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Treatment of oropharyngeal candidiasis in immunocompetent and immunocompromised patients

Massimo Petruzzi1* and Fedora Della Vella1
  • 1 Università degli Studi di Bari, Interdisciplinary Department of Medicine, Italy

Oral candidiasis is a common opportunistic infection of the oral cavity caused by an overgrowth of yeasts that belong to the genus Candida, the most common being Candida albicans. Predisposing and inducing factors are fundamental for infection development and its chronicity. The development of acute and/or chronic forms of oropharyngeal candidiasis is linked to different causes depending on the immunocompetence or immunocompromise of the patient. However, it is not possible to define exactly a patient as immunocompromised or immunosuppressed, because there are no universally recognized guidelines or cut-off values. Conventionally, are classified as immunocompromised subjects, those with AIDS or HIV infection, radio and chemo-treated patients, patients treated with immunosuppressive drugs, including bone marrow and solid organs transplanted. Non-immunosuppressed patients suffering from recurrent Candida infections are those who wear removable prostheses, those subjected to prolonged antibiotic therapy or who take hypo-salivation inducing drugs. Finally, it’s recognizable a separate category of individuals, who are not properly immunocompromised but present alterations of the normal immune homeostasis, i.e. patients with a para-physiological state (elderly and newborn), diabetics, patients affected by Sjögren’s Syndrome or APECED or malnourished people. Before taking any therapeutic action, it is imperative to recognize the basic condition that promoted Candida adhesion, proliferation and penetration in the context of the oral mucosa, to remove it or at least control it. An oral swab for the detection of mycetes and an eventual antimycogramm are essential in order to set a therapy as more focused, effective and limiting the phenomena of drug resistance. Polyenics (amphotericin B, nystatin, natamycin), azoles (imidazoles and triazoles), allylamines, analogues of DNA, nikkomycins and echinocandins are the main drugs available for the management of oropharyngeal candidiasis (Neppelenbroek et al., 2014). Topical treatment is the first instance therapy in the uncomplicated cases of oral candidiasis. Systemic therapy is indicated in those patients who do not respond to topical therapy or have a high risk of developing a candidemia (Epstein and Polsky, 1998). The clinical practice guideline for the management of candidiasis edited by the Infectious Diseases Society of America and published in 2016, provides important indications for the treatment of the oropharyngeal candidiasis (Pappas et al., 2016). For mild candidiasis, clotrimazole troches, 10 mg 5 times daily (not available in Italy) or miconazole mucoadhesive buccal tablet 50 -mg applied to the mucosal surface over the canine fossa once daily for 7–14 days are recommended (strong recommendation; high-quality evidence). As second choice (strong recommendation; moderate-quality evidence) nystatin suspension (100 000 U/mL) 4–6 mL 4 times daily, or 1–2 nystatin pastilles (200 000 U each) 4 times daily, for 7–14 days (not available in Italy) are recommended. For moderate to severe disease, oral fluconazole, 100–200 mg daily, for 7–14 days is recommended (strong recommendation; high-quality evidence). For fluconazole-refractory disease, itraconazole solution, 200 mg once daily, or posaconazole suspension, 400 mg twice daily for 3 days then 400 mg daily for up to 28 days, is recommended (strong recommendation; moderate-quality evidence). In AIDS/HIV patients, oral candidiasis is one of the first clinical manifestations occurring with a CD4 count <200cells/µL. The HAART therapy has dramatically changed the course of this infectious disease, including the prevalence of oropharyngeal candidiasis and its resistance to treatment. In particular, antifungal treatment in AIDS/HIV patients aims to prevent and treat Candida infection and manages the eventual drug resistance. Primary prevention (Prophylaxis) reduces the risk of infection but is not associated with higher survival rates and increases the risk of resistance to azoles. Prevention is recommended in case of recurrent episodes of candidiasis (more than 3 episodes per year). Oral fluconazole, 100–200 mg 3 times per week, is recommended. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published in 2012 the guidelines for the treatment of oropharyngeal candidiasis in AIDS/HIV patients that includes fluconazole (100mg/qd for 7 days) as a first-line drug (level of recommendation A – level of evidence I). As second choice, the ESCMID suggests miconazole mucoadhesive tablets or itraconazole oral solution (level of recommendation B – level of evidence I). No evidence of topical therapy efficacy for oropharyngeal candidiasis in AIDS/HIV patients is demonstrated. The resistance to fluconazole is an eventuality that requires the alternative use of posaconazole or voriconazole. Amphotericin B or echinocandin is mandatory in case of a diffuse resistance to the azoles (Pienaar et al., 2010;Lortholary et al., 2012). In bone marrow transplanted patients, the severe induced immunosuppression requires high doses of fluconazole (400mg/qd), while weak evidence exists in solid organ transplanted patients. Interactions between cyclosporine and azoles should be carefully considered. The antifungal treatment is finalized to prevent and avoid episodes of candidemia and deep mycosis (Lortholary et al., 2012). In people with immunosuppression following cancer treatment (chemo-radio), the meta-analytic analysis performed by Clarkson et al, suggests that absorbed (ketoconazole, itraconazole or fluconazole) or partially absorbed antifungal drugs (miconazole and clotrimazole) are efficacious in preventing and treating oropharyngeal candidiasis compared with placebo or non-absorbed antifungal drugs (Clarkson et al., 2007). Oral solution of nystatin for oral rinses is not recommended for prophylaxis and/or treatment of Candida infection in immunosuppressed patients. Its action on oropharyngeal mucosa is not adequate because few seconds of contact on the mucosal surface does not allow an efficacious antifungal effect. Moreover, nystatin does not act on the gastrointestinal Candida reservoir. Nystatin is recommended in pregnancy instead of azoles due to their toxicity for the foetus (Gotzsche and Johansen, 2014;Lyu et al., 2016). About the 54% of denture wearers suffered from denture stomatitis (DS) but only limited evidence is available for its treatment. Although several meta-analyses have been published on the efficacy of different DS treatments, no definitive guidelines exist (Di Stasio et al., 2018). Topical and systemic fluconazole and nystatin are more effective than placebo but in studies in which placebo was orabase or an adhesive paste, no statistical differences was observed. The mechanical trauma attenuation, the correct denture hygiene and the removal during the night, are the fundamentals for the DS remission. Chlorhexidine, hexetidine, sodium iodide showed the same efficacy of polyenes or azoles in DS patients’ management. The physical treatment using microwave (850 W for 1min. 3 times/week or 650 W for 6 min) or photodynamic therapy is comparable to the nystatin oral suspension. Miconazole, clotrimazole and amorolfine lacquer, usually used in onychomycosis, are also effective if applied on the prosthetic base (Petruzzi et al., 2010;Emami et al., 2014;Papadiochou and Polyzois, 2018). New pharmacological, behavioural and immunological approaches will be available in the next future in order to prevent and/or treat oropharyngeal candidiasis. Modification of oral microbiome thanks to the probiotics, specific dietetic regimes, vaccination and other new specific and less toxic drugs are promising alternatives for oropharyngeal candidiasis management (Rodrigues et al., 2018).

