Synonyms: candidosis

This article gives an overview of candidal infections, with detailed information on oral, oesophageal, skin and invasive candidal infections.

There are separate articles on Systemic Mycoses, Fungal Lung Infections, Fungal Nail Infections and Vaginal and Vulval Candidiasis. Illustrations of skin and mouth candidal infections are available on Dermnet NZ.¹

Candida spp. are yeast-like fungi which can form true hyphae and pseudohyphae. They may be part of the normal body flora, or may become an invasive pathogen. Candidal infection varies from a benign local mucosal membrane infection to disseminated disease; it can involve any organ. Severe disease is associated with an immunodeficiency, e.g. malignancy, HIV infection or immunosuppressive therapy.²

Epidemiology and risk factors^1,3

• Up to 60% of healthy people are asymptomatic carriers of Candida spp. (as a commensal in the gastrointestinal tract).⁴
• Candidal infection is the most common cause of invasive fungal infections in hospital patients.

Risk factors²

Risk factors for candidal infection are:

• Broad-spectrum antibiotics
• Central venous catheters or parenteral nutrition
• Immunocompromise:⁵
  • T cell disorders, which tend to cause mucocutaneous candidal infections.
  • Neutrophil disorders, which tend to cause invasive candidiasis (IC).
• Corticosteroid treatment or Cushing's disease
• Diabetes mellitus
• Renal replacement therapy
• Implanted prostheses
• Radiotherapy
• Intensive care or prolonged ventilation
• Gastrointestinal (GI) tract surgery

Other risk factors for mucocutaneous candidiasis are:

• Pregnancy or high oestrogen contraceptive pill
• Iron deficiency
• Underlying skin disease, e.g. psoriasis, dermatitis
• General debility, e.g. cancer or malnutrition
• Local factors - heat, moisture, skin maceration, topical corticosteroids
• Extremes of age

Aetiology^6,7

Superficial (mucocutaneous) infections:

• Candida albicans is the usual cause. It is commonly a commensal in the mouth and GI tract, and is often found in the vagina.
• Less common species causing superficial infection include C. glabrata, C. dubliniensis, and C. parapsilosis. There is evidence that the first two species are more common now in oral infection in patients with HIV and C. glabrata in vaginal candidosis. There has been a shift from C. albicans towards other candidal species recently.

Invasive infection:

• C. albicans is the most common cause.
• Other species may be isolated, particularly in cases of endocarditis - for example, C. parapsilosis.
• Candida tropicalis has been implicated in infections of patients with neutropenia.
• Non-albicans Candida spp. are now more frequent causes of systemic infection and are important to recognise, as their antifungal susceptibility may differ from C. albicans.
• Portals of entry include the GI tract (common), skin, and urinary tract (rare).

Oral candidiasis⁴

Types of oral candidiasis

• Pseudomembranous oral candidiasis (oral thrush):
  • Curd-like white patches in the mouth. The white pseudomembrane can be easily removed, leaving an underlying red base that is usually painless (in contrast with leucoplakia, which cannot be rubbed off).
  • Most common in neonates.
• Acute erythematous oral candidiasis (acute atrophic oral candidiasis):
  • Marked erythema and soreness, especially on the the tongue.
  • Often follows oral thrush.
  • Common after oral antibiotics.
• Chronic erythematous oral candidiasis (denture stomatitis or chronic atrophic oral candidiasis):
  • Redness of the denture-bearing area - rarely also soreness.
  • Common in denture users.
• Chronic plaque-like oral candidiasis (chronic hyperplastic oral candidiasis):
  • Persistent firm, white plaques on the cheek or tongue, that are not easily removed.
  • Most common in smokers and men >30 years.
• Median rhomboid glossitis:
  • A central, red, area of papillary atrophy of the tongue.
  • Usually in smokers or those using corticosteroid inhalers.
  • Can cause recurrent/chronic candidiasis.
• Angular cheilitis:
  • Redness, fissuring, and soreness at the angle of the mouth.
  • Can be due either to candida or to bacterial infection (mainly Staphylococcus aureus).
  • Contributing factors are older age, ill-fitting dentures, immunocompromise, vitamin B12 deficiency or anaemia.

Diagnosis of oral candidiasis

• Swabs/culture and serology are generally not useful because candidal organisms are commonly found in healthy people.
• Swabs may be relevant for suspected drug resistance, e.g. in HIV-positive patients.

