian selection systems, it is
obvious that antibiotics generate resistance. It is

also obvious to most that if more antibiotics are
used, resistance will be more prevalent. So why
do investigators such as Herman Goossens and
colleagues wish to prove the obvious: that there is
a correlation between use and resistance?
The answer is that the obvious correlation is
not at all obvious when considered carefully.
Turnidge and Christiansen. Lancet Feb 2005: 548 - 549.
CONCLUSIONS and RECOMMENDATIONS
Both patient-level and ecological studies of antibiotic use and

resistance confirm causal relationship
No agreement on which methods of measurement of

antibiotic use and resistance correlate best with selection of
resistance
Limited understanding of host and bacterial interaction to link

antibiotic exposure with emergence of resistance (host
factors, clonality, fitness, virulence, pathogenicity)
Pk/Pd studies are needed to investigate association of

antibiotic exposure with acquisition or progression from
colonisation towards infection (resistance mechanism,
interaction, duration of treatment, dose, time effect)
Prospective human studies are needed to better define and

quantify the risks associated with antibiotic exposure
If you cannot
measure it,
you cannot
improve it
Lord Kelvin, 1824-1907
Back up slides
Consumption Units in Ambulatory Care
Consumption unit
Definition
Measurement unit
DID
Number of Defined Daily Doses (DDD) per

1000 inhabitants per day
Number of packages per 1000 inhabitants per
day
Number of prescriptions per 1000 inhabitants
per day
Number of persons concerned per 1000
inhabitants per day
DDD
PID
PrID
personsID
Packages
Prescriptions
Persons
Mechanisms of Emergence of Antibiotic Resistance

at the Individual Level

AB
exposure
De novo resistance
upregulation
AB
exposure
Susceptible strain
Resistant strain
De novo resistance
Eradication of the
susceptible population
De Novo Resistance:
Example of S. pneumoniae Collected from Nasal Swabs of a Child
Given a Single Dose of Azithromycin
Datea
Serotype Azithromycin BOX

MIC (g/ml)
type
MLSTb
ermB mefA/E
23S rRNA
L4
L22
4 Dec 2001
22F
0.5
698
Negc
Neg
2059A
Neg
Neg
3 Jan 2002
22F
>256
698
Neg
Neg
2059G
Neg
Neg
29 Jan 2002 22F
>256
698
Neg
Neg
NDd
ND
ND
A single 125-mg dose of azithromycin was given on 6 December 2001.
MLST, multilocus sequence type
Neg, negatieve
d ND,
not done.
J Clin Microbiol. 2007, 45:4090-4091
Upregulation of Resistance:
Example of Non-fermenters (Pseudomonas, Acinetobacter)
Rice L., CID 2008; 46: 491-6
Independant Predictors of Respiratory Tract Infection with

Carbapenem Resistant P. aeruginosa Isolates
Patients: 351 adult patients with P. aeruginosa infection
44% were infected with carbapenem-resistant P.

aeruginosa
Independent predictors in the 30 days before detection of

resistance to carbapenems:
Prior receipt of mechanical ventilation for 11 days or

more
Prior exposure to fluoroquinolones for 3 days or

more
Prior exposure to carbapenems for 3 days or more

Lodise et al., Infect Control Hosp Epidemiol, 2007; 28: 959-65
Effect of Single Course of Josamycin and Erythromycin on

Resistant Oral Streptococci in Saliva
Number of volunteers:
Antibiotic course (prophylaxis for oral and dental

procedures):
16 (8 with each drug)
tablets of 1.5 g followed by 0.5 g after 6 hours
Sampling:
saliva collected before, 1.5 and 6 h after first dose,

then after 2, 7, 30 and 90 days
Maskell et al J Antimicrob Chemother 1990; 26: 539-48
Geometric Mean % of Oral Resistant Streptococci
Josamycin
Erythromycin
Maskell et al J Antimicrob Chemother 1990; 26: 539-48
Conclusions
De novo emergence of resistance or upregulation in the

susceptible target pathogen under treatment is uncommon,
but the risk may increase with longer duration of treatment
Benefit of short antibiotic treatment for specific

drug/bug/disease combinations
Horizontal transfer of resistance genes is of much

greater importance, and results in immediate selection of
the resistant (commensal) population after exposure to
antibiotics, which may last for months/years
No difference between short and long antibiotic

treatment
Effect of Amoxicillin Therapy

on Resistant Carriage:
High-dose (90 mg/kg/day BID),
Short-course (5 days)
Standard-dose (40 mg/kg/day BID),
course-standard (10 days)
Schrag et al, JAMA 2001; 286: 49-56
Flow of Participants Through the Intention-To-Treat Trial
Pneumococcal Nasopharyngeal Colonization and Prevalence

of Penicillin Nonsusceptibility at Days 0, 5, 10, 28
Odds Ratios for Penicillin-Resistant Streptococcus pneumoniae (PRSp)

