UNIVERSITAS PEMBANGUNAN NASIONAL VETERAN JAKARTA JOURNAL READING ORAL CANDIDIASIS

UNIVERSITAS PEMBANGUNAN NASIONAL “VETERAN” JAKARTA JOURNAL READING ORAL CANDIDIASIS

Disusun untuk Memenuhi Syarat Mengikuti Ujian Kepaniteraan Klinik di Bagian Kulit dan Kelamin Rumah Sakit Umum Daerah Ambarawa

Diajukan Kepada : Pembimbing : dr. Hiendarto, Sp.KK Disusun Oleh : Ayu Farah Ummamah

1220221145

Kepaniteraan Klinik Departemen Kulit dan Kelamin FAKULTAS KEDOKTERAN – UPN ”VETERAN” JAKARTA Rumah Sakit Umum Daerah Ambarawa PERIODE 27 Mei – 30 Juni 2013

LEMBAR PENGESAHAN KOORDINATOR KEPANITERAAN KULIT DAN KELAMIN Journal reading dengan judul :

ORAL CANDIDIASIS

Diajukan untuk Memenuhi Syarat Mengikuti Ujian Kepaniteraan Klinik di Departemen Kulit dan Kelamin Rumah Sakit Umum Daerah Ambarawa

Disusun Oleh: Ayu Farah Ummamah

1220221145

Telah disetujui oleh Pembimbing: Nama pembimbing

Tanda Tangan

dr. Hiendarto, Sp.KK

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Mengesahkan: Koordinator Kepaniteraan Kulit dan Kelamin

dr. Hiendarto, Sp.KK NIP. 197308042009091001

Tanggal

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International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491

Vol 2, Issue 4, 2010

Review Article

ORAL CANDIDIASIS: A REVIEW

YUVRAJ SINGH DANGI1, MURARI LAL SONI1, KAMTA PRASAD NAMDEO1 Institute of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur (C.G.) – 49500 Email: [email protected] Received: 13 Jun 2010, Revised and Accepted: 16 July 2010 ABSTRACT Candidiasis, a common opportunistic fungal infection of the oral cavity, may be a cause of discomfort in dental patients. The article reviews common clinical types of candidiasis, its diagnosis current treatment modalities with emphasis on the role of prevention of recurrence in the susceptible dental patient. The dental hygienist can play an important role in education of patients to prevent recurrence. The frequency of invasive fungal infections (IFIs) has increased over the last decade with the rise in at‐risk populations of patients. The morbidity and mortality of IFIs are high and management of these conditions is a great challenge. With the widespread adoption of antifungal prophylaxis, the epidemiology of invasive fungal pathogens has changed. Non‐albicans Candida, non‐fumigatus Aspergillus and moulds other than Aspergillus have become increasingly recognised causes of invasive diseases. These emerging fungi are characterised by resistance or lower susceptibility to standard antifungal agents. Oral candidiasis is a common fungal infection in patients with an impaired immune system, such as those undergoing chemotherapy for cancer and patients with AIDS. It has a high morbidity amongst the latter group with approximately 85% of patients being infected at some point during the course of their illness. A major predisposing factor in HIV‐infected patients is a decreased CD4 T‐cell count. The majority of infections are due to C. albicans although other species such as C. glabrata, C. tropicalis, C. krusei and C. parapsilosis are increasingly isolated. The systemic azoles, ketoconazole, fluconazole and itraconazole, have been an important benefit in treatment. To date, resistance has primarily been a problem with fluconazole in AIDS. However, it is important that measures are instituted to prevent the spread of resistant strains and the development of cross‐ resistance. Although the NCCLS has established a reference method to measure in vitro susceptibility, besides already published papers, more data are necessary to demonstrate that resistance correlates with clinical failure. Keywords: Candidiasis INTRODUCTION Oral candidiasis is one of the most common, treatable oral mucosal infections seen in persons with human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS)1.Oral candidiasis can be a frequent and significant source of oral discomfort, pain, loss of taste, and aversion to food. Candida albicans carriage and a history of oral candidiasis are other significant risk factors for oral candidiasis2. The infection is caused by Candida Albicans, a dimorphic fungal organism that typically is present in the oral cavity in a non‐ pathogenic state in about one‐half of healthy individuals. Normally present as a yeast, the organism, under favorable conditions, has the ability to transform into a pathogenic (disease causing) hyphael form. Conditions that favor this transformation include broad‐spectrum antibiotic therapy, xerostomia, immune dysfunction (secondary to systemic diseases such as diabetes or the use of immune suppressant medications), or the presence of removable prostheses. Furthermore, about one in four patients with lichen planus will have superimposed candidiasis. Unless the patient is severely immunocompromised, the infection is generally limited to the superficial mucosa and skin. Invasive candidiasis infection is rare, with disseminated disease even more so. This superficial nature of the infection makes oral candidiasis so amenable to treatment. Several antifungal agents can be used topically. For topical agents, successful therapy depends on adequate contact time (2 minutes) between the agent and the oral mucosa. Treatment duration varies from 7 to 14 days, with therapy minimally continued for 2 to 3 days beyond the last clinical signs and symptoms. Topical agents have the benefit of few side effects at normal therapeutic doses because of their lack of gastrointestinal absorption. However, sucrose containing topical agents can be cariogenic when used over prolonged time periods3, such that adjunctive topical fluoride therapy may be needed. Systemic antifungals have the advantage of once‐daily dosing and simultaneous treatment of fungal infections at multiple body sites. However, these antifungals have more side effects, and selection requires consideration of important drug interactions. The present work reviews the common clinical types of oral candidiasis, its diagnosis, and current treatment modalities with emphasis on the role of prevention of recurrence in the susceptible dental patient. The dental hygienist can play an important role in the education of patients to prevent recurrence. Candidiasis is a common oral and perioral opportunistic infection that usually results from overgrowth of endogenous Candida fungal