Management of oral candidiasis

When to admit or refer

• Admit to hospital if there are systemic symptoms, the patient is unwell or if there are oesophageal symptoms (dysphagia or retrosternal pain) - particularly if there is immunocompromise.
• Obtain specialist advice if there is:
  • Widespread candidiasis
  • No response to treatment (below)
  • Recurrent episodes (may be immunocompromised)
  • Breakthrough candidiasis on preventative treatment (may be drug-resistant)
  • Chronic plaque-like oral candidiasis not responding to treatment (needs biopsy)
• Symptomatic oral candidal infection is rare in healthy adults⁴ - if present, consider investigating for underlying illness, e.g. immunocompromise.

Treatment - children

• Use topical treatment for ≥7 days or until 2 days after symptoms clear.
• First choice is miconazole gel, but beware drug interactions and liver dysfunction.
• Otherwise, use nystatin suspension (no significant contra-indications).
• Infants - note that miconazole gel is not licensed age <4 months, however:
  • Some doctors feel this is an unnecessary limitation (arose from concerns about choking if the gel is administered incorrectly to young babies).
  • The correct method of use is to smear 1 ml of miconazole oral gel round the mouth and gums with a finger after feeds four times a day.
• After 7 days, change to nystatin suspension if not responding to miconazole gel.

Treatment - immunocompetent adults

• Mild or localised oral candidiasis:
  • Use topical treatment for 7 days and continue until 2 days after symptoms clear.
  • Options are oral miconazole gel or nystatin suspension. Note: miconazole cautions re drug interactions and liver disease.
• Extensive or severe oral candidiasis:
  • Oral fluconazole 50 mg/day for 7 days.
• Candidiasis persisting after 7 days' treatment:
  • If not responding to miconazole, change to nystatin.
  • If taking fluconazole, continue treatment for another week.

Treatment - adults taking immunosuppressive treatment

• Obtain specialist advice if the patient is taking ciclosporin, tacrolimus or chemotherapy.
• Patients taking oral corticosteroids or disease-modifying antirheumatic drugs:
  • Mild/localised oral candidiasis - topical treatment (as above).
  • Extensive/severe oral candidiasis - fluconazole 50-100 mg/day for 7 days.
  • Follow-up after 7 days.
  • Have a low threshold for admission/specialist advice (as above); also consider if a full blood count is indicated.

Treatment - HIV-positive adults

• Have a low threshold for hospital admission (as above).
• Obtain specialist advice before treatment if:
  • Severe/extensive oral candidiasis
  • Previous fluconazole treatment was ineffective
  • Already taking antifungal prophylaxis
• Otherwise, use oral fluconazole 100 mg/day for 7-14 days, reviewing after 7 days.
• Highly active antiretroviral therapy (HAART) is also part of the treatment, and antifungal prophylaxis may help prevent recurrence.³

Prevention of oral candidiasis

• Patients taking oral/inhaled steroids - good inhaler technique, spacer device, rinse mouth with water after use.
• Denture wearers - thorough cleaning of dentures, leave them out at night, ensure they fit correctly.
• Smoking cessation.

Oesophageal candidiasis³

Presentation:

• Dysphagia, pain on on swallowing food or fluids, and/or retrosternal pain, usually with oropharyngeal candidiasis.
• This combination of symptoms is predictive of oesophageal candidiasis.
• Most often associated with treatment of haematopoietic or lymphatic malignancies.
• In HIV patients, it is an AIDS-defining illness.

Diagnosis:

• A therapeutic trial of fluconazole for patients is useful; most patients will respond within 7 days of treatment.
• Definitive diagnosis is by endoscopy.

Management of oesophageal candidiasis:

• Consider admission to hospital - oesophageal candidiasis is a life-threatening infection.^3,4
• Treat for 14-21 days; the following treatment options are suggested (USA guidelines):
  • First-line treatment options are:
    • Oral fluconazole (200-400 mg daily).
    • Intravenous (IV) fluconazole, an echinocandin, e.g. capsofungin, or amphotericin B.
  • Second-line drugs are oral itraconazole oral solution, IV posaconazole or IV voriconazole.
• For AIDS patients, HAART is advised to prevent recurrence.

Candidal vulvovaginitis

See separate article Vaginal and Vulval Candidiasis.

