TheThe discoverydiscovery ofof ““ClostridiumClostridium”” andand itsits clinicalclinical impact:impact: AnAn insightinsight intointo thethe historyhistory ofof medicinemedicine

Conference on New Frontiers in Microbiology and Infectious Diseases

Villars-sur Ollon 2008

Roland J Koerner Sunderland Royal Hospital, UK ThoseThose whowho cannotcannot rememberremember thethe pastpast areare condemnedcondemned toto repeatrepeat itit

George Santanyana (1863 - 1952) The Life of Reason The discovery of “Clostridium” and its clinical impact: An insight into the history of medicine DesireDesire ofof manman “to“to makemake sensesense outout ofof illness”illness” Hippocrates of Cos (460 to 377 B.C.): Imbalance of four humours associated with four elements causes disease: blood and fire : hot and dry yellow bile and air : hot and wet black bile and earth : cold and dry phlegm and water : cold and wet

Separation of practice of medicine from superstition and religion. The discovery of “Clostridium” and its clinical impact: An insight into the history of medicine

DesireDesire ofof manman “to“to makemake sensesense outout ofof illness”illness” Claudius Galen (A.D. 129 – A.D. 216) Anatomical and physiological studies: interpretation of findings within Hippocrates’ concept of imbalance of four humours. He influenced practice of medicine into 17th century. The discovery of “Clostridium” and its clinical impact: An insight into the history of medicine

DesireDesire ofof manman “to“to makemake sensesense outout ofof illness”illness” Paracelsus (1493-1541) “…the profound understanding of nature and its secrets are expected from a doctor.” TimeTime lineline ofof microbiologymicrobiology 15461546 -- GirolamoGirolamo FracastoroFracastoro:: “De“De contagionecontagione seminariaseminaria morbimorbi etet seminariaseminaria contagiumcontagium””

16741674 –– AntonyAntony vanvan LeeuwenhookLeeuwenhook:: “Animalcules“Animalcules minimissimeminimissime””

17491749 –– CarolusCarolus Linnaeus:Linnaeus: systemsystem ofof binominalbinominal nomenglaturenomenglature andand classificationclassification ofof plantsplants

18351835 –– AgostinoAgostino MM BassiBassi:: muscaridinemuscaridine ofof silkwormsilkworm isis causedcaused byby aa fungusfungus TimeTime lineline ofof microbiologymicrobiology

18381838 –– ChristianChristian GG EhrenbergEhrenberg:: ““InfusionstierchenInfusionstierchen””:: Bacterium,Bacterium, SpirilliumSpirillium,, VibrioVibrio,, SpirochaetaSpirochaeta

18401840 -- FriedrichFriedrich GJGJ HenleHenle:: ““PathologischePathologische UntersuchungenUntersuchungen”” ““GermGerm theorytheory ofof diseasedisease””

18491849 –– FerdinandFerdinand Cohn:Cohn: carminecarmine andand haematoxylinhaematoxylin forfor stainingstaining ofof histologicalhistological sectionssections TimeTime lineline ofof microbiologymicrobiology

18581858 –– RudolphRudolph VirchowVirchow:: ““CellularpathologieCellularpathologie””::

18611861 –– LoiusLoius Pasteur:Pasteur: ““anaanaëërobiesrobies””:: butyricbutyric acidacid fermentationfermentation byby bacteriabacteria inin thethe absenceabsence ofof oxygenoxygen

18651865 –– JeanJean AA VilleminVillemin:: demonstratesdemonstrates thatthat TBTB isis causedcaused byby aa specificspecific infectiousinfectious causecause

18651865 –– JuliusJulius FF CohnheimCohnheim:: confirmsconfirms VilleminVillemin’’ss findingsfindings TimeTime lineline ofof microbiologymicrobiology 18721872 –– FerdinandFerdinand CohnCohn:: ““UntersuchungenUntersuchungen üüberber BakterienBakterien””:: establishesestablishes ““BacteriologyBacteriology”” asas aa separateseparate sciencescience

