Clinical Topic A-Z Clinical Speciality

Candida - oral

Candida - oral
D002180Candidiasis, Oral
Infections and infestationsOral health
2013-07-01Last revised in July 2013

Candida - oral - Summary

Oral candidiasis is a fungal infection of the oral mucosa, most commonly caused by Candida albicans. Candidal infections tend to be opportunistic in nature and rarely affect healthy adults.

Types of oral candidal infection include:

Pseudomembranous oral candidiasis (often called oral thrush). This is most common in infants and immunocompromised people and presents with white patches on the cheeks, gums, and palate. These are easily removed, revealing an underlying red base that is not usually painful.

Erythematous oral candidiasis (also known as atrophic oral candidiasis). This commonly occurs after oral antibiotic treatment and presents with marked soreness and erythema, particularly on the dorsum of the tongue. It often follows oral thrush.

Chronic erythematous oral candidiasis (denture stomatitis or chronic atrophic oral candidiasis). This presents with redness, and rarely soreness, in the denture-bearing area and affects up to 50% of denture wearers.

Median rhomboid glossitis - a central, red, demarcated area of papillary atrophy of the tongue which is usually seen in smokers or people using corticosteroid inhalers.

Chronic plaque-like oral candidiasis (chronic hyperplastic oral candidiasis). This presents with persistent firm, white plaques on the cheek or tongue that are not easily removed. It is most common in men older than 30 years of age, and in smokers, and may indicate premalignant changes in the oral mucosa.

Comorbidities increasing the risk of candidal infection include diabetes mellitus, severe anaemia, and immunocompromise (such as chemotherapy, radiotherapy, HIV infection, and AIDS).

Other risk factors include poor dental hygiene, local trauma, smoking, broad spectrum antibiotics, inhaled or oral corticosteroids, malnutrition, and a deficiency in iron, folate, or vitamin B12.

When treating an immunocompetent child or adult:

Topical treatment should be prescribed for 7 days, with treatment continued for 2 days after symptoms resolve.

Miconazole oral gel is first-line treatment (off-label use in children younger than 4 months of age). Care should be taken when applying the gel to the mouth of infants and young children due to the risk of choking.

Nystatin suspension (off-label use in neonates) should be offered if miconazole oral gel is unsuitable.

In an adult with extensive or severe candidiasis, a course of oral fluconazole should be prescribed. A specialist should be contacted for advice if a child has extensive or severe candidiasis.

People taking immunosuppressive treatment or people who are HIV positive often need more intensive treatment following specialist advice.

Admission to hospital should be arranged if there is widespread infection (such as oesophageal candidiasis characterized by difficulty or pain on swallowing, or retrosternal pain), or the person is systemically unwell.

Referral should be arranged, or a specialist contacted for advice, if the person:

Has extensive or severe oral candidiasis.

Does not respond adequately to treatment.

Has recurrent episodes of oral candidal infection, or there is suspicion of immunocompromise.

Referral for biopsy should be considered for people with chronic plaque-like oral candidiasis that is unresponsive to treatment.

Have I got the right topic?

0months3060monthsBoth

This CKS topic covers the assessment and management of oral candidiasis in both immunocompetent and immunocompromised people.

This CKS topic does not cover the management of oral candidiasis in people receiving palliative care (see Palliative cancer care - oral).

There are separate CKS topics on Aphthous ulcer, Candida - female genital, Candida - skin, Herpes simplex - oral, and Sore throat - acute.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in July 2013

January 2014 — minor update. Text updated in line with the Summary of Product Characteristics for miconazole oral gel in the Prescribing Information section to highlight the risk of choking in infants and young children when miconazole oral gel is applied to the mouth [ABPI Medicines Compendium, 2013].

December 2013 — minor update. Text updated to reflect that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has suspended the marketing authorisation for oral ketoconazole, and it should not be prescribed for the treatment of fungal infections [MHRA, 2013].

August 2013 — minor update to the text to reflect recent guidance from the European Medicines Agency regarding the use of oral ketoconazole [MHRA, 2013].

July 2013 — reviewed. A literature search was conducted in June 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. No major changes to recommendations have been made.

Previous changes

November 2012 — minor update. The links to the electronic medicines website (www.medicines.org.uk) have been updated.

October 2009 — minor update. Minor wording change regarding the use of miconazole oral gel in children aged 4 months and less. Issued in October 2009.

April to September 2009 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. There are no major changes to the recommendations.

September 2008 — minor correction to the Changes section. Issued in September 2008.

May 2008 — minor update to remove nystatin pastilles because they have been discontinued. Text regarding nystatin pastilles has been removed as well as prescriptions. Minor update to text to reflect the change in licence for miconazole oral gel. Issued June 2008.

April 2008 — minor update to the text for oral ketoconazole, this now reflects the most recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance.

July 2007 — minor update to text and prescription added for miconazole oral gel (children under 2 years).

July to September 2006 — reviewed. Validated in December 2006 and issued in January 2007.

This guidance has been reviewed, restructured and updated following a full literature review. There are no major changes to the recommendations. An evidence section has been added.

October 2005 — minor technical update. Issued in November 2005.

October 2003 — written. Validated in December 2003 and issued in February 2004.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 June 2013.

HTAs (Health Technology Assessments)

No new HTAs since 1 June 2013.

Economic appraisals

No new economic appraisals relevant to England since 1 June 2013.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 June 2013.

Primary evidence

No new randomized controlled trials published in the major journals since 1 June 2013.

Observational studies published since the last revision of this topic:

Molgaard-Nielsen, D., Pasternak, B., and Hviid, A. (2013) Use of oral fluconazole during pregnancy and the risk of birth defects. New England Journal of Medicine 369(9), 830-839.

New policies

No new national policies or guidelines since 1 June 2013.

New safety alerts

No new safety alerts since 1 June 2013.

Changes in product availability

No changes in product availability since 1 June 2013.

Goals and outcome measures

Goals

To diagnose oral candidal infection and assess its severity and extent

To treat oral candidal infection in immunocompetent people with topical or oral antifungal drugs

To prevent recurrence of candidal infection in immunocompetent people

To appropriately manage people with oral candidal infection who are immunosuppressed through drugs or immunocompromised through HIV or other conditions

To admit people with invasive or systemic candidiasis

To refer people who cannot be adequately managed in primary care

Background information

Definition

What is it?

Oral candidiasis is a fungal infection of the oral mucosa, most commonly caused by Candida albicans, although it can occasionally be caused by other candida species (for example C. glabrata, C. krusei, and C. tropicalis).

There are three main types of candidal infection of the mouth:

Pseudomembranous oral candidiasis (often called oral thrush) is most common in infants and immunocompromised people.

Erythematous oral candidiasis is also known as atrophic oral candidiasis. Dental stomatitis is a common manifestation of this type of candidal infection.

Hyperplastic oral candidiasis (plaque-like oral candidiasis) is usually chronic, and may indicate premalignant changes in the oral mucosa.

Candidal infections tend to be opportunistic in nature and rarely affect healthy adults.

[Akpan and Morgan, 2002; Samaranayake et al, 2009; Hay and Ashbee, 2010]

Prevalence

How common is it?

Candida species are common commensals in the gastrointestinal tract; up to 60% of healthy people are asymptomatic carriers.

Symptomatic oral candidal infection is rare in healthy adults.

Young children and infants, older debilitated people, and people with compromised or suppressed immune systems tend to be most affected.

About 5% of newborns, increasing to 14% in the fourth week of life, before decreasing gradually thereafter.

Up to 10% of debilitated, older people.

Up to 84–100% of people who are HIV-positive.

[Hoppe, 1997a; Samaranayake et al, 2009; Hay and Ashbee, 2010]

Risk factors

What are the risk factors for developing oral candidal infection?

Comorbidities that increase the risk of candidal infection include:

Diabetes mellitus (Type 1 and 2).

Other endocrine disorders, including undiagnosed hypo-endocrine states (such as hypothyroidism or Addison's disease).

Severe anaemia.

Immunocompromise or systemic immunosuppression. This covers a wide spectrum of conditions, such as:

Haematological cancer (for example acute leukaemia).

Chemotherapy and radiotherapy (for the treatment of cancer).

HIV infection and AIDS.

Other (generally avoidable) risk factors include:

Poor dental hygiene, including inadequate denture hygiene (especially if the person has a carbohydrate-rich diet).

