special web call: biofilms...may 31, 2016 · borrelia burgdorferi in vitro. eur j microbiol...
TRANSCRIPT
Special Web Call: Biofilms
PaulS.Anderson
©2016PSAnderson–www.ConsultDrAnderson.com
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Conflict of interest:
• None
• IhavenofinancialconnectiontoANYlab,productorcompanymentioned
• SpecificproductsmentionedareexamplesofitemsIusecommonlyinpractice
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Next Regularly Scheduled Webcalls:
June BloodPressuremedications–PrescribingandTaperingtipsInthiswebcallDr.Andersonwilldescribetheclinicallyrelevantissuessurroundingthechoiceof,dosingforandtaperingoffofanti-hypertensivemedications.Howbesttodoit?Howtousenaturalmedicationsintheprocess?CaseexamplesandQ&Aincluded.CMETotal1.5hours–OfthatpharmacologyCMEis1.5hoursJuly Steroids–PrescribingandTaperingtipsInthiswebcallDr.Andersonwilldescribetheclinicallyrelevantissuessurroundingthechoiceof,dosingforandtaperingoffofsteroidmedications.Howbesttodoit?Howtousenaturalmedicationsintheprocess?CaseexamplesandQ&Aincluded.CMETotal1.5hours–OfthatpharmacologyCMEis1.5hours
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Today's Topic Overview
BIOFILMS
• Discussionabouttheissuessurroundingbiofilmtherapies
• DiscussionofthesafeusesofbiofilmTxwithRx:
• Testing,dosingandfollowupwillbediscussed.
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Biofilms
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Summary
Biofilmsarebetterunderstoodthaneverbeforeastotheirmedical
relevanceinhumanillness.
Thisportionofthesessionisdesignedtopresentresearchedand
clinicallyverifiedtherapiesforbiofilmswhichcanbeappliedinchronic
diseasecare.
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Biofilm Summary by Stephen E. Fry, MD
Biofilmsareconsideredtheruleinnatureratherthantheexception.Ifyouhavechronicinfection,biofilmsmaybeanunderlyingcause.Many,ifnotmost,microorganismsformandpersistincohesivecommunitystructurestermedbiofilms.Thesecellssecreteagelatinousintracellularsubstanceconsistingofanextracellularpolysaccharide(sugar),DNA,andproteinmatrix.Biofilmsareoftenfoundattachedtolivingandinertstablesurfacesthathaveaconstantliquidflowthatbringsnutrientsandremoveswasteproductsfromthebiofilms.Biofilmsoftenarenotcomposedofasingleorganism,butcontaintwoormoreorganismsmakingsignificantcontributionstothebiologicalstability,characteristics,andbehavioroftheresultingbiofilm.
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Biofilm Summary by Stephen E. Fry, MD
Organismsfoundwithinbiofilmshavedistinctgeneticexpressionandfunctionalbehaviorcomparedtoindividualorganismssubsistinginanindividualplanktonicstate.Theestablishmentandlifecycleofbiofilmsonsurfacestypicallyproceedthroughfourmainstages:1) InitialAttachment,2)IrreversibleAttachment,3)Various
MaturationPhases,4)ActiveDispersionorBlebbing/Fragmenting.Manymicroorganismsspendmostoftheirlifecycleinapersistentbiofilmstateswitchingtofreelivingorplanktonicphasesonlyduringbriefperiodswhenenvironmentalconditionsarefavorable.
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Overview
• InthepastthreeyearsweundertookaprojecttomergetheolderandemergingsciencearoundBiofilmsinhumanillnesswithclinicalpractice.
• ThiswascompletedatAndersonMedicalSpecialtyAssociateswiththecooperationofourpatientswithchronicinfectiousillnesses.
• Theseslidessummarizetheconceptsandtheirsuccessfulimplementationinthispopulation.
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Biofilm Overview
• “Biofilm”isgenerallyagroupofbioticorganismswhichhaveaprotectivematrixofmetallo-mineralandorganicmoleculecoating.Thiscomplexprotectstheorganismsfromanti-infectivetherapiesandcreatea“super-biotic”organismcolony.• Abiofilmcanformalmostanywherewherewaterispresent.
• Thehumangut• Thebloodstream• Teeth.(thestickycoatingonteethafternobrushingyourteethisBiofilm.)