microorganisms. There are many species of Candida (Table 1)4 but C. albicans is the fungal microorganism most often encountered in the ambulatory general practice dental patient. Changes in the oral environment that can predispose or precipitate oral candidiasis include: antibiotics, corticosteroids, dry mouth (xerostomia), diabetes mellitus, nutritional deficiencies, and immunosuppressive diseases and therapy1. Saliva contains antifungal proteins including histatins and calprotectin that help protect patients from Candida infections5. These protective proteins are absent in a patient who has xerostomia. Individuals who use corticosteroid asthma inhalers must rinse their mouths with water after each use to reduce their chances of developing oral candidiasis. Excellent oral hygiene, including brushing and flossing of the teeth twice daily and maintenance of adequate intraoral moisture, is critical in the prevention of candidiasis recurrence in the susceptible patient. Fluconazole, a novel bis‐triazole antifungal agent introduced in 1990, has systemic effects that may be beneficial for other fungal infections. Subjects in the fluconazole prophylactic arm of one antifungal placebo‐ controlled trial showed improvement of dermatophytoses, such as tinea pedis, onychomycosis, and tinea cruris6. In addition, systemic fluconazole prophylaxis may prevent esophageal and vaginal candidiasis7, cryptococcemia, histoplasmosis, and other deep fungal infections. Unlike ketoconazole, fluconazole is not altered by changes in gastric acidity and carries less risk of hepatotoxicity; however, many of the same drug interactions are possible. A newly raised concern about the wide spread use of fluconazole is the potential for development of azole‐resistant Candida albicans and selection of non‐ albicans Candida species, which also increase in prevalence with immune decline and further complicate management of some individuals8,9,10. Causative organisms Candida spp. Among the fungal pathogens, Candida spp. are the most predominant causes of invasive infections. The annual incidence of Candida associated BSIs ranged from 6 to 23 per 100 000 persons in the USA11,12 and from 2.53 to 11 per 100 000 persons in European countries13. In various reports, Candida spp. accounted for 8–10% of nosocomial BSIs11. Rising incidences of candidaemia have been reported throughout the world in the past two decades11,13,14. The

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major predisposing factors included surgical intervention, intensive care treatment, solid tumour or haematological malignancies, use of steroids and premature birth13. Crude mortality rates remain high despite advances in medical care, ranging from 30% to 50% 11,12,13. More than 95% of Candida‐associated BSIs are caused by five major species: C. albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei12,13,15,16. Candida parapsilosis occurs with high frequency in premature neonates and in patients with vascular catheters 17,18. Candida glabrata infections are rare in infants and children but are significantly more common in the elderly19. Candida tropicalis plays an important role as a cause of invasive diseases in patients with haematological malignancy20. Overall, the non‐albicans Candida spp. have shown an increasing trend as causative pathogens in BSIs21 with a 10–11% increment over a 6.5‐year period in a global report21. With the more widespread use of fluconazole, the emergence of C. glabrata and C. krusei has been reported in the USA22,23. However, the role of species with lower susceptibility to azoles has been limited in other areas. New triazoles, such as voriconazole and posaconazole, and the echinocandins are active against these two species, although cross‐resistance was noted within the azoles in some C. glabrata strains. Aspergillus spp. Aspergillus spp. are commonly found in soil, water and decaying material all over the world. Unlike invasive candidiasis, invasive aspergillosis (IA) occurs predominantly in highly immunocompromised patients24,25,26. The main affected populations are patients with haematological malignancies and/or those receiving haematopoietic stem cell transplantation (HSCT)27. IA is also an emerging condition in patients with other causes of immunosuppression, such as solid organ transplantation, advanced acquired immunodeficiency syndrome (AIDS) and treatment with newer immunosuppressive agents such as infliximab28. The usual route of infections for IA is inhalation of Aspergillus conidia. The most frequently involved sites of IA are sinuses, lungs, brain and disseminated infection. IA is associated with a high mortality rate, which exceeds 50% in most reports. Higher mortality rates were noted in patients receiving HSCT compared with patients receiving solid organ transplants (68% vs. 41%; P < 0.0001), in patients with central nervous system disease (88% vs. 53%; P = 0.0005) and in non‐neutropenic compared with neutropenic patients (89% vs. 60%; P < 0.05)29. Other moulds Zygomycetes are fungi belonging to the order Mucorales, which form broad hyphae and are generally non‐septate. Genera that are able to cause invasive diseases include Rhizopus, Rhizomucor, Absidia and Cunninghamella30,31. Infections due to zygomycetes are classically characterised by vascular invasion, leading to thrombosis and tissue necrosis. Zygomycetes are susceptible to amphotericin B but generally resistant to most triazoles and the echinocandins. Breakthrough zygomycosis has been reported in patients receiving voriconazole or caspofungin prophylaxis, as these agents lack activity against zygomycetes32,33. Voriconazole and posaconazole have been reported as successful treatments for fusariosis. Clinical spectrum of the disease Infection with Candida Albicans presents mainly in any of four forms: pseudomembranous candidiasis, hyperplastic candidiasis, erythematous candidiasis, or angular cheilitis. Patients may exhibit one or a combination of any of these presentations. Angular cheilitis, for example, will frequently be seen in combination with erythematous candidiasis in denture wearers (Table 3). Pseudomembranous candidiasis Pseudomembranous candidiasis, commonly known as “thrush,” is the form often seen in neonates. It can also be seen in patients receiving topical corticosteroid therapy or in immune suppressed patients. In fact, the presence of pseudomembranous candidiasis in a seemingly healthy adult may be an indication of underlying systemic disease, such as infection with the human immunodeficiency virus (HIV). Pseudomembranous candidiasis presents as multiple white plaques of material resembling cottage cheese that can easily be wiped away. These plaques consist of tangled aggregates of hyphae. The underlying

