Antibiotikaresistens
Niels Frimodt-Møller
Professor, overlæge dr.med.
Klinisk Mikrobiologisk Afd.,
Hvidovre Hospital
Behandlingsmuligheder af danske
multiR bakterier
Resterende antibiotika til
behandling af alvorlige infektioner:
NDM-1 Klebsiella pneumoniae:
tige-poly
2
(New Deldi metallo-betalactamase)
VancoR,gentaR,ampiR E.faecium:
(bakteriæmi-isolat)
* Synercid ikke markedsført i DK
lin,dapto,syn*
3*
Resistensforhold hos bakterier fra bloddyrkninger – EARS-Net 2009
Streptococcus pneumoniae: (PNSP)
E. Coli
ESBL
MRSA
K.pneum
ESBL
KPC
Selected antibiotic resistance
prevalences in various pathogens
Author, ref
Country
Xin et al. AAC
2009
China
Bhengrai et al.,
Chemother
2010
Bacterium
Antibiotic
Resistance
rate
Mycoplasma
pneumoniae
Macrolide
46/50 (92%)
India
Chlamydia
trachomatis
Macrolide &
tetracycline
8/21 (38%)
Abadi et al.,
J Micro, 2011
Iran
Helicobacter
pylori
Macrolide
129/197 (65%)
Ma et al.,
Zonghua 2011
China
Mycobacterium
tuberculosis
Rifampicin
105/243 (43%)
Mishra et al.,
Trop Doct 2012
India
MDR
83/223 (37%)
NF-M 2012
MRSA in the Nordic countries
30
Sweden
Finland
Denmark
Norway
25
Iceland
20
15
10
5
0
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
Incidence (No/100.000)
35
SSAC MRSA WP
http://www.srga.org/SSA
C/doc/2005/SSAC_MRS
Areport_2004.pdf
Frekvensen af ESBL hos E.coli i Danmark
Resultater af lokale og nationale prævalensundersøgelser:
%
19
96
20
01
20
03
20
06
20
07
20
09
20
11
8
7
6
5
4
3
2
1
0
ESBL-blod
ESBL-hosp urin
År
Omkostninger ved resistens
Mortality and Hospital Stay Associated with Resistant
Staphylococcus aureus and Escherichia coli Bacteremia:
Estimating the Burden of Antibiotic Resistance in Europe
de Kraker et al. Plos Med 2011, Epub 2011 Oct 11
•
•
•
•
Trends established by EARSS were used to determine the
trajectories for MRSA and G3CREC prevalence until 2015.
In 2007, 27,711 episodes of MRSA BSIs were associated with
5,503 excess deaths and 255,683 excess hospital days in the
participating countries, whereas 15,183 episodes of G3CREC
BSIs were associated with 2,712 excess deaths and 120,065
extra hospital days.
The total costs attributable to excess hospital stays for MRSA
and G3CREC BSIs were 44.0 and 18.1 million Euros (63.1
and 29.7 million international dollars), respectively.
Based on prevailing trends, the number of BSIs caused by
G3CREC is likely to rapidly increase, outnumbering the number
of MRSA BSIs in the near future.
Mortality and delay in effective therapy associated with
ESBL production in Enterobacteriaceae
bacteraemia: a systematic review and meta-analysis
Schwaber & Carmeli, JAC, 2007, 60: 913-20
Mortality:
Mortality and delay in effective therapy associated with
ESBL production in Enterobacteriaceae
bacteraemia: a systematic review and meta-analysis
Schwaber & Carmeli, JAC, 2007, 60: 913-20
Delay in effective therapy:
Antibiotic resistance:
Clinical consequences
Odds Ratio (95% CI)
for mortality
S.aureus: MR vs MS
1,93 (1,54 – 2,42)*
Cosgrove et al. CID 2003;36:53-59
E. coli: FQ-R vs FQ-S
4,41 (1,03 – 18,81)*
Lautenbach et al. CID 2005;41:923-9
Enterococcus: VR vs VS
2,52 (1,9 - 3,4)*
DiazGranados et al. CID 2005;41:327-33
S.pneumoniae: PenR vs PenS
1,29 (1,04 – 1,59)*
Tleyjeh et al. CID 2006;42:778-97
* P < 0.05
Antibiotikaresistens og empirisk behandling
Standardregime ved sepsis i flg. Medicin.DK:
Cefuroxim + Gentamicin + (evt. Metronidazol)
MRSA, ESBL, VGRE ?
Alternativer: Vancomycin, Pip/Tazo, Meropenem
Problemer: Pris, selektion af R, dårligere effekt ?
MethicillinR S.aureus: Cost of change in
empirical treatment (+ vancomycin) if
increased incidence of MRSA
• 150.000 blood cultures/year
• 2/3 receives empirical treatment
– Extra vancomycin coverage in 2 days
– 1300 Dkr (180 Euro) per treatment
130 mill. Dkr / year
(~ 18 mill. Euro / year)
Nye antibiotika ?
