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J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral

Journal section: Oral Medicine and Pathology doi:10.4317/jced.51798 Publication Types: Review http://dx.doi.org/10.4317/jced.51798

Current treatment of : A literature review

Carla Garcia-Cuesta 1, Maria-Gracia Sarrion-Pérez 2, Jose V. Bagán 3

1 Dentist. Postgraduate in Oral Medicine 2 Associate profesor of Oral Medicine Unit. Department of Stomatology. University of Valencia 3 Chairman of Oral Medicine. Oral Medicine Unit. Department of Stomatology. University of Valencia. Head of the Department of Stomatology and Maxilofacial Surgery. Valencia University General Hospital

Correspondence: Avd. / Maestro Rodrigo 13-16 Garcia-Cuesta C, Sarrion-Pérez MG, Bagán JV. Current treatment of oral 46015 Valencia, Spain candidiasis: A literature review. J Clin Exp Dent. 2014;6(5):e576-82. [email protected] http://www.medicinaoral.com/odo/volumenes/v6i5/jcedv6i5p576.pdf

Article Number: 51798 http://www.medicinaoral.com/odo/indice.htm © Medicina Oral S. L. C.I.F. B 96689336 - eISSN: 1989-5488 Received: 19/06/2014 eMail: [email protected] Accepted: 26/07/2014 Indexed in: Pubmed Pubmed Central® (PMC) Scopus DOI® System

Abstract Candidiasis or oral candidosis is one of the most common human opportunistic fungal of the oral cavity. This pathology has a wide variety of treatment which has been studied until these days. The present study offers a literature review on the treatment of oral candidiasis, with the purpose of establish which treatment is the most suitable in each case. Searching the 24 latest articles about treatment of candidiasis it concluded that the incidence depends on the type of the candidiasis and the virulence of the . Although and were the most drugs used locally, fluconazole oral suspension is proving to be a very effective drug in the treatment of oral candidiasis. Fluconazole was found to be the drug of choice as a systemic treatment of oral candidiasis. Due to its good properties, its high acceptance of the patient and its efficacy compared with other antifungal drugs. But this drug is not always effective, so we need to evaluate and distinguish others like itraconazole or keto- conazole, in that cases when strains resist to fluconazole.

Key words: Candidiasis, treatment, , fluconazole, nystatin.

Introduction Table 1. Predisposing factors. The incidence of fungal infections has been increasing Systemic Local over the last decades, being more prevalent in developed Hormonal disorders Epithelial changes countries (1). An increase incidence of the infections is Physiological disorders Poor associated with some predisposing factors (Table 1) as Endocrine disorders Loss of vertical dimension the use of , , prolonged therapy with Immunologic disorders Poor fitting dentures antibiotics, local trauma, , endocrine disor- Xerostomia ders, increased longevity of people, among other states Drug therapy that diminish the quality of defense of the individual (2). Alcohol Oral candidiasis is one of the most common clinical fea- tures of those patients infected with the human immuno- Oropharyngeal candidiasis is caused by the genus Can- deficiency virus [HIV], this manifestation was seen in dida; it is possible to isolate about 150 species. Many up to 90% of individuals infected with HIV (3). of these remain as a commensal micro-organism in hu-

