Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases
Society of America
Peter G. Pappas,1 Carol A. Kauffman,Clinical Infectious Diseases 2009; 48:503–35
Oropharyngeal Candidiasis: Etiology, Epidemiology, Clinical Manifestations, Diagnosis, and Treatment
Crest Oral-B at dentalcare.com Continuing Education Course, February 3, 2011
INTRODUCTION Synonyms- candidosis, moniliasis, thrush
Kolnick (1980) stated that it is a dimorphic yeastlike fungus candida
albicans commonly occuring in oral cavity.
Bredicevsky et al (1984) reported from a study of 140 healthy children
that 45% of 3- 5.5 yrs age and 65% of 6- 12 yrs of age were candida
carriers.
In earlier study 52% of normal adults were carriers.
This review provides a comprehensive overview of the etiology, clinical
presentations, diagnosis, and management strategies of oral candidosis
commonly encountered in dental practice.
Wood & Goaz 3rd Edi
Etiology
More than 95% of Candida associated infections are ‐
caused by five major species: C. albicans, Candida
glabrata, Candida parapsilosis, Candida tropicalis etc
Candida parapsilosis occurs with high frequency in
premature neonates and in patients with vascular
catheters.
Candida glabrata infections are common in the elderly.
Candida tropicalis plays an important role as a cause of
invasive diseases in patients with haematological
malignancy.
Marr K, Seidel K, White T, Bowden R. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Inf Dis2000;181:309–16.
PATHOGENESIS some changes must takes place in the local environment to produce conditions
favourable to its relative overgrowth and tissue invasion. Following changes have
been identified-
A proportional change in compititive flora will predispose a person to candidiasis.
A drastic reduction in the resistence of the tissues also favors the infection.
In recent years, the number of immunocompromised individuals increased due
to various factors including increasing incidence like Diabetes, Prolonged average
life expectancies, Broadspectrum antibiotics, Immuno suppressive agents,
Invasive surgical procedures such as solid organ or bone marrow transplantation,
HIV infection etc
B.G. Tarcın, Oral Candidosis: Aetiology, Clinical Manifestations,Diagnosis and Management, J Mar Uni I of H Sci Vol: 1,2, 2011;141-150
PREDISPOSING FACTORS
SYSTEMIC FACTORS LOCAL FACTORS
Physiological factors Infancy, old age Endocrine disorders Diabetes mellitus, hypothyroidism Nutritional factors Iron, folic acid, vitamin B12 deficiency Blood dyscrasias and malignancies Acute leukemia, agranulocytosis Immune defects,
immunosuppression AIDS, thymic aplasia
Xerostomia Sjogren’s syndrome,
radiotherapy, medications Medications Broad spectrum antibiotics,
corticosteroids High-carbohydrate diet Dentures Smoking
B.G. Tarcın, Oral Candidosis: Aetiology, Clinical Manifestations,Diagnosis and Management, J Mar Uni I of H Sci Vol: 1,2, 2011;141-150
Xerostomia:
Saliva contains IgA which inhibits binding of Candida albicans to mucosal surfaces.
It also provides a flushing action which removes Candida albicans from oral cavity.
In case of xerostomia both these actions are absent because of lack of saliva
production, so chances of candidiasis is more in oral cavity.
Xerostomia is also seen in case of anticancer treatment and irradiation which
increases the proliferation of candidal cells and resistance of Candida cells to
antifungal drugs.
Xerostomia is also seen in case of Sjogren’s syndrome because of lymphocytic
infiltration and destruction of salivary glands.
Diabetes Mellitus:
Growth of Candida albicans thrives on increased levels of glucose in saliva which
increases the ability of Candida albicans to adhere to oral mucous membranes.
Medicines:
Prolonged use of antibiotics depletes normal oral flora and enables proliferation
of Candida albicans in the oral cavity. In asthmatic patients due to use of steroid
inhalers. Steroid aerosols interfere with the normal balance of microflora and
favor the proliferation of candida albicans. Whereas systemic steroids cause
suppression of the immune system.
ACCORDING TO WOOD & GOAZ 3RD EDI.
