1. MUCOCUTANEOUS CANDIDIASIS
Dr. Riina Rautemaa-Richardson
Infectious Diseases Consultant
Wythenshawe Hospital, Manchester University NHS FT

2. Intended Learning objectives
To understand the morphology, pathogenesis and spread of Candida species.
To identify the various clinical syndromes caused by Candida species.
To know the different presentations of oropharyngeal candidiasis.
To know how to diagnose oropharyngeal candidiasis.
To be aware of the various options of treatment.

3. Introduction
Over 20 species of Candida yeasts can cause infection in humans.
Divided into Candida albicans and Non-Candida albicans species (NAC).
Normal resident yeasts on skin, mucous membranes, GI tract without symptoms.
30-50% of healthy individual have Candida in mouth & GI tract.
The fungal infection caused by Candida can be called ‘candidiasis’ or ‘candidosis’.

4. Candida species
Candida albicans Most prevalent and pathogenic of all the Candida species.
Non Candida albicans (NAC)
C. glabrata - commonest
C. parapsilosis
C. tropicalis
C. krusei
Rarer species
C. orthopsilosis (parapsilosis complex)
C. guilliermondii
C. rugosa.
C. lusitaniae
C. kefyr
C. zeylanoides
C. dubliniensis (albicans complex)
The photo shows C. albicans on cornmeal agar, which is the best medium for conventional identification of different species.

5. morphology Pinched cells that fail to separate.
Source: Delma et al . Eukaryot Cell. 2011; 10(9): 1173–1182
Coevolution of Morphology and Virulence in Candida Species
Pinched cells that fail to separate.

6. Morphological evolution
Ability to change morphological forms confers increased virulence
Delma et al . Eukaryot Cell Sep; 10(9): 1173–1182
Coevolution of Morphology and Virulence in
Candida Species
Delma et al. Eukaryot Cell. 2011;10(9): 1173–1182

7. Characteristics of Candida species
Dimorphic (ability to exist as hyphae or yeast cells)
Versatile and adaptable to different anatomical sites.
Commonly found as commensals on skin, GIT & vagina.
Individuals often colonized by 1 strain in different anatomical sites.
Ability to cause disease due to weakened host immune system and virulence factors.
Immunity is site-specific.

8. Transmission Endogenous. Exogenous
Overgrowth of commensal yeasts and translocation through the gut wall into the bloodstream.
Persistent Candida species carriage in the oral cavity is common with higher colonization rate in young children and denture wearers.
Exogenous
Hands of health care workers
Vaginal canal during birth
Devices e.g. urinary catheters & IV cannula

9. Pathogenesis
Overgrowth of commensal yeasts which adhere to various medical devices surfaces or host tissues & have ability to evade host defences
Majority of infections are associated with biofilm growth which can be drug resistant.
Morphological transformation of C. albicans species
Production of hydrolytic and phospholipase enzymes that damage tissues
Host factors that impair immunity or critically ill patients

10. Virulence factors Adherence to host tissue and medical devices.
Biofilm formation
Hydrolytic enzymes.

11. Colonisation or infection?
Fungal load?
Formation of hyphae?
Presence of biofilms?
Invasion?
Elicitation of immune responses?
Tissue damage?

12. What is a biofilm?
Highly structured communities of microorganisms that are surface- associated or attached to each other.
They have a protective extracellular matrix that encloses them which is self produced.
Over 80% microorganisms exist in biofilms and majority of human infections involve a biofilm.
source: Eukaryotic Cell April 2005 vol. 4 no

13. Changing Epidemiology
Increase in prevalence of candidiasis.
Likely relationship with increased use of medical devices.
Increase infections due to Non-Candida albicans (NAC) species.
Increase in antifungal resistant yeasts.
Geographical variations in infections due to NAC species.

