This is the end? MRSA

Transcription

1 This is the end? MRSA Olivier Denis Ecole de Santé Publique, Université Libre De Bruxelles Les Mardis de l Infectiologie CHU Liège mars 2018

2 Staphylococcus aureus Gram positive cocci in clusters First described by Sir Alexander Ogston in 1882 Natural habitat Commensal flora of animals including humans Reservoir: anterior nare, perineum, throat,... Prevalence: 30% Dynamic of carriage in humans Persistent 20% Transient 60% non-carrier (20%)

3 Staphylococcus aureus Major opportunistic pathogen responsible for infections both in hospitals and in the community Clinical manifestations Pyogenic infections : Skin and soft tissue infections to endocarditis Toxin mediated diseases : SSSS, SFP, TSS Master of creating/picking up resistance determinants Plasmid SCCmec Plasmid Tn4001 Plasmid Tn1546 Mutation 1942 Pen R 1961 Oxa R 1969 Genta R 1997 Vanco I 2002 Vanco R

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5 Penicillin resistant S. aureus (PRSA) Production of penicillinase Encoding by blaz located on plasmids Inhibited by clavulanic acid Tested by cefinase test or by disk diffusion method Difficult to detect in coagulase negative staphylococci Susceptible Resistant

6 Methicillin-resistant S. aureus (MRSA) Acquisition of mec gene Additional PBP2a showing low affinity to -lactams Cross-resistance to all -lactams, except for the novel anti- MRSA cephalosporins Four different types described: meca, mecb, mecc, mecd A mec gene type encompasses mec genes sharing 70% nucleotide sequence identity with their respective prototype. Found in Staphylococci and Marcococcus Ito t. et al. Antimicrob Agents Chemother 2012;4997

7 Staphylococcal cassette chromosome mec The mec gene is integrated into mobile genetic element Present at one copy Staphylococcal cassette chromosome mec (SCCmec) Chromosomal insertion at the attb SCC at the end of orfx Often contain plasmids or transposons carrying resistance genes Subdivided into types I to XII mec gene complex (meca (homologue) gene PBP2a) ccr gene complex : Responsible for the movement (excision and integration) from and into the bacterial chromosome mec gene ccr gene complex complex SCCmec J3 A R1 I J2 B A J1

8 Staphylococcal Cassette Chromosome mec Classification according to Types: combination of mec and ccr Variants: difference into junkyard regions. SCCmec Type ccr Type mec I (1B) 1 A1B1 B II (2A) 2 A2B2 A III (3A) 3 A3B3 A IV (2B) 2 A2B2 B V (5C2) 5 C1 C2 VI (4B) 4 A4B4 B VII (5C1) 5 C1 C1 VIII (4B) 4 A4B4 A IX (1C2) 1 A1B1 C2 X (7C1) 7 A1B6 C1 XI (8E) 8 A1B3 E XII (9C2) 9 C2 C2 08/05/2015 Hiramatsu et al. Infect Chemother 2013;45(2): Wu Z et al. AAC 2015; 59:7597.

9 Staphylococcal Cassette Chromosome mec plasmid Methicillin-susceptible S. aureus orfx SCCmec Chromosome plasmid Methicillin-resistant S. aureus orfx Chromosome

10 High diversity of SCCmec elements with the emergence of new types including mec and variants SCCmec «dropout» with lost of major parts of the SCCmec element including mec gene Lead to false-positive and false-negative results Need to adapt continuously the assay Last version able to detect SCCmec types I-XI Becker K et al. JCM 2016

11 The distribution of MSSA and MRSA among the various clonal complexes Acquisition of SCCmec is a very rare event Evidence that the SCCmec elements are distributed within certain lineages at higher frequency Chambers HF et al. Nature Microbiol Reviews 2009;629

12 Plasmid-mediated mecb gene Asymptomatic carriage in a hospitalized patient in Germany Belonging to a sporadic genotype spa type t091 Attachment site attb locus and orfx intact Negative for PBP2a detection Resistant to cefoxitin (32 mg/l) and oxacillin (12 mg/l) Susceptible to ceftaroline and ceftobiprole Integrated into a 84.6 kb multidrug resistance plasmid Becker K et al EID 2018

13 Plasmid-mediated mecb gene Multidrug resistance plasmid Contains multiple genes encoding resistance to Aminoglycosides Macrolides-Lincosamides Tetracycline Penicillin Transfer through bacteriophage transduction Putative livestock origin Becker K et al EID 2018

14 Borderline oxacillin resistant S. aureus (BORSA) Methicillin and/or oxacillin resistance but lacking the mec determinants Hyper-producers of β-lactamase hydrolyzing semisynthetic β- lactamase resistant penicillins (methicillin, oxacillin) Mutations in native pbp genes conferring low affinities of PBPs to β-lactams Mutations in pbp4-promotor and genes (gdpp, yjbh) involved in PBP4-overproduction Frequency: rare Argudin M et al. submitted