18761876 –– JohnJohn TyndallTyndall:: ““TyndalizationTyndalization””:: basisbasis forfor finalfinal movemove fromfrom ““doctrinedoctrine ofof spontaneousspontaneous generationgeneration ofof micromicro-- organismsorganisms inin nutrientnutrient fluidsfluids”” CarlCarl WeigertWeigert:: methylenemethylene blueblue forfor microscopymicroscopy inin aequeousaequeous suspensionsuspension RobertRobert KochKoch:: ““DieDie AetiologieAetiologie derder MilzbrandkrankheitMilzbrandkrankheit”” ConfirmationConfirmation ofof ““GermGerm TheoryTheory ofof Disease”Disease TimeTime lineline ofof microbiologymicrobiology 18781878 –– ErnstErnst AbbAbbéé:: numericalnumerical apertureaperture andand oiloil immersionimmersion microscopymicroscopy

18801880 –– AdamAdam PrazmowskiPrazmowski:: “Clostridium”“Clostridium” termterm forfor anaerobicanaerobic bacteriumbacterium thatthat formsforms spindlespindle--shapedshaped endosporesendospores

18841884 –– RobertRobert KochKoch:: ““DieDie AetiologieAetiologie derder TuberculoseTuberculose”” ““KochKoch--HenleHenle PostulatesPostulates”” TimeTime lineline ofof “immunology”“immunology”

500500 –– ChinaChina:: ““smallpoxsmallpox immunizationimmunization”” byby blowingblowing drieddried scabsscabs intointo nostrilsnostrils

17151715 –– GiacommoGiacommo PylariniPylarini:: descriptiondescription ofof “vaccination”“vaccination” ofof childrenchildren againstagainst smallpoxsmallpox inin 17011701 inin ConstantinopleConstantinople

17171717 –– MaryMary MM MontaguMontagu:: ““ingraftingingrafting”” ofof childrenchildren inin ConstantinopleConstantinople TimeTime lineline ofof “immunology”“immunology”

17211721 –– CottonCotton MatherMather andand ZabdielZabdiel BoylstonBoylston ““smallpoxsmallpox inoculationinoculation”” duringduring anan epidemicepidemic inin BostonBoston

–– HansHans Sloane:Sloane: experimentalexperimental smallsmall poxpox ““variolationvariolation”” onon condemnedcondemned prisonersprisoners atat NewgateNewgate prisonprison asas permittedpermitted byby KingKing GeorgeGeorge II

17641764 –– AngeloAngelo GattiGatti:: publishespublishes inoculationinoculation againstagainst smallpoxsmallpox usingusing puspus fromfrom infectedinfected personspersons TimeTime lineline ofof “immunology”“immunology”

17741774 –– BenjaminBenjamin JestyJesty:: useuse ofof materialmaterial fromfrom cowpoxcowpox lesionslesions forfor vaccinationvaccination againstagainst smallpoxsmallpox

17761776 –– GeorgeGeorge Washington:Washington: inoculationinoculation ofof wholewhole armyarmy againstagainst smallpoxsmallpox usingusing materialmaterial fromfrom infectedinfected patientspatients

17781778-- EdwardEdward JennerJenner:: ““AnAn inquiryinquiry intointo thethe causescauses andand effectseffects ofof thethe variolaevariolae vaccine,vaccine, aa diseasedisease discovereddiscovered inin somesome ofof thethe westernwestern countriescountries ofof England,England, particularlyparticularly Gloucestershire,Gloucestershire, andand knownknown byby thethe namename ofof CowCow PoxPox”” TimeTime lineline ofof “immunology”“immunology”

18811881 –– LouisLouis Pasteur:Pasteur: ““SurSur lesles virusvirus--vaccinsvaccins dudu cholcholéérara desdes poulespoules etet dudu charbonscharbons””

18841884 –– EliasElias MetschnikoffMetschnikoff:: ““ÜÜberber eineeine SproSproßßpilzerkrankungpilzerkrankung derder DaphnienDaphnien.. BeitragBeitrag derder LehreLehre üüberber denden KampfKampf derder PhagozytenPhagozyten gegengegen KrankheitserregerKrankheitserreger””

18901890 –– BehringBehring andand KitasatoKitasato ““ŰŰberber dasdas ZustandekommenZustandekommen derder DiphtherieDiphtherie--ImmunitImmunitäätt undund derder TetanusTetanus-- ImmunitImmunitäätt beibei ThierenThieren”” DiscoveryDiscovery ofof C.C.tetanitetani

