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A relatively few antimycotic agents with minimal toxicity and side-effects are available as compared to a plethora of antibiotics. The principal antimycotic agents used in oral mycoses fall into two main groups. These agents are used for treatment of different forms of oral candidosis.

1. Polyenes: Nystatin and amphotericin B.

2. Azoles: Imidazoles and triazoles.

Polyenes

They are commonly used for treatment of oral candidosis.

Amphotericin B

Mode of action It acts by inhibiting fungal growth through an interaction with ergosterol. It exerts either a fungicidal or fungistatic effect, depending on the concentration used.

Polyenes bind more effectively to ergort than to other mammalian sterols.

Spectrum of activity It includes most fungi that cause disease in humans, including Candida species.

Absorption Amphotericin B is poorly absorbed from gastrointestinal tract.

Administration It is usually administered intravenously or used topically.

Adverse effects The most common adverse effect of systemic use is nephrotoxicity. Hypokalaemia and mild anaemia are also common. Other rare effects include acute hypersensitive reactions, including anaphylaxis.

Drug interactions Amphotericin B may potentiate nephrotoxicity of other agents such as aminoglycosides and cyclosporins; Its use with glucocorticoids may lead to electrolyte disturbances, particularly hypokalaemia.

Preparations and dosage The available preparations for oral delivery are ointment, suspension, cream and lozenges.

• Oral systemic dose for adults is 100 to 200 mg 6 hourly. Lozenges can be given 8 hourly to a maximum of 80 mg/day

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Principles of Oral and Maxillofacial Surgery

• Oral suspension: 1ml 8 hourly, retained in the mouth (after food), in contact with the lesions

• IV infusions: administered at 0.25 mg/kg/day for both adults and children.

Nystatin

Mode of action It is the most popular agent for treating superficial infections of C. albicans.

It should be used topically, however, it may be used orally for the treatment of mucocutaneous infection caused by C. albicans.

Nystatin is similar to that of amphotericin B. It has both fungicidal and fungistatic activity depending upon its concentration.

Adverse effects It causes systemic toxicity.

Preparations Nystatin is available in the form of creams, tablets, suspensions, oral rinses, gels and pastilles. Oint-ment is used for the treatOint-ment of angular cheilitis.

Tablets (5,00,000 IU) used for the treatment of oral candidiasis. Suspension is used for young children and noncompliant patients. Oral rinse is relatively ineffec-tive, because of short contact time with oral lesions.

The oral rinse contains sugar and increases the risk of dental caries. Pastilles and lozenges can be sucked slowly and therefore have a longer duration of action.

These forms of administration, by the virtue of sweet-ened formulations, result in better patient compliance, and prolonged retention. This results in a better fungicidal action than suspension. Pastilles are ideal for treatment of Candida associated denture stomatitis.

However, because of their sucrose content, there is increased risk of developing dental caries. A slow-released form offers rapid clinical improvement in cases of oral candidiasis. This form, is to be kept in mouth and not swallowed, is sugar free and offers prolonged contact time. It is more effective than pastilles; the effect lasting for upto a week after treatment.

The various topical preparations of nystatin in the treatment of oral candidiasis can be summarized as follows:

• Dissolved vaginal pessaries (1,00,000 IU) one pastille four times a day

• Ointment/cream to be applied to commissures three times daily

• Oral suspension (1,00,000 units/ml) four times daily, continued for several days after healing.

Azole Antifungal Agents

These agents are classified into two groups:

1. Imidazoles: Clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, miconazole, sulconazole and tioconazole.

2. Triazoles: Fluconazole and itraconazole.

Azoles are becoming popular in the management of oral candidiasis. The agent, fluconazole is the drug of choice in treatment of oropharyngeal candidiasis in HIV infection.

Mode of action Azoles act by inhibiting the cytochrome p-450 enzymes that are involved in synthesis of fungal cell membranes. Clotrimazole, econazole, fenticonazole, isoconazole, miconazole, sulconazole and tioconazole are all used for local treatment. Miconazole can also be given by mouth for oral and intestinal infections.

Ketoconazole, fluconazole and itraconazole are used for both local and systemic candidiasis.

Clotrimazole

Clotrimazole is primarily a fungistatic, with a broad spectrum of activity both anticandidal and antistaphylococcal. It is mainly used for superficial infections of oral cavity, skin and vagina caused by Candida. As a cream it is useful in the treatment of angular cheilitis due to its dual action.

Adverse reactions are mild and rare; in the form of local skin irritation, nausea and vomiting.

Preparations It is available in the form of cream, and lozenges: 1 precent cream is applied three times daily while lozenges are available in 10 mg units, dissolved in the mouth five times a day

Miconazole

Like clotrimazole it has broad spectrum of activity against fungi including C. albicans and also against staphylococci. Hence it is useful in the treatment of angular cheilitis. It can be given topically, intravenously or intrathecally. It is effective in all types of oral candidiasis. Systemic use of miconazole has been taken over by less toxic drugs such as ketoconazole and fluconazole.

Adverse effects Rare with topical use. The most common effect after intravenous use is thrombophlebitis. Drugs of azole group are known to enhance anticoagulant effect of oral anticoagulants such as warfarin.

Preparations It is available in the form of tablets, oral gel, intravenous injections, topical and vaginal prepara-tions. Cream is used in the treatment of angular cheilitis.

It has been formulated into a lacquer, which is effective in treatment of Candida associated denture stomatitis (Dumicoat 50 mg/g). Application of the contents of one bottle to upper surface of upper denture after thorough cleansing and drying, repeated twice at intervals of one week, is recommended. A single application of miconazole lacquer over fitting surface

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of denture, as a slow delivery, is capable of reducing the numbers of Candida on denture surfaces for a substantial period of time.

