IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

BASIC PRINCIPLES OF IMMUNODEFICIENCY TREATMENT

Fungal Infections in Immunocompromised Patients

Over recent decades, there has been a clear upward trend in the incidence of fungal infections alongside improvements in their diagnostic detection. Yeasts and Molds rank among the ten most frequent pathogens identified in clinical settings. The precise reasons why invasive fungal infections have become increasingly prevalent over the last few decades remain not fully understood. Meanwhile, it is evident that both patient-related and environmental factors play crucial roles in the Pathogenesis of invasive fungal infections. Fungi represent The most significant causative agents of opportunistic infections specifically in immunocompromised patients.

Over the past 40 years, continuous advancements in radiation Chemotherapy and surgical approaches have led to remarkable successes in treating oncological and hemato-oncological diseases. Furthermore, the possibilities of allogeneic and autologous Bone Marrow transplantation (BMT), as well as solid organ transplantation, significantly improve patients' chances of recovery. Such therapeutic regimens employ not only cytostatic but also immunosuppressive drugs to ensure graft survival and function. However, these treatments are frequently complicated by bacterial and fungal infections, particularly in patients with neutropenia and/or immunosuppression. Approximately 7% of fevers of unknown origin in hospital settings and up to 50% in hemato-oncology departments are caused by fungi.

Additionally, the risk group for developing infections includes patients with secondary immunodeficiency associated with chronic viral infections, complications following abdominal surgeries, extensive severe Burns, as well as premature low-birth-weight neonates and newborns who underwent intensive care (parenteral Nutrition and massive antibiotic therapy) during their first days of life.

Concomitant risk factors for developing invasive fungal infections include broad-spectrum Antibiotics administered for more than 14 days, high-calorie parenteral nutrition, prolonged mechanical ventilation, Shock, extensive burns, prior fungal infections, corticosteroids, H2-receptor blockers, and bacterial Sepsis.

Pathogenesis and causes of invasive fungal infections. In Ukraine, where there are no endemic foci of particularly dangerous fungal infections, opportunistic fungi play the leading role in The Structure of myco-pathology.

The most common causative agents of fungal infections are Yeast-like fungi (Candida spp., Cryptococcus spp., Cryptococcus neoformans) and molds (Aspergillus spp., Penicillium spp., Mucor spp.), and less frequently - Fusarium spp., Zygomycetes, and Trichosporon beigelii. Infection with Aspergillus and other mycelial fungi typically occurs through the inhalation of airborne fungal spores. Aspergillus spp. are characterized by invasive growth through the Bronchi into the lung tissue, damaging Blood Vessels and causing subsequent hemorrhages, necroses, and pulmonary parenchyma infarctions.

Colonization of the gastrointestinal tract by yeast-like fungi, such as Candida spp., can occur via saprophytic microflora or nosocomial pathogens transmitted through inadequate hand hygiene by medical staff.

From a modern perspective, two fundamentally different mechanisms of candidiasis pathogenesis are recognized: invasive and non-invasive candidiasis. Invasive candidiasis is driven by the penetration of the filamentous form of Candida into host Tissues, leading to systemic candidiasis with visceral organ involvement. Non-invasive candidiasis develops without the transformation of the fungus into its filamentous form, occurring through proliferation within the lumen of a hollow, resorbing organ (such as the intestine) or On the surface of the Skin and mucous membranes. The pathogenesis of candidiasis is driven by the onset and progression of dysbiosis and mixed infections within the intestinal lumen and on epithelial surfaces, alongside the resorption of products derived from abnormal nutrient Fermentation and fungal metabolites.

The Development of recurrent candidiasis is influenced by both incomplete eradication of fungi from the mucous membrane and reinfection, whether exogenous or endogenous.

Neutrophilic granulocytes, monocytes, and macrophages constitute the primary defense mechanisms of the host Organism against Candida spp. and Aspergillus spp., making cytostatic-induced prolonged neutropenia exceptionally dangerous for the patient. Severe and prolonged neutropenia (<0.1 x 10⁹/L for >10 days) carries a high probability of developing severe disseminated fungal infection, which frequently results in patient mortality (Table 89). An additional risk factor for severe disseminated fungal infection is the administration of high doses of corticosteroids, as these medications impair the function of immunocompetent Cells and may also stimulate the growth of Aspergillus spp.

Class="center">Table 89. Fungal diseases in patients with neutropenia

T-lymphocytes (CD4+ cells) play a vital role in combating fungal infections. In T-Cell immunodeficiency, the likelihood of Infections caused by Pneumocystis carinii, Cryptococcus neoformans, and endemic pathogens rarely encountered in Europe (such as Histoplasma capsulatum) increases significantly.

In HIV infection, the count of T-lymphocytes progressively declines, making the risk of contracting these infections—often with fatal outcomes for such patients—extremely serious (Table 90).

