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Folie 1

  1. 1. MRSA– MethicillinresistantStaphylococcusAureus–<br />Florian Schneider<br /> – med in spe – <br />CurrentHealth Problems in Students‘ Home Countries<br />UniverzitaKarlova v Praze - Department of Hygiene<br />LékařskáFakulta v Hradci Králové<br />Šimkova 870<br /> 500 01 Hradec Králové<br />
  2. 2. MRSA – General Problem<br /><ul><li>Bacteria found in hospitals are special majority developed a resistance against antibiotics used there! </li></ul> patient’s original bacterial flora (natural & sensitive to antibiotics) becomes gradually replaced (contaminated) by these resistant bacteria (artificially evolved by continuous exposure to antibiotics)<br /><ul><li>One certain bacterial strain is again and again mentioned in this relation: the Staphylococcus aureus, which is tagged by resistancy to methicillinantibiotics. Thus: Methicillin (also: Oxacillin) Resistant Staphylococcus Aureus (MRSA // ORSA)
  3. 3. Example: Patients coming to the hospital for first time have only 20 % of their skin bacteria resistant to antibiotics. Patients coming for a second or third time (the patients who were in the hospital previously) already have 60% of their skin bacteria resistant to antibiotics!</li></ul> To “escape” the contamination with bacteria resistant to antibiotics, limit the stay in a hospital to the shortest possible!<br />
  4. 4. Staphylococcus Aureus<br />Methicillin<br />Clinical relevance<br />Preventive Strategies<br />
  5. 5. Staphylococcus – The Variants<br />Twotypesofstaphylococcus: (relatedtocolour in Agar medium)<br /><ul><li>Whitepigmented type „Staphylococcus pyogenes albus“ </li></ul>spheric, clusters, mostfrequentskinbacterium, gram-positive, lowplasmacoagulase-activity, (present in 30% of all clean orthopedicoperationwounds  all withoutcomplications!)<br />  not dangerousin thisconfiguration<br />  relevant mainly in operationsofjoints<br /><ul><li>Yellowpigmented type „Staphylococcus pyogenes aureus“ (aureus (gr.) = golden)</li></ul>  highplasmacoagulase-activity  highpathogenityand also highletality<br />  clinically a majorproblem!<br />Plasmacoagulase: activation-factorforprothrombin (analogoustoFactor V & X or Ca2+ )  condensationoffibrin-networkserveasprotectionofs.aureusbacteria(thebacteriabecomehiddenunderlayeroffibrinandotherplasmaproteins) <br /> Test forplasmacoagulase-activityneedsat least 24 hours (toolongforemergencysituations); Clumping-Factortest(physiologicallysimilarfunctionof CFs andplasmacoag.) givesresultswithin 1-2 min<br />
  6. 6. Staphylococcus Aureus – Clinical Relevance<br />Importanceoftests:<br /><ul><li>Antibiotics areoptimalonlyfor a certain type / strainofbacteria; e.gthe gram-behavior (gram-positive or -negative)
  7. 7. MRSA: total determinationofstraincomprises
  8. 8. mecA-gene,
  9. 9. mecR- & mecI-gene,
  10. 10. femA-D gene
  11. 11. 10-12 othergenetic</li></ul>  too time consumingforimmediatetreatment in urgent cases (upto 3-4 days)<br /> Most importanttestforimmediatetreatment: gram-test<br />
  12. 12. Staphylococcus Aureus – Characteristics<br />Microscopy / Culture:<br /><ul><li>Bacterium, gram-positive (bluestaining in Lugol-solution due topresenceofmureinshell (peptidoglycans))
  13. 13. Formation ofclusters(staphyle (gr.) = bunchofgrapes)
  14. 14. Size: 0,8 – 1,2 μm
  15. 15. Nonmotile, nospore-formation</li></ul>Growth:<br /><ul><li>Fakultative anaerob
  16. 16. @ [10 ; 45]°C , in wide pH-Spectrum, also in highNaCl-conc. (upto 10%)
