special web call: biofilms...may 31, 2016 · borrelia burgdorferi in vitro. eur j microbiol...

Special Web Call: Biofilms

PaulS.Anderson

(c)PSAnderson-www.ConsultDrA.com-2016 1

Conflict of interest:

• None

•  IhavenofinancialconnectiontoANYlab,productorcompanymentioned

•  SpecificproductsmentionedareexamplesofitemsIusecommonlyinpractice

2(c)PSAnderson-www.ConsultDrA.com-2016

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

Today's Topic Overview

BIOFILMS

• Discussionabouttheissuessurroundingbiofilmtherapies

• DiscussionofthesafeusesofbiofilmTxwithRx:

•  Testing,dosingandfollowupwillbediscussed.

Biofilms

Summary

Biofilmsarebetterunderstoodthaneverbeforeastotheirmedical

relevanceinhumanillness.

Thisportionofthesessionisdesignedtopresentresearchedand

clinicallyverifiedtherapiesforbiofilmswhichcanbeappliedinchronic

diseasecare.

Biofilm Summary by Stephen E. Fry, MD

Biofilmsareconsideredtheruleinnatureratherthantheexception.Ifyouhavechronicinfection,biofilmsmaybeanunderlyingcause.Many,ifnotmost,microorganismsformandpersistincohesivecommunitystructurestermedbiofilms.Thesecellssecreteagelatinousintracellularsubstanceconsistingofanextracellularpolysaccharide(sugar),DNA,andproteinmatrix.Biofilmsareoftenfoundattachedtolivingandinertstablesurfacesthathaveaconstantliquidflowthatbringsnutrientsandremoveswasteproductsfromthebiofilms.Biofilmsoftenarenotcomposedofasingleorganism,butcontaintwoormoreorganismsmakingsignificantcontributionstothebiologicalstability,characteristics,andbehavioroftheresultingbiofilm.

Biofilm Summary by Stephen E. Fry, MD

Organismsfoundwithinbiofilmshavedistinctgeneticexpressionandfunctionalbehaviorcomparedtoindividualorganismssubsistinginanindividualplanktonicstate.Theestablishmentandlifecycleofbiofilmsonsurfacestypicallyproceedthroughfourmainstages:1)  InitialAttachment,2)IrreversibleAttachment,3)Various

MaturationPhases,4)ActiveDispersionorBlebbing/Fragmenting.Manymicroorganismsspendmostoftheirlifecycleinapersistentbiofilmstateswitchingtofreelivingorplanktonicphasesonlyduringbriefperiodswhenenvironmentalconditionsarefavorable.

Overview

•  InthepastthreeyearsweundertookaprojecttomergetheolderandemergingsciencearoundBiofilmsinhumanillnesswithclinicalpractice.

•  ThiswascompletedatAndersonMedicalSpecialtyAssociateswiththecooperationofourpatientswithchronicinfectiousillnesses.

•  Theseslidessummarizetheconceptsandtheirsuccessfulimplementationinthispopulation.

Biofilm Overview

•  “Biofilm”isgenerallyagroupofbioticorganismswhichhaveaprotectivematrixofmetallo-mineralandorganicmoleculecoating.Thiscomplexprotectstheorganismsfromanti-infectivetherapiesandcreatea“super-biotic”organismcolony.• Abiofilmcanformalmostanywherewherewaterispresent.

•  Thehumangut•  Thebloodstream•  Teeth.(thestickycoatingonteethafternobrushingyourteethisBiofilm.)

•  InmostcasesthebiofilmmatrixisabletoprotecttheorganismcolonyfromeventhehighestandstrongestdosesofAntibiotics.

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.

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

Oral Biofilm Rx: Results

Phase-1(attachment/earlybiofilm) Phase-2LaterBiofilm

• Ascomparedtopreventivephase-1agents?• Ascomparedtootherphase-2agents?BOTTOMLINE:YOUCANNOTTREATPHASE-2BIOFILMS(whichallyourchronicallyillfolkshave)WITHPHASE-1THERAPIES.

Biofilm Agents – A Spectrum: 1-Prevention

•  Enzymes

•  Aromatics

•  Tannins

•  Phenolics

•  Xylitol,Stevia

•  Blackcumin

•  Etc…

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.

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.

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.

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).

Biofilm Agents – A Spectrum: 2- Active Therapy

• AntimicrobialTherapies

•  Natural(includingBlackCumin)

•  Synthetic

• DirectBiofilmDisruption

•  Agentsthatactuallydisruptand“open”thebiofilm

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.

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]

•  TheformulashouldmeetthecriteriaforadditionofEDTA,andshould

begiveninaccordancewithacceptedmonitoringandfollowupof

EDTAtherapies–BUT-theadditionistypicallymuchlowerofadose

ofCa-EDTAthanachelationprotocol.

•  IFEDTAisusedsomemineralscannotbeadministeredonthesame

day:Fe,Zn,Cu.

Astothequestionof“CanIjustrunmynormalEDTAchelationprotocolthen

doanIVofotherAnti-infective/Immunetherapies?”

•  Sure.Inmostcaseshoweverthefullchelationprotocolusedforheavy

metalsisnotneededtoachievetheseeffects.

•  **SeetheIIVNTPcourse“EDTAChelationandHeavyMetalToxicologyfor

detailsonheavymetaltreatment.[www.ivnutritionaltherapy.com]

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

Bismuth:

• Multiplereferencesexistastothesynergyofbismuthwithbiofilm

disruption.

• DONOTUSEIVBISMUTHATTHISTIME–STICKWITHORAL.

*NOTE-Thereisaphysicianwholosthislicensebykillingapatient

withIVBismuth–itisnotneededasanIVadditiveandisnotreadyto

beusedIV!