Carriage According to Duration of the Last Antibiotic Used During the
Previous 30 Days (cutoff: 5 days).
No. of
No. of
PRSp
Unadjusted
Adjusted
Children
Carriers
OR (95% Cl)
Value
OR (95% Cl)
Value
No use
780
10
1.0
Long (
136
3.5 (1.3-9.8)
.02
3.9 (1.4-11.2)
Short
23
Not applicable
.9
Not included
No use
835
11
1.0
Long
91
4.4 (1.5-12.8)
.01
5.2 (1.5-18.1)
Short
15
Not applicable
.9
Not included
No use
877
14
1.0
Long
53
2.4 (0.5-10.9)
.2
2.3 (0.5-1.7)
Short
11
Not applicable
.9
Not included
Variable
Last lactam
1.0
.01
Last aminopenicillin
1.0
.003
Last cephalosporin
1.0
.3
Guillemot et al. JAMA, 1998; 279:365-370
CONCLUSIONS
Standardised method for surveillance of AB use is required
Hospitals should report on different indicators
Benchmarking AB use is a powerful tool to identify problems:
Monthly data, stratified by specific populations, different indicators, definitions

provided
Unknown which indicator is most predictive of AB resistance
Ecological effects of AB use on resistance often confirmed by individual effects
(Pharmacodynamic) studies are needed to investigate association of AB

exposure with acquisition or progression from colonization towards infection
Host- and bacterial-level studies are needed to link individual AB exposure with
emergence of resistance (typing, pathogenicity, pK/pD, etc)
Fluoroquinolone Use and the Risk for MRSA

MRSA cases
MSSA cases
OR (95% Cl)
p value
OR (95% Cl)
p value
Levofloxacin
3.38 (1.94 to 5.90)
<0.001
0.69 (0.34 to 1.40)
0.30
Ciprofloxacin
2.48 (1.32 to 4.67)
0.005
0.47 (0.21 to 1.02)
0.06
Lung disease
3.94 (2.43 to 6.40)
<0.001
2.33 (1.43 to 3.81)
<0.001
Renal disease
1.98 (1.03 to 3.80)
0.04
Penicillin
1.78 (0.93 to 3.39)
0.08
Primary covariates
Other covariates
Metronidazole
1.92 (1.10 to 3.37)
0.02
1.29 (0.65 to 2.56)
0.46
ICU stay
5.33 (3.28 to 8.68)
<0.001
4.60 (2.90 to 7.30)
<0.001
Emergent admission 1.74 (1.09 to 2.78)
0.02
1.90 (1.17 to 3.08 )
0.01
Weber et al., Emerg Infect Dis 2003; 9: 1415-22
EFFECT
Genodiversity of resistant Pseudomonas aeruginosa

isolates in relation to antimicrobial usage density and
resistance rates in intensive care units
Jonas et al, Infect Control Hosp Epidemiol 2008; 29: 350 - 7
Imipenem Usage Density and Resistance Rate in

ICUs with Low (circles) and High (triangles)
Genodiversity of Resistant Strains
Jonas et al, Infect Control Hosp Epidemiol 2008; 29: 350 - 7
Confounder: Colonisation Pressure
Bonten et al. Arch Intern Med 2008; 158: 1127-1132
Confounder: Underlying Illness and