TheThe discoverydiscovery ofof C.C.tetanitetani isis thethe perfectperfect successsuccess storystory ofof thethe newlynewly establishedestablished sciencessciences ofof bacteriologybacteriology andand immunology.immunology. DiscoveryDiscovery ofof C.C.tetanitetani

400400 B.C:B.C: Hippocrates:Hippocrates: DescriptionDescription ofof aa clinicalclinical conditioncondition compatiblecompatible withwith tetanustetanus 18841884:: ConfirmationConfirmation ofof transmissibility:transmissibility: CarleCarle andand RattoneRattone injectinject puspus obtainedobtained fromfrom patientpatient withwith tetanustetanus intointo testtest animals.animals. 1884:1884: A.A. NicolaierNicolaier producesproduces tetanustetanus byby inoculatinginoculating soilsoil intointo animalsanimals 1886:1886: J.RosenbaumJ.Rosenbaum describesdescribes ““ClostridiaClostridia”” inin humanhuman woundwound secretionssecretions DiscoveryDiscovery ofof C.C.tetanitetani

1889: KitasatoKitasato isolatesisolates C.C.tetanitetani fromfrom aa humanhuman victimvictim andand confirmsconfirms itsits pathogenicpathogenic rolerole byby applyingapplying KochKoch’’ss postulates.postulates

1890:1890: KitasatoKitasato demonstratesdemonstrates inin addition:addition: ¾ that tetanus toxin causes clinical picture of tetanus ¾ that “antiserum” can prevent tetanus ¾ that “antiserum” is highly specific DiscoveryDiscovery ofof C.C.tetanitetani

1891:1891: AvailabilityAvailability ofof ““TetanusTetanus antiserumantiserum”” forfor therapeutictherapeutic purposespurposes DiscoveryDiscovery ofof C.C.botulinumbotulinum

TheThe discoverydiscovery ofof C.C.botulinumbotulinum isis thethe perfectperfect successsuccess storystory ofof thethe newlynewly establishedestablished sciencessciences ofof bacteriologybacteriology andand epidemiology.epidemiology. DiscoveryDiscovery ofof C.C.botulinumbotulinum

900:900: TheThe ByzantineByzantine EmperorEmperor LeoLeo VIVI bannsbanns consumptionconsumption ofof bloodblood sausagessausages becausebecause ofof associationassociation withwith fatalfatal foodfood poisoningpoisoning compatiblecompatible withwith botulismbotulism 1820:1820: JustinusJustinus KernerKerner:: completecomplete descriptiondescription ofof clinicalclinical conditioncondition ofof ““WurWurßßtvergiftungtvergiftung”” oror ““BotulismusBotulismus”” asas associatedassociated withwith consumptionconsumption ofof sausages:sausages: ¾ comparative epidemiology ¾ intoxication of animals ¾ “self intoxication” with diluted extract from suspected sausage DiscoveryDiscovery ofof C.C.botulinumbotulinum

1897:1897: EmileEmile vanvan ErmengenErmengen:: ““UeberUeber eineneinen neuenneuen anaanaëërobenroben BacillusBacillus undund seineseine BeziehungenBeziehungen zumzum BotulismusBotulismus.. ¾ Formulation of a case definition ¾ Confirmation of epidemiological association with consumption of suspicious bacon ¾ Fulfilment of Koch’s postulates

LateLate 2020th century:century: ExplorationExploration ofof botulinumbotulinum toxintoxin forfor painpain therapytherapy ManagementManagement ofof infectioninfection

ControversyControversy aboutabout thethe treatmenttreatment ofof infectiousinfectious diseases:diseases: 1.1. ImmuneImmune therapytherapy

Emil von Behring Kitasato Shibasaburo 1845-1917 1853-1931 ManagementManagement ofof infectioninfection

ControversyControversy aboutabout thethe treatmenttreatment ofof infectiousinfectious diseases:diseases: 1. Immune therapy 2.2. ChemotherapyChemotherapy ““MagicMagic bulletbullet””

Paul Ehrlich 1854-1915 ManagementManagement ofof infectioninfection

PaulPaul Ehrlich:Ehrlich: 1909: Introduction of Salvarsan for the treatment of syphillis

1912: Introduction of Neo-Salvarsan for the treatment of syphillis ManagementManagement ofof infectioninfection

