Description of the drug FLUCONAZOLE

CANDIDIASIS OF THE ESOPHAGUS

Candidiasis is an infectious disease of the mucous membranes, skin and internal organs caused by yeast-like fungi of the genus Candida. Esophageal candidiasis (OC), which is a manifestation of visceral candidiasis, occupies a prominent place among infectious lesions of the esophagus. In recent years, there has been a tendency to increase the frequency of CP, especially in patients with impaired immunity. The growth of candidiasis infection is largely due to an increase in the number of patients with HIV infection, advances in transplantation and immunosuppressive therapy, and the uncontrolled use of antibiotics. KP occurs in 0.7-1.5% of gastroenterological patients [5, 6].

The problem with severe fungal infections caused by opportunistic pathogens is that they are difficult to treat and can be fatal. The mortality rate for invasive candidal infections has been found to be 34% [16].

Etiopathogenesis. Candida species are the most common esophageal pathogen, most notably Candida albicans, with occasional occurrences of C. tropicalis, C. parapsilosis, C. glabrata, C. lusitania, and C. krusei. These microorganisms are normal components of the oral flora and their growth is inhibited by bacterial commensals. Infection with fungi such as Candida, which are widespread in the environment, occurs through endogenous or exogenous routes. Endogenous infection is associated with the activation of saprophytic fungi; exogenous infection can occur through direct contact with carriers of infection or from the environment. If the host's body is not weakened, many fungi do not exhibit their pathogenic properties. Research in recent years has shown that the source of fungal dissemination is the intestines, and candidiasis of the oral cavity, genitals, and esophagus is a manifestation of systemic candidiasis. The likelihood of developing systemic damage depends both on the properties of the microorganism itself (their number, virulence, genetic and species heterogeneity of the population), and on the state of the macroorganism, especially its immune system, nutritional status and abdominal blood flow [3, 17].

Favorable conditions for the development of the infectious process are created by various violations of the physiological, anatomical and immunological mechanisms of the body's defense. Factors that provoke the occurrence of esophageal candidiasis include the use of antibiotics, inhaled or injected corticosteroids, antacid therapy or a hypochlorhydric state, diabetes mellitus, alcoholism, the consequences of intoxication, malnutrition, old age, impaired motility of the esophagus or esophageal obstruction, organ and bone marrow transplantation , enteral and especially parenteral nutrition, etc. A weakened immune system can lead to candidiasis infection. In diabetes mellitus, elevated blood glucose levels promote fungal growth because hyperglycemia impairs granulocyte function. Hypofunction of the parathyroid glands and adrenal glands leads to disruption of calcium-phosphorus metabolism, which causes hidden spasmophilia of the esophagus, thereby reducing its local protective capabilities [9]. Impaired nutritional status due to a lack of protein in the body and low calorie food affects the state of the immune system and creates the preconditions for the development of candidiasis [3]. Risk factors for candidiasis include a decrease in the acidity of gastric juice (pH 7.4 is optimal for the growth of Candida fungi, and when the pH shifts to 4.5, fungal growth is completely inhibited) [3, 4, 7].

The pathological manifestations of KP are varied. At first, the affected areas of the esophagus have the appearance of individual whitish or yellowish lesions raised above the mucous membrane. Later, these lesions can merge, forming dense plaques with the introduction of the fungus into the submucosa or pseudomembranous deposits with the penetration of the fungus into the muscular layer and blood vessels [9]. Films that form on the esophageal mucosa in especially severe cases can almost completely close the lumen of the esophagus. Plaque consists of desquamated epithelial cells that mix with fungi, inflammatory cells and bacteria. Microscopic examination reveals uniformly colored yeast-like cells and filaments of mycelium of Candida fungi [9]. True ulceration is observed infrequently and in most cases is observed in immunosuppressed patients with granulocytopenia [29]. Sometimes necrosis of the esophageal wall occurs and phlegmonous inflammation of the esophagus and mediastinum develops, which can become one of the causes of death of the patient [1].

There is a morphological classification, according to which all cases of KP are divided into three groups depending on the severity of the process, that is, depending on the depth of damage to its wall: 1st group - individual whitish plaques with the introduction of pseudomycelium of the fungus between the epithelial cells; 2nd group - membranous plaques merging with each other and forming vast fields, while filaments of pseudomycelium grow not only the mucosa, but also the submucosa; Group 3 - pseudomembranous overlays, combined with deep changes, in which the threads of the fungus penetrate deeply into the thickness of the muscle tissue [10].

Clinical manifestations and complications. Symptoms of the disease are practically absent in 25-30% of patients suffering from KP, especially in immunocompetent individuals. However, most patients present with complaints related to damage to the gastrointestinal tract. The most typical clinical manifestations of KP are dysphagia and, somewhat less commonly, odynophagia. The severity of esophageal symptoms ranges from moderate difficulty swallowing to severe pain, resulting in the inability to eat and the development of secondary dehydration. In severe odynophagia, there may be other causes or co-infection, especially in patients with AIDS. Much less frequently, patients may complain of chest pain not associated with swallowing, heartburn, nausea, sometimes vomiting with the release of films (pseudomembranes), decreased appetite and weight, and the appearance of loose stools with mucus (see figure) [4, 9, 29].

Physical examination may be helpful in KP. Approximately two thirds of patients with

AIDS and esophageal candidiasis have candidal stomatitis. KP is observed in patients with chronic mucocutaneous candidiasis, which is a severe form of candidal infection and is more often observed with dysfunction of the adrenal glands and parathyroid glands [29].

Complications of esophageal candidiasis are rare. Esophageal bleeding can be observed in severe cases of the disease, accompanied by the formation of erosions, ulcers, and be associated with coagulopathy; perforation may develop. Secondary obstruction of the lumen by mycetoma has been described. Necrosis rarely occurs with the development of phlegmonous inflammation of the esophagus and mediastinum [1]. In severe cases, specific esophagitis can be complicated by the development of candidiasis sepsis [6].

