UNIVERSITAS PEMBANGUNAN NASIONAL VETERAN JAKARTA

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ORAL CANDIDIASIS



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di Bagian Kulit dan Kelamin
Rumah Sakit Umum Daerah Ambarawa




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Pembimbing : dr. Hiendarto, Sp.KK

Disusun Oleh :
Ayu Farah Ummamah 1220221145


Kepaniteraan Klinik Departemen Kulit dan Kelamin
FAKULTAS KEDOKTERAN UPN VETERAN JAKARTA
Rumah Sakit Umum Daerah Ambarawa
PERIODE 27 Mei 30 Juni 2013



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Journal reading dengan judul :

ORAL CANDIDIASIS


Diajukan untuk Memenuhi Syarat Mengikuti Ujian Kepaniteraan Klinik
di Departemen Kulit dan Kelamin
Rumah Sakit Umum Daerah Ambarawa




Disusun Oleh:

Ayu Farah Ummamah 1220221145


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dr. Hiendarto, Sp.KK ............................. .............................



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dr. Hiendarto, Sp.KK
NIP. 197308042009091001

ReviewArticle
ORALCANDIDIASIS:AREVIEW

YUVRAJSINGHDANGI
1
,MURARILALSONI
1
,KAMTAPRASADNAMDEO
1

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
management of these conditions is a great challenge.With the widespread adoptionof antifungal prophylaxis,theepidemiology of invasivefungal
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
patients with AIDS. It has a high morbidity amongst the latter group with approximately 85% of patients being infected at some point during the
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,itisimportantthatmeasuresareinstitutedtopreventthespreadofresistantstrainsandthe developmentofcross
resistance.AlthoughtheNCCLShasestablishedareferencemethodtomeasureinvitrosusceptibility,besidesalreadypublishedpapers,moredata
arenecessarytodemonstratethatresistancecorrelateswithclinicalfailure.
Keywords:Candidiasis

INTRODUCTION
Oral candidiasis is one of the most common, treatable oral mucosal
infectionsseen in persons with human immunodeficiency virus (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
candidiasis
2
.TheinfectioniscausedbyCandidaAlbicans,adimorphic
fungal organism that typically is present in the oral cavity in a non
pathogenic state in about onehalf of healthy individuals. Normally
present as a yeast, the organism, under favorable conditions, has the
abilitytotransformintoapathogenic(diseasecausing)hyphaelform.
Conditions that favor this transformation include broadspectrum
antibiotic therapy, xerostomia, immune dysfunction (secondary to
systemic diseases such as diabetes or theuse of immune suppressant
medications), or the presence of removable prostheses. Furthermore,
about onein four patients withlichen planus will havesuperimposed
candidiasis. Unless the patient is severely immunocompromised, the
infection is generally limited to the superficial mucosa and skin.
Invasive candidiasis infection is rare, with disseminated disease even
moreso.Thissuperficialnatureoftheinfectionmakesoralcandidiasis
so amenable to treatment. Several antifungal agents can be used
topically. For topical agents, successful therapy depends on adequate
contact time (2 minutes) between the agent and the oral mucosa.
Treatment duration variesfrom 7 to 14days, withtherapyminimally
continuedfor2to3daysbeyondthelastclinicalsignsandsymptoms.
Topical agents have the benefit of few side effects at normal
therapeutic doses because of their lack ofgastrointestinal absorption.
However, sucrose containing topical agents can be cariogenic when
used over prolonged time periods
3
, such that adjunctive topical
fluoride therapy may be needed. Systemic antifungals have the
advantage of oncedaily dosing and simultaneous treatment of fungal
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. There are many species of Candida (Table 1)
4
but C.
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, dry mouth (xerostomia), diabetes
mellitus, nutritional deficiencies, and immunosuppressive diseases
and therapy
1
. Saliva contains antifungal proteins including histatins
and calprotectin that help protect patients from Candida infections
5
.
Theseprotectiveproteinsareabsentinapatientwhohasxerostomia.
Individuals who use corticosteroid asthma inhalers must rinse their
mouths with water after each use to reduce their chances of
developingoralcandidiasis.Excellentoralhygiene,including brushing
and flossing of the teeth twice daily and maintenance of adequate
intraoral moisture, is critical in the prevention of candidiasis
recurrenceinthesusceptiblepatient.
Fluconazole, a novel bistriazole antifungal agent introduced in 1990,
hassystemiceffectsthatmaybebeneficialforotherfungalinfections.
Subjectsinthefluconazoleprophylacticarmofoneantifungalplacebo
controlled trial showed improvement of dermatophytoses, such as
tinea pedis, onychomycosis, and tinea cruris
6
. In addition, systemic
fluconazole prophylaxis may prevent esophageal and vaginal
candidiasis
7
, cryptococcemia, histoplasmosis, and other deep fungal
infections. Unlike ketoconazole, fluconazole is not altered 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
individuals
8,9,10
.
Causativeorganisms
Candidaspp.
Among the fungal pathogens, Candida spp. are the mostpredominant
causes of invasive infections. The annual incidence of Candida
associated BSIs ranged from 6 to 23 per 100 000 persons in the
USA
11,12
and from 2.53 to 11 per 100 000 persons in European
countries
13
. In various reports, Candida spp. accounted for 810% of
nosocomial BSIs
11
. Rising incidences of candidaemia have been
reported throughout the world in the past two decades
11,13,14
. The
International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491 Vol 2, Issue 4, 2010
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37