Candidal skin infections⁸

Presentation

• Soreness and itching.
• The appearance of the affected skin is variable; there may be:
  • Red, moist skin area with a ragged, peeling edge, and possibly pustules or papules at the margin. There may be satellite lesions (pustules or erythema) surrounding the margin.
  • Pustules which are thin-walled with a red base.
  • Yellow-white scale on the surface (looks like curds).
  • In the foot or hand web spaces - maceration (moist damaged skin) with a thick horny layer.

There are different forms of cutaneous candidiasis:¹

• Intertrigo (skinfold infection).
• Candidal nail infections - chronic paronychia or onychomycosis (see separate article - Fungal Nail Infections).
• Napkin dermatitis.
• Balanitis.
• Chronic mucocutaneous candidiasis:⁹
  • A rare condition, usually beginning in childhood, with persistent and prolonged Candida infections of skin and mucous membranes.
  • May be due to genetic predisposition, endocrinopathies, T cell disorders or low immunoglobulin levels.
• Candidal folliculitis.
• Generalised cutaneous candidiasis (rare):
  • A widespread rash, worse in skinfolds and extremities, with pruritus.
• Skin lesions in patients with invasive candidiasis (IC) - see below.

When to investigate

Swabs are not usually required, but take standard bacteriology swabs for microscopy and culture if:

• The diagnosis is unclear, or bacterial infection is suspected.
• There is no improvement after initial treatment.
• The patient is immunocompromised.
• Systemic treatment is considered.

Look for an underlying cause if there is widespread or recurrent candidiasis (see Risk factors, above).

Treatment

• Usually, topical imidazole cream, e.g.clotrimazole, econazole, ketoconazole, or miconazole.
• If there is problematic itch or inflammation, consider adding a mild corticosteroid cream for 7-14 days .
• Oral fluconazole 50 mg/day for 2-4 weeks if:
  • Topical treatment is ineffective
  • There is widespread infection
  • The patient is immunocompromised (depending on the severity of infection and the level of immunocompromise)
• Review after 2 weeks of fluconazole treatment.
• If not improving, obtain specialist advice.

Invasive candidal infections^2,3

• The term invasive candidiasis (IC) encompasses a variety of severe candidal infections:
  • The most common form is candidaemia (about 60% of cases).⁷
  • Any internal organ can be affected (disseminated candidiasis or deep organ infection, below).
• Usually there is underlying risk factor, e.g. immunocompromise, intensive care, implants or indwelling catheters.
• Invasive candidiasis is life-threatening. Systemic candidiasis has an estimated mortality rate of about 70-80%.⁴

IC diagnosis:^3,10

• Prompt diagnosis is important, but often difficult.
• Have a low index of suspicion and prompt treatment in at-risk patients - e.g. in neutropenic patients, start antifungal therapy if there are >4 days of persistent fever despite antibiotics.
• Cultures:
  • Blood cultures should be taken, but lack sensitivity (probably <50%) and usually become positive late.
  • Culture of body fluids or tissues as appropriate.
  • Various rapid tests are available to identify the Candida spp. from cultures.
• Ultrasound and/or CT scans are useful in abdominal or renal tract infections. Again, radiological signs may appear late.
• Echocardiography for suspected cardiac involvement.
• Tissue biopsy and culture - if feasible.
• Endoscopy for suspected upper GI infections.
• Serological tests:
  • These detect components of the fungal cell wall or antibodies directed against these antigens (e.g. mannan or anti-mannan). So far, these tests have performed well in clinical studies.
  • Molecular tests for detection of candidal DNA are under development.

Candidaemia

Presentation

• Risk factors, including prolonged intravenous catheterisation
• Fever/chills unresponsive to broad-spectrum antibiotics
• May have macronodular skin lesions (see below), candidal endophthalmitis, multiorgan infection (see below) or, rarely, septic shock
• Characteristic skin lesions may be present in some patients with candidaemia or disseminated candidiasis. These are erythematous, firm, nontender macronodular lesions with discrete borders. Biopsy of these lesions shows yeast cells, hyphae, or pseudohyphae, with cultures positive for Candida spp. in approximately 50% of cases

Treatment

Current treatment guidelines recommend:³

• First-line treatment:
  • Non-neutropenic patients - intravenous fluconazole or an echinocandin (echinocandins are preferred for severe illness, recent azole exposure or likely C. glabrata).
  • Neutropenic patients - an echinocandin, a lipid formulation of amphotericin B or voriconazole. Fluconazole can be used in less ill patients with no recent azole exposure.
• Second-line treatments and species-specific treatments are detailed in recent USA guidelines.³
• Remove central venous catheters if possible in non-neutropenic patients; consider catheter removal in neutropenic patients.
• Fundoscopy (dilated) within first week.
• Blood cultures to assess for clearance of candida.
• If there are no complications, continue treatment for 2 weeks after clinically well, resolution of neutropenia and clearance from bloodstream.