3 Basic Types- 1. pseudomembranous 2. chronic hyperplastic 3. atrophic red lesions
PRIMARY Acute formsPseudomembranousErythematous Chronic formsPseudomembranousErythematousHyperplastic (nodular or plaque-like) Candida-associated lesionsDenture stomatitisMedian rhomboid glossitisAngular cheilitis Keratinized primary lesions superinfected with
CandidaLeukoplakiaLichen planusLupus erythematosus SECONDARYOral manifestations of systemic dsPseudomembranous mucocutaneous candidosis
Type Site C / f Image Pseudo membranous ("thrush")
Buccal mucosa, tongue, palate, uvula
White thick plaques that, when removed, leave an erythematous bleeding surface Varies according to the extent and severity but includes burning, pain, and taste changes
Erythematous or atrophic
Palate, tongue Diffuse erythema Soreness
Angular cheilitis
Angles of mouth Cracking and inflammation of the corner of the mouth Pain, soreness, and/or burning
Chronic hyperplastic candidiasis / candidal leukoplakia
Lip commisures, cheeks, palate, and tongue, skin, nails
chronic form of oralCandidiasis, firm white Nonscrappable leathery plaque
Type Site C/F Image
Median Rhomboid Glossitis (hyperplastic)
located in the central area of the dorsum ofthe tongue
Erythematous patches ofatrophic papillae, chronic atrophic candidiasis, nodular,
Chronic Multifocal Candidiasis
Dorsum of tongue & midline of the hard palate (kissing lesions),
multiple areas of chronic atrophic wartlike growths. Asso with dentures, ortho appliances etc
Immunocompromised (HIV)- associated Candidiasis
Gingiva, dorsum of tongue
Asso with ANUG
Associated syndromes
Candidiasis is also a common manifestation of a variety of other
immunodeficiencies, including
Severe combined immunodeficiency syndrome,
DiGeorge syndrome,
Hereditary myeloperoxidase deficiency
Chediak-Higashi syndrome.
Farah CS, Ashman RB, Challacombe SJ. Oral candidosis. Clin Dermatol. 2000;18: 553-562.
D/D C/F Candidiasis
Chemical burn h/o medicament application, non scrappable
scrappable
Superficial bacterial infection h/o other ds, medication, bacterial colonies
Fungal colonies
Traumatic ulcer h/o trauma No
Necrotic ulcer of systemic diseases
Associated with Systemic ds like leukemia, sickle cell anemia,
uremia.
Sec- inf to systemic ds
Mucous patch of syphillis Descrete, small, white necrotic lesion
Diffuse
Gangrenous stomatitis Flat, Green slough, noma, foul odour, painful
Raised, white
Differential Diagnosis By Wood & Goaz 3rd Edi
Lab diagnosis
Samples Whitish patches from mucous membrane of
mouth Sputum
Samples•Whitish patches from mucous membrane of mouth•Sputum
Method of collection•Sterile swabs
Direct examination (Microscopy)
A smear taken from the lesion is fixed on to microscope slides and then stained either by the gram stain or by the periodic acid Schiff (PAS) technique. Using these methods, candidal hyphae and yeasts appear either dark blue(Gram-stain) or red/purple (PAS)
Germ tube test (Reynold’s-Braude Phenomenon)•Culture of candida treated with sheep/normal human serum is incubated at 37 C for 2-4 hours•No constriction seen at the point of attachment to the yeast cell•Appear in 2 hours for C.albicans
Chlamydospore formation•Suspected strain of Candida isolates gron on CMA or rice starch agar and incubated at 25 C•Formation of large, highly refractile, thick walled, terminal chlamydospores in 2-3 days of incubation
Fungal culture•Sabouraud Dextrose Agar + Antibiotics ( Cream, Pasty, Smooth colonies in 3-4 days of incubation at 37 C)•Cornmeal Agar (Characteristic terminal chlamydospores, yeast cells and pseudohyphae in clusters at 25 C)•CHROM agar (light green to bluish green colonies)
Biochemical tests•Sugar assimilation and fermentation tests are used for identification of species.•C. albicans ferment Glucose and Maltose with acid and gas production, but not sucrose and lactose.•Pale pink coloration in Tetrazolium reduction medium
Sabourauds dextrose agar Swabs streaked onto Sabourauds dextrose agar. Incubated at 37 degree Celcius for 3 days. Creamy moist colonies Microscopically : Yeast cells, Pseudohyphae and
Blastoconidia Sputum cultures have NO VALUE. ALL depends on the OVERGROWTH OF Candida yeast.
