Zigomikoz

Description:

Zigomikoz (фикомикоз)  - the general designation of the opportunistic mycoses caused by representatives of various childbirth of the class Zygomycetes.

Zigomikoz not really often found disease, in comparison with other opportunistic mycoses, such as candidiasis and aspergillomycosis. The first case of a zigomikoz is described by Paultauf in 1885. Its description rather full for the assumption that an infestant is Absidia corymbifera. At first the majority of activators of a zigomikoz carried to sort Mucor mushrooms, however after them repeatedly classified in various childbirth and families of an order Mucorales.

Soon became obvious that among activators of a zigomikoz Rhizopus spp prevail., but not Mucor spp. In process of accumulation of information on this pathology, communication of a zigomikoz with oncological diseases, a diabetes mellitus, prolonged use of antibiotics, corticosteroids, Deferoxaminum, immunosuppressors became obvious.

In process of improvement of diagnosis the range of activators extended. Along with representatives of the sorts Rhizopus, Mucor and Absidia, began to identify types of the sorts Rhizomucor, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp.

Respectively, descriptions of a clinical picture of a disease also became more various. If earlier allocated preferential rinotserebralny, pulmonary and disseminated forms of a zigomikoz, then gastrointestinal, skin and hypodermic forms, allergic reaction and asymptomatic colonization became so far also known.

With improvement of clinical laboratory methods became possible to establish the diagnosis at earlier stages of a disease, and thanks to developments of new surgical methods of treatment and progress of anti-mycotic therapy now, it is possible to avoid 100% of a lethality which accompanied a zigomikoz in recent times.

Reasons of a zigomikoz:

Activators of a zigomikoz – the lowest mushrooms in a kingdom of mushrooms are representatives of independent department - Zygomycota. This department is divided into two classes: Trichomycetes which are not pathogenic for the person, and Zygomycetes which contains pathogenic types.

The class Zygomycetes is subdivided into three orders: Mucorales, Mortierellales and Entomophthorales. The order of Mucorales is divided into five families: Mucoraceae, Cunninghamellaceae, Saksenaeaceae, Thamnidiaceae, Syncephalastraceae. Carry representatives of the sorts Rhizopus, Mucor, Absidia, Rhizomucor and Apophysomyces to the Mucoraceae family - the most frequent activators of zigomikoz.

Zigomikoz preferential cause sort Rhizopus micromycetes in people, mainly, of Rhizopus oryzae and Rhizopus microsporus. More rare infestants are Mucor spp. (M. indicus, M. circinelloides, etc.). In the Cunninghamellaceae family only Cunninghamella bertholletiae is pathogenic for the person.

The sort Saksenaea includes only Saksenaea vasiformis. Cokeromyces (the representative of families of a stvo of Thamnidiaceae) also has one appearance which can colonize intestines and the urogenital treatise. Syncephalastrum racemosum and Mortierella wolfii do not cause a disease in the person, but are activators of a zigomikoz at cattle.

The order of Entomophthorales includes two Ancylistaceae families (with the sort Conidiobolus) and Basidiobolaceae (with the sort Basidiobolus). All cases of the person bazidiobolomikozy are caused by a type of Basidiobolus ranarum. The sort Conidiobolus contains several types, pathogenic for mammals. The main causative agent of diseases at the person Conidiobolus coronatus is considered. Most of members of an order of Entomophthorales are pathogens of insects and other invertebrates. Cases of a bazidiobolomikoz and a konidiobolomikoz at the person are noted in tropical regions, is preferential in Africa, Asia, Central America.

Apparently from the given classification, the main activators of a zigomikoz belong to the Mucoraceae family.

Mushrooms of the class Zygomycetes are widespread everywhere. They live in the soil, often meet in the decaying waste and foodstuff, especially - in bread and grain. The small size a dispute (on average - 6,6 microns) promotes distribution by air, even by means of insignificant fluctuations of air flows, on long distances.

Representatives of the Mucorales family can be revealed in laboratory as kontaminat or pollutants of the studied material or Wednesday.