mucosa may be erythematous, but ulceration would not be expected. While symptoms are typically mild for this form of infection, patients may complain of a slight tingling sensation or a foul taste. Identification of the fungal pseudohyphae within exfoliative cytologic preparations, often utilizing periodic acid Schiff and/or Papanicolaou stained preparations, is the optimal standard for the diagnosis of all candidiasis, although the highest yield of positive cytology smears is with pseudomembranous candidiasis34. Atrophic Candidiasis Atrophic candidiasis exhibits a diffusely reddened, often relatively dry mucosa. The red areas are often confined to mucosa underlying dental appliances such as partial dentures or orthodontic retainers. Approximately 26% of patients with complete dentures have atrophic candidiasis35. Hyperplastic candidiasis This form has been referred to as “candidal leukoplakia,” although this terminology should probably be avoided. Like leukoplakia, hyperplastic candidiasis will present as a white plaque that cannot be wiped away by the clinician. Unlike leukoplakia, however, lesions should completely resolve with routine antifungal therapy. Erythematous candidiasis Many conditions fall under the spectrum of erythematous candidiasis. As the term implies, lesions clinically appear red or erythematous. While any mucosal site may be affected, erythematous candidiasis commonly involves the tongue and palate. A form of erythematous candidiasis that is especially common involves the hard palate and gingiva beneath a denture or removable partial denture. Angular cheilitis The final clinical presentation of oral candidiasis infection is angular cheilitis. This form presents as cracking, peeling, or ulceration involving the corners of the mouth. It will frequently be seen in combination with one of the other forms of candidiasis infection, such as the erythematous type. Patients with a reduced vertical dimension of occlusion, secondary to severe attrition or worn dentures, are particularly susceptible to the development of angular cheilitis. This is due to the increased folding of the soft tissue that is frequently seen at the corners of the mouth, creating a haven for the organism. Several over‐the‐counter (OTC) medications including miconazole nitrate and clotrimazole creams, and prescription nystatin or ketoconazole creams are available to topically treat angular cheilitis. Topical miconazole nitrate 2% cream is valuable in that it is effective against both Candida and Staphyolococcus aureus. Dental professionals should be cautious when recommending OTC topical antifungals to patients who are using the anticoagulant warfarin. The combination increases the risk of excessively prolonged coagulation periods, due to interference with the liver enzymes that aid in the metabolism of warfarin36. Angular cheilitis is typically clinically diagnosed based on the uni‐ or bilateral presence of asymptomatic or painful red cracks or fissures at the corners of the mouth. Angular cheilitis may be caused by candidiasis (20%), mixed candidial bacterial infections (60%), or bacteria alone (20%)37. Treatment For the normal healthy patient, the treatment of oral candidiasis is relatively simple and effective. Typically, topical medications are adequate. A commonly prescribed anti‐fungal agent, nystatin oral suspension, will usually resolve most infections. However, topical medications must be in contact with the organism to eliminate it. Since patients are usually unable to hold liquids in their mouths more than briefly, clotrimazole troches are an effective alternative. These are dissolved slowly in the oral cavity, allowing the drug to be present for greater length of time. Intraoral candidiasis Topical agents include nystatin suspension and clotrimazole troches, which should be allowed to dissolve slowly in the mouth five times daily for 14 days. Patients should avoid eating or drinking for 20 minutes after using clotrimazole troches. Intraoral appliances should 37


be removed during the treatment as the medication works topically and must be in contact with the tissue. Systemic prescription antifungal agents include ketoconazole38, fluconazole39, and itraconazole40.

appliance should be free of debris and concretions. Household chlorine bleach, although effective and inexpensive, can cause damage to dental metals, acrylic, and tissue‐conditioning materials42. To avoid damage to prosthetic appliances, a germicide deodorizer containing sodium benzoate, citrate, and disodium phosphate (Oral Safe, Great Lakes Orthodontics, Tonawanda, NY) can be used to soak the appliance for six hours. This solution can be reused for one week and is harmless if ingested43. Another technique utilizes five minutes of microwave irradiation. Applying 60 Hz at full power to a complete acrylic denture in eight ounces of water can effectively sterilize acrylic and most soft denture liners44.

Prosthodontic appliances With any case of oral candidiasis, if the patient utilizes a removable prosthodontic appliance it is important to disinfect the appliance, because the porous material or surface biofilm can serve as a reservoir of fungal microorganisms and contribute to relapse or reinfection41. Disinfection of dental appliances is a two‐step process. First, the

Table 1: Species of Oral Candida Species of Oral Candida C. albicans C. glabrata C. guillermondii C. krusei C. parapsilosis C. pseudotropicalis C. stellatoidea C. tropicalis Table 2: Topical antifungal medications Topical antifungal medications Dosage form/ strength OTC Miconazole cream 2% Clotrimazole cream 1% Prescription Ketoconazole cream 2% Nystatin ointment 100,000 units/gram Nystatin topical powder 100,000 units/gram Nystatin oral suspension 100,000 units/gram Betamethasone dipropionate clotrimazole cream Clotrimazole troches 10 mg Amphotericin B 100 mg/ml

Indication Angular cheilitis Angular cheilitis Angular cheilitis Angular cheilitis Denture stomatitis Intraoral candidasis Chloronic angular cheilitis Intraoral candidasis Intraoral candidasis