GerhardGerhard DomagkDomagk:: 1935:1935: IntroductionIntroduction ofof thethe firstfirst sulphonamidesulphonamide ProntosilProntosil ManagementManagement ofof infectioninfection

ControversyControversy aboutabout thethe treatmenttreatment ofof infectiousinfectious diseases:diseases:

1.1. ImmuneImmune therapytherapy 2.2. MagicMagic bulletbullet 3.3. SurgerySurgery DiscoveryDiscovery ofof C.perfringensC.perfringens

The discovery of C.perfringens is the perfect success story of the newly established science of Bacteriology howeverhowever itsits treatmenttreatment isis controversialcontroversial !! DiscoveryDiscovery ofof C.perfringensC.perfringens

400 BC: Hippocrates: Description of a clinical condition compatible with gas gangrene

25 AD: Celsus provides similar evidence

18541854--18561856 CrimeanCrimean War:War: N.I.N.I. PirogoffPirogoff describesdescribes classicalclassical clinicalclinical presentation,presentation, alsoalso knownknown asas ““hospitalhospital gangrenegangrene”” DiscoveryDiscovery ofof C.perfringensC.perfringens 1892:1892: WelchWelch andand NuttallNuttall:: BacillusBacillus aerogenesaerogenes capsulatuscapsulatus Welch WH, Nuttall GHF. A gas-producing bacillus ( Bacillus aerogenes capsulatus, Nov. Spec.) capable of rapid development in the body after death. Bull Johns Hopkins Hosp Baltimore.1892;3:81–91.

1893:1893: EE FraenkelFraenkel:: Bacillus.Bacillus. phlegmonisphlegmonis emphysematosaeemphysematosae E Fraenkel: Ueber die Aetiologie der Gasphlegmonen (Phlegmone emphytematosa) Zentralblatt für Bakteriology und Parasitenkunde, 1893, Vol 13, 13-16

1893:1893: EE FraenkelFraenkel:: UeberUeber GasphlegmonenGasphlegmonen Detailed study about various clinical presentations

1896:1896: WelchWelch andand FlexnerFlexner confirmconfirm thatthat bothboth isolatesisolates areare inin factfact thethe samesame speciesspecies DiscoveryDiscovery ofof C.perfringensC.perfringens

19141914--1918:1918: WorldWorld WarWar II

““EpidemicEpidemic ofof GasGas GangreneGangrene””

WhatWhat happenedhappened ?? HistoryHistory ofof woundwound managementmanagement

15131513 –– GiovanniGiovanni dada VigaViga ““PracticaPractica copiosacopiosa inin chirugicachirugica””

15361536 –– AmbroiseAmbroise ParParéé:: LigationLigation ofof bloodblood vesselsvessels andand improvedimproved ““woundwound balsambalsam””

17xx17xx –– Hunter:Hunter: inflammationinflammation leadsleads toto woundwound healinghealing

JamesJames Cook:Cook: ApplicationApplication ofof teatea treetree leafsleafs ontoonto woundswounds

18011801 –– JohnJohn RolloRollo:: banningbanning ofof ““woundwound spongessponges”” “the (combat) wound must forthwith be enlarged . . . so that there may be free passage for both the puss or matter . . . obtained therein”

Ambroise Paré (1510-1590) French Army Surgeon …establish the making of a deep incision to explore a wound, remove dead tissue, and provide drainage - credited with coining the term “debridement”

Pierre Joseph Desault (1744-1795) French Military Surgeon Dominique Jean Larrey (1766-1842) Napoleon’s Surgeon

Debridement for: • the release of ecchymotic wounds • removal of foreign bodies • uncover and ligate arteries • “freshen up” skin edges Amputation • if debridement unlikely to succeed

HistoryHistory ofof woundwound managementmanagement

1919th Century:Century: OngoingOngoing controversy:controversy:

AggressiveAggressive surgicalsurgical interventionintervention

versusversus

CarefulCareful conservativeconservative approachapproach The American Civil War (1861 – 1865) • Only 3% of “shot” wounds to the extremities were incised (debrided) • Debridement was thought to hasten inflammation and gas gangrene • Amputation was the Orthopedic Surgery of Choice • Mini ball (.50 cal) missile – Low velocity – Highly inaccurate – Little damage outside the missile tract

DiscoveryDiscovery ofof C.perfringensC.perfringens

19141914--1918:1918: WorldWorld WarWar II

““EpidemicEpidemic ofof GasGas GangreneGangrene””

WhatWhat happenedhappened ?? World War I

• Debridement was a technique that belonged to antiquity. • Debridement was felt to be too invasive and of doubtful benefit.