Diagnostics. Suspicion of esophageal candidiasis should arise in any patient if there are risk factors for the development of esophageal infection and complaints of dysphagia and odynophagia. The presence of candidal stomatitis confirms this diagnosis, but in its absence, damage to the esophagus is also not excluded.

Barium x-ray of the esophagus is usually used for initial evaluation before endoscopy. However, in the early stages of candidal esophagitis, X-ray examination of the esophagus does not have much diagnostic value, since it reflects only nonspecific changes common to all esophagitis [2]. Classic radiographic signs of acute esophagitis caused by Candida spp. are linear or irregular filling defects with clear edges. In severe cases of candidal esophagitis, fusion of lesions occurs, which is why large filling defects sometimes form clusters in the form of bunches of grapes [2]. In this case, the esophagus acquires a “shaggy” (“hairy”) appearance, simulating ulceration [25]. The presence of large, well-circumscribed ulcers is not a sign of candidal esophagitis. Impaired motility and narrowing of the lumen of the esophagus due to pseudomembranes may occur. It should be remembered that a normal barium radiograph of the esophagus does not exclude esophageal candidiasis. Due to severe odynophagia, the patient will not be able to drink barium, which makes X-rays of the esophagus difficult [29].

The double contrast radiological method is considered more informative for the diagnosis of candidal esophagitis, the effectiveness of which reaches 70% [26].

A cytology brush and balloon catheter are used to quickly diagnose esophageal infections without endoscopy. These instruments can be easily inserted through the nasal passages or the mouth through a protective probe that prevents contamination. The material obtained from the protected brush or balloon catheter after it is removed from the esophagus is evaluated cytologically and culturally. The technique using protected brushes has a sensitivity of 88% and a specificity of almost 100% [26].

The cytological method involves staining impression smears or swab sediment from a cytological brush in search of active forms of Candida - budding yeast cells, pseudomycelium and mycelium. The cultural method involves placing the test material on Sabouraud's glucose-enriched medium or other media, in order to then judge the etiology of the infectious process in the esophagus by the nature of the colonies formed.

Endoscopic examination of the esophagus is the most sensitive and specific method for diagnosing esophageal candidiasis. The endoscopic picture of KP is most often characterized by the presence of easily removable fibrinous loose overlays of white or yellow color, under which easily wounded and/or edematous mucosa is found. Catarrhal and erosive-ulcerative esophagitis are less common [19]. Candida spp. rarely causes true ulceration. The presence of an ulcer in candidal esophagitis is often a sign of an additional pathological process in the esophagus [29]. There are various endoscopic classifications of esophageal candidiasis (Tables 1 and 2).

During endoscopy, affected areas of the mucosa may be subjected to brush biopsy for cytological examination or biopsy for histological diagnosis. When ulcers are identified endoscopically, repeated biopsies help rule out the presence of coexisting pathological processes. Cytological examination of brush biopsy material has a higher sensitivity level than histological examination of biopsy specimens for mild superficial candidiasis because microorganisms may be washed off the tissue surface during processing of the biopsy material [19]. In rare cases, positive cytology in the presence of negative histology indicates colonization rather than infection. For more severe candidiasis of the esophagus, the greatest diagnostic value is histological examination of mucosal biopsies using special staining for neutral mucopolysaccharides according to Schiff PAS (CHIK reaction) or according to Gomori with silver hexamethylenetetramine. Only histological examination demonstrates invasion of the mycelium or pseudomycelium of the fungus deep into the tissue of the esophagus.

Skin testing and serological tests are not very informative for diagnosing esophageal candidiasis.

Treatment. There are many oral and intravenous medications that are used to treat candidiasis esophagitis. Despite the relatively wide choice of drugs, the treatment of KP is an urgent problem, since some drugs are not effective enough, others have serious side effects; In addition, there is currently an increase in resistance to antifungal drugs.

When treating KP, oral therapy should initially be prescribed; intravenous administration is used only in case of refractory disease or if there are contraindications to oral use of medications. Patients with moderate severity of the disease and minimal immunocompromise require a short course of therapy using systemically absorbed drugs such as oral azole. Immunocompromised transplant patients and AIDS patients with KP are best treated with longer courses of azole. In patients with granulocytopenia, when there is a significant risk of dissemination of Candida infection, the use of intravenous systemic drugs (azoles, amphotericin B) is justified [29].

The arsenal of modern antifungal agents is quite wide. Antifungal drugs of several groups are used to treat esophageal candidiasis. The most effective drugs are from the azole group. Non-absorbable azoles (clotrimazole, miconazole) are used orally; however, systemic drugs from this group (ketoconazole, fluconazole and itraconazole) are more effective. These drugs, like others in the azole group, alter fungal cell membrane permeability through cytochrome P450 (CYP)-dependent interference with ergosterol biosynthesis, resulting in fungal cell damage and death. New triazoles (itraconazole and fluconazole) have higher affinity similarity than imidazoles (miconazole and ketoconazole) for fungal CYP enzymes [14]. Although other drugs, such as miconazole, clotrimazole, and nystatin, can be used to treat candidal stomatitis, as well as to prevent esophageal lesions, these drugs are less effective as the main group of drugs for the treatment of KP [24].

Clotrimazole and miconazole are imidazole drugs. Clotrimazole tablets and miconazole for oral use are currently available. However, they are not absorbed from the gastrointestinal tract. These drugs can be used for mild candidiasis of the esophagus in people without immunodeficiency.