References

1. Clarkson, J.E., Worthington, H.V., and Eden, O.B. (2007). Interventions for preventing oral candidiasis for patients with cancer receiving treatment. Cochrane Database Syst Rev, CD003807. 2. Di Stasio, D., Lauritano, D., Minervini, G., Paparella, R.S., Petruzzi, M., Romano, A., Candotto, V., and Lucchese, A. (2018). Management of denture stomatitis: a narrative review. J Biol Regul Homeost Agents 32, 113-116. 3. Emami, E., Kabawat, M., Rompre, P.H., and Feine, J.S. (2014). Linking evidence to treatment for denture stomatitis: a meta-analysis of randomized controlled trials. J Dent 42, 99-106. 4. Epstein, J.B., and Polsky, B. (1998). Oropharyngeal candidiasis: a review of its clinical spectrum and current therapies. Clin Ther 20, 40-57. 5. Gotzsche, P.C., and Johansen, H.K. (2014). Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev, CD002033. 6. Lortholary, O., Petrikkos, G., Akova, M., Arendrup, M.C., Arikan-Akdagli, S., Bassetti, M., Bille, J., Calandra, T., Castagnola, E., Cornely, O.A., Cuenca-Estrella, M., Donnelly, J.P., Garbino, J., Groll, A.H., Herbrecht, R., Hope, W.W., Jensen, H.E., Kullberg, B.J., Lass-Florl, C., Meersseman, W., Richardson, M.D., Roilides, E., Verweij, P.E., Viscoli, C., Ullmann, A.J., and Group, E.F.I.S. (2012). ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS. Clin Microbiol Infect 18 Suppl 7, 68-77. 7. Lyu, X., Zhao, C., Yan, Z.M., and Hua, H. (2016). Efficacy of nystatin for the treatment of oral candidiasis: a systematic review and meta-analysis. Drug Des Devel Ther 10, 1161-1171. 8. Neppelenbroek, K.H., Seo, R.S., Urban, V.M., Silva, S., Dovigo, L.N., Jorge, J.H., and Campanha, N.H. (2014). Identification of Candida species in the clinical laboratory: a review of conventional, commercial, and molecular techniques. Oral Dis 20, 329-344. 9. Papadiochou, S., and Polyzois, G. (2018). Hygiene practices in removable prosthodontics: A systematic review. Int J Dent Hyg 16, 179-201. 10. Pappas, P.G., Kauffman, C.A., Andes, D.R., Clancy, C.J., Marr, K.A., Ostrosky-Zeichner, L., Reboli, A.C., Schuster, M.G., Vazquez, J.A., Walsh, T.J., Zaoutis, T.E., and Sobel, J.D. (2016). Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 62, e1-50. 11. Petruzzi, M., Grassi, F.R., Nardi, G.M., Martinelli, D., Serpico, R., Luglie, P.F., and Baldoni, E. (2010). Sodium iodide associated to salicylic acid in the topical management of chronic oral candidiasis: a randomized trial. J Biol Regul Homeost Agents 24, 381-384. 12. 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 Database Syst Rev, CD003940. 13. Rodrigues, C.F., Rodrigues, M.E., and Henriques, M.C.R. (2018). Promising alternative therapeutics for oral candidiasis. Curr Med Chem.

Keywords: Oropharyngeal candidiasis, Immunodepression, Denture stomatitis, candidiasis treatment, Nystatin, Azoles

Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.

Presentation Type: oral presentation

Topic: Oral Diseases

Citation: Petruzzi M and Della Vella F (2019). Treatment of oropharyngeal candidiasis in immunocompetent and immunocompromised patients. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00085

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Received: 27 Nov 2018; Published Online: 09 Dec 2019.

* Correspondence: Prof. Massimo Petruzzi, Università degli Studi di Bari, Interdisciplinary Department of Medicine, Bari, 70121, Italy, massimo.petruzzi@uniba.it