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 Moore, 2004] 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, 2008] and the British National Formulary [BNF 57, 2009].
• 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, 2008].
• The manufacturers of oral fluconazole [ABPI Medicines Compendium, 2007b] and miconazole oral gel [ABPI Medicines Compendium, 2008a] 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, 2008]. For more information, see the relevant Summary of Product Characteristics in the electronic Medicines Compendium (eMC) http://emc.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 effective 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, 2006].
• 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, 2007], 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, 2007].
• Fluconazole is systemically absorbed, which is an advantage for widespread candidal infection.

Drugs that are not recommended

• Miconazole mucoadhesive buccal tablets are currently undergoing post-marketing surveillance (black triangle) and are licensed for the treatment of oropharyngeal candidiasis in immunocompromised people [ABPI Medicines Compendium, 2008b].
• 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, 2008]. For these reasons, CKS recommends seeking specialist advice before prescribing this formulation.
• Oral itraconazole should be reserved for people with fluconazole-resistant candidiasis [BNF 57, 2009]. Specialist advice should be obtained before initiating itraconazole therapy because of the increased risk of drug interactions and adverse effects.
• Oral ketoconazole should only be prescribed for the treatment of chronic mucocutaneous candidiasis (that cannot be treated topically because of the site, extent of the lesion, or deep infection of the skin), and in people resistant to or intolerant of both fluconazole and itraconazole [MHRA, 2008].
• 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 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 57, 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 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 57, 2009].
• 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.