Thiols (Mono and Di)

Dithiols:

•  DMPS(IVandOraluse)

•  DMSA(Oraluse)

Monothiols:

•  ALA(OralorIVuse)

•  NAC(OralorIVuse)

•  Glutathione(IVuse)•  Manythiolreferences.Somearelistedaboveinthebismuthsection.

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.

Considerations in Biofilm Therapy: EDTA

• OralBismuth-Thiolcomplex•  1–3capsulesQDawayfromfood

•  EDTA•  Ca-NA2EDTAaddedtoHDIVCorABXIV200-300mg•  NA2EDTAaddedtoHDIVCorABXIV50-100mg•  **OralCaEDTAascompoundedcapsuleorLiposphericpreparationfromAllergyResearchGrouporQuicksilver:4capsulesor2teaspoons

•  Silver•  IVonseparateday•  Ororal23ppmSilverHydrosol15mLQID

General Doses in Biofilm Therapy:

•  Thiols

•  DMSA:

•  Orally300-500mgPOawayfromfoodBIDdaypriortoandoftheIV

anti-infectiveprotocol

•  DMPS:

•  25-50mggiveninaseparatebagfollowingtheIVanti-infective

protocol

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.

Oral Biofilm Rx: Results

• Ascomparedtopreventivephase-1agents?• Ascomparedtootherphase-2agents?BOTTOMLINE:YOUCANNOTTREATPHASE-2BIOFILMS(whichallyourchronicallyillfolkshave)WITHPHASE-1THERAPIES.

Oral Biofilm Rx: FAQ

•  Isn’tbismuthtoxic?

•  Notinthisform.Thisisneitherbismuthnorthiol.Thereasonareactiveform

ofbismuthandthiol(s)aremixedistocreateaNEWmolecule.Thenew

moleculeiswhatdisruptsthebiofilm.

• Won’titchelatemypatient?

•  Sameanswer–no.TheDithiolisboundtothebismuthsothetoxicityof

bismuthandchelatingabilityofthethiolsarenegated.

• Doestheinitiationofimmunesymptomsafterstartingtheagent

meanitisnotworking?

•  No.Infactitmeansitisworking.Youmayneedmoreanti-infective,

endocrine,inflammatoryorothersupportasthesymptomsmeanthe

immunesystemmaybe“seeing”theIDagentsforthefirsttime(dueto

openingofthebiofilm).

Oral Biofilm – Bismuth-Thiol Complex

• Morethanthesumofitsparts

• Pharmacologyverydifferentfromindividualparts

Biofilm Rx: FAQ

•  InallyourresearchandhumantrialisIVadministeredbiofilmtherapy

morelikelyto“stirup”oraggravateapatientorisoralbiofilmRx

morelikely?

•  InalmosteverycasewehaveseenMUCHmoreaggravationinoralbiofilm

therapy.FarlesswithIVtherapies.

•  ThisislikelyduetothefactthatbiofilmsarethoughttostartintheGItract.

Free Bismuth

Metallo-attractivePortionToxicmetal/ReactivePortion

Free Thiol

StablePortionChelatingPortion

Bismuth-Thiol Complex

Non-toxicandnonchelatingportionsareonthe“outside”andaimintothebiofilmmatrixviabismuthmoietyattraction–createa“wedgeeffect”.

BUGS-BUGS

Bismuth-Thiol Complex

Non-toxicandnonchelatingportionsareonthe“outside”andaimintothebiofilmmatrixviabismuthmoietyattraction–createa“wedgeeffect”.

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)

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

Oral Biofilm Rx:

• Normaltrialisfor60–120daysduringotheranti-infectivetherapy•  Maybeusedmuchlongerifclinicallyindicated

• Usualtrajectoryoftherapy:•  First30-60daysmayhavenochange

•  Eventually(whenthebiofilmRxbreaksthebiofilmopen)thepatientwilltypicallyexhibitsignsofanimmunereaction.Thiscanbeanycytokinebasedreaction.

•  Thisisthetimewhenabalancemustbestruck:

Oral Biofilm Rx:

•  Thebalanceisbetweenallowingtheimmunereactionandtheanti-infectivetherapiestoworkandnothavingthepatientbetoouncomfortable.

•  Theissueisenoughsupportwithoutsuppressingtheimmunesystemsoitcanreactfully.

Biofilm Rx Support:

•  This“balanceisgainedtypicallybyallowingthebiofilmRxtocontinueandmodulatinganti-infectiveRxalongwithenoughAdrenal(andoccasionallyThyroid)support.

•  Ifthepatientisonnon-Rxadrenalsupporttheymayneed5-10Xthedoseforatime.

•  Iftheyareonlowdosehydrocortisoneandadrenalsupporttheyoftenwillneedmorehydrocortisone(sometimes2-4Xforatime).

What is next?

• Afteryouhavebrokenthroughthebiofilmandtherapyisprogressing(whichmaytake3-12months)thenyoucanphaseinthe“phase-1”agentstocleanupthebiofilmsthataremostclinicallysignificant–AND–keepthemfromre-forming.

References

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.

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

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.

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.

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.

9.Hoa,M.,etal.,Biofilmsandchronicotitismedia:aninitialexplorationintotheroleofbiofilmsinthepathogenesisofchronicotitismedia.AmJOtolaryngol,2010.31(4):p.2415.10.Jarvensivu,A.,etal.,Candidayeastsinchronicperiodontitistissuesandsubgingivalmicrobialbiofilmsinvivo.OralDis,2004.10(2):p.10612.

11.Klotz,S.A.,Fungaladherencetothevascularcompartment:acriticalstepinthepathogenesisofdisseminatedcandidiasis.ClinInfectDis,1992.14(1):p.3407.

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.

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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