Antimicrobial resistance up shit creek without a paddle? Gunnar Kahlmeter Klinisk mikrobiologi Landstinget Kronoberg

Antimicrobial resistance up shit creek without a paddle? Gunnar Kahlmeter Klinisk mikrobiologi Landstinget Kronoberg

ECDC, Czech ministerial conferance, Prague Maj 2009

Normalflora - bakterier Nose Staphylococcus aureus (30 50 % of adults), KNS Throat Skin 50 % av dessa har S.aureus på händerna i ett godtyckligt valt ögonblick S.aureus, S.pyogenes (GAS), Anaeroba bakterier S.aureus, P.acnes, KNS m fl Transient skin flora: foreign S.aureus, E.coli, Enterococci, Klebsiella, Acinetobacter, m fl Perineum Gut S.aureus, E.coli, Klebsiella, Enterococci, P.acnes S.aureus, E.coli, Klebsiella, Enterococci

Bacteria are contagious resistant or not

Why resistance development? Bacteria multiply every 15 minutes! Bacteria: 100 generations = 24 hours 1000 generations = 10 days Man: 100 generations = 2000 years 1000 generations = 20 000 years The Masters of Evolution!

Varför ökar antibiotikaresistens? Why increasing resistance? 1. Anrikning av resistenta bakterier i bakteriepopulationer genom närvaro (bruk och missbruk) av antibiotika (= selektion) Selection of resistant bacteria in bacterial populations through the presence of (use, misuse and abuse) antibiotics (selection)

Varför ökar antibiotikaresistens? Why increasing resistance? 1. Anrikning av resistenta bakterier i bakteriepopulationer genom närvaro (bruk och missbruk) av antibiotika (= selektion) 2. Spridning av resistensgener mellan bakterier Spread of resistance genes between bacteria

Varför ökar antibiotikaresistens? Why increasing resistance? 1. Anrikning av resistenta bakterier i bakteriepopulationer genom närvaro (bruk och missbruk) av antibiotika (= selektion) 2. Spridning av resistensgener mellan bakterier 3. Spridning av resistenta bakterier mellan människor och mellan människor och övrig miljö. Spread of resistant bacteria between individuals and between individuals and the environment.

Varför ökar antibiotikaresistens? Why increasing resistance? 1. Anrikning av resistenta bakterier i bakteriepopulationer genom närvaro (bruk och missbruk) av antibiotika (= selektion) 2. Spridning av resistensgener mellan bakterier 3. Spridning av resistenta bakterier mellan människor och mellan människor och övrig miljö. 4. Epidemier epidemier och pandemier med antibiotikaresistenta bakterier under hela perioden 1960 2007 Epidemics of bacteria with resistance.

Resistance development Selection Dissemination

Resistance development Selection Amount and type of antibiotic Dissemination Presence of contagious, resistant bacteria, the environment, behaviour of individuals and the receptivity of the individual.

Hattstugans dagis

Environment Selection AND dissemination IVA, KIVA, THIVA, NIVA, Neonatal +++/+++ The hospital ++/++ Home for the elderly +/++ Daycare +/++ Pig farm (+)+/++ Subway -/++ School -/+ My house in the forest -/-

Environment Selection + Dissemination Organisation of the community daycare elderly animal husbandry behaviour (food and feeds, water, religion, ) Organisation of health care standard, single room availability, distance between beds, isolation capacity. staffing patient turnover. infection control measures and compliance..

Bacteria are contagious resistant or not

Addenbrooke s hospital 1990 MRSA control by containment and the breakdown. 800 700 600 500 400 300 EMRSA-16 200 100 0 1990-1 1990-2 1991-1 1991-2 1992-1 1992-2 1993-1 1993-2 1994-1 1994-2 1995-1 1995-2 1996-1 1996-2 1997-1 1997-2 1998-1 1998-2 1999-1 1999-2 2000-1 2000-2 2001-1 2001-2 New patient isolates half year Farrington et al Q J Med 1998; 91: 539-548

Hospitals affected by EMRSA-3, EMRSA-15, or EMRSA-16 Number of Hospitals 150 125 100 75 50 25 0 EMRSA-15 EMRSA-16 EMRSA-3 1993 1994 1995 1996 1997 Year PHLS Communicable Disease Report 1997; 7 (22): 191

(Sweden) (UK) Data from EARSS

MRSA 2009 EARS-NET, ECDC

Prevalence of MRSA among 422 emergency units across USA. SSTI. Emergency dept, severe SSTI: MRSA 59% (97% USA300) S. aureus isolated from 320 of 422 pts 7/13 (54%) 11/28 (39%) 4/20 (20%) 24/47 (51%) 18/30 (60%) 26/42 (62%) 43/58(74%) 46/69 (67%) 32/58 (55%) 17/25 (68%) 23/32 (72%) Moran GJ et al. N Engl J Med 2006;355:666-74.