• InmostcasesthebiofilmmatrixisabletoprotecttheorganismcolonyfromeventhehighestandstrongestdosesofAntibiotics.
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Who has biofilms?
• Everyone–butnotallareclinicallysignificant.
• Thosewithpositivelabtitersthatwon’tclearwithstandardofcaretreatment
• Thosewhoclearoneinfectiononlytogetanotheroranothergroup
• ThosewithchronicGIinfectionsthatareunresponsivetotreatment
• Anychronicallyillperson
• Etc…(c)PSAnderson-www.ConsultDrA.com-2016 11
Can we test for biofilms?
• Let’sdiscuss…
• FryLabs(Scottsdale,Arizona)canrunbiofilmassays.
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Biofilm Agents – A Spectrum:
1.Prevention:A. Inhibit:QuorumSensing
I. Organismcellsignalingwithauto-inducerswhichdeterminesgeneexpression,virulence,resistance,andthedevelopmentofbiofilms.
B. Inhibit:InitialAttachmentofBiofilmColoniesC. Inhibit:OrganismEffluxPump/MultiDrugResistancePump
Inhibitors2.Activetherapies:
A. Bacteriostatic&‘cidalagentsB. Directbiofilmdisruptionagents
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Oral Biofilm Rx: Results
Phase-1(attachment/earlybiofilm) Phase-2LaterBiofilm
• Ascomparedtopreventivephase-1agents?• Ascomparedtootherphase-2agents?BOTTOMLINE:YOUCANNOTTREATPHASE-2BIOFILMS(whichallyourchronicallyillfolkshave)WITHPHASE-1THERAPIES.
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Biofilm Agents – A Spectrum: 1-Prevention
• Enzymes
• Aromatics
• Tannins
• Phenolics
• Xylitol,Stevia
• Blackcumin
• Etc…
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Badet C, Furiga A, Thébaud N. Effect of xylitol on an in vitro model of oral biofilm. Oral Health Prev Dent. 2008;6(4):337-41. PMID: 19178100 AbstractTheaimofthepresentstudywastoexaminewhetherxylitol,atdifferentconcentrations,inhibitstheformationofanexperimentalmodeloforalbiofilm.Biofilmsofsixbacterialspecies(Streptococcusmutans,Streptococcussobrinus,Lactobacillusrhamnosus,Actinomycesviscosus,PorphyromonasgingivalisandFusobacteriumnucleatum)werepreparedonhydroxyapatite(HA)discsaccordingtotheZürichBiofilmModel.Xylitolwastestedattwoconcentrations,1%and3%.Attheendoftheirdesignatedincubationtimes,someHAdiscsweredestinedforconfocallaserscanningmicroscopy(CLSM)andtheotherswereharvestedusingasterilesurgicalinstrument.Aliquotsofharvestedbiofilmsweredilutedandplatedontospecificmedia.Aftera48-hanaerobicincubationat37degreesC,thecolony-formingunits(CFUs)werecounted.CLSMimagesshowedthatonlyasmallamountofisolatedbacteriawasobservedonthesurfaceofHAdiscs.Cultureofharvestedbiofilmsshowedaninhibitioninthegrowthofdifferentspeciesincludedinthebiofilms.Xylitolhasaclearinhibitoryeffectontheformationoftheexperimentalbiofilms.Thisstudyshowsthatxylitolisnotonlyefficientininhibitingtheacidproductionofcariogenicbacteria,butalsoinpreventingtheformationofamultispeciesbiofilm;itconfirmstherelevanceoftheuseofthispolyolforthepreventionoforaldiseasescausedbydentalplaque.