e576 J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis

mans, which could act as an opportunistic pathogens of- tion; Appropriate use of antifungal drugs, evaluating the ten associated with predisposing factors attributed to the efficacy / toxicity ratio in each case. organism, thereby causing acute or chronic infections When choosing between some treatments it will take (4). The most important of these species is C. albicans, into account the type of Candida, its clinical pathology which is most commonly isolated from the oral cavity and if it is enough with a topical treatment or requires a and is believed to be more virulent in humans, occurring more complex systemic type (8), always evaluating the in approximately 50% of the cases of candidiasis. ratio efficacy and toxicity (9). The different drugs are Clinically there are a number of different types of oral contained in table 3. candidiasis (Table 2). Therefore the choice of therapy is Regular oral and dental hygiene with periodic oral exa- guided by the type of candidiasis. mination will prevent most cases of oral candidiasis, so The diagnosis of oral candidiasis is essentially clinical it is need to make the patient aware of oral hygiene mea- and is based on the recognition of the lesions by the pro- sures. Oral hygiene involves cleaning the teeth, buccal fessional, which can be confirmed by the microscopic cavity, , and dentures. As well as the use of anti- identification of Candida (5). The techniques available Candida rinses such as or , so for the isolation of Candida in the oral cavity include that they can penetrate those areas where the brush does direct examination or cytological smear, culture of mi- not. In addition, the need to remove the dentures at night croorganisms and which is indicated for cases of and wash it consciously, leaving it submerged in a disin- hiperplasic candidiasis because this type could present fectant solution like Chlorhexidine (10). (6). This study provides a literature review of the treatment The treatment of oral candidiasis is based on four fun- of oral candidiasis and its objectives are to establish ge- daments (7): making an early and accurate diagnosis of neral guidelines for treatment of oral candidiasis; Assess the infection; Correcting the predisposing factors or un- the drug of choice for local treatment of oral candidiasis; derlying diseases; Evaluating the type of Candida infec- Assess the systemic treatment for oral candidiasis.

Table 2. Clinical classification. Acute Chronic Other lesions Pseudomembranous Pseudomembranous Angular Erythematous Erythematous Denture-associated erythematous Hyperplastic Median rhomboid

Table 3. Antifungal agents. Vademecum. DRUG FORMULATION DOSE ADVERSE EFFECT

Anfotericin b 50mg for infusion 100-200mg/6h Renal, cardiovascular, spinal and neurological

Nystatin Suspension 60ml 4-6ml / 6h Well tolerated. Ointment 30g 2 to 4 applications / day Tablets 2 every 8h Uncommon Nausea, vomiting, gastrointestinal effects

Clotrimazole Gel 1% 3 times / day Occasionally Skin irritation, burning sensation Tablets 10mg 5 times / day Miconazole Gel 100mg /6h Uncommon Burning, irritation, nausea, diarrhea,

Ketoconazole Gel 2% 3 times/ day Nausea, vomiting Tablets 200mg 1-2/day Abdominal pain. Suspension 30 or 10cc Fluconazole Tablets 50 - 100mg/day Nausea, vomiting, diarrhea, abdominal pain. Suspension 10mg/ml Itraconazole Capsule 100-200mg/day Nausea, vomiting, diarrhea, abdominal pain.

