© Springer-Verlag Berlin Heidelberg 2015
Edvaldo Antonio Ribeiro Rosa (ed.)Oral Candidosis10.1007/978-3-662-47194-4_4
4. Antifungals for Candidosis Treatment
(1)
School of Health and Biosciences, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil
Abstract
The available treatments for oral candidosis have proved to be more efficacious with the use of new and known antifungal drugs. The success of these is directly related to the correct diagnosis, identification, and correction of etiological factors and the commitment of the patient. In the absence of some of these factors, the antifungal therapy results only in a brief relief from disease, triggering relapses. This chapter presents the main drugs used in the treatment of oral and oropharyngeal candidosis, their functioning in the human body, and their mechanism of action in the destruction of the pathogenic agent.
Keywords
AntifungalsCandidosisTreatmentPolyenic agentsAmphotericin BNystatinImidazoleTriazoleKetoconazoleClotrimazoleItraconazoleFluconazolePosaconazoleMiconazoleCaspofunginMicafunginAnidulafungin
The available treatments for oral candidosis have been proved to be more efficacious with the use of new and known antifungal drugs.
The success of these is directly related to the correct diagnosis, identification, and correction of etiological factors and the commitment of the patient. In the absence of some of these factors, the antifungal therapy results only in a brief relief from disease, triggering relapses (Akpan and Morgan 2002).
During treatment, harmful habits such as smoking should be completely eliminated or reduced. Oral hygiene needs to be improved, especially in cases of patients that use oral removable prosthesis since disruption of the biofilm produced by Candida sp. consists of an important adjunct factor in the healing process (Giannini and Shetty 2011).
For healthy individuals, the treatment of oral candidosis is relatively simple and effective, and the use of topic medications quite suitable. The first chosen drugs are Nystatin oral suspension, clotrimazole tablets, and amphotericin B of oral suspension. For the success of this treatment, proper contact of the oral mucosa with the drug is required (2 min). If the patient is using intraoral devices such as dentures, they must be removed during the application of the drug. The treatment has a variable duration of 7–14 days, continuing for 2–3 days after the disappearance of clinical signs and symptoms of the infection (Li et al. 2014; Melkoumov et al. 2013).
Topical agents at therapeutic doses have few side effects due to lack of gastrointestinal absorption; however, they contain sucrose, which is cardiogenic, and if used for longer periods, the patient may require adjunct therapy fluorine, as a prevention to the development of caries.
Systemic antifungal such as ketoconazole, fluconazole, and itraconazole have the advantage of once daily dosing and simultaneously treat other fungal infections at multiple body sites. However, these drugs have more side effects, and their selection should consider important interactions with other medicines (Muzyka and Glick 1995).
In immunocompromised patients, such as HIV infected, oral candiosis may lead to secondary complications such as oropharyngeal candidosis. For those at high risk of developing the disease, antifungal prophylaxis is indicated (Vazquez 2010).
Due to the effectiveness of this therapy for the treatment of oropharyngeal candidosis, low mortality, the possibility of interactions with other drugs, and the yearly cost per patient of prophylaxis, the US Public Health Service and the Infectious Disease Society of America do not recommend routine prophylaxis as primary in the United States. There is also a growing concern about azole-resistant fungal strains, as a consequence of chronic suppressive therapy in HIV patients (Pappas et al. 2009; Patel et al. 2012).
This chapter presents the main drugs used in the treatment of oral and oropharyngeal candidosis, their functioning in the human body, and their mechanism of action in the destruction of the pathogenic agent.
Polyenic Agents
This group of drugs is of great clinical use because it presents broad spectrum of activity against common superficial and deep fungal diseases. This class of drugs acts specifically in ergosterol (sterol of fungal cell membrane, absent in animal cells). The drug–ergosterol interaction is able to increase the permeability of the fungal membrane, causing the formation of pores or channels, leading to disturbances in the ionic balance and loss of potassium, sodium, and intracellular ions (Kerridge 1986; Park and Kang 2011).