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P. A. S. Theophilus, M. J. Victoria, K. M. Socarras, K. R. Filush, K. Gupta, D. F. Luecke, and E. Sapi. Effectiveness of Stevia Rebaudiana Whole Leaf Extract Against the Various Morphological Forms of
Borrelia Burgdorferi in Vitro. Eur J Microbiol Immunol (Bp). 2015 Dec; 5(4): 268–280. Published online 2015 Nov 12. doi: 10.1556/1886.2015.00031. PMCID: PMC4681354
Inthisstudy,weevaluatedtheeffectivenessofwholeleafSteviaextractagainstB.burgdorferispirochetes,persisters,andbiofilmformsinvitro.Thesusceptibilityofthedifferentformswasevaluatedbyvariousquantitativetechniquesinadditiontodifferentmicroscopymethods.TheeffectivenessofSteviawascomparedtodoxycycline,cefoperazone,daptomycin,andtheircombinations.OurresultsdemonstratedthatSteviahadsignificanteffectineliminatingB.burgdorferispirochetesandpersisters.SubcultureexperimentswithSteviaandantibioticstreatedcellswereestablishedfor7and14daysyielding,noand10%viablecells,respectivelycomparedtotheabove-mentionedantibioticsandantibioticcombination.WhenSteviaandthethreeantibioticsweretestedagainstattachedbiofilms,SteviasignificantlyreducedB.burgdorferiforms.ResultsfromthisstudysuggestthatanaturalproductsuchasStevialeafextractcouldbeconsideredasaneffectiveagentagainstB.burgdorferi.
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Fatemeh Forouzanfar, Bibi Sedigheh Fazly Bazzaz, and Hossein Hosseinzadeh. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on
antimicrobial effects. Iran J Basic Med Sci. 2014 Dec; 17(12): 929–938. PMCID: PMC4387228
AllfindingsdiscussedaboveindicatethatN.sativaseedshaveantimicrobialeffectsagainstdifferentpathogens,includingbacteria,viruses,schistosomaandfungus.Blackcuminseedintraditionalmedicineandinrecentyearsforthetreatmentofmicrobialdiseaseshasbeenusedwithoutanyreportedsideeffects.Therefore,thisplantcanprovideavaluableagentformicrobialdiseases.However,additionalstudiesarerequiredtoevaluateandexplorethespecificcellularandmolecularmechanismsoftheantimicrobialeffectsofN.sativa,aloneorincombinationwithotherdrugs.
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Park SR, et al. Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat Commun. 2016. PMID
26880271
And–onthehorizon:Pathogenicmicroorganismsoftenhavetheabilitytoattachtoasurface,buildingacomplexmatrixwheretheycolonizetoformabiofilm.Thiscellularsuperstructurecandisplayincreasedresistancetoantibioticsandcauseserious,persistenthealthproblemsinhumans.Herewedescribeahigh-throughputinvitroscreentoidentifyinhibitorsofAcinetobacterbaumanniibiofilmsusingalibraryofnaturalproductextractsderivedfrommarinemicrobes.AnalysisofextractsderivedfromStreptomycesgandocaensisresultsinthediscoveryofthreepeptidicmetabolites(cahuitamycinsA-C),withcahuitamycinCbeingthemosteffectiveinhibitor(IC50=14.5 μM).BiosynthesisofcahuitamycinCproceedsviaaconvergentbiosyntheticpathway,withoneofthestepsapparentlybeingcatalysedbyanunlinkedgeneencodinga6-methylsalicylatesynthase.EffortstoassessstarterunitdiversificationthroughselectivemutasynthesisleadtoproductionofunnaturalanaloguescahuitamycinsDandEofincreasedpotency(IC50=8.4and10.5 μM).
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Biofilm Agents – A Spectrum: 2- Active Therapy
• AntimicrobialTherapies
• Natural(includingBlackCumin)
• Synthetic
• DirectBiofilmDisruption
• Agentsthatactuallydisruptand“open”thebiofilm
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Considerations in Active Biofilm Therapy:
• OralBismuth
• EDTA
• Silvernanoparticles
• Anti-infective:• H2O2/HDIVC/Ge/Zn/etc…etc…
• Anti-infectiveagentsPO/IV
• Thiols• [Mono-]ALA,NAC,Glutathione
• [Di-]DMSA,DMPS
• OralBismuth-ThiolComplex
• Neitherbismuthnorthiolalonebuta
newmolecule.
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Biofilm Protocols and EDTA:
• AlthoughatopicofgreatlengthwedoemployCalcium-disodiumEDTAandNa2-EDTAasadditivetosomeImmuneandAntibioticIVformulasasanaugmentforpatientswhomayhaveBiofilmissues.
SelectedEDTA-BiofilmReferences:[PMID:22941091;PMID:18594291;PMID:17909983;PMID:22029913;PMID:22941091;http://dx.doi.org/10.1016/j.fm.2011.07.009]
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Biofilm Protocols and EDTA:
• TheformulashouldmeetthecriteriaforadditionofEDTA,andshould
begiveninaccordancewithacceptedmonitoringandfollowupof
EDTAtherapies–BUT-theadditionistypicallymuchlowerofadose
ofCa-EDTAthanachelationprotocol.