Ketoconazole (nizoral, oronazole) is an imidazole derivative and, when taken daily in a dose of 200 to 400 mg, gives a good effect in the treatment of esophageal candidiasis. In AIDS patients who usually require higher doses of ketoconazole, the daily dose can be increased, if nausea does not occur, to the maximum (800 mg). Ketoconazole penetrates well into various organs and tissues, but poorly through the blood-brain barrier. The drug is well absorbed from the gastrointestinal tract, but requires an acidic environment for optimal absorption. With gastric hypochlorhydria and the use of antacids, its bioavailability decreases. To improve absorption, ketoconazole should be taken 2 hours before taking antiulcer medications. Approximately 10-25% of AIDS patients experience decreased gastric acid secretion. Ketoconazole can cause a temporary blockade of the synthesis of testosterone and cortisol [6, 8, 29].

Itraconazole (Sporanox) belongs to the group of triazoles, like ketoconazole, and is prescribed at a dose of 200 mg per day. Further increases in the dose lengthen the half-life of the drug and increase its effectiveness. The absorption of intraconazole decreases when the pH of gastric juice decreases [23]. Ketoconazole and itraconazole are metabolized in the liver and excreted in the bile. The half-lives of these two drugs are 7 to 10 hours and 24 to 42 hours, respectively [14]. No dose adjustment is required in patients with renal failure.

Fluconazole (Diflucan, Diflazon, Forkan, Flucostat - domestic fluconazole) is a water-soluble triazole and is prescribed at a dose of 100 mg per day. Fluconazole is a drug whose absorption is independent of gastric pH and is significantly more effective in the treatment of esophageal candidiasis in AIDS than ketoconazole (200 mg daily) [21]. Fluconazole is available for oral and intravenous use. It is minimally metabolized and excreted unchanged in the urine. Fluconazole has a high tissue tropism and does not affect the synthesis of androgens and penetrates well through the blood-brain barrier. Unlike ketoconazole and intraconazole, it is highly soluble in water and minimally protein bound. The drug has a long half-life (approximately 30 hours, unless renal function is impaired and the presence of food or hypochlorhydria does not alter absorption), allowing it to be taken once daily. It has been shown that the administration of fluconazole improves immune parameters in the T- and B-systems [18]. Both fluconazole and itraconazole can be taken orally as solutions. These forms may be more effective than tablets because they enhance the local effect and improve absorption.

Adverse effects of ketoconazole, fluconazole and itraconazole are primarily dose dependent and include nausea, hepatotoxicity, decreased steroid production and cyclosporine metabolism [14]. In rare cases, ketoconazole can cause fatal hepatitis [12]. A slight increase in aminotransferases is a common side effect of all three drugs, but this should not be used as an excuse to discontinue them. The effect on steroidogenesis is most pronounced with ketoconazole. Reversible inhibition of gonadal and adrenal steroid synthesis by ketoconazole may occur when the dose exceeds 400 mg per day [27]. At recommended doses, fluconazole and itraconazole do not affect steroidogenesis. As a result of their effects on hepatic microsomal enzymes, all three azoles inhibit the metabolism of cyclosporine, which leads to an increase in the level of cyclosporine in the blood; this effect is most pronounced with ketoconazole [14].

Another main group of antifungal agents is polyene antibiotics, represented by amphotericin and nystatin. These drugs irreversibly bind to sterols in fungal cell membranes, thereby altering the permeability properties of the membrane, disrupting its barrier function and causing cell death. Nystatin (anticandin, mycostatin, fungicidin) is practically not absorbed from the gastrointestinal tract. It is used to treat candidal stomatitis, but is less effective in cases of esophageal candidiasis. In addition, the effectiveness, safety and ease of use of azole derivatives make it possible to consider nystatin as a second-line therapy. Amphotericin B (amphostat, fungizone) is the only polyene antibiotic for parenteral administration. It is not absorbed in the gastrointestinal tract, is used intravenously, penetrates well into various organs and tissues, and is excreted from the body by the kidneys. The half-life is 24-48 hours, but with systematic use it can increase to 15 days due to accumulation in tissues [8]. Although amphotericin B is the most effective drug used to treat systemic mycoses, its use in the treatment of KP is limited due to serious side effects. Side effects of amphotericin include neurotoxicity, hematoxicity, nephrotoxicity, local irritation (phlebitis), allergic reactions, dyspeptic disorders, fever, etc. [8]. The most adverse side effect resulting from long-term use of amphotericin is nephrotoxicity, which is usually reversible. This medication is now available as an oral solution and lozenges. In patients with KP who are refractory to treatment with fluconazole or other azoles, low doses of intravenous amphotericin B (10 to 20 mg daily) may be effective. The total dose of the drug for the treatment of esophageal candidiasis ranges from 100 to 200 mg [29].

Flucytosine is a drug with a narrow spectrum of antifungal activity that works by interfering with RNA translation. It is incorporated into fungal cells, where it is converted into 5-fluorouracil and inhibits thymidylate synthetase. This oral drug, which is given at a dose of 50 to 150 mg/kg per day every 6 hours, can be used in combination with amphotericin B, but it should not be used as monotherapy because fungi quickly become resistant to it. In addition, flucytosine monotherapy appears to be only moderately effective [12].

The newest class of antifungal drugs are candins, which interfere with the synthesis of the fungal wall. They are effective against most Candida species, including C. krusei. The first studies showed that capsofungin, which represents this group of drugs, was as effective in KP as amphotericin B [16].

When treating patients with KP, one should take into account the presence of resistance, which has now increased significantly due to the widespread use of azoles. If resistance develops, it is often useful to increase the azole dose. If this is not enough, switch to another drug from this group or use an oral solution of itraconazole [13], which must be prescribed in higher doses due to frequently observed cross-resistance. When a high dose (i.e. 400 mg daily) of fluconazole is not enough, switch to intravenous amphotericin B, and the result is achieved in 90% of cases. Resistance to amphotericin is rare [29].

In table 3 presents the treatment of candidal esophagitis depending on the function of lymphocytes and granulocytes.

