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MRSA – Methicillin resistant Staphylococcus Aureus –

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  1. MRSA– MethicillinresistantStaphylococcusAureus– Florian Schneider – med in spe – CurrentHealth Problems in Students‘ Home Countries UniverzitaKarlova v Praze - Department of Hygiene LékařskáFakulta v Hradci Králové Šimkova 870 500 01 Hradec Králové

  2. MRSA – General Problem • Bacteria found in hospitals are special majority developed a resistance against antibiotics used there!  patient’s original bacterial flora (natural & sensitive to antibiotics) becomes gradually replaced (contaminated) by these resistant bacteria (artificially evolved by continuous exposure to antibiotics) • 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) • 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!  To “escape” the contamination with bacteria resistant to antibiotics, limit the stay in a hospital to the shortest possible!

  3. Staphylococcus Aureus • Methicillin • Clinical relevance • Preventive Strategies

  4. Staphylococcus – The Variants Twotypesofstaphylococcus: (relatedtocolour in Agar medium) • Whitepigmented type „Staphylococcus pyogenes albus“ spheric, clusters, mostfrequentskinbacterium, gram-positive, lowplasmacoagulase-activity, (present in 30% of all clean orthopedicoperationwounds  all withoutcomplications!)  not dangerousin thisconfiguration  relevant mainly in operationsofjoints • Yellowpigmented type „Staphylococcus pyogenes aureus“ (aureus (gr.) = golden)  highplasmacoagulase-activity  highpathogenityand also highletality  clinically a majorproblem! Plasmacoagulase: activation-factorforprothrombin (analogoustoFactor V & X or Ca2+ )  condensationoffibrin-networkserveasprotectionofs.aureusbacteria(thebacteriabecomehiddenunderlayeroffibrinandotherplasmaproteins)  Test forplasmacoagulase-activityneedsat least 24 hours (toolongforemergencysituations); Clumping-Factortest(physiologicallysimilarfunctionof CFs andplasmacoag.) givesresultswithin 1-2 min

  5. Staphylococcus Aureus – Clinical Relevance Importanceoftests: • Antibiotics areoptimalonlyfor a certain type / strainofbacteria; e.gthe gram-behavior (gram-positive or -negative) • MRSA: total determinationofstraincomprises • mecA-gene, • mecR- & mecI-gene, • femA-D gene • 10-12 othergenetic  too time consumingforimmediatetreatment in urgent cases (upto 3-4 days) Most importanttestforimmediatetreatment: gram-test

  6. Staphylococcus Aureus – Characteristics Microscopy / Culture: • Bacterium, gram-positive (bluestaining in Lugol-solution due topresenceofmureinshell (peptidoglycans)) • Formation ofclusters(staphyle (gr.) = bunchofgrapes) • Size: 0,8 – 1,2 μm • Nonmotile, nospore-formation Growth: • Fakultative anaerob • @ [10 ; 45]°C , in wide pH-Spectrum, also in highNaCl-conc. (upto 10%) • 1 – 2 mm big & pigmentedcolonies gram-negative gram-positive S.aureus in clusters

  7. StaphylococcusAureus – Natural Resistance Resistance toenviron- mental influencesSurvivalpossible* • High salt-resistance 7,5 – 10 % [NaCl] • High temperature-resistance 60°C / 15-30 min • High Resistance in environment: - artificiallycontaminatedplasticslab: > 7 days - matrices: > 70 days - cottoncloth: > 100 days - blankets: > 200 days • High tolerancetodehydration: - contaminated, driedpus: ~ 70 days * Microbial Survival in the Environent, Mitscherlich/Marth, 1984

  8. Staphylococcus Aureus – Characteristics Pathogenicfactors: • CellularFactors: • Protein A • Clumping-Factor • Mureinshell(Polysaccharides) • ExtracellularFactors: • Plasmacoagulase • Fibrinolysin • Hemolysin • Leukocidine • Hyaluronidase • Extracellularpolymericsubstances • Exfoliative-toxins • Toxic-Shock-Syndrome-toxins • Enzymes: lipases, nucleases, proteases • Bacteriocine S. aureus after 1day-cultivation in a Petri dish  Strongly virulent (Virulence = capability to cause infections by prodution of bact. poisons