major predisposing factors included surgical intervention, intensive

care treatment, solid tumour or haematological malignancies, use of
steroids and premature birth
13
. 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
tropicalisandCandidakrusei
12,13,15,16
.Candidaparapsilosisoccurswith
high frequency in premature neonates and in patients with vascular
catheters
17,18
. Candida glabrata infections are rare in infants and
children but are signicantly more common in the elderly
19
. Candida
tropicalis plays an important role as a cause of invasive diseases in
patients with haematological malignancy
20
. Overall, the nonalbicans
Candida spp. have shown an increasing trend as causative pathogens
in BSIs
21
with a 1011% increment over a 6.5year period in a global
report
21
.Withthemorewidespreaduseofuconazole,theemergence
ofC.glabrataandC.kruseihasbeenreportedintheUSA
22,23
.However,
theroleofspecieswithlowersusceptibilitytoazoleshasbeenlimited
in other areas. New triazoles, such as voriconazole and posaconazole,
and the echinocandins are 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
patients
24,25,26
. 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
iniximab
28
. 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
with centralnervous system disease(88% vs.53%; P = 0.0005) and in
nonneutropeniccomparedwithneutropenicpatients(89%vs.60%;P<
0.05)
29
.
Othermoulds
Zygomycetes are fungi belonging to the order Mucorales, which form
broad hyphae and are generally nonseptate. Genera that are able to
cause invasive diseases include Rhizopus, Rhizomucor, Absidia and
Cunninghamella
30,31
. 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
zygomycetes
32,33
. Voriconazole and posaconazole have been reported
assuccessfultreatmentsforfusariosis.
Clinicalspectrumofthedisease
InfectionwithCandidaAlbicanspresentsmainlyinany of four forms:
pseudomembranous candidiasis, hyperplastic candidiasis,
erythematous candidiasis, or angular cheilitis. Patients may exhibit
one or a combination of any of these presentations. Angular cheilitis,
for example, will frequently be seen in combination with
erythematouscandidiasisindenturewearers(Table3).
Pseudomembranouscandidiasis
Pseudomembranous candidiasis, commonly known as thrush, is the
form often seen in neonates. It can also be seen in patients 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
mucosa may be erythematous, but ulceration would not be expected.
While symptoms are typically mild for this form of infection, patients
may complain of a slight tingling sensation or a foul taste.
Identification of the fungal pseudohyphae within exfoliative cytologic
preparations, often utilizing periodic acid Schiff and/or Papanicolaou
stained preparations, is the optimal standard for the diagnosis of all
candidiasis, although the highest yield of positive cytology smears is
withpseudomembranouscandidiasis
34
.
AtrophicCandidiasis
Atrophiccandidiasisexhibitsadiffuselyreddened,oftenrelativelydry
mucosa.Theredareasareoftenconfinedtomucosaunderlyingdental
appliances such as partial dentures or orthodontic retainers.
Approximately26%ofpatientswithcompletedentureshaveatrophic
candidiasis
35
.
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
as the erythematous type. Patients with a reduced vertical dimension
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.
Topical miconazole nitrate 2% cream is valuable in that it is effective
against both Candida and Staphyolococcus aureus. Dental
professionals should be cautious when recommending OTC topical
antifungals to patients who are using the anticoagulant warfarin. The
combination increases the risk of excessively prolonged coagulation
periods, due to interference with the liver enzymes that aid in the
metabolism of warfarin
36
. Angular cheilitis is typically clinically
diagnosed based ontheuni orbilateral presence ofasymptomatic or
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
patients are usually unable to hold liquids in their mouths more than
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
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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 ketoconazole
38
, fluconazole
39
, and
itraconazole
40
.
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 reinfection
41
.
Disinfection of dental appliances is a twostep process. First, the
applianceshouldbefreeofdebrisandconcretions.Householdchlorine
bleach,althougheffectiveandinexpensive,cancausedamagetodental
metals, acrylic, and tissueconditioning materials
42
. To avoid damage
to prosthetic appliances, a germicide deodorizer containing sodium
benzoate, citrate, and disodium phosphate (Oral Safe, Great Lakes
Orthodontics, Tonawanda, NY) can be used to soak the appliance for
sixhours.Thissolutioncanbereusedforoneweekandisharmlessif
ingested
43
. Another technique utilizes five minutes of microwave
irradiation.Applying60Hzatfullpowertoacompleteacrylicdenture
in eight ounces of water can effectively sterilize acrylic and most soft
dentureliners
44
.