  17. 17. 1 – 2 mm big & pigmentedcolonies</li></ul> gram-negative gram-positive<br />S.aureus in clusters<br />
  18. 18. StaphylococcusAureus – Natural Resistance<br />Resistance toenviron-<br />mental influencesSurvivalpossible*<br /><ul><li>High salt-resistance 7,5 – 10 % [NaCl]
  19. 19. High temperature-resistance 60°C / 15-30 min
  20. 20. High Resistance in environment:</li></ul>- artificiallycontaminatedplasticslab: > 7 days<br /> - matrices: > 70 days<br /> - cottoncloth: > 100 days<br /> - blankets: > 200 days<br /><ul><li>High tolerancetodehydration:</li></ul>- contaminated, driedpus: ~ 70 days<br />* Microbial Survival in the Environent, Mitscherlich/Marth, 1984<br />
  21. 21. Staphylococcus Aureus – Characteristics<br />Pathogenicfactors:<br /><ul><li>CellularFactors:
  22. 22. Protein A
  23. 23. Clumping-Factor
  24. 24. Mureinshell(Polysaccharides)
  25. 25. ExtracellularFactors:
  26. 26. Plasmacoagulase
  27. 27. Fibrinolysin
  28. 28. Hemolysin
  29. 29. Leukocidine
  30. 30. Hyaluronidase
  31. 31. Extracellularpolymericsubstances
  32. 32. Exfoliative-toxins
  33. 33. Toxic-Shock-Syndrome-toxins
  34. 34. Enzymes: lipases, nucleases, proteases
  35. 35. Bacteriocine</li></ul>S. aureus after 1day-cultivation in a Petri dish<br /> Strongly virulent (Virulence = capability to cause infections by prodution of bact. poisons<br />
  36. 36. Staphylococcus Aureus – Diseases<br />Inflammatory & pyogenic diseases:<br /><ul><li>Carbuncle
  37. 37. Abscesses
  38. 38. Furuncle</li></ul>(collection of pus)<br />(perifollicular, inflammated spot)<br />(=group of furuncles, with deep purulent inflammation)<br />Details: http://www.infektionsnetz.at/InfektionenHautinfektionenBakterien.phtml (Roche AG)<br />
  39. 39. Staphylococcus Aureus – Diseases<br />Emphysem<br /><ul><li> Parotitis
  40. 40. Pneumonia</li></ul>(=loss of elastic recoil of lungs and following collapse of pulmon. bronchioles & alveoli)<br />
  41. 41. Staphylococcus Aureus – Diseases<br />Mastoiditis<br /><ul><li>Otitis Media
  42. 42. Osteomyelitis</li></ul>(acute or chronic)<br />(might arise from otitis media)<br />(Interesting: http://osteomyelitis.stanford.edu/pages/case06.html)<br /><ul><li>Endocaditis
  43. 43. Sepsis</li></ul>Sono + Doppler<br />
  44. 44. Staphylococcus Aureus – Diseases<br />Toxinmediated Diseases:<br /><ul><li>Nutritional intoxication </li></ul> nausea, cramps, vomiting, diarrhoe, hallucinations, … <br /><ul><li> Staphylococcal Scalded Skin Syndrome (SSSS) (Dermatitis exfoliativa)</li></ul> itching, lethargy, fever, hypothermia <br />  detach of epidermis from dermis due to exotoxins A + B <br />  fluid filled blisters (thin walled  easily rupture)<br />  Ritter‘s Disease of the Newborn  most severe form of SSSS<br /><ul><li>Toxic Shock Syndrome (TSS):</li></ul> high fever, low blood pressure, confusion, coma, mulit-organ failure, death<br /> characteristic rash ressembles sunburn & can involve any region of the body (lips, mouth, eyes, palm, soles)<br /> desquamation occurs after 10-14 days<br />
  45. 45. StaphylococcusAureus – Misc. information<br /><ul><li>Transmission pathways:
  46. 46. endogenously(S.aureusisspreadthroughouttheinfectedpacient‘sbodybybodyfluids; areabletoovercomebbborbmbbyimpairementofthesestructures)
  47. 47. exogenously(e.g. contactwithcontaminatedhands, skin, instruments)
  48. 48. Strong adherencetosyntheticsurfaces</li></ul>(developmentof „disinfectivesynthetics“  surfacesthatpreventadherence)<br /><ul><li>Resistanttomany environmental factors