Length of Stay
MRSA cases
MSSA cases
OR (95% Cl)
p value
OR (95% Cl)
p value
Levofloxacin
3.38 (1.94 to 5.90)
<0.001
0.69 (0.34 to 1.40)
0.30
Ciprofloxacin
2.48 (1.32 to 4.67)
0.005
0.47 (0.21 to 1.02)
0.06
Lung disease
3.94 (2.43 to 6.40)
<0.001
2.33 (1.43 to 3.81)
<0.001
Renal disease
1.98 (1.03 to 3.80)
0.04
Penicillin
1.78 (0.93 to 3.39)
0.08
Primary covariates
Other covariates
Metronidazole
1.92 (1.10 to 3.37)
0.02
1.29 (0.65 to 2.56)
0.46
ICU stay
5.33 (3.28 to 8.68)
<0.001
4.60 (2.90 to 7.30)
<0.001
Emergent admission 1.74 (1.09 to 2.78)
0.02
1.90 (1.17 to 3.08 )
0.01
Weber et al., Emerg Infect Dis 2003; 9: 1415-22
Confounder: Virulence
Adhesion to fibronection sigB Null S. aureus
grown in either the absene or presence of 4
g of ciprofloxacin
Li et al., Antimicrob Agents Chemother. 2005; 49: 916-24
Confounder: Duration of Treatment
Objective:
Estimate the probability of carbapenem resistance

among P. aeruginosa isolates
Method:
Retrospective, cross-sectional study
Adult inpatients with respiratory tract infection
Log-binomial regression
Results:
Independent predictors of carbapenem resistance

were
prior receipt of mechanical ventilation for 11 days or more
prior exposure to fluoroquinolones and to carbapenems for 3
days or more
Lodisi et al., ICHE 2007; 28: 959 - 65
Confounder: Community Use
MacDougall et al. Clin Infect Dis 2005; 41: 435-440
Is Antibioticagebruik
ALTIJD
gecorreleerd met
Resistentie?
Yearly prevalence of macrolide-resistant S. pyogenes distributed by

age group and phenotype in Belgium during 1999-2003
Year
Total S. pyogenes screened
1999
598
2000
336
2001
633
2002
1226
2003
1073
Isolated from adults [mean age, 34.7 years; SD,

11.1 years; range, 17 to 91 years]
220
144
245
469
453
(36.7%) (43.1%) (38.7%) (38.2%) (42.0%)
Isolated from children [mean age, 7.2 years; SD,

3.5 years; range, 3 months to 16.9 years]
357
172
367
6756
552
(59.6%) (51.2%) (58.0%) (55.0%) (51.0%)
81
41
73
215
96
(14%) (12%) (12%) (18%)
(9%)
23
16
29
82
38
(4%)
(5%)
(5%)
(7%)
(4%)
56
22
44
126
50
(9%)
(7%)
(7%)
(10%)
(5%)
49/81
10/41
28/73 68/215 54/96
(8%)
(3%)
(4%)
(6%)
(5%)
32/81
29/41
39/73 141/215 38/96
(5%)
(9%)
(6%)
(12%)
(4%)
2/41
6/73
7/215
4/96
(1%)
(1%)
(1%)
(0.4%)
Macrolide-resistant S. pyogenes
Isolated from adults
Isolated from children
cMLS phenotype
M phenotype
iMLS phenotype
Malhotra-Kumar et al., Emerg. Infect. Dis., 2005
Temporal changes in the distribution of major PFGE and emm types

among the two major macrolide-resistant S. pyogenes phenotypes in
Belgium during 1999-2003
MacrolideResistant
Phenotype
cMLS
M
No (%) of Macrolide-Resistant S. pyogenes

PFGE cluster Frequency 1999
2000
2001
2002
2003
(emm type) (n=506) (n=81) (n=41) (n=73) (n=215) (n=96)
1 (emm 22)
70
45 (56%) 7 (17%) 9 (12%) 7 (3%)
2 (2%)
4 (emm 28)
45
4 (5%) 15 (7%) 26 (27%)
23 (emm 11)
28
1 (1%) 6 (3%)
21 (22%)
1001 (emm 1)
128
7 (9%) 12 (29%) 23 (32%) 80 (37%) 6 (6%)
1002 (emm 4 )
28
2 (2.5%) 2 (5%) 7 (10%) 7 (3%)
10 (10%)
Malhotra-Kumar et al., Emerg. Infect. Dis., 2005
Temporal changes in prevalence of

fluoroquinolone non-susceptible S. pyogenes
Year
Fluoroquinolone non-susceptible
S. pyogenes
No. of adults with fluoroquinolone
non-susceptible S. pyogenes
1999
2000
28/598 29/336
(4.6%) (8.6%)
17/220 13/145
(7.8%) (9.0%)
2001
59/633
(9.3%)
19/245
(7.8%)
2002
36/1226
(2.9%)
11/469
(2.3%)
No. of children with fluoroquinolone