Table 90. Fungal infections in HIV-infected patients

The risk of developing an invasive fungal infection in patients is driven by two categories of factors, each of which is critical, with their combination posing an exceptional danger:

1. Environmental factors: the presence of mycelial fungal spores (including Aspergillus spp. spores) in the air during construction and renovation work and in wall cracks (requiring special attention to the clinical facility's condition); presence of mold on indoor plants, which must be strictly prohibited in wards housing neutropenic patients; presence of mold in food products (including nuts, bread, salads, fruits, and spices such as black pepper). Yeast-like fungi (primarily of the genus Candida) can cause typical nosocomial infections due to the presence of pathogen cells on inadequately sanitized hands of medical personnel; for this reason, food contamination (mainly fruit juices) is also possible.

2. Patient-related factors: the risk of fungal infection is typically determined by multiple synergistic factors; in patients with malignancies, additional risk factors include prolonged cytopenia following polychemotherapy, impaired cellular Immunity, and extensive fungal colonization of the body, primarily by Candida spp. (involvement of more than two body sites).

An effective strategy involves assessing the risk level for each patient group, implementing prompt diagnostic measures at the earliest symptoms, and initiating adequate therapy early. It must be remembered that fungal complications are likely to develop by a certain point following the onset of the primary disease in high-risk patients.

Causative agents of invasive fungal infections

Fungal infections observed in immunocompromised patients fall into three main categories:

- caused by the most common opportunistic fungi of the genera Candida and Aspergillus, which can manifest as superficial infections of the skin and mucous membranes in immunocompetent patients;

- caused by obligate pathogens such as Histoplasma capsulatum and Coccidioides immitis, which can also occur in patients without immune defects. These pathogens are capable of causing severe disseminated infections in patients with AIDS and oncological diseases. It is believed that such infections developing after cytostatic Treatment are largely a reactivation of latent infection. Patients with HIV infection and malignant lymphomas are particularly susceptible to these pathogens;

- caused by rare opportunistic fungi:

✵ phaeohyphomycosis, caused by pathogens such as Curvularia spp., Bipolaris spp., Alternaria spp.;

✵ hyalohyphomycosis, induced by Fusarium spp., Scedosporium apiospermum;

✵ zygomycosis, caused by Rhizopus spp., Mucor spp., Absidia spp.

Aspergillosis. Filamentous fungi of the genus Aspergillus are ubiquitous

in nature. Among them, the most clinically significant are Aspergillus fumigatus (accounting for about 90% of aspergillus-related diseases), A. niger (ear canal infections), A. flavus (colonization and paranasal sinus infections), as well as A. terreus and A. nidulans.

With the increasing intensity of chemotherapy and the integration of bone marrow and solid organ transplantation into clinical practice, the incidence of invasive aspergillosis has risen. Initially, such complications were observed almost exclusively in patients with refractory acute myeloid leukemia (AML); subsequently, aspergillosis also began to develop in patients with neutropenia following intensive remission induction therapy for AML.

Candidiasis. Invasive infections caused by Representatives of the genus Candida (predominantly C. albicans) are the most frequent mycoses in patients with oncohematological diseases across many clinics. C. tropicalis, C. krusei, C. glabrata, C. parapsilosis, and C. guilliermondii are less common. In some clinics, C. tropicalis and C. glabrata have acquired particular importance as causes of central venous catheter-related bloodstream infections. The increasing proportion of non-albicans Candida species may be related to the widespread prophylactic use of fluconazole. Most of these infections stem from endogenous colonization, although nosocomial acquisition is occasionally noted. The primary risk factor for invasive candidiasis is prolonged granulocytopenia.

Unlike aspergillosis, candidiasis can present as both superficial and invasive infections. Recently, a previously unknown species, Candida dubliniensis, has been described and is most frequently detected in throat swabs of HIV-infected patients. This pathogen can also be isolated from granulocytopenic patients. In low-birth-weight premature infants, C. parapsilosis is a frequent cause of catheter-associated fungemia.

Other fungal infections. Other noteworthy fungal infections include zygomycosis (mucormycosis) and cryptococcosis, which are primarily observed in patients with AIDS. Zygomycosis ranks after candidiasis and aspergillosis in frequency. The most common CAUSATIVE AGENT OF zygomycosis is Rhizopus arrhizus. The onset of this disease resembles aspergillosis. Infection occurs through the inhalation of airborne spores, leading to involvement of the Paranasal Sinuses and Lungs, and less frequently, the skin.

In recent years, an increase in rare fungal infections (hyalohyphomycosis, phaeohyphomycosis, trichosporonosis) has been noted in Cancer patients. It has been established that "harmless" fungi traditionally considered non-pathogenic—such as Geotrichum candidum ("dairy mold"), Saccharomyces cerevisiae ( baker's yeast), and Rhodotorula spp.—can cause fatal infections in immunocompromised patients.

