What is Zygomycosis (Phycomycosis)?
Zygomycosis (phycomycosis) is the general designation of opportunistic mycoses, caused by representatives of various genera of the class Zygomycetes.
Zygomycosis is not a very common disease, compared with other opportunistic mycoses, such as candidiasis and aspergillosis. The first case of zygomycosis was described by Paultauf in 1885. Its description is sufficiently complete to suggest that the causative agent of the disease is Absidia corymbifera. At first, most of the causative agents of zygomycosis were attributed to the fungi of the genus Mucor, but later they were reclassified into different genera and families of the order Mucorales.
It soon became apparent that among the causative agents of zygomycosis, Rhizopus spp. Prevail, and not Mucor spp. With the accumulation of information about this pathology, the connection of zygomycosis with cancer, diabetes mellitus, long-term use of antibiotics, corticosteroids, deferoxamine, immunosuppressors became apparent.
As diagnostics improved, the spectrum of pathogens expanded. Along with representatives of the genera Rhizopus, Mucor and Absidia, species of the genera Rhizomucor, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp.
Accordingly, the descriptions of the clinical picture of the disease also became more diverse. If previously, predominantly rhinocerebral, pulmonary, and disseminated forms of zygomycosis were isolated, then gastrointestinal, skin and subcutaneous forms, an allergic reaction, and asymptomatic colonization have also become known.
With the improvement of clinical and laboratory methods, it became possible to establish the diagnosis at earlier stages of the disease, and thanks to the development of new surgical methods of treatment and the successes of antimycotic therapy at the present time, 100% mortality, which accompanied zygomycosis in the recent past, is avoided.
Causes of Zygomycosis (Phycomycosis)
The causative agents of zygomycosis – lower fungi in the kingdom of fungi are representatives of an independent division – Zygomycota. This department is divided into two classes: Trichomycetes, which are not pathogenic for humans, and Zygomycetes, which contains pathogenic species.
The Zygomycetes class is divided into three orders: Mucorales, Mortierellales, and Entomophthorales. The order of Mucorales is divided into five families: Mucoraceae, Cunninghamellaceae, Saksenaeaceae, Thamnidiaceae, Syncephalastraceae. The family of Mucoraceae includes representatives of the genera Rhizopus, Mucor, Absidia, Rhizomucor and Apophysomyces – the most frequent causative agents of zygomycosis.
Zygomycosis in humans is mainly caused by micromycetes of the genus Rhizopus, mainly Rhizopus oryzae and Rhizopus microsporus. Less commonly, the causative agents of the disease are Mucor spp. (M. indicus, M. circinelloides, etc.). In the Cunninghamellaceae family, only Cunninghamella bertholletiae is pathogenic to humans.
The genus Saksenaea includes only Saksenaea vasiformis. Cokeromyces (representative of the family Thamnidiaceae) also has one species that can colonize the intestine and urogenital tract. Syncephalastrum racemosum and Mortierella wolfii do not cause disease in humans, but are the causative agents of zygomycosis in cattle.
The order Entomophthorales includes two families Ancylistaceae (with the genus Conidiobolus) and Basidiobolaceae (with the genus Basidiobolus). All human cases of basidiobolomycosis are caused by the Basidiobolus ranarum species. The genus Conidiobolus contains several species pathogenic for mammals. Conidiobolus coronatus is considered the main causative agent of human disease. Most members of the Entomophthorales order are pathogens of insects and other invertebrates. Cases of basidiobolicosis and conidiobolicosis in humans have been reported in tropical regions, mainly in Africa, Asia, and Central America.
As can be seen from the above classification, the main causative agents of zygomycosis belong to the family of Mucoraceae.
Mushrooms of the class Zygomycetes are widespread. They live in the soil, often found in rotting waste and food, especially in bread and grain. The small size of the spores (on average – 6.6 microns) contributes to the spread through the air, even with the help of slight fluctuations in air flow over long distances.
Representatives of the Mucorales family can be identified in the laboratory as contaminants or contaminants of the material or medium under investigation.