non-susceptible S. pyogenes
11/357 14/172 38/368

(3.1%) (8.1%) (10.4%)
21/675
(3.1%)
Malhotra-Kumar et al., J. Antimicrob. Chemother., 55: 320-5, 2005
Temporal changes in emm type distribution of fluoroquinolone nonsusceptible and susceptible S. pyogenes
Year
Emm -type distribution of fluoroquinolone non-susceptible S.
pyogenes
emm 6
emm 75
Others
Emm -type distribution of fluoroquinolone-susceptible S. pyogenes

emm 1
emm 4
emm 22
emm 6
emm 75
1999
26/28
(92.8%)
0/28
(0.0%)
2/28
(7.1%)
13/172
(7.6%)
22/172
(12.8%)
37/172
(21.5%)
1/172
(0.5%)
2/172
(1.2%)
2000
28/29
(96.5%)
0/29
(0.0%)
1/29
(3.4%)
16/84
(19.0%)
15/84
(17.9%)
13/84
(15.5%)
0/84
(0.0%)
3/84
(3.6%)
2001
47/59
(79.6%)
7/59
(11.8%)
5/59
(8.4%)
37/171
(21.6%)
27/171
(15.8%)
19/171
(11.1%)
1/171
(0.6%)
2/171
(1.2%)
2002
14/36
(38.8%)
16/36
(44.4%)
6/36
(16.6%)
70/200
(35.0%)
21/200
(10.5%)
8/200
(4.0%)
1/200
(0.5%)
0/200
(0.0%)
Temporal and geographical distribution of the two major

fluoroquinolone non-susceptible S. pyogenes clones in Belgium
Community
The link between outpatient use of macrolides

(DDD/1,000 inh./day) and erythromycin resistance
among Group A Streptococci in Finland:
Proportion of local resistant isolates was related to

local erythromycin use (P=0.006 by logistic
regression analysis)
Seppl et al., Clin. Infect. Dis.; 21:1378-85, 1995
The effect of changes in the consumption of

macrolides on erythromycin resistance in Group A
Streptococci in Finland
Decrease of macrolide consumption was associated

with a decrease of resistance to erythromycin
Seppl et al., N. Engl. J. Med.; 337: 441-46, 1997
Consumption of Macrolides and Resistance

in GAS in Finland
Macrolide consumption
Azithromycin consumption
Macrolide resistance
3,5
20
18
2,5
12
10
1,5
8
6
4
0,5
2
20
00
99
98
97
96
95
94
93
92
91
90
89
88
87
86
85
84
83
82
81
80
0
79
YearData provided by P. Huovinen
% resistant
14
78
DDD/1,000 inh./day
16
Link between Antibiotic Use and Resistance in

Hospitals: Not so obvious...
Many other variables, such as:
Infection control practises
Colonisation pressure
Genodiversity of strains
Underlying illness
Potency of the drug
Length of Stay (LOS)
Duration of treatment
Community use
Animal use
and most have not been studied properly
There Are Many Mis-Matches Between Antibiotic

Patient-Physician contact
Prescription, Use, Consumption
and Exposure
Antibiotic prescription
Over the
Drug bought (= antibiotic use)
counter
At the time of prescription
At another time
Drug consumed
Drug consumed at any other
time
At the time of infection
Personal Another
Another
person
At another time
Personal
Another
person
Personal
person
Correlation Between Penicillin Use and Prevalence of

Penicillin-resistant S. pneumoniae
50
Penicillin-resistant S. pneumoniae (%)
FR
40
ES
30
PT
HU
SI
20
10
HR
PL BE
IE
LU
IT
CZ
FI
NL
0
0
DE
AT
UK SW
DK
10
12
14
16
18
Consumption of Penicillin (J01C) in DID, AC 2000

Organism year of
isolation [source of
information]
Antibiotic
resistance
Antibiotic use ATC group

(year of data)
No. of
countries
Spearman
correlation (r)
(confidence interval)
P-value
S. pneumoniae
2001
[7]
Penicillin
Penicillin J01C
(2000)
19
0.84
(0.62-0.94)
<0.001
Goossens H, et al. Lancet. 2005; 51:Suppl 365(9459):579-587.
73
Multivariate Time Series Analysis for Monthly MRSA (R2 = 0.56) at