Table 3: Clinical classification Clinical classification Angular chelitis Chronic atrophic (erythematous) Denture stomatitis Endocrine‐candidiasis syndrome Hyperplastic (Candidial leukoplakia) Inflammatory papillary hyperplasia Median rhomboid glossitis Mucocutaneous Pseudomembranous Xerostomia Such patients may require maintenance therapy of twice daily 0.12% chlorhexidine gluconate mouthrinses after an acute or chronic episode of oral candidiasis is under control. Recent developments For many years, amphotericin B deoxycholate remained the mainstay of treatment for IFIs27. The major limitations of its usage are the substantial adverse effects such as fever, chills, nausea and vomiting, electrolyte abnormalities and, most importantly, nephrotoxicity45. In the 1990s, the introduction of the two azoles fluconazole and itraconazole represented a considerable advance in antifungal therapy. However, the use of fluconazole is hampered by its narrow spectrum, and the use of itraconazole is limited due to absorption

problems46. New therapeutic agents have now been developed that provide better antifungal activities and lower toxicities (Table 2, 4 and 5). Extendedspectrum triazoles Second‐generation triazoles act predominantly by inhibition of the cytochrome P450 (CYP450)‐dependent conversion of lanosterol to ergosterol47. This leads to an accumulation of toxic 14‐ ‐methylsterols and a depletion of membrane‐associated ergosterol. This change in cell membrane properties results in inhibition of cell growth or cell death. Antifungal agents in this class include voriconazole, which was approved for the treatment of fungal infections in 2002, and posaconazole, which received US Food and Drug Administration (FDA) approval in September 2006. Clinical trials of ravuconazole have not

38


yet been completed. Voriconazole is available both in intravenous (i.v.) and oral formulations. The bioavailability of the oral formulation is >90% but is decreased to 80% by fatty foods48. Both i.v. and oral formulations are given as a twice‐daily dosage. A loading dose is needed to achieve steady‐state concentration rapidly (6 mg/kg twice daily on Day 1 followed by 4 mg/kg twice daily)48. Posaconazole is available only in oral formulation (400–800 mg/day in divided doses). Administering posaconazole with a meal, in a suspension rather than a tablet and in divided doses increases its oral bioavailability49. Posaconazole is excreted mainly in the faeces and a minor portion is metabolised in the liver through glucuronidation49. Dosage adjustment for oral voriconazole and posaconazole is not necessary in patients with renal

insufficiency or in patients receiving dialysis50,51. The concentrations of voriconazole in cerebrospinal fluid (CSF) are ca. 50% of plasma concentrations, and concentrations in brain tissue are higher than those in the CSF52. Voriconazole and posaconazole are very broad‐ spectrum antifungal agents. As with other azoles, they appear to be fungistatic against most yeasts but have a fungicidal effect against the filamentous moulds53. Voriconazole and posaconazole are very active against most Candida spp., including C. krusei, C. glabrata and those strains that are resistant to fluconazole54,14. For Aspergillus spp., voriconazole and posaconazole are very potent against many species, including A. terreus, which is resistant to amphotericin B, and A. fumigatus, which is resistant to itraconazole 55,56. They are active against some but not all strains of opportunistic moulds56,57,58,59,60 .

Table 4: Systemic antifungal medications Systemic antifungal medications Dosage form/ strength Indication Ketoconazole tablet 200 mg Intraoral candidasis Fluconazole tablet 100 mg Intraoral candidasis Itraconazole tablet 100 mg Intraoral candidasis Table 5: Antifungal drugs for treatment of oropharyngeal candidiasis Generic name Amphotericin B Clotrimazole Fluconazole

Proprietary name Fungizone Mycelex Diflucan

Itraconazole

Sporanox

Ketoconazole Nystatin

Nizoral Mycostatin

Formulation 100 mg/ml oral suspension 10 mg troche 100 mg tablet 10 mg/ml oral suspension 40 mg/ml oral suspension 100 mg capsule 10 mg/ml oral suspension 200 mg tablet 100,000 units/ml oral suspension 200,000 units/ml pastille 500,000 units/ml tablet 100,000 units/ml vaginal tablet

Echinocandins The echinocandins are large lipopeptide molecules that inhibit synthesis of ‐1, 3‐d‐glucan, which is an essential component of the cell wall of many fungi but is absent in mammals61. Inhibition of ‐1,3‐d‐ glucan synthase interferes with fungal cell wall synthesis, which leads to osmotic instability and death of the fungal cell61. Until now, caspofungin, micafungin and anidulafungin are the only echinocandin agents approved for clinical use. All echinocandin preparations to date are for i.v. use only62. The three agents share similar pharmacological characteristics, with some variations62. A once‐daily dosing regimen is optimal based on concentration‐dependent pharmacodynamics and prolonged post‐antifungal effects53,63,64. A loading dose is recommended for caspofungin (75 mg loading on Day 1 followed by 50 mg/day) and anidulafungin (200 mg loading on Day 1 followed by 100 mg/day), but not for micafungin (50–150 mg/day)65,64. Caspofungin and micafungin are degraded mainly in the liver64 whilst anidulafungin uniquely undergoes chemical degradation in the blood65. All three agents are poor substrates for the hepatic CYP450 enzyme system. Therefore, unlike triazoles, the CYP450‐ independent metabolism and degradation of echinocandins reduces concern about drug–drug interactions61. Echinocandins have very low MICs against clinically significant Candida spp., including C. albicans, C. tropicalis, C. glabrata, C. krusei, C. lusitaniae and Candida dubliniensis66,59,67,68. Rationale for and against antifungal combinations The original use of antifungal combination therapy was in the treatment of cryptococcal meningitis in patients who did not have AIDS. Amphotericin B was the first agent available for successfully treating invasive mycoses, but there have been major problems with systemic toxic reactions associated with its infusion and

nephrotoxicity69. Indeed, several trials have demonstrated that when flucytosine is included in the treatment regimen, the dose of amphotericin B could be reduced, thereby decreasing somewhat its toxicity70,71. The dose of amphotericin B was subsequently increased and response rates to therapy, with or without flucytosine, improved72,73. At present, we are faced with an increasing incidence of serious invasive fungal mycoses and a high mortality rate secondary to these infections74,75,76,77. REFERENCES 1. 2. 3.