The main route of entry of the zygomycetes into the patient’s body is respiratory. For example, outbreaks of rhinocerebral or pulmonary forms of zygomycosis have been repeatedly noted among workers who participated in excavations, construction or in contact with contaminated air conditioner filters.
The second in frequency is the percutaneous route of penetration of zygomycetes (injection sites, especially for drug addicts, when tattooing, insect bites, burns, maceration).
Zygomycetes may penetrate into the gastrointestinal tract along with food (with fermented milk, with dried bread products, with alcoholic beverages obtained from grain), as well as when taking herbal or homeopathic remedies contaminated with spores.
Spore penetration into the body was also noted through contaminated instruments used for various manipulations (injections, insertion of probes, taking scrapings, etc.), which is especially important in cancer patients.
Recently, many attempts have been made to systematize the available data on this disease. In one of the retrospective studies conducted in the United States, all described clinical cases of zygomycosis from 1940 to 2003 were considered. in the USA, which turned out to be 929. The study revealed that the incidence of zygomycosis is 1.7 cases per 1,000,000 people per year, i.e. approximately 500 cases per year.
In studies based on pathological-anatomical findings, it was shown that the prevalence of zygomycosis ranges from 1 to 5 cases per 10,000 autopsies. Invasive zygomycosis develops less frequently than invasive candidiasis and aspergillosis. However, in patients with a higher risk of developing opportunistic infections, for example, in recipients of hematopoietic stem cell transplants (TCSC), the prevalence of zygomycosis is just as high – from 2 to 3%.
The average age of patients with zygomycosis is 38-40 years, most of them (65%) are men. The most common clinical forms of the disease are: sinusitis (39%), lung damage (24%), skin (19%) and disseminated process (23%). Mortality depends on the clinical form and background disease and is, according to different researchers, from 36% to 85%.
Risk factors
Zygomycosis, like many other invasive mycoses, develops predominantly in immunocompromised patients. The main risk factors for this category of patients are: decompensated diabetes mellitus, cancer and hematological pathology, neutropenia (the absolute number of neutrophils is less than 0.5 × 109 / l for 1 week or more), AIDS, the condition after organ transplantation and TCSC.
Long-term immunosuppressive and cytostatic therapy, long-term administration of glucocorticoids and deferoxamine are also of great importance.
Recently, a number of cases of zygomycosis have been described in recipients of allogeneic transplants of internal organs during voriconazole prophylaxis. All these cases indicate an increase in the frequency of zygomycosis in patients receiving voriconazole as a pre- and postoperative preparation, but the exact role of this drug in increasing the susceptibility of patients to zygomycosis is not clear.
Most of the described cases, with voriconazole therapy, developed in patients who received high doses of corticosteroids for the underlying pathology. However, the uniformity of cases of zygomycosis in patients receiving this antimycotic deserves attention. Voriconazole has a wide spectrum of action against Aspergillus spp., Candida spp., Scedosporium spp., Opaco (feo) hyphomycetes, but it is inactive against zygomycetes. Therefore, it can be assumed that voriconazole, preventing the development of other invasive mycoses, increases the life expectancy of patients with immunodeficiencies, while increasing the likelihood of infection with zygomycetes.
The same phenomenon is characteristic of prophylaxis with itraconazole, the use of which can also be regarded as an independent risk factor for the development of zygomycosis. There are reports of the development of zygomycosis in patients who received caspofungin or caspofungin with voriconazole.
Pathogenesis during Zygomycosis (Phycomycosis)
Zygomycetes, getting into the body of a healthy person, die as a result of the action of mononuclear and polymorphonuclear phagocytes, as well as due to the effect of serum redox systems. When clinical observations revealed that phagocytes play a major role in preventing the development of infection. The same researchers have shown that patients with neutropenia are at increased risk of zygomycosis. In addition, impaired functional ability of phagocytes is also a risk factor for the development of zygomycosis. It is known that hyperglycemia and acidosis cause a violation of the killer activity of phagocytes and other damage mechanisms. It is also known that long-term corticosteroid therapy impairs the functional abilities of bronchoalveolar macrophages, as a result of which they cannot prevent the germination of spores after infection.