Table1:SpeciesofOralCandida
SpeciesofOralCandida
C.albicans
C.glabrata
C.guillermondii
C.krusei
C.parapsilosis
C.pseudotropicalis
C.stellatoidea
C.tropicalis

Table2:Topicalantifungalmedications
Topicalantifungalmedications
Dosageform/strength Indication
OTC
Miconazolecream2% Angularcheilitis
Clotrimazolecream1% Angularcheilitis
Prescription
Ketoconazolecream2% Angularcheilitis
Nystatinointment100,000units/gram Angularcheilitis
Nystatintopicalpowder100,000units/gram Denturestomatitis
Nystatinoralsuspension100,000units/gram Intraoralcandidasis
Betamethasonedipropionateclotrimazole
cream
Chloronicangularcheilitis
Clotrimazoletroches10mg Intraoralcandidasis
AmphotericinB100mg/ml Intraoralcandidasis

Table3:Clinicalclassification
Clinicalclassification
Angularchelitis
Chronicatrophic(erythematous)
Denturestomatitis
Endocrinecandidiasissyndrome
Hyperplastic(Candidialleukoplakia)
Inflammatorypapillaryhyperplasia
Medianrhomboidglossitis
Mucocutaneous
Pseudomembranous

Xerostomia
Such patients may require maintenance therapy of twice daily 0.12%
chlorhexidinegluconatemouthrinsesafteranacuteorchronicepisode
oforalcandidiasisisundercontrol.
Recentdevelopments
Formanyyears,amphotericin B deoxycholate remainedthe mainstay
of treatment for IFIs
27
. The major limitations of its usage are the
substantial adverse effects such as fever, chills, nausea and vomiting,
electrolyte abnormalities and, most importantly, nephrotoxicity
45
. 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
problems
46
. 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
ergosterol
47
.This leadsto anaccumulationoftoxic14methylsterols
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
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39

yetbeencompleted.Voriconazoleisavailablebothinintravenous(i.v.)
andoralformulations.
Thebioavailabilityoftheoralformulationis>90%butisdecreasedto
80% by fatty foods
48
. 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
posaconazolewith a meal,in a suspension rather thana tablet and in
divided doses increases its oral bioavailability
49
. Posaconazole is
excretedmainlyinthefaecesandaminorportionismetabolisedinthe
liver through glucuronidation
49
. Dosage adjustment for oral
voriconazoleandposaconazoleisnotnecessaryinpatientswithrenal
insufciencyorinpatientsreceivingdialysis
50,51
.Theconcentrationsof
voriconazole in cerebrospinal uid (CSF) are ca. 50% of plasma
concentrations, and concentrations in brain tissue are higher than
those in the CSF
52
. Voriconazole and posaconazole are very broad
spectrum antifungal agents. As with other azoles, they appear to be
fungistaticagainstmostyeastsbuthaveafungicidal effectagainstthe
lamentous moulds
53
. Voriconazole and posaconazole are very active
against most Candida spp., including C. krusei, C. glabrata and those
strains that are resistant to uconazole
54,14
. For Aspergillus spp.,
voriconazole and posaconazole are very potent against many species,
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
moulds
56,57,58,59,60
.

Table4:Systemicantifungalmedications
Systemicantifungalmedications
Dosageform/strength Indication
Ketoconazoletablet200mg Intraoralcandidasis
Fluconazoletablet100mg Intraoralcandidasis
Itraconazoletablet100mg Intraoralcandidasis

Table5:Antifungaldrugsfortreatmentoforopharyngealcandidiasis
Genericname Proprietaryname Formulation
AmphotericinB Fungizone 100mg/mloralsuspension
Clotrimazole Mycelex 10mgtroche
Fluconazole Diflucan 100mgtablet
10mg/mloralsuspension
40mg/mloralsuspension
Itraconazole Sporanox 100mgcapsule
10mg/mloralsuspension
Ketoconazole Nizoral 200mgtablet
Nystatin Mycostatin 100,000units/mloralsuspension
200,000units/mlpastille
500,000units/mltablet
100,000units/mlvaginaltablet