15 BORSA, Belgium, isolates collected by NRC for S.aureus for oxacillin/cefoxitn suscpetiblity discrepancy 32 isolates were mec-negative but cefoxitin (MIC 4 12 mg/)l and/or oxacillin (MIC mg/l) resistant Mechanism of resistance β-lactamase hyperproducers (n=12) Mutations in native PBPs or promotor of PBP4 (n = 20) Belonging to various genotypes Clinical significance? Argudin M et al. submitted

16 Anti-MRSA cephalosporins Ceftaroline and ceftobiprole New anti-mrsa cephalosporin Increased affinity to PBP2a Low emergence of ceftaroline resistant S. aureus From mutations in native pbp genes (PBP2 and PBP3) or meca Overexpression of pbp4 gene Lahiri SD JAC 2016

17 MSSA full susceptible with MIC range mg/l MRSA higher MIC range mg/l 1.4% of MRSA isolates showed MICs > 1 mg/l Mutations in meca gene and in genes encoding native PBPs including PBP1, PBP2, PBP3 and PBP4 Argudin M et al. JAC 2017; 72:56-59

18 Percent of isolates New anti-mrsa cephalosporins Ceftaroline Resistant if MIC > 1 mg/l MRSA MSSA MIC (mg/l) Argudin M et al. JAC 2017; 72:56-59

19 Glycopeptide breakpoints for Staphylococci

20 Definitions for glycopeptide non-susceptible S. aureus According to the mechanism of resistance vana-mediated high-level glycopeptide resistance Non-vanA-mediated low level resistance to glycopeptide VISA and hvisa for isolates with non-vana-mediated low-level resistance Vancomycin resistant S. aureus (GRSA) Isolates with high-level resistance to vancomycin (MIC >8 mg/l). Vancomycin intermediate S. aureus (GISA) Isolates with low-level resistance to vancomycin (MIC 4-8 mg/l). Heterogeneous vancomycin intermediate S. aureus (hgisa) Isolates susceptible to vancomycin (MICs 2mg/L) but with subpopulations (1 in 10 6 cells) with vancomycin MIC >2 mg/l by population analysis

21 Vancomycin resistance in Staphylococcus aureus Susceptible population Hetero low-level resistance (hvisa) Heterogenous population 10-6 to 10-9 resistant bacteria Low-level resistance (VISA) Homogenous population High resistance (VRSA) Homogenous population

22 Low level resistance Genetic environment Multiple point mutations leading to modified peptidoglycans synthesis No van genes and not linked to methicillin resistance Thickness of cell wall synthesis of peptidoglycan, autolytic activity, residues D-Alanyl-D- Alanine Absorption of GLYCOPEPTIDES into bacterial cell wall before extern membrane surface Low level resistance and reversible Teicoplanin > vancomycin MIC to vancomycin 4 8 mg/l Denis O. et al. JAC 2002;50:755 Hiramatsu K The Lancet Infect. Dis. 1:147

23 McGuinness W et al. Yale J Biol Med 2017; 90:

24 McGuinness W et al. Yale J Biol Med 2017; 90:

25 Mechanism of high level resistance Transfer of Tn1546 carrying vana gene E. faecalis S. aureus Modification of peptidoglycan synthesis Substitution of D-Ala-D-Ala by D-Ala-D-Lac affinity to vancomycin 10 3 High level resistance Vancomycin >> teicoplanin MIC vancomycin > mg Frequency Only about 30 cases reported from USA, India, Iran, Brazil and Portugal Gould IM Lancet Infect. Dis 2012

26 vana-type vancomycin resistance in S. aureus McGuinness W et al. Yale J Biol Med 2017; 90:

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28 Linezolid resistance Two mechanisms of resistance Mutations in domain V of 23S rrna (G2576T) or other genes encoding ribosomal proteins Methylation of nucleotide A2503 = transferable mechanism cfr gene located on plasmids PhLOPS A resistance phenotype ABC transporter encoded by optra gene only in S. sciuri Described in Staphylococcus aureus and CoNS isolates from animals and humans including Belgium Resistance: rare (<1%) but outbreaks occured Diaz L et al. AAC 2012 Morales G et al. CID 2012 Sánchez García M et al. JAMA 2010

29 cfr-positive MRSA ST398 LA-MRSA ST398 Resistance to chloramphenicol and clindamyin Linezolid susceptible? Not detected by disk diffusion using CLSI guidelines MIC to linzolid = 12 mg/l