14. Clinical syndromes Candida vulvo-vaginitis.
Hypersensitivity
Candida vulvo-vaginitis.
Candida perianal dermatitis.
Candida balanitis.
Skin and nail infections.
Oral candidiasis.
Sepsis and disseminated disease.
Immune-suppression

15. Oropharyngeal candidiasis

16. Etiology of oral candidiasis
Candida albicans - most prevalent.
Rare causes
C. glabrata (increases with increasing age)
C. krusei
C. tropicalis

17. Risk factors (1) Impaired systemic defense mechanism: Infancy Diabetes
Malnutrition
Immunosuppression:
Primary.
Acquired.eg medications, cancer, HIV
Impaired local defense:
Decreased saliva production.
Topical corticosteroids including inhalers.
Radiotherapy to head and neck

18. Risk factors (2) Altered normal flora: Antibiotics Reflux Diabetes
Infancy
High carbohydrate diet
Poor oral hygiene:
Mixed oral biofilm on non-renewing surfaces like endotracheal tubes (ETT), nasogastric tubes (NGT)

19. Significance of oral candidiasis
Potential for systemic invasion.
Can facilitate mucosal invasion by other microbes including S. aureus.
Symptom causation - nutrition, impaired speech.
Development of resistance, especially associated with biofilm formation.

20. Clinical presentation

21. Clinical forms THREE distinct clinical forms:
Pseudomembranous candidiasis (thrush)
Erythematous candidiasis (atrophic)
Hyperplastic candidiasis (Candida leukoplakia)
Denture stomatitis?

22. Pseudomembranous candidiasis
Most common form.
White raised lesions on tongue, mucosa, palate, tonsils.
May become confluent plaques.
Painless.
Can be dislodged or
Scraped off to reveal
Bleeding base.
Source: slide share

23. Thrush

25. Erythematous candidiasis (1)
Often associated with broad spectrum antibiotics, steroids and HIV infection.
Flat red lesion usually on tongue or palate.
Painful with difficulty feeding especially swallowing solids.
Pain maybe worsened by hot or cold liquids.

26. Erythematous candidiasis (2)
Almost symmetric, asymptomatic red lesion involving the midline of the posterior dorsal tongue.
Palatal erythematous candidiasis

27. Hyperplastic candidiasis
Often on the buccal mucosa. Rarely on tongue
Often asymptomatic and associated with smoking or local trauma
Can undergo malignant transformation
Possibility of hyperplastic lesion with C. albicans superinfection

28. Angular cheilitis
Usually develops in association with other forms of oral candidiasis.
Scaling, erythematous fissures at the corners of the mouth associated with infection by Candida albicans
Source of picture 1:
Wanda et al. Common Oral Lesions: Part I. Superficial Mucosal Lesions
Am Fam Physician. 2007;75(4):

29. Differential Diagnoses
Contact dermatitis to oral hygiene product.
All-cause cheilitis
Herpes labialis
Lichen planus

30. Herpes infections Herpes labialis Herpes simplex
Source: DermNet New Zealand.
Source: Ruderfer D. Herpes Simplex 1& 2 paediatrics in Review 2015; 36 (2) :

31. Apthous ulcers

32. Lichen planus
Source: DermNet New Zealand.

33. DIAGNOSIS

34. Diagnosis Clinical - mainly Microbiological. White plaques
Localized erythema & inflammation
Essential to rule out other causes of similar presentation
Microbiological.

35. Microbiologic Diagnosis
Microscopy after staining.
Fungal culture to identify yeast species and conduct drug susceptibility tests.
Quantity of yeast helps differentiate colonizer from pathogen though not very precise

36. Microscopy: Direct smear examination
Scrape the material with a spatula.
Spread on glass slide then air dry.
Fix with alcohol
Stain with periodic Acid Schiff reagent (PAS) or potassium hydroxide (KOH) 10%.
Examine under a microscope

37. Direct smear exam Staining with KOH PAS staining
Source : Slideshare.net &
PAS staining

38. Culture
Specimen collection: - oral swab. - imprint culture. - oral rinse - Direct sonication of foreign body e.g. ETT, nasogastric tube etc. Culture media - Sabouraud dextrose agar (SDA)
University of Adelaide mycology online