Incidence of Invasive Fungal Infections

Aspergillosis. Invasive aspergillosis (IA) is most frequently observed in patients with granulocytopenia due to AML and hematopoietic stem cell transplantation (HSCT) induced by cytostatic drugs, affecting up to 20% of patients. IA is less common in patients following liver transplantation (5–15%), Heart-lung transplantation (10%), and renal transplantation (<5%). The most common form of IA is invasive pulmonary aspergillosis (IPA).

Differences in the incidence of IA among various patient categories are driven by the varying intensity of immunosuppressive (including corticosteroid) therapy. The combination of prolonged neutropenia and intensive pharmacologic immunosuppression is the primary risk factor. However, the incidence of IPA following HSCT has decreased in recent years and, according to some data, is less than 5%; this is likely due to The Use of high-efficiency particulate air (HEPA) filtration and the early initiation of antifungal therapy at the first suspicion of aspergillosis. In any case, a "low" incidence of IA should not provide a false sense of security, as the mortality rate for this disease can exceed 90% in certain patient categories.

Candidiasis. Oropharyngeal candidiasis occurs in approximately 30% of cancer patients following chemotherapy and in more than 90% of patients with AIDS. Candida esophagitis is diagnosed in about 20% of AIDS patients, serving as the initial symptom of the disease in roughly 11% of them. The exact incidence of candida esophagitis in patients with oncological and oncohematological disorders and transplant recipients remains unknown. Precipitating factors typically include broad-spectrum antibiotics prescribed for fever of unknown origin and glucocorticoids administered to treat graft-versus-host disease (GVHD) following allogeneic HSCT or organ transplant rejection.

Invasive candidiasis occurs in approximately 25% of patients after HSCT, typically during the period of neutropenia, 1 to 2 weeks post-transplant. Mortality from candidemia reaches 40%, and up to 90% in cases of multi-organ involvement.

Following liver transplantation, invasive candidiasis is noted in 18–30% of cases, with mortality exceeding 75%. Risk factors include graft rejection and intra-abdominal infection.

In patients with AIDS, superficial candidiasis, candiduria, and central venous catheter-related infections predominate.

Other fungal infections. In addition to the aforementioned zygomycosis, cryptococcosis holds significant clinical importance. Cryptococcosis is most frequently observed in AIDS patients, diagnosed in 5–12% of such individuals, with central nervous system cryptococcosis serving as the presenting manifestation of AIDS in about 4%. In neutropenic patients, this disease is extremely rare and is not typically included in the Differential Diagnosis for fever of unknown origin.

Nevertheless, in patients with lymphoproliferative disorders (Hodgkin's lymphoma, chronic Lymphocytic Leukemia) undergoing combination chemotherapy, the incidence of cryptococcosis can reach 8%.

Following solid organ transplantation, the incidence of cryptococcosis reaches up to 3%. In the majority of these cases, the Clinical presentation corresponds to chronic meningitis preceded by pulmonary symptoms.

Clinical Presentation, Diagnosis, Treatment, and Prophylaxis of Invasive Mycoses

Aspergillosis can be divided into three categories:

✵ Superficial: infections of the ear canal and cornea, as well as primary skin lesions;

✵ Non-invasive: allergic Bronchitis and aspergilloma in patients with preexisting cavitary pulmonary disease (primarily tuberculosis);

✵ Invasive: typically manifests in neutropenic patients; only acute invasive and chronic necrotizing forms are distinguished.

Acute invasive aspergillosis in immunocompromised patients is the most severe form of the disease, characterized by fungal invasion into the lung tissue and/or paranasal sinuses. This can lead to dissemination to other Organs, such as the central nervous system, liver, and Kidneys. Invasive pulmonary aspergillosis may present as a localized or diffuse lesion of the pulmonary parenchyma (most commonly in leukemias and post-HSCT) and/or as ulcerative tracheobronchitis (more frequently seen in lung transplant recipients and AIDS patients). The clinical course is frequently fulminant.

The most critical prognostic factor determining the patient's outcome is the rapid recovery of a normal granulocyte count. Dissemination is observed in approximately 25% of patients with invasive pulmonary aspergillosis.

Chronic necrotizing aspergillosis has a more protracted course and typically occurs in patients without granulocytopenia or following hematopoietic recovery. The primary symptoms of pulmonary involvement are cough and progressively worsening dyspnea; in hepatic involvement, elevated serum liver Enzymes are noted. Without treatment, chronic necrotizing aspergillosis can be fatal.

Diagnosing invasive aspergillosis during the patient's lifetime is challenging.

In immunocompetent patients, this infection is generally asymptomatic.

In high-risk patients, an invasive fungal infection should be suspected at the very first suspicious symptoms.