30 Humans 1464 S. aureus isolates from 2013 to 2015 sent by 167 laboratories 30 resistant to chloramphenicol, clindamycin and/or linezolid One cfr-positive MRSA belonging to CC398 collected from patient with SSI Linezolid MIC = 12 mg/l Animals Occasionally found in S. aureus and non S. aureus Pigs, veals Peeters LEJ et al. Vet Microbiol 2015 Angeles Argudin M et al Res Vet Science 2015

31 Transmission pathways of antimicrobial resistance among different habitats and ecosystems Livestock animals Direct contact Consumption Acute/chronic care facilities Wildlife Environmental pollution Pets Direct contacts Household exposure Community Travel Environment Soil Water Manure/sewage

32 Epidemic waves of Hospital-associated MRSA First HA-MRSA wave (1960- mid 1970s) Almost monoclonal belonging to CC8 Archaic clone ST250-SCCmec I Especially in Europe (Denmark, France, Switzerland, UK) and USA By the 1980s, archaic clone disappeared and was replaced by descendents or new emerging clones Descendents of archaic clone : Iberian clone SCCmec Type I (34.4 kb)

33 Epidemic waves of Hospital-associated MRSA Second HA-MRSA wave (mid-1970s 1980s) Acquisition of the meca gene both in new cassettes and in new MSSA strains (rare event) Initially belonging to CC5, CC8 and CC30 SCCmec II + III Clones : New-York/Japan, Brazilian/Hungarian, UK-EMRSA 16 kdp ccra/b 2 Tn554 mec pub1 f 10 dc s SCCmec Type II (52 kb) SCCmec Type III (66 kb) ccra/b c 3 YTn55 4 mec pt18 1 pi25 8 Tn55 4 YccrA/ B

34 Epidemic waves of Hospital-associated MRSA Third HA-MRSA wave (late 1980s-) Acquisition of the new smaller SCCmec IV New HA-MRSA clones (i.e. CC 22, CC 45) Transfer of SCCmec IV to CC 5 and CC8 Accounts for more than 90% of HA-MRSA in the world Clones : UK-EMRSA 15, Berlin, Pediatric, Lyon ccra/b 2 or 4 Dmec dcs SCCmec Type IV (20-24 kb)

35 Berlin ST45-IV Iberian ST247-I UK EMRSA-2/-6 ST8-IV Brazil./Hungarian ST8-III NY/Japan ST5-II Paediatric ST5-IV South. German ST228-I UK EMRSA-15 ST22-IV UK EMRSA-16 ST36-II

36 Percent hospitals Secular trends of MRSA clonal distribution National Surveillance, hospitals, Belgium A1-ST247-SCCmec I B2-ST45-SCCmec IV C3-ST5-SCCmec IV 90 A20-ST8-SCCmec IV G10-ST5-SCCmec II L1-ST22-SCCmec IV Years (number of hospitals)

37 % of MRSA MRSA proportion from S. aureus bacteremia, EARSS, 1999 to Den Neth Lux Ger Bel Gre Por UK Net/Pages/index.aspx Source: ECDC

38 Global approach to the control of endemic MRSA Reduce AB use Education Restriction Stop transmission Hand hygiene Isolation Identify carriers Screening Universal or targeted Eliminate reservoirs decolonization

39 MRSA/ S. aureus (%) n-mrsa/1000 admissions MRSA in Belgian acute care hospitals Proportion of S. aureus clinical isolates and incidence of nosocomial acquisition, ,4% 4,1/1000 pts 1 st Guidelines 2,2/1000 pts 15,4% 4/1000 pts 30,0% 2 nd Guidelines AB stewardship committee Hand hygiene 15,9% 4,5 4 3,5 3 2,5 2 1,5 1 1,1/1000 pts 0,5 0 0 Source: National surveillance, B. Jans Resistance rate

40 MRSA carriage at hospital admission, previous contacts with healthcare setting Known carriage 34,1% Contact with hospitals 17,1% Contact with NHs 12,1% Unknown 14% Community 14,8% Contact with hospital and NH 7,8%

41 % MRSA-carriage in NHs Incidence of nosocomial MRSA in hospitals Evolution of MRSA carriage (%) in hursing home resisdents, Belgium: , ,5 3 2,5 2 1, , NHs (1997) 4.9 % MRSA 24 NHs (2000) 4.7 % MRSA (0% - 14%) 60 NHs (2005) 19 % MRSA (2% - 43%) 60 NHs (2011) 12.2 % MRSA (0% - 36%) 29 NHs (2015) 9.0% (0% - 22%)

42 Geographic distribution of epidemic MRSA clones in hospitals and nursing homes, 2005 Nursing homes (n = 587 isolates) Hospitals (n = 326 isolates) Denis O. et al. JAC 2009