• IFEDTAisusedsomemineralscannotbeadministeredonthesame
day:Fe,Zn,Cu.
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Biofilm Protocols and EDTA:
Astothequestionof“CanIjustrunmynormalEDTAchelationprotocolthen
doanIVofotherAnti-infective/Immunetherapies?”
• Sure.Inmostcaseshoweverthefullchelationprotocolusedforheavy
metalsisnotneededtoachievetheseeffects.
• **SeetheIIVNTPcourse“EDTAChelationandHeavyMetalToxicologyfor
detailsonheavymetaltreatment.[www.ivnutritionaltherapy.com]
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Silver and Biofilms
SilverHydrosol(i.e.23ppmsilverhydrosol)areallIuse.Idonotuse“colloidal”forms.• AsamatterofprotocoltheSilverHydrosolIVcannotbegivenonthesamedaywiththechelators.• SilvernanoparticlesimpedethebiofilmformationbyPseudomonasaeruginosaandStaphylococcusepidermidis.ColloidsSurfBBiointerfaces.2010Sep1;79(2):340-4.doi:10.1016/j.colsurfb.2010.04.014.Epub2010Apr22.PMID:20493674
• Martinez-GutierrezF,BoegliL,AgostinhoA,SánchezEM,BachH,RuizF,JamesG.Anti-biofilmactivityofsilvernanoparticlesagainstdifferentmicroorganisms.Biofouling.2013;29(6):651-60.doi:10.1080/08927014.2013.794225.Epub2013Jun4.PMID:23731460
• BjarnsholtT,Kirketerp-MøllerK,KristiansenS,PhippsR,NielsenAK,JensenPØ,HøibyN,GivskovM.SilveragainstPseudomonasaeruginosabiofilms.APMIS.2007Aug;115(8):921-8.PMID:17696948
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Bismuth:
• Multiplereferencesexistastothesynergyofbismuthwithbiofilm
disruption.
• DONOTUSEIVBISMUTHATTHISTIME–STICKWITHORAL.
*NOTE-Thereisaphysicianwholosthislicensebykillingapatient
withIVBismuth–itisnotneededasanIVadditiveandisnotreadyto
beusedIV!
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Thiols (Mono and Di)
Dithiols:
• DMPS(IVandOraluse)
• DMSA(Oraluse)
Monothiols:
• ALA(OralorIVuse)
• NAC(OralorIVuse)
• Glutathione(IVuse)• Manythiolreferences.Somearelistedaboveinthebismuthsection.
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https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjqmLb3zs_LAhUEzWMKHQpuDSUQjB0IBg&url=https%3A%2F%2Fcommons.wikimedia.org%2Fwiki%2FFile%3ADMSA-(2S%2C3S)https://www.google.com/search?q=ala+structure&rlz=1C1CHFX_enUS659US659&espv=2&biw=1366&bih=667&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiDt-vLz8_LAhVU32MKHWULCL8Q_AUIBigB#tbm=isch&q=alpha+lipoic+acid+structure&imgrc=xFmpm-rxDdyL7M%3A
Biofilm Concepts:
• Stackanti-infectiveIV’s(H2O2,HDIVC,Ge,Zn,Antibioticsetcetc…)alongwiththeIVchelators(EDTAformsandathiolappropriatelyadministered).
• GiveoralBismuth-Thiolcomplex
• Maybegivendailyifdesiredbutnotatthesametimeasanyotherproductordrugthatissensitivetobinding.
• Manyclinicsusehighdoseenzymes,Aromatics,Xylitol…orally(betweenmeals)daybeforeandoftheIVaswell.Somedothemdaily.