In the treatment of candidal esophagitis in patients with AIDS, the first-line drugs are ketoconazole and fluconazole, with fluconazole being preferred. Due to better tolerability, it is primarily indicated for patients at an advanced stage of the disease who have many comorbidities. If swallowing is impaired, parenteral forms of fluconazole can be used. If first-line drugs are ineffective, drugs from the reserve group (amphotericin B, itraconazole), which are more toxic and/or more expensive, are used. Etiotropic therapy of esophageal candidiasis, in addition to the main course of treatment, requires maintenance treatment, which can be lifelong (Table 4) [4].

Treatment of candidiasis against the background of severe immunodeficiency and leukopenia is a difficult task. Along with antifungal therapy, it is important to restore the pool of neutrophil leukocytes and their functional activity, since neutrophil leukocytes are one of the main links in the defense mechanism against Candida spp. It is proposed as an additional agent in the treatment of candidal infection against the background of neutropenia to use granulocyte colony-stimulating factor, which reduces the deficiency of myeloperoxidase in neutrophil leukocytes and enhances their oxygen-dependent anti-candidal activity [7]. A good effect has been obtained from the endoscopic administration of granulocyte concentrate and high-intensity pulsed laser radiation to patients with KP, which improves immune functions [5].

Thus, to achieve success in patients with severe fungal infections, including candidiasis, an integrated approach to diagnosis and treatment is advisable. Increased survival will be facilitated by prompt diagnosis followed by the selection of effective specific antifungal therapy and therapeutic measures aimed at increasing the number of granulocytes and stimulating phagocytosis [16].

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Indications, side effects and contraindications for taking Fluconazole

The instructions from the manufacturer indicate the individual pathologies for which the drug is prescribed. The list is presented:

• various forms of invasive candidiasis;
• damage to the mucous membrane of the oral cavity, pharynx and esophagus by fungi;
• candiduria, chronic atrophic and mucocutaneous candidiasis that appears in patients with dentures;
• non-invasive lesions of the bronchopulmonary region;
• genital fungal infection, including acute vaginal form and exacerbations;
• dermatomycosis affecting the body, feet and groin;
• onychomycosis, pityriasis versicolor.

Fluconazole is indicated for patients to prevent exacerbations of chronic fungal infections. Can be used to prevent disease in people undergoing radiation or cytotoxic therapy.

The list of contraindications includes:

• individual intolerance to the component composition;
• treatment with Terfenadine, Astemizole;
• children's age, up to four years.

Patients need increased caution during therapeutic procedures with Fluconazole:

• with renal, liver failure;
• a rash that occurs against the background of a superficial fungal infection;
• organic pathologies of the heart;
• when undergoing therapy with medications that affect electrolyte balance and the uniformity of heart contractions.

Fluconazole is not used during pregnancy and breastfeeding. There is no reliable information about the safety of the drug - this group of patients was not affected during clinical trials. During therapy, women must use reliable contraception.

During therapeutic procedures, a number of patients experience the following adverse reactions:

• stool disturbances, discomfort in the abdominal area;
• attacks of nausea, headache;
• increased gas formation, dermatological rashes;
• anaphylaxis, hepatotoxic effects;
• weakness, fatigue, fever;
• increased sweating, hepatitis, jaundice;
• anemia, urticaria, swelling of the face;
• sleep disturbances with insomnia, involuntary muscle tremors;
• change in taste, obsessive itching, Quincke's edema.

If unusual reactions occur, the patient should report them to the attending physician. The specialist will review the treatment regimen and select a more suitable medication.

Currently, the problem of mycotic diseases is acquiring important social significance. The increase in the incidence of mycoses is associated with many factors, primarily with the active use of antibacterial drugs in medical practice, which undoubtedly increases not only the incidence of candidiasis, but also mycoses caused by filamentous fungi. This is also facilitated by the use of cytostatics, corticosteroids and other drugs with immunosuppressive properties. The development of mycosis is promoted by a combination of many reasons associated with the urbanization of modern life of the population [1–4].

The wide distribution of fungi in nature, their constant presence both in the environment and in the body, makes contact and infection of humans inevitable. Particularly alarming is the increase in the number of patients with deep mycoses, which include some mycoses of the ENT organs.

Currently, approximately 100,000 species of microscopic fungi have been identified, of which more than 400 species are capable of causing infections in humans, but about 100 species are of real importance in clinical practice [5].

An analysis of clinical and laboratory studies conducted at the Moscow Scientific and Practical Center of Otorhinolaryngology showed the increasing importance of fungal pathology among general ENT morbidity. So, in 2010-2011. among patients with chronic inflammatory pathology of the ENT organs who applied to the mycology room of the Center’s advisory department, fungal infection was detected in 23% [6].

In this regard, the problem of mycoses of the ENT organs remains relevant, which determined the purpose of this work: to familiarize otorhinolaryngologists with modern principles of diagnosis and treatment of mycoses of the upper respiratory tract and ear, varying in localization and nature of clinical manifestations.

Nosological forms of fungal diseases of the ENT organs are otomycosis, pharyngomycosis, laryngomycosis, fungal infection of the nasal cavity and paranasal sinuses. There are superficial mycoses, which affect the skin, mucous membrane, external auditory canal, pharyngeal cavity, and deep mycoses affecting, for example, the SNP, the postoperative cavity of the middle ear, accompanied by invasion of the fungus not only into the epithelium, but also into surrounding tissues.

According to our data, in recent years, the frequency of detection of pharyngomycosis is 45%, otomycosis - 42%, mycosis of the nasal cavity and SNP - 8%, laryngomycosis -5% among all patients with mycosis of the ENT organs [3, 7].

The proportion of otomycosis among otitis of other etiologies reaches 25.3%, pharyngomycosis in chronic pharyngitis and tonsillitis - 26%. Fungal infection of the larynx in chronic laryngitis reaches 15%; in chronic inflammation of the nose and SNP, the share of the fungal process is 7%.

