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Diphtheria , Corynebacterium diphtheria
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Corynebacterium diphtheria

  1. 1. Corynebacterium Diphtheria Dr.T.V.Rao MD. Dr.T.V.Rao MD 1
  2. 2. Diphtheria• Greek diphtheria (leather hide)• Caused by Aerobic Gram +ve rods• Corynebacterium diphtheria• Exotoxin production only if infected by virus phage infected carrying toxin gene Dr.T.V.Rao MD 2
  3. 3. Corynebacterium• Gram + Non Acid fast, Non motile,• Irregularly stained with granules,• Club shaped swelling at one or both ends so the name• Important Pathogen Corynebacterium diphtheria,Diptheros meaning leather, Dr.T.V.Rao MD 3
  4. 4. What is Diphtheria• An infection of local tissue of URT with production of toxin which causes systemic effects on Heart and Peripheral tissues, Dr.T.V.Rao MD 4
  5. 5. Definition• Diphtheria is an acute, toxin- mediated disease caused by toxigenic Corynebacterium diphtheria.• It’s a very contagious and potentially life-threatening bacterial disease. Dr.T.V.Rao MD 5
  6. 6. Definition• It’s a localized infectious disease, which usually attacks the throat and nose mucous membrane Dr.T.V.Rao MD 6
  7. 7. Etiology• C. diphtheriae is an aerobic gram- positive bacillus. – Pleomorphic, club-end – Non-spore-forming – Non-acid-fast – Non-motile Dr.T.V.Rao MD 7
  8. 8. Etiology• The major virulence determinant is an exotoxin, diphtheria toxin. After binding to the host cells, the active subunit will interrupt the protein synthesis of the target host cell and results in cell death.• Toxoid made from diphtheria toxin can be used as vaccine. Dr.T.V.Rao MD 8
  9. 9. Etiology• There are three biotypes — gravis, Intermedius, and mitis. The most severe clinical type of this disease is associated with the gravis biotype, but any strain may produce toxin. Dr.T.V.Rao MD 9
  10. 10. Pathogenesis• Entry ------ the bacilli multiply locally in the throat and elaborate a powerful exotoxin ----- produce local and systemic symptoms. Local lesions :• Exotoxin causes necrosis of the epithelial cells and liberates serous and fibrinous material which forms a grayish white pseudo membrane• The membrane bleeds on being dislodged• Surrounding tissue is inflamed and edematous Dr.T.V.Rao MD 10
  11. 11. Fauces ( throat )Fauces : - two pillars of mucous membrane.Anterior : known as the palatoglossal arch andPosterior : the palatopharyngeal arch Dr.T.V.Rao MD 11Between these two arches is the palatine tonsil.
  12. 12. Typical Presentation of Bull Neck Dr.T.V.Rao MD 12
  13. 13. Local manifestation Depend on the site of Faucial lesion: diphtheria : Nasal diphtheria : • Redness and• Unilateral or bilateral serosanguineous ( blood and swelling over serous fluid ) discharge from Fauces the nose• • Exudates on the Excoriation of upper lip• Toxemia is minimal tonsils coalesces to form grayish white pseudo membrane • Regional lymph nodes are inflamed • Sore throat and 13 Dr.T.V.Rao MD
  14. 14. Dr.T.V.Rao MD 14
  15. 15. Corynebacterium diphtheria• Slender rods• Clubbing at both ends• Pleomorphic• Non capsulate / Acid fast Gram +• Granules are composed of polymetapohosphate• Staining with Lofflers methylene blue show bluish purple metachromatic granules. with polar bodies, Dr.T.V.Rao MD 15
  16. 16. Dr.T.V.Rao MD 16
  17. 17. Staining methods• Grams method•Alberts stain•Neissers stain•Ponders stain•On staining seen asPairs, Appear as v and L letters, resembling Chinese letter pattern or also called cuneiform arrangement. Dr.T.V.Rao MD 17