Echinocandins
The echinocandins are large lipopeptide molecules that inhibit
synthesisof1,3dglucan,whichisanessentialcomponentofthecell
wall of many fungi but is absent in mammals
61
. Inhibition of 1,3d
glucansynthaseinterfereswithfungalcellwallsynthesis,whichleads
to osmotic instability and death of the fungal cell
61
. Until now,
caspofungin, micafungin and anidulafungin are the only echinocandin
agentsapprovedforclinicaluse.Allechinocandinpreparationstodate
are for i.v. use only
62
. The three agents share similar pharmacological
characteristics,withsomevariations
62
.Aoncedailydosingregimenis
optimal based on concentrationdependent pharmacodynamics and
prolongedpostantifungaleffects
53,63,64
.
A loading dose is recommended for caspofungin (75 mg loading on
Day1followedby50mg/day)andanidulafungin(200mgloading on
Day 1 followed by 100 mg/day), but not for micafungin (50150
mg/day)
65,64
. Caspofungin and micafungin are degraded mainly in the
liver
64
whilst anidulafunginuniquelyundergoeschemical degradation
in the blood
65
. All three agents are poor substrates for the hepatic
CYP450 enzyme system. Therefore, unlike triazoles, the CYP450
independent metabolism and degradation of echinocandins reduces
concernaboutdrugdruginteractions
61
.Echinocandinshaveverylow
MICsagainstclinicallysignicantCandidaspp.,includingC.albicans,C.
tropicalis, C. glabrata, C. krusei, C. lusitaniae and Candida
dubliniensis
66,59,67,68
.
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
treating invasive mycoses, but there have been major problems with
systemic toxic reactions associated with its infusion and
nephrotoxicity
69
. 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
toxicity
70,71
.
ThedoseofamphotericinBwassubsequentlyincreasedandresponse
ratestotherapy,withorwithoutflucytosine,improved
72,73
.Atpresent,
we are faced with an increasing incidence of serious invasive fungal
mycoses and a high mortality rate secondary to these
infections
74,75,76,77
.
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Tinjauan : Kandidiasis Oral

YUVRAJ SINGH DANGI1, MURARI LAL SONI1, KAMTA PRASAD NAMDEO1
Institute of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur (C.G.) 49500 Email:
yuvi2006@gmail.com

Abstrak
Kandidiasis oral adalah infeksi jamur oportunistik yang berasal dari rongga mulut yang dapat
menjadi penyebab ketidaknyamanan pada pasien. Jurnal ini akan membahas tentang jenis-jenis
kandidiasis, dimana pengobatan saat ini menekankan pada pencegahan kekambuhan pasien gigi.
Peran perawat juga sangat penting dalam memberikan edukasi kepada pasien dalam mencegah
kekambuhan. Frekuensi infeksi jamur invasif (IFI) telah meningkat selama beberapa dekade
terakhir, dimana sebanding dengan kenaikan populasi pasien yang berisiko. Morbiditas dan
mortalitas IFI yang tinggi menyebabkan pengelolaan keadaan ini merupakan suatu tantangan
besar. Dengan meluasnya pencegahan antijamur, epidemiologi jamur patogen yang invasif telah
berubah. Jamur selain Candida albicans, Aspergillus fumigatus, dan Aspergillus spp. lainnya
menjadi semakin diakui sebagai penyebab penyakit invasif. Jamur jenis ini ditandai dengan
resistensi atau kerentanan yang lebih rendah terhadap agen antijamur standar. Kandidiasis oral
adalah infeksi jamur yang umumnya terjadi pada pasien dengan sistem kekebalan tubuh yang
rendah, seperti pada pasien yang sedang menjalani kemoterapi untuk kanker dan pasien AIDS.
Faktor predisposisi utama pada pasien yang terinfeksi HIV adalah jumlah sel T CD4 menurun.
Sebagian besar infeksi disebabkan oleh C. albicans meskipun spesies lain seperti C. glabrata, C.
tropicalis, C. krusei dan C. parapsilosis juga dapat menyebabkan terjadinya kandidiasis oral.
Pengobatan sistemik seperti ketokonazol, flukonazol dan itrakonazol sangat bermanfaat dalam
pengobatan infeksi jamur. Sampai saat ini, resistensi flukonazol masih menjadi masalah dalam
pengobatan AIDS. Namun, langkah-langkah yang dilakukan lembaga-lembaga saat ini
dikhususkan untuk mencegah penyebaran strain resisten dan pengembangan resistensi silang.