External fungal otitis, fungal otitis media and fungal infection of the postoperative middle ear cavity occur in 69, 18 and 13% of cases of otomycosis, respectively. The main causative agents of external fungal otitis are molds of the genus Aspergillus

(65%),
Penicillium
(5%), with mycosis of the postoperative cavity the proportion of mold fungi reaches 95%, while with fungal otitis media, yeast-like fungi of the genus
Candida
(79%).
In some cases, fungal diseases of the ears can be caused by fungi of the genera Mucor, Alternaria
, etc. In 17% of cases, we noted a combined infection with
Aspergillus
spp.
and Candida
spp.
in combination with representatives of Staph.
spp and
Pseudomonas
spp.
Infection with two or more species of fungi Aspergillus
spp.
+ Candida
spp.,
Aspergillus
spp.
+ Candida
spp.
+ Alternaria alternata
occurs in 1% of observations.

Candida are the leading pathogens

(97-99% of observations).

In mycosis of the nasal cavity and SNP, mold fungi account for up to 78% of the lesions. The main pathogen is a fungus of the genus Aspergillus

, species -
fumigatus
and
niger
, in some cases, in immunocompromised patients, fungal diseases of SNP can be caused by fungi of the genera
Mucor, Alternaria, Rhizopus, Rhizomucor
, etc.

Basically, all these types of fungi belong to the group of opportunistic fungi and cause disease only under certain conditions that predispose to the development and reproduction of fungi, ensuring their transition from saprophyte to the realization of pathogenic properties.

Among the risk factors for the development of mycoses of the ENT organs, the leading positions are occupied by iatrogenic immunodeficiency states that develop as a result of massive antibiotic therapy, long-term use of glucocorticoid and immunosuppressive drugs for oncological and autoimmune diseases. Mycoses of the ENT organs often accompany severe somatic pathologies, such as HIV infection and AIDS, diabetes mellitus, thyroid dysfunction, agranulocytosis, anemia, bronchial asthma, etc.

The pathogenesis of mycosis consists of adhesion (attachment of the fungus to the surface of the mucous membrane or to the skin), colonization of fungi and their invasive growth. In severe forms of ENT mycosis, the next stage is the generalization of the process: the penetration of fungi into the blood with dissemination and the appearance of secondary foci of mycosis in various organs and tissues. This is especially true for fungi of the genus Aspergillus

spp., the pathogenicity factor of which is their ability to grow at 37 °C, the presence of enzymes (protease, phospholipase), toxins (aflatoxin, fumagillin, etc.), pronounced angioinvasiveness and the ability to evade immune surveillance due to the production of inhibitors of the phagocytic function of macrophages and neutrophils, for example gliotoxin [1, 5].

A factor contributing to the development of otomycosis is, first of all, trauma. When the skin and mucous membrane are damaged, paths are opened for the fungus to penetrate deep into the tissues, and protective reactions at the site of damage are weakened. In addition, the secreted secretion of the injured integumentary epithelium is a good nutrient medium for the proliferation of fungi. Thus, a paradoxical phenomenon has been noted: fungal diseases of the outer ear more often occur in extremely careful people who intensively use cotton swabs and other objects to clean their ears, injuring the skin of the external auditory canal and often causing traumatic invasion of the pathogen. Speaking about the need for proper, gentle removal of excess sulfur, it should be remembered that its presence in a small amount in the ear canal is necessary, since it not only mechanically protects the skin, but also carries out bactericidal and fungicidal functions.

The occurrence of a fungal infection of the outer ear is often preceded by water entering the ear during bathing or removing wax plugs by washing. Long-term local use of glucocorticoid drugs, antibiotics, and antiseptics for otorrhea, which accompanies a purulent-inflammatory process in the middle ear, leads to the development of otomycosis in 20% of cases.

Surgical sanitation of the middle ear in the absence of a positive effect from previous courses of antibacterial therapy, local and physiotherapeutic conservative treatment often entails the development of fungal infection of the postoperative cavity. Perhaps in such cases there is undiagnosed fungal otitis media. Surgical treatment in this case can be performed only after negative repeated mycological studies.

Otomycosis can also develop when working in dusty conditions and in pressure complexes with high pressure and humidity.

Fungal infection of the pharynx and larynx often develops in patients after massive high-dose antibacterial therapy, long-term systemic use at a dose exceeding 0.3 mg/kg/day (in terms of prednisolone) for more than 3 weeks, and local use of inhaled forms of corticosteroids for hormone-dependent bronchial asthma. A stay in the intensive care unit for more than 10 days, accompanied by laryngeal intubation for more than 5 days, significantly increases the risk of developing mycoses. Smoking, the use of removable dentures and their improper treatment contribute to the development of mycosis of the pharynx and larynx.

Mycosis of the nasal cavity as an independent disease is extremely rare, usually due to trauma to the nasal mucosa in HIV-infected people. More often, the fungal process affects the maxillary sinuses after foreign bodies enter them (filling material when filling the canals of the 4th-7th teeth of the upper jaw).

Complaints and clinical manifestations of mycosis of the ENT organs

are determined by the characteristics of vegetation and parasitism of certain types of fungi and are largely determined by the localization of the pathological process.

In all forms of mycotic diseases of the upper respiratory tract and ear, there is a specific discharge in the form of crusts, plaques, thick caseous or liquid secretions, the color, quantity and consistency of which depend on the type of fungus and the phase of its development. The clinical picture, despite the diversity of pathogens, has a number of specific features. Main complaints with mycotic otitis media

- discharge from the ear, formation of “plugs” in the external auditory canal, itching, pain, ear congestion.

Thus, with otomycosis caused by dermatophytes, the skin of the auricle, postauricular area and external auditory canal is mainly affected. Patients are concerned about itching and peeling of the skin of the affected area. In the external auditory canal there is dry discharge in the form of plaque and films. Inflammatory phenomena are not expressed. Accelerated formation of sulfur plugs was noted.