Typical Clinical symptoms of invasive aspergillosis in neutropenic patients include acute unilateral pleuritic chest pain, cough, dyspnea, and less commonly, hemoptysis; Auscultation reveals findings similar to those of pleuropneumonia. Differential diagnosis should include Pulmonary Embolism. Often, the initial manifestation of an invasive fungal infection is antibiotic-refractory neutropenic fever, along with nodular infiltrates on chest radiography and computed tomography, sinusitis of undetermined Etiology, epistaxis, periorbital pain and edema, skin lesions (fungal emboli), central nervous system involvement, and brain abscess (neurological symptoms, altered mental status).

Aspergillosis of the paranasal sinuses and disseminated aspergillosis, including central nervous system involvement, are significantly less common than invasive pulmonary aspergillosis. Skin lesions presenting as papular elements with central necrosis may indicate disseminated aspergillosis, making a biopsy essential.

Chest radiography does not always reveal characteristic abnormalities. The detection of nodular or, less frequently, diffuse infiltrates necessitates computed tomography to rule out invasive aspergillosis. CT findings are characteristic and appear earlier than those on chest radiographs (Table 91). A nodular infiltrate with a "halo sign" is typical.

Definitive signs of invasive aspergillosis are, in most cases, apparent only after the resolution of granulocytopenia. In some instances, the diagnosis can be established solely through biopsy, which is quite difficult to perform during the period of hematopoietic aplasia. Therefore, many centers utilize bronchoscopy (with bronchoalveolar lavage) to obtain the necessary diagnostic material. Alternatively, specimens can be acquired via transthoracic fine-needle aspiration biopsy.

An important diagnostic tool is the Polymerase Chain Reaction (PCR), used to analyze material obtained via bronchoalveolar lavage or puncture. Detection of Aspergillus-specific DNA in the blood by PCR is also feasible. Microbiological cultures rarely detect the pathogen in blood cultures, and routine serological tests are similarly insufficient. Untreated invasive aspergillosis is invariably fatal. In high-risk patients, antifungal therapy is far from always successful.

Treatment of aspergillosis. Because the prognosis is unfavorable in most cases, treatment must adhere to the following principles: suspect and diagnose aspergillosis as early as possible; initiate antifungal therapy immediately; strive to rapidly restore granulocyte levels and discontinue (or, if impossible, reduce the dose of) corticosteroids (Table 91).

Table 91. Diagnosis and treatment of Fungal Infections in Immunocompromised Patients

Currently, the treatment of choice for invasive aspergillosis is intravenous administration of amphotericin B (amphocil), a lipid complex (ampholip), or liposomal amphotericin B (ambisome) (Tables 91, 92). Adverse effects of amphotericin B include nephrotoxicity and infusion-related reactions: fever, chills, and bronchospasm.

For invasive aspergillosis, the required dose of amphotericin B is 1 mg/kg/day, with a maximum dose of up to 1.5 mg/kg/day. One administration method involves starting with an initial dose of 0.1 mg/kg/day and gradually increasing it (over 2-3 days) to the therapeutic dose. However, this approach is unsuitable for high-risk patients who require urgent treatment. An alternative approach involves a test dose of 1 mg of amphotericin B administered over 30 minutes, followed by the full daily dose. In some clinics, the full daily dose (1 mg/kg) of amphotericin B is administered on the first day of treatment without a test dose.

Infusion of amphotericin B should take 2-4 hours. In the event of severe adverse reactions, prophylactic administration of antihistamines (or administration upon symptom onset) is indicated, and in very severe cases, corticosteroids.

Liposomal formulations of amphotericin B (Ambisome) and lipid complex (Ampholip) have been proposed as alternative agents. The efficacy of Ambisome in invasive aspergillosis is higher than or comparable to that of conventional amphotericin B; this corresponds to the dosing regimens: 3-5 mg/kg for Ambisome, 3 mg/kg for Amphocil, and 5 mg/kg for Ampholip.

Another alternative is the use of azole derivatives, itraconazole and voriconazole (Tables 91, 92). A notable feature of itraconazole is that the required loading dose is 600-800 mg During the first five days, and it is currently available only in an oral formulation. The clinical role of itraconazole can be defined as "maintenance therapy," meaning patients are switched to itraconazole after a therapeutic response has been achieved with amphotericin B administration.

Alongside medical therapy, surgical intervention is performed for vital indications (e.g., life-threatening Hemorrhage from vessels damaged by fungal invasion) and can be successfully carried out even during the period of hematopoietic aplasia, provided there is transfusion support with platelet concentrates and packed red Blood Cells.

Nosocomial invasive aspergillosis most frequently affects patients who have undergone myeloablative therapy for acute leukemias or HSCT. Because Aspergillus spp. spores are present in indoor air, preventive measures must be implemented to reduce spore concentration or eliminate them entirely. This applies primarily to HSCT units. The Methods used for this purpose include high-efficiency particulate air (HEPA) filtration, positive-pressure room ventilation (air is continuously "pushed" outward through special openings along with dust, fungal spores, etc.), and laminar air flow rooms.