  18. 18. Cultural characters• Need enrichment Media• Contain• Blood, Serum or Egg 37 c ph 7.4• Aerobic/Facultative anaerobic.• Commonly used medium• Loeffler serum slope,• Tellurite Blood agar, Dr.T.V.Rao MD 18
  19. 19. Gram +ve Bacilli and Colonies Dr.T.V.Rao MD 19
  20. 20. Culturing• Selective & differential medium• Corynebacterium are resistant to tellurite – Reduced to tellurium• Forms deposit in colonies – Colonies appear dark• Biotypes – gravis, Intermedius, mitis Dr.T.V.Rao MD 20
  21. 21. Growing on Culture Plates• Loffler serum slope Grows rapidly in 6 -8 hours, Small white opaque disks Turns to yellow Tellurite blood agar Modified Mac Leod Hoyles medium. Dr.T.V.Rao MD 21
  22. 22. Commonly used medium• Tellurite blood agar Contains tellurite 0.04 tellurite Inhibits other bacteria• Produce Grey/Black colonies. Dr.T.V.Rao MD 22
  23. 23. Classification of McLeodClassified in to 3 Types1 Gravis2 Intermedius3.MitisGravis produce Most serious HemorrhagicParalytic complications - EpidemicIntermedius HemorrhagicMitis - obstructive complications, EndemicGeographic locations differTesting for toxigenicity is more important, Dr.T.V.Rao MD 23
  24. 24. Biochemical Reactions• Acid Glucose,Galactose Maltose, DextrinDo not produce acid with Lactose, Mannitol, sucrose.All fermentation reactions tested in Hiss serum sugarsUrease test negative.Proteolytic Dr.T.V.Rao MD 24
  25. 25. Toxin• Pathogenicity associated with Toxin• Gravis/Intermedius 95-99% are toxigenic• Mitis 80 – 85%• Some abundant others poorly• Toxin production park William 8• Toxin M W 62,000 0.0001 can kill guinea pig Dr.T.V.Rao MD 25
  26. 26. Diphtheria toxin: Part A• Active site• Enzyme• Blocks protein synthesis – ADP-ribosyl transferase – elongation factor 2 (EF2)• Specific for mammalian cells – Prokaryotes have different EF2 Dr.T.V.Rao MD 26
  27. 27. Diphtheria Toxin: Part B• Binding Site• Binds to cell receptor• Bound receptor internalized• Endosome – Hydrolyzed by protease – Disulfide broken – Part A released Dr.T.V.Rao MD 27
  28. 28. Activation of Diphtheria Toxin A A A B B B B A Dr.T.V.Rao MD 28
  29. 29. Toxin ( Contd )• Toxin contain two components A 24,000 B 38,000A produce toxigenicity by proteolytic effectB Produce bindingToxin + Formalin = ToxoidWhat is Toxoid – Antigenic, not toxigenicTox + Corynephage Toxin production Dr.T.V.Rao MD 29
  30. 30. Toxin ( contd )• Need iron 0.1 mg/liter.• Toxin inhibits protein synthesis• Fragment A catalyzes the transfer of ADP ribose from the Nicotinamide adenine dinucleotide ( NAD ) to the eukaryotic elongation factor 2 /(Fragment A inhibits polypeptide chain elongation in the presence of Nicotinamide adenine dinucleotide by inactivating elongation factor• Causes involvement with affinity. Myocarditis, Adrenals Nerve endings, Dr.T.V.Rao MD 30
  31. 31. Antigenic structure• Gravis 13,• Intermedius 4• Mitis 40• Bacteriophage typing 15 types Dr.T.V.Rao MD 31
  32. 32. Resistance• Can be killed at 580 c in 10 mt 1000 c in 1 mtSurvive in Blankets, Floor dust, toys inanimate objects Dr.T.V.Rao MD 32
  33. 33. Pathogenicity• Bacteria Invade, Colonise,Proliferate• Bacteria are lysogenized by Beta phage• Produce toxin,• Kills epithelial and Neutrophils,• Produce Pharyngitis and cutaneous lesions. Dr.T.V.Rao MD 33
  34. 34. Pathogenicity• Incubation 3 – 4 days / one day• Faucal / Nasal /Laryngeal / Otic / Conjunctiva,/Genital / Vulvae CoetaneousDiphtheria is a toxemic condition. Malignant Sever toxemia ,Adenitis Bull neck Circulatory failureSeptic Gangrene , pseudo membrane. Dr.T.V.Rao MD 34