  49. 49. Colonisationofskinandmucosa(colonisation  infection)
  50. 50. 10 – 40 % ofhealthypopulation (nose, pharynx, perineum)
  51. 51. 45 – 65 (80) % ofclinical personal (62% vestibulumnasi, 5 % on hands)
  52. 52. Great importance in nosokomial infections(secondaryinfections)</li></li></ul><li>StaphylococcusAureus – Misc. information<br /><ul><li>Multiresistance (insensitivitytomorethanoneclassofantibiotics) </li></ul>  verynarrowvarietyoftreatment  pathogen-specifictherapy, Anti-biogramm<br /><ul><li>High incidencewithgrowingtendency (28 103 cases*)
  53. 53. Significantlyincreasedmortalityfor Sepsis (1108 avoidabledeaths*)
  54. 54. Verycost intensive (427 Mio. €*)
  55. 55. 1 MRSA-colonisation 1647,94 €*
  56. 56. 1 MRSA-infectionupto 14 360 $*
  57. 57. Escalatingsituation (Spain, Italy, France, GB, Japan & USA  almostuncontrollable)  world-wideproblem</li></ul>*Data related to Germany, 2005; Source: Martin Wernitz, Klinikum Friedrichshain, Berlin<br />
  58. 58. Methicillin – Discovery of Antibiotics<br />Timetable<br />1928: Discovery of Penicillin<br />After 1940: General use of Penicillin<br />1944: Resistance to Penicillin<br />Alexander Flemming, St.Mary‘s Hospital, London<br /> Remark: before the discovery of antibiotics infections with S.aureus were in 90% of all cases lethal! („preantibiotic stage“)<br />Penicillin saved many lives during 2nd World War<br />
  59. 59. Methicillin – New Type of Antibiotics<br /><ul><li>Beecham, 1959: developmentofpenicillinase- resistant Penicillin </li></ul>  Methicillinoptimallyworkes/edagainstbacteria, thatproduceenzymesforinactivationofantibiotics<br />  β-lactam-ring isstearicallyblocked, so penicillin-asesarehardlyableto bind it<br />  instable in acidicenvironment (parenterallyapplied) <br />  subgroupwithnarrowerfieldoftreatment<br />  optimal: grampositive & β-lactamresistantbact.<br />  today‘sderivativesused: Oxacillin, Dicloxacillin, Flucloxacillin<br />Chemical stucture of Methicillin; <br /> β –lactam-ring is in the centre!<br />
  60. 60. Methicillin – Discovery of Antibiotics<br />Timetable<br />1928: Discovery of Penicillin<br />After 1940: General use of Penicillin<br />1944: Resistance to Penicillin<br />1959: Discovery of penicillinase-resistant Penicillins<br />1961: resistance to penicillinase-resistant Penicillins<br />
  61. 61. MethicillinResistantStaphylococcusAureus – MRSA – <br />Background<br />Synonym: Oxacillin-resistant S.aureus (ORSA) ( in laboratory tests mainly search for oxacillin (comprises resistance to methicillin))<br />„Multi-resistant S.aureus“ (commonly for resistances for other non-β-lactam-antibiotics<br />History:<br />1959: Introduction Methicillin<br />1961: First discovery of MRSA<br />Global distribution<br />Increasing significance as a pathogen for nosokomial infections <br />Percentage of all S.aureus isolates in Germany: 22,6 %<br />Some MRSA-strains: increased capability for epidemic spreading („epidemic Virulence“)<br />Quick colonisation of contact persons (patients)<br />
  62. 62. MRSA – Development in Germany<br />
  63. 63. MRSE – Development in Germany<br />
  64. 64. Development of Penicillin-Resistance<br />
  65. 65. Methicillin – Resistancemechanism<br />Resistencemechanism<br />Mutations in mecA-Gene<br />Structural different Penicillin-Binding-Protein (PBP 2  PBP 2a)<br />Small affinity for Methicillin/Oxacillin/β-lactam-antibiotics<br />Cross-resistance to all β-lactam-antibiotics (including Cephalosporines & Carbapenemes<br />