Udvikling af nye antibiotika - 2012
Theuretzbacher Int J Antibact Ag 2012
Sammenhæng mellem antibiotika
forbrug og - resistens
Frequency of drug resistance in E. coli from
patients with acne vulgaris treated with
tetracykline (250 mg/d)
% Resistens
Møller et.al. AAC 1977, 11: 388-91
90
80
70
60
Before RD
1 wk
4 wks
> 4 wks
50
40
30
20
10
0
Res. strains
R plasmids
Multiple R
Gullberg et al. (2011) Selection of Resistant Bacteria at Very Low Antibiotic
Concentrations. PLoS Pathog 7(7):e1002158
S. Typhi and Tetracyklin; Competition experiments at different sizes of populations
and concentrations of antibiotic (MIC of tetracyklin = 1,5 mg/l)
S/R:
10:1
S/R:
1000:1
S/R:
100:1
S/R:
10000:1
Gullberg et al. (2011) Selection of Resistant Bacteria at Very Low Antibiotic
Concentrations. PLoS Pathog 7(7):e1002158
S. Typhi and Tetracyklin
S
Green indicates a concentration interval where
the susceptible strain (blue line) will outcompete the resistant strain
(red line). Orange (sub-MIC selective window) and red (traditional
mutant selective window) indicate concentration intervals where the
resistant strain will outcompete the susceptible strain.
R
Ross, J.I et al. Antibiotic-resistant acne: lessons from Europe.
British Journal of Dermatology 2009, 148 (3), 467-478.
Erythromycin
Tetracykline
Clindamycin
Resistance to any one tested
Oprica, C. & Nord, C. E.
European surveillance study on the antibiotic susceptibility of
Propionibacterium acnes.
Clinical Microbiology & Infection 11 (3), 204-213.
Carriage of resistant P. acnes on skin of untreated close contacts to
patients with acne
Ross, J.I et al. Antibiotic-resistant acne: lessons from Europe.
British Journal of Dermatology 148 (3), 467-478.
% of
patients
90
80
70
60
50
40
30
20
10
0
Hungary
Italy
Greece
Spain
Ross, J.I et al. Antibiotic-resistant acne: lessons from Europe.
British Journal of Dermatology 148 (3), 467-478.
Resistant P. acnes on skin
Yes
No
Dermatologists,
treating acne
25 (64%)
14
Physicians, other
dept.s
0 (0%)
27
25
41
Total
Azithromycin: Selection of resistant
S. pneumoniae during treatment for trachoma
% Resistance
RD, single dose azithromycin
Leach et.al. CID 1997; 24: 356-62
Erythromycin resistens hos Gr. A streptokokker
og forbrug af makrolider i Finland 1982-96
Introduktion af nye makrolider
Resistens, %
DDD/1000 indb/dag
% af30
total
DDD/1000
25
indb./dag
20
2,0
15
10
1,0
5
0
82 83 84 85
Seppäläet.al. NEJM 1997;337;441-6
86 87 88 89
90 91 92
93 94 95
96
No. invasive ERSP per 100,000 inh.
Invasive Erythromycin-Resistant Streptococcus
pneumoniae (ERSP) and Consumption of Macrolides
(J01MA) in Danish Counties, 1995-99
Multiple linear regression model for prediction
of no. invasive ERSP per 100,000 inhabitants
1,2
1
0,8
Antimicrobial
consumption
Standardized
regression
coefficient
t
P
Erythromycin
0.359
3.870
<0.001
Azithromycin
0.952
10.256
<0.001
0,6
0,4
R2=0.41
P<0.001
0,2
0
1
1,5
2
2,5
3
3,5
Consumption of macrolides
(J01MA, DDD per 1,000 inh.-days)
R2=0.76, all variables Ln transformed.
Source: Nielsen HUK, et al. 41st ICAAC, Chicago (IL), 16-19/12/2001, #1867.
19
96
20
01
20
03
20
06
20
07
20
09
20
11
8
7
6
5
4
3
2
1
0
ESBL-blod
ESBL-hosp urin
70% CTX-M-15
CTX-M typer ses i
stigende grad hos
produktionsdyr og
relaterede
kødprodukter
DANMAP 2010
Antibiotic consumption in Danish hospitals
2000 - 10
47/53 ESBL case control studier: Ab beh. sign. risikofaktor, især cef.og kinoloner
ESBL and intestinal colonisation in mice
• Cefuroxime and cefotaxime treatment appear to select for
the CTX-M 15 producing strain, but not the TEM-52
Bojsen et al. 2010
Sammenhæng mellem antibiotika og resistens
Mutation el. introduktion
af stamme med
erhvervet resistens
Antibiotika
Årsag til resistensudvikling
selektion
Årsag til resistensudvikling
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Selektion Selektion Selektion Selektion Selektion Selektion Selektion
Selektion Selektion Selektion Selektion Selektion Selektion Selektion
Selektion Selektion Selektion Selektion Selektion Selektion Selektion
Selektion Selektion Selektion Selektion Selektion Selektion Selektion
Årsager til spredning af resistens
Bakterien
• Spredning af resistente
bakterier, evt. kloner
e.g. makrolidR pneumokok,
MRSA, VRE
Individet
• Direkte smitte mellem
individer (luft, kontakt,
fækal-oral)
• Spredning af resistensgener
e.g. ESBL, vanA
(plasmider, transposoner
mm)
• Indirekte smitte via
hospitalspersonale,
fødevarer, vand osv
Udvikling af resistens (1): Mutation i inficerende
bakterie under behandling
• Erythromycin el. clindamycinR hos Staph. aureus
• Ciprofloxacin R hos S. typhi/typhimurium
• Rifampicin og Isoniazid R hos M. tuberculosis
• Streptomycin R hos E. coli
= relativt sjældent
Udvikling af resistens (2): Import af resistente
kloner – spredning mellem mennesker
•
Staph. aureus MethicillinR in Denmark
Jessen O et al. N Engl J Med. 1969; 281: 627-35.