Disseminated candidiasis (deep organ infection)^2,3

General points

• Any internal organ, or multiple organs, may be affected (listed below).
• Presents with fever unresponsive to broad-spectrum antibiotics, and features of sepsis; there may be septic shock.
• Characteristic skin lesions may be present (see under Candidaemia, above).
• Blood cultures may be negative in about 50% of cases.

Treatment of disseminated candidiasis

This involves:

• Systemic antifungal therapy (prolonged treatment in many cases):
• Specific recommendations for different organ infections are detailed in current guidelines.³
• Removal of the source of infection or of the precipitating factors, if feasible (e.g. remove indwelling devices, treatment of immunocompromise).
• Surgical debridement may be appropriate.

Types of disseminated candidiasis

The following deep organ candidal infections can occur.

Cardiovascular system:¹¹

• Endocarditis
• Myocarditis
• Pericarditis
• Suppurative thrombophlebitis
• Candidal infection of pacemakers, implantable cardiac defibrillators and ventricular assist devices

Respiratory system:

• Candida isolated from respiratory secretions - this rarely indicates invasive candidiasis; candida is common in respiratory secretions and cultures from them.
• Candidal pneumonia, lung abscess or tracheobronchitis - these are rare.
• Laryngeal candidiasis - is uncommon and mainly associated with malignancies.

Abdominal organs:

• Candidal peritonitis - may be a complication of peritoneal dialysis¹²
• Chronic disseminated candidiasis (hepatosplenic candidiasis):¹³
  • This is a form of systemic candidiasis, occurring in patients with a haematological malignancy and neutropenia. It develops during the recovery phase of a neutropenic episode.
  • Clinical features are fever (unresponsive to broad-spectrum antibiotics), abdominal pain, tender hepatosplenomegaly, vomiting, dysphagia and jaundice.
  • It may be a form of inflammatory immune reconstitution syndrome.
• Non-oesophageal gastrointestinal candidiasis:
  • This most commonly involves the stomach or small intestine
• Candidal cholecystitis (rare)

Renal tract:

• Asymptomatic cystitis:
  • Candida is found in up to 10% of urine cultures; treatment is not usually indicated, except in high-risk patients, e.g. low birth weight neonates, neutropenia, or urological procedures.
• Symptomatic cystitis
• Pyelonephritis
• Urinary fungus balls:
  • These are due to accumulation of fungal material in the renal pelvis; the balls can occur anywhere in the urinary collecting system.
  • May cause intermittent urinary tract obstruction with anuria and renal insufficiency.
• Candidal prostatitis and epididymo-orchitis (rare).

CNS Candidiasis:

• Meningitis
• Granulomatous vasculitis
• Diffuse cerebritis with microabscesses
• Mycotic aneurysms

Ocular candidiasis:¹⁴

• Chorioretinitis
• Vitritis
• Endophthalmitis

Candidal osteoarticular infection:

• Septic arthritis
• Osteomyelitis (including sternal osteomyelitis following sternotomy)
• Infection of prosthetic device
• Costochondritis (rare)
• Myositis (rare)

Obstetric and neonatal candida infections

Neonatal invasive candidiasis (IC):¹⁵

• This is an important cause of mortality and morbidity in very low birthweight (VLBW) infants; those who are extremely preterm or low birthweight are most at risk.
• C. albicans and C. parapsilosis are the most common species found in neonates.
• The usual treatment agents are amphotericin B and fluconazole.
• There is some evidence to support the use of prophylactic oral, topical or systemic antifungal agents in VLBW infants in the neonatal intensive care unit.^16,17