University of Geneva Hospitals in Switzerland (02/2000 09/2006)
Variable
Lag (months)
Fluoroquinolone use
(DDD/100 patient-days)
Third-generation cephalosporin
use (DDD/100 patient-days)
Macrolide use
Cefepime use
(DDD/100 bed-days)
Piperacillin/tazobactam use
Coefficient
T test
P value
0.010
2.71
0.009
0.014
2.15
0.035
0.012
3.19
0.002
0.014
2.56
0.013
0.041
2.97
0.004
Hand hygiene
campaign
-0.032
-5.81
<0.0001
Autoregressive term
Moving average term
1
1
0.546
-0.732
3.24
-4.46
0.002
<0.0001
Vernaz et al, J Antimicrob Chemother 2008; 62:601-7.
Multivariate Time Series Analysis for Monthly HA-MRSA (R2 = 0.78) at

Antrim Area Hospital in Nothern Ireland (01/2000 12/2004)
Variable
Lag (months)
Fluoroquinolone use
(DDD/100 bed-days)
use (DDD/100 bed-days)
Macrolide use
(DDD/100 bed-days)
Amoxicillin/clavulanic acid
use (DDD/100 bed-days)
Alcohol-based handrub
bulk orders
Alhohol-impregnated wipes
(no./100 bed-days)
Patients actively screened
for MRSA (no./100 bed-days)
Patients admitted with MRSA
(no./100 bed-days)
Autoregressive term
Moving average term
Coefficient
T test
P value
0.00481
4.905
<0.0001
0.0273
6.080
<0.0001
0.00212
2.149
0.0376
0.00349
5.365
<0.001
3
4
-0.0390
-0.0755
-2.619
-4.932
0.0123
<0.0001
-0.000345
-6.956
<0.0001
-0.00721
-2.357
0.0233
2
4
2
0.223
-0.552
-0.980
7.162
-4.250
-1382.67
<0.0001
0.0001
<0.0001
Aldeyab et al, J Antimicrob Chemother 2008; 62: 593-600
Multivariate Time Series Analysis for Monthly HA-MRSA Infection (R2 =

0.66) at Freiburg University Medical Center in Germany (01/2003 10/2007)
Variable
Lag (months)
Fluoroquinolone use
4
Second generation cephalosporin
1
3-4
Lincosamide use
2
Alcohol-based handrub
Patients admitted with MRSA

(no./1000 patient-days)
Autoregressive term (MRSA)
Coefficient
T test
P value
1.12
2.73
0.01
1.41
2.39
0.023
1.03
2.03
0.05
.42
2.04
0.05
3-7
-5.37
-5.93
<0.001
0
1
0.43
-0.33
2.14
-1.97
0.04
0.057
Kaier et al, Inf Control Hosp Epidemiol 2009; 30: 346-53
Phenotypic Basis of
Mechanisms of Resistance
AB
exposure
De novo resistance
Upregulation
Susceptible strain
Resistant strain
de novo resistance
AB
exposure
Eradication of the
susceptible population
Luxembourg
Netherlands
Norway
Poland
Portugal
0%
Greece
Hungary
100%
100%
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
Slovakia
Iceland
Slovenia
Ireland
Spain
1997
1998
1999
2000
2001
2002
2003
20%
Israel
Italy
1997
1998
1999
2000
2001
2002
2003
40%
1997
1998
1999
2000
2001
2002
2003
40%
1997
1998
1999
2000
2001
2002
2003
60%
1997
1998
1999
2000
2001
2002
2003
60%
1997
1998
1999
2000
2001
2002
2003
80%
1997
1998
1999
2000
2001
2002
2003
80%
1997
1998
1999
2000
2001
2002
2003
100%
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
2000
2001
2002
2003
100%
1997
1998
1999
2000
2001
2002
2003
Germany
1997
1998
1999
2000
2001
2002
2003
France
1997
1998
1999
2000
2001
2002
2003
Finland
1997
1998
1999
2000
2001
2002
2003
Estonia
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
2000
2001
2002
2003
0%
1997
1998
1999
2000
2001
2002
2003
Trends of the Relative Outpatient Use of MLS Antibiotics in

25 European Countries, 1997-2003
20%
Sweden
UK
Coenen S, et al. J Antimicrob Chemother. 2006; 58: 418-422.
Inversion of the ERY-R S. pyogenes Phenotypes

in Portugal, 1998-2003
Percent
100
50
Silva-Costa C, et al. Antimicrob Agents Chemother. 2005; 49:2109-2111.
Macrolide use (J01F)
Azithromycin use (J01FA10)
Clarithromycin use (J01FA09)
Erythromycin use (J01FA01)
Rates of erythromycin resistance
Rates of clindamycin resistance
250
30%
25%
200
20%
150
15%
100
10%
50
5%
0%
1994
1995
1996
1997
1998
Year
Dias R, et al. J Antimicrob Chemother. 2004; 54:1035-1039.
1999
2000
2001
2002
Rates of erythromycin resistance
No. of packages/1000 inhabitants/year
Emergence of Invasive ERY-R S. pneumoniae in