WW hh yy ?? UnderstandingUnderstanding ofof physiologyphysiology ofof woundwound healinghealing (at about 1900)

Trauma to tissue and blood vessels

Blood leaks into wound cavity

Tissue thromboplastion + free Ca2+ Prothrombin to thrombin

Fibrinogen to fibrin

Inflammatory response leads to migration of leucoytes/macrophages

(Formation of pus if infected)

At bottom of wound formation of connective tissue

Formation of granulations

Re-epithelisation from wound edges …… PhysiologyPhysiology ofof woundwound healinghealing Trauma to tissue and blood vessels Contamination: environment, hands, Blood leaks into wound cavity surgical instruments

Tissue thromboplastion + free Ca2+ Bacteria enter wounds Prothrombin to thrombin Wound infection

Fibrinogen to fibrin abscess gangrene Inflammatory response leads to migration of leucoytes/macrophages etc

Formation of pus

At bottom of wound formation of connective tissue

Formation of granulations

Re-epithelisation from wound edges

Reconstitutio ad defectum World War I

• Soldiers on both sides lived under atrocious conditions • Battle fields were farmland fertilized with manure:

Bacterial epidemiology (Zeissler 1928): C.perfringens 100% C.novyi 64% C.tetani 27% C.septicum 8% C.septicum 2%

Zeissler, Raßfeld: Die anaerobe Sporenflora der europäischen Kriegsschauplätze 1917. (1928) Kriegs. U. Konst. Path; 5, p 2ff World War I

•• SoldiersSoldiers onon bothboth sidessides livedlived underunder atrociousatrocious conditionsconditions •• BattleBattle fieldsfields werewere farmlandfarmland fertilizedfertilized withwith manuremanure •• PenetratingPenetrating injuriesinjuries werewere alwaysalways associatedassociated withwith deepdeep inoculationinoculation ofof fragmentsfragments ofof uniformuniform tissuetissue contaminatedcontaminated withwith bacterialbacterial sporesspores intointo severelyseverely damageddamaged tissuetissue World War I •• TheThe energyenergy ofof ““projectilesprojectiles”” increasedincreased dramatically:dramatically: –– ExplosiveExplosive artilleryartillery shellsshells (shrapnel)(shrapnel) –– MassMass productionproduction ofof machinemachine gunsguns –– HighHigh velocity,velocity, highhigh accuracyaccuracy riflesrifles Progress in warfare technology Progress in warfare technology Full metal jacket 7.62mm Russian AK-47 / Chinese SKS Soft point lead missile Belgium 1914 “Gentlemen Surgeons, do not abuse injured soldiers with frivolous and unnecessary surgeries”

World War I

WhatWhat lessonslessons werewere learned?learned? Ambulance de l’Ocean La Panne, Belgium 12 miles from the front Antoine Depage DepageDepage’’ss PrinciplesPrinciples ofof WarWar SurgerySurgery

• Treat all penetrating wounds as contaminated • Resurrected the Napoleonic War practice of deep incisional wound exploration • Advocated the excision of non-viable tissue DePageDePage formallyformally described:described:

Primary Closure (suture immediate) invites suppuration and gangrene… of little use in combatant’s wounds Delayed Primary Closure (suture primative retardé) Secondary Closure (suture secondaire) EpidemiologyEpidemiology ofof gasgas gangrenegangrene inin WWWW II

Varies, depending on sources:

British data: 120/1000 ⇨ 25% mortality German data: approx 150,000 deaths 2nd to gas gangrene

US data (Middle east): 3.6 in 1000 ManagementManagement ofof gasgas gangrenegangrene

1.1. ImmuneImmune therapytherapy 2.2. SurgerySurgery ManagementManagement ofof infectioninfection afterafter 19181918

1.1. ImmuneImmune therapytherapy 2.2. SurgerySurgery ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: PenicillinPenicillin

1887:1887: LouisLouis PasteurPasteur andand JulesJules FF JoubertJoubert observedobserved inhibitioninhibition ofof anthraxanthrax culturescultures byby mouldsmoulds