High-risk patients are prophylactically prescribed intravenous amphotericin B at a dose of 0.3-0.5 mg/kg/day three times a week. While this prophylaxis can reduce the incidence of invasive aspergillosis, overall patient survival may also be reduced due to drug toxicity. Nevertheless, many medical centers employ this prophylactic regimen.

Oral prophylaxis with itraconazole (200-600 mg/day) reduces the incidence of invasive fungal infections. Although itraconazole lacks significant toxicity, achieving a therapeutic plasma concentration is not always guaranteed. To prevent breakthrough fungal infections, voriconazole is also prescribed at 3 mg/kg IV or 200 mg orally every 12 hours.

Candidiasis. Classification of candidiasis based on the depth of the lesion:

✵ superficial candidiasis involving mucous membranes (Oral Cavity, Pharynx, Esophagus, colon, Vagina) and/or skin, such as oral candidiasis;

✵ superficial invasive candidiasis with the infection spreading beyond the basement membrane, but without organ parenchyma involvement;

✵ acute deep disseminated candidiasis affecting the parenchymal organs and nervous system, such as endophthalmitis or endocarditis;

✵ chronic deep disseminated candidiasis, such as hepatosplenic candidiasis;

✵ candidemia with Isolation of the pathogen from the bloodstream.

The Clinical forms of candidiasis are highly diverse; the primary ones include: candidiasis of the skin, nail folds, and nails, oral mucosa, genitalia, respiratory tract and ear, digestive tract, candidal meningitis, candidal endocarditis, pericarditis, myocarditis; candidal thrombophlebitis; candidal Osteomyelitis, Arthritis, mediastinitis; intra-abdominal abscesses, Peritonitis, splenic, hepatic, and pancreatic abscesses associated with Candida spp.; candidal endophthalmitis; candidemia; and acute hemoblastosis-associated candidiasis.

In some patients, following hematopoietic stem cell transplantation (HSCT) during the granulocytopenic period, disseminated candidiasis may develop, involving the liver, spleen, kidneys, heart, gastrointestinal tract, Peritoneum, lungs, brain, and skin. Therefore, upon detection of candidemia, additional evaluation is mandatory to identify foci of dissemination (computed tomography of the abdominal organs, dilated-pupil ophthalmoscopy, etc.). The pathogens involved are C. albicans (7%-12%) and other Candida species, predominantly C. tropicalis (25%-38%).

Hepatosplenic candidiasis is a form typical of granulocytopenic patients, typically preceded by antibiotic-refractory neutropenic fever with or without pathogen isolation from blood cultures. In addition to prolonged febrile or subfebrile fever, a hallmark of hepatosplenic candidiasis is elevated serum gamma-glutamyl transpeptidase and alkaline phosphatase levels, indicating cholestasis. Blood cultures in these patients are virtually always negative. As granulocyte counts recover, the fever usually subsides; however, hyperfermentemia and characteristic radiological signs of liver and spleen involvement emerge (computed tomography, Magnetic Resonance imaging) (Table 91).

When hepatosplenic candidiasis is suspected, computed tomography, magnetic resonance imaging, or abdominal ultrasound must be performed. Percutaneous liver biopsy to obtain material for microbiological analysis often proves ineffective, although the diagnosis is occasionally established based on the examination of biopsy specimens.

Mucosal candidiasis affecting the oropharynx, esophagus, and vagina is typically easy to recognize macroscopically due to characteristic white plaques. Typical symptoms include dry Mouth, thirst, burning sensation at the affected sites, dysphagia, and vaginal discharge.

Microscopic examination is required to confirm the diagnosis. Colonization is defined as a situation where the pathogen is detected in two or more distinct anatomical sites. This condition carries a high risk of progression to invasive candidiasis.

Identifying Candida species during microbiological testing is necessary for the following reasons: infections caused by certain non-albicans Candida species are more likely to disseminate and follow a more severe course with higher mortality rates. Furthermore, specific Candida species, such as C. krusei and C. glabrata, exhibit low susceptibility to fluconazole.

Similar to invasive aspergillosis, diagnosing disseminated candidiasis is challenging; differential diagnosis should be conducted in the same manner as for neutropenic fever syndrome. The diagnosis is established by detecting candidemia, although blood cultures identify no more than 60% of acute disseminated candidiasis cases. Serological tests are used adjunctively, but their efficacy does not exceed 50%. PCR diagnostics are also employed in patients with disseminated candidiasis.

The main clinical and laboratory signs of candidiasis include: clinical and histological signs of fungal infections; hyperthermia resistant to broad-spectrum antibiotics; positive serological reactions; multifocal Candida colonization in patients with risk factors; isolation of Candida fungi from blood and other sterile anatomical sites; and detection of fungal endophthalmitis.

