Antibiotikaresistens. Niels Frimodt-Møller Professor, overlæge dr.med. Klinisk Mikrobiologisk Afd., Hvidovre Hospital

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1 Antibiotikaresistens Niels Frimodt-Møller Professor, overlæge dr.med. Klinisk Mikrobiologisk Afd., Hvidovre Hospital

2 Behandlingsmuligheder af danske multi R bakterier Resterende antibiotika til behandling af alvorlige infektioner: NDM-1 Klebsiella pneumoniae: tige-poly 2 (New Deldi metallo-betalactamase) Vanco R,genta R,ampi R E.faecium: lin,dapto,syn* 3* (bakteriæmi-isolat) * Synercid ikke markedsført i DK

3 Resistensforhold hos bakterier fra bloddyrkninger EARS-Net 2009 Streptococcus pneumoniae: (PNSP) E. Coli ESBL MRSA K.pneum ESBL KPC

4 Selected antibiotic resistance prevalences in various pathogens Author, ref Country Bacterium Antibiotic Resistance rate Xin et al. AAC 2009 China Mycoplasma pneumoniae Macrolide 46/50 (92%) Bhengrai et al., Chemother 2010 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

5 MRSA in the Nordic countries Incidence (No/ ) Sweden Finland Denmark Norway Iceland SSAC MRSA WP C/doc/2005/SSAC_MRS Areport_2004.pdf

6 Frekvensen af ESBL hos E.coli i Danmark Resultater af lokale og nationale prævalensundersøgelser: % År ESBL-blod ESBL-hosp urin

7 Omkostninger ved resistens

8 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 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.

9 Mortality and delay in effective therapy associated with ESBL production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis Schwaber & Carmeli, JAC, 2007, 60: Mortality:

10 Mortality and delay in effective therapy associated with ESBL production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis Schwaber & Carmeli, JAC, 2007, 60: Delay in effective therapy:

11 S.aureus: MR vs MS Antibiotic resistance: Clinical consequences Odds Ratio (95% CI) for mortality 1,93 (1,54 2,42)* Cosgrove et al. CID 2003;36:53-59 E. coli: FQ-R vs FQ-S Lautenbach et al. CID 2005;41:923-9 Enterococcus: VR vs VS DiazGranados et al. CID 2005;41: S.pneumoniae: PenR vs PenS 4,41 (1,03 18,81)* 2,52 (1,9-3,4)* 1,29 (1,04 1,59)* Tleyjeh et al. CID 2006;42: * P < 0.05

12 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?

13 MethicillinR S.aureus: Cost of change in empirical treatment (+ vancomycin) if increased incidence of MRSA 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)

14 Nye antibiotika?

15 Udvikling af nye antibiotika Theuretzbacher Int J Antibact Ag 2012

16 Sammenhæng mellem antibiotika forbrug og - resistens

17 Frequency of drug resistance in E. coli from patients with acne vulgaris treated with tetracykline (250 mg/d) Møller et.al. AAC 1977, 11: % Resistens Res. strains R plasmids Multiple R Before RD 1 wk 4 wks > 4 wks

18 Gullberg et al. (2011) Selection of Resistant Bacteria at Very Low Antibiotic Concentrations. PLoS Pathog 7(7):e 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: 100:1 S/R: 1000:1 S/R: 10000:1

19 Gullberg et al. (2011) Selection of Resistant Bacteria at Very Low Antibiotic Concentrations. PLoS Pathog 7(7):e S. Typhi and Tetracyklin S R 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.

20 Ross, J.I et al. Antibiotic-resistant acne: lessons from Europe. British Journal of Dermatology 2009, 148 (3), Erythromycin Clindamycin Tetracykline Resistance to any one tested

21 Oprica, C. & Nord, C. E. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes. Clinical Microbiology & Infection 11 (3),

22 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), % of patients Hungary Italy Greece Spain

23 Ross, J.I et al. Antibiotic-resistant acne: lessons from Europe. British Journal of Dermatology 148 (3), Resistant P. acnes on skin Yes No Dermatologists, treating acne Physicians, other dept.s 25 (64%) 14 0 (0%) 27 Total 25 41

24 Azithromycin: Selection of resistant S. pneumoniae during treatment for trachoma % Resistance RD, single dose azithromycin Leach et.al. CID 1997; 24:

25 Erythromycin resistens hos Gr. A streptokokker og forbrug af makrolider i Finland Introduktion af nye makrolider % af total Resistens, % DDD/1000 indb/dag DDD/1000 indb./dag 2,0 1, Seppäläet.al. NEJM 1997;337;441-6

26 Invasive Erythromycin-Resistant Streptococcus pneumoniae (ERSP) and Consumption of Macrolides (J01MA) in Danish Counties, No. invasive ERSP per 100,000 inh. 1,2 1 0,8 0,6 0,4 0,2 0 R 2 =0.41 P< ,5 2 2,5 3 3,5 Consumption of macrolides (J01MA, DDD per 1,000 inh.-days) Multiple linear regression model for prediction of no. invasive ERSP per 100,000 inhabitants Antimicrobial consumption Standardized regression coefficient Erythromycin <0.001 Azithromycin <0.001 R 2 =0.76, all variables Ln transformed. t P Source: Nielsen HUK, et al. 41st ICAAC, Chicago (IL), 16-19/12/2001, #1867.

27 ESBL-blod ESBL-hosp urin % CTX-M-15 CTX-M typer ses i stigende grad hos produktionsdyr og relaterede kødprodukter DANMAP 2010

28 Antibiotic consumption in Danish hospitals /53 ESBL case control studier: Ab beh. sign. risikofaktor, især cef.og kinoloner

29 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

30 Sammenhæng mellem antibiotika og resistens Mutation el. introduktion af stamme med erhvervet resistens Antibiotika

31 Årsag til resistensudvikling selektion

32 Årsag til resistensudvikling 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 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

33 Årsager til spredning af resistens Bakterien Spredning af resistente bakterier, evt. kloner e.g. makrolid R 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

34 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

35 Udvikling af resistens (2): Import af resistente kloner spredning mellem mennesker Staph. aureus Methicillin R in Denmark Jessen O et al. N Engl J Med. 1969; 281: Strep. pneumoniae Penicillin R in Iceland Vilhelmsson et al. JCM, 2000; 38: Strep. pyogenes Macrolide R in Norway Littauer et al AAC, 2006; 50: Clostr. difficile ribotype 027 in Denmark Søes et al. Euro Surveill. 2009;14

36 Udvikling af resistens (2): Import af resistente kloner spredning mellem mennesker Selekteres/Co-selekteres af: Cephalosporiner, fluorkinoloner Staph. aureus Methicillin R in Denmark Jessen O et al. N Engl J Med. 1969; 281: Penicilliner, Cephalosporiner, Tetracykliner, Sulfa, Trimethoprim Strep. pneumoniae Penicillin R in Iceland Vilhelmsson et al. JCM, 2000; 38: Tetracykliner, makrolider Strep. pyogenes Macrolide R in Norway Littauer et al AAC, 2006; 50: Cephalosporiner, fluorkinoloner Clostr. difficile ribotype 027 in Denmark Søes et al. Euro Surveill. 2009;14 Kloners succes afhænger af antibiotika tryk

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38 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.

39 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 DDD = defined daily dose

40 Kan antibiotikaresistens forsvinde igen?

41 Enterokokker hos produktionsdyr: Eksempel på sammenhæng mellem fald i forbrug og fald i resistens Danmap 2009

42 Monthly Tetracycline Prescription Rate, Denmark, 01/ / No. prescr. per 1,000 inh. 4 Change in subsidization: from 50 to 0% Months Source: Danish Medicines Agency, 2000.

43 Monthly Tetracycline Prescription Rate and Tetracycline Resistance in S. aureus Blood Isolates, Denmark, 01/ / Change in subsidization: from 50 to 0% Tetracycline-R S. aureus Blood Isolates (%, 5-month moving average) Tetracycline Use (# prescriptions per 1,000 inhabitants) 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.

44 Belgian Campaigns Outpatient antibiotic use in Belgium in packages per 1,000 inhabitants per day July - June

45 Antibiotic Resistance of S. pneumoniae in Belgium National Reference Centre S. pneumoniae (University Leuven)

46 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!

47 Hvad skal vi satse vores penge på? Nye antibiotika? Rationelt forbrug + infektionskontrol? Theuretzbacher 2012 Andre behandlingsformer, vaccination? de Kraker et al. Plos Med 2011 Nye antibiotika el. vacciner markedsført: >10 år