Typing of Candida strains•Serotyping•Isoenzyme profiling•Morphotyping•Resistence patternImmunodiagnosis•PCR based tests for candida-DNA detection•Detection of Candida albicans- derived molecules•ELISA, RIA, CIE, PHA and LPA
Detection of metabolites•Detection of D-mannose and D-arabinitol in sera by gas liquid chromatography•G-test for detection of glucan
Skin tests•It is not useful for diagnosis but is used to evaluate cell mediated immunity.
Animal Pathogenicity•Tests on rabbits and mice for susceptibility to different candidia species
Clinical microbiology, 2nd edition, B.S.Nagoba, Asha Pichare
TREATMENT
Treatment Topical therapy used for milder forms.
Extensive disease in patients with immunosuppression (most notably,
disease in HIV/AIDS patients), and disease in which there are symptoms
that suggest esophageal involvement (e.g., pain on swallowing) are best
treated with systemic therapy.
Prolonged suppressive therapy may be required if the immunosuppressive
condition does not remit.
Antifungal Chemotherapy: Mild Nystatin Oral Suspension
Nystatin is a polyene antifungal agent. It binds to ergosterol
in fungal plasma membrane and through pore-forming
mechanisms increase membrane permeability, effects
leakage of essential cellular components, and promotes cell
death.
To reduce the risk of relapse, treatment should be continued for
at least 48 hours after the elimination of all signs and
symptoms associated with the infection. The oral suspension
may also be used as holding solution for prostheses when they
are removed from the oral cavity.
Common adverse effects of nystatin include contact mucositis
and Stevens-Johnson syndrome.
Clotrimazole Troches
Clotrimazole is an azole antifungal agent. It blocks 14α-sterol
demethylase, a fungus specific cytochrome enzyme that
initiates the conversion of lanosterol to ergosterol. This leads
to structural and functional plasma membrane damage and
cell death.
Clotrimazole troches may be effective in the treatment of mild
oropharyngeal candidiasis refractory to nystatin. However,
since clotrimazole troches contain sucrose, their long-term
use may be a problem in caries-prone patients. Common
adverse effects include pruritus and a burning sensation.
Moderate to Severe Infections Fluconazole
Fluconazole is an azole antifungal agent.
It blocks 14α-sterol demethylase (the enzyme responsible for the
demethylation of lanosterol to egrosterol); and promotes structural
and functional plasma membrane damage, and cell death.
Its clinical activity is well established against most candida
species.
Following oral administration fluconazole is well absorbed (100%
bioavailability) and diffuses freely into saliva.
Common adverse effects- nausea, vomiting, diarrhea, abdominal
pain.
Hepatotoxicity is a rare serious adverse effect.
Amphotericin B
It is a polyene obtained from Strptomyces nodosus. It is active against a wide range of yeast and fungi. Dose orally 50- 100 mg qid Fungizone , candid B Adverse effects- High toxicity, chills, fever,nausea,
vomiting, dyspnoea
Itraconazole, Posaconazole, and
Voriconazole These azole antifungal agents have a broader spectrum of
activity than fluconazole.
Fluconazole- refractory infections should be treated
initially with itraconazole solution or posaconazole
suspension.
Voriconazole is recommended when treatment with other
azole antifungal agents has failed.
Caspofungin, Micafungin, and Anidulafungin
Are echinocandins.
They inhibit the synthesis of β (1, 3)-D-glucan, an essential
component of the fungal cell wall. The echinocandins are active
against most Candida spp., including those resistant to the azoles.