The exact mechanisms by which ketoacidosis, hyperglycemia, and steroids disrupt the function of phagocytes remain unknown.
Recently revealed an important clinical feature of increased susceptibility to zygomycosis in patients with an increased content of free iron in serum. Over the past two decades, it has become known that patients receiving deferoxamine are significantly more likely to develop zygomycosis. As it turned out, Rhizopus spp. uses deferoxamine to provide itself with iron necessary for vital activity. It has been proven that Rhizopus spp. can accumulate 8-40 times more iron than Aspergillus fumigatus and Candida albicans. A linear correlation was found between the increase in iron consumption of Rhizopus spp. and his height.
Additional data from animal studies highlight the need for Rhizopus spp. in the gland. Administration of deferoxamine or free iron into the organism infected with Rhizopus spp. animals dramatically increases the mortality of the latter. Finally, in the same experiments, it was demonstrated that other iron chelators are not used as fungal siderophores and do not provide an opportunity for the zygomycosis pathogens to proliferate.
Patients with diabetic ketoacidosis have a high risk of developing rhinocerebral zygomycosis. Repeated observations have shown that in patients with metabolic acidosis, the level of free iron in serum increases. Probably, under conditions of acidosis, iron is released from transport proteins. In the serum with a low pH that supports the growth of R.oryzae, an increased content of free iron was found (69 g / dl, N up to 13 g / dl). It has been proven that blood serum (pH 7.3-6.88) taken from patients with diabetic ketoacidosis supports the growth of Rhizopus oryzae, and the alkaline environment (pH 7.78-8.38) does not.
Summarizing all the above, we can draw the following conclusions:
- The main defense mechanisms against zygomycetes are: phagocytosis of pathogens by neutrophils, tissue macrophages and endothelial cells, which also regulate the tone and permeability of the vascular wall, the binding of free serum iron by specialized proteins. Acting in concert, these mechanisms prevent the penetration of infection into the tissues and the subsequent endovascular damage.
- People with risk factors reveal violations of protection mechanisms. For example, in diabetic ketoacidosis, the low pH of serum causes the release of iron transport proteins, which creates favorable conditions for the growth of zygomycetes. Defects in the mechanisms of phagocytic protection (deficiency of neutrophils or the violation of their functions) caused by corticosteroids or hyperglycemia with acidosis, diabetic ketoacidosis, contribute to the proliferation of zygomycetes.
- Adhesion and damage to endothelial cells by zygomycetes leads to angioinvasion of the fungus, vascular thrombosis, subsequent tissue necrosis and the spread of fungal infection.
Damage and penetration of the microorganism through the endothelial cells lining the walls of blood vessels is probably one of the highlights in the pathogenesis of the disease. Resting conidia of R. oryzae can penetrate into the subendothelium using matrix proteins. Conidia have been found to attach to subendothelial matrix proteins significantly better than micromycete hyphae.
Attention is drawn to the fact that damage to endothelial cells occurs in the case when R. oryzae conidia were not viable. The exact mechanisms by which dead zygomycetes cause tissue damage remains unclear.
The main pathological sign of zygomycosis is the presence of an extensive angioinvasive process with vascular damage, thrombosis and necrosis of the surrounding tissues. This is probably due to the affinity of the zygomycetes to the endothelium of the arteries, and the veins, as a rule, are not affected.
The listed histopathological signs are characteristic for any localization of zygomycosis. So, with the penetration of the infection in the brain, foci of softening of the tissues are observed, and along the periphery – hemorrhages. In the histological specimen of the lung, massive hemorrhages with emboli, calcification sites corresponding to the old lesions are detected. With the defeat of the gastrointestinal tract determine ulcers ranging in size from 3 to 4 cm with black necrotic areas in the center of the lesions.