Risk factors for invasive candidiasis include: prolonged broad-spectrum antibacterial therapy; isolation of Candida spp. from two or more anatomical sites; scheduled hemodialysis; multiple transfusions of blood components and products; prolonged stay in an intensive care unit; venous catheterization; prolonged Urinary Bladder catheterization; parenteral nutrition, particularly with lipid emulsions; enteral tube feeding; abdominal surgeries, especially for hollow organ perforations and acute pancreatitis; degree II-III burns, severe traumatic brain injury, Polytrauma; severe infections (sepsis, peritonitis, intra-abdominal abscesses); immunosuppressive states (Diabetes Mellitus, use of immunosuppressants, prolonged corticosteroid therapy, tumor chemotherapy and radiotherapy, HIV infection); and diarrhea or severe mucositis.

Since most cases involve central venous catheter (CVC)-associated candidemia, the CVC must be promptly removed in clinically unstable patients. If the patient is clinically stable, provided adequate antifungal therapy is administered, one may wait for hematopoiesis recovery until granulocytes reach 1.0 x 10⁹/L and platelets 50 x 10⁹/L to minimize the risk of hemorrhage.

Treatment of Candidiasis. Currently, there are 4 groups of antifungal drugs: polyenes, azoles, allylamines, and drugs of other classes (Table 91).

Amphotericin B. The broadest spectrum of antifungal activity belongs to the polyene antibiotic amphotericin B. It remains the gold standard for treating invasive mycoses, though it is associated with high toxicity. The recommended dose is 0.5-1 mg/day for 10-14 days. Lipid-associated formulations of amphotericin offer several advantages. Parenteral administration of amphotericin B is reserved for infections caused by fungi resistant to fluconazole, notably C. krusei and C. glabrata, as well as for aspergillosis.

The approach to using amphotericin B for invasive candidiasis (candidemia, candida esophagitis, and disseminated infection) is practically identical to that for invasive aspergillosis, but the dosage is 0.5-0.7 (maximum 1.0) mg/kg/day (Tables 91, 92).

Nystatin is poorly absorbed from the intestine and is not administered parenterally. Its indications are limited to oropharyngeal candidiasis, superficial esophageal candidiasis, and non-invasive intestinal candidiasis (Table 92).

Azole derivatives include imidazoles (clotrimazole, miconazole, ketoconazole), 1st-generation triazoles (fluconazole, itraconazole), and 2nd-generation triazoles—fluconazole derivatives (voriconazole, ravuconazole) and itraconazole derivatives (posaconazole and albaconazole). These drugs feature a broad spectrum of activity, ease of use, and limited toxicity, making them the drugs of choice for treating invasive mycoses.

Fluconazole. For superficial and invasive candidiasis (candidemia and hepatosplenic candidiasis), azole derivatives are prescribed, primarily fluconazole at 100 mg/day for oropharyngeal candidiasis and 800 mg/day for disseminated candidiasis (Tables 91, 92). The prophylactic dose of fluconazole is 50-400 mg/day (averaging 6 mg/kg/day).

Because some non-albicans Candida species have low susceptibility to fluconazole, life-threatening conditions require initial therapy with amphotericin B, potentially combined with fluconazole. Fluconazole treatment is initiated after pathogen identification and patient stabilization. Fluconazole is administered at 75-100 mg/kg/day in 4 divided doses in combination with amphotericin B (Tables 91, 92). A fluconazole dose of 150 mg/kg/day is excessively high and can induce myelosuppression in the absence of serum concentration monitoring. Uncommon complications include nausea, vomiting, diarrhea progressing to enterocolitis, hepatotoxicity, exanthema, and central nervous system disturbances (headache, altered consciousness). Depending on the local epidemiological situation, approximately 5% of C. albicans strains prove to be primarily resistant to fluconazole. Consequently, fluconazole should be used exclusively as part of combination therapy.

Voriconazole. The primary difference between voriconazole and its predecessor, fluconazole, is its broader spectrum of antifungal activity. Voriconazole inhibits the Synthesis of the 14α-demethylase enzyme, which is involved in The production of ergosterol, a vital component of the fungal cell membrane. Voriconazole is administered at a dose of 0.2-0.4 g/day, either orally or via intravenous infusion (Table 92).

Ravuconazole has a chemical structure similar to that of fluconazole and voriconazole. It exhibits a broad spectrum of activity, including against multidrug-resistant strains. It is active against Candida spp., including C. krusei and C. glabrata, as well as Scedosporium spp., Aspergillus spp., and Cryptococcus neoformans. Ravuconazole is prescribed at a dose of 5 to 10 mg/kg/day.

Terbinafine (Lamisil) is a broad-spectrum agent active against dermatophytes, molds (including Aspergillus), and dimorphic fungi, possessing primary fungicidal action and exceptionally high efficacy in systemic mycoses. Terbinafine is prescribed at a dose of 250 mg daily for 4 weeks.