Local trauma, including mucosal irritation.

Lifestyle, in particular smoking.

Recent or concomitant use of drugs that promote candidal growth, particularly broad spectrum antibiotics and inhaled or oral corticosteroids.

Malnutrition, including a high-carbohydrate diet, or a deficiency in iron, folate, or vitamin B12.

[Akpan and Morgan, 2002; Gonsalves et al, 2007; Samaranayake et al, 2009; Hay and Ashbee, 2010; DermNet NZ, 2013]

Diagnosis

Diagnosis of oral candida

Diagnosis

How do I know my patient has it?

Diagnosis of oral candidal infection is made by identifying clinical features and ruling out other causes that may resemble oral candidiasis. Images of oral candidiasis can be found at www.dermnetnz.org.

Pain is the main presenting symptom, and can make eating and drinking difficult.

Loss or altered sense of taste may occur.

Oral candidal infection may be asymptomatic.

The clinical features vary according to the type of candidal infection:

Pseudomembranous oral candidiasis (oral thrush):

Presents with patches of curd-like white pseudomembrane on the cheeks, gums, and palate. These are easily removed, revealing an underlying red base that is not usually painful.

Most commonly occurs in the first few weeks of life.

Acute erythematous oral candidiasis (acute atrophic oral candidiasis):

Presents with marked soreness and erythema, particularly on the dorsum of the tongue, and often follows on from oral thrush.

Commonly occurs after treatment with oral antibiotics.

Chronic erythematous oral candidiasis (denture stomatitis or chronic atrophic oral candidiasis):

Presents with redness, and rarely soreness, in the denture-bearing area.

Affects up to 50% of denture wearers.

Chronic plaque-like oral candidiasis (chronic hyperplastic oral candidiasis):

Presents with mild symptoms, with persistent firm, white plaques on the cheek or tongue, that are not easily removed.

Is most common in men older than 30 years of age, and in smokers.

Median rhomboid glossitis:

Presents with a central, red, demarcated area of papillary atrophy of the tongue (from the posterior midline just anterior to the circumvallate papillae).

Is usually seen in smokers or people using corticosteroid inhalers, and can lead to recurrent or chronic atrophic candidal infection.

Angular cheilitis:

Presents with redness, fissuring, and soreness at the angle of the mouth, and may be caused by bacterial infection (principally Staphylococcus aureus) as well as yeast (candida) species.

Tends to occur in older people (particularly those with reduced facial height or with ill-fitting dentures), younger immunocompromised people, and people with vitamin B12 deficiency or anaemia.

Swabs to detect Candida albicans, or antibody serology, do not help to diagnose oral candidal infection because healthy people carry the organism.

[Gonsalves et al, 2007; Samaranayake et al, 2009; Hay and Ashbee, 2010]

Differential diagnosis

What else might it be?

Leukoplakia is defined as a white patch or plaque on the mucosa that cannot be rubbed off [Scully and Hegarty, 2010].

It may be caused by chronic exposure to irritants (particularly tobacco), or chronic infection (particularly oral candidal infection).

It is most commonly a benign condition, but may be premalignant.

Biopsy of leukoplakia is required to distinguish benign lesions from premalignant lesions.

Lichen planus is an inflammatory condition that affects 1–2% of adults, and is described as reticular or erosive.

Reticular lichen planus is characterized by bilateral, asymptomatic, white, lacy, striations (or papules) on the posterior buccal mucosa. This form is easily identifiable and does not usually require further investigation.

Erosive lichen planus manifests as zones of tender erythema and painful ulcers surrounded by white, radiating striae. It may require biopsy to rule out serious causes.

Hairy tongue results from elongation of the filiform papillae on the dorsum of the tongue. It is associated with poor oral hygiene and overuse of mouthwashes.

Erythema migrans (also known as geographic tongue or benign migratory glossitis) is an inflammatory disorder affecting 1–3% of the population, and is associated with atopic conditions and psoriasis. It is characterized by central erythema caused by atrophy of the filiform papillae, and surrounding (slightly elevated) white-yellow borders.

[Gonsalves et al, 2007; Breathnach, 2010; Scully and Hegarty, 2010]

Management

Management

Scenario: Children : covers the management of oral candidiasis in infants and children younger than 16 years of age.

Scenario: Adults (not immunocompromised) : covers the management of oral candidiasis in people 16 years of age or older who are not markedly immunocompromised, including people who have diabetes, use inhaled corticosteroids, or wear dentures.

Scenario: Adults (immunosuppressive treatment) : covers the management of oral candidiasis in adults who are receiving treatment that may cause immunosuppression, including oral corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), and chemotherapy and/or radiotherapy.

Scenario: Adults (HIV positive) : covers the management of people who have oral candidiasis and who are HIV-positive.

Scenario: Children

Scenario: Treatment of oral candida in children

0months143monthsBoth

Treatment

How should I treat oral candidiasis in a child?

Prescribe topical treatment for 7 days (and advise the person to continue treatment for 2 days after symptoms resolve).

Offer miconazole oral gel first-line (off-label use in children younger than 4 months of age).

Offer nystatin suspension (off-label use in neonates) if miconazole oral gel is unsuitable (for example if the child has liver dysfunction or is taking medication extensively metabolized by the liver).

If the infection has not resolved after 7 days, and:

There has been some response, extend the course of miconazole oral gel for a further week.

Miconazole has had little or no effect despite adequate adherence, offer a 7-day course of oral nystatin suspension.

If the child is using an inhaled corticosteroid, provide advice on the prevention of oral candidal infection (see Inhaled corticosteroids).

If the child has extensive or severe candidiasis, consider seeking specialist advice.

Basis for recommendation

Basis for recommendation

Recommendations for the assessment and treatment of oral candidiasis in children are in line with expert opinion published in Rook's Textbook of Dermatology [Hay and Ashbee, 2010] and narrative reviews [Akpan and Morgan, 2002; Gonsalves et al, 2007; Samaranayake et al, 2009].

First line treatment

Miconazole

Oral candidal infection is common in young children and infants (affecting up to to 40% of infants) because their immune system is immature. There is good evidence from two comparative randomized controlled trials (RCTs) that topical miconazole is considerably more effective than nystatin suspension for the treatment of oral candidal infection in infants (although there is a lack of placebo-controlled trials for either drug) [Hoppe and Hahn, 1996; Hoppe, 1997b].

Oral candidal infection is less common in older children, and consequently there is a lack of direct evidence from RCTs in this group. However, its use is supported by pharmacological principles, historical use, and extrapolation of clinical data from trials in younger children and infants.

Nystatin

Nystatin suspension is not suitable as first-line treatment because two comparative RCTs found that it is not as effective as topical miconazole in the treatment of infants with oral candidal infection [Hoppe and Hahn, 1996; Hoppe, 1997b].

Fluconazole

There is evidence from one RCT that oral fluconazole is more effective than nystatin suspension [Goins et al, 2002], but fluconazole is not recommended for use in children without seeking expert advice.

Fluconazole is extensively absorbed and has the potential for adverse effects, and its use is associated with increasing levels of candidal resistance (especially in C. glabrata or C. krusei) [Samaranayake et al, 2009].

The use of fluconazole in children is generally felt to be unnecessary for what is considered to be a minor illness [Su et al, 2008].

Second line treatment

About 85% of infants experience clinical cure with miconazole after 1 week, increasing to 99% after 2 weeks [Hoppe, 1997b]. Therefore, it is worth considering an additional week of treatment if the initial course is not fully effective.

If miconazole has proved ineffective, it could be due to the presence of a resistant candidal organism (such as C. glabrata or C. krusei). Nystatin has a broader spectrum of antimycotic activity than miconazole, and may be an effective alternative [Samaranayake et al, 2009].

Admission and referral

When should I admit or refer a child with oral candidiasis?

Admit the child if there is widespread infection (such as oesophageal candidiasis, characterized by difficulty or pain on swallowing, or retrosternal pain), or the child is systemically unwell.

Refer or seek specialist advice if the child:

Has extensive or severe oral candidiasis.

Does not respond adequately to at least 2 weeks of treatment with miconazole and/or nystatin.

Has recurrent episodes of oral candidal infection, or there is suspicion the child is immunocompromised.

Basis for recommendation

Basis for recommendation

Admission

Systemic candidiasis, or candidal infection spreading to the oesophagus, is a life-threatening infection requiring immediate intervention by specialists [Pappas et al, 2009].