  9. Staphylococcus Aureus – Diseases • Inflammatory & pyogenic diseases: • Furuncle • Carbuncle • Abscesses (perifollicular, inflammated spot) (=group of furuncles, with deep purulent inflammation) (collection of pus) Details: http://www.infektionsnetz.at/InfektionenHautinfektionenBakterien.phtml (Roche AG)

  10. Staphylococcus Aureus – Diseases • Parotitis • Pneumonia • Emphysem (=loss of elastic recoil of lungs and following collapse of pulmon. bronchioles & alveoli)

  11. Staphylococcus Aureus – Diseases • Otitis Media • Osteomyelitis • Mastoiditis (acute or chronic) (might arise from otitis media) (Interesting: http://osteomyelitis.stanford.edu/pages/case06.html) • Endocaditis • Sepsis Sono + Doppler

  12. Staphylococcus Aureus – Diseases • Toxinmediated Diseases: • Nutritional intoxication •  nausea, cramps, vomiting, diarrhoe, hallucinations, … • Staphylococcal Scalded Skin Syndrome (SSSS) (Dermatitis exfoliativa) •  itching, lethargy, fever, hypothermia •  detach of epidermis from dermis due to exotoxins A + B •  fluid filled blisters (thin walled  easily rupture) •  Ritter‘s Disease of the Newborn  most severe form of SSSS • Toxic Shock Syndrome (TSS): •  high fever, low blood pressure, confusion, coma, mulit-organ failure, death •  characteristic rash ressembles sunburn & can involve any region of the body (lips, mouth, eyes, palm, soles) •  desquamation occurs after 10-14 days

  13. StaphylococcusAureus – Misc. information • Transmission pathways: • endogenously(S.aureusisspreadthroughouttheinfectedpacient‘sbodybybodyfluids; areabletoovercomebbborbmbbyimpairementofthesestructures) • exogenously(e.g. contactwithcontaminatedhands, skin, instruments) • Strong adherencetosyntheticsurfaces (developmentof „disinfectivesynthetics“  surfacesthatpreventadherence) • Resistanttomany environmental factors • Colonisationofskinandmucosa(colonisation  infection) • 10 – 40 % ofhealthypopulation (nose, pharynx, perineum) • 45 – 65 (80) % ofclinical personal (62% vestibulumnasi, 5 % on hands) • Great importance in nosokomial infections(secondaryinfections)

  14. StaphylococcusAureus – Misc. information • Multiresistance (insensitivitytomorethanoneclassofantibiotics)  verynarrowvarietyoftreatment  pathogen-specifictherapy, Anti-biogramm • High incidencewithgrowingtendency (28 103 cases*) • Significantlyincreasedmortalityfor Sepsis (1108 avoidabledeaths*) • Verycost intensive (427 Mio. €*) • 1 MRSA-colonisation 1647,94 €* • 1 MRSA-infectionupto 14 360 $* • Escalatingsituation (Spain, Italy, France, GB, Japan & USA  almostuncontrollable)  world-wideproblem *Data related to Germany, 2005; Source: Martin Wernitz, Klinikum Friedrichshain, Berlin

  15. Methicillin – Discovery of Antibiotics Timetable • 1928: Discovery of Penicillin • After 1940: General use of Penicillin • 1944: Resistance to Penicillin Alexander Flemming, St.Mary‘s Hospital, London  Remark: before the discovery of antibiotics infections with S.aureus were in 90% of all cases lethal! („preantibiotic stage“) Penicillin saved many lives during 2nd World War

  16. Methicillin – New Type of Antibiotics • Beecham, 1959: developmentofpenicillinase- resistant Penicillin  Methicillinoptimallyworkes/edagainstbacteria, thatproduceenzymesforinactivationofantibiotics  β-lactam-ring isstearicallyblocked, so penicillin-asesarehardlyableto bind it  instable in acidicenvironment (parenterallyapplied)  subgroupwithnarrowerfieldoftreatment  optimal: grampositive & β-lactamresistantbact.  today‘sderivativesused: Oxacillin, Dicloxacillin, Flucloxacillin Chemical stucture of Methicillin;  β –lactam-ring is in the centre!