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Tinjauan : Kandidiasis Oral YUVRAJ SINGH DANGI1, MURARI LAL SONI1, KAMTA PRASAD NAMDEO1 Institute of Pharmaceutical Sciences, Guru Ghasidas Central University, Bilaspur (C.G.) – 49500 Email: [email protected]

Abstrak Kandidiasis oral adalah infeksi jamur oportunistik yang berasal dari rongga mulut yang dapat menjadi penyebab ketidaknyamanan pada pasien. Jurnal ini akan membahas tentang jenis-jenis kandidiasis, dimana pengobatan saat ini menekankan pada pencegahan kekambuhan pasien gigi. Peran perawat juga sangat penting dalam memberikan edukasi kepada pasien dalam mencegah kekambuhan. Frekuensi infeksi jamur invasif (IFI) telah meningkat selama beberapa dekade terakhir, dimana sebanding dengan kenaikan populasi pasien yang berisiko. Morbiditas dan mortalitas IFI yang tinggi menyebabkan pengelolaan keadaan ini merupakan suatu tantangan besar. Dengan meluasnya pencegahan antijamur, epidemiologi jamur patogen yang invasif telah berubah. Jamur selain Candida albicans, Aspergillus fumigatus, dan Aspergillus spp. lainnya menjadi semakin diakui sebagai penyebab penyakit invasif. Jamur jenis ini ditandai dengan resistensi atau kerentanan yang lebih rendah terhadap agen antijamur standar. Kandidiasis oral adalah infeksi jamur yang umumnya terjadi pada pasien dengan sistem kekebalan tubuh yang rendah, seperti pada pasien yang sedang menjalani kemoterapi untuk kanker dan pasien AIDS. Faktor predisposisi utama pada pasien yang terinfeksi HIV adalah jumlah sel T CD4 menurun. Sebagian besar infeksi disebabkan oleh C. albicans meskipun spesies lain seperti C. glabrata, C. tropicalis, C. krusei dan C. parapsilosis juga dapat menyebabkan terjadinya kandidiasis oral. Pengobatan sistemik seperti ketokonazol, flukonazol dan itrakonazol sangat bermanfaat dalam pengobatan infeksi jamur. Sampai saat ini, resistensi flukonazol masih menjadi masalah dalam pengobatan AIDS. Namun, langkah-langkah yang dilakukan lembaga-lembaga saat ini dikhususkan untuk mencegah penyebaran strain resisten dan pengembangan resistensi silang. Kata Kunci : Kandidiasis

Pendahuluan Kandidiasis oral adalah infeksi yang sering terjadi terutama di bagian mukosa dan kebanyakan terdapat pada pasien HIV atau AIDS. Kandidiasis oral menyebabkan ketidaknyamanan daerah mulut seperti nyeri, hilangnya pengecapan, dan keengganan untuk makan. Faktor risiko kandidiasis oral lainnya adalah carrier Candida albicans dan riwayat kandidiasis oral. Infeksi ini disebabkan oleh Candida albicans yaitu jamur dimorfik yang biasanya terdapat dalam rongga mulut sebagai non-patogen pada sekitar satu setengah orang yang sehat. Jamur ini biasanya hidup sebagai ragi, dimana pada kondisi yang menguntungkan, dapat berubah menjadi patogen (bentuk hifa) seperti pada kondisi yang sedang menjalani terapi antibiotik spektrum luas, xerostomia, penurunan sistem kekebalan tubuh (penyakit sistemik sekunder seperti diabetes atau penggunaan obat yang menekan sistem kekebalan tubuh). Sekitar satu dari empat pasien dengan liken planus akan menderita kandidiasis superimposed. Infeksi umumnya terbatas pada mukosa superfisial dan kulit, kecuali pasien dengan immunocompromised yang parah. Infeksi kandidiasis oral merupakan infeksi superfisial dimana pengobatannya adalah secara topikal dengan waktu kontak antara agen dan mukosa mulut selama 2 menit. Durasi pengobatan bervariasi dari 7 sampai 14 hari. Pengobatan topikal memiliki sedikit efek samping karena tidak terjadi penyerapan di sistem gastrointestinal, sedangkan antijamur sistemik keuntungannya adalah dosisnya hanya sekali sehari dan dapat mengobati infeksi jamur di beberapa lokasi dalam tubuh. Namun, antijamur ini memiliki efek samping yang lebih banyak dan harus dipertimbangkan dalam interaksi obat. Jurnal ini mengkaji tentang jenis kandidiasis oral, diagnosis, dan pengobatan serta pencegahan terhadap kekambuhan pada pasien gigi yang rentan. Kandidiasis adalah infeksi oportunistik daerah oral dan perioral yang biasanya disebabkan oleh pertumbuhan jamur Candida endogen yang berlebih. Terdapat banyak spesies Candida (Tabel 1) tetapi C. albicans adalah jamur yang paling sering dijumpai dalam praktek gigi. Perubahan lingkungan di mulut dapat mempengaruhi atau memicu kandidiasis oral seperti: penggunaan antibiotik, kortikosteroid, mulut kering (xerostomia), diabetes mellitus, kekurangan gizi, dan penyakit imunosupresif. Air liur mengandung protein antijamur seperti histatin dan calprotectin yang dapat membantu melindungi pasien dari infeksi Candida. Protein pelindung ini tidak terdapat pada pasien dengan xerostomia. Pasien asma yang menggunakan inhaler kortikosteroid harus mencuci daerah mulut dengan air setelah menggunakan inhaler untuk mengurangi kemungkinan terjadinya kandidiasis oral. Kebersihan mulut seperti menyikat gigi dua kali sehari dan