Referral

The British National Formulary recommends referral for investigation if candidal infection fails to respond to 1–2 weeks of treatment [BNF 65, 2013].

Oral candidal infection that becomes chronic in an infant or child is unusual and requires further assessment by a specialist. Treatment options that may be suitable for initiation in secondary care include oral fluconazole [Samaranayake et al, 2009].

Scenario: Adults (not immunocompromised)

Scenario: Treatment of oral candida in adults who are not immunocompromised

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Management

How should I manage oral candidiasis in an otherwise healthy person?

Exclude risk factors such as HIV infection, cancer, diabetes, anaemia, or haematinic deficiencies.

Oral candidiasis is uncommon in people other than infants, denture wearers, and the elderly. In otherwise healthy people, candidiasis may be the first presentation of an undiagnosed risk factor.

For localized or mild oral candidal infection, prescribe topical treatment for 7 days (and advise the person to continue treatment for 2 days after symptoms resolve).

Offer miconazole oral gel first-line.

Offer nystatin suspension if miconazole is unsuitable.

For extensive or severe candidiasis, prescribe oral fluconazole 50 mg a day for 7 days.

If the infection has not resolved after 7 days, offer treatment for a further week.

If there has been some response to miconazole, extend the course for a further week.

If miconazole has had little or no effect despite adequate adherence, offer a 7-day course of oral nystatin suspension.

If oral fluconazole has not resolved the infection, extend the course for a further week.

Advise good dental hygiene and to give up smoking if applicable (see the CKS topic on Smoking cessation).

If the person is using an inhaled corticosteroid, provide advice on the prevention of oral candidal infection (see Inhaled corticosteroids).

If the person wears dentures, advise about hygiene measures to aid healing and prevent recurrence (see Dentures).

If the person has diabetes, review diabetic control and manage accordingly, particularly if there are recurrent episodes of oral candidal infection (see the CKS topic on Diabetes - type 2). If the person is taking miconazole or fluconazole with a sulphonylurea drug (for example tolbutamide, glipizide and related drugs):

Treatment does not need to be interrupted or monitored.

Advise the person to seek medical advice if they have symptoms of hypoglycaemia (for example nervousness, sweating, and/or trembling).

The following treatments are not recommended for initiation in primary care:

Itraconazole.

Ketoconazole.

Amphotericin.

Basis for recommendation

Basis for recommendation

Recommendations for the assessment and treatment of oral candidal infection are in line with expert opinion published in Rook's Textbook of Dermatology [Hay and Ashbee, 2010] and narrative reviews [Akpan and Morgan, 2002; Gonsalves et al, 2007; Samaranayake et al, 2009].

Excluding risk factors

Expert opinion from a review article states that oral candidiasis is common in infants, but in adults it may signify immune deficiency or other illness [Gonsalves et al, 2007]. There are several different immune mechanisms which affect susceptibility to oral candidiasis, for example, the depression of cell mediated immunity in people with leukaemia, lymphoma, carcinomatosis, and AIDS [Hay and Ashbee, 2010]. Therefore, CKS recommends excluding risk factors when an otherwise healthy person presents with oral candidiasis.

First line treatment

Miconazole

Miconazole has a broad spectrum of activity against fungal and yeast species, and has some additional activity against some Gram-positive bacteria, making it useful in the treatment of angular cheilitis (which is sometimes caused by Staphylococcal aureus) [Pappas et al, 2009; Samaranayake et al, 2009].

There is a lack of direct evidence from randomized controlled trials (RCTs) to support the use of topical miconazole in the treatment of oral candidiasis in otherwise healthy adults. However, its use is supported by pharmacological principles, historical use, and extrapolation of clinical data from trials in other groups (such as infants and people who are immunosuppressed).

Nystatin

There is a lack of evidence from RCTs to support the effectiveness of nystatin suspension in the treatment of oral candidal infection in otherwise healthy adults. However, data extrapolated from trials in infants and immunosuppressed people suggest it is not as effective as topical miconazole or fluconazole, and therefore not suitable as first-line treatment.

Fluconazole

Fluconazole has a broad range of antifungal activity, including against candida species [Pappas et al, 2009; Samaranayake et al, 2009]. Although there is a lack of evidence from RCTs to show the efficacy of oral fluconazole in otherwise healthy people, data extrapolated from trials in infants and immunosuppressed people suggest it is an effective option. Fluconazole is not routinely recommended for first-line treatment of mild and localized candidiasis because:

It is systemically absorbed, and may cause adverse effects.

Its use is associated with increasing levels of candidal resistance (especially Candida glabrata or C. krusei) [Laudenbach and Epstein, 2009].

Dental hygiene and smoking

Poor dental hygiene has been identified as a risk factor for oral candidal infection [Samaranayake et al, 2009], although there is a lack of evidence to show improved hygiene is beneficial.

Smoking is regarded as a significant cause of oral candidal infection, particularly median rhomboid glossitis. Smoking cessation alone may clear infection in these people [Akpan and Morgan, 2002].

Diabetes and oral candidal infection

There is conflicting evidence from several observational studies as to whether diabetes is a cause of oral candidal infection.

The presence of Candida has been associated with poor glycaemic control by some studies [Hill et al, 1989; Aly et al, 1992; Guggenheimer et al, 2000]. However, other studies found no relationship between oral candidal carriage/growth and antidiabetic therapy or glycaemic controls [Bartholomew et al, 1987; Belazi et al, 2005; Kumar et al, 2005].

The discrepancies between studies may reflect differences in methodology, such as variation in sampling techniques and selection of control populations [Soysa et al, 2006].

It is generally accepted that an association between diabetes and oral candidal infection is plausible, and most experts agree that good control of blood glucose is important in the long-term management of oral candidiasis [Soysa et al, 2006]. This will also have other wide-reaching benefits.

Drugs not recommended for initiation in primary care

Oral itraconazole should be reserved for people with fluconazole-resistant candidiasis [BNF 65, 2013]. Specialist advice should be obtained before initiating itraconazole therapy because of the increased risk of drug interactions and adverse effects.

Oral ketoconazole — the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has suspended the marketing authorisation for oral ketoconazole, and it should not be prescribed for the treatment of fungal infections [MHRA, 2013j]. The decision was made because some people taking these medicines may be at an increased risk of liver damage and the risk outweighs the benefits. Alternative antifungal treatments are available.

Oral amphotericin is not recommended as there is a lack of trial evidence to show its efficacy in the treatment of oral candidal infection. It is sometimes used as adjunct to other systemic antimycotic drugs.

Inhaled corticosteroids

How should I prevent oral candidiasis in people using inhaled corticosteroids?

Oral candidal infections (particularly median rhomboid glossitis), and associated adverse effects such as dysphonia and pharyngitis, are common dose-related adverse effects associated with inhaled corticosteroids.

To prevent future episodes of oral candidal infection advise:

Good inhaler technique.

Rinsing the mouth with water (or cleaning a child's teeth) after inhalation, to remove any drug particles.

Using a spacer device to reduce the impaction of particles in the oral cavity.

Stepping down the dose of inhaled corticosteroid when appropriate.

For further information on reducing the adverse effects associated with inhaled corticosteroids, see the section on Adverse effects of inhaled corticosteroids in the CKS topic on Asthma.

Basis for recommendation

Basis for recommendation

Inhaled corticosteroids and oral candidiasis

Deposition of inhaled corticosteroids in the mouth is thought to have a localized immunosuppressive effect on the mucosa, leading to an increased risk of oral candidiasis.

A systematic review and meta-analysis of randomized controlled trials (RCTs) found that inhaled corticosteroids significantly increased the incidence of oral candidal infection, dysphonia, and pharyngitis compared with placebo at all doses studied, and regardless of the device used [Rachelefsky et al, 2007].

Management of inhaled corticosteroids

The recommendation to use good inhaler technique and wash the mouth after use aims to minimize the exposure of corticosteroid on the oral mucosa [Rachelefsky et al, 2007].

A large-volume spacer device reduces oropharyngeal deposition by filtering out larger particles, and is useful for use with pressurized metered-dose inhalers [DTB, 2000].

Dentures

How should I manage oral candidiasis caused by dentures?

Treat the acute infection with miconazole oral gel if the candidiasis is mild or localized (or if angular cheilitis is present), or treat with oral fluconazole if the infection is more widespread or severe.