The main way of penetration of zigomitset to the patient's organism - respiratory. For example, repeatedly noted flashes of rinotserebralny or pulmonary forms of a zigomikoz at the workers participating in excavation, construction or contacting to the contaminated filters of conditioners.

The second for frequency is the chrezkozhny way of penetration of zigomitset (the place of injections, especially - at addicts, during the drawing tattoos, stings of insects, burns, maceration).

Penetration of zigomitset into digestive tract together with food stuffs (with the fermented milk, with the dried-up grain products, with the alcoholic beverages received from grain) is possible, and also at reception contaminated by disputes phyto - or homeopathic remedies.

Noted also penetration into an organism a dispute through the contaminated tools used at various manipulations (an injection, introduction of probes, capture of scrapings, etc.) that is especially urgent at oncological patients.

Recently repeatedly carried out attempts of systematization of the available data on this disease. In one of retrospective researches conducted to the USA all described clinical cases of a zigomikoz from 1940 to 2003 in the USA which there were 929 were considered. At a research it is revealed that the frequency of a zigomikoz makes 1,7 cases on 1000000 people a year, i.e. about 500 cases a year.

At the researches based on the pathoanatomical conclusions it is shown that prevalence of a zigomikoz makes from 1 to 5 cases on 10 000 openings. Invasive зигомикоз develops less than invasive candidiasis and an aspergillosis. However patients with higher risk have development of opportunistic infections, for example, at recipients - the transplants of stem hemopoietic cells (TSHC), prevalence of a zigomikoz is so high - from 2 to 3%.

Average age of patients zigomikozy makes 38-40 years, most of them (65%) - men. The most often found clinical forms of a disease are: sinusitis (39%), damage of lungs (24%), skin (19%) and the disseminated process (23%). The lethality depends on a clinical form and a background disease and makes, according to different researchers, from 36% to 85%.

Risk factors
Zigomikoz, as well as many other invasive mycoses, develops preferential at immunokomprometirovanny patients. The main factors of risk at this category of patients are: a dekompensirovanny diabetes mellitus, onko-and hematologic pathology, a neutropenia (absolute number of neutrophils less 0,5×109/л within 1 week or more), AIDS, a state after organ transplantation and TSKK.

Also long immunosuppressive and cytostatic therapy, long reception of glucocorticoids and Deferoxaminum is of great importance.

Recently a number of cases of emergence of a zigomikoz at recipients of allogenic transplants of internals against the background of prevention vorikonazoly was described. All these cases indicate increase in frequency of a zigomikoz at the patients receiving in quality before - and postoperative preparation вориконазол, but the exact role of this drug in increase in predisposition of patients to a zigomikoz is not clear.

The majority of the described cases, against the background of therapy vorikonazoly, developed at the patients receiving high doses of corticosteroids concerning the main pathology. However uniformity of cases of emergence of a zigomikoz at the patients receiving this antimycotic deserves attention. Vorikonazol possesses a broad spectrum of activity concerning Aspergillus spp., Candida spp., Scedosporium spp., опако (фео) gifomitset, but it is inactive concerning zigomitset. Therefore, it is possible to assume what вориконазол, preventing development of other invasive mycoses, increases life expectancy of patients with immunodeficiencies, at the same time increasing probability of infection with their Zygomycetes.

The same phenomenon is characteristic of prevention itrakonazoly which use can also be regarded as independent risk factor for development of a zigomikoz. There are messages on development of a zigomikoz in the patients receiving каспофунгин or каспофунгин with vorikonazoly.

Pathogeny:

Zygomycetes, getting to an organism of the healthy person, perish as a result of action of mononuclear and polimorfonoyaderny phagocytes, and also thanks to influence of oxidation-reduction systems of blood serum. At clinical observations it is revealed that phagocytes possess the main role in prevention of development of an infection. The same researchers proved that patients with a neutropenia are in group of the increased risk of emergence of a zigomikoz. Besides, disturbance of functional capacity of phagocytes also is risk factor of development of a zigomikoz. It is known that the hyperglycemia and acidosis cause disturbance of killerny activity of phagocytes, other mechanisms of damage. From vestno also that long therapy by corticosteroids breaks functional capacities of bronchoalveolar macrophages therefore they cannot prevent germination a dispute after infection.

