Evolvement of MRSA in Denmark

1. Evolvement of MRSA in Denmark R. Skov Head of Staphylococcus Laboratory National Center for Antimicrobials and Infection Control Statens Serum Institut Copenhagen, Denmark Dear Mr chaiman and distinguished audience, thank you for the invitation to visit your beatiful country and to talk of the Evolvement of MRSA in Denmark �Dear Mr chaiman and distinguished audience, thank you for the invitation to visit your beatiful country and to talk of the Evolvement of MRSA in Denmark �

2. Definition of MRSA S. aureus, resistant to all ?-lactam antibiotics penicillins, cephalosporins, monobactams and carbapenems The resistance mechanism is production of PBP2a an extra cell wall synthesizing enzyme with poor affinity towards ?-lactams Encoded by the mecA gene Often also resistant to other classes of antibiotics MRSA is S. aureus that is resistant to all beta-lactam antibiotics. The resistance mechanism is production of PBP2a an extra cell wall synthesizing enzyme with poor affinity towards ?-lactam antibiotics. It is encoded by the the mecA gene MRSA is furthermore often also resistant to other classes of antibiotics MRSA is S. aureus that is resistant to all beta-lactam antibiotics. The resistance mechanism is production of PBP2a an extra cell wall synthesizing enzyme with poor affinity towards ?-lactam antibiotics. It is encoded by the the mecA gene MRSA is furthermore often also resistant to other classes of antibiotics

3. Definition of MRSA mecA is situated in a gene cassette named �Staphylococcal chromosome cassette -mec� Large genetic element (22-67 kb) mecA is inherited vertically In very rare cases it is transferred horizontally The origin of the SCCmec cassette is unknown Sequence based typing is now used for naming MRSA strains Multi Locus Sequence Typing (MLST) ST , CC SCCmec mecA is situated in a gene cassette named the �Staphylococcal cassette chromosome-mec� SCCmec. This is a Large genetic element (22-67 kb) and mecA is almost entirely inherited vertically. It is only in very rare cases it is transferred horizontally � the actual number of horizontal transfer is not known but transfer to successful S. aureus strains seems to have happened less than 30 times in the history. The origin of the SCCmec cassette is unknown and an equivalent is not present in MSSA Sequence based typing is now used for naming MRSA strains: the principal method is Multi Locus Sequence Typing (MLST) which leads to an ST type for the individual strain and to a CC type for which family this strain belong to mecA is situated in a gene cassette named the �Staphylococcal cassette chromosome-mec� SCCmec. This is a Large genetic element (22-67 kb) and mecA is almost entirely inherited vertically. It is only in very rare cases it is transferred horizontally � the actual number of horizontal transfer is not known but transfer to successful S. aureus strains seems to have happened less than 30 times in the history. The origin of the SCCmec cassette is unknown and an equivalent is not present in MSSA Sequence based typing is now used for naming MRSA strains: the principal method is Multi Locus Sequence Typing (MLST) which leads to an ST type for the individual strain and to a CC type for which family this strain belong to

4. Why is MRSA a problem I MRSA is resistant to the most potent group of anti � staphylococcal antibiotics i.e. ?-lactam antibiotics MRSA infections have increased morbidity and mortality Why is MRSA a problem MRSA is resistant to the most potent group of anti � staphylococcal antibiotics: the ?-lactam antibiotics and MRSA infections are associated with increased morbidity and mortality which is llustrated by the metaanalysis by Cosgrove and co-workers� Why is MRSA a problem MRSA is resistant to the most potent group of anti � staphylococcal antibiotics: the ?-lactam antibiotics and MRSA infections are associated with increased morbidity and mortality which is llustrated by the metaanalysis by Cosgrove and co-workers�

5. Why is MRSA a problem II MRSA infections are more expensive to treat Infections vs no infections All infections (Wernitz, CMI, 2005,466) Prolonged stay in hospitals (14-28 days) Additional costs (5000 - 29000 �) Compared to MSSA infections Bacteremia � (Cosgrove, ICHE,2005,166) Prolonged stay in hospitals 2 days Additional costs 7000 $ Prolonged rehabilitation MRSA is also a societal problem as MRSA infections are very costly. In this slide two examples are given � with additional costs between 5 and 29.000 US $ To this figure you have to add the cost for prolonged rehabilitation but also that in MRSA endemic countries the empiric treatment � the antibiotic treatment you give patients before the etiology is known - has to cover for MRSA by adding additional antibiotics MRSA is also a societal problem as MRSA infections are very costly. In this slide two examples are given � with additional costs between 5 and 29.000 US $ To this figure you have to add the cost for prolonged rehabilitation but also that in MRSA endemic countries the empiric treatment � the antibiotic treatment you give patients before the etiology is known - has to cover for MRSA by adding additional antibiotics