Advise hygiene measures to aid healing and prevent recurrence:

Leave the dentures out for at least 6 hours in each 24-hour period to promote healing of the gums. If the gums are inflamed they may benefit from the dentures being left out for longer.

Clean dentures by brushing and then soaking them in a disinfectant solution (for example chlorhexidine or hexetidine) overnight. The dentures can be soaked in any solution marketed to sterilize baby's bottles (providing the dentures contain no metal).

Allow the dentures to air-dry after disinfection — this also kills adherent Candida.

Brush the mucosal surface regularly with a soft brush.

See a dentist to correct ill-fitting dentures.

Basis for recommendation

Basis for recommendation

Recommendations for denture hygiene measures are based on expert opinion from narrative reviews [Wilson, 1998; Akpan and Morgan, 2002].

Chlorhexidine is an antiseptic that has broad-spectrum activity, including antimycotic activity against candida species. It can be used as an effective disinfectant for dentures and inhibits adhesion of candida [Ellepola and Samaranayake, 2001].

A small, open-label, comparative, randomized controlled trial in 61 people found that twice-daily rinses with the antiseptic hexetidine resulted in a significant reduction in the amount of Candida albicans present in saliva, compared with pretreatment levels (no control group was included) [Koray et al, 2005].

Follow up

When should I follow up a person with oral candidiasis?

Follow up people who have extensive or severe oral candidiasis (requiring oral fluconazole) after 7 days. If treatment has not been fully effective, consider:

Extending the course of fluconazole for a further week.

Referral.

Basis for recommendation

Basis for recommendation

Follow-up recommendations for people with oral candidal infection are pragmatic, and reflect what CKS considers to be good clinical practice.

Oral candidiasis is unusual in otherwise healthy people, but anecdotal and extrapolated evidence indicates that treatment is effective, and follow up is rarely necessary for mild, localized candidal infection. However, it is reasonable to follow up extensive or severe candidiasis to ensure the infection has cleared and complications have not developed.

There are no clinical data on which to base decisions if initial treatment is not fully effective. However, extending treatment or switching to nystatin (which may be effective against resistant organisms) or oral fluconazole (which has a systemic effect) are reasonable options before expert advice or referral are sought [Samaranayake et al, 2009].

Admission and referral

When should I admit or refer an otherwise healthy adult with oral candidiasis?

Admit the person if there is widespread infection (such as oesophageal candidiasis, characterized by difficulty or pain on swallowing, and retrosternal pain), or there is evidence of systemic illness (candidaemia).

Seek specialist advice or consider referral if the diagnosis is in doubt, or if the person:

Has severe, extensive, widespread, or recurrent episodes of oral candidiasis.

Does not respond adequately to treatment with oral fluconazole (or consider swabbing).

Has breakthrough candidal infection while receiving preventive treatment (which may indicate candidal resistance).

Consider referring for biopsy those people with chronic plaque-like oral candidiasis that is unresponsive to treatment.

Basis for recommendation

Basis for recommendation

Admission

Systemic candidiasis, or candidal infection spreading to the oesophagus, is a life-threatening infection requiring immediate intervention by specialists [Pappas et al, 2009]. Systemic candidiasis has an estimated mortality rate of 71–79% [Akpan and Morgan, 2002].

Referral

The British National Formulary recommends referral for investigation if candidal infection fails to respond to 1–2 weeks of treatment [BNF 65, 2013].

Severe, extensive, widespread, or recurrent episodes of oral candidiasis are unusual in otherwise healthy people, and may indicate underlying immunocompromise that requires further investigation.

Infection that is unresponsive to fluconazole may indicate the development of resistance, the presence of a resistant organism (such as Candida glabrata or Candida krusei), or bacterial superinfection [Samaranayake et al, 2009]. It may be reasonable to swab for the presence of resistant organisms in this group [Akpan and Morgan, 2002].

Chronic plaque-like oral candidiasis may be a feature of premalignant change [Samaranayake et al, 2009]. Biopsy may be indicated, especially if the candidiasis is unresponsive to treatment.

Scenario: Adults (immunosuppressive treatment)

Scenario: Treatment of oral candida in adults receiving immunosuppressive treatment

144months3060monthsBoth

Treatment

How should I treat a person who is receiving immunosuppressant drugs?

Seek specialist advice before prescribing antifungal treatment for people:

Taking ciclosporin or oral tacrolimus (especially if these drugs are being used to suppress tissue rejection following transplantation).

Receiving chemotherapy.

For people taking oral corticosteroids or disease-modifying anti-rheumatic drugs (DMARDs):

If oral candidiasis is mild and localized, prescribe topical treatment for 7 days (continue for 2 days after symptoms resolve):

Offer miconazole oral gel first-line.

Offer nystatin suspension if miconazole is unsuitable.

If oral candidiasis is extensive or severe, prescribe oral fluconazole 50 mg to 100 mg a day, for 7 days.

If there is suspicion that DMARDs are causing marked immunosuppression, seek specialist advice and ensure blood parameters are being adequately monitored (see the CKS topic on DMARDs).

Follow up all people after 7 days of treatment.

Advise good dental hygiene and to give up smoking if applicable (see the CKS topic on Smoking cessation).

The following treatments are not recommended for initiation in primary care:

Miconazole mucoadhesive buccal tablets.

Oral itraconazole.

Oral ketoconazole.

Oral amphotericin.

Basis for recommendation

Basis for recommendation

Recommendations for the assessment and treatment of oral candidal infection in people taking immunosuppressive drugs are in line with expert opinion from a textbook [Hay and Ashbee, 2010] and narrative reviews [Akpan and Morgan, 2002; Gonsalves et al, 2007; Samaranayake et al, 2009].

Seeking specialist advice for people taking ciclosporin or tacrolimus

Published information on clinically significant drug interactions is reviewed in the textbook Stockley's drug interactions [Baxter and Preston, 2013b] and the British National Formulary [BNF 65, 2013].

Fluconazole is known to interact with ciclosporin, and this has been confirmed by numerous case series and case reports, which have shown clinically-important increases in the circulating concentration of ciclosporin. This can potentially give rise to nephrotoxicity which is of critical importance for people who have undergone kidney transplantation. This interaction could also plausibly occur with miconazole oral gel.

Case series and case reports have shown that fluconazole increases the circulating concentration of tacrolimus through the same mechanism as with ciclosporin (cytochrome P450 inhibition). This can also result in nephrotoxicity.

Seeking specialist advice for people receiving chemotherapy

People receiving chemotherapy are likely to be taking drugs that cause complex interactions which are difficult to manage in primary care.

Management of people with marked immunosuppression caused by chemotherapy or radiotherapy is primarily carried out in secondary care under specialist direction. If there is any doubt about management, referral should be considered or specialist advice sought, as the consequences of widespread or invasive candidiasis are particularly serious in people who are immunosuppressed [Pappas et al, 2009; Samaranayake et al, 2009].

Treating people taking oral corticosteroids

Oral corticosteroids can be used concomitantly with oral fluconazole and miconazole.

Although there are theoretical concerns over the interaction between azole antimycotic drugs and oral corticosteroids, these have not been shown to be important. One case series indicated that ketoconazole may increase the circulating levels of prednisolone, but this is unlikely to be clinically significant [Baxter and Preston, 2013b].

The manufacturers of oral fluconazole [ABPI Medicines Compendium, 2013au] and miconazole oral gel [ABPI Medicines Compendium, 2013bn] do not list oral corticosteroids as significant drug interactions.

Treatment of people taking disease-modifying anti-rheumatic drugs (DMARDs)

DMARDs do not generally interact with antifungal drugs [Baxter and Preston, 2013b]. For more information, see the relevant Summary of Product Characteristics in the electronic Medicines Compendium (eMC) www.medicines.org.uk.

Miconazole

Miconazole has a broad spectrum of activity against fungal and yeast species, and has some additional activity against some Gram-positive bacteria, making it useful in the treatment of angular cheilitis (which is sometimes caused by Staphylococcal aureus) [Pappas et al, 2009; Samaranayake et al, 2009].

There is a lack of published evidence from randomized controlled trials (RCTs) to support the use of miconazole oral gel in people with oral candidiasis who are receiving immunosuppressant drugs. However, it is reasonable to suppose it is effective based on historical use, clinical experience, and extrapolation of data in other groups.

An RCT showed miconazole in a buccal tablet formulation was as effective as miconazole gel in people receiving treatment for cancer [Bensadoun et al, 2008].