Exact mechanisms as a result of which ketoacidosis, the hyperglycemia and steroids break functions of phagocytes remain unknown.

Recently revealed important clinical feature of the raised susceptibility to a zigomikoz of patients with the increased content of free iron in blood serum. Within two last decades it became known that the patients receiving Deferoxaminum get sick zigomikozy much more often. As it appeared, Rhizopus spp. uses Deferoxaminum to provide itself with iron, necessary for life activity. It was proved that Rhizopus spp. can accumulate at 8-40 times more gland, than Aspergillus fumigatus and Candida albicans. Revealed linear correlation between increase in consumption of Rhizopus spp iron. and its growth.

The additional data obtained in experiments on animals underline requirement of Rhizopus spp. in iron. Introduction of Deferoxaminum or free iron to an organism of the infected Rhizopus spp. animals are sharply raised by a lethality of the last. At last, in the same experiments it is shown that other helator of iron are not used as siderofor by mushrooms and do not provide an opportunity to activators of a zigomikoz to proliferate.

At patients with diabetic ketoacidosis the risk of development of a rinotserebralny zigomikoz is high. By repeated observations it is proved that at patients with a metabolic acidosis the level of free iron in blood serum increases. Possibly, in the conditions of acidosis iron of transport proteins is released. In blood serum with the low pH supporting R.oryzae growth found the increased content of free iron (69 g/dl, N do13 g/dl). It is proved that blood serum (pH 7,3-6,88) taken from patients with diabetic ketoacidosis supports Rhizopus oryzae growth, and the alkaline environment (pH 7,78-8,38) is not.

Summing up above and above stated, it is possible to draw the following conclusions:
1. The main mechanisms of protection against zigomitset are: phagocytosis of pathogens neutrophils, fabric macrophages and endothelial cells which regulate also a tone and permeability of a vascular wall, binding of free iron of blood serum specialized proteins. Working in coordination, these mechanisms prevent penetration of an infection into fabrics and the subsequent endovascular damage.
2. At people with risk factors reveal disturbances of mechanisms of protection. For example, at diabetic ketoacidosis low pH of blood serum is the reason of release of iron of transport proteins that creates favorable conditions for growth of zigomitset. Defects in mechanisms of phagocytal protection (deficit of quantity of neutrophils or disturbance of their function) caused by corticosteroids or a hyperglycemia with acidosis, diabetic ketoacidosis promote proliferation of zigomitset.
3. Adhesion and damage of endothelial cells by Zygomycetes leads to a mushroom angioinvaziya, vascular thrombosis, the subsequent necrosis of fabrics and spread of a fungal infection.

Damage and penetration of a microorganism through the endothelial cells covering walls of blood vessels probably is one of highlights in a disease pathogeny. The based conidiums of R. oryzae can get into a subendothelium by means of matrix proteins. It is revealed that conidiums are attached to subendothelial matrix proteins much better, than hyphas of micromycetes.

The fact that damage of endothelial cells happens also in that case when conidiums of R. оryzae were impractical attracts attention. Exact mechanisms by means of which the died Zygomycetes cause damage of fabrics remains not clear.

The main pathomorphologic sign of a zigomikoz is existence of extensive angioinvasive process with damage of vessels, thrombosis and a necrosis of surrounding fabrics. It is probably connected with a tropnost of zigomitset to an endothelium of arteries, and veins, as a rule, are not surprised.

The listed histopathological signs are characteristic of any localization of a zigomikoz. So, at penetration of an infection into a brain observe the centers of a softening of fabrics, and on the periphery - a hemorrhage. In a tissue specimen laid down whom reveal massive hemorrhages with emboluses, the sites of calcification corresponding to the old centers of defeat. At a gastrointestinal tract disease define ulcers from 3 to 4 cm in size with black necrotic sites in the center of the centers.

Symptoms of a zigomikoz:

Allocate 5 main clinical options of a disease. As a rule, they are connected with localization of primary center and entrance infection atriums. Distinguish зигомикоз rinotserebralny (≈ 50% of all cases), pulmonary (≈ 20%), skin (≈ 10%), gastrointestinal (≈ 10%) and disseminated, and also others, more rare, disease forms.

