International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 2, Issue 4, 2010

ReviewArticle

ORALCANDIDIASIS:AREVIEW

YUVRAJSINGHDANGI1,MURARILALSONI1,KAMTAPRASADNAMDEO1
InstituteofPharmaceuticalSciences,GuruGhasidasCentralUniversity,Bilaspur(C.G.)49500Email:yuvi2006@gmail.com Received:13Jun2010,RevisedandAccepted:16July2010 ABSTRACT Candidiasis,acommonopportunisticfungalinfectionoftheoralcavity,maybeacauseofdiscomfortindentalpatients.Thearticlereviewscommon clinical types of candidiasis, its diagnosis current treatment modalities with emphasis on the role of prevention of recurrence in the susceptible dental patient. The dental hygienist can play an important role in education of patients to prevent recurrence. The frequency of invasive fungal infections(IFIs)hasincreasedoverthelastdecadewiththeriseinatriskpopulationsofpatients.ThemorbidityandmortalityofIFIsarehighand managementoftheseconditionsisagreatchallenge.Withthewidespreadadoptionofantifungalprophylaxis,theepidemiologyofinvasivefungal pathogenshaschanged.NonalbicansCandida,nonfumigatusAspergillusandmouldsotherthanAspergillushavebecomeincreasinglyrecognised causes of invasive diseases. These emerging fungi are characterised by resistance or lower susceptibility to standard antifungal agents. Oral candidiasis is a common fungal infection in patients with an impaired immune system, such as those undergoing chemotherapy for cancer and patientswithAIDS.Ithasahighmorbidityamongstthelattergroupwithapproximately85%ofpatientsbeinginfectedatsomepointduringthe courseoftheirillness.AmajorpredisposingfactorinHIVinfectedpatientsisadecreasedCD4Tcellcount.ThemajorityofinfectionsareduetoC. albicans although other species such as C. glabrata, C. tropicalis, C. krusei and C. parapsilosis are increasingly isolated. The systemic azoles, ketoconazole, fluconazole and itraconazole, have been an important benefit in treatment. To date, resistance has primarily been a problem with fluconazoleinAIDS.However,itisimportantthatmeasuresareinstitutedtopreventthespreadofresistantstrainsandthedevelopmentofcross resistance.AlthoughtheNCCLShasestablishedareferencemethodtomeasureinvitrosusceptibility,besidesalreadypublishedpapers,moredata arenecessarytodemonstratethatresistancecorrelateswithclinicalfailure. Keywords:Candidiasis INTRODUCTION Oral candidiasis is one of the most common, treatable oral mucosal infectionsseeninpersonswithhumanimmunodeficiencyvirus(HIV) infection or acquired immune deficiency syndrome (AIDS)1.Oral candidiasiscanbeafrequentandsignificantsourceoforaldiscomfort, pain,lossoftaste,andaversiontofood.Candidaalbicanscarriageand a history of oral candidiasis are other significant risk factors for oral candidiasis2.TheinfectioniscausedbyCandidaAlbicans,adimorphic fungal organism that typically is present in the oral cavity in a non pathogenic state in about onehalf of healthy individuals. Normally presentasayeast,theorganism,under favorableconditions, hasthe abilitytotransformintoapathogenic(diseasecausing)hyphaelform. Conditions that favor this transformation include broadspectrum antibiotic therapy, xerostomia, immune dysfunction (secondary to systemicdiseasessuchasdiabetesortheuseofimmunesuppressant medications),orthepresenceofremovableprostheses.Furthermore, aboutoneinfourpatientswithlichenplanuswillhavesuperimposed candidiasis. Unless the patient is severely immunocompromised, the infection is generally limited to the superficial mucosa and skin. Invasivecandidiasisinfectionisrare,withdisseminateddiseaseeven moreso.Thissuperficialnatureoftheinfectionmakesoralcandidiasis so amenable to treatment. Several antifungal agents can be used topically.Fortopicalagents,successfultherapy dependsonadequate contact time (2 minutes) between the agent and the oral mucosa. Treatmentdurationvariesfrom7to14days,withtherapyminimally continuedfor2to3daysbeyondthelastclinicalsignsandsymptoms. Topical agents have the benefit of few side effects at normal therapeuticdosesbecauseoftheirlackofgastrointestinalabsorption. However, sucrose containing topical agents can be cariogenic when used over prolonged