Clotrimazole (another drug of the imidazole class) was effective in an RCT in people with candidiasis who were HIV-positive [Pienaar et al, 2010].

Miconazole oral gel was more effective than nystatin in infants with oral candidiasis [Hoppe and Hahn, 1996; Hoppe, 1997b].

Nystatin

Nystatin has been used as an active control in people receiving treatment for cancer [Worthington et al, 2010], and has generally not been found to be as effective as other antimycotic drugs, and is therefore not suitable as first-line treatment [Samaranayake et al, 2009].

Fluconazole

Fluconazole has a broad range of antifungal activity, including against candida species [Pappas et al, 2009; Samaranayake et al, 2009]. It is suitable for people who are receiving immunosuppressant drugs who have extensive or severe candidiasis.

There is limited evidence that oral ketoconazole (an azole drug similar to fluconazole) is effective in the treatment of people with oral candidiasis who are receiving treatment for cancer [Worthington et al, 2010].

Fluconazole is systemically absorbed, which is an advantage for widespread candidal infection.

Drugs that are not recommended

Miconazole mucoadhesive buccal tablets are licensed for the treatment of oropharyngeal candidiasis in immunocompromised people [BNF 65, 2013].

This formulation of miconazole has been shown by non-inferiority RCTs to be to of similar effectiveness to miconazole oral gel (in people receiving treatment for cancer [Bensadoun et al, 2008]) and oral ketoconazole (in people who are HIV-positive [van Roey et al, 2004]).

However, this formulation is considerably more expensive than miconazole oral gel, and it is not currently recommended by the Scottish Medicines Consortium [Scottish Medicines Consortium, 2011b]. For these reasons, CKS does not recommend it.

Oral itraconazole should be reserved for people with fluconazole-resistant candidiasis [BNF 65, 2013]. Specialist advice should be obtained before initiating itraconazole therapy because of the increased risk of drug interactions and adverse effects.

Oral ketoconazole — the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has suspended the marketing authorisation for oral ketoconazole, and it should not be prescribed for the treatment of fungal infections [MHRA, 2013j]. The decision was made because some people taking these medicines may be at an increased risk of liver damage and the risk outweighs the benefits. Alternative antifungal treatments are available.

Oral amphotericin is not recommended as there is a lack of trial evidence of its efficacy in the treatment of oral candidal infection. It is sometimes used as adjunct to other systemic antimycotic drugs [Laudenbach and Epstein, 2009].

Dental hygiene and smoking

Poor dental hygiene has been identified as a risk factor for oral candidal infection [Samaranayake et al, 2009], although there is a lack of evidence to show improved hygiene is beneficial.

Smoking is regarded as a significant cause of oral candidal infection, particularly median rhomboid glossitis. Smoking cessation alone may clear infection in these people [Akpan and Morgan, 2002].

Follow up

When should I follow up a person with oral candidiasis who is taking immunosuppressant drugs?

Follow up people after 7 days. If treatment has not been fully effective despite adequate adherence:

For people receiving topical treatment, consider:

Extending the course of treatment for a further week.

Switching to nystatin suspension or oral fluconazole.

For people receiving oral fluconazole, consider extending the course of treatment for a further week, and increasing the dose to 100 mg per day.

Basis for recommendation

Basis for recommendation

Follow up for all people is a pragmatic recommendation, and reflects what CKS considers to be good clinical practice. Oral candidal infection is a serious cause or morbidity and mortality in people who are immunosuppressed, and it is reasonable to ensure treatment has been satisfactory and complications have not developed.

CKS found no clinical data on which to base decisions if initial treatment is not fully effective in people receiving concomitant immunosuppressive drugs.

Extending treatment, or switching to nystatin (which may be effective against resistant organisms) or oral fluconazole (which has a systemic effect) are reasonable options before expert advice or referral are sought, provided deterioration has not occurred [Samaranayake et al, 2009].

The dose of fluconazole may also be increased in unusually difficult candidal infections [BNF 65, 2013].

Admission and referral

When should I admit or refer a person with oral candidiasis who is taking immunosuppressive treatment?

Admit the person if there is widespread and invasive infection (such as oesophageal candidiasis, characterized by difficulty or pain on swallowing, and retrosternal pain), or there is evidence of invasive candidiasis or systemic illness (candidaemia). Lower the threshold for admission in people who are markedly immunocompromised.

Seek specialist advice or consider referral if the diagnosis is in doubt, or if the person:

Has unexplained severe or extensive oral candidal infection, or recurrent episodes of oral candidiasis.

Does not respond adequately to treatment with oral fluconazole (consider swabbing).

Has breakthrough oral candidiasis whilst receiving preventive antifungal treatment.

Has clinical features that preclude management in primary care.

Consider referring for biopsy those people with chronic plaque-like oral candidiasis that is unresponsive to treatment.

Basis for recommendation

Basis for recommendation

Admission

Systemic candidiasis, or candidiasis spreading to the oesophagus, is a life-threatening infection requiring immediate intervention by specialists [Pappas et al, 2009]. Systemic candidiasis has an estimated mortality rate of 71–79% [Akpan and Morgan, 2002]. It is reasonable to maintain a low threshold for admission in people who are immunosuppressed, as systemic illness in this group may be more likely and particularly serious.

Referral

The British National Formulary recommends referral for investigation if candidal infection fails to respond to 1–2 weeks of treatment [BNF 65, 2013].

People who have chronic or recurrent oral candidal infection because of concomitant use of immunosuppressive drugs require specialist care and management options.

Infection that is unresponsive to fluconazole, or breakthrough candidiasis while taking preventive treatment, may indicate the development of resistance, the presence of a resistant organism (such as Candida glabrata or Candida krusei), or bacterial superinfection [Samaranayake et al, 2009]. It may be reasonable to swab for the presence of resistant organisms in this group [Akpan and Morgan, 2002].

Chronic, plaque-like, oral candidiasis may be a feature of premalignant change [Samaranayake et al, 2009]. Biopsy may be indicated, especially if it is unresponsive to treatment.

Scenario: Adults (HIV positive)

Scenario: Treatment of oral candida in adults who are HIV positive

144months3060monthsBoth

Treatment

How should I treat oral candidiasis in a person who is HIV-positive?

Admit the person if there is widespread and invasive infection (such as oesophageal candidiasis, which may present with retrosternal pain), or the person is systemically unwell.

Seek specialist advice before starting treatment if:

Oral candidiasis is extensive or severe.

If treatment with fluconazole for a previous episode of candidiasis was ineffective.

Prescribe oral fluconazole 100 mg for 7 days provided the person is more than 16 years of age, and:

Is otherwise well, and

The infection is mild and not extensive, and

Is not taking prophylactic antimycotic treatment.

Review after 7 days. If the infection has not completely resolved, consider prescribing a further 7 days of fluconazole.

Do not treat with:

Topical antifungal drugs.

Oral itraconazole, ketoconazole, and amphotericin.

Basis for recommendation

Basis for recommendation

Recommendations for the assessment and treatment of oral candidal infection are in line with expert opinion published in Rook's Textbook of Dermatology [Hay and Ashbee, 2010] and narrative reviews [Akpan and Morgan, 2002; Gonsalves et al, 2007; Samaranayake et al, 2009].

Admission

Systemic candidiasis, or candidiasis spreading to the oesophagus, is a life-threatening infection requiring immediate intervention by specialists [Pappas et al, 2009]. Systemic candidiasis has an estimated mortality rate of 71–79% [Akpan and Morgan, 2002]. It is reasonable to maintain a low threshold for admission in people who are immunocompromised as systemic illness in this group may be particularly serious.

Fluconazole

Fluconazole has a broad range of antifungal activity, including against candida species [Pappas et al, 2009; Samaranayake et al, 2009]. It is recommended as first-line treatment in people who are HIV-positive.

There is good evidence from several randomized controlled trials (RCTs) that, in the treatment of people with oral candidal infection who are HIV-positive, fluconazole is more effective than nystatin and clotrimazole, and there is conflicting evidence that it is equally effective or more effective than oral ketoconazole [Pienaar et al, 2010].

Fluconazole is systemically absorbed, which is an advantage for widespread candidal infection.

Drugs not recommended

Topical drugs (or drugs that are poorly absorbed), are not recommended because evidence from RCTs suggests they are not as effective as systemic drugs [Pienaar et al, 2010].