39. Biopsy Especially for diagnosis of hyperplastic candidiasis.
Mainly to rule out squamous
cell carcinoma.
Histopathological exam
shows epithelial parakeratosis with
polymorphonuclear leukocytes in the
superficial layers.
PAS-stained slides show the presence of Candida hyphae.
Candida albicans in a section of lung, confirming an invasive Candida pneumonia. Both yeasts and hyphae are visible. Candida is staining Gram positive.
Source:://

40. MANAGEMENT

41. Goals of management Address underlying condition/risk factor
Appropriate antifungal agents through the proper route
Considering alternative diagnosis
Prevention

42. Underlying conditions
Mechanical/surgical disruption of biofilm
Proper management of underlying disease or condition.
Proper glycemic control in diabetes
Improved oral self-care
Proper steroid inhaler use with mouth rinsing

43. Disrupting the biofilm
Drugs penetrate biofilm poorly
Azoles do not inhibit biofilm formation on surfaces and have no activity against preformed biofilms
Potential for selection of resistant strains
Mouth washes (especially those containing chlorhexidine) disrupt biofilm formation
Ramage G et al Commercial mouthwashes are more effective than azole antifungals against Candida albicans biofilms in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111:456-60
Ramage et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:456-60

44. Suggested management algorithm
Source:
Rautemaa & Ramage.Crit Rev Microbiol Nov;37(4):328-36

45. Antifungal Drug therapy
Topical
Systemic
Minimal absorption from GI tract.
Few drug to drug interactions
Safe in children.
High local drug levels achieved.
Examples: nystatin, buccal miconazole
Can be used in combination with topical antifungals.
Need high concentrations and adequate saliva to reach adequate local levels.
Preferred for immunocompromised due to high relapse rates with topical agents.
Oral: fluconazole, itraconazole, posaconazole.
IV: fluconazole & amphotericin B

46. Options for immunocompetent infants & neonates
Nystatin oral suspension
Dose:
1ml (100,000units/ml)
every 4 -6 hours
Oral Fluconazole
Dose: 3mg/kg daily
Miconazole gel
Apply 2-4 times daily
Spontaneous cure in neonates by 3-8 weeks has been reported

47. Options for immunocompetent older children & Adolescents
Clotrimazole troches
Dose: 1troche
(10mg)
five times daily
Nystatin
Suspension
Dose: 4-6ml (100,000units/ml)
every 6 hours
Miconazole
Buccal tablet
Dose: 50mg once daily
Fluconazole
Dose:
mg daily

48. Options for patients with immunosuppression
Fluconazole- preferred agent. Dose: mg/ day for 7-14 days Itraconazole suspension (or capsules) Dose: mg/day for 14 days. Other options for fluconazole refractory disease: oral posaconazole suspension, oral amphotericin B.

49. Response to treatment Oral symptoms resolve in 2-5 days.
Relapse is common especially for HIV infected not on ART.
Managing underlying condition is KEY.

50. Unresponsive oral candidiasis
Why?
Resistant organism.
Uncontrolled underlying condition e.g. HIV/Diabetes.
Failure to remove/eradicate biofilm.
Alternative diagnosis.
Chronic mucocutaneous candidiasis.

51. Managing resistant organisms
Increasing the dose of fluconazole to mg for adults.
Oral itraconazole or posaconazole suspension for prolonged period (up to 4 weeks)
Amphotericin B oral suspension (500mg 4x daily) may be used.
IV amphotericin B or IV caspofungin

52. Chronic mucocutaneous candidiasis (CMC)
Recurrent persistent superficial candidiasis often caused by C. albicans.
Genetic defect in STAT1 (AIRE) or CARD9 most common. They are IL17 deficient But may be sporadic and not linked to genetics
Onset in infancy for majority.
Significant morbidity.
Rarely disseminates

53. Prevention
Good oral self-care including use of chlorhexidine mouth washes when necessary.
Rinse the mouth after steroid inhaler use
HAART if HIV positive.
Smoking cessation.
Prophylactic antifungals for secondary prevention.
Avoid azoles due to resistance selection.
Pulse therapy with nystatin or amphotericin solutions.
Probiotics and alternative agents

54. END