1928:1928: AlexanderAlexander FlemingFleming observedobserved antianti--staphylococcalstaphylococcal activityactivity ofof P.P.notatumnotatum

1938:1938: HowardHoward WalterWalter FloreyFlorey initiatedinitiated researchresearch toto produceproduce stablestable penicillinpenicillin

1944:1944: PfizerPfizer (USA)(USA) producesproduces penipenicillincillin GG atat industrialindustrial scalescale ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: sulphonamidessulphonamides

GerhardGerhard DomagkDomagk:: 1935:1935: IntroductionIntroduction ofof thethe firstfirst sulphonamidesulphonamide ProntosilProntosil ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: sulphonamidessulphonamides

GerhardGerhard DomagkDomagk:: 1935:1935: IntroductionIntroduction ofof thethe firstfirst sulphonamidesulphonamide ProntosilProntosil

Mortality secondary to puerperal fever in England and Wales per 10,000 Bynum WF, Porter R (1993) Companion Encyclopedia of the History of Medicine DiscoveryDiscovery ofof C.perfringensC.perfringens

ControversyControversy aboutabout thethe treatmenttreatment ofof gasgas gangrenegangrene

ImmuneImmune therapytherapy

versusversus

ChemotherapyChemotherapy ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: sulphonamidessulphonamides

GerhardGerhard DomagkDomagk:: 1935:1935: IntroductionIntroduction ofof thethe firstfirst sulphonamidesulphonamide ProntosilProntosil ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: TreatmentTreatment ofof gasgas gangrenegangrene

GerhardGerhard DomagkDomagk:: 1941:1941: IntroductionIntroduction ofof MarfanilMarfanil

benzyl-amine-4-sulphon-amide ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: TreatmentTreatment ofof gasgas gangrenegangrene

GerhardGerhard DomagkDomagk:: 1941:1941: IntroductionIntroduction ofof MarfanilMarfanil

benzyl-amine-4-sulphon-amide

Pfaff, Gasbrand und Gasbrandprophylaxe. D. Dtsch Mil.arzt (1944), 9, 315ff Mitchell GAG, Ress WS, Robinson CN, Lancet 635, May 13, 1944 ConceptConcept ofof antimicrobialantimicrobial chemotherapy:chemotherapy: TreatmentTreatment ofof gasgas gangrenegangrene TreatmentTreatment ofof gasgas gangrenegangrene atat endend ofof WWWW IIII

1.1. Antibiotics:Antibiotics: MarfanilMarfanil oror penicillinpenicillin 2.2. PolyvalentePolyvalente gasgas gangrenegangrene antiserumantiserum 3.3. SurgerySurgery CurrentCurrent PrinciplePrinciple ofof DebridementDebridement (some things never change)

• Explore the wound – Define the damage, follow the trajectory of the missile – Radiographs are key to finding metal/foreign bodies & fractures – Always incise parallel to the axis of the extremity – Release all compartment’s fascia • Excise nonviable tissue and debris ModernModern SurgicalSurgical Management:Management: cABCcABC’’ss ++ • All non-viable tissue is excised in hours of wounding – Muscle excision (4C’s) • Colour • Consistency • Contractility • Circulation • All debris is removed • Involved compartments are released • Dressing change in the OR in 2 – 3 days • DPC if the wound is clean • Appropriate antibiotic coverage ThoseThose whowho cannotcannot rememberremember thethe pastpast areare condemnedcondemned toto repeatrepeat itit

George Santanyana (1863 - 1952) The Life of Reason TheThe discoverydiscovery ofof ““ClostridiumClostridium”” andand itsits clinicalclinical impact:impact: AnAn insightinsight intointo thethe historyhistory ofof medicinemedicine InIn conclusion:conclusion: The discovery of Clostridium spp contributed to the development of essential principles of microbiology and the subsequent advancement of therapeutic approaches provided the basis for future cures and preventive strategies in health care:

• C.botulinum: preservation of food and using the toxin as a therapeutic agent • C.tetani: passive and active immunisation • C.perfringens: combination of different (“ancient”) therapeutic approaches leads ultimately to improved outcome AcknowledgementAcknowledgement

I would like to thank my colleague

Lieutenant Colonel Ben Banerjee Consultant Surgeon Clin Senior Lecturer Sunderland Royal Hospital for the inspiring discussions and some of the material presented.