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Considerations in Biofilm Therapy: EDTA
• OralBismuth-Thiolcomplex• 1–3capsulesQDawayfromfood
• EDTA• Ca-NA2EDTAaddedtoHDIVCorABXIV200-300mg• NA2EDTAaddedtoHDIVCorABXIV50-100mg• **OralCaEDTAascompoundedcapsuleorLiposphericpreparationfromAllergyResearchGrouporQuicksilver:4capsulesor2teaspoons
• Silver• IVonseparateday• Ororal23ppmSilverHydrosol15mLQID
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General Doses in Biofilm Therapy:
• Thiols
• DMSA:
• Orally300-500mgPOawayfromfoodBIDdaypriortoandoftheIV
anti-infectiveprotocol
• DMPS:
• 25-50mggiveninaseparatebagfollowingtheIVanti-infective
protocol
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General Doses in Biofilm Therapy:
• Thiols• ALA:
• Orally300-500mgBIDdaybeforeandoftheIVanti-infectiveprotocol–OR-20-100mggiveninaseparatebagfollowingtheIVanti-infectiveprotocol
• NAC:• Orally500-1000mgBIDdaybeforeandoftheIVanti-infectiveprotocol–OR-250-500mggiveninaseparatebagfollowingtheIVanti-infectiveprotocol
• Glutathione:• Astolerated,pernormalIVrules.Doseof1-4grams.
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Oral Biofilm Rx: Results
Phase-1(attachment/earlybiofilm) Phase-2LaterBiofilm
• Ascomparedtopreventivephase-1agents?• Ascomparedtootherphase-2agents?BOTTOMLINE:YOUCANNOTTREATPHASE-2BIOFILMS(whichallyourchronicallyillfolkshave)WITHPHASE-1THERAPIES.
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Oral Biofilm Rx: FAQ
• Isn’tbismuthtoxic?
• Notinthisform.Thisisneitherbismuthnorthiol.Thereasonareactiveform
ofbismuthandthiol(s)aremixedistocreateaNEWmolecule.Thenew
moleculeiswhatdisruptsthebiofilm.
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Oral Biofilm Rx: FAQ
• Won’titchelatemypatient?
• Sameanswer–no.TheDithiolisboundtothebismuthsothetoxicityof
bismuthandchelatingabilityofthethiolsarenegated.
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Oral Biofilm Rx: FAQ
• Doestheinitiationofimmunesymptomsafterstartingtheagent
meanitisnotworking?
• No.Infactitmeansitisworking.Youmayneedmoreanti-infective,
endocrine,inflammatoryorothersupportasthesymptomsmeanthe
immunesystemmaybe“seeing”theIDagentsforthefirsttime(dueto
openingofthebiofilm).
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Oral Biofilm – Bismuth-Thiol Complex
• Morethanthesumofitsparts
• Pharmacologyverydifferentfromindividualparts
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Biofilm Rx: FAQ
• InallyourresearchandhumantrialisIVadministeredbiofilmtherapy
morelikelyto“stirup”oraggravateapatientorisoralbiofilmRx
morelikely?
• InalmosteverycasewehaveseenMUCHmoreaggravationinoralbiofilm
therapy.FarlesswithIVtherapies.
• ThisislikelyduetothefactthatbiofilmsarethoughttostartintheGItract.
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Free Bismuth
Metallo-attractivePortionToxicmetal/ReactivePortion
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Free Thiol
StablePortionChelatingPortion
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Bismuth-Thiol Complex
Non-toxicandnonchelatingportionsareonthe“outside”andaimintothebiofilmmatrixviabismuthmoietyattraction–createa“wedgeeffect”.
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BUGS-BUGS
Bismuth-Thiol Complex
Non-toxicandnonchelatingportionsareonthe“outside”andaimintothebiofilmmatrixviabismuthmoietyattraction–createa“wedgeeffect”.
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BUGS-BUGS
So-“suddenly”theimmunesystem“sees”theBUGS!Anti-infectivesubstancesandimmuneactivitybeginthefighttheydidn’tknowwasneededbefore.
Oral Biofilm Rx:
• IhaveworkedwithImprimispharmacy(US)tomake“Biosolve-PA”capsulesbasedonthestrongestingredientsavailableinthestudiesmentioned.• Initialtestingonhumansshowsverygoodtolerance.