Drugs not recommended for initiation in primary care

Oral itraconazole should be reserved for cases of fluconazole-resistant candidiasis [BNF 65, 2013]. Specialist advice should be obtained before initiating itraconazole therapy because of the increased risk of drug interactions and adverse effects.

Oral ketoconazole — the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has suspended the marketing authorisation for oral ketoconazole, and it should not be prescribed for the treatment of fungal infections [MHRA, 2013j]. The decision was made because some people taking these medicines may be at an increased risk of liver damage and the risk outweighs the benefits. Alternative antifungal treatments are available.

Oral amphotericin is not recommended as there is a lack of trial evidence of efficacy in the treatment of oral candidiasis. It is sometimes used as an adjunct to other systemic antimycotic drugs [Laudenbach and Epstein, 2009].

Admission and referral

When should I admit a person with oral candidiasis who is HIV-positive?

Admit the person if there is widespread and invasive infection (such as oesophageal candidiasis, characterized by difficulty or pain on swallowing, and retrosternal pain), or the person is systemically unwell.

Seek specialist advice or consider referral if the diagnosis is in doubt, or if the person:

Has been lost to specialist follow up.

Has severe, extensive, widespread, or recurrent episodes of oral candidiasis.

Does not respond adequately to treatment with oral fluconazole (consider swabbing).

Has breakthrough candidiasis while taking preventive treatment (this may indicate candidal resistance).

Consider referring for biopsy those people with chronic plaque-like oral candidiasis that is unresponsive to treatment.

Basis for recommendation

Basis for recommendation

Admission

Systemic candidiasis, or candidiasis spreading to the oesophagus, is a life-threatening infection requiring immediate intervention by specialists [Pappas et al, 2009]. Systemic candidiasis has an estimated mortality rate of 71–79% [Akpan and Morgan, 2002]. It is reasonable to maintain a low threshold for admission in people who are immunocompromised, as systemic illness in this group may be particularly serious.

Referral

The British National Formulary recommends referral for investigation if candidal infection fails to respond to 1–2 weeks treatment [BNF 65, 2013].

People who have chronic or recurrent oral candidal infection because of concomitant use of immunosuppressive drugs require specialist care.

Infection that is unresponsive to fluconazole, or breakthrough candidiasis while taking preventive treatment, may indicate the development of resistance, the presence of a resistant organism (such as Candida glabrata or Candida krusei) or bacterial superinfection [Samaranayake et al, 2009]. It may be reasonable to swab for the presence of resistant organisms in this group [Akpan and Morgan, 2002].

Chronic plaque-like oral candidiasis may be a feature of premalignant change [Samaranayake et al, 2009]. Biopsy may be indicated, especially if it is unresponsive to treatment.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Miconazole oral gel

Miconazole oral gel

Children

Children

Miconazole oral gel (20 mg/mL) is rarely contraindicated in children.

Advise the child (or carer) to:

Apply the gel directly to the affected area with a clean finger, and to leave it in contact with the mucosa for as long as possible.

Miconazole gel is not licensed in children under 4 months of age because of the risks of choking if it is not applied carefully.

Care should be taken to ensure that the gel does not obstruct the throat in infants (avoid application to the back of the throat and subdivide doses if necessary).

Gel must not be applied to the nipple of a breastfeeding woman for administration to an infant, due to the risk of choking.

The oral gel should be applied:

Two to four times a day in neonates, after feeds.

Twice a day in infants and children under 6 years of age, after feeds or food.

Four times a day in children older than 6 years of age, after food.

[ABPI Medicines Compendium, 2013; BNF for Children, 2013]

Adults

Adults

Miconazole oral gel (20 mg/mL) is first-line treatment; it is not usually suitable for people:

With liver dysfunction.

Taking drugs that are extensively metabolized by the liver, such as warfarin, statins, and some immunosuppressive drugs (for example ciclosporin).

Miconazole oral gel (which is partially absorbed) is an inhibitor of cytochrome P450 3A4 and 2C9. As a precaution, it is not recommended for concomitant use with other drugs that are metabolized by these isoenzymes (particularly if they have a narrow therapeutic window).

There is a theoretical risk that imidazole and azole drugs will interact with sulphonylurea antidiabetic drugs through inhibition of cytochrome P450 enzymes and subsequent increases in sulphonylurea concentrations. However, in clinical practice, only isolated case reports have recorded this phenomenon [Baxter and Preston, 2013], and their concomitant use is not regarded as an absolute contraindication by the manufacturers of Daktarin® [ABPI Medicines Compendium, 2013b].

Advise the person to apply the gel directly to the affected area with a clean finger four times a day, and to leave it in contact with the mucosa for as long as possible.

[ABPI Medicines Compendium, 2013b; BNF 65, 2013]

Nystatin suspension

Nystatin suspension

Nystatin suspension (100,000 units/mL) has no significant contraindications. Advise the person (or carer) to take nystatin four times a day after food or drink, and to keep the suspension in contact with the affected areas for as long as possible.

[ABPI Medicines Compendium, 2013c; BNF 65, 2013; BNF for Children, 2013]

Fluconazole - oral

Fluconazole - oral

Use with caution in people:

People taking concomitant drugs that are known to prolong the QT interval and drugs that are extensively metabolized by the liver, such as warfarin, statins, or some immunosuppressant drugs (such as ciclosporin).

Fluconazole is an inhibitor of cytochrome P450 3A4 and 2C9. As a precaution, it is not recommended for concomitant use with other drugs that are metabolized by these isoenzymes (particularly if they have a narrow therapeutic window).

Azole drugs interact with sulphonylurea antidiabetic drugs through inhibition of the cytochrome P450 enzymes and subsequently increases sulphonylurea concentrations. However, in clinical practice, only isolated case reports have recorded this phenomenon [Baxter and Preston, 2013]. The manufacturer advises frequent monitoring of blood glucose and appropriate reduction in sulphonylurea dose with co-administration.

The most common adverse effects of fluconazole are gastrointestinal, and include nausea, vomiting, bloating, diarrhoea, and abdominal discomfort.

Oral fluconazole 100 mg a day for 7 days is appropriate for adults who are immunocompromised because of HIV infection.

[ABPI Medicines Compendium, 2013c; BNF 65, 2013]

Disease-modifying anti-rheumatic drugs (DMARDs)

Disease-modifying anti-rheumatic drugs (DMARDs)

The following DMARDs do not significantly interact with fluconazole or miconazole (for other drugs, consult the relevant Summary of Product Characteristics at www.medicines.org.uk):

Sodium Aurothiomalate.

Azathioprine.

Hydroxychloroquine.

Leflunomide.

Methotrexate.

Penicillamine.

Sulfasalazine.

[ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013a; BNF 65, 2013]

Evidence

Evidence

Supporting evidence

Young children and infants

Evidence on antifungal drugs in young children and infants

CKS identified no placebo-controlled trials that unequivocally show the efficacy of antifungal drugs in the treatment of oral candidal infection in infants and young children. However, three comparative randomized controlled trials (RCTs) provide good evidence that topical miconazole and oral fluconazole are more effective than topical or oral nystatin for this purpose.

An open-label RCT in 95 immunocompetent infants (2–17 months of age) with oral candidiasis, randomized them to receive one of two nystatin oral gel formulations or a miconazole oral gel formulation [Hoppe and Hahn, 1996].

After 14 days of treatment, the clinical cure rate was 85.1% in the miconazole group, and significantly less in the two nystatin groups (42.8%, p < 0.0007, and 48.5%, p < 0.004 respectively).

This means that for every two or three children treated with miconazole, an extra child would achieve clinical cure compared with nystatin (NNT 2–3).

An open-label RCT in 227 immunocompetent infants (less than 1 year of age) randomized them to receive either miconazole oral gel (25 mg dose) or nystatin oral suspension (100,000 unit dose) for the treatment of oral thrush [Hoppe, 1997a].

After 12 days, clinical cure was higher in the miconazole group (99%) than the nystatin group (54%, p < 0.0001, NNT 2).

Miconazole was associated with an eradication rate (through microbiological testing) of 55.7%, compared with 13.0% for nystatin (p < 0.0001, NNT 3).

Adverse effects (mainly gastrointestinal) were rare and similar for each group (4.5% for miconazole compared with 3.5% for nystatin).