6. Why is MRSA a problem III Anti-MRSA antibiotics has to be administered empirically Increased use of antibiotics will inevitably lead to increased resistance not only in staphylococci but also in other species. Vancomycin resistant enterococci (VRE) Vancomycin resistant MRSA VISA (GISA) VRSA (vanA positive) 4 isolates in USA This both have a direct economical cost but also an ecologic cost as increased use of antibiotics inevitably will lead to increased resistance not only in staphylococci but also in other species. This has been illustrated by emergence of Vancomycin resistant enterococci (VRE) Vancomycin resistant MRSA VISA (GISA) VRSA (vanA positive) 4 isolates in USA I will now turn to the history of MRSA in DenmarkThis both have a direct economical cost but also an ecologic cost as increased use of antibiotics inevitably will lead to increased resistance not only in staphylococci but also in other species. This has been illustrated by emergence of Vancomycin resistant enterococci (VRE) Vancomycin resistant MRSA VISA (GISA) VRSA (vanA positive) 4 isolates in USA I will now turn to the history of MRSA in Denmark

7. The first MRSA was reported in England in 1961 only two years after the discovery of methicillin. S. aureus has been surveillanced in Denmark by the Staphylococcus Laboratory since 1957. The first MRSA was found in Denmark in 1962. In the following years only very few isolates were found. In 1966 an increase was observed and all S. aureus isolates has thereafter been systematically tested for methicillin resistance. From 1966 to 1968 the number of MRSA increased dramatically to 20% of all isolates and 46 % of SAB isolates. From around 1970 the frequency of MRSA rapidly declined again � I will come back to this � and from the mid-seventies up to 2002 the frequency has been at a stable low level. However� The first MRSA was reported in England in 1961 only two years after the discovery of methicillin. S. aureus has been surveillanced in Denmark by the Staphylococcus Laboratory since 1957. The first MRSA was found in Denmark in 1962. In the following years only very few isolates were found. In 1966 an increase was observed and all S. aureus isolates has thereafter been systematically tested for methicillin resistance. From 1966 to 1968 the number of MRSA increased dramatically to 20% of all isolates and 46 % of SAB isolates. From around 1970 the frequency of MRSA rapidly declined again � I will come back to this � and from the mid-seventies up to 2002 the frequency has been at a stable low level. However�

8. MRSA in Denmark 1994-2005 As shown in this slide the number of MRSA cases although very low is increasing epidemically. It is however not only in Denmark that the frequency of MRSA is increasing�.As shown in this slide the number of MRSA cases although very low is increasing epidemically. It is however not only in Denmark that the frequency of MRSA is increasing�.

9. This also happens in the other Nordic countries which all too have very low level endemicity of MRSA and looking at Europe�.This also happens in the other Nordic countries which all too have very low level endemicity of MRSA and looking at Europe�.

10. This slide show the frequence for MRSA in bacteremia in Europe in 2003 and if you compare with 2004 the levels have also increased in Spain, the Netherlands and Greece. Well lets turn back to DenmarkThis slide show the frequence for MRSA in bacteremia in Europe in 2003 and if you compare with 2004 the levels have also increased in Spain, the Netherlands and Greece. Well lets turn back to Denmark

11. As you can see in this slide resistance in S. aureus towards streptomycine and tetracycline was found prior to methicilin and were even at a higher level. But why the disappearance of MRSA? Well� As you can see in this slide resistance in S. aureus towards streptomycine and tetracycline was found prior to methicilin and were even at a higher level. But why the disappearance of MRSA? Well�

12. Reasons for the disappearance of MRSA in Denmark Almost entirely a monoclonal outbreak Archaic clone (ST250; CC 8; SCCmec I) � phagetype 83A, resistant to PSTM First of all practically all isolates from that period � not only in Denmark but also in the rest of the world - belonged to one clone and a great deal of the reduction was due to other S. aureus strains outcompeted this clone. But �First of all practically all isolates from that period � not only in Denmark but also in the rest of the world - belonged to one clone and a great deal of the reduction was due to other S. aureus strains outcompeted this clone. But �

13. in Denmark we managed to get it to almost zero. In other European countries as illustrated here from a hospital in Paris - the numbers fell too, but not to zero and soon started to rise again. The success in Denmark can be attributed to a number of initiatives taken....in Denmark we managed to get it to almost zero. In other European countries as illustrated here from a hospital in Paris - the numbers fell too, but not to zero and soon started to rise again. The success in Denmark can be attributed to a number of initiatives taken....