memelihara kelembaban intraoral sangat penting dalam pencegahan kandidiasis terutama pada pasien yang rentan. Flukonazol merupakan antijamur yang ditemukan pada tahun 1990 dan memiliki efek sistemik yang dapat bermanfaat untuk infeksi jamur lainnya. Percobaan flukonazol untuk profilaksis dimana menggunakan kontrol placebo menunjukkan perbaikan dermatofitosis, seperti tinea pedis, onikomikosis, dan tinea kruris. Selain itu, flukonazol sistemik dapat mencegah kandidiasis esofagus dan vagina, kriptokokemia, histoplasmosis, dan infeksi jamur lainnya. Tidak seperti ketokonazol, flukonazol tidak dipengaruhi oleh keasaman lambung dan memiliki sedikit risiko hepatotoksisitas serta dapat berinteraksi dengan obat lainnya. Penelitian terbaru tentang penggunaan flukonazol berpotensi terhadap resistensi Candida albicans dan spesies lainnya.

Spesies Penyebab Kandidiasis Oral C. albicans C. glabrata C. guillermondii C. krusei C. parapsilosis C. pseudotropicalis C. stellatoidea C. tropicalis Tabel 1: Spesies Penyebab Kandidiasis Oral Organisme Penyebab Candida spp. Di antara jamur patogen, Candida spp. merupakan jamur yang paling dominan menyebabkan infeksi invasif. Angka kejadian Candida dalam satu tahun berdasarkan BSI berkisar 6-23 per 100.000 orang di USA dan 2,53-11 per 100 000 orang di Eropa. Dalam berbagai laporan, Candida spp. menyebabkan 8-10% infeksi nosokomial dan insiden kandidaemia telah dilaporkan terjadi di seluruh dunia dalam dua dekade terakhir. Faktor predisposisi utama termasuk intervensi bedah, perawatan intensif, keganasan hematologi, dan penggunaan steroid. Angka kematian tetap tinggi meskipun terdapat kemajuan dalam perawatan medis, mulai dari 30% sampai 50%. Lebih dari 95% infeksi spesies Candida berdasarkan BSI disebabkan oleh: C.

albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis dan Candida krusei. Candida parapsilosis memiliki prevalensi yang tinggi pada neonatus prematur dan pada pasien dengan kateter vaskular. Infeksi Candida glabrata jarang terjadi pada bayi dan anak-anak tetapi biasanya pada usia lebih tua. Candida tropicalis menjadi penyebab penyakit invasif pada pasien dengan keganasan hematologi. Triazoles baru seperti vorikonazol, posaconazole, dan echinocandins aktif terhadap C. glabrata dan C. krusei, meskipun resistansi silang tercatat dalam azoles di beberapa strain C. glabrata. Aspergillus spp. Aspergillus spp. biasanya ditemukan di dalam tanah dan air di seluruh dunia. Tidak seperti kandidiasis invasif, aspergillosis invasif (IA) terjadi terutama pada pasien immunocompromised, seperti pasien dengan keganasan hematologis atau yang menerima transplantasi haematopoietic stem cell (HSCT). Aspergillosis invasif juga dapat terjadi pada pasien dengan imunosupresi, seperti pada pasien yang sedang menjalani transplantasi organ padat, AIDS, dan pengobatan dengan imunosupresif terbaru seperti infliximab. Rute awal terinfeksi invasif aspergillosis adalah dengan menghirup Aspergillus konidia dan organ yang paling sering terkena adalah sinus, paruparu, dan otak. Insidensi kematian tercatat tinggi pada pasien yang menerima HSCT dibandingkan dengan pasien menerima transplantasi organ padat (68% vs 41%, P <0,0001), pasien dengan penyakit sistem saraf pusat (88% vs 53%, P = 0,0005) dan non-neutropenia dibandingkan dengan pasien neutropenia (89% vs 60%, P < 0,05). Jamur Lainnya Zygomycetes yang termasuk dalam genus Mucorales merupakan jamur yang memiliki hifa dan umumnya tidak bersepta. Genus lainnya yang dapat menyebabkan penyakit invasif adalah Rhizopus, Rhizomucor, Absidia dan Cunninghamella. Infeksi karena Zygomycetes klasik ditandai dengan invasi vaskular yang dapat menyebabkan trombosis dan jaringan nekrosis. Zygomycetes sensitif terhadap amfoterisin B tetapi umumnya tahan terhadap sebagian triazoles dan echinocandins. Penelitian pada pasien yang mendapat pengobatan vorikonazol atau caspofungin sebagai profilaksis menunjukkan bahwa antijamur ini kurang memiliki aktivitas terhadap zygomycetes, sedangkan penggunaan vorikonazol dan posaconazole telah dilaporkan sebagai pengobatan yang efektif untuk fusariosis.