For otomycosis caused by mold fungi ( Aspergillus, Penicillium, Mucor

etc.), the skin of the external auditory canal, the postoperative cavity, and less often the middle ear cavity and the skin of the auricle are affected. The patient experiences severe pain, severe hearing loss, and dizziness. The discharge looks like “wet newspaper.” The symptoms of inflammation are significantly pronounced. After removal of the pathological discharge, granulations are visualized, the skin is damaged and bleeds easily. The disease can occur as necrotizing external otitis with damage to the bones of the skull.

With candidal otomycosis, the middle ear cavity and the skin of the external auditory canal are affected. Upon examination, maceration and infiltration, reminiscent of weeping eczema, are determined. The process often spreads to the skin of the auricle and the area behind the ear. Pain and itching are moderate. Some patients in the acute stage may have complaints of increased body temperature, headache, increased sensitivity of the auricle and postauricular area.

Mycotic otitis media and mycosis of the postoperative cavity are characterized by the following clinical manifestations: hearing loss, noise in the ear, pain, discharge from the ear, periodic itching, congestion and dizziness.

Otomycosis, like other types of specific inflammation, has a chronic course with a subtle onset of the disease, its gradual development and significant duration. The development of a fungal disease is possible at any age; frequent exacerbations and relapses of the disease during treatment are typical.

For fungal infections of the pharynx

patients complain of discomfort in the throat, burning sensation, dryness, rawness, and soreness, which may be more pronounced than with bacterial pharyngitis. Painful symptoms are moderate; when swallowing and eating irritating foods, the pain intensifies. Sometimes patients note irradiation of pain in the submandibular region, on the anterior surface of the neck and in the ear. Depending on the degree of damage, pseudomembranous, hyperplastic, granulomatous and erosive-ulcerative clinical forms of pharyngomycosis are distinguished. Specific signs of the clinical picture of pharyngomycosis are the presence of plaque, swelling of the mucous membrane and pronounced general symptoms of intoxication; frequent (up to 10 times a year) exacerbations are also characteristic.

For fungal infection of the larynx

patients are worried about pain in the throat and on the front surface of the neck, a feeling of “rolling a lump” in the throat and neck, not associated with swallowing, constant hoarseness, rapid fatigue of the voice, and an unproductive cough. On examination, congestive hyperemia of the mucous membrane of the larynx, swelling of the mucous membrane of the vocal folds, and fibrin deposits are characteristic, when removed, the eroded surface is exposed. Often the fungal process is one-sided, which must be differentiated from cancer and tuberculosis.

Fungal infection of the nose and SNP

divided into invasive and non-invasive forms. Invasive forms include acute (fulminant) and chronic forms. Non-invasive ones include fungal body and allergic fungal sinusitis.

Invasive forms of fungal infection of the SNP are extremely unfavorable in predicting the outcome of the disease. The fulminant form of SNP damage is most often caused by fungi belonging to the class Zygomycetes. This form of the disease occurs in patients with severe immunodeficiency, decompensated diabetic ketoacidosis, neutropenia, and burn disease. Zygomycosis is characterized by an extremely severe course and, without active antifungal therapy and early surgical treatment, usually ends in death.

The chronic form occurs as chronic sinusitis with reactive phenomena from surrounding tissues. Accompanied by copious purulent nasal discharge in the morning, severe pain in the projection of the affected SNP.

The fungal body is quite often a “diagnostic finding” when performing a CT scan of the ED and in some patients is asymptomatic.

With allergic fungal sinusitis, in addition to polyps in the nasal cavity and SNP, a thick, viscous secretion is detected in the lumen of the latter.

Lack of awareness among otorhinolaryngologists regarding the diagnosis of fungal infection of the ENT organs is often the reason for their late and/or incorrect diagnosis. This creates difficulties in treatment and leads to a chronic course of the disease.

Diagnosis of fungal disease of ENT organs

, like any infectious disease, is established only on the basis of complex laboratory mycological research methods. A pronounced clinical picture of a disease similar to a fungal infection, no matter how characteristic it may be, is not the basis for making a final diagnosis of mycosis.

Diagnosis of mycosis is carried out in the following areas:

1. Microscopy of pathological discharge.

2. Inoculation of pathological discharge on various elective nutrient media to isolate fungal cultures and their generic and species identification.

3. Determination of the sensitivity of isolated fungi to antifungal drugs.

4. Radiation diagnostics in cases of damage to the nose and special organs.

Sampling of biological material from the ear is carried out using an attic probe or a Volkmann spoon. Pathological discharge from the deep parts of the external auditory canal is placed between two fat-free sterile slides and microscoped at 100, 200 and 400 times magnification.

In the active stage of aspergillosis and mucorosis with abundant formation of mycotic masses with aerial mycelium, we recommend using an operating otorhinolaryngological microscope (otomicroscopic method of express diagnostics) for diagnosis.

If a fungal infection of the pharynx and larynx is suspected, microscopy of scrapings from the mucous membrane of the oral cavity, pharynx, tonsils, taken with a swab to detect elements of the fungus, and seeding of material from the affected areas of the mucous membranes are performed.

The main method for diagnosing mycosis of SNP is culture of aspirate or rinsing water (puncture using a Kulikovsky needle according to the usual method) with mandatory identification of the pathogen. A histological examination of the biopsy material is also carried out.

In addition to microscopy of native material, microscopic examination of preparations stained using the Romanowsky-Giemsa method is performed. The most informative method that reliably identifies the causative agent of the disease is staining the preparation with solutions of calcofluor white, followed by fluorescent microscopy. For mycological diagnosis, pathological material is inoculated on elective media (Saburo, Chapek, wort agar, etc.). Types of yeast-like fungi of the genus Candida

determined by morphological characteristics and the nature of fermentation of sugars. Inoculation of the material is carried out using the standard method [1, 2, 5]. To clarify the diagnosis, in some cases it is necessary to carry out serological, allergological and histological studies [2, 5].