Ketoconazole (Nizoral) at a daily dose of 200-400 mg clears mucosal thrush plaques within 24-72 hours. Resolution of skin lesions requires 2-9 weeks. It is available in 200 mg tablets (Table 92).

Itraconazole (Intrungar), at a concentration 100 times lower than that of ketoconazole, inhibits the incorporation of 14C-acetate into fungal ergosterol, thereby achieving a fungicidal or fungistatic effect. The drug's efficacy has been demonstrated in infections caused by Candida, Aspergillus, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Sporothrix schenckii across various routes of transmission. Itraconazole penetrates well and distributes into organs and tissues, where its concentration is 2 to 5 times higher than plasma levels. The drug is used to treat superficial and systemic mycoses. Itraconazole is administered at 100 mg daily for 15 days (Table 92).

Itraconazole (Orungal) inhibits the synthesis of ergosterol in the fungal cell membrane, which accounts for its antifungal effect. Itraconazole is active against Candida albicans, other Candida species, Aspergillus spp., Trichosporon spp., Geotrichum spp., Cryptococcus neoformans, dermatophytes, and yeast-like fungi, including Fonsecaea spp., Histoplasma spp., Pseudallescheria boydii, and Penicillium marneffei. For oral candidiasis, it is prescribed at 100 mg once daily for 15 days; for vulvovaginal candidiasis, 200 mg once daily for 3 days; for superficial candidiasis, 100 mg once daily for 7 days. For infections involving highly keratinized skin areas, such as the palms and soles, adjunctive treatment of 100 mg/day for an additional 15 days is recommended.

Posaconazole is a derivative of itraconazole. The drug has very low Water solubility and is currently available only in oral formulations. Posaconazole is distinguished by a broad spectrum of activity. It exhibits high efficacy against yeasts, including Candida spp. and Cryptococcus neoformans, as well as most filamentous fungal pathogens, particularly multidrug-resistant Scedosporium and Fusarium spp. A key feature of posaconazole is its activity—unlike most other antifungals—against agents of zygomycosis, specifically Rhizopus, Mucor, and Absidia spp.

Albaconazole is characterized by a broad in vitro spectrum of activity, acting against Candida spp., Aspergillus spp., and Paecilomyces spp.

Echinocandins represent a novel class of antifungals with a unique MECHANISM OF ACTION involving the blockade of 1,3-β-D-glucan synthesis, an essential Structural and functional component of the fungal Cell wall. Because 1,3-β-D-glucan is absent in human cells, echinocandins are exceptionally well tolerated with a minimal incidence of adverse effects.

Caspofungin is a semisynthetic, water-soluble lipopeptide derived from the fermentation products of the fungus Glarea lozoyensis. Caspofungin exhibits fungicidal activity against Candida spp., including azole-resistant (C. krusei), azole-susceptibility-reduced (C. glabrata), and amphotericin B-resistant (C. lusitaniae) strains. Caspofungin is inactive against Cryptococcus neoformans and exerts a fungistatic effect on Aspergillus fumigatus, A. flavus, A. niger, and A. terreus. Caspofungin is prescribed at a loading dose of 70 mg on the first day, followed by 50 mg daily.

Micafungin is a synthetic agent obtained via chemical modification of fermentation products from the fungus Coleophoma empedri. It possesses a broad in vitro spectrum of activity that includes C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis, notably encompassing strains resistant to azoles and amphotericin B. It is active against Aspergillus spp., although its action against them is not fungicidal. Like all echinocandins, micafungin lacks activity against Cryptococcus, Fusarium, and Trichosporon spp.

Anidulafungin shares a spectrum of activity similar to that of caspofungin and micafungin. It demonstrates high in vitro activity against Candida spp., including strains resistant to fluconazole and itraconazole, while showing lower activity against C. famata and C. parapsilosis. Against Aspergillus spp., anidulafungin is more active than both itraconazole and amphotericin B.

The duration of treatment for candidemia should be at least 14 days, and for disseminated infection, at least until the foci of infection are cleared. In each case, the duration of therapy is determined by the clinical presentation.

One approach to reducing the incidence of invasive candidiasis is the long-term oral administration of fluconazole at 100-400 mg/day or itraconazole at 100 mg/day (Table 92). In other instances, the choice of antifungal agent should be guided by data on patient colonization by Candida species or other pathogens.

Enteral therapy is advantageously combined with the topical application of antifungal ointments and liquids. Despite the positive clinical response observed throughout the treatment course and in the immediate post-treatment period, drug discontinuation frequently leads to a gradual relapse of fungal infections. Therefore, treatment regimens for chronic candidiasis must be individualized.