Kata Kunci : Kandidiasis



Pendahuluan
Kandidiasis oral adalah infeksi yang sering terjadi terutama di bagian mukosa dan kebanyakan
terdapat pada pasien HIV atau AIDS. Kandidiasis oral menyebabkan ketidaknyamanan daerah
mulut seperti nyeri, hilangnya pengecapan, dan keengganan untuk makan. Faktor risiko
kandidiasis oral lainnya adalah carrier Candida albicans dan riwayat kandidiasis oral. Infeksi ini
disebabkan oleh Candida albicans yaitu jamur dimorfik yang biasanya terdapat dalam rongga
mulut sebagai non-patogen pada sekitar satu setengah orang yang sehat. Jamur ini biasanya
hidup sebagai ragi, dimana pada kondisi yang menguntungkan, dapat berubah menjadi patogen
(bentuk hifa) seperti pada kondisi yang sedang menjalani terapi antibiotik spektrum luas,
xerostomia, penurunan sistem kekebalan tubuh (penyakit sistemik sekunder seperti diabetes atau
penggunaan obat yang menekan sistem kekebalan tubuh). Sekitar satu dari empat pasien dengan
liken planus akan menderita kandidiasis superimposed. Infeksi umumnya terbatas pada mukosa
superfisial dan kulit, kecuali pasien dengan immunocompromised yang parah. Infeksi kandidiasis
oral merupakan infeksi superfisial dimana pengobatannya adalah secara topikal dengan waktu
kontak antara agen dan mukosa mulut selama 2 menit. Durasi pengobatan bervariasi dari 7
sampai 14 hari. Pengobatan topikal memiliki sedikit efek samping karena tidak terjadi
penyerapan di sistem gastrointestinal, sedangkan antijamur sistemik keuntungannya adalah
dosisnya hanya sekali sehari dan dapat mengobati infeksi jamur di beberapa lokasi dalam tubuh.
Namun, antijamur ini memiliki efek samping yang lebih banyak dan harus dipertimbangkan
dalam interaksi obat. Jurnal ini mengkaji tentang jenis kandidiasis oral, diagnosis, dan
pengobatan serta pencegahan terhadap kekambuhan pada pasien gigi yang rentan. Kandidiasis
adalah infeksi oportunistik daerah oral dan perioral yang biasanya disebabkan oleh pertumbuhan
jamur Candida endogen yang berlebih. Terdapat banyak spesies Candida (Tabel 1) tetapi C.
albicans adalah jamur yang paling sering dijumpai dalam praktek gigi. Perubahan lingkungan di
mulut dapat mempengaruhi atau memicu kandidiasis oral seperti: penggunaan antibiotik,
kortikosteroid, mulut kering (xerostomia), diabetes mellitus, kekurangan gizi, dan penyakit
imunosupresif. Air liur mengandung protein antijamur seperti histatin dan calprotectin yang
dapat membantu melindungi pasien dari infeksi Candida. Protein pelindung ini tidak terdapat
pada pasien dengan xerostomia. Pasien asma yang menggunakan inhaler kortikosteroid harus
mencuci daerah mulut dengan air setelah menggunakan inhaler untuk mengurangi kemungkinan
terjadinya kandidiasis oral. Kebersihan mulut seperti menyikat gigi dua kali sehari dan
memelihara kelembaban intraoral sangat penting dalam pencegahan kandidiasis terutama pada
pasien yang rentan.
Flukonazol merupakan antijamur yang ditemukan pada tahun 1990 dan memiliki efek sistemik
yang dapat bermanfaat untuk infeksi jamur lainnya. Percobaan flukonazol untuk profilaksis
dimana menggunakan kontrol placebo menunjukkan perbaikan dermatofitosis, seperti tinea
pedis, onikomikosis, dan tinea kruris. Selain itu, flukonazol sistemik dapat mencegah kandidiasis
esofagus dan vagina, kriptokokemia, histoplasmosis, dan infeksi jamur lainnya. Tidak seperti
ketokonazol, flukonazol tidak dipengaruhi oleh keasaman lambung dan memiliki sedikit risiko
hepatotoksisitas serta dapat berinteraksi dengan obat lainnya. Penelitian terbaru tentang
penggunaan flukonazol berpotensi terhadap resistensi Candida albicans dan spesies lainnya.









Tabel 1: Spesies Penyebab Kandidiasis Oral

Organisme Penyebab
Candida spp.
Di antara jamur patogen, Candida spp. merupakan jamur yang paling dominan menyebabkan
infeksi invasif. Angka kejadian Candida dalam satu tahun berdasarkan BSI berkisar 6-23 per
100.000 orang di USA dan 2,53-11 per 100 000 orang di Eropa. Dalam berbagai laporan,
Candida spp. menyebabkan 8-10% infeksi nosokomial dan insiden kandidaemia telah dilaporkan
terjadi di seluruh dunia dalam dua dekade terakhir. Faktor predisposisi utama termasuk
intervensi bedah, perawatan intensif, keganasan hematologi, dan penggunaan steroid. Angka
kematian tetap tinggi meskipun terdapat kemajuan dalam perawatan medis, mulai dari 30%
sampai 50%. Lebih dari 95% infeksi spesies Candida berdasarkan BSI disebabkan oleh: C.
Spesies Penyebab Kandidiasis Oral
C. albicans
C. glabrata
C. guillermondii
C. krusei
C. parapsilosis
C. pseudotropicalis
C. stellatoidea
C. tropicalis
albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis dan Candida krusei.
Candida parapsilosis memiliki prevalensi yang tinggi pada neonatus prematur dan pada pasien
dengan kateter vaskular. Infeksi Candida glabrata jarang terjadi pada bayi dan anak-anak tetapi
biasanya pada usia lebih tua. Candida tropicalis menjadi penyebab penyakit invasif pada pasien
dengan keganasan hematologi. Triazoles baru seperti vorikonazol, posaconazole, dan
echinocandins aktif terhadap C. glabrata dan C. krusei, meskipun resistansi silang tercatat dalam
azoles di beberapa strain C. glabrata.