Chorioamnionitis (rare):¹⁸

• May cause fetal death.
• May result in cutaneous congenital candidiasis - a very rare disease comprising a generalised rash at, or shortly after, birth and usually without other signs or symptoms, which is always secondary to candidal chorioamnionitis; it is is essentially benign and self-limiting.¹⁹

Placental infection (rare).²⁰

Document references

1. Dermnet NZ. Candida infection. Website of New Zealand Dermatological Society. Updated June 2009.
2. Hidalgo JA, Vazquez JA. Candidiasis. emedicine, updated January 2010.
3. Pappas PG, Kauffman CA, Andes D, et al; Clinical practice guidelines for the management of candidiasis: 2009 update by Clin Infect Dis. 2009 Mar 1;48(5):503-35. [abstract]
4. Candida - oral, Clinical Knowledge Summaries (September 2009)
5. Kumar P; Clarke M; Clinical Medicine, 6th Ed, (2005). WB Saunders: London.
6. Hay RJ in Oxford Textbook of Medicine, 4th Edition. Eds; Warrell DA et al. OUP 2003.
7. Gafter-Gvili A, Vidal L, Goldberg E, et al; Treatment of invasive candidal infections: systematic review and meta-analysis. Mayo Clin Proc. 2008 Sep;83(9):1011-21. [abstract]
8. Candida - skin, Clinical Knowledge Summaries (March 2009)
9. Dermnet NZ. Chronic mucocutaneous candidiasis. New Zealand Dermatological Society, updated June 2009.
10. Mean M, Marchetti O, Calandra T; Bench-to-bedside review: Candida infections in the intensive care unit. Crit Care. 2008;12(1):204. Epub 2008 Jan 22. [abstract]
11. Falcone M, Barzaghi N, Carosi G, et al; Candida infective endocarditis: report of 15 cases from a prospective multicenter Medicine (Baltimore). 2009 May;88(3):160-8. [abstract]
12. Matuszkiewicz-Rowinska J; Update on fungal peritonitis and its treatment. Perit Dial Int. 2009 Feb;29 Suppl 2:S161-5. [abstract]
13. Pagano L, Mele L, Fianchi L, et al; Chronic disseminated candidiasis in patients with hematologic malignancies. Haematologica. 2002 May;87(5):535-41. [abstract]
14. Shah CP, McKey J, Spirn MJ, et al; Ocular candidiasis: a review. Br J Ophthalmol. 2008 Apr;92(4):466-8. [abstract]
15. Chapman RL; Prevention and treatment of Candida infections in neonates. Semin Perinatol. 2007 Feb;31(1):39-46. [abstract]
16. Austin N, Darlow BA, McGuire W; Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003478. [abstract]
17. Clerihew L, Austin N, McGuire W; Prophylactic systemic antifungal agents to prevent mortality and morbidity in Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003850. [abstract]
18. Meizoso T, Rivera T, Fernandez-Acenero MJ, et al; Intrauterine candidiasis: report of four cases. Arch Gynecol Obstet. 2008 Aug;278(2):173-6. Epub 2008 Jan 24. [abstract]
19. Diana A, Epiney M, Ecoffey M, et al; "White dots on the placenta and red dots on the baby": congential cutaneous Acta Paediatr. 2004 Jul;93(7):996-9. [abstract]
20. Delprado WJ, Baird PJ, Russell P; Placental candidiasis: report of three cases with a review of the literature. Pathology. 1982 Apr;14(2):191-5. [abstract]

Internet and further reading

• Gullo A; Invasive fungal infections: the challenge continues. Drugs. 2009;69 Suppl 1:65-73. doi: 10.2165/11315530-000000000-00000. [abstract]
• Gafter-Gvili A, Vidal L, Goldberg E, et al; Treatment of invasive candidal infections: systematic review and meta-analysis. Mayo Clin Proc. 2008 Sep;83(9):1011-21. [abstract]
• Brecht M, Clerihew L, McGuire W; Prevention and treatment of invasive fungal infection in very low birthweight Arch Dis Child Fetal Neonatal Ed. 2009 Jan;94(1):F65-9. Epub 2008 Oct 6. [abstract]
• Blyth CC, Palasanthiran P, O'Brien TA; Antifungal therapy in children with invasive fungal infections: a systematic Pediatrics. 2007 Apr;119(4):772-84. [abstract]
• Hedayati T, Choi J; Candidiasis. eMedicine, April 2009.

Acknowledgements