  66. 66. Staphylococcus Aureus – Genetic Background of Methicillin-Resistancy<br />Normal procedure:β-Lactam-antibiotics(ABs) boundstabletotheactivecentreof a PBP (Penicillin-Binding-Protein) disturbthesynthesisofthecellmembrane<br />  stop ofbacterialgrowth  autolysis / apoptosis<br /> PBPs aremembraneboundenzymes, responsiblefortheformationof<br />peptidoglycansofthecellcoat//wall<br />  normal: PBPs 1-4 (sortedbyweight)<br />Mutationsof PBP-determininggeneticareasgiveraisetonew PBP structure:<br />  PBP 2a isformed(codedbymecA-gene, significantloweraffinitytoβ-Lactam-antibiotics); takesoverthephysiologicfunctionof PBPs 1-4  AB ineffective  bacterial wall remainsintact<br />  such resistantbacteriaproduce an enzymebreaking down attached ABs, theβ-Lactamase<br />  „intrinsicresistance“<br /><ul><li>In caseof MRSA a total determinationofstraincomprises:</li></ul> 1. mecA-gene (78 kDa, mostimportant  PBP 2a)<br /> 2. mecR- & mecI-gene (regulatory genes, repressor-fct. on transcriptionofmecA-gene!) <br /> 3. femA-D gene ( ‘‘ ‘‘ )<br /> 4. auxiliary genes (10-12 othergeneticelementsthatinfluencetheexpressionof PBPs )<br /> PBP 2a is major genetic feature for MRSA-Detection !!!<br />
  67. 67. MRSA – ResistantPhenotypes in Germany<br />Epidemic MRSA in german hospitals (Resistancephenotypes)<br /> *Epid. Bull. 42/2004<br />** Epid. Bull. 41/2005<br />
  68. 68. MRSA-strains, localisation,<br />Germany, 2004*<br />*Epid. Bull. 41/2004<br />
  69. 69. MRSA – Analysis of Resistance to different Antibiotics, Erlangen, 2004<br />Resistance of MRSA totestedantibiotics<br /><ul><li>Penicillin 100 %
  70. 70. Ampicillin 100 %
  71. 71. Oxacillin 100 %
  72. 72. Amoxicillin/Clavulansäure 100 %
  73. 73. Cefazolin 100 %
  74. 74. Cefotiam 100 %
  75. 75. Imipenem 100%
  76. 76. Ciprofloxacin 94 %
  77. 77. Erythromycin 89 %
  78. 78. Clindamycin 89 %
  79. 79. Gentamicin 33 %
  80. 80. Cotrimoxazol 4 %
  81. 81. Fosfomycin 3 %
  82. 82. Vancomycin ( Linozolin) 0 %</li></li></ul><li>Clinical Relevance – Other AntibioticResistances<br />Abbreviations<br /><ul><li>MSSA methicillin-sensitive S.aureus
  83. 83. MRSA methicillin-resistantS.aureus
  84. 84. VISA vancomycin-intermediate sensitive S.aureus
  85. 85. GISA glycopeptid-intermediate sensitive S.aureus
  86. 86. VRSA vancomycin-resistantS.aureus</li></ul>Timetable<br /><ul><li>1956: Discovery Vancomycin
  87. 87. 1958: IntroductionofVancomycin
  88. 88. 1996: Discovery of VISA
  89. 89. 2002: Discovery of VRSA  actual „reserve-antibiotic“ isLinozolid (last lineofdefence); only in severecases  developmentofresistance must berestricted!</li></li></ul><li>Clinical Relevance – MRSA on ICUs<br />Types of Infections associated with MRSA (Jan/2003 – Dec/2003, acc. to KISS)*<br />Type of Infection Percentage<br /> ________________________________________<br /> Pneumonia 48 %<br /> Bronchitis 10 %<br /> Sepsis 10%<br /> Postoperative woundinfections 18%<br /> Skininfections 5 %<br /> Infections of urinary tract 3 %<br /> others 6 %<br />*Epid. Bull 41/2004<br />
  90. 90. Clinical Relevance – Nosokomial Infections<br />FrequencyofS.aureusfor nosokomial infections in Germany (KISS*)<br />Data forIntensive Care Units, Jan/1997 – Dec/2003**<br /><ul><li>Pneumoniaassoc. toartificialventilation: 24% rank 1
  91. 91. Bronchitis assoc. toartificialventilation: 26% rank 1
  92. 92. CVF-assoc. Sepsis: 15% rank2</li></ul>2. Data of postoperative woundinfections, Jan/1997 – Dec/2002***<br /><ul><li>Obstetrics: 19% rank1
  93. 93. Vascularsurgery: 39% rank1