Treatment

You should always start with eliminating the pathogen. Correction of general and local predisposing factors is carried out in parallel or in the second stage.

When treating a patient with mycosis of the ENT organs, it is necessary to take into account all possible conditions under which this disease arose specifically in this patient with a view to their possible elimination. It is necessary to identify and treat diabetes mellitus, blood diseases, gastrointestinal tract, and immune deficiency. The role of allergies in the pathogenesis of the disease should be taken into account, since mushrooms have pronounced allergenic properties, and hyposensitizing therapy should be carried out in parallel with etiotropic therapy.

Selection of rational antifungal therapy for mycosis of ENT organs

presents certain difficulties. On the one hand, a large number of antimycotic drugs expands the possibilities of treating fungal infections that differ in both localization and type of pathogen. On the other hand, it requires the clinician to have increased awareness of the spectrum and characteristics of their action (fungicidal or fungistatic), pharmacokinetics, compatibility with antibacterial drugs, side effects, etc. The ideal treatment is with an antimycotic that has the least toxic and greatest therapeutic effect, which is not always possible, especially in acute forms of fungal disease, when the choice of drug is made empirically, since the pathogenic fungus is not immediately identified and tests can take a long time. Determining the choice of drug are the results of laboratory mycological studies of the sensitivity of fungi isolated from a particular patient to known antifungal drugs.

Fungal disease of the oropharynx - pharyngomycosis is caused mainly by yeast-like fungi of the genus Candida

, which largely determines treatment tactics. Limited acute candidiasis of the tonsils, which developed as a result of antibacterial therapy, usually heals quickly after stopping the administration of antibiotics and performing only local antifungal treatment. However, widespread lesions of the mucous membrane of the oropharynx, with a tendency to chronicity and recurrence, require a long course of treatment using local and general antimycotic therapy. For systemic therapy, a drug from the azole group, fluconazole (mycoflucan), is used orally at a dose of 100-200 mg once a day. Treatment should be continued for another 14 days after clinical improvement. If such treatment is ineffective, itraconazole (200 mg per day orally) or amphotericin B (1 ml 4 times a day orally, or >0.3 mg/kg per day intravenously) is used [1, 8-10].

In the systemic treatment of pharyngomycosis caused by molds, it is advisable to use itraconazole and amphotericin B, which have a fungicidal effect not only on yeast-like fungi, but also on mold fungi of the genera Aspergillus, Mucor, Penicillium

[12].

In addition to systemic treatment, local treatment is also recommended. During treatment, the pharynx after meals should be lubricated with a solution of clotrimazole at a rate of 10 mg 5 times a day, or nystatin tablets should be dissolved/chewed after meals at a dose of 250-500 thousand units 4-5 times a day. For chronic tonsillitis of fungal etiology, courses of washing the lacunae of the tonsils every other day or 1-2 times a week at least 10 times with solutions of antiseptics with antifungal action (miramistin, quinozol, clotrimazole solution) [10, 11].

Drug therapy for mycosis of SNP always accompanies and/or precedes surgical treatment. In the treatment of fungal infections of the nose and SNP, both general and local measures are provided. For invasive forms of fungal infection of the maxillary sinuses, the most effective is a combination of drug antifungal and surgical treatment. To eliminate the Aspergillus infection at this location, surgical treatment is almost always necessary. Surgical intervention consists of performing radical surgery on the affected sinus using the extranasal method with complete removal of all pathologically altered tissues. In the postoperative period, daily rinsing with antiseptics and antimycotics (amphotericin B, miramistin, pimafucin suspension, clotrimazole) is carried out.

In acute toxic forms of invasive aspergillosis of SNP, antifungal therapy is mandatory. Voriconazole or lipid amphotericin B is used [1, 13]. It is possible to use caspofungin and amphotericin B. After stabilization of the process, treatment with itraconazole. The duration of use of antimycotics depends on the clinical picture of the disease and its course, but should continue for at least 14 days after clinical and laboratory cure [1, 2, 9].

For candidiasis of the nose and SNP, it is necessary to combine the use of systemic antifungals with local antifungal drugs. The drug of choice is fluconazole (mycoflucan), which is prescribed once a day at a dose of 50-200 mg. The course of therapy cannot be less than 14 days. If treatment with standard doses of fluconazole is ineffective, it is possible to increase the dosage to 400 mg/day, or prescribe itraconazole 200 mg/day [10].

Patients with allergic fungal sinusitis are advised to undergo surgery to completely remove the polypous mucous membrane and the viscous “rubber-like” contents of the sinus [1, 13]. In the early postoperative period, it is necessary to wash the SNP twice with an aqueous solution of amphotericin B. It is advisable to prescribe topical nasal corticosteroids to prevent relapse no earlier than 20 days after surgery.

Only in case of resistance to other antimycotics, amphotericin B is used for the treatment of candidal lesions of the nose and SNP (intravenous 0.3 mg/kg per day for 3-7 days). Treatment is carried out under the supervision of biochemical studies of liver and kidney function, since amphotericin B has a pronounced nephro- and hepatotoxic effect.

The specificity of the treatment of fungal infection of the larynx is the widespread use of the inhalation method for administering drugs. The effectiveness of the aerosol method for inflammatory diseases of the larynx is determined by the direct effect of the drug on the site of the disease and the higher concentration of the drug at the site of the lesion. With this method of administration, inhalations with the water-soluble sodium salt of nystatin or levorin are effective, especially for candidiasis. Treatment is carried out for 15-20 minutes 1-2 times a day. The initial course of treatment is 12-15 procedures. In case of resistance to other antimycotics, 12-15-day courses of aerosol therapy with amphotericin B are carried out. All patients with laryngomycosis, in addition to inhalation therapy, must undergo systemic therapy with antimycotics. The drug of choice is fluconazole (mycoflucan) once a day at a dose of 100-200 mg, in severe cases - 300 mg/day) [11]. For patients whose fungal disease in the larynx is accompanied by the formation of a large amount of viscous secretion, it is advisable to carry out inhalations with proteolytic enzymes that selectively break down necrotic masses and dilute the viscous exudate for their better removal. For this, inhalations with chemopsin and chemotrypsin (150 mg in 5 ml of saline) can be recommended.