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Material and Methods As first choice for local treatment has been for years the A Medline-PubMed search was made using the fo- nystatin at doses of 100 000 IU/ml [5ml 4 times daily] llowing key words: “ oral candidiasis” OR “oral candi- and amphotericin b at 50mg [5ml 3 times per day]. This dosis” AND amphotericin, “oral candidiasis” OR “oral choice is because they are poorly absorbed by the in- candidosis” AND nystatine, “oral candidiasis” OR “oral testinal tract and therefore most of the antifungal is ex- candidosis” AND miconazole, “oral candidiasis” OR creted without undergoing any change, thereby reducing “oral candidosis” AND ketoconazole, “oral candidiasis” hepatotoxicity (14). However, the unpleasant taste and OR “oral candidosis” AND , “oral candidia- prolonged pattern compromise treatment compliance by sis” OR “oral candidosis” AND fluconazole, “oral can- the patient (14-16). didiasis” OR “oral candidosis” AND itraconazole, “oral Throughout the years it has been studying the effective- candidiasis” OR “oral candidosis” AND treatment, “oral ness of other drugs like fluconazole oral solution. Many candidiasis” OR “oral candidosis” AND “antifungal authors have focused on evaluating the efficacy and therapy”.The key words were validated by the MeSH safety of fluconazole oral solution for the treatment of [Medical Subject Headings] dictionary, with use of the oropharyngeal candidiasis, especially pseudomembra- boolean operator “AND” to relate them. nous type, giving good results, although many studies The following limits for inclusion of the studies were esta- are still needed (14-18). blished: articles published from 2000, publications in En- In a recent study conducted in 19 patients with pseudo- glish and Spanish and publications of studies in humans. membranous candidiasis show that fluconazole suspen- All systematic reviews, clinical trials, meta-analysis and sion in distilled water [2mg/ml] reaches a 95% cure. comparative studies were considered in this review. The guideline was to rinse with 5ml of the drug solution A total of 109 articles were identified, of which 30 were for 1 minute and then spit it out and repeat this action selected after reading the abstracts. Following analysis 3 times a day for 1 week. Another study which inclu- of the 30 articles, we finally included a total of 24, since ded 36 children with pseudomembranous candidiasis those publications that did not fit the aims of the present showed that fluconazole oral suspension 10mg/ml dose study were excluded. gave better results than nystatin. The main problem was the poor adherence of the nystatin to the and Results thus the quick ingestion of the suspension, resulting in a A total of 24 articles were found about antifungal lower efficiency (14). treatment, of which 20 were clinical trials, 3 systematic On the other hand, in another study comparing amphote- reviews and 1 a clinical case (Table 4). ricin b suspension, the fluconazole oral suspension gave better results in terms of the eradication of Candida (16). Discussion The same was corroborated by Taillandier et al. (18), which reported that fluconazole oral suspension was as Candida infection today is highly prevalent, especia- effective as amphotericin b, but it was better accepted lly the increase in carriers of removable dentures and by the patient. poor oral hygiene society. Depending on its virulence, Fluconazole oral suspension is administered in a dosage location and type of candidiasis there will carry on one of 10 mg / ml aqueous suspension by administering 5 ml treatment or another. daily for 7 or 14 days. Different studies show that it is First has been supported the use of conservative mea- a very effective drug against pseudomembranous candi- sures before starting drug treatment, promoting good diasis, as it has good adhesion to the surface of the oral oral hygiene along with removing the dentures at night, mucosa and a rapid symptomatic response. It also offers thereby it will benefit the removal of the layer the convenience of a one-daily dosing, which may ex- generated in the prosthetic surface (11). Dentists should plain the better patient compliance (14-18). also correct the predisposing factors and underlying di- Another topic drug widely used is miconazole (19). seases and try to promote the use of oral and We found it in the form of gel, applying it directly on antibacterial rinses such as Chlorhexidine or Hexetidine the affected area, at doses of 200-500 mg per day, divi- (12). These measures are very effective in patients with ded into 4 times. Despite its good properties it has the denture (12). It was also found in the study of drawback of possible interaction with other drugs, such Cross et al. (13) that in patients with good oral hygiene as warfarin. This is because the antifungal inhibit the en- the recurrence of candidiasis after 3 years was lower. zyme cytochrome P-450, which affects the clearance of Regarding the pharmacological treatment of candidiasis certain drugs (20,21). In addition, this drug is absorbed can be distinguished between two procedures. Topical by the intestine, therefore care must be taken when is drugs, which are applied to the affected area and treat administrated. superficial infections and systemic drugs those that are It has been introduced in the market an alternative pre- prescribed when the infection is more widespread and sentation of miconazole. A one-daily miconazole 50 mg has not been enough with the topical therapy.