  94. 94. Heart surgery: 40% rank1
  95. 95. Traumatology/Orthopaedics 40% rank1
  96. 96. General-/Abdominal surgery 12% rank3</li></ul>* KISS = Krankenhaus-Infektions-Surveillance-System <br />** Epidemiologisches Bulletin 41/2004<br />*** Epidemiologisches Bulletin 36/2003<br />
  97. 97. Clinical Relevance – MRSA on ICUs*<br /><ul><li>accordingto KISS**
  98. 98. 1997: MRSA-percentageof all S.aureus: 8 %
  99. 99. 2003: MRSA-percentageof all S.aureus: 30 %
  100. 100. Primary S.aureus – Sepsis
  101. 101. MRSA-percentageof all S.aureus: 37,8 %
  102. 102. Nosokomial pneumonia
  103. 103. MRSA-percentageof all S.aureus: 21,5 %</li></ul>*Epid. Bull. 5/2005<br />**KISS = Krankenhaus Infektions Surveillance System<br />
  104. 104. StaphylococcusAureus – Situation in Europe – 2004* – <br />Staphylococcus aureus: proportion of invasive isolates resistant to oxacillin (equivalents) in 2004<br />* European Antibiotic Resistance Surveillance System (EARSS), Annual Report 2004<br />
  105. 105. StaphylococcusAureus – Situation in USA – Summaryof 1993 - 2005*<br />
  106. 106. MRSA – Preventive Strategies<br />Identification, aquisition, evaluation<br />Implementation of suitable hygienic sanctions<br />Rehabilitation of MRSA-carriers<br />Controlled & reasonable use of antibiotics<br />
  107. 107. MRSA – Preventive Strategies<br />Identification, aquisition, evaluation<br />§ 23 IfSG: Nosokomial Infections, Resistances<br /> „(1) Chiefs of hospitals and facilities for ambulant operations are committed, to register and evaluate the designated nosokomial infections and the appearance of pathogenes with special resistances and multiresistances in a continuous transcript.<br /> The records according to article (1) have to be stored for at least ten years.<br /> At request of the responsible public health department access has to be granted.“<br /> According to law it is a duty to record all data on nosokomial and epidemic infections. This data is evaluated in each hospital; the main centre in germany for disease control is the Robert-Koch-Institute (RKI). <br />No warranty for the translation ;)<br />
  108. 108. MRSA – Preventive Strategies<br />Implementationofhygienicsanctions*<br /><ul><li>RecommendationoftheCommissionforhospitalhygieneandInfectionprevention, e.g. relatingto:
  109. 109. Accomodation
  110. 110. Protectionagainstcontamination
  111. 111. Disinfection
  112. 112. Patient-transfers
  113. 113. Realisation candifferfromhospitaltohospital (but minimumstandard must alwaysbeachieved)</li></ul>Rehabilitation of MRSA-carriers<br /><ul><li>Antispetic / disinfectivemeasures
  114. 114. Sometimes in combinationwithantibioticmeasures
  115. 115. Goodresults in countries withlow MRSA-prevalence
  116. 116. Resultdependant on pre-existingdefects</li></li></ul><li>MRSA – Preventive Strategies<br />Controlled use of antibiotics<br />Therapy only at Infection NOT in case of a colonisation<br />Therapy (usually): Vancomycin (+ Combinative Partner Antibiotics)<br /> decreased incidence of resistant subpopulations<br />Decrease the pressure of selection (resistance-formation)<br />
  117. 117. Sources<br />www.wikipedia.com / .de<br />Google-picture-pool<br />Robert-Koch-Institut (www.rki.de)  MRSA + S. aureus<br />Epidemiologisches Bulletin (RKI) 36/03, 41/04, 41/05<br />www.infektionsnetz.de (Roche AG)<br />Dr. Bernd Kunz, Klinikum Erlangen<br />Martin Wernitz, Klinikum Friedrichshain, Berlin<br />

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