Portugal and Link to Antimicrobial Use
Rate of erythromycin resistance (Ln)
Correlation Between Azithromycin Use and Rates of

ERY-R S. pneumoniae, 1994-2002
No. of packages/1000 inhabitants/year
Dias R, et al. J Antimicrob Chemother. 2004; 54:1035-1039.
Outpatient MLS Use in the US and Europe in 2004

(DID: DDD/1000 inhabitants/day)
US
Europe
ATC code
Corresponding antibiotics (sub)class
DID
(%)
DID
(%)
J01F
Macrolides, lincosamides, and
3.52
(14.14)
2.98
(15.66)
Short-acting macrolides
0.43
(1.73)
0.48
(2.54)
Intermediate-acting macrolides
1.16
(4.66)
1.71
(8.96)
Long-acting macrolides
1.68
(6.74)
0.53
(2.77)
streptogramins:
J01FF
Lincosamides
0.25
(1.02)
0.16
(0.85)
J01FG
Streptogramins
<0.01
(0.00)
0.10
(0.55)
Quality Criteria for Scoring by Two Reviewers
Reliable measure of antibiotic exposure
A reliable measure of resistance
Unbiased control selection
Ability to identify incident cases
Adjustment for key confounders

The Relationship Between Antibiotic Use and Resistance:: The Not So Obvious Evidence

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Relationship Between Antibiotic Use and Resistance:: The Not So Obvious Evidence

Uploaded by

Copyright:

Available Formats

The Relationship between Antibiotic

Use and Resistance:

Antibiotic Use and Resistance

As in all similar Darwinian selection systems, it is

obvious that antibiotics generate resistance. It is

Turnidge and Christiansen. Lancet Feb 2007: 548 - 549.

Analyze the consumption of

Discuss the link with resistance

Measuring antibiotic use:

Measuring antibiotic use:

Link between macrolide use and resistance

which numerator and which denominator?

from ecological data to individual data and back to ecological data

Systematic Review and Meta-analysis

Conclusions and recommendations

Correlation between Aggregate Gentamicin Use and Resistance among

Goossens H, et al. Lancet 1986;2: 804.

How to Measure Antibiotic Use in Hospitals?

Weight (g or kg or units of treatment)

Per month or year

Numerator: DDDs or DOT?

5 patients admitted to ward X

Treated with antibiotic Y (DDD = 1 g)

1/5 patients treated with 3 g/daily/10 days

Aggregated number of DDD: 30

Aggregated number of DOT: 10

3/5 patients treated with 1 g/daily/10 days

Aggregated number of DDD: 30

Aggregated number of DOT: 30

Denominator: OBD or AD?

6 years (Jan 2000- Jan 2006

Drug consumption for J01

Times Series Analysis

Ansari et al., J Antimicrob Chemother, 2010

Time Series Regression Model

B = occupied bed days

L = estimated length of stay

Dmi = seasonal dummies with coefficients i s that capture the shift in

DDD Change: Total

DDD, DBD & DAD

Time Trends of Antibiotic Use in Hospital 4

DDD/100 Bed days

DDD/ 100 Admissions

Measuring antibiotic use:

Measuring antibiotic use:

Link between macrolide use and resistance

which numerator and which denominator?

from ecological data to individual data and back to ecological data

Systematic Review and Meta-analysis

Conclusions and recommendations

Total Outpatient Antibiotic Use in 27

DDD per 1000 inhabitants and per day

Other (J01 classes)

Goossens H, et al. Clin Infect Dis. 2007;44:1091-1095.

Volume of Antibiotic Use: DID

It is the assumed average maintenance dose per

It is a method to express exposure, to a given drug

Outpatient Antibiotic Use in Belgium

Antibiotic Resistance of S. pneumoniae in Belgium.

National Reference Centre S. pneumoniae (University Leuven)

Outpatient Antibiotic Use in Belgium

Other J01 classes

Goossens H. et al. Eurosurveillance 2008; 13:10 -13