When treating otomycosis, local and systemic drugs are used. For local treatment of mold lesions in the ear, the most effective are naftifine, nitrofungin, terbinafine (exifin), and for candidiasis - clotrimazole, terbinafine (exifin), naftifine. An indispensable condition for local therapy is preliminary thorough cleaning of the ear using endoscopic equipment or an operating microscope. Ear toileting is performed only by a doctor using an attic probe and a padded cotton pad moistened with an antimycotic drug. Thorough toileting of the ear is given special importance, since even a small amount of mycotic masses significantly lengthens the course of treatment until complete recovery.

In case of external fungal otitis, it is necessary to thoroughly clean the anterior inferior part of the external auditory canal. In case of fungal otitis media, mycotic masses are completely removed from the area of ​​perforation of the eardrum. The postoperative cavity of the middle ear is cleaned in the same way - the entire cavity is thoroughly cleaned, especially in the posterior section, behind the spur. Before treatment, if polyps and granulations are present, they are removed or extinguished with a 20% solution of silver nitrate.

Local treatment with antifungal drugs must be carried out for at least 3-4 weeks under mandatory laboratory control (cultures before, during and after the end of the course of treatment). Local treatment is carried out by placing cotton wool moistened with a fungicidal preparation into the ear, which is left for 5-10 minutes 2-4 times a day, depending on the activity of the fungal process.

For systemic therapy of candidal lesions, the most effective is fluconazole (mycoflucan) - 50-200 mg per day for 14 days. For mold mycoses - itraconazole 200 mg/day for 14 days, terbinafine (exifin) - 250 mg/day for 16 days. If necessary, the course of treatment is repeated after 7 days.

The criterion for the effectiveness of treatment is complete clinical cure within a month, confirmed by both the clinical picture and negative results of mycological research [1, 9].

Quite often, with otitis externa, only a local effect on the mycotic focus of infection is carried out, while with fungal otitis media and mycosis of the postoperative cavity, systemic therapy is mandatory.

Since fungal diseases of the upper respiratory tract and ear are prone to recurrence, dynamic follow-up of the patient is necessary for timely implementation of preventive courses of antifungal treatment. Analysis of our own results of treating patients with ENT mycoses using the above drugs allows us to conclude that they are highly effective, accompanied by the elimination of fungi that cause the disease and normalization of the clinical picture [7, 8, 10].

In general, with proper treatment of mycoses of the ENT organs, therapy is quite effective. Unsatisfactory results are largely explained by the lack of awareness of doctors about the clinical manifestations of mycoses, incorrect diagnostic tactics, as a result of which adequate etiotropic treatment is delayed and carried out at a later stage, when the disease has already spread and become chronic.

Fluconazole, 150 mg, capsules, 1 pc.

When used simultaneously with warfarin, fluconazole increases prothrombin time (by 12%), and therefore bleeding may develop (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time must be constantly monitored.

After oral administration of midazolam, fluconazole significantly increases midazolam concentrations and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally than when administered intravenously. If concomitant benzodiazepine therapy is necessary, patients taking fluconazole should be monitored for an appropriate benzodiazepine dose reduction.

With the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, incl. ventricular fibrillation/flutter (ari). The use of fluconazole at a dose of 200 mg 1 time / day and cisapride at a dose of 20 mg 4 times / day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concomitant use of cisapride and fluconazole is contraindicated.

In patients after kidney transplantation, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine concentrations. However, with repeated doses of fluconazole at a dose of 100 mg/day, no changes in cyclosporine concentrations were observed in bone marrow recipients. When using fluconazole and cyclosporine concomitantly, it is recommended to monitor the concentration of cyclosporine in the blood.

Repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in plasma concentrations of fluconazole by 40%. An effect of this magnitude does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but this should be taken into account.

With the simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily intake of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and when taking 300 mg of fluconazole 1 time per day week - AUC of ethinyl estradiol and norethindrone increase by 24% and 13%, respectively. Thus, repeated use of fluconazole in the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentrations. With this combination, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.

Concomitant use of fluconazole and rifabutin may lead to increased serum concentrations of the latter. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

The simultaneous use of fluconazole and rifampicin leads to a decrease in AUC by 25% and the duration of T1/2 of fluconazole by 20%. In patients concomitantly taking rifampicin, the advisability of increasing the dose of fluconazole must be considered.

Fluconazole, when taken simultaneously, leads to an increase in T1/2 of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide). In patients with diabetes mellitus, fluconazole and oral sulfonylureas can be prescribed together, but the possibility of hypoglycemia should be taken into account.

The simultaneous use of fluconazole and tacrolimus leads to an increase in plasma concentrations of the latter. Cases of nephrotoxicity have been described. Patients with this combination should be carefully monitored.

With the simultaneous use of azole antifungals and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established, however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

When used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of developing theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.

When used simultaneously with fluconazole, an increase in zidovudine concentrations is observed, which is likely due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was found.

When zidovudine 200 mg every 8 hours for 7 days was used in HIV-infected patients with or without fluconazole 400 mg/day with an interval of 21 days between the two regimens, a significant increase in zidovudine AUC was found (74%) when used simultaneously with fluconazole. Patients receiving this combination should be monitored for side effects of zidovudine.

The simultaneous use of fluconazole with astemizole or other drugs whose metabolism is carried out by isoenzymes of the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Patients with such combinations should be carefully monitored.