Ketoconazole

Mode of action It is effective against a wide spectrum of fungi including Candida.

Absorption Unlike other imidazoles, it is readily absorbed after oral administration.

Indications Its main indication is secondary oral candidiasis; such as chronic mucocutaneous candidiasis.

Adverse effects The most common adverse reactions are gastrointestinal intolerance with nausea and vomiting.

Hepatotoxicity is rare. It causes depression of testo-sterone biosynthesis, which manifests as painful gynecomastia, loss of libido and sometimes loss of hair.

It is also a potential teratogen.

Interactions It interacts with many drugs. With non-sedative antihistamine, such as terfenadine and astemi-zole, and can lead to arrhythmias, and tachycardia.

With cyclosporin, there can be profound immunosup-pression and life-threatening renal dysfunctions.

Concomittant use of rifampicin, decreases ketoconazole concentrations.

Preparations It is available in the form of tablets, suspen-sions and creams. Two percent cream is applied to commissures three times a day in chronic hyperplastic candidiasis. Systemic dose is 200 to 400 mg daily.

Fluconazole

Fluconazole is water-soluble and does not require a low gastric pH for absorption. It is poorly bound to plasma proteins and is eliminated by kidney.

Mode of action It has a broad spectrum of antifungal activity. It differs from other azoles in that it has an excellent absorption from gastrointestinal tract; and is weakly protein bound in serum. Unlike other azoles, it is not metabolized in humans, and is excreted largely through kidney approximately 80 percent unchanged.

It has a high systemic absorption and is now considered a drug of choice for candidiases in HIV disease, in 200 mg weekly doses.

Adverse effects Fluconazole is well-tolerated. The adverse effects such as nausea, headache, and gastro-intestinal discomfort are usually mild. It may cause elevation of liver enzymes and an allergic rash. It should be avoided in pregnancy as it may cause embryotoxicity.

Interactions Interactions are lesser than the agents mentioned earlier. Being a structural analogue to other azoles, it also shows similar interactions. Nonsedative antihistaminics such as terfenadin and astemizole should not be administered along with fluconazole.

Fluconazole can lead to high serum concentrations of many drugs by decreasing their metabolism in liver.

Hence decreased clearance of cyclosporin may result in significant immunosuppression, leukopenia and renal dysfunction. Similarly, interactions with other drugs such as phenytoin, warfarin and hypoglycaemics, fluconazole can produce toxic concentrations in serum, prolonged prothrombin times.

Preparations It is available in capsule and intravenous formulations. The adult dose for treating oropharyngeal candidiasis is 50 mg daily for 7 to 14 days; and 50 mg daily for 14 to 30 days for oesophageal candidiasis.

Itraconazole

Itraconazole is water-insoluble and lipophilic drug, and requires a lower pH for ionization than ketoconazole.

It is highly protein bound and excreted in bile. It is well-absorbed after oral administration and has a wide spectrum of activity, including species. It is effective in various superficial mycoses including oral candidiasis due to C. albicans, C. krusei and C glabrata. As the last two are resistant to fluconazole, itraconazole is the drug of choice in treatment of fluconazole-resistant Candida.

Adverse effects Generally, it is well-tolerated. Gastro-intestinal disturbances are rare.

Interactions Similar to fluconazole.

Preparations It is available in capsule and oral solution forms. The adult oral dose is 100 mg daily for fifteen days for oropharyngeal candidiasis.

Disadvantages of using azoles

1. All azoles are fungistatic. This factor should be considered in treating chronic infections in immunocompromised patients.

2. None of azoles is entirely beneficial.

3. They are expensive.

4. Hepatotoxicity may be common to all of them and the potential for endocrine toxicity exists particularly at higher doses.

Resistance The emergence of resistance to triazoles, particularly to fluconazole is a serious clinical problem in patients with HIV disease.

Metronidazole

It is effective in anaerobic infections and acute necrotizing ulcerative gingivitis (ANUG).

Metroni-114

Principles of Oral and Maxillofacial Surgery

dazole is used with one of the penicillins, usually, amoxycillin to treat acute orofacial infections with an anaerobic component of causative microorganisms.

Metronidazole, can also be used in combination with cephalosporins for treating anaerobic infections where there is penicillin allergy or any other contraindication.

Spectrum of activity It is very effective against a wide range of Gram-positive and negative bacteria including Bacteriodes, Clostridia and Spirochaetes.

Indications ANUG has been successfully treated with metronidazole. It has also been successfully used in chronic destructive periodontal disease and juvenile peridontitis.

Administration, absorption and distribution Metronidazole is absorbed from gastrointestinal tract. It competes with food for absorption. It is widely distributed through body fluids after administration. It crosses placental barrier and appears in breast milk.

Excretion Metronidazole is excreted in urine which may be coloured red-brown. Impaired renal and hepatic function can prolong presence of the drug in serum. It is also excreted in saliva and breast milk in similar concentrations to plasma.

Toxic effects and contraindications

1. Studies in humans have shown no evidence of carcinogenicity, however, teratogenic effects are possible.

2. Blood dyscrasias are reported. Blood investigations are recommended if the therapy exceeds ten days.

Metronidazole should be avoided in patients with blood dyscrasias.

3. CNS pathology: Metronidazole affects patients with CNS pathology such as depression or psychosis. The reported effects are convulsions, dizziness, vesti-bular symptoms, hypotension and hallucinations, etc. Metronidazole is contraindicated in patients who are taking phenytoin.

4. Metronidazole may enhance the effects of warfarin and prolong coagulation time. In such patients, the assistance from physician is obtained to supervise warfarin therapy.