Symptoms of Zygomycosis (Phycomycosis)
There are 5 main clinical variants of the disease. As a rule, they are associated with the localization of the primary focus and the entrance gate of the infection. Zygomycosis of rynocerebral (≈ 50% of all cases), pulmonary (≈ 20%), skin (≈ 10%), gastrointestinal (≈ 10%) and disseminated, as well as other, more rare, forms of the disease are distinguished.
As a rule, different options develop in patients due to certain risk factors. For example, in patients with diabetic ketoacidosis, the development of a rhinocerebral disease is typical and is much less common than pulmonary or disseminated. Why ketoacidosis most often develops exactly the rhinocerebral form of zygomycosis remains unclear. Perhaps, in patients with ketoacidosis or acidosis of other origin, an increase in the amount of free iron in serum as a result of a violation of its binding to transport proteins is important.
Among patients treated with deferoxamine, the disseminated variant of the course prevails, which means that an increase in free iron in the blood serum cannot explain the more frequent occurrence of the rhinocerebral variant in ketoacidosis. Disorders of chemotaxis and phagocytosis in conditions of hyperglycemia and acidosis also cannot explain this phenomenon.
Patients with neutropenia often develop pulmonary, and not rhinocerebral zygomycosis.
The relationship between risk factors for skin / subcutaneous zygomycosis is much more obvious, since the development of the disease is associated with damage to the skin barrier under the influence of any traumatic factor and the subsequent introduction of the pathogen from the soil, through maceration, through direct access (intravenous catheter) or injection sites.
Rinocerebral zygomycosis remains the most common form of the disease, since it accounts for 30 to 50% of all cases of this infection. Approximately 70% of episodes of this variant of zygomycosis are diagnosed in patients with diabetic ketoacidosis, more rarely in patients undergoing bone marrow transplantation or with prolonged neutropenia. The clinic is non-specific and similar in the early stages of the disease with symptomatic bacterial sinusitis or inflammation of paraorbital tissue. Patients suffer from pain in the eyeball or the front of the skull, impaired skin sensitivity, conjunctival hyperemia, decreased visual acuity and soft tissue swelling. Fever is absent in 50% of patients, leukocytosis is noted in cases when patients retain bone marrow function. If the infection is not diagnosed, the process usually spreads from the ethmoid labyrinth to the orbit, which leads to dysfunction of the paraorbital muscles and ptosis.
When the infection spreads, necrosis of the hard palate forms, visual impairment progresses, ultimately resulting in blindness and / or retinal infarction, cavernous sinus thrombosis as a result of involvement in process n. oculus or arteriole lesions.
Involvement of cranial nerves in the process of V and VII can lead to loss of sensory sensitivity of the face, ptosis. The infection can also spread through the back wall of the orbit or the main sinus in the CNS. The first sign of infection through the dura mater to the brain may be nosebleeds. When the central nervous system is involved in the process, as a result of the angioinvasive nature of the infection, cavernous sinus thrombosis, obliteration and thrombosis of the internal carotid artery, resulting in cerebral infarction, occur. Such a lesion can lead to the hematogenous spread of the infection with the formation (or without) mycotic aneurysm.
Lung lesions are most commonly detected in patients with leukemia receiving chemotherapy or in recipients of TCSC. Patients with diabetic ketoacidosis can also develop pulmonary zygomycosis, although this form of infection is less common and often subacute.
The pulmonary variant develops as a result of inhalation of zygomycete spores or the spread of infection by hematogenous and / or lymphogenous. The clinical picture is also non-specific. Patients complain of shortness of breath, cough, chest pain, fever. The angioinvasive process usually ends with necrosis of the lung parenchyma, which, in turn, can lead to massive bleeding and death, if a large blood vessel is involved in the process.
If pulmonary zygomycosis is not diagnosed in a timely manner, the process hematogenously spreads to other organs. Mortality in this variant of zygomycosis from 50-70% to 95%, if pulmonary zygomycosis is part of a disseminated process.