14. Reasons for the disappearance of MRSA in Denmark II Almost entirely a monoclonal outbreak Establishment of decentralized clinical microbiology Concerted action! Focus on infection control precautions in hospitals Restrictive use of antibiotics At this period decentralized clinical microbiology was established� the microbiologists all MDs not only managed the laboratory but consulted infected patients. There was a concerted action with focus on infection control precautions in hospitals and not least A restrictive use of antibiotics � the latter illustrated here by 3 distinguished microbiologists which toured Denmark lecturing on proper antibiotic usage � which lead to a significant decrease in the usage of antibiotics in general and of tetracycline and streptomycine in particular. At this period decentralized clinical microbiology was established� the microbiologists all MDs not only managed the laboratory but consulted infected patients. There was a concerted action with focus on infection control precautions in hospitals and not least A restrictive use of antibiotics � the latter illustrated here by 3 distinguished microbiologists which toured Denmark lecturing on proper antibiotic usage � which lead to a significant decrease in the usage of antibiotics in general and of tetracycline and streptomycine in particular.

15. Several and different kinds of studies has shown a correlation between exposure to antibiotics and likelihood for MRSASeveral and different kinds of studies has shown a correlation between exposure to antibiotics and likelihood for MRSA

16. It is not the only player � as seen in this slide the frequency of MRSA vary enormously within the same country - but before we discuss infection control procedures�It is not the only player � as seen in this slide the frequency of MRSA vary enormously within the same country - but before we discuss infection control procedures�

17. Evolution of MRSA I will show you a model of the evolution in MRSA which in fact give us some important understanding of the observed epidemiology I will show you a model of the evolution in MRSA which in fact give us some important understanding of the observed epidemiology

18. In my mind the MRSA era so far can be divided into at least 3 important periods. The first has been discussed. The second wave started in the mid seventies and was caused by introduction of two other SCCmec catsettes II and III�In my mind the MRSA era so far can be divided into at least 3 important periods. The first has been discussed. The second wave started in the mid seventies and was caused by introduction of two other SCCmec catsettes II and III�

19. MRSA - Evolution 1. MRSA �wave� Almost monoclonal - Archaic klon (ST250; CC 8; SCCmec I) 2. MRSA �wave� Acquisition of the mecA gene both in new cassettes and in new MSSA strains (rare event) SCCmec I+ II + III Dominated by few clones (CC8, CC5) Hospital associated MRSA These casettes are considerably larger and carry other resistance genes � for example against erythomycin and gentamicin. As said in the beginning acquisition and horizontal spread are very rare events and it is therefore not surprising that this wave were caused by only few clonal lineages (CC8, CC5) Furthermore they were almost entirely linked to hospitals probably due to their huge SCCmec genes which demanded an antibiotic selection pressure to survive The third wave started by the introduction of a 4th SCCmec type in the late 1980�ies.. These casettes are considerably larger and carry other resistance genes � for example against erythomycin and gentamicin. As said in the beginning acquisition and horizontal spread are very rare events and it is therefore not surprising that this wave were caused by only few clonal lineages (CC8, CC5) Furthermore they were almost entirely linked to hospitals probably due to their huge SCCmec genes which demanded an antibiotic selection pressure to survive The third wave started by the introduction of a 4th SCCmec type in the late 1980�ies..

20. MRSA - Evolution 3. MRSA �wave� � part 1 Acquisition of the new smaller SCCmec IV New hospital associated MRSA clones (i.e. CC 22, CC 30, CC 45) Transfer of SCCmec IV to CC 5 and CC8 >90% of hospital acquired MRSA world wide belongs to only 5 clonal complexes (CC 5, CC8, CC 22, CC 30, CC 45) These CC (+ CC80) are also the major CCs in Denmark! Where S. aureus again adapted and came up with a much smaller SCCmec cassette. This cassette has given rise to three new pandemic lineages (CC22, CC30 and CC45) and furthermore also is found in the old CC5 and CC 8 lineages. These 5 lineages accounts for more than 90% of HA-MRSA in the world � however the relative proportion differ considerably in different countries. Also in Denmark these are the most abundant lineages together with the CA CC80 clone. Which brings me to part 2 of the 3rd wave.. Where S. aureus again adapted and came up with a much smaller SCCmec cassette. This cassette has given rise to three new pandemic lineages (CC22, CC30 and CC45) and furthermore also is found in the old CC5 and CC 8 lineages. These 5 lineages accounts for more than 90% of HA-MRSA in the world � however the relative proportion differ considerably in different countries. Also in Denmark these are the most abundant lineages together with the CA CC80 clone. Which brings me to part 2 of the 3rd wave..