time periods3, such that adjunctive topical fluoride therapy may be needed. Systemic antifungals have the advantageofoncedailydosingandsimultaneoustreatmentoffungal infections at multiple body sites. However, these antifungals have more side effects, and selection requires consideration of important drug interactions. The present work reviews the common clinical types of oral candidiasis, its diagnosis, and current treatment modalities with emphasis on the role of prevention of recurrence in the susceptible dental patient. The dental hygienist can play an important role in the education of patients to prevent recurrence. Candidiasisisacommonoralandperioralopportunisticinfectionthat usually results from overgrowth of endogenous Candida fungal microorganisms.TherearemanyspeciesofCandida(Table1)4butC. albicans is the fungal microorganism most often encountered in the ambulatory general practice dental patient. Changes in the oral environment that can predispose or precipitate oral candidiasis include:antibiotics,corticosteroids,drymouth(xerostomia), diabetes mellitus, nutritional deficiencies, and immunosuppressive diseases and therapy1. Saliva contains antifungal proteins including histatins and calprotectin that help protect patients from Candida infections5. Theseprotectiveproteinsareabsentinapatientwhohasxerostomia. Individuals who use corticosteroid asthma inhalers must rinse their mouths with water after each use to reduce their chances of developingoralcandidiasis.Excellentoralhygiene,includingbrushing and flossing of the teeth twice daily and maintenance of adequate intraoral moisture, is critical in the prevention of candidiasis recurrenceinthesusceptiblepatient. Fluconazole,anovelbistriazoleantifungalagentintroducedin1990, hassystemiceffectsthatmaybebeneficialforotherfungalinfections. Subjectsinthefluconazoleprophylacticarmofoneantifungalplacebo controlled trial showed improvement of dermatophytoses, such as tinea pedis, onychomycosis, and tinea cruris6. In addition, systemic fluconazole prophylaxis may prevent esophageal and vaginal candidiasis7, cryptococcemia, histoplasmosis, and other deep fungal infections.Unlikeketoconazole, fluconazole is notaltered by changes ingastricacidityandcarrieslessriskofhepatotoxicity;however,many of the same drug interactions are possible. A newly raised concern about the wide spread use of fluconazole is the potential for developmentofazoleresistantCandidaalbicansandselectionofnon albicans Candida species, which also increase in prevalence with immune decline and further complicate management of some individuals8,9,10. Causativeorganisms Candidaspp. Amongthefungalpathogens,Candidaspp.arethemostpredominant causes of invasive infections. The annual incidence of Candida associated BSIs ranged from 6 to 23 per 100 000 persons in the USA11,12 and from 2.53 to 11 per 100 000 persons in European countries13. In various reports, Candida spp. accounted for 810% of nosocomial BSIs11. Rising incidences of candidaemia have been reported throughout the world in the past two decades11,13,14. The

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major predisposing factors included surgical intervention, intensive care treatment, solid tumour or haematological malignancies, use of steroids and premature birth13. Crude mortality rates remain high despite advances in medical care, ranging from 30% to 50% 11,12,13. More than 95% of Candidaassociated BSIs are caused by ve major species: C. albicans, Candida glabrata, Candida parapsilosis, Candida tropicalisandCandidakrusei12,13,15,16.Candidaparapsilosisoccurswith high frequency in premature neonates and in patients with vascular catheters 17,18. Candida glabrata infections are rare in infants and children butare signicantly more commonin theelderly19. Candida tropicalis plays an important role as a cause of invasive diseases in patients with haematological malignancy20. Overall, the nonalbicans Candidaspp.haveshownanincreasingtrendascausativepathogens inBSIs21witha1011%incrementovera6.5yearperiodinaglobal report21.Withthemorewidespreaduseofuconazole,theemergence