  17. Methicillin – Discovery of Antibiotics Timetable • 1928: Discovery of Penicillin • After 1940: General use of Penicillin • 1944: Resistance to Penicillin • 1959: Discovery of penicillinase-resistant Penicillins • 1961: resistance to penicillinase-resistant Penicillins

  18. MethicillinResistantStaphylococcusAureus – MRSA – Background • Synonym: Oxacillin-resistant S.aureus (ORSA) ( in laboratory tests mainly search for oxacillin (comprises resistance to methicillin)) • „Multi-resistant S.aureus“ (commonly for resistances for other non-β-lactam-antibiotics • History: • 1959: Introduction Methicillin • 1961: First discovery of MRSA • Global distribution • Increasing significance as a pathogen for nosokomial infections • Percentage of all S.aureus isolates in Germany: 22,6 % • Some MRSA-strains: increased capability for epidemic spreading („epidemic Virulence“) • Quick colonisation of contact persons (patients)

  19. MRSA – Development in Germany

  20. MRSE – Development in Germany

  21. Development of Penicillin-Resistance

  22. Methicillin – Resistancemechanism Resistencemechanism • Mutations in mecA-Gene • Structural different Penicillin-Binding-Protein (PBP 2  PBP 2a) • Small affinity for Methicillin/Oxacillin/β-lactam-antibiotics • Cross-resistance to all β-lactam-antibiotics (including Cephalosporines & Carbapenemes

  23. Staphylococcus Aureus – Genetic Background of Methicillin-Resistancy Normal procedure:β-Lactam-antibiotics(ABs) boundstabletotheactivecentreof a PBP (Penicillin-Binding-Protein) disturbthesynthesisofthecellmembrane  stop ofbacterialgrowth  autolysis / apoptosis PBPs aremembraneboundenzymes, responsiblefortheformationof peptidoglycansofthecellcoat//wall  normal: PBPs 1-4 (sortedbyweight) Mutationsof PBP-determininggeneticareasgiveraisetonew PBP structure:  PBP 2a isformed(codedbymecA-gene, significantloweraffinitytoβ-Lactam-antibiotics); takesoverthephysiologicfunctionof PBPs 1-4  AB ineffective  bacterial wall remainsintact  such resistantbacteriaproduce an enzymebreaking down attached ABs, theβ-Lactamase  „intrinsicresistance“ • In caseof MRSA a total determinationofstraincomprises: 1. mecA-gene (78 kDa, mostimportant  PBP 2a) 2. mecR- & mecI-gene (regulatory genes, repressor-fct. on transcriptionofmecA-gene!) 3. femA-D gene ( ‘‘ ‘‘ ) 4. auxiliary genes (10-12 othergeneticelementsthatinfluencetheexpressionof PBPs )  PBP 2a is major genetic feature for MRSA-Detection !!!

  24. MRSA – ResistantPhenotypes in Germany Epidemic MRSA in german hospitals (Resistancephenotypes) *Epid. Bull. 42/2004 ** Epid. Bull. 41/2005

  25. MRSA-strains, localisation, Germany, 2004* *Epid. Bull. 41/2004

  26. MRSA – Analysis of Resistance to different Antibiotics, Erlangen, 2004 Resistance of MRSA totestedantibiotics • Penicillin 100 % • Ampicillin 100 % • Oxacillin 100 % • Amoxicillin/Clavulansäure 100 % • Cefazolin 100 % • Cefotiam 100 % • Imipenem 100% • Ciprofloxacin 94 % • Erythromycin 89 % • Clindamycin 89 % • Gentamicin 33 % • Cotrimoxazol 4 % • Fosfomycin 3 % • Vancomycin ( Linozolin) 0 %

  27. Clinical Relevance – Other AntibioticResistances Abbreviations • MSSA methicillin-sensitive S.aureus • MRSA methicillin-resistantS.aureus • VISA vancomycin-intermediate sensitive S.aureus • GISA glycopeptid-intermediate sensitive S.aureus • VRSA vancomycin-resistantS.aureus Timetable • 1956: Discovery Vancomycin • 1958: IntroductionofVancomycin • 1996: Discovery of VISA • 2002: Discovery of VRSA  actual „reserve-antibiotic“ isLinozolid (last lineofdefence); only in severecases  developmentofresistance must berestricted!