21. MRSA Evolution 3. MRSA �wave� � part 2 Acquisition of the SCCmec IV into completely different lineages which can multiply and spread outside the hospital environment Community acquired MRSA i.e. CC 1and CC 80 (the European community acquired clone) SCCmec IV also transferred into completely different S. aureus lineages which are able to multiply and spread outside the hospital environment: the Community acquired MRSA � CA MRSA poses new challenges for combating MRSA � this brings me to discuss infection control another crucial part of the combat SCCmec IV also transferred into completely different S. aureus lineages which are able to multiply and spread outside the hospital environment: the Community acquired MRSA � CA MRSA poses new challenges for combating MRSA � this brings me to discuss infection control another crucial part of the combat

22. Development of MRSA in invasive S. aureus infections in UK: This changed the situation from control to �no control� within few months in 1993 � The problem is now that big that it was a serious part of the campaign at the last election in UK!This changed the situation from control to �no control� within few months in 1993 � The problem is now that big that it was a serious part of the campaign at the last election in UK!

23. Epidemiology has changed The epidemiology of MRSA has changedThe epidemiology of MRSA has changed

24. New epidemiology - Denmark Most MRSA cases have not had connection to foreign healthcare facilities. Onset of MRSA infections is no longer confined to hospitals. A significant proportion of infections have community onset In several cases no risk factors for contracting MRSA have been identified. Outbreaks of MRSA have been reported from nursing homes in several regions In Denmark Most MRSA cases today have not had connection to foreign healthcare facilities. Onset of MRSA infections is no longer confined to hospitals. A significant proportion of infections have community onset and in several cases no risk factors for contracting MRSA have been identified. we have also observed outbreaks of MRSA from nursing homes in several regions This change has happened at the same time as we have observed the increase in MRSA� In Denmark Most MRSA cases today have not had connection to foreign healthcare facilities. Onset of MRSA infections is no longer confined to hospitals. A significant proportion of infections have community onset and in several cases no risk factors for contracting MRSA have been identified. we have also observed outbreaks of MRSA from nursing homes in several regions This change has happened at the same time as we have observed the increase in MRSA�

25. Diagnosis of MRSA infections in Denmark As illustrated in this slide where you can see that most of the increase has been in infections diagnosed outside hospitals � shown in the yellow bar) The appearance of CA-MRSA was first described � As illustrated in this slide where you can see that most of the increase has been in infections diagnosed outside hospitals � shown in the yellow bar) The appearance of CA-MRSA was first described �

26. CA-MRSA is reported from virtually all the European countries as well as from the rest of the world.CA-MRSA is reported from virtually all the European countries as well as from the rest of the world.

27. New epidemiology- control of influx The increase of MRSA in the community in otherwise healthy people has led to increased introduction of MRSA to hospitals, which has resulted in an increasing number of intra-hospital transmissions / outbreaks. Control of influx In Denmark the increase of MRSA in the community in otherwise healthy people has led to increased introduction of MRSA to hospitals, which has resulted in an increasing number of intra-hospital transmissions / outbreaks - as shown by the red bar Again made control of influx essentialIn Denmark the increase of MRSA in the community in otherwise healthy people has led to increased introduction of MRSA to hospitals, which has resulted in an increasing number of intra-hospital transmissions / outbreaks - as shown by the red bar Again made control of influx essential

28. Coping with MRSA outside hospitals Reduction (absolute or relative) in areas where A very strict MRSA infection control is upheld Barrier nursing in primary care Sjukhushygienprojektet i Egentliga Finland Treatment of carriers of MRSA Urth,ICHE, 26, 144 But how to cope with CA MRSA � well very few investigations has been published. Ii the Nordic countries two different procedures has been found to be effective in reducing the no. of MRSA In Finland by using very strict infection control precautions when nursing patients in elderly homes and clinics and in Denmark by treatment of carriers of MRSA.But how to cope with CA MRSA � well very few investigations has been published. Ii the Nordic countries two different procedures has been found to be effective in reducing the no. of MRSA In Finland by using very strict infection control precautions when nursing patients in elderly homes and clinics and in Denmark by treatment of carriers of MRSA.

29. Type of infections CA was almost completely dominated by skin and soft tissue infections whereas a variety of infections was seen in HA-MRSA casesCA was almost completely dominated by skin and soft tissue infections whereas a variety of infections was seen in HA-MRSA cases

30. Age distribution of MRSA infections

31. MRSA infections in Denmark, 2004 (N = 408)