As already mentioned, the risk of developing zygomycosis is increased in patients with damage to the skin. Typically, the pathogen enters the body during trauma, when soil, plant fragments (spikes), etc. enter the wound. In patients with diabetes and other immunocompromised patients, skin lesions may develop at the injection site or fixation of catheters. It is possible for micromycetes to penetrate through the drains, contaminated surgical instruments or through the endotracheal tube fixation sections in patients on artificial lung ventilation (ALV).
Skin zygomycosis occurs locally, but very aggressively. The process can spread to the subcutaneous tissue, adipose tissue, muscle, fascia, and even bone. Secondary vascular invasion can lead to hematogenous spread of the process and damage to internal organs. Skin and subcutaneous zygomycosis lead to rapid tissue necrotization and death of patients in approximately 50% of cases. In the case of timely surgical intervention (removal of the affected areas) and adequate antifungal therapy, localized zygomycosis can proceed favorably.
Zygomycosis of the digestive tract is a relatively rare disease. It develops mainly in newborns and children of the first year of life when ingested zygomycetes in the body with food. Most often, gastrointestinal zygomycosis develops in the early neonatal period as a manifestation of the disseminated process.
Necrotizing enterocolitis caused by zygomycetes was first described in newborns in the early neonatal period. The cases of adult patients with neutropenia are rare. A gastrointestinal variant of zygomycosis has also been described in patients with other immunodeficiencies, such as AIDS and systemic lupus erythematosus, as well as in recipients of TCSC. The stomach, colon and small intestine are most often affected. Cases of liver damage were associated with the administration of spores contaminated with medicinal herbs. Since the process arises acutely and develops “rapidly”, the diagnosis is established, as a rule, posthumously. The symptomatology in this case is diverse and non-specific. Patients most often suffer from abdominal pain, bloating, nausea, vomiting, fever and the presence of unchanged blood in the stool. Perhaps the development of intraperitoneal abscess. The diagnosis can be made by biopsy during surgery or endoscopy.
Cases of iatrogenic gastrointestinal zygomycosis were reported as a result of the introduction of nutritional mixtures to patients via a nasogastric tube, in the preparation process of which wooden applicators contaminated with zygomycetes were used. In these patients, the disease debuted with gastrointestinal bleeding. The diagnosis was made on the basis of obtaining culture from aspirates of gastric contents.
The disseminated process arises as a result of the hematogenous spread of the pathogen, which is possible from any source of primary infection. Pulmonary variant zygomycosis in patients with neutropenia occurs with a high frequency of dissemination. Less commonly, the process can spread in a hematogenous and / or lymphogenous manner in patients with primary lesions of the paranasal sinuses, the gastrointestinal tract or the skin (more often in burn patients).
Foci with disseminated zygomycosis are more often localized in the brain and lung tissue, much less often in the spleen, heart, skin and other organs. Damage to the brain, as a result of hematogenous and / or lymphogenous spread of the infection, differs from cerebral zygomycosis resulting from the rhinocerebral process. In patients with a disseminated form, with the penetration of zygomycetes into the central nervous system, central neurological symptoms begin to increase and / or coma of central genesis develops. Mortality in such cases reaches 100%. Even without damage to the central nervous system, with a disseminated zygomycosis, the mortality rate is 90%. In case of zygomycosis in TSCA recipients, the overall mortality rate for 1 year is 95%.
There are other, more rare, clinical forms of zygomycosis. The causative agents of zygomycosis can cause an infectious process in virtually any organ. For example, perhaps isolated damage to the brain, endocardium, kidney; these variants of zygomycosis are found mainly in drug addicts. Some authors have described cases of lesions of the zygomycetes of the bones, organs of the mediastinum, trachea, kidneys, peritoneum (during peritoneal dialysis). This section also includes zygomycetema syndrome of the superior vena cava and otitis of the external ear.
Zygomycosis is usually not characteristic of AIDS patients, but periodically report on the occurrence of this infection in this group of patients.
Diagnosis of Zygomycosis (Phycomycosis)
Zygomycosis is characterized by very high mortality, so the diagnosis should be immediate, but this is hampered by the nonspecificity of clinical and radiographic signs and the very rapid development of the disease.