Aspergillus spp.
Aspergillus spp. biasanya ditemukan di dalam tanah dan air di seluruh dunia. Tidak seperti
kandidiasis invasif, aspergillosis invasif (IA) terjadi terutama pada pasien immunocompromised,
seperti pasien dengan keganasan hematologis atau yang menerima transplantasi haematopoietic
stem cell (HSCT). Aspergillosis invasif juga dapat terjadi pada pasien dengan imunosupresi,
seperti pada pasien yang sedang menjalani transplantasi organ padat, AIDS, dan pengobatan
dengan imunosupresif terbaru seperti infliximab. Rute awal terinfeksi invasif aspergillosis adalah
dengan menghirup Aspergillus konidia dan organ yang paling sering terkena adalah sinus, paru-
paru, dan otak. Insidensi kematian tercatat tinggi pada pasien yang menerima HSCT
dibandingkan dengan pasien menerima transplantasi organ padat (68% vs 41%, P <0,0001),
pasien dengan penyakit sistem saraf pusat (88% vs 53%, P = 0,0005) dan non-neutropenia
dibandingkan dengan pasien neutropenia (89% vs 60%, P < 0,05).

Jamur Lainnya
Zygomycetes yang termasuk dalam genus Mucorales merupakan jamur yang memiliki hifa dan
umumnya tidak bersepta. Genus lainnya yang dapat menyebabkan penyakit invasif adalah
Rhizopus, Rhizomucor, Absidia dan Cunninghamella. Infeksi karena Zygomycetes klasik ditandai
dengan invasi vaskular yang dapat menyebabkan trombosis dan jaringan nekrosis. Zygomycetes
sensitif terhadap amfoterisin B tetapi umumnya tahan terhadap sebagian triazoles dan
echinocandins. Penelitian pada pasien yang mendapat pengobatan vorikonazol atau caspofungin
sebagai profilaksis menunjukkan bahwa antijamur ini kurang memiliki aktivitas terhadap
zygomycetes, sedangkan penggunaan vorikonazol dan posaconazole telah dilaporkan sebagai
pengobatan yang efektif untuk fusariosis.

Spektrum Klinis Penyakit
Infeksi Candida albicans dapat berupa salah satu dari empat bentuk: kandidiasis
pseudomembran, kandidiasis hiperplastik, kandidiasis eritematosus, dan angular cheilitis. Pasien
dapat menunjukkan satu atau kombinasi dari bentuk infeksi. Angular cheilitis misalnya sering
terlihat dalam kombinasi dengan kandidiasis eritematosus dalam pemakai gigi palsu. (Tabel 3).

Klasifikasi Klinis
Angular Chelitis
Atrofi Kronik (Eritematosus)
Denture Stomatitis
Sindrom Kandidiasis-Endokrin
Hiperplastik (Leukoplakia Kandidiasis)
Hiperplasia Papilar Inflamatori
Glositis Rhomboid Median
Mukokutaneus
Pseudomembranosus

Tabel 3: Klasifikasi Klinis

Kandidiasis Pseudomembran
Kandidiasis pseudomembran umumnya dikenal sebagai "thrush" dan sering terdapat pada
neonatus. Hal ini juga dapat terlihat pada pasien yang menerima terapi kortikosteroid topikal atau
pada pasien dalam pengobatan yang menekan sistem kekebalan tubuh. Terdapatnya infeksi
kandidiasis pseudomembran pada orang yang sehat mungkin merupakan indikasi dari penyakit
sistemik seperti infeksi HIV. Kandidiasis pseudomembran dapat terlihat sebagai plak putih yang
menyerupai keju yang dapat dengan mudah dihilangkan. Plak ini terdiri dari hifa-hifa yang tidak
beraturan dan terdapat pada mukosa dengan dasar eritema. Gejala biasanya ringan seperti
mengeluh kesemutan ringan atau rasa kotor didaerah mulut. Untuk mengidentifikasi pseudohifa
jamur dapat menggunakan sitologi eksfoliatif, asam Schiff atau Papanicolaou yang merupakan
standar optimal untuk diagnosis semua jenis kandidiasis, dimana hasil tertinggi sitologi positif
adalah pseudomembran candidiasis.


Kandidiasis Atrofi
Kandidiasis atrofi terlihat dalam bentuk eritema difus dan sering terdapat pada mukosa yang
kering seperti pada pengguna gigi palsu parsial atau pasien ortodentik. Sekitar 26% pasien
dengan gigi palsu lengkap telah mengalami kandidiasis atrofi.

Kandidiasis hiperplastik
Bentuk ini disebut sebagai "kandida leukoplakia," meskipun sekarang terminologi ini mungkin
harus dihindari. Seperti leukoplakia, kandidiasis hiperplastik berbentuk plak putih yang tidak
dapat dibersihkan oleh dokter sekalipun dan lesi ini harus diobati dengan terapi antijamur yang
rutin.