As a rule, different options develop at patients in connection with certain risk factors. For example, at patients with diabetic ketoacidosis development of rinotserebralny option of a disease is typical and is much more rare pulmonary or disseminated. Why at ketoacidosis rinotserebralny form of a zigomikoz develops remains not clear more often. Perhaps, at patients with ketoacidosis or acidosis of other origin increase in amount of free iron in blood serum as a result of binding disturbance by his transport squirrels matters.

Among the patients receiving Deferoxaminum the disseminated current option prevails, so, increase in free iron in blood serum cannot explain more frequent emergence of rinotserebralny option at ketoacidosis. In the conditions of a hyperglycemia and acidosis this phenomenon cannot explain disturbance of a chemotaxis and phagocytosis too.

At patients with a neutropenia the pulmonary, but not rinotserebralny option of a zigomikoz develops more often.

Communication of risk factors for dermo / hypodermic option of a zigomikoz as development of a disease is connected with damage of a skin barrier under the influence of any injuring factor and the subsequent implementation of the activator from the soil, through macerations, through direct access (an intravenous catheter) or places of injections is much more obvious.

Rinotserebralny зигомикоз remains the most frequent form of a disease as makes from 30 to 50% of all cases of this infection. About 70% of episodes of this option of a zigomikoz diagnose for patients with diabetic ketoacidosis, is more rare - at the patients who transferred transplantation of marrow or with a long neutropenia. The clinic is not specific and similar at early stages of a disease to symptomatology of bacterial sinusitis or an inflammation of paraorbital cellulose. Patients are disturbed by pains in an eyeglobe or a front part of a skull, disturbance of sensitivity of skin, a conjunctiva hyperemia, decrease in visual acuity and hypostasis of soft tissues. Fever is absent at 50% of patients, the leukocytosis is noted when at patients function of marrow is kept. If the infection is not diagnosed, process usually extends from a trellised labyrinth to an orbit that leads to dysfunction of paraorbital muscles and a ptosis.

At spread of an infection the necrosis of a hard palate forms, the vision disorders, eventually, which are coming to the end with a blindness and/or a heart attack of a retina, thrombosis of a cavernous sine as a result of involvement in process of n. oculus or defeat of arterioles progress.

Involvement in process can lead V and VII cranial nerves to loss of touch sensitivity of the person, a ptosis. The infection can also extend through a back wall of an orbit or the main bosom in TsNS. Nasal bleeding can be the first sign of penetration of an infection through a firm meninx in a brain. When involving in process of TsNS as result of angioinvasive nature of an infection, there is thrombosis of a cavernous sine, an obliteration and the fibrinferments of an internal carotid artery which are coming to the end with a brain heart attack. Similar defeat can lead to hematogenous spread of an infection with formation (or without) mycotic aneurism.

Damage of lungs is most often revealed at the patients with a leukosis receiving chemotherapy or at recipients of TSKK. At patients with diabetic ketoacidosis can also develop pulmonary зигомикоз though this form of an infection occurs at them less often and proceeds often subacutely.

The pulmonary option develops as a result of inhalation a dispute of zigomitset or spread of an infection in the hematogenous and/or lymphogenous way. The clinical picture is also not specific. Patients complain of short wind, cough, thorax pains, fever. Angioinvasive process, as a rule, comes to the end with a lung parenchyma necrosis which, in turn, can lead to massive bleeding and a lethal outcome, when involving in process of a large blood vessel.

If pulmonary зигомикоз do not diagnose timely, process gematogenno extends to other bodies. A lethality at this option of a zigomikoz from 50-70% to 95% if pulmonary зигомикоз it appears a part of the disseminated process.

As it was already mentioned, the risk of development of a skin zigomikoz is increased at patients with damage of integuments. Usually the activator gets into an organism during an injury when there is a hit in a wound of the soil, fragments of plants (thorns), etc. At the patients having diabetes and other immunokomprometirovanny patients, damage of skin can develop in places of injections or fixations of catheters. Penetration of micromycetes through drainages, the contaminated surgical tools or through sites of fixation of an endotracheal tube at the patients who are on the artificial ventilation of the lungs (AVL) is possible.