ofC.glabrataandC.kruseihasbeenreportedintheUSA22,23.However, theroleofspecieswithlowersusceptibilitytoazoleshasbeenlimited inotherareas.Newtriazoles,suchasvoriconazoleandposaconazole, and the echinocandinsare active against these two species,although crossresistance was noted within the azoles in some C. glabrata strains. Aspergillusspp. Aspergillus spp. are commonly found in soil, water and decaying material all over the world. Unlike invasive candidiasis, invasive aspergillosis(IA)occurspredominantlyinhighlyimmunocompromised patients24,25,26. The main affected populations are patients with haematological malignancies and/or those receiving haematopoietic stem cell transplantation (HSCT)27. IA is also an emerging condition in patients with other causes of immunosuppression, such as solid organ transplantation,advancedacquiredimmunodeciencysyndrome(AIDS) and treatment with newer immunosuppressive agents such as iniximab28. The usual route of infections for IA is inhalation of Aspergillusconidia.ThemostfrequentlyinvolvedsitesofIAaresinuses, lungs, brain and disseminated infection. IA is associated with a high mortality rate, which exceeds 50% in most reports. Higher mortality rates were noted in patients receiving HSCT compared with patients receivingsolidorgantransplants(68%vs.41%;P<0.0001),inpatients withcentralnervoussystemdisease(88%vs.53%;P=0.0005)andin nonneutropeniccomparedwithneutropenicpatients(89%vs.60%;P< 0.05)29. Othermoulds ZygomycetesarefungibelongingtotheorderMucorales,whichform broad hyphae and are generally nonseptate. Genera that are able to cause invasive diseases include Rhizopus, Rhizomucor, Absidia and Cunninghamella30,31. Infections due to zygomycetes are classically characterised by vascular invasion, leading to thrombosis and tissue necrosis.ZygomycetesaresusceptibletoamphotericinBbutgenerally resistant to most triazoles and the echinocandins. Breakthrough zygomycosis has been reported in patients receiving voriconazole or caspofungin prophylaxis, as these agents lack activity against zygomycetes32,33. Voriconazole and posaconazole have been reported assuccessfultreatmentsforfusariosis. Clinicalspectrumofthedisease InfectionwithCandidaAlbicanspresentsmainlyinanyoffourforms: pseudomembranous candidiasis, hyperplastic candidiasis, erythematous candidiasis, or angular cheilitis. Patients may exhibit oneoracombinationofanyofthesepresentations.Angularcheilitis, for example, will frequently be seen in combination with erythematouscandidiasisindenturewearers(Table3). Pseudomembranouscandidiasis Pseudomembranouscandidiasis,commonlyknownasthrush,isthe formoftenseeninneonates.Itcanalso beseeninpatients receiving topical corticosteroid therapy or in immune suppressed patients. In fact, the presence of pseudomembranous candidiasis in a seemingly healthy adult may be an indication of underlying systemic disease, such as infection with the human immunodeficiency virus (HIV). Pseudomembranouscandidiasispresentsasmultiplewhiteplaquesof material resembling cottage cheese that can easily be wiped away. Theseplaquesconsistoftangledaggregatesofhyphae.Theunderlying mucosamaybeerythematous,butulcerationwouldnotbeexpected. Whilesymptomsaretypicallymildforthisformofinfection,patients may complain of a slight tingling sensation or a foul taste. Identificationofthe fungalpseudohyphaewithinexfoliative cytologic preparations,often utilizingperiodicacidSchiffand/or Papanicolaou stained preparations, is the optimal standard for the diagnosis of all candidiasis, although the highest yield of positive cytology smears is withpseudomembranouscandidiasis34. AtrophicCandidiasis Atrophiccandidiasisexhibitsadiffuselyreddened,oftenrelativelydry mucosa.Theredareasareoftenconfinedtomucosaunderlyingdental appliances such as partial dentures or orthodontic retainers. Approximately26%ofpatientswithcompletedentureshaveatrophic candidiasis35. Hyperplasticcandidiasis Thisformhasbeenreferredtoascandidalleukoplakia,althoughthis terminology should probably be avoided. Like leukoplakia, hyperplasticcandidiasiswillpresentasawhiteplaquethatcannotbe