Spektrum Klinis Penyakit Infeksi Candida albicans dapat berupa salah satu dari empat bentuk: kandidiasis pseudomembran, kandidiasis hiperplastik, kandidiasis eritematosus, dan angular cheilitis. Pasien dapat menunjukkan satu atau kombinasi dari bentuk infeksi. Angular cheilitis misalnya sering terlihat dalam kombinasi dengan kandidiasis eritematosus dalam pemakai gigi palsu. (Tabel 3). Klasifikasi Klinis Angular Chelitis Atrofi Kronik (Eritematosus) Denture Stomatitis Sindrom Kandidiasis-Endokrin Hiperplastik (Leukoplakia Kandidiasis) Hiperplasia Papilar Inflamatori Glositis Rhomboid Median Mukokutaneus Pseudomembranosus Tabel 3: Klasifikasi Klinis Kandidiasis Pseudomembran Kandidiasis pseudomembran umumnya dikenal sebagai "thrush" dan sering terdapat pada neonatus. Hal ini juga dapat terlihat pada pasien yang menerima terapi kortikosteroid topikal atau pada pasien dalam pengobatan yang menekan sistem kekebalan tubuh. Terdapatnya infeksi kandidiasis pseudomembran pada orang yang sehat mungkin merupakan indikasi dari penyakit sistemik seperti infeksi HIV. Kandidiasis pseudomembran dapat terlihat sebagai plak putih yang menyerupai keju yang dapat dengan mudah dihilangkan. Plak ini terdiri dari hifa-hifa yang tidak beraturan dan terdapat pada mukosa dengan dasar eritema. Gejala biasanya ringan seperti mengeluh kesemutan ringan atau rasa kotor didaerah mulut. Untuk mengidentifikasi pseudohifa jamur dapat menggunakan sitologi eksfoliatif, asam Schiff atau Papanicolaou yang merupakan standar optimal untuk diagnosis semua jenis kandidiasis, dimana hasil tertinggi sitologi positif adalah pseudomembran candidiasis.

Kandidiasis Atrofi Kandidiasis atrofi terlihat dalam bentuk eritema difus dan sering terdapat pada mukosa yang kering seperti pada pengguna gigi palsu parsial atau pasien ortodentik. Sekitar 26% pasien dengan gigi palsu lengkap telah mengalami kandidiasis atrofi. Kandidiasis hiperplastik Bentuk ini disebut sebagai "kandida leukoplakia," meskipun sekarang terminologi ini mungkin harus dihindari. Seperti leukoplakia, kandidiasis hiperplastik berbentuk plak putih yang tidak dapat dibersihkan oleh dokter sekalipun dan lesi ini harus diobati dengan terapi antijamur yang rutin. Kandidiasis Eritematosus Lesi klinis tampak merah atau eritematosa dan sering terjadi pada lidah dan palatum. Kandidiasis eritematosa juga dapat terlihat di tempat sekitar gigi tiruan yang lepas pasang. Angular cheilitis Lesi klinis angular cheilitis terlihat seperti retakan, terkelupas, ataupun ulserasi di bagian sudut mulut. Bentuk ini dapat terlihat juga dalam kombinasi dengan jenis kandidiasis lainnya seperti kandidiasis eritematosus. Beberapa obat over-the-counter (OTC) termasuk miconazole nitrat, clotrimazole krim, nistatin atau krim ketokonazol topikal dapat mengobati angular cheilitis. Topikal krim mikonazol nitrat 2% sudah terbukti efektif terhadap Candida dan Staphyolococcus aureus. Dokter gigi harus berhati-hati jika merekomendasikan OTC topikal antijamur kepada pasien yang menggunakan warfarin antikoagulan. Hal ini dapat meningkatkan risiko koagulasi berlebihan berkepanjangan, karena gangguan pada enzim hati yang membantu dalam metabolisme warfarin. Angular cheilitis didiagnosis berdasarkan adanya asimtomatik uni-atau bilateral ataupun tedapat nyeri pada lesi seperti retakan atau fisura di sudut mulut. Angular cheilitis dapat disebabkan oleh candidiasis (20%), campuran candidiasis dan infeksi bakteri (60%), atau bakteri saja (20%).

Pengobatan Untuk pasien normal dan sehat, pengobatan kandidiasis oral relatif sederhana dan efektif. Biasanya dapat digunakan obat topikal ataupun nistatin oral. Namun, obat topikal harus langsung berkontak dengan organisme untuk dapat menghilangkannya. Kandidiasis Intraoral Obat topikal seperti suspensi nistatin dan clotrimazole troches dapat digunakan untuk mengobati kandidiasis intraoral dengan cara perlahan-lahan dalam mulut lima kali sehari selama 14 hari. Pasien tidak diperbolehkan makan atau minum selama 20 menit setelah menggunakan clotrimazole troches. Obat antifungi sistemik lain juga dapat digunakan seperti ketoconazole, fluconazole, dan itraconazole. Peralatan Prostodontik Pasien yang menggunakan alat removable untuk prostodontik harus menggunakan alat yang steril karena permukaan dari bahannya memiliki pori atau biofilm yang dapat berfungsi sebagai reservoir mikroorganisme jamur dan berkontribusi untuk menyababkan kekambuhan atau reinfeksi. Desinfeksi peralatan gigi harus melalui dua proses. Pertama, alat harus bebas dari kotoran. Peralatan rumah tangga seperti pemutih klorin meskipun efektif dan murah, dapat menyebabkan kerusakan pada gigi dan jaringan. Untuk menghindari kerusakan dapat digunakan bahan pembasmi kuman yaitu zat yang mengandung natrium benzoat, sitrat, dan disodium fosfat dengan cara direndam selama enam jam. Cara ini dapat digunakan kembali satu minggu kemudian dan tidak berbahaya jika tertelan. Teknik lainnya adalah menggunakan iradiasi microwave selama lima menit. Xerostomia Pasien xerostomia memerlukan terapi pemeliharaan dua kali sehari menggunakan obat kumur klorheksidin glukonat 0,12% pasca episode akut atau kronis kandidiasis oral. Perkembangan terbaru Selama bertahun-tahun, amfoterisin B deoxycholate tetap menjadi pengobatan utama IFI. Keterbatasan utama penggunaannya adalah efek samping yang substansial seperti demam,

menggigil, mual dan muntah, kelainan elektrolit dan nefrotoksisitas. Pada tahun 1990-an, pengenalan terhadap dua azoles yaitu flukonazol dan itrakonazol mewakili kemajuan yang cukup besar di pengobatan antijamur. Namun, penggunaan flukonazol terhambat karena spektrumnya sempit dan penggunaan itrakonazol terbatas karena dapat menyebabkan gangguan penyerapan. Pengobatan terbaru kini telah dikembangkan dan memberikan efek yang lebih baik sebagai antijamur dan dapat menurunkan toksisitas (Tabel 2, 4 dan 5). Obat Antifungi Topikal Bentuk Sediaan dan Dosis