An open-label pilot RCT in 34 infants randomized them to receive oral suspensions of fluconazole or nystatin [Goins et al, 2002]. At the end of the treatment course (7 days for fluconazole and 10 days for nystatin):

Clinical cure rate was significantly higher for children receiving fluconazole (100%) than nystatin (32%, p < 0.0001, NNT 2).

Microbiological eradication was significantly higher for children receiving fluconazole (73%) than nystatin (6%, p < 0.0001, NNT 2).

No adverse effects were reported in either group.

Older children and adults

Evidence on antifungal drugs in older children and adults

CKS identified no randomized controlled trials (RCTs) to verify the efficacy of antifungal drugs in the treatment of oral candidal infection in healthy children (more than 2 years of age) and adults. Instead, their effectiveness is suggested by known pharmacological principles, historical use, and extrapolation of clinical data from other groups.

Miconazole is an imidazole antimycotic drug with a broad spectrum of activity against fungal and yeast species, and additional activity against some Gram-positive bacteria. Fluconazole and itraconazole are azole antimycotic drugs with a broad range of activity, including against candida species [Pappas et al, 2009; Samaranayake et al, 2009].

Oral candidiasis is rare in otherwise healthy children and adults, and consequently this group has not been the subject of RCTs. However, both the imidazole and azole group of antifungals have been historically used for this purpose and anecdotal evidence suggests they are effective. In addition, it is reasonable to extrapolate clinical data from other groups of people to support this. For more information, see the evidence on Young children and infants and People with immunosuppression.

People with immunosuppression

Evidence on antiviral drugs in people with immunosuppression

People with HIV

Evidence on antiviral drugs in people with HIV

There have been no placebo-controlled trials to show the effectiveness of any intervention for the treatment of oral candidal infection in people with HIV, but evidence from comparative randomized controlled trials (RCTs) indicates that fluconazole, itraconazole, ketoconazole, and clotrimazole are effective treatments, with nystatin being less effective. There is good evidence from placebo-controlled trials that fluconazole can be used to prevent oral candidiasis, without causing an increase in the risk of drug-refractory candidiasis.

A Cochrane systematic review (search date: July 2009) identified 33 RCTs with 3445 participants that investigated the effectiveness of interventions for both the prevention and treatment of oral candidiasis in children and adults with HIV [Pienaar et al, 2010].

Treatment. No placebo-controlled trials were identified for the treatment of oral candidiasis. The following comparative trials were reported:

Fluconazole compared with nystatin. One RCT (n = 167) found that fluconazole resulted in better clinical cure (relative risk [RR] 1.69, 95% CI 1.27 to 2.23) and mycological cure (RR 10.37, 95% CI 3.89 to 27.66) than nystatin. This meant that for every three people treated with fluconazole compared with nystatin, one extra person would experience clinical cure (NNT 3, 95% CI 2 to 7).

Fluconazole compared with ketoconazole. Two RCTs (n = 83) found fluconazole was more effective than ketoconazole in terms of clinical cure (RR 1.50, 95% CI 1.04 to 2.15). However, one trial in children detected no difference (RR 1.13, 95% CI 0.86 to 1.49). Combining the results for adults and children, there was no significant difference in clinical cure between fluconazole and ketoconazole (RR 1.27, 95% CI 0.97 to 1.66).

Itraconazole compared with ketoconazole. Two RCTs (n = 434) found no difference in clinical cure (RR 1.05, 95% CI 0.94 to 1.16).

Clotrimazole compared with ketoconazole. Two RCTs (n = 358) found no difference in clinical cure (RR 1.47, 95% CI 0.92 to 1.42).

Fluconazole compared with clotrimazole. Two RCTs (n = 358) found fluconazole to be superior to clotrimazole in terms of mycological cure (RR 1.47, 95% CI 1.16 to 1.87).

Itraconazole compared with clotrimazole. One RCT (n = 123) found itraconazole to be superior to clotrimazole in terms of mycological cure (RR 2.20, 95% CI 1.43 to 3.39).

Gentian violet (RR 5.28, 95% CI 1.23 to 22.55, 96 people) and ketoconazole (RR 5.22, 95% CI 1.21 to 22.53, 92 people) were both found to be superior to nystatin in terms of clinical cure by single RCTs.

A single high dose of fluconazole compared with a standard fluconazole treatment regimen. One RCT (n = 220) compared a single high dose of fluconazole (750 mg) with a standard treatment regimen (fluconazole 150mg per day for 14 day) and showed no statistically significant difference in clinical cure rate between the two regimens (RR 1.00, 95% CI 0.94 to 1.06).

Prevention. Several trials were identified that compared fluconazole with placebo or no treatment and different regimens of fluconazole with each other.

Five RCTs (n = 599) that compared fluconazole with placebo found the drug to be effective at preventing oral candidal infection (RR 0.61, 95% CI 0.50 to 0.74). One trial in 65 participants that used no treatment as the comparator also found fluconazole to be effective (RR 0.16, 95% CI 0.08 to 0.34).

One RCT (n = 62) found continuous treatment with fluconazole to be superior to intermittent treatment (RR 0.37, 95% CI 0.15 to 0.92).

One RCT (n = 413) found no statistically significant difference between continuous and intermittent use of fluconazole in preventing oral candidiasis in people with HIV (RR1.05; 95% CI 0.55 to 2.01).

Conclusion. The authors of the review concluded that fluconazole, ketoconazole, itraconazole, and clotrimazole were effective treatments for oral candidiasis, and fluconazole was effective at preventing the infection.

People receiving chemotherapy

Evidence on antifungal drugs in people receiving chemotherapy

There is limited evidence from one randomized controlled trial (RCT) that ketoconazole is effective in the treatment of oral candidal infection in people receiving treatment for cancer, but there is a lack of data to verify this or support the efficacy of other drugs. There is good evidence from RCTs that antifungal drugs that are absorbed from the gastrointestinal tract are effective at preventing oral candidiasis in this group.

Treatment

A Cochrane systematic review (search date: June 2010) identified ten RCTs suitable for inclusion that investigated the effectiveness of interventions for oral candidiasis in people receiving treatment for cancer [Worthington et al, 2010].

Some of the studies were described as being at high or moderate risk of bias.

One RCT (n = 56) found that ketoconazole was more effective than placebo in terms of complete eradication of candidiasis (risk ratio [RR] 3.61, 95% CI 1.47 to 8.88).

One RCT (n = 13) found no difference between oral clotrimazole and placebo in terms of complete eradication of candidiasis (RR 3.43, 95% CI 0.51 to 22.94).

Several comparative trials found no difference in effectiveness between individual antifungal drugs. This included a meta-analysis of three RCTs in 207 participants that compared absorbed drugs (fluconazole or ketoconazole) with drugs that are not absorbed (nystatin or clotrimazole). There was clinical eradication in favour of the absorbed drugs (RR 1.22, 95% CI 0.84 to 1.77).

One RCT (n = 282) found no statistical difference between a mucoadhesive buccal miconazole tablet and miconazole gel (1.16, 95% CI 0.91 to 1.47). Both treatments had a good safety profile.

The authors concluded the evidence to support the use of antifungal drugs to treat oral candidal infection in people receiving chemotherapy was 'weak and unreliable' although ketoconazole may be of some benefit.

Prevention

A Cochrane systematic review (search date: June 2006) investigated the effectiveness of interventions for the prevention of oral candidal infection in people receiving treatment for cancer [Clarkson et al, 2007].

Twenty eight trials in 4226 participants were deemed suitable for inclusion.

Seven RCTs in 1153 participants compared drugs absorbed from the gastrointestinal tract with placebo or no treatment, and found they significantly reduced the risk of infection (RR 0.47, 95% CI 0.29 to 0.78, p = 0.12). Assuming an average infection rate of 20% (data derived from placebo arms), this means that nine people would need to be treated for one person to benefit (NNT 9, 95% CI 7 to 13).

Eight RCTs in 382 participants found that drugs that were not absorbed were not significantly better than placebo or no treatment at preventing oral candidal infection (RR 0.68, 95% CI 0.46 to 1.02).

The authors concluded that there is strong evidence from RCTs that drugs absorbed, or partially absorbed, from the gastrointestinal tract are effective at preventing oral candidiasis, but that drugs that are not absorbed are not.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on the primary care management of oral candida.

Search dates

April 2009 - June 2013

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.

exp Candidiasis, Oral/ (mucosal adj candida).tw.