wiped away by the clinician. Unlike leukoplakia, however, lesions shouldcompletelyresolvewithroutineantifungaltherapy. Erythematouscandidiasis Manyconditionsfallunderthespectrumoferythematouscandidiasis. As the term implies, lesions clinically appear red or erythematous. While any mucosal site may be affected, erythematous candidiasis commonly involves the tongue and palate. A form of erythematous candidiasis that is especially common involves the hard palate and gingivabeneathadentureorremovablepartialdenture. Angularcheilitis The final clinical presentation of oral candidiasis infection is angular cheilitis. This form presents as cracking, peeling, or ulceration involving the corners of the mouth. It will frequently be seen in combinationwithoneoftheotherformsofcandidiasisinfection,such astheerythematoustype.Patientswithareducedverticaldimension of occlusion, secondary to severe attrition or worn dentures, are particularlysusceptibletothedevelopmentofangularcheilitis.Thisis duetotheincreasedfoldingofthesofttissuethatisfrequentlyseenat thecornersofthemouth,creatingahavenfortheorganism. Several overthecounter (OTC) medications including miconazole nitrate and clotrimazole creams, and prescription nystatin or ketoconazole creams are available to topically treat angular cheilitis. Topicalmiconazolenitrate2%creamisvaluableinthatitiseffective against both Candida and Staphyolococcus aureus. Dental professionals should be cautious when recommending OTC topical antifungalstopatientswhoareusingtheanticoagulantwarfarin.The combination increases the risk of excessively prolonged coagulation periods, due to interference with the liver enzymes that aid in the metabolism of warfarin36. Angular cheilitis is typically clinically diagnosedbasedontheuniorbilateralpresenceofasymptomaticor painful red cracks or fissures at the corners of the mouth. Angular cheilitis may be caused by candidiasis (20%), mixed candidial bacterialinfections(60%),orbacteriaalone(20%)37. Treatment For the normal healthy patient, the treatment of oral candidiasis is relatively simple and effective. Typically, topical medications are adequate. A commonly prescribed antifungal agent, nystatin oral suspension, will usually resolve most infections. However, topical medicationsmustbeincontactwiththeorganismtoeliminateit.Since patientsareusuallyunabletoholdliquidsintheirmouthsmorethan briefly, clotrimazole troches are an effective alternative. These are dissolvedslowlyintheoralcavity,allowingthedrugtobepresentfor greaterlengthoftime. Intraoralcandidiasis Topical agents include nystatin suspension and clotrimazole troches, which should be allowed to dissolve slowly in the mouth five times daily for 14 days. Patients should avoid eating or drinking for 20 minutes after using clotrimazole troches. Intraoral appliances should 37

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be removed during the treatment as the medication works topically and must be in contact with the tissue. Systemic prescription antifungal agents include ketoconazole38, fluconazole39, and itraconazole40. Prosthodonticappliances With any case of oral candidiasis, if the patient utilizes a removable prosthodontic appliance it is important to disinfect the appliance, becausetheporousmaterialorsurfacebiofilmcanserveasareservoir of fungal microorganisms and contribute to relapse or reinfection41. Disinfection of dental appliances is a twostep process. First, the applianceshouldbefreeofdebrisandconcretions.Householdchlorine bleach,althougheffectiveandinexpensive,cancausedamagetodental metals, acrylic, and tissueconditioning materials42. To avoid damage to prosthetic appliances, a germicide deodorizer containing sodium benzoate, citrate, and disodium phosphate (Oral Safe, Great Lakes Orthodontics, Tonawanda, NY) can beused to soaktheappliance for sixhours.Thissolutioncanbereusedforoneweekandisharmlessif ingested43. Another technique utilizes five minutes of microwave irradiation.Applying60Hzatfullpowertoacompleteacrylicdenture ineightouncesofwatercaneffectivelysterilizeacrylicand mostsoft dentureliners44.