Indikasi

OTC Krim mikonazol 2%

Angular cheilitis

Krim clotrimazol 1%

Angular cheilitis

Prescription Krim ketokonazol 2%

Angular cheilitis

Salep nistatin 100.000 unit/gram

Angular cheilitis

Bedak topikal nistatin 100.000 unit/gram

Denture stomatitis

Suspensi oral nistatin 100.000 unit/gram

Kandidiasis intraoral

Betamethasone dipropionate clotrimazole

Angular cheilitis kronik

Clotrimazole troches 10 mg


Amfoterisin B 100 mg/ml

Kandidiasis intraoral Tabel 2: Obat Antifungi Topikal

Obat Antifungi Sistemik Bentuk Sediaan dan Dosis

Indikasi

Ketokonazol tab 200 mg


Flukonazol tab 100 mg


Itrakonazol tab 100 mg


Tabel 4: Obat Antifungi Sistemik

Nama Generik

Nama Dagang

Formula

Amfoterisin B

Fungizone

Suspensi oral 100 mg/ml

Clotrimazole

Mycelex

Troche 10 mg

Flukonzole

Diflucan

Tab 100 mg Suspensi oral 10 mg Suspensi oral 40 mg

Itraconazole

Sporanox

Kapsul 100 mg Suspensi oral 10 mg

Ketoconazole

Nizoral

Tab 200 mg

Nistatin

Mikostatin

Suspensi oral 100.000 unit/ml Pastille 200.000 unit/ml Tab 500.000 unit/ml Tablet vagina 100.000 unit/ml

Tabel 5: Obat Antifungi untuk Kandidiasis Oral Triazole sebagai Spektrum Luas Generasi kedua triazoles bekerja dengan cara menghambat sitokrom P450 (CYP450) yang mengubah lanosterol ke ergosterol. Hal ini menyebabkan akumulasi toksik 14–methylsterols dan penipisan membran. Perubahan sifat membran sel menyebabkan terhambatnya pertumbuhan sel atau kematian sel. Antijamur yang termasuk kedalam golongan ini adalah vorikonazol yang tersedia dalam bentuk intravena dan bentuk oral. Bioavailabilitas bentuk oral > 90% tetapi dapat menurun menjadi 80% bila dikonsumsi bersama makanan berlemak. Pemberian secara intravena dan dalam bentuk oral diberikan dengan dosis dua kali sehari. Loading dose diperlukan untuk mencapai steady-state dengan konsentrasi cepat (6 mg / kg dua kali sehari pada hari 1 diikuti oleh 4 mg / kg dua kali sehari). Posaconazole hanya tersedia dalam bentuk oral (400-800 mg / hari dalam dosis terbagi). Penggunaan posaconazole dengan makanan dapat meningkatkan bioavailabilitas. Posaconazole diekskresikan terutama di feses dan sebagian kecil dimetabolisme di hati. Vorikonazol dan posaconazole adalah antijamur spektrum luas. Seperti azoles lain, keduanya berfungsi sebagai fungistatik terhadap sebagian besar ragi tetapi memiliki efek fungisida terhadap filamen jamur. Vorikonazol dan posaconazole sangat efektif terhadap

sebagian Candida spp., termasuk C. krusei, C. glabrata dan strain yang resisten terhadap fluconazole. Untuk Aspergillus spp., vorikonazol dan posaconazole sangat bermanfaat dalam menghambat banyak spesies, termasuk A. terreus, yang resisten terhadap amfoterisin B, dan A. fumigatus, yang resisten terhadap itraconazole. Echinocandins Echinocandins adalah molekul lipopeptida besar yang dapat menghambat sintesis -1, 3-d-glucan, yang merupakan komponen penting dari sel dinding jamur sehingga dapat menyebabkan ketidakstabilan osmotik dan kematian sel jamur. Sampai saat ini, caspofungin, micafungin dan anidulafungin adalah satu-satunya echinocandin yang disetujui penggunaannya dalam klinis. Semua penggunaan echinocandin adalah secara intravena. Loading dose yang dianjurkan untuk caspofungin adalah 75 mg pada hari pertama diikuti oleh 50 mg / hari dan anidulafungin adalah 200 mg pada hari pertama diikuti oleh 100 mg / hari, sedangkan untuk micafungin adalah 50-150 mg / hari. Caspofungin dan micafungin terdegradasi terutama di liver sementara anidulafungin mengalami degradasi kimia di darah. MIC echinocandins sangat rendah terhadap Candida spp., Termasuk C. albicans, C. tropicalis, C. glabrata, C. krusei, C. lusitaniae dan Candida dubliniensis. Alasan Penggunaan Kombinasi Antijamur Amfoterisin B adalah obat pertama yang berhasil mengobati mikosis invasif, tetapi dapat menyebabkan reaksi toksik sistemik. Beberapa percobaan telah menunjukkan jika amfoterisin B dikombinasikan dengan flusitosin, dosisnya dapat dikurangi sehingga mengurangi efek toksisitasnya. Saat ini, kita dihadapkan dengan meningkatnya insiden serius dari jamur invasif dan tingkat kematian yang tinggi akibat infeksi ini.

UNIVERSITAS PEMBANGUNAN NASIONAL VETERAN JAKARTA JOURNAL READING ORAL CANDIDIASIS

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