Kandidiasis Eritematosus
Lesi klinis tampak merah atau eritematosa dan sering terjadi pada lidah dan palatum. Kandidiasis
eritematosa juga dapat terlihat di tempat sekitar gigi tiruan yang lepas pasang.

Angular cheilitis
Lesi klinis angular cheilitis terlihat seperti retakan, terkelupas, ataupun ulserasi di bagian sudut
mulut. Bentuk ini dapat terlihat juga dalam kombinasi dengan jenis kandidiasis lainnya seperti
kandidiasis eritematosus. Beberapa obat over-the-counter (OTC) termasuk miconazole nitrat,
clotrimazole krim, nistatin atau krim ketokonazol topikal dapat mengobati angular cheilitis.
Topikal krim mikonazol nitrat 2% sudah terbukti efektif terhadap Candida dan Staphyolococcus
aureus. Dokter gigi harus berhati-hati jika merekomendasikan OTC topikal antijamur kepada
pasien yang menggunakan warfarin antikoagulan. Hal ini dapat meningkatkan risiko koagulasi
berlebihan berkepanjangan, karena gangguan pada enzim hati yang membantu dalam
metabolisme warfarin. Angular cheilitis didiagnosis berdasarkan adanya asimtomatik uni-atau
bilateral ataupun tedapat nyeri pada lesi seperti retakan atau fisura di sudut mulut. Angular
cheilitis dapat disebabkan oleh candidiasis (20%), campuran candidiasis dan infeksi bakteri
(60%), atau bakteri saja (20%).



Pengobatan
Untuk pasien normal dan sehat, pengobatan kandidiasis oral relatif sederhana dan efektif.
Biasanya dapat digunakan obat topikal ataupun nistatin oral. Namun, obat topikal harus langsung
berkontak dengan organisme untuk dapat menghilangkannya.

Kandidiasis Intraoral
Obat topikal seperti suspensi nistatin dan clotrimazole troches dapat digunakan untuk mengobati
kandidiasis intraoral dengan cara perlahan-lahan dalam mulut lima kali sehari selama 14 hari.
Pasien tidak diperbolehkan makan atau minum selama 20 menit setelah menggunakan
clotrimazole troches. Obat antifungi sistemik lain juga dapat digunakan seperti ketoconazole,
fluconazole, dan itraconazole.

Peralatan Prostodontik
Pasien yang menggunakan alat removable untuk prostodontik harus menggunakan alat yang
steril karena permukaan dari bahannya memiliki pori atau biofilm yang dapat berfungsi sebagai
reservoir mikroorganisme jamur dan berkontribusi untuk menyababkan kekambuhan atau
reinfeksi. Desinfeksi peralatan gigi harus melalui dua proses. Pertama, alat harus bebas dari
kotoran. Peralatan rumah tangga seperti pemutih klorin meskipun efektif dan murah, dapat
menyebabkan kerusakan pada gigi dan jaringan. Untuk menghindari kerusakan dapat digunakan
bahan pembasmi kuman yaitu zat yang mengandung natrium benzoat, sitrat, dan disodium fosfat
dengan cara direndam selama enam jam. Cara ini dapat digunakan kembali satu minggu
kemudian dan tidak berbahaya jika tertelan. Teknik lainnya adalah menggunakan iradiasi
microwave selama lima menit.

Xerostomia
Pasien xerostomia memerlukan terapi pemeliharaan dua kali sehari menggunakan obat kumur
klorheksidin glukonat 0,12% pasca episode akut atau kronis kandidiasis oral.

Perkembangan terbaru
Selama bertahun-tahun, amfoterisin B deoxycholate tetap menjadi pengobatan utama IFI.
Keterbatasan utama penggunaannya adalah efek samping yang substansial seperti demam,
menggigil, mual dan muntah, kelainan elektrolit dan nefrotoksisitas. Pada tahun 1990-an,
pengenalan terhadap dua azoles yaitu flukonazol dan itrakonazol mewakili kemajuan yang cukup
besar di pengobatan antijamur. Namun, penggunaan flukonazol terhambat karena spektrumnya
sempit dan penggunaan itrakonazol terbatas karena dapat menyebabkan gangguan penyerapan.
Pengobatan terbaru kini telah dikembangkan dan memberikan efek yang lebih baik sebagai
antijamur dan dapat menurunkan toksisitas (Tabel 2, 4 dan 5).