Sweden - MRSA

The UK: Could the MRSA epidemic have been prevented? fewer people better economy different health care culture early warning better and more isolation facilities more infection control nurses In the UK, where many doctors traditionally have worn a tie to work the latest slogan is: Gynecologists have always preferred bow-ties (fluga) maybe they have a good reason!

MDR ESBL AmpC XDR NDM-1 PDR KPC MBL IMP intestinal bacteria with increasing complexity of resistance mechanisms and increasing multiresistance: E.coli, Klebsiella, Pseudomonas, Acinetobacter, Salmonella, Shigella, m fl VIM VRE XDRTB

ESBL 2002

CTX-M clusters CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-9 CTX-M-25 CTX-M-9,14,17,18 CTX-M-1,3,15 CTX-M-40 CTX-M-26 CTX-M-3,15 CTX-M-9 CTX-M-3,15 CTX-M-9,16 CTX-M-2 Endemicity Sporadic reports CTX-M-2,4,5 CTX-M-3,15 CTX-M-3,15 CTX-M-15 CTX-M-3,15 CTX-M-1,15,32 CTX-M-14 CTX-M-9,14 CTX-M-1,10,15,32 CTX-M-2 CTX-M-15 CTX-M-2, 5 CTX-M-1,3,10,15 CTX-M-9,14,18,19,20,21 CTX-M-1,15,32 CTX-M-2 CTX-M-4,6 CTX-M-1,3,15,33 Cantón, Novais, Valverde, Machado, Peixe, Baquero, Coque. Clin Microbiol Infect 2007; (in press)

ESBL 2008

EXTENDED SPECTRUM ß-LACTAMASES Increased prevalence of ESBL producing isolates in all European countries. Increasingly common in the community. More common in E. coli than in K. pneumoniae Increasingly common in other Enterobacteriaceae ESBL-producers are almost always multidrug resistant Increased complexity of population structure - High clonal variability coexisting with clonal spread - Horisontal spread of strains and of genetic elements (plasmids, In-Tn)

Multi-resistance in E. coli, humans 15% 12.1% 12.1% 12.0% 12.4% 10.4% 10.8% 10% 5% 8.8% 7.8% 4.1% 3.1% 3.5% 0.6% 0.8% 1.1% 5.5% 4.7% 1.7% 1.7% 6.4% 6.2% 2.9% 2.2% 6.7% 3.4% 0% 2002 2003 2004 2005 2006 2007 2008 2009 R to 2 antimicrobial classes R to 3 antimicrobial classes R to 4 antimicrobial classes Combined resistance (R) of Escherichia coli to aminopenicillins, third generation cephalosporins, fluoroquinolones and aminoglycosides. EARSS/EARS Net 2002 2009 (22 countries/198 labs). Data: EARSS / EARS-Net. Analysis: Carlo Gagliotti

ESBL CARBA-A (KPCs) Canada USA Puerto Rico Colombia UK/Ireland Holland Belgium France Spain Norway Italy Sweden Greece Israel Finland Poland Hungary India South Korea China Brazil Argentina Enterobacteriaceae K. pneumoniae, K. oxytoca, E. coli, S. marcescens, P. mirabilis, S. enterica, C. freundii, Enterobacter sp., Raoultella spp. P. aeruginosa, P. putida, A. baumannii Courtesy Örjan Samuelsen, Tromsö, Norway

IMP (1992) VIM (1999) SPM-1 (2002) GIM-1 (2004) SIM-1 (2005) AIM-1 (2008) KHM-1 (2008) NDM-1 (2008) DIM-1 (2009)