  35. 35. Pathogenicity• Hemorrhagic Epistaxis , Purpura General Bleeding tendencyAsphyxia , Acute circulatory failure,Paralysis Pneumonia, Septic shock, Otitis media. Toxemia, Necrotic changesDeath in Guinea pigs Dr.T.V.Rao MD 35
  36. 36. Diphtheria• Nasopharyngeal diphtheria – Pharyngeal – Laryngeal• Cutaneous diphtheria• Systemic complications DIAGNOSIS MUST BE CLINICAL!!!! Dr.T.V.Rao MD 36
  37. 37. Clinical features• Malaise, Sore throat, Fever• Adherent grey pseudo membrane• Nasal ulcers,• Obstruction of larynx and lower airways,• Difficulty in swallowing• Lead to Myocarditis, Peripheral neuritis,• Paralysis of limbs, Dr.T.V.Rao MD 37
  38. 38. Diphtheria Clinical FeaturesIncubation period 2-5 days (range, 1-10 days)May involve any mucous membraneClassified based on site of infection anterior nasal pharyngeal and tonsillar laryngeal cutaneous ocular genital Dr.T.V.Rao MD 38
  39. 39. Diphtheria Clinical FeaturesIncubation period 2-5 days (range, 1-10 days)May involve any mucous membraneClassified based on site of infection anterior nasal pharyngeal and tonsillar laryngeal cutaneous ocular genital Dr.T.V.Rao MD 39
  40. 40. Thick Membrane Dr.T.V.Rao MD 40
  41. 41. Dr.T.V.Rao MD 41
  42. 42. Pseudo membrane Dr.T.V.Rao MD 42
  43. 43. Skin Lesions Dr.T.V.Rao MD 43
  44. 44. Pathogenicity1 Faucial Diphtheria very common,• Malignant or Hyper toxic toxemia Marked adenitis, circulatory failure,• Paralytic sequale2 Septic ulceration cellulitis, gangrene Epistaxis Bleeding tendency, Dr.T.V.Rao MD 44
  45. 45. Complications• Asphyxia - causing mechanical obstruction.• May need tracheotomy• Circulatory failure.• Post Diphtheria paralysis Dr.T.V.Rao MD 45
  46. 46. Non toxigenic clinical manifestations• Bacteria can produce 1. Endocarditis, 2.Meingitis, 3 Cerebral abscess. 4 Osteoarthritis. Dr.T.V.Rao MD 46
  47. 47. Dr.T.V.Rao MD 47
  48. 48. Dr.T.V.Rao MD 48
  49. 49. Laboratory Diagnosis• Specific treatment is more important than Laboratory Diagnosis.1 Isolation of Diphtheria bacilli.2.Testing for toxigenicity, Dr.T.V.Rao MD 49
  50. 50. Collection of Specimens• Throat swabs• Smear examinations Gram s staining, Alberts, PondersImmunoflorescent methodsCultures on Loeffers serum slope Tellurite Blood agar, Blood agar. Dr.T.V.Rao MD 50
  51. 51. Dr.T.V.Rao MD 51
  52. 52. Isolation of C.diptheria• Serum slope – Growth in 6 – 8 hours,• Stain with Neissers stain Alberts stain• Bacilli have metachromatic granules,• Tellurite Blood agar takes two days for manifestation of colonies, Dr.T.V.Rao MD 52
  53. 53. Virulence tests,• In Vivo and In Vitro• In Vivo in Animals• Subcutaneous tests Inject broth from culture into two Guinea pigs, 0.8 mlOne animal given 500 units of antitoxinOther no Vaccine.Animal not given antitoxin will dieLoss of Animals. Restricts its testing. Dr.T.V.Rao MD 53
  54. 54. Intracutaneous Method• One animal given 500 units before toxin• Other 50 units after Toxin• So the Animals can be saved Dr.T.V.Rao MD 54
  55. 55. In Vitro Testing• Elek s Gel precipitation testing• Filter paper impregnated with Diphtheria antitoxin 1000 Units / ml• Tested on the horse serum agar• Positive / Negative /Test strains tested for Immunodiffusion• Line of precipitation – test positive• Other methods testing in Tissue cultures. Dr.T.V.Rao MD 55
  56. 56. Toxigenicity TestsIn Vitro Elek testIn Vivo Animal inoculation rabbit skin test- necrosis guinea pig challenge test- lethal low [Fe 2+] induces toxin Dr.T.V.Rao MD 56
  57. 57. Dr.T.V.Rao MD 57
  58. 58. Schick Test ( Out dated ) – Schick test: It is an intradermal test, the test is carried out by injecting intradermally into the skin of forearm 0.2 ml of diphtheria toxin, while into the opposite arm is injected as a control, the same amount of toxin which has been inactivated by heat. Dr.T.V.Rao MD 58