Bioavailability- 100%
Intravenous only
Doses- caspofungin- CANCIDAS, starting dose of 70mg then
50mg/day
Micafungin- , MICAMINE, 150mg od, prophylaxis 50mg/d
Anidulafungin- ERAXIS- 100mg single loading dose on day 1 then
50mg/day for 14 days
Adverse effects- impaire lever function, sensitivity reaction,
nausea, vomitting, headache, dyspnea, anemia
Very expensive
Topical antifungal medications Brand name Indication
Miconazole cream 2% Angular cheilitis
Clotrimazole cream 1% Angular cheilitis
Ketoconazole cream 2% Angular cheilitis
Nystatin ointment 100,000 units/gram Mycostatin Angular cheilitis
Nystatin topical powder 100,000 units/gram Mycostatin Denture stomatitis
Nystatin oral suspension 100,000 units/gram Mycostatin Intraoral candidiasisBetamethasone dipropionate clotrimazole cream
Choloronic Angular cheilitis
Clotrimazole troches 10 mg Mycelex Intraoral candidiasis
Amphotericin B 100 mg/ml Fungizone Intraoral candidiasis
Drug Dosage Brand name
Ketoconazole tablet 200 mg Nizoral,
Fluconazole tablet 100 mg Diflucan
Itraconazole tablet 100 mg Sporanox
caspofungin: 70 mg, then 50 mg
Cancidas (MSD)Casfung (Glenmark)Caspogin (Cipla)Casporan (Ranbaxy)
micafungin: 100 mg Micamine (Astellas )
anidulafungin: 200 mg Eraxis (MERK, pfizer)
Treatment Guidelines for Candidiasis • CID 2009:48
Prevention
Appropriate medical treatment of the many predisposing systemic
factors and local measures such as meticulous oral hygiene,
management of xerostomia, and the maintenance of optimally
functioning and clean prostheses may prevent or minimize the
incidence of clinical oropharyngeal candidiasis.
These measures should include proper brushing of all oral tissues and
all surfaces of prostheses, removing prostheses at regular intervals
to allow for normal circulation in the supporting tissues, and periodic
evaluation of prostheses for proper tissue adaption.
Chlorhexidine (CHX) mouthwash can
help to prevent oral candidiasis in people
undergoing CANCER TREATMENT.
ASTHMATIC patients could REDUCE the
risk of oral thrush by washing mouth
with WATER after using INHALER.
Review of the literature
Shown in his study that 0.2% chlorhexidine gluconate mouth rinses have clinical
benefit in the treatment of oral candidiasis. However, there are reports of reduced
efficacy of Nystatin when used in combination with chlorhexidine gluconate, and
therefore it is often advised to delay Nystatin treatment for 30 min after the use
of chlorhexidine mouthwash
Once-daily regimen of Fluconazole may be an excellent systemic therapeutic
choice with few side effects and drug interactions.
Topical antifungal therapy may be continued as it reduces the dose and duration
of the systemic treatment required.
B.G. Tarcın, Oral Candidosis: Aetiology, Clinical Manifestations,
Diagnosis and Management, J Mar Uni I of H Sci Vol: 1,2, 2011;141-150
Joel B. Epstein, Sol Silverman, Jacob Fleischmann, Oral Fungal Infections, 170- 179
Erythematous candidiasis controlled after A 1-week course of fluconazole (100 mg/D).
Acutely painful pseudomembranous candidiasis of the palate. B, signs and symptoms were controlled after 200 mg ketoconazole Daily for 3 days.
Painful candidiasis of tongue present for 3 weeks treated with clotrimazole (100 mg troches) dissolved Orally twice daily for 1 week controlled the signs and symptoms.
Hyperplastic candidiasis, was completely reversed with 400 mg ketoconazole daily for 1 week in a patient with xerostomia caused by head and neck radiation therapy. Because of constant recurrences, the patient was maintained and controlled using nystatin troches (100,000 U) dissolved orally up to 3 times a day.before and after 3 days of treatment
Jon A. Sangeorzan, Epidemiology of Oral Candidiasis in HIV-Infected Pati ents: Colonizati on, Infecti on, Treatment, and Emergence of Fluconazole Resistance, 1994, The American
Journal of Medicine, Vol 97, 339- 46
conducted a prospective observational study of 92 patients over 1 year,
including a nonblinded, randomized treatment trial of thrush with
clotrimazole troches or oral fluconazole.
Clinical cure rates were similar with fluconazole (96%) and clotrimazole
(91%), but mycologic cure was better with fluconazole (49%) than
clotrimazole (27%).
Drug Dosage
Nystatin Pastilles or lozenges: 200,000U qid x 7-14 daysSuspension: 500,000 Units by swish & swallow qid x 7-14 days
Clotrimazole Suck on 1 troche 5x day x 7-14 days
Fluconazole 100 mg/d x 7-14 days 200mg for immunosuppressed patients and/or severe OPC
Itraconazole Suspension: 200 mg (20 ml) qid by swish & swallow without food x 7-14 daysCapsules: 200 mg/day (taken with food) x 2-4 weeks
Ketoconazole 200- 400 mg/day x 7-14 days
Capsofungin 70mg loading dose followed by 50mg/day
Amphotericin B 30-40mg/day for pts without neutropenia 40-50 mg/day for pts with neutropenia.
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