43 Spread outside the hospital environment 1 st wave : Community-associated MRSA (late 1990s) Acquisition of the SCCmec IV and other small SCCmec Distinct lineages - not just descendants of HA-MRSA strains Solitary reports of CA-MRSA goes back to the 1980s (US, Australia, Europe) Emerging in hospitals (USA and Asia) in 2000s Described as being less multi-resistant Highly dependant on clonal background ST59 and ST80 are often multi-resistant Most of the dominant CA-MRSA strains produce the PVL

44 World distribution of PVL positive CA-MRSA clones Five lineages dominate: ST80-IV (European), ST8-IV (USA300), ST30-IV (Pacific/Oceania), ST59- IV/V (Taiwan),ST1-IV (USA400) DeLeo FR et al. Lancet 2010: 1557

45 Molecular typing of CA-MRSA PVL positive in Belgium from 2003 to 2015 CA-MRSA USA 300 Reference laboratory for staphylococci and MRSA Denis et al. JAC 2005; Brauner J et al. EJCMID 2012, Naesens R et al. JMM 2009

46 Spread outside the hospital environment 2 nd wave : Livestock-associated MRSA (2000s) Almost belonging to one genotype CC398 Highly frequent in Europe but also in the USA Acquisition of the SCCmec V but also IV, VII new variants (IX, X) Often multi-resistant To antibiotics and heavy metals (Zn,..) High diversity of resistance genes PVL negative, staphylococcal enterotoxin negative High prevalence in some human populations Veal farmers (58%), pig farmers (38%), Veterinarians (7.5%) (Belgium) Found in hospitals in countries (The Netherlands) and regions (Flanders) with high prevalence LA-MRSA Cystic fibrosis patients living in region with high density of livestock animals

47 MRSA carriage among veterinarians in Belgium and Denmark Garcia-Graells C et al. Epidemiol. Infect 2011

48 Human clade associated with bacteriophage 3 Immune Evasion Cluste Absence of tetm gene encoding tetracycline resistance MSSA LA-MRSA MRSA tetm gene Bacteriophage 7

49 Lifestock-associated CC398 MRSA Multi-resistant To antibiotics High diversity of resistance genes Tetracycline: tetm, tetk, tetl, Aminoglycosides MLS: erma, ermc, ermt,... To heavy metals (Zn,..) Absence of gene encoding toxins PVL, TSST-1 enterotoxin negative

50 Epidemiology and host range mecc MRSA found in multiple host species across Europe Sweden Norway Finland Scotland Denmark England The Netherlands Germany Ireland France Belgium Unfrequent less than 1% Austria Switzerland Spain

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52 mecc - MRSA CMI oxacilline : 6 mg/l CMI céfoxitine : 24 mg/l Positive PCR mecc

53 Conclusions Methicillin resistance mechanisms Diversification with new mec genes SCCmec and plasmids (new) Low resistance to linezolid, glycopeptides and ceftaroline Decrease incidence of nosocomial MRSA in hospitals and NHs Global approach to stop transmission within healthcare facilities AB stewardship, screening, decontamination and isolation Hand hygiene (++++++) Moving epidemiology New reservoirs in community and animals New risk factors of MRSA carriage : veterinarians, farmers, geographical location (?)

54 Team and collaborations Hôpital Erasme ULB Bruxelles Magali Dodemont Claire Nonhoff Ariane Deplano Maria Argudin Sandrine Roisin Ricardo De Mendonca Cristina Garcia-Graells Stien Vandendriessche «Les filles des ana» CHU Dinant-Godinne UCL Namur Youri Glupczynski Daniel Te-Din Huang Pierre Bogaerts Caroline Bauraing Didier Schoevaerdts Institute of Public Health Béatrice Jans Katrien Latour Boudewijn Catry Clinical laboratories in Belgium We acknowledge all microbiologists colleagues for referring strains to the NRC in Belgium. Funding Belgian Ministry of Social Affairs through a funds within the Health Insurance System. BAPCOC FP7 - Pilgrim CODA-CERVA P Butaye G Willems M. Dispas W.Vanderhaeghen

55 Questions????

56 MRSA transmission between humans and pets Transmission within households, veterinary hospitals and farms Dogs, cats but also rabbits, parrots, horses HA-MRSA ST22-SCCmec IV, ST8-SCCmec II Transmission of nurse to her baby and dog PVL- positive CA-MRSA ST80-SCCmec IV, USA300 ST8-SCCmec IV Familial outbreaks with recurrent infection Rankin S. et al. Vet Microb. 2005:108 van Duijkeren E. et al. JCM. 2005:43 Vitale CB et al. EID 2006:12 van Duijkeren E. et al. EID 2004:10 Strommenger B. et al. JAC 2006:57

57 Distribution of LA-MRSA CC398 Farmers versus pigs, 2007 Farmers Pigs Denis o. et al. EID 2009