  59. 59. Interpretation• Negative reaction: If a person had immunity to diphtheria, no reaction will be observed on either arm.• Positive reaction: An area of in duration 10-15 mm in diameter generally appears within 24-36 hours reaching its maximum development by 4-7 days, the control arm shows no change. The person is susceptible to diphtheria.• False positive reaction: A red flush develops in both arms, the reaction fades very quickly, and disappears by 4th day. This is an allergic type of reaction found in certain individuals• Combined reaction: the control arm shows pseudo positive reaction and the test arm is true +ve reaction, susceptible and need vaccination Dr.T.V.Rao MD 59
  60. 60. Schick Test• Injection of toxin I D• Produces redness/erythemati c in 2-4 days• No reaction – Protective immunity present. Dr.T.V.Rao MD 60
  61. 61. Dr.T.V.Rao MD 61
  62. 62. Epidemiology• Eradicated in developed nations,• Children between 2 – 5 years.• A symptomatic carriers• Person to person contact.• Carriers spread.• Prolonged contact. Dr.T.V.Rao MD 62
  63. 63. Prophylaxis• Immunization• Active – Passive• Both passive and Active.• Herd Immunity.• Schick test• Immunization with Antitoxin Dr.T.V.Rao MD 63
  64. 64. Active Immunization.• Toxoid – Toxin treated with Formaldehyde• Absorbed Toxoid• Given by Intramuscular route• Given in DTP –Triple Vaccine• Primary Immunization• Three Doses of DPT at least 4 weeks apart.• Non vaccinated• Three doses of Toxoid four weeks apart• One dose after One Year. Dr.T.V.Rao MD 64
  65. 65. PreventionVaccination: Immunisation with diphtheria toxoid,combined with tetanus and pertussis toxoid (DTPvaccine), should be given to all children at two,three and four months of age. Booster doses aregiven between the ages of 3 and 5 .The child is given a further booster vaccinebefore leaving school and is then considered tobe protected for a further 10 years (16 – 18years). Dr.T.V.Rao MD 65
  66. 66. Passive Immunization• Given in Acute infections• Give Subcutaneously• 500 – 1000 Units of Antitoxin• Given as Horse Serum• Combined in Acute Infections ( Both Active Immunization with Toxoid and Antitoxin. Dr.T.V.Rao MD 66
  67. 67. Treatment• Antibiotic not useful in Acute infections,• Antitoxin a must.• Anti toxin obtained from horse serum• Mild 20,000 to 40,000• Moderate 40,000 to 60,000• Severe 80,000 to 1,00,000• Commonly used antibiotics,• Penicillin parentally,• Oral Erythromycin Dr.T.V.Rao MD 67
  68. 68. Diphtheria EpidemiologyReservoir Human carriers Usually asymptomaticTransmission Respiratory Skin and fomites rarelyTemporal pattern Winter and springCommunicability Up to several weeks without antibiotics Dr.T.V.Rao MD 68
  69. 69. Treating Contacts• All contacts are advised to receive 500 mg Erythromycin 4 times a day. Dr.T.V.Rao MD 69
  70. 70. Dr.T.V.Rao MD 70
  71. 71. Other Corynebacterium• C.ulcerans• Like C.diptheria• Gravis type gelatin liquefied• Transmitted through cows Milk• Erythromycin effective.• Diphtheria antitoxin is protective. Dr.T.V.Rao MD 71
  72. 72. Diptheroids• Resembles C.diptheria• Commensals in throat, skin,• C.hofmani• C.xerosi• Propioniebacterium• P.acnes P.granulosum Dr.T.V.Rao MD 72
  73. 73. • Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students in Developing World • Email • Dr.T.V.Rao MD 73
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Corynebacterium diphtheria


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