First of all, it is necessary to exclude zygomycosis in patients with atypically flowing sinusitis, pneumonia or fever of unknown origin against the background of decompensated diabetes, severe neutropenia and immunosuppression. Diagnosis is based on the identification of the pathogen in the material from the lesions. Currently, methods for the diagnosis of zygomycosis are being developed.
Most often, zygomycetes are determined by microscopy of the substrates studied, more rarely by sowing. The pathogen is very rarely isolated in blood cultures, even with disseminated zygomycosis. Therefore, it is microscopy of material from lesions with calcofluor stain with white or specific methods that is the main method for early diagnosis of zygomycosis. At the same time, a characteristic wide (10-50 micron) non-septate or rare-septate mycelium, branching at a right angle, is revealed. However, due to the low diagnostic value of microscopy and seeding aspirate from the nose, sputum and BAL, it is often necessary to repeat the study. It should be noted that the storage of the material in the refrigerator, homogenization of it before sowing, etc. may also reduce the likelihood of excretion of zygomycetes in culture.
In addition to mycological methods, important components of successful diagnosis are computed tomography (CT) and magnetic resonance imaging (MRI), which help not only to identify lesions, but also to determine the extent of surgical intervention – the main treatment for invasive zygomycosis.
Diagnostic methods:
- CT scan or radiography of the lungs;
- MRI or CT, radiography of the paranasal sinuses, with neurological symptoms – MRI or CT of the brain;
- obtaining material from lesions;
- microscopy and seeding of material from lesions, separated from the paranasal sinuses, sputum, BAL, biopsy material;
- histological examination of biopsy material.
Diagnostic criteria:
clinical or radiological (CT, MRI, etc.) signs of a local infection in combination with the detection of zygomycetes by microscopy, histological examination and / or seeding of material from the lesion.
Treatment of Zygomycosis (Phycomycosis)
In the tactics of treatment of zygomycosis, four factors must be considered: the speed of diagnosis, the treatment of the underlying disease (if possible, the complete elimination of risk factors), the surgical removal of the affected tissues and the corresponding antifungal therapy.
Naturally, the results of therapy significantly depend on the successful treatment of the underlying disease. So, in patients with diabetes mellitus the level of sugar and the pH of blood serum should be normalized. If possible, after the diagnosis of zygomycosis, it is necessary to stop therapy or reduce the prescribed dose of deferoxamine, immunosuppressants, corticosteroids. In addition, it must be remembered that these surveys in the early stages of the disease are often negative or have minor changes.
We already know that the X-ray picture lags behind the clinical manifestations in this category of patients, but negative results do not aim at stopping the diagnostic search, especially if there is a characteristic symptom. The appearance of characteristic changes in the tissues may also be delayed. At the initial stage of the fungal infection, the mucosa may look healthy and viable during endoscopic examination. Therefore, if the suspicion of zygomycosis is serious enough, then to clarify the diagnosis, blind biopsies of the sinus mucosa and / or thickened paraorbital muscles should be done.
They often underestimate the rate of spread of infection, because patients can maintain normal intelligence and inadequately treat their condition. In addition, it must be remembered that antifungal therapy is not the only solution to the problem; it is more correct to combine different treatment methods.
Zygomycosis is a rapidly progressing infection, and antifungal therapy alone is often not enough to control the infection.
The causative agents of zygomycosis can be resistant to amphotericin B (AMB) and, even if the pathogen is sensitive to the antifungal drug used in vitro, but it may not be effective in vivo.
In addition, angioinvasia, thrombosis, tissue necrosis can be either at the sites of entry of zygomycetes into the macroorganism, or at sites remote from the entrance gate of the infection. In these cases, it is necessary, as soon as possible, to take biopsies from all suspicious sites, followed by microscopy and culture.
Surgical intervention is necessary in the presence of massive tissue necrosis that occurs in zygomycosis, which cannot be prevented only by antimycotics. In rhinocerebral zygomycosis, early surgical treatment of the infected sinus and the corresponding paraorbital areas may possibly prevent the spread of infection. To confirm the effectiveness of the previous manipulation it may be necessary to re-examine the sinuses and the orbit.