Amphotericin B
Derived from Streptomyces nodosus cultures, microorganisms found in soil (Giannini and Shetty 2011; Vazquez 2010; Pappas et al. 2009; Klotz 2006; Sharon and Fazel 2010; Thompson et al. 2010; Neville et al. 2002). Gold and colleagues discovered this macrolide in 1956. It acts by increasing the permeability of the cell membrane of fungi, leading to loss of cytoplasmic constituents. Depending on the type of fungus, the drug concentration, and the pH of the medium, it presents fungicides and fungistatic functions.
Absorption, Distribution, and Excretion:
This drug has little absorption in the skin or mucous membrane, and is held by the gastrointestinal tract. Only a small amount of amphotericin B is available in the bloodstream and has pharmacological action, since over 90 % of it is present in plasma and bind to plasma proteins.
The exact pathway of the drug is unknown; however, it is known that most of it is biotransformed and slowly eliminated through the kidneys. Its features are found in the urine up to 2 months or more after the administration. It displays a plasma half-life of approximately 15 days.
In patients with renal disease, it is not necessary to adjust the dose of this medicine. Approximately 2–5 % of each dose is present in the urine, while individuals are subjected to daily therapy.
Therapeutic Use
Oral solution (trade name suggested Fungizone®). Mouthwash with 1 mL of the solution (100 mg) for 14 days, four times a day, preferably after meals and before bedtime.
In systemic infection, amphotericin B is administered intravenously at doses from 0.4 to 0.6 mg/kg/day for 4 weeks or more (trade name suggested Anforicin B® 50 mg).
Adverse Effects:
Nausea, vomiting, rash, diarrhea, and gastrointestinal disorders. Intravenously, amphotericin B is the most toxic antibiotic in use currently and may lead to hypotension, fever, nausea, abdominal pain, and more. In this via, all patients show some degree of nephrotoxicity and may have thereby stopped treatment. For individuals with preexisting liver problems, undergoing treatment for over a month, the monitoring of liver function is indicated.
Amphotericin B has no significant drug interactions.
Nystatin
Discovered in the 1950s, by the New York State Health Laboratory, it was the first effective treatment for the cure of oral candidosis (Giannini and Shetty 2011; Melkoumov et al. 2013; Muzyka and Glick 1995; Vazquez 2010; Pappas et al. 2009; Park and Kang 2011; Klotz 2006; Neville et al. 2002; Greenspan 1994). Derived from Streptomyces noursei culture, this macrolide resembles in its structure the amphotericin B. It can be both fungistatic and fungicidal and has reduced activity compared to amphotericin B. It is the most used for oral candidosis and used in immunocompromised patients as prophylactic treatment.
Because of its bitter taste, this drug is difficult to be accepted by patients. Laboratories add certain amount of sucrose and flavoring to its formulation. Therefore, patients with xerostomia, and because of this, oral candidosis, are more susceptible to the development of caries.
Absorption, Distribution, and Excretion:
Poorly absorbed by the gastrointestinal tract, skin, and mucous membranes, the action of this drug starts as soon as it comes in contact with the pathogen, in oral or intestinal cavity.
Significant concentrations of nystatin may occasionally appear in the plasma of patients with renal impairment during oral therapy with standard doses.
After oral administration, most nystatin is eliminated unchanged in the feces. Due to its high systemic toxicity, nystatin is not administered parenterally.
Therapeutic Use:
Oral solution (trade name suggested Micostatin®). In adults and children mouthwash with subsequent swallowing of 4 to 6 mL of the solution (1: 100,000 IU).
Neonates and preterm with low birth weight should receive 1 mL of this solution. Lactating children should receive 2 mL, which can be applied to the flexible stem of aid or gauze. This treatment must be continued for 14 days, four times a day, preferably after meals and before bedtime.
Tablets (brand name suggested Mycostatin Tablet®). One or two tablets (200,000–400,000 IU) dissolved in the mouth four times daily for 14 days.
Adverse Effects:
Nausea, diarrhea, and vomiting at high doses of the drug.
