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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