(candida OR candidal OR candidiasis OR candidoses OR candidosis OR moniliasis OR thrush).tw AND (oral or oropharyngeal or oro-pharyngeal or oropharynx or mouth).tw

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSH subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

Infectious Diseases Society of America

American Academy of Oral Medicine

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

References

ABPI Medicines Compendium (2013) Summary of product characteristics for Diflucan 50mg hard capsules. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013) Summary of product characteristics for Daktarin Oral Gel. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013) Summary of product characteristics for Nystan Oral Suspension (Ready - Mixed). Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

ABPI Medicines Compendium (2013) Summary of product characteristics for Daktarin Oral Gel. Electronic Medicines CompendiumDatapharm Communications Ltd. www.medicines.org.uk [Free Full-text]

Akpan, A. and Morgan, R. (2002) Oral candidiasis. Postgraduate Medical Journal 78(922), 455-459. [Abstract] [Free Full-text]

Aly, F.Z., Blackwell, C.C., Mackenzie, D.A. et al. (1992) Factors influencing oral carriage of yeasts among individuals with diabetes mellitus. Epidemiology & Infection 109(3), 507-518. [Abstract] [Free Full-text]

Bartholomew, G.A., Rodu, B. and Bell, D.S. (1987) Oral candidiasis in patients with diabetes mellitus: a thorough analysis. Diabetes Care 10(5), 607-612. [Abstract]

Baxter, K. and Preston, C.L. (Eds.) (2013) Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management. 10th edn. London: Pharmaceutical Press.

Belazi, M., Velegraki, A., Fleva, A. et al. (2005) Candidal overgrowth in diabetic patients: potential predisposing factors. Mycoses 48(3), 192-196. [Abstract]

Bensadoun, R.J., Daoud, J., El Gueddari, B. et al. (2008) Comparison of the efficacy and safety of miconazole 50-mg mucoadhesive buccal tablets with miconazole 500-mg gel in the treatment of oropharyngeal candidiasis: a prospective, randomized, single-blind, multicenter, comparative, phase III trial in patients treated with radiotherapy for head and neck cancer. Cancer 112(1), 204-211. [Abstract] [Free Full-text]

BNF 65 (2013) British National Formulary. 65th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.

BNF for Children (2013) British National Formulary for Children 2013-2014. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain.

Breathnach, S.M. (2010) Lichen planus and lichenoid disorders. In: Burns, T., Breathnach, S., Cox, N. and Griffiths, C. (Eds.) Rook's textbook of dermatology. 8th edn. Oxford: Wiley-Blackwell. 41.1-41.28.

Clarkson, J.E., Worthington, H.V. and Eden, O.B. (2007) Interventions for preventing oral candidiasis for patients with cancer receiving treatment (Cochrane Review). The Cochrane Library. Issue 1. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

DermNet NZ (2013) Oral candidiasis. New Zealand Dermatological Society Incorporated. http://dermnetnz.org [Free Full-text]

DTB (2000) Inhaler devices for asthma. Drug & Therapeutics Bulletin 38(2), 9-14. [Abstract]

Ellepola, A.N. and Samaranayake, L.P. (2001) Adjunctive use of chlorhexidine in oral candidoses: a review. Oral Diseases 7(1), 11-17. [Abstract]

Goins, R.A., Ascher, D., Waecker, N. et al. (2002) Comparison of fluconazole and nystatin oral suspensions for treatment of oral candidiasis in infants. Pediatric Infectious Disease Journal 21(12), 1165-1167. [Abstract]

Gonsalves, W.C., Chi, A.C. and Neville, B.W. (2007) Common oral lesions: part I. Superficial mucosal lesions. American Family Physician 75(4), 501-507. [Abstract] [Free Full-text]

Guggenheimer, J., Moore, P.A., Rossie, K. et al. (2000) Insulin-dependent diabetes mellitus and oral soft tissue pathologies: II. Prevalence and characteristics of Candida and candidal lesions. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics 89(5), 570-576. [Abstract]

Hay, R.J. and Ashbee, H.R. (2010) Mycology. In: Burns, T., Breathnach, S., Cox, N. and Griffiths, C. (Eds.) Rook's textbook of dermatology. 8th edn. Chichester: Wiley-Blackwell. 36.1-36.93.

Hill, L.V., Tan, M.H., Pereira, L.H. and Embil, J.A. (1989) Association of oral candidiasis with diabetic control. Journal of Clinical Pathology 42(5), 502-505. [Abstract] [Free Full-text]

Hoppe, J.E. (1997) Treatment of oropharyngeal candidiasis and candidal diaper dermatitis in neonates and infants: review and reappraisal. Pediatric Infectious Disease Journal 16(9), 885-894.

Hoppe, J.E. (1997) Treatment of oropharyngeal candidiasis in immunocompetent infants: a randomized multicenter study of miconazole gel vs. nystatin suspension. The Antifungals Study Group. Pediatric Infectious Disease Journal 16(3), 288-293. [Abstract]

Hoppe, J.E. and Hahn, H. (1996) Randomized comparison of two nystatin oral gels with miconazole oral gel for treatment of oral thrush in infants. Antimycotics Study Group. Infection 24(2), 136-139. [Abstract]

Koray, M., Ak, G., Kurklu, E. et al. (2005) Fluconazole and/or hexetidine for management of oral candidiasis associated with denture-induced stomatitis. Oral Diseases 11(5), 309-313. [Abstract]

Kumar, B.V., Padshetty, N.S., Bai, K.Y. and Rao, M.S. (2005) Prevalence of Candida in the oral cavity of diabetic subjects. Journal of the Association of Physicians of India 53(Jul), 599-602. [Abstract]

Laudenbach, J.M. and Epstein, J.B. (2009) Treatment strategies for oropharyngeal candidiasis. Expert Opinion on Pharmacotherapy 10(9), 1413-1421. [Abstract]

MHRA (2013) Press release: oral ketoconazole-containing medicines should no longer be used for fungal infections. Medicines and Healthcare Products Regulatory Agency. www.mhra.gov.uk [Free Full-text]

MHRA (2013) Oral ketoconazole: do not prescribe or use for fungal infections—risk of liver injury outweighs benefits. Drug Safety Update 7(1), S1. [Free Full-text]

Pappas, P.G., Kauffman, C.A., Andes, D. et al. (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clinical Infectious Diseases 48(5), 503-535. [Abstract] [Free Full-text]

Pienaar, E., D., Young, T. and Holmes, H. (2010) Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children (Cochrane Review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Rachelefsky, G.S., Liao, Y. and Faruqi, R. (2007) Impact of inhaled corticosteroid-induced oropharyngeal adverse events: results from a meta-analysis. Annals of Allergy, Asthma and Immunology 98(3), 225-238. [Abstract]

Samaranayake, L.P., Keung, L.W. and Jin, L. (2009) Oral mucosal fungal infections. Periodontology 2000 49(1), 39-59.

Scottish Medicines Consortium (2011) Miconazole (Loramyc) (resubmission). Scottish Medicines Consortium. www.scottishmedicines.org.uk [Free Full-text]

Scully, C. and Hegarty, A. (2010) The oral cavity and lips. In: Burns, T., Breathnach, S., Cox, N. and Griffiths, C. (Eds.) Rook's textbook of dermatology. 8th edn. Oxford: Wiley-Blackwell. 69.1-69.129.

Soysa, N.S., Samaranayake, L.P. and Ellepola, A.N. (2006) Diabetes mellitus as a contributory factor in oral candidosis. Diabetic Medicine 23(5), 455-459. [Abstract]

Su, C.W., Gaskie, S., Jamieson, B. and Triezenberg, D. (2008) What is the best treatment for oral thrush in healthy infants? Journal of Family Practice 57(7), 484-485.

van Roey, J., Haxaire, M., Kamya, M. et al. (2004) Comparative efficacy of topical therapy with a slow-release mucoadhesive buccal tablet containing miconazole nitrate versus systemic therapy with ketoconazole in HIV-positive patients with oropharyngeal candidiasis. Journal of Acquired Immune Deficiency Syndromes 35(2), 144-150. [Abstract]

Wilson, J. (1998) The aetiology, diagnosis and management of denture stomatitis. British Dental Journal 185(8), 380-384. [Abstract]

Worthington, H.V., Clarkson, J.E., Khalid, T. et al. (2010) Interventions for treating oral candidiasis for patients with cancer receiving treatment (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]