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´Table 4. Summarized articles. Author/ Year Article Type of article Drug Dose Conclusions / Sample Manfredi et In vitro antifungal susceptibility to Clinical trial Itraconazole In vitro Those strains that were al. (11) 2006 six antifungal agents of 229 Miconazole preparations resistant to fluconazole Candida isolates from patients n=821 Ketoconazole also were resistant to with mellitus Fluconazole other drugs. Anfotericin b Koray et al. Fluconazole and/or hexetidine for Clinical trial Hexetidine rinse 2/d Supports the use of (12) management of oral candidiasis Heksoral® or 2005 associated with denture-induced n=61 0,1% hexetidine as a first stomatitis Fluconazole 50 mg 1/d choice. Zolax® cap- Conservative i sules ntervention Cross et al. Evaluation of the recurrence of Clinical trial Itraconazole 10ml 2/d Best systemic (13) denture stomatitis and Candida rinse 100mg 2/d- itraconazole 2004 colonization in a small group of n=22 Itraconazole 15d patients who received itraconazole capsules Goins et al. Comparison of fluconazole and ny- Clinical trial Nystatin sus- 1ml Fluconazole more (14) statin oral suspension for treatment n=19 pension 4/d-10d effective 2002 of oral candidiasis in infants Fluconazole n=15 suspension 10mg/ml (Diflucan®) 1/d-7d Epstein et al. Fluconazole mouthrinses for oral Clinical trial Fluconazole 5ml 3/d Clinical improvements (15) candidiasis in postirradiation oral solution 2002 transplant, and other patients n=19 Lefebvre et A comparative study of the Clinical trial Fluconazole 5 ml (50 mg) Better accepted the al. (16) efficacy and safety of fluconazole n=123 oral solution 1/d fluconazole 2002 oral suspension and 5ml amphotericin B oral suspension in n=120l 5ml- 3/d patients with mucositis Anfotericin b 7-14 d oral solution 5ml Sholapurkar Comparison of efficacy of Clinical trial Fluconazole 5ml Mayor cure rate with et al. (17) fluconazol mouthrinse and n= 27 3/d -14d fluconazole 2009 clotrimazole mouthpaint in the treatment of oral candidiasis n= 28 Clotrimazole mouthpaint 3/d Taillander et A comparison of fluconazole oral Clinical trial Fluconazole 5ml(50mg) No significant al. (18) suspension and amprotericin B oral n=150 oral suspension 1/d difference 2000 suspension in older patients with oropharyngeal candidosis n= 155 Anfotericin b 5ml- 3/d oral suspension Isham et al. Antifungal activity of miconazole Clinical trial Miconazole In vitro pre- Miconazole presents (19) 2010 against recent Candida strains n=25 paration great inhibitory activity Pemberton et Miconazole oral gel and drug Clinical case Miconazole gel 125mg/d 3d Decreased the al. (20) interactions clearance of some 2004 drugs and is absorbed by the intestine Miki et al. Warfarin and miconazole oral gel Systematic Miconazole gel 200-400 mg/d Interactions with other (21) interactions: analysis and therapy review drugs 2011 recommendations based on clinical data and a pharmacokinetic model Collins et al. Management of oropharyngeal Systematic Miconazole 50mg 1/d Limited systemic (22) candidiasis with localized oral review buccal tablets absorption. Good 2011 miconazole therapy: efficacy, efficacy safety, and patient acceptability Vazquez et al. Miconazole Mucoadhesive Tablets: Systematic Miconazole 50mg 1/d Little systemic (23) A Novel Delivery System review mucoadhesive absorption. 2012 n=25 tablets 94.7% efficacy