Obat Antifungi Topikal
Bentuk Sediaan dan Dosis Indikasi
OTC
Krim mikonazol 2% Angular cheilitis
Krim clotrimazol 1% Angular cheilitis
Prescription
Krim ketokonazol 2% Angular cheilitis
Salep nistatin 100.000 unit/gram Angular cheilitis
Bedak topikal nistatin 100.000 unit/gram Denture stomatitis
Suspensi oral nistatin 100.000 unit/gram Kandidiasis intraoral
Betamethasone dipropionate clotrimazole Angular cheilitis kronik
Clotrimazole troches 10 mg Kandidiasis intraoral
Amfoterisin B 100 mg/ml Kandidiasis intraoral

Tabel 2: Obat Antifungi Topikal







Tabel 4: Obat Antifungi Sistemik

Obat Antifungi Sistemik
Bentuk Sediaan dan Dosis Indikasi
Ketokonazol tab 200 mg Kandidiasis intraoral
Flukonazol tab 100 mg Kandidiasis intraoral
Itrakonazol tab 100 mg Kandidiasis intraoral
Nama Generik Nama Dagang Formula
Amfoterisin B Fungizone Suspensi oral 100 mg/ml
Clotrimazole Mycelex Troche 10 mg
Flukonzole Diflucan Tab 100 mg
Suspensi oral 10 mg
Suspensi oral 40 mg
Itraconazole Sporanox Kapsul 100 mg
Suspensi oral 10 mg
Ketoconazole Nizoral Tab 200 mg
Nistatin Mikostatin Suspensi oral 100.000 unit/ml
Pastille 200.000 unit/ml
Tab 500.000 unit/ml
Tablet vagina 100.000 unit/ml

Tabel 5: Obat Antifungi untuk Kandidiasis Oral

Triazole sebagai Spektrum Luas
Generasi kedua triazoles bekerja dengan cara menghambat sitokrom P450 (CYP450) yang
mengubah lanosterol ke ergosterol. Hal ini menyebabkan akumulasi toksik 14methylsterols dan
penipisan membran. Perubahan sifat membran sel menyebabkan terhambatnya pertumbuhan sel
atau kematian sel. Antijamur yang termasuk kedalam golongan ini adalah vorikonazol yang
tersedia dalam bentuk intravena dan bentuk oral. Bioavailabilitas bentuk oral > 90% tetapi dapat
menurun menjadi 80% bila dikonsumsi bersama makanan berlemak. Pemberian secara intravena
dan dalam bentuk oral diberikan dengan dosis dua kali sehari. Loading dose diperlukan untuk
mencapai steady-state dengan konsentrasi cepat (6 mg / kg dua kali sehari pada hari 1 diikuti
oleh 4 mg / kg dua kali sehari). Posaconazole hanya tersedia dalam bentuk oral (400-800 mg /
hari dalam dosis terbagi). Penggunaan posaconazole dengan makanan dapat meningkatkan
bioavailabilitas. Posaconazole diekskresikan terutama di feses dan sebagian kecil dimetabolisme
di hati. Vorikonazol dan posaconazole adalah antijamur spektrum luas. Seperti azoles lain,
keduanya berfungsi sebagai fungistatik terhadap sebagian besar ragi tetapi memiliki efek
fungisida terhadap filamen jamur. Vorikonazol dan posaconazole sangat efektif terhadap
sebagian Candida spp., termasuk C. krusei, C. glabrata dan strain yang resisten terhadap
fluconazole. Untuk Aspergillus spp., vorikonazol dan posaconazole sangat bermanfaat dalam
menghambat banyak spesies, termasuk A. terreus, yang resisten terhadap amfoterisin B, dan A.
fumigatus, yang resisten terhadap itraconazole.

Echinocandins
Echinocandins adalah molekul lipopeptida besar yang dapat menghambat sintesis -1, 3-d-glucan,
yang merupakan komponen penting dari sel dinding jamur sehingga dapat menyebabkan
ketidakstabilan osmotik dan kematian sel jamur. Sampai saat ini, caspofungin, micafungin dan
anidulafungin adalah satu-satunya echinocandin yang disetujui penggunaannya dalam klinis.
Semua penggunaan echinocandin adalah secara intravena. Loading dose yang dianjurkan untuk
caspofungin adalah 75 mg pada hari pertama diikuti oleh 50 mg / hari dan anidulafungin adalah
200 mg pada hari pertama diikuti oleh 100 mg / hari, sedangkan untuk micafungin adalah 50-150
mg / hari. Caspofungin dan micafungin terdegradasi terutama di liver sementara anidulafungin
mengalami degradasi kimia di darah. MIC echinocandins sangat rendah terhadap Candida spp.,
Termasuk C. albicans, C. tropicalis, C. glabrata, C. krusei, C. lusitaniae dan Candida
dubliniensis.

Alasan Penggunaan Kombinasi Antijamur
Amfoterisin B adalah obat pertama yang berhasil mengobati mikosis invasif, tetapi dapat
menyebabkan reaksi toksik sistemik. Beberapa percobaan telah menunjukkan jika amfoterisin B
dikombinasikan dengan flusitosin, dosisnya dapat dikurangi sehingga mengurangi efek
toksisitasnya. Saat ini, kita dihadapkan dengan meningkatnya insiden serius dari jamur invasif
dan tingkat kematian yang tinggi akibat infeksi ini.