In patients with pulmonary zygomycosis, a combination of surgical treatment with antimycotic drugs also improves survival rates compared to using only antifungal treatment [60-63]. The authors of one of the studies found in their work a reduction in mortality of up to 11% with a combination of methods, compared with 68%, in cases where patients received only antimycotics.
Unfortunately, for clinicians, the choice of antimycotics used to treat this pathology is limited. This is associated with extremely high mortality in zygomycosis, with a low percentage of cure of this disease with deliberate monotherapy and with other causes.
A reliable analysis of the effectiveness of various treatment strategies has not yet been made. This prompted researchers to conduct tests on animals, in which they managed to create well-controlled models for the application of various classes of antimycotics.
Until recently, only polyenes, which, unfortunately, were highly toxic: amphotericin B (AMB) and its lipid complex, which turned out to be quite effective in recommended doses – from 1 to 1.5 mg / kg / day, were included in the antifungal therapy for zygomycosis.
Currently, very little information about the mechanisms of action of the drug, it is not known its molecular interaction with resistant microorganisms. But it should be noted that they are developing a series of new methods that can change the results currently available and soon become quite accessible.
The AMB lipid complex is significantly less toxic than AMB, and can be given in higher doses for a longer period of time. However, the use of high doses of the AMB lipid complex is associated with unfavorable economies, for example, for comparison: the cost of treatment of AMB at a dose of 1 mg / kg / day costs, on average, US $ 5 per day, and AMB of the lipid complex at therapeutic doses from 5 to 15 mg / kg / day varies between US $ 500 and US $ 3000. Both drugs are quite effective and are now included in the standards of treatment for zygomycosis. An international agreement has been adopted, according to which treatment of zygomycosis should be started with high doses of AMV lipid complex.
In experiments on animals with disseminated zygomycosis (pathogen – R. orzazae), on the background of diabetic ketoacidosis, high doses of liposomal AmB (LАМB) were used for treatment – 15 mg / kg / day, which was more effective than using AmV at a dose of 1 mg / kg / days The result of the study – a decrease in mortality by almost half. Further, in support of LАМB as a drug of choice, one can cite the results of a recent retrospective review of 120 cases of zygomycosis in patients with hematologic pathology. In this review, the survival rate increased by up to 67% in the treatment of LАМB, compared to 39% of cases when AmB was prescribed to patients (P = 0.02, χ2). Given the retrospective nature of the review, there is the possibility of unreliable results, however, according to the main collected retrospective clinical data, AMB was less effective compared to LАМB.
In animal studies, it was shown that the LАМB content in the brain was 5 times higher than the concentration of AMB (lipid complex) in the same tissues. It turned out that the content of the AMB lipid complex in the brain is below the level of the actual AMB, despite the fact that the AMB lipid complex was administered in higher doses (5 times). In addition, in experiments on animals with disseminated zygomycosis (the causative agent is R. oryzae), when using the AMB lipid complex in doses of 5, 20, or 30 mg / kg / day, the survival rates did not improve (compared to placebo or AMB).
Separate reports on the comparative efficacy of LАМB and AMB (lipid complex) have been published, but no definite conclusions can be made on this subject. At present, when analyzing experimental data on animal testing and retrospective analysis of zygomycosis therapy in humans, the best clinical effect was observed when prescribing high doses of LАМB (especially for CNS lesions), which indicates the need to use it as a drug of choice, and high doses of AMV lipid complex – as a reserve drug.
There are ambiguous observations about the effectiveness of other antimycotics in zygomycosis. For example, itraconazole is a drug that is in vitro effective against the fungi of the order of Mucorales. A report was published on successful monotherapy of zygomycosis with itraconazole, there is also evidence that prophylactic treatment with this drug may be a risk factor for the occurrence of this disease. In addition, animal experiments have shown that itraconazole is ineffective against Rhizopus and Mucor spp., Even when the isolate was sensitive in vitro; on the contrary, itraconazole was effective in vivo against Absidia spp. (MIC 0.03 g / ml). Thus, the use of itraconazole can be considered as an alternative therapy in situations where pathogens are sensitive to this drug.