Table1:SpeciesofOralCandida SpeciesofOralCandida C.albicans C.glabrata C.guillermondii C.krusei C.parapsilosis C.pseudotropicalis C.stellatoidea C.tropicalis Table2:Topicalantifungalmedications Topicalantifungalmedications Dosageform/strength OTC Miconazolecream2% Clotrimazolecream1% Prescription Ketoconazolecream2% Nystatinointment100,000units/gram Nystatintopicalpowder100,000units/gram Nystatinoralsuspension100,000units/gram Betamethasonedipropionateclotrimazole cream Clotrimazoletroches10mg AmphotericinB100mg/ml Table3:Clinicalclassification Clinicalclassification Angularchelitis Chronicatrophic(erythematous) Denturestomatitis Endocrinecandidiasissyndrome Hyperplastic(Candidialleukoplakia) Inflammatorypapillaryhyperplasia Medianrhomboidglossitis Mucocutaneous Pseudomembranous Xerostomia Suchpatientsmayrequiremaintenancetherapyoftwicedaily0.12% chlorhexidinegluconatemouthrinsesafteranacuteorchronicepisode oforalcandidiasisisundercontrol. Recentdevelopments Formanyyears,amphotericinBdeoxycholateremainedthemainstay of treatment for IFIs27. The major limitations of its usage are the substantialadverse effects suchas fever, chills, nauseaandvomiting, electrolyte abnormalities and, most importantly, nephrotoxicity45. In the 1990s, the introduction of the two azoles uconazole and itraconazole represented a considerable advance in antifungal therapy. However, the use of uconazole is hampered by its narrow spectrum, and the use of itraconazole is limited due to absorption problems46. New therapeutic agents have now been developed that providebetterantifungalactivitiesandlowertoxicities(Table2,4and 5). Extendedspectrumtriazoles Secondgeneration triazoles act predominantly by inhibition of the cytochrome P450 (CYP450)dependent conversion of lanosterol to ergosterol47.Thisleadstoanaccumulationoftoxic14methylsterols andadepletionofmembraneassociatedergosterol.Thischangeincell membranepropertiesresultsininhibitionofcellgrowthorcelldeath. Antifungal agents in this class include voriconazole, which was approved for the treatment of fungal infections in 2002, and posaconazole,whichreceivedUSFoodandDrugAdministration(FDA) approval in September 2006. Clinical trials of ravuconazole have not Indication Angularcheilitis Angularcheilitis Angularcheilitis Angularcheilitis Denturestomatitis Intraoralcandidasis Chloronicangularcheilitis Intraoralcandidasis Intraoralcandidasis

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yetbeencompleted.Voriconazoleisavailablebothinintravenous(i.v.) andoralformulations. Thebioavailabilityoftheoralformulationis>90%butisdecreasedto 80% by fatty foods48. Both i.v. and oral formulations are given as a twicedaily dosage. A loading dose is needed to achieve steadystate concentration rapidly (6 mg/kg twice daily on Day 1 followed by 4 mg/kg twice daily)48. Posaconazole is available only in oral formulation (400800 mg/day in divided doses). Administering posaconazolewithameal,inasuspensionratherthanatabletandin divided doses increases its oral bioavailability49. Posaconazole is excretedmainlyinthefaecesandaminorportionismetabolisedinthe liver through glucuronidation49. Dosage adjustment for oral voriconazoleandposaconazoleisnotnecessaryinpatientswithrenal Table4:Systemicantifungalmedications Systemicantifungalmedications Dosageform/strength Indication Ketoconazoletablet200mg Intraoralcandidasis Fluconazoletablet100mg Intraoralcandidasis Itraconazoletablet100mg Intraoralcandidasis Table5:Antifungaldrugsfortreatmentoforopharyngealcandidiasis Genericname AmphotericinB Clotrimazole Fluconazole Itraconazole Ketoconazole Nystatin Proprietaryname Fungizone Mycelex Diflucan Sporanox Nizoral Mycostatin Formulation 100mg/mloralsuspension 10mgtroche 100mgtablet 10mg/mloralsuspension 40mg/mloralsuspension 100mgcapsule 10mg/mloralsuspension 200mgtablet 100,000units/mloralsuspension 200,000units/mlpastille 500,000units/mltablet 100,000units/mlvaginaltablet insufciencyorinpatientsreceivingdialysis50,51.Theconcentrationsof voriconazole in cerebrospinal uid (CSF) are ca. 50% of plasma concentrations, and concentrations in brain tissue are higher than those in the CSF52. Voriconazole and posaconazole are very broad spectrum antifungal agents. As with other azoles, they appear to be fungistaticagainstmostyeastsbuthaveafungicidaleffectagainstthe lamentousmoulds53.Voriconazoleandposaconazoleareveryactive against most Candida spp., including C. krusei, C. glabrata and those strains that are resistant to uconazole54,14. For Aspergillus spp., voriconazoleandposaconazoleareverypotentagainstmanyspecies, including A. terreus, which is resistant to amphotericin B, and A. fumigatus,which is resistant to itraconazole 55,56. They are active against some but not all strains of opportunistic moulds56,57,58,59,60 .