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Author/ Year Article Type of article Drug Dose Conclusions / Sample Czerninski et A novel sustained-release Clinical trial Clotrimazole 5 times/d Varnish more al. (24) clotrimazole varnish for local treatment of varnish and prolonged effect 2010 oral candidiasis n= 14 troches Oji et al. (25) Evaluation and treatment of oral Clinical trial Nystatin rinses 5ml For HIV patients, 2008 candidiasis in HIV/AIDS patient in (micostatin®) 4/d- 14d more effective the Enugu, Nigeria n=29 Ketoconazole 200mg/ d systemic treatment tablets 14d (ketoconazole) (nizoral®) Bensadoun et Comparison of the efficacy and safety of Clinical trial Miconazole 50mg 1/d Best treatment plan al. (26) miconazole 50-mg mucoadhesive buccal mucoadhesive the mucoadhesive 2008 tablets with miconazole 500-mg gel in the n=141 tablets tablets treatment of oropharyngeal Miconazole gel 125mg 4/d candidiasis Koks et al. Prognostic factors for the clinical Clinical trial Fluconazole 100mg/d Great efficacy of (27) effectiveness of fluconazole in the capsules fluconazole 2002 treatment of oral candidiasis in HIV-1- n=28 Diflucan ® infected individuals Lyon et al. Correlation between adhesion, Clinical trial Fluconazole In vitro Fluconazole (28) production, and preparations reduces 2006 susceptibility to fluconazole inCandida n=99 and cell albicans obtained from dentures wearers colonization Oude Lashof An open multicentre Clinical trial Fluconazole 100mg 1/d- Fluconazole better et al. (29) comparative study of the efficacy, safety capsules 10d result 2004 and tolerance of fluconazole and n=252 itraconazole in the treatment of cancer 200mg 1/d- patients with oropharyngeal candidiasis Itraconazole 15d capsules Kuriyama et In vitro susceptibility of oral Clinical trial Fluconazole In vitro Some Candida al. (30) Candida to seven antifungal agents Itraconazole preparations species are resistant 2005 n=521 Voriconazole to antifungal drugs Ketoconazole Miconazole Anfotericin b Nystatin Brito et al. In vitro antifungal susceptibility of Clinical trial Anfotericin b In vitro pre- Antifungal agents (31) Candida spp. Oral isolates from HIV- n=71 cepas de Fluconazole parations showed good 2011 positive patients and control individuals Cándida Flucytosine activity against the Nystatin strains Ketoconazole Ally et al. A randomized, double-blind, Comparative Fluconazole 200mg 1/d Voriconazole was at (32) double-dummy, multicenter trial of clinical trial capsules least as effective as 2001 voriconazole and fluconazole in the Voriconazole 200mg 1/d fluconazole treatment of in n=256 capsules immunocompromised patients Khozeimeh et Comparative evaluation of Clinical trial Ketoconazole 200mg 1/d Miconazole al. (33) ketoconazole tablet and topical systemic mucoadhesive 2010 ketoconazole 2% in orabase in treatment n=30 Ketoconazole 2% 2/d tablet used as of Candida-infected denture stomatitis. topical first-line treatment Miconazole 50 mg because of its good mucoadhesive tolerance tablet Van Roey et Comparative efficacy of topical therapy Clinical trial Miconazole 10mg Miconazole al. (34) with a slow-release mucoadhesive buccal mucoadhesive mucoadhesive 2004 tablet containing miconazole nitrate n=167 tablet tablets were as versus systemic therapy with 400 mg effective as other ketoconazole in HIV-positive patients n=165 Ketoconazole 1/d- 14d systemic drugs with oropharyngeal candidiasis tablets