  28. Clinical Relevance – MRSA on ICUs Types of Infections associated with MRSA (Jan/2003 – Dec/2003, acc. to KISS)* Type of Infection Percentage ________________________________________ Pneumonia 48 % Bronchitis 10 % Sepsis 10% Postoperative woundinfections 18% Skininfections 5 % Infections of urinary tract 3 % others 6 % *Epid. Bull 41/2004

  29. Clinical Relevance – Nosokomial Infections FrequencyofS.aureusfor nosokomial infections in Germany (KISS*) • Data forIntensive Care Units, Jan/1997 – Dec/2003** • Pneumoniaassoc. toartificialventilation: 24% rank 1 • Bronchitis assoc. toartificialventilation: 26% rank 1 • CVF-assoc. Sepsis: 15% rank2 2. Data of postoperative woundinfections, Jan/1997 – Dec/2002*** • Obstetrics: 19% rank1 • Vascularsurgery: 39% rank1 • Heart surgery: 40% rank1 • Traumatology/Orthopaedics 40% rank1 • General-/Abdominal surgery 12% rank3 * KISS = Krankenhaus-Infektions-Surveillance-System ** Epidemiologisches Bulletin 41/2004 *** Epidemiologisches Bulletin 36/2003

  30. Clinical Relevance – MRSA on ICUs* • accordingto KISS** • 1997: MRSA-percentageof all S.aureus: 8 % • 2003: MRSA-percentageof all S.aureus: 30 % • Primary S.aureus – Sepsis • MRSA-percentageof all S.aureus: 37,8 % • Nosokomial pneumonia • MRSA-percentageof all S.aureus: 21,5 % *Epid. Bull. 5/2005 **KISS = Krankenhaus Infektions Surveillance System

  31. StaphylococcusAureus – Situation in Europe – 2004* – Staphylococcus aureus: proportion of invasive isolates resistant to oxacillin (equivalents) in 2004 * European Antibiotic Resistance Surveillance System (EARSS), Annual Report 2004

  32. StaphylococcusAureus – Situation in USA – Summaryof 1993 - 2005*

  33. MRSA – Preventive Strategies • Identification, aquisition, evaluation • Implementation of suitable hygienic sanctions • Rehabilitation of MRSA-carriers • Controlled & reasonable use of antibiotics

  34. MRSA – Preventive Strategies Identification, aquisition, evaluation • § 23 IfSG: Nosokomial Infections, Resistances „(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. The records according to article (1) have to be stored for at least ten years. At request of the responsible public health department access has to be granted.“  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). • No warranty for the translation ;)

  35. MRSA – Preventive Strategies Implementationofhygienicsanctions* • RecommendationoftheCommissionforhospitalhygieneandInfectionprevention, e.g. relatingto: • Accomodation • Protectionagainstcontamination • Disinfection • Patient-transfers • Realisation candifferfromhospitaltohospital (but minimumstandard must alwaysbeachieved) Rehabilitation of MRSA-carriers • Antispetic / disinfectivemeasures • Sometimes in combinationwithantibioticmeasures • Goodresults in countries withlow MRSA-prevalence • Resultdependant on pre-existingdefects

  36. MRSA – Preventive Strategies Controlled use of antibiotics • Therapy only at Infection NOT in case of a colonisation • Therapy (usually): Vancomycin (+ Combinative Partner Antibiotics)  decreased incidence of resistant subpopulations • Decrease the pressure of selection (resistance-formation)

  37. Sources • www.wikipedia.com / .de • Google-picture-pool • Robert-Koch-Institut (www.rki.de)  MRSA + S. aureus • Epidemiologisches Bulletin (RKI) 36/03, 41/04, 41/05 • www.infektionsnetz.de (Roche AG) • Dr. Bernd Kunz, Klinikum Erlangen • Martin Wernitz, Klinikum Friedrichshain, Berlin