Resultat (Lena Nilsson & Magnus Hermann 2010 (to be published): Totalt analyserades 578 fecesprover avseende ESBL. Siffror inom parentes anger antal prov där mikroorganism med förekomst av ESBL påvisades. Prov för: Allmän fecesodling Fecesodling Livsmedelsarbete C. difficileprov Rotavirus Tropikmedicinsk us EHEC Totalt april 2008 25 (1) 25 (2) 25 (0) - - - 75 aug-sept 2008 25 (3) 25 (2) 25 (0) 25 (0) 25 (3) 25 (1) 150 nov 2008 25 (2) 25 (2) 25 (0) - - - 75 jan-feb 2009 26 (2) 26 (3) 26 (1) - - - 78 feb-apr 2010 100 (6) 100 (14) - - - - 200 Totalt 201 (14) 201 (23) 101 (1) 25 (0) 25 (3) 25 (1) 578 Utlandsvistelse enligt remiss 79/201 201/201 4/101 1/25 3/25 3/25 291/578 - innebär att ESBL-analys ej utfördes I de analyserade proverna påvisades ESBL i 42 prover dvs ESBL förekom i drygt 7%. Av analyserna med påvisad ESBL-förekomst var 39 st E.coli och 1st Klebsiella pneumoniae (Serbien). I 2 av analyserna påvisades både E.coli och K.pneumoniae (Kina, Thailand).

Resistance to anti-tubercular drugs: MDR-TB among new TB cases 1994-2007 5.3 % of all TB cases are MDR-TB XDR-TB present in 45 countries 489,000 new MDR-TB cases in 2006 Up to 22% of MDR-TB are XDR-TB in the former Soviet Union Source: Global Project on Anti-Tuberculosis Drug Resistance Surveillance, WHO, 2008 and Anti-Tuberculosis Drug Resistance in the World, Volume 4, WHO, 2008 Source: Anti-tuberculosis drug resistance in the world, Volume 4, 2008

Konsekvenser av resistensutveckling Empirisk antibiotikabehandling misslyckas..och adekvat terapi fördröjs Smala, skonsamma och billiga medel överges till fördel för breda potenta och dyra medel! Längre behandlingsoch vårdtider Verksamheter tvingas upphöra Kostnaden för antibiotikabehandling ökar! Nya kostnader för vårdens organisation Medicinska behandlingar ifrågasättas -etik - rationalitet Driver resistens! - ekonomi Påverkar patientens val av vård! Ökad sjukdomsbörda och mortalitet Huvuden rullar!

Resistance development - consequences Failing empiric antibiotic therapy..delays adequate therapy Increased morbidity and mortality Longer treatment and hospital stay Cheap & narrow spectrum drugs are abandoned for expensive broad spectrum! Heads roll! Drives cost! Medical practices are questioned! -ethics -rational -cost Drives resistance! Influences the patient s choice of care!

Antibiotikaresistens kostar lidande, död och pengar! Sepsis 30d mortalitet (alla orsaker) S.aureus (EJ MRSA) 1415 (75.9) 17.7 % MRSA 450 (24.1) 30.0 % Behandling Pen, cef, karb. 1151 (61.7) 13.9 % Vankomycin 518 (27.8) 25.7 % Ingen 73 (3.9) 76.7 % John Turnidge and Despina Kotsanas, on behalf of the Australia New Zealand Cooperative on Outcomes in Staphylococcal Sepsis (ANZCOSS, 2008).

Finns det något ljus i tunneln? Any light in the tunnel?

No

One strategy after another fails! Any new antibiotics in the pipeline? Kan vi minska bruk och missbruk av antibiotika? Kan antibiotikaresistens vändas? Kan vi stoppa spridningen av resistenta bakterier i befolkningen? Kan vi stoppa spridningen av resistenta bakterier inom vård och omsorg?

Bad bugs need new drugs

New antibiotics? Antimicrobial Class of antibiotics Will it help overcome resistance? Several Glykopeptide No (Ceftobiprol Cephalosporine No/Y) (Iclaprim Folic acid antagonist No) Ceftarolene Cephalosporine No/Y Cef + inhibitor (several) Cephalosporine+inh No/Y Anti-M. tuberculosis Several?

One strategy after another fails! Kommer det NYA antibiotika? Can we reduce the use and abuse of antibiotics? Are we good at it? Kan antibiotikaresistens vändas? Kan vi stoppa spridningen av resistenta bakterier i befolkningen? Kan vi stoppa spridningen av resistenta bakterier inom vård och omsorg?