• Formula:• DMPS25mg/AlphaLipoicAcid100mg/BismuthSubnitrate200mgperCapsule• Ideallynosubstitutions• DMSA100mgcansubforDMPS• BismuthSubcitratecansubforSubnitrate(willmakeproductweaker)
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Oral Biofilm Rx:
• “Biosolve-PA”[Imakenomoneyfromthemanufactureorsaleofthisagent]dosing:• Approximatesthemostpotent–mostresearchedbiofilmdrugs• Usesthemost(available)formsandcombinationsofmedicationchemistry
• DOSE:• 1capQDawayfromfood,3Xaweekforoneweekasatestdose• 1-4capsQDtoBIDawayfromfood3-5Xaweek• Extradoses(onthe“offdays”)arehelpfulindermatologicflaresduringtherapyfordermatologicand‘Herx’typereactions
• Onceanimmunologicreactionisreachedthedosemayneedtobedecreasedasneeded
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Oral Biofilm Rx:
• Normaltrialisfor60–120daysduringotheranti-infectivetherapy• Maybeusedmuchlongerifclinicallyindicated
• Usualtrajectoryoftherapy:• First30-60daysmayhavenochange
• Eventually(whenthebiofilmRxbreaksthebiofilmopen)thepatientwilltypicallyexhibitsignsofanimmunereaction.Thiscanbeanycytokinebasedreaction.
• Thisisthetimewhenabalancemustbestruck:
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Oral Biofilm Rx:
• Thebalanceisbetweenallowingtheimmunereactionandtheanti-infectivetherapiestoworkandnothavingthepatientbetoouncomfortable.
• Theissueisenoughsupportwithoutsuppressingtheimmunesystemsoitcanreactfully.
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Biofilm Rx Support:
• This“balanceisgainedtypicallybyallowingthebiofilmRxtocontinueandmodulatinganti-infectiveRxalongwithenoughAdrenal(andoccasionallyThyroid)support.
• Ifthepatientisonnon-Rxadrenalsupporttheymayneed5-10Xthedoseforatime.
• Iftheyareonlowdosehydrocortisoneandadrenalsupporttheyoftenwillneedmorehydrocortisone(sometimes2-4Xforatime).
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What is next?
Phase-1(attachment/earlybiofilm) Phase-2LaterBiofilm
• Afteryouhavebrokenthroughthebiofilmandtherapyisprogressing(whichmaytake3-12months)thenyoucanphaseinthe“phase-1”agentstocleanupthebiofilmsthataremostclinicallysignificant–AND–keepthemfromre-forming.
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References
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Selected Bismuth / Biofilm References:
• Domenico,P.,B.A.Cunha,andR.J.Salo,ThePotentialofBismuth-ThiolsforTreatmentandPreventionofInfection.InfectMed,2000.17(2):p.123-127.
• Domenico,P.,etal.,CombatingAntibioticResistancewithBismuth-Thiols.Res.Adv.inAntimicrob.Agents&Chemother.,2003.3:p.79-85.
• Domenico,P.,etal.,Enhancementofbismuthantibacterialactivitywithlipophilicthiolchelators.AntimicrobAgentsChemother,1997.41(8):p.1697-703.
• Wu,C.L.,etal.,Subinhibitorybismuth-thiolsreducevirulenceofPseudomonasaeruginosa.AmJRespirCellMolBiol,2002.26(6):p.731-8.
• Microbionunpublisheddata.
• Domenico,P.,etal.,SurfaceantigenexposurebybismuthdimercaprolsuppressionofKlebsiellapneumoniaecapsularpolysaccharide.InfectImmun,1999.67(2):p.664-9.
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Selected Bismuth / Biofilm References:
• Huang,C.T.andP.S.Stewart,ReductionofpolysaccharideproductioninPseudomonasaeruginosabiofilmsbybismuthdimercaprol(BisBAL)treatment.JAntimicrobChemother,1999.44(5):p.601-5.
• Domenico,P.,etal.,Activitiesofbismuththiolsagainststaphylococciandstaphylococcalbiofilms.AntimicrobAgentsChemother,2001.45(5):p.1417-21.
• Zhang,H.,etal.,Inhibitionofbacterialadherenceonthesurfaceofstentsandbacterialgrowthinbilebybismuthdimercaprol.DigDisSci,2005.50(6):p.1046-51.
• Alipour,M.,etal.,AttenuationofPseudomonasaeruginosavirulencefactorsandbiofilmsbyco-encapsulationofbismuthethanedithiolwithtobramycininliposomes.JAntimicrobChemother,2010.65(4):p.684-93.