Nystatin liposomal (encapsulated in liposomes) has low systemic cytotoxicity, showing more effectiveness in cases of resistance to amphotericin B.
The polyene derivative, despite its high antifungal activity, has a poor intestinal absorption, which makes its use in the treatment of oral candidosis limited.
Cases of resistance to the use of polyenic are rare; however, if it occurs, it is due to a reduction of the amount of ergosterol constituent of the fungal cell wall.
It has no drug interaction with other drugs.
Imidazole and Triazole Agents
Developed in 1970, these drugs inhibit sterol 14-α-demethylase, a small set of enzymes dependant on cytochrome P450. There is blockade of ergosterol production, causing accumulation of substances and impairment of the functions responsible for fungal growth (Cupp-Vickery et al. 2001).
These agents are also capable of inhibiting the transformation of yeast cells of Candida spp. in hyphae, which makes the microorganism less aggressive (Park and Kang 2011).
Ketoconazole
It was the first drug used for the treatment of systemic candidosis orally (Giannini and Shetty 2011; Muzyka and Glick 1995; Vazquez 2010; Pappas et al. 2009; Park and Kang 2011; Klotz 2006; Sharon and Fazel 2010; Thompson et al. 2010; Neville et al. 2002; Greenspan 1994; Van Roey et al. 2004). Only in rare cases of resistance to other antifungals the prescription of ketoconazole is necessary.
According to the Food and Drug Administration (FDA), ketoconazole cannot be used as initial therapy for the treatment of oral candidosis. If it is used for more than 2 weeks by the patient, liver function studies are recommended, since 1 in 10,000 develops idiosyncratic drug toxicity.
Responsible for inhibiting the production of estradiol and testosterone, it may cause abnormalities in the menstrual cycle and gynecomastia.
Absorption, Distribution, and Excretion:
Well absorbed by the gastrointestinal tract, since its content remains acid. Drugs that increase gastric pH (antacids and antihistamines), rifampicin and antagonists of the histamine H2 receptor and omeprazole lower its absorption.
Distributed to the tissue and tissue fluids, it has poor penetration into the central nervous system, except when used at high doses. It is extensively metabolized by the liver and excreted in bile and urine, where the active drug concentrations are very low. In the blood, 84 % of ketoconazole bind to plasmatic proteins (albumin); 15 % to erythrocytes and remains in the free form.
The metabolism of this drug is not altered by azotemia (biochemical alteration in the compounds of nitrogen/nitrogen in renal function), by hemodialysis, or peritoneal dialysis. The presence of moderate hepatic impairment has no effect on its blood concentration.
Ketoconazole inhibits the metabolism of cyclosporine, phenytoin, sulfonylureas, warfarin and antihistamines, terfenadine, and astemizole. Isoniazid, antibiotic used to treat tuberculosis, increases its metabolism.
The bioavailability of the drug is reduced in patients with achlorhydria, especially those with AIDS, who must ingest acidifying agents like orange juice prior to the administration of ketoconazole.
Interactions of ketoconazole with macrolide antibiotics, enhancing agents of gastrointestinal motility and some antihistamines, may lead to cardiac arrhythmias with potentially life threatening.
Clotrimazole
More tolerated by patients because it has better taste than the nystatin (Giannini and Shetty 2011; Muzyka and Glick 1995; Pappas et al. 2009; Park and Kang 2011; Sharon and Fazel 2010; Thompson et al. 2010; Neville et al. 2002; Greenspan 1994; Sangeorzan et al. 1994).
Absorption, Distribution, and Excretion:
Its absorption by the gastrointestinal tract is poor, being insoluble in aqueous medium. It is metabolized by the liver and excreted with the feces together with the unabsorbed drug.
Therapeutic Use:
Tablets (brand name suggested Mycelex oral tablets®). One tablet (10 mg) dissolved slowly in the mouth, five times a day, for 14 days.
Adverse Effects:
Nausea and vomiting. Patients with hepatic impairment should be evaluated periodically, because in 15 % of patients treated with this drug there was a slight increase in the number of liver enzymes. No significant drug interactions.
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