Relatively recently proposed voriconazole, which has a wide spectrum of action, but is not effective in vitro against micromycetes from the order of Mucorales.
At the same time, posaconazole and ravuconazole are effective against zygomycosis pathogens. In animal experiments with disseminated zygomycosis, posaconazole was more effective than itraconazole, but less than AmB. The number of reports of successful treatment with posoconazole in combination with AMB in patients with rhinocerebral zygomycosis, whose pathogens were previously resistant to therapy, is increasing.
Caspofungin is the first member of the echinocandin class. It was registered in the United States as a drug that has minimal activity against in vitro zygomycosis pathogens]. However, the accuracy of the tests remains unclear, since in animal experiments R. oryzae was used as an infectious agent, although it is known that it produces an enzyme that inactivates caspofungin. Also published data on the combined use of caspofungin (1 mg / kg / day) with the AMB lipid complex (5 mg / kg / day), in which synergism of their actions is noted. This combination increased the survival rate of experimental animals by 50% (compared to monotherapy only with caspofungin or AMV lipid complex).
Clinical experience with cuspofungin for the treatment of zygomycosis is still poor. In the literature there are data only one of the major clinical observations of patients with zygomycosis, treated with caspofungin as monotherapy or in combination with voriconazole.
The emergence of another drug from the group of echinocandins – Micafungin encourages experts in the prospects of treatment. Micafungin is undergoing clinical trials in many countries, and there are reports of positive experiences with its use. Echinocandins can play the role of reserve drugs for the treatment of zygomycosis, especially in combination with polyenes.
The important role of iron metabolism in the pathogenesis of zygomycosis is a prerequisite to the possibility of using iron-binding drugs in unison with antifungal therapy. Experimental data on the effects of such drugs in vitro on R. oryzae are described. Unlike deferoxamine, they prevent the microorganism from using iron for its growth. Moreover, while deferoxamine significantly worsened the course of disseminated zygomycosis caused by R. oryzae, one of the mentioned drugs more than doubled the survival rate. They propose the use of hyperbaric oxygenation in addition to the standard of treatment for this pathology, especially for patients with rhinocerebral and skin forms of zygomycosis. Probably, higher oxygen pressure improves the neutrophil’s killer capacity; In addition, high oxygen pressure makes it difficult for spores to germinate and mycelium grows in vitro. Whether hyperbaric oxygenation actually improves the outcome of therapy for patients with zygomycosis, it will be possible to establish through appropriate clinical trials.
Some authors consider it necessary to include cytokines in the standard of zygomycosis therapy, justifying this by the fact that they increase the killer capacity of phagocytes in relation to zygomycetes in vitro. A recent publication describes a good effect of treating a rhinocerebral form of zygomycosis in a child with leukemia after joining the standard therapy of γ-interferon and a colony-stimulating factor.
Forecast
Previously, the diagnosis of zygomycosis has always been fatal for the patient. Although mortality in this pathology remains high, at this stage, full recovery is possible with early diagnosis of the disease and the appointment of appropriate antimycotic therapy in conjunction with surgery. Overall survival in various forms of zygomycosis is approximately 50%, although this figure can grow up to 85% depending on the clinical variant, the speed of diagnosis and adequacy of therapy. It is known that rhinocerebral zygomycosis has higher survival rates than pulmonary and disseminated because it is usually diagnosed earlier. In pulmonary zygomycosis, the lethality is 65%, since this option is more difficult to diagnose, and it develops more often in patients with severe neutropenia. In one large study, it was shown that only 44% of cases of pulmonary zygomycosis were diagnosed during the life of patients, the percentage of survival among them was about 20%. In another study, where 93% of cases were diagnosed while patients were living, survival was 73%. Mortality among patients with disseminated zygomycosis approaches 100%.