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mucoadhesive buccal tablet. It has a limited systemic zole capsules. But when fluconazole failed, itraconazole absorption. Its performance is mostly local and it has a was prescribed to these patients, having good results. So convenient application form. Patients are instructed to it is said that it was a good drug for fluconazole-resistant apply the rounded side of the 50 mg tablet to the upper Candida strains (29). gum region just above the right or left incisor following As it has been suggested above, it may happen that the brushing of teeth in the morning. The tablet should be Candida strains were not susceptible to fluconazole, and held in place until dissolved (22,23). It has the advanta- it has not any effect. In that case it will be used other drugs ge of being applied once daily instead 5 times a day with like itraconazole or newest ones as voriconazole (30). clotrimazole (24), and 4 times daily with nystatin (25). Keeping always in mind that strains which were resistant It has been demonstrated the effectiveness of this new to fluconazole were also resistant to other drugs (31). form of administration in the study of Bensadoun et al. The new triazol antifungal voriconazole [200 mg per (26). 141 patients with head and neck cancer with cli- day] has been shown to be a potent drug. Ally et al. (32) nical signs and symptoms of oropharyngeal candidiasis compared the efficacy of voriconazole and fluconazole received 50 mg mucoadhesive tablets of miconazole in the treatment of esophageal candidiasis. The success daily or 125 mg miconazole gel four times per day. Cli- rate was 98.3% for voriconazole and 95.1% for fluco- nical improvement was not significant between the two nazole. The results show clearly that voriconazole is at groups, but the mucoadhesive tablets exhibited higher least as effective as fluconazole in the treatment of can- salivary concentrations and better tolerance for the pa- didiasis. It suggests that this new agent may be a use- tient. Despite being more expensive, offers an effective, ful alternative for fluconazole-resistant Candida strains safe, and well tolerated topical treatment for oropharyn- (32). Because of being a new there are little strains resis- geal candidiasis (22,23,26). tant to voriconazole. The voriconazole has an important - Systemic treatment: role in the treatment of candidiasis (30), although it is In spite of knowing the efficacy of the drugs listed abo- still not fully established in the market, so many more ve, when it comes to a more generalized candidiasis or studies and research would be needed. immunocompromised patients, these would not be suffi- There have been several studies comparing topical and cient. For those cases would have to resort to treatment systemic drugs. In a study to treat denture stomatitis have with systemic drugs (25). been compared the use of ketoconazole tablets [200mg Since its introduction, fluconazole has been used to treat daily] with topical ketoconazole [2% twice daily] and systemic Candida infections because of its efficacy and miconazole mucoadhesive tablets (33). Due to the ad- good tolerability. The appropriate dose is between 50- verse effects of ketoconazole (31) like nausea, vomiting 100 mg daily (27). Furthermore, when dealing with im- and gastrointestinal problems it has been supported the munocompromised patients, such as those HIV-infected, use of other drugs when treating prosthetic candidiasis or cancerous, this drug has good effects doubling the (34). Thus the use of miconazole mucoadhesive tablet dose (28,29). Its efficacy has been demonstrated (27). was established as the drug of first line of defense for The dose was individualized depending on the severity this type of candidiasis. and type of candidiasis. Patients with pseudomembra- General treatment guidelines include after the comple- nous type started with 100 mg fluconazole daily; patients tion of an early diagnosis, the correction of predisposing with erythematous variety started with 50 mg fluconazo- factors or underlying diseases and maintaining a good le. Therefore, according to the clinic and the virulence oral hygiene. Moreover using antiseptic agents such as of the infection the dose would be titrated, giving good Chlorhexidine or Hexetidine, as well as removing den- results, and increasing the guideline in those cases whe- tures at night. All of that in order to obtain well results in re the fungal infection did not decrease (27). the treatment of oral candidiasis as first line of defense, To support the efficacy of this drug it has been compared continuing the application of antifungal drugs. Begin- with other systemic antifungal agents (29). In one ran- ning with local treatment and keeping up the systemic domized study, the efficacy of fluconazole [100mg per ones for those patients who do not respond to topical day for 10 days] and itraconazole [200mg per day for treatment or in immunocompromised patients. 15 days] was compared in patients with oropharyngeal It has recently been found that fluconazole oral suspen- candidiasis. The results were a clinical and mycologi- sion as a local treatment, at a dose of 2 mg/ml 3 times cal improvement of 66% for the first group and 54% for daily or 10 mg /ml once daily, gives good clinical results, those treated with itraconazole. The main conclusion of besides the better patient compliance due to the dosage this study is that in patients with oropharyngeal candi- and its pleasant taste. Despite not being currently the diasis, fluconazole has a significantly better clinical and most widely used locally because it requires further cli- mycological cure rate compared with itraconazole. The nical studies. Nowadays the most used drugs remains in failures of itraconazole may be explained by drug in- nystatin solution which contain 100 000 IU / ml [5ml 4 teractions and the unpredictable absorption of itracona- times daily] and miconazole gel [200 to 500 mg per day

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divided into 4 doses]. Moreover miconazole mucoad- 19. Isham N, Ghannoum MA. Antifungal activity of miconazole hesive tablets [50 mg once daily] which are considered against recent Candida strains. Mycoses. 2010;53:434-7. 20. Pemberton MN, Oliver RJ, Theaker ED. Miconazole oral gel and effective in the treatment of oropharyngeal candidiasis, drug interactions. Br Dent J. 2004;196:529-31. but their high cost is one of the main problems. 21. Miki A, Ohtani H, Sawada Y. Warfarin and miconazole oral gel Fluconazole at doses between 50-100 mg per day is the interactions: analysis and therapy recommendations based on clinical systemic drug of choice because it has high efficacy and data and a pharmacokinetic model. J Clin Pharm Ther. 2011;36:642- 50. tolerability by the patient. However it is important to 22. Collins CD, Cookinham S, Smith J. 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