• Domenico,P.,etal.,BisEDTandRIPactinsynergytopreventgraftinfectionsbyresistantstaphylococci.Peptides,2004.25(12):p.2047-53.31MicrobionCorporationIChemistryforLifeTM
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Selected Bismuth-thiol references:
• MaryamVarposhti,AhyaAbdiAli,ParisaMohammadi.SynergisticEffectsofBismuthThiolsandVariousAntibioticsAgainstPseudomonasaeruginosaBiofilm.JundishapurJMicrobiol.7(3):e9142.March2014.DOI:10.5812/jjm.9142• J.P.Folsom,B.Baker,P.S.Stewart.Invitroefficacyofbismuththiolsagainstbiofilmsformedbybacteriaisolatedfromhumanchronicwounds.JournalofAppliedMicrobiology111,989–996ª2011TheSocietyforAppliedMicrobiology• ActivitiesofBismuthThiolsagainstStaphylococciandStaphylococcalBiofilms.ANTIMICROBIALAGENTSANDCHEMOTHERAPY,May2001,p.1417–1421.0066-4804/01/$04.0010DOI:10.1128/AAC.45.5.1417–1421.2001.
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Background Biofilm References • Bryers,J.D.,Medicalbiofilms.BiotechnolBioeng,2008.100(1):p.1-18.• Gilbert,P.,P.J.Collier,andM.R.Brown,Influenceofgrowthrateonsusceptibilitytoantimicrobialagents:biofilms,cellcycle,dormancy,andstringentresponse.AntimicrobAgentsChemother,1990.34(10):p.1865-8.
• Zimmerli,W.,etal.,Pathogenesisofforeignbodyinfection:descriptionandcharacteristicsofananimalmodel.JInfectDis,1982.146(4):p.487-97.
• Murdoch,D.R.,etal.,InfectionoforthopedicprosthesesafterStaphylococcusaureusbacteremia.ClinInfectDis,2001.32(4):p.647-9.
• Costerton,J.W.,L.Montanaro,andC.R.Arciola,Biofilminimplantinfections:itsproductionandregulation.IntJArtifOrgans,2005.28(11):p.1062-8.
• Hostetler,S.G.,etal.,DischargePatternsofInjury-relatedHospitalizationswithanAcuteWoundintheUnitedStates.Wounds,2006.18(12):p.340-351.
• AmericanBurnAssociation.BurnincidenceandtreatmentintheUS:2000factsheet2000;Availablefrom:http://www.ameriburn.org.
• Vindenes,H.andR.Bjerknes,Microbialcolonizationoflargewounds.Burns,1995.21(8):p.575-579.
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Biofilm Bibliography by Stephen E. Fry, MD 1.Costerton,J.W.,P.S.Stewart,andE.P.Greenberg,Bacterialbiofilms:acommoncauseofpersistentinfections.Science,1999.284(5418):p.131822.2.AlMutairi,D.andS.J.Kilty,Bacterialbiofilmsandthepathophysiologyofchronicrhinosinusitis.CurrOpinAllergyClinImmunol,2010.
3.Busscher,H.J.,etal.,Biofilmformationondentalrestorativeandimplantmaterials.JDentRes,2010.89(7):p.65765.
4.Cernohorska,L.andP.Slavikova,[AntibioticresistanceandbiofilmformationinPseudomonasaeruginosastrainsisolatedfrompatientswithurinarytractinfections].EpidemiolMikrobiolImunol,2010.59(4):p.1547.
5.Crawford,R.W.,etal.,GallstonesplayasignificantroleinSalmonellaspp.gallbladdercolonizationandcarriage.ProcNatlAcadSciUSA,2010.107(9):p.43538.
6.Cushion,M.T.,M.S.Collins,andM.J.Linke,BiofilmformationbyPneumocystisspp.EukaryotCell,2009.8(2):p.197206.
7.HallStoodley,L.andP.Stoodley,Evolvingconceptsinbiofilminfections.CellMicrobiol,2009.11(7):p.103443.
8.Haussler,S.andM.R.Parsek,Biofilms2009:newperspectivesattheheartofsurfaceassociatedmicrobialcommunities.JBacteriol,2010.192(12):p.29419.
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11.Klotz,S.A.,Fungaladherencetothevascularcompartment:acriticalstepinthepathogenesisofdisseminatedcandidiasis.ClinInfectDis,1992.14(1):p.3407.