Echinocandins The echinocandins are large lipopeptide molecules that inhibit synthesisof1,3dglucan,whichisanessentialcomponentofthecell wall of many fungi but is absent in mammals61. Inhibition of 1,3d glucansynthaseinterfereswithfungalcellwallsynthesis,whichleads to osmotic instability and death of the fungal cell61. Until now, caspofungin,micafunginandanidulafunginaretheonlyechinocandin agentsapprovedforclinicaluse.Allechinocandinpreparationstodate arefori.v.useonly62.Thethreeagentssharesimilarpharmacological characteristics,withsomevariations62.Aoncedailydosingregimenis optimal based on concentrationdependent pharmacodynamics and prolongedpostantifungaleffects53,63,64. A loading dose is recommended for caspofungin (75 mg loading on Day1followedby50mg/day)andanidulafungin(200mgloadingon Day 1 followed by 100 mg/day), but not for micafungin (50150 mg/day)65,64.Caspofunginandmicafunginaredegradedmainlyinthe liver64whilstanidulafunginuniquelyundergoeschemicaldegradation in the blood65. All three agents are poor substrates for the hepatic CYP450 enzyme system. Therefore, unlike triazoles, the CYP450 independent metabolism and degradation of echinocandins reduces concernaboutdrugdruginteractions61.Echinocandinshaveverylow MICsagainstclinicallysignicantCandidaspp.,includingC.albicans,C. tropicalis, C. glabrata, C. krusei, C. lusitaniae and Candida dubliniensis66,59,67,68. Rationaleforandagainstantifungalcombinations The original use of antifungal combination therapy was in the treatment of cryptococcal meningitis in patients who did not have AIDS. Amphotericin B was the first agent available for successfully treatinginvasive mycoses,but there have beenmajorproblemswith systemic toxic reactions associated with its infusion and nephrotoxicity69. Indeed, several trials have demonstrated that when flucytosine is included in the treatment regimen, the dose of amphotericin B could be reduced, thereby decreasing somewhat its toxicity70,71. ThedoseofamphotericinBwassubsequentlyincreasedandresponse ratestotherapy,withorwithoutflucytosine,improved72,73.Atpresent, we are faced with an increasing incidence of serious invasive fungal mycoses and a high mortality rate secondary to these infections74,75,76,77. REFERENCES 1. 2. 3. Greenspan D. Treatment of oral candidiasis in HIV infection. OralSurgOralMedOralPathol1994;78:2115. MacPhailLA,HiltonJF,DoddCL,GreenspanD.Prophylaxiswith nystatin pastilles for HIVassociated oral candidiasis. J Acquir ImmuneDeficSyndr1996;12:4706. Pons V, Greenspan D, LozadaNur F, MacPhail L, Gallant JE, Tunkel A, et al. Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oralsuspensions.ClinInfectDis1997;24:12047. Scully C, el Kabir M, Samaranyake LP. Candida and oral candidosis: A review. Crit Rev Oral Biol Med 1994;5(2):125 157. Challacombe SJ. Immunologic aspects of oral candidiasis. Oral SurgOralMedOralPathol1994;78(2):202210. Stevens DA, Greene SI, Lang OS. Thrush can be prevented in patients with acquired immunodeficiency syndrome and the acquired immunodeficiency syndromerelated complex. Randomized,doubleblind,placebocontrolledstudyof100mg oralfluconazoledaily.ArchInternMed1991;151:245864 SchumanP,CappsL,PengG,VazquezJ,ElSadrW,GoldmanAI, et al. Weekly fluconazole for the prevention of mucosal 39

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