Prolonged antibacterial therapy necessitates the prophylaxis of fungal infections. Nystatin is a widely used prophylactic agent; however, it is effective for preventing candidiasis strictly within the intestinal lumen, as its systemic absorption does not exceed 3-5%. Consequently, the drugs of choice are triazoles (fluconazole, itraconazole) administered intermittently as loading doses.

In preventing candidiasis among patients with severe underlying conditions that serve as predisposing factors (such as diabetes mellitus or immunodeficiencies), only systemic azoles and amphotericin B are effective. Triazoles—specifically fluconazole and itraconazole—should be the preferred systemic antimycotics.

When treating pregnant women, topical antimycotics may be prescribed on an as-needed basis strictly during the second and third trimesters. Systemic antimycotics are not recommended during Pregnancy.

Cryptococcosis. Infection occurs via the inhalation of contaminated air and dust. Pneumonia develops in immunocompromised patients, most frequently in those receiving immunosuppressive therapy. Pneumonia (often clinically diagnosed as "pneumonia of unclear etiology") is typically followed by dissemination, which manifests as cryptococcal meningitis. Classic symptoms of this meningitis include headache, lethargy, signs of elevated intracranial pressure, and cranial nerve palsies. Meningism is observed in approximately half of patients and is even less frequent in individuals with AIDS.

The diagnosis of cryptococcosis is established by isolating cryptococci from blood or CEREBROSPINAL FLUID (CSF) cultures. Lumbar puncture typically reveals elevated CSF pressure. CSF analysis may show pleocytosis (though not invariably), elevated protein levels, and reduced glucose levels. Microscopic examination may reveal characteristic encapsulated yeast cells. Cryptococcal antigen is detectable in CSF and blood in approximately 90% of cases; this method remains a simple and reliable diagnostic tool and can be used for screening when cryptococcosis is suspected. Microbiological culture of CSF on specialized media (e.g., BACTEC) is also a highly sensitive diagnostic method.

Cryptococcal meningitis in immunocompromised patients, much like invasive aspergillosis, is invariably fatal if left untreated, even when the disease follows a subacute course. Early diagnosis, along with parameters such as CSF pressure, holds significant prognostic value. Mortality from cryptococcal meningitis is particularly high among non-AIDS immunocompromised patients.

The therapy of choice for cryptococcosis is a combination regimen: amphotericin B (0.7-1.0 mg/kg/day) plus fluconazole (100-150 mg/kg/day, divided into 4 doses). In patients with AIDS, the fluconazole dose is 400 mg/day. This initial induction therapy should last for at least 14 days, followed by maintenance therapy with fluconazole at 400 mg/day for eight weeks. In mild cases, primary monotherapy with fluconazole or itraconazole is an option (Tables 91, 92). The probability of complete recovery is relatively modest. Treatment must be continued until microbiological clearance of the CSF is achieved and the cryptococcal antigen titer in the CSF drops to 1:8 or lower. Itraconazole is also effective for cryptococcal meningitis and can serve as an alternative to fluconazole, although its poor penetration across the blood-brain barrier must be taken into account.

Prophylaxis for cryptococcosis is relevant exclusively for AIDS patients with a CD4+ T-lymphocyte count <0.2 × 10⁹/L. In such cases, the standard prophylactic approach is lifelong administration of fluconazole at 100-200 mg/day. Because the epidemiological prevalence of cryptococcosis varies significantly across regions, such primary prophylaxis is not universally implemented.

Other fungal infections are rare; consequently, their diagnosis relies on culture-based investigation of various biosubstrates (blood, CSF, tissue) and histological analysis of biopsy specimens. Serological tests are not well-established, with the exception of histoplasmosis.

The therapy of choice for virtually all opportunistic fungal infections is a combination of amphotericin B and fluconazole, or ambisome monotherapy. Amphotericin B is ineffective against Candida lusitaniae and Scedosporium spp., and has limited efficacy in treating mycoses caused by zygomycetes, Trichosporon beigelii, and Fusarium spp.

Empirical therapy for fever of unknown origin. The aforementioned therapeutic approaches are recommended when the infectious agent has been identified. Quite often, however, particularly in the Cytology/cytology/16.html">Early stages of a fungal infection (with the exception of fungemia), isolating the causative agent is not possible. Diagnostic challenges and high mortality rates among neutropenic patients with invasive fungal infections—which are frequently diagnosed only at autopsy—have driven the development of empirical antimycotic therapy. This approach is indicated in cases of febrile illness refractory to antibiotics. A fever is considered refractory if the elevated Temperature persists for 5–7 days despite broad-spectrum antibiotic therapy. Amphotericin B at a dose of 0.5–0.6 mg/kg/day is established as the standard of care in such situations. Fluconazole may also be utilized for empirical therapy, and liposomal amphotericin B serves as a viable alternative (Tables 91, 92).

Table 92. Antifungal agents: Key characteristics and administration guidelines