•
Strep. pneumoniae PenicillinR in Iceland
Vilhelmsson et al. JCM, 2000; 38: 1375-81
•
Strep. pyogenes MacrolideR in Norway
Littauer et al AAC, 2006; 50:1896-9.
•
Clostr. difficile ribotype 027 in Denmark
Søes et al. Euro Surveill. 2009;14
Udvikling af resistens (2): Import af resistente
kloner – spredning mellem mennesker
Selekteres/Co-selekteres af:
Cephalosporiner, fluorkinoloner
•
Staph. aureus MethicillinR in Denmark
Jessen O et al. N Engl J Med. 1969; 281: 627-35.
Penicilliner, Cephalosporiner, Tetracykliner, Sulfa, Trimethoprim
•
Strep. pneumoniae PenicillinR in Iceland
Vilhelmsson et al. JCM, 2000; 38: 1375-81
Tetracykliner, makrolider
•
Strep. pyogenes MacrolideR in Norway
Littauer et al AAC, 2006; 50:1896-9.
Cephalosporiner, fluorkinoloner
•
Clostr. difficile ribotype 027 in Denmark
Søes et al. Euro Surveill. 2009;14
Kloners
succes
afhænger
af
antibiotika
tryk
Antibiotic consumption in primary care, Europe 2007
Total outpatient antibiotic use in EU/EEA countries
*Total use, i.e. including inpatients, for Cyprus, Estonia, Greece and Lithuania.
**2006 data for Germany, Greece, Iceland and Lithuania; 2005 data for Poland and United Kingdom.
***Reimbursement data, which do not include over-the-counter sales without prescription.
Data source: ESAC 2007.
Relation between Antibiotic use and
Resistance in Pneumococci in EU-countries
(Bronzwear et.al. Emerg Infect Dis 2002, 8)
Streptococcus pneumoniae: (PNSP)
Vs.
The logodds of resistance to penicillin among invasive isolates of Streptoccus pneumoniae (PNSP;
ln(R/[1-R])) is regressed against outpatient sales of beta-lactam antibiotics in 11 European countries;
antimicrobial resistance data are from 1998 to 1999 and antibiotic sales data are from 1997. DDD =
defined daily dose
Kan antibiotikaresistens
forsvinde igen ?
Enterokokker hos produktionsdyr: Eksempel på
sammenhæng mellem fald i forbrug og fald i resistens
Danmap 2009
Monthly Tetracycline Prescription
Rate, Denmark, 01/1994-12/1999
5
No. prescr.
per 1,000 inh.
4
Change in subsidization: from 50 to 0%
3
2
1
0
Months
Source: Danish Medicines Agency, 2000.
Monthly Tetracycline Prescription Rate and
Tetracycline Resistance in S. aureus Blood
Isolates, Denmark, 01/1994-12/1999
6
Change in subsidization: from 50 to 0%
Tetracycline-R
S. aureus
Blood Isolates
(%, 5-month
moving average)
5
4
3
Tetracycline Use
(# prescriptions per
1,000 inhabitants)
2
1
0
Months
Average delay = 4 months
+1 prescr./1,000 inh.-month  +1.2 %R
Source: Johansen HL, Danish Medicines Agency, and Elsberg C, Statens Serum Inst., 2000.
Belgian Campaigns 2002-2010 Outpatient
antibiotic use in Belgium in packages per 1,000 inhabitants per
day – July - June
Antibiotic Resistance of
S. pneumoniae in Belgium 1985-2009
National Reference Centre S. pneumoniae (University Leuven)
Antibiotika og resistens
• Antibiotika selekterer for resistens
• Resistensudvikling sker oftest der, hvor der er mange
bakterier: I normalfloraen på hud og slimhinder
• Resistente bakterier spredes: Direkte smitte, via
fødevarer mm (import!)
• Resistens medfører en omkostning for bakterien =
fald i ”fitness”
• Stigning/fald i forbrug -> stigning/fald i resistens
• Brug antibiotika rigtigt!
Hvad skal vi satse vores penge på ?
• Nye antibiotika ?
Theuretzbacher 2012
Andre behandlingsformer, vaccination ?
Rationelt forbrug +
infektionskontrol ?
de Kraker et al. Plos Med 2011
Nye antibiotika el.
vacciner
markedsført: >10 år