Seasonal variation of outpatient antibiotic use in 11 European countries with quarterly data for 1997-2003 35 Greece DDD / 1000 inhabitants / day 30 25 20 15 10 5 Portugal Belgium Ireland Finland Iceland Slovenia UK Sweden Denmark 0 1997 1998 1999 2000 2001 2002 2003 Netherlands

Försäljning av antibiotika i de nordiska länderna 1978-2008 www.strama.se

One strategy after another fails! Kommer det NYA antibiotika? Kan vi minska bruk och missbruk av antibiotika? Is antimicrobial resistance reversible? Kan vi stoppa spridningen av resistenta bakterier i befolkningen? Kan vi stoppa spridningen av resistenta bakterier inom vård och omsorg?

4,50 4,00 3,50 3,00 2,50 2,00 1,50 1,00 0,50 0,00 Trimethoprim and trimethoprim-sulfamethoxazole use (prescriptions /1000 inh), 2000-2006 Jan-00 Mar-00 May-00 Jul-00 Sep-00 Nov-00 Jan-01 Mar-01 May-01 Jul-01 Sep-01 Nov-01 Jan-02 Mar-02 May-02 Jul-02 Sep-02 Nov-02 Jan-03 Mar-03 May-03 Jul-03 Sep-03 Nov-03 Jan-04 Mar-04 May-04 Jul-04 Sep-04 Nov-04 Jan-05 Mar-05 May-05 Jul-05 Sep-05 Nov-05 Jan-06 Mar-06 May-06 Jul-06 Sep-06 Nov-06 Red = Kronoberg county Blue = Sweden TRICK-studien, Kronobergs län, M.Sundquist et al 2008

30,0% 25,0% 20,0% 15,0% 10,0% 5,0% 0,0% E. coli resistance rates in, Kronoberg county 1991-2006 (Resistance defined as nonsusceptibles using epidemiological cut-offs) trimethoprim Oct-90 Mar-91 Jul-91 Dec-91 May-92 Oct-92 Mar-93 Aug-93 Jan-94 Jun-94 Nov-94 Apr-95 Sep-95 Feb-96 Jul-96 Dec-96 Apr-97 Sep-97 Feb-98 Jul-98 Dec-98 May-99 Oct-99 Mar-00 Aug-00 Jan-01 Jun-01 Nov-01 Apr-02 Sep-02 Jan-03 Jun-03 Nov-03 Apr-04 Sep-04 Feb-05 Jul-05 Dec-05 May-06 Oct-06 TRICK-studien, Kronobergs län, M.Sundquist et al 2008

One strategy after another fails! Kommer det NYA antibiotika? Kan vi minska bruk och missbruk av antibiotika? Kan antibiotikaresistens vändas? Can we prevent dissemination of multiresistant bacteria in society? Kan vi stoppa spridningen av resistenta bakterier inom vård och omsorg?

Screening of congress participants Pig-health 2006, Copenhagen 2006: 272 from 38 countries screened 34 (12.5%) positive for MRSA ESBL KPC

What to do? Should I accept being admitted or referred to a ward with dire AMR problems (MRSA, ESBLs, KPCs, MDR)?

Avoid organised living for the elderly! Do not agree to babysit grandchildren! Do not travel unless already in an unfortunate area! Don t go south on vacation! Try dog-sleighing in Spitsbergen. If you go south - do not swap normal flora with the locals! - bring your own food! - don t have sex unless you have to and then only if you brought a partner! If you end up in hospital make them use alcohol rub so you can see it!

One strategy after another fails! Kommer det NYA antibiotika? Kan vi minska bruk och missbruk av antibiotika? Kan antibiotikaresistens vändas? Kan vi stoppa nya resistensmekanismer? Kan vi stoppa spridningen av resistenta bakterier i befolkningen? Can we prevent the dissemination of multiresistant bacteria in healthcare?

Battling crossinfectons - Your measures can prevent patients and staff from being crossinfected! This strategy. is logical! demands no intellectual capacity! instantly effective!

Diagnostic clinical microbiology Rapid diagnostics Rapid susceptibilty testing Rapid typing (outbreak control) Expert advice on antibiotics Infection Control Expert advice Resource planning Recommendations Education Outbreak management Strategies for the future Infectious Diseases Isolation Expert advice on antibiotics

Thank you! And good luck with the meeting!