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Biofilm Bibliography by Stephen E. Fry, MD 12.Miller,V.M.,etal.,Evidenceofnanobacteriallikestructuresincalcifiedhumanarteriesandcardiacvalves.AmJPhysiolHeartCircPhysiol,2004.287(3):p.H111524.13.Tang,H.andY.Xu,[Bacterialbiofilmsandchronicosteomyelitis].ZhongguoXiuFuChongJianWaiKeZaZhi,2010.24(1):p.10811.14.Tapiainen,T.,etal.,BiofilmformationbyStreptococcuspneumoniaeisolatesfrompaediatricpatients.Apmis,2010.118(4):p.25560.15.Tunpiboonsak,S.,etal.,RoleofaBurkholderiapseudomalleipolyphosphatekinaseinanoxidativestressresponse,motilities,andbiofilmformation.JMicrobiol,2010.48(1):p.6370.16.Aulik,N.A.,etal.,Mannheimiahaemolyticaanditsleukotoxincauseneutrophilextracellulartrapformationbybovineneutrophils.InfectImmun,2010.78(11):p.445466.17.Behrendt,J.H.,etal.,NeutrophilextracellulartrapformationasinnateimmunereactionsagainsttheapicomplexanparasiteEimeriabovis.VetImmunolImmunopathol,2010.133(1):p.18.18.Dolgushin,IIandS.AndreevaIu,[Neutrophilextracellulartraps:methodofdetectionandassessmentofbacterialtrappingefficacy].ZhMikrobiolEpidemiolImmunobiol,2009(2):p.657.19.Ermert,D.,A.Zychlinsky,andC.Urban,Fungalandbacterialkillingbyneutrophils.MethodsMolBiol,2009.470:p.293312.20.Gupta,A.K.,etal.,NeutrophilNETs:anovelcontributortopreeclampsiaassociatedplacentalhypoxia?SeminImmunopathol,2007.29(2):p.1637.21.Gupta,A.K.,etal.,ActivatedendothelialcellsinduceneutrophilextracellulartrapsandaresusceptibletoNETosismediatedcelldeath.FEBSLett,2010.584(14):p.31937.
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Biofilm Bibliography by Stephen E. Fry, MD 22.Hakkim,A.,etal.,ActivationoftheRafMEKERKpathwayisrequiredforneutrophilextracellulartrapformation.NatChemBiol,2010.23.Hakkim,A.,etal.,Impairmentofneutrophilextracellulartrapdegradationisassociatedwithlupusnephritis.ProcNatlAcadSciUSA,2010.107(21):p.98138.
24.Jann,N.J.,etal.,NeutrophilantimicrobialdefenseagainstStaphylococcusaureusismediatedbyphagolysosomalbutnotextracellulartrapassociatedcathelicidin.JLeukocBiol,2009.86(5):p.115969.
25.Li,P.,etal.,PAD4isessentialforantibacterialinnateimmunitymediatedbyneutrophilextracellulartraps.JExpMed,2010.207(9):p.185362.
26.Marcos,V.,etal.,CXCR2mediatesNADPHoxidaseindependentneutrophilextracellulartrapformationincysticfibrosisairwayinflammation.NatMed,2010.16(9):p.101823.
27.Pilsczek,F.H.,etal.,AnovelmechanismofrapidnuclearneutrophilextracellulartrapformationinresponsetoStaphylococcusaureus.JImmunol,2010.185(12):p.741325.
28.Urban,C.F.,etal.,NeutrophilextracellulartrapscaptureandkillCandidaalbicansyeastandhyphalforms.CellMicrobiol,2006.8(4):p.66876.
29.vonKockritzBlickwede,M.,etal.,Phagocytosisindependentantimicrobialactivityofmastcellsbymeansofextracellulartrapformation.Blood,2008.111(6):p.307080.
30.Wang,Y.,etal.,Histonehypercitrullinationmediateschromatindecondensationandneutrophilextracellulartrapformation.JCellBiol,2009.184(2):p.20513.
31.Wartha,F.,etal.,Neutrophilextracellulartraps:castingtheNEToverpathogenesis.CurrOpinMicrobiol,2007.10(1):p.526.
32.Wartha,F.andB.HenriquesNormark,ETosis:anovelcelldeathpathway.SciSignal,2008.1(21):p.pe25.
33.Ellis,J.E.,M.Prochazka,andS.E.Fry,EvidenceforInVivoHematologicBiofilmCommunitiesin3PatientswithALS.5thASMConf.onBiofilms,2009.158.
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Attendedthewebinar“SafeUsesofBiofilmTherapies”givenonlineliveorviarecordingonorafter05-31-2016.
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