Skin зигомикоз proceeds locally, but it is very aggressive. Process can extend in hypodermic cellulose, fatty tissue, muscles, a fascia and, even, bones. The secondary vascular invasion can bring to гемато to gene distribution of process and damage of internals. Skin and hypodermic зигомикоз lead to a bystry nekrotization of fabrics and a lethal outcome of patients approximately in 50% of cases. In case of timely executed surgical intervention (removal of affected areas) and adequate antifungalny therapy localized skin зигомикоз can favorably proceed.

Zigomikoz of bodies of a GIT – rather rare disease. It develops, mainly, at newborns and children of the 1st year of life at hit of zigomitset in an organism with food. More often gastrointestinal зигомикоз develops in the early neonatal period as manifestation of the disseminated process.

The necrotic coloenteritis caused by Zygomycetes was for the first time described, at newborns in the early neonatal period. Cases of adult patients with a neutropenia are single. The Gatrointestinalny option of a zigomikoz was described also at patients with other immunodeficiencies, such as AIDS and a system lupus erythematosus, and also at recipients of TSKK. Most often the stomach, thick and thin guts are surprised. Cases of damage of a liver were connected with reception of the officinal herbs contaminated by disputes. As process arises sharply and develops "promptly", the diagnosis is established, as a rule, posthumously. The symptomatology in this case is various and is not specific. The most often sick are disturbed by an abdominal cavity pains, abdominal distention, nausea, vomiting, fever and availability of not changed blood in a chair. Development of intraperitoneal abscess is possible. The diagnosis can be established by means of a biopsy during surgery or endoscopy.

The cases of an iatrogenic gastrointestinal zigomikoz which resulted from introduction to patients via the nazogastralny probe of nutritious mixes in the course of which preparation used the wooden applicators contaminated by Zygomycetes were described. At these patients the disease debuted gastrointestinal bleeding. The diagnosis was established on the basis of obtaining culture from aspirates of gastric contents.

The disseminated process results from hematogenous distribution of the activator which is possible from any center of primary infection. The pulmonary option of a zigomikoz at patients with a neutropenia proceeds with high frequency dissiminations. Less often process can extend in the hematogenous and/or lymphogenous way at patients with primary damage of adnexal bosoms of a nose, GIT or skin (is more often - at burn patients).

The centers at the disseminated zigomikoz are localized in a brain and pulmonary fabric more often, is much more rare – in a spleen, heart, skin and other bodies. Damage of a brain, as a result of hematogenous and/or lymphogenous spread of an infection, differs from the cerebral zigomikoz which resulted from rinotserebralny process. At patients with the disseminated form, at penetration of zigomitset into TsNS, the central neurologic symptomatology begins to accrue and/or the coma of the central genesis develops. The lethality in such cases reaches 100%. Even without defeat of TsNS, at the disseminated zigomikoz the lethality makes 90%. At a zigomikoza at recipients of TKSK the over-all mortality within 1 year makes 95%.

Take place and other, more rare, clinical forms of a zigomikoz. Activators of a zigomikoz can cause infectious process actually in any body. For example, perhaps isolated damage of a brain, an endocardium, kidneys; these options of a zigomikoz occur, mainly, at addicts. Some authors described defeat cases Zygomycetes of bones, bodies of a mediastinum, a trachea, kidneys, peritoneums (at peritoneal dialysis). Include the syndromes of an upper vena cava and otitis of an outside ear caused by Zygomycetes in the same section.

Zigomikoz is usually not characteristic of patients AIDS, but periodically report about developing of this infection at this group of patients.

Diagnosis:

Zigomikoz is characterized by very high lethality therefore diagnosis has to be immediate, however it is interfered by not specificity of clinical and radiographic signs and very bystry development of a disease.

First of all, it is necessary to exclude зигомикоз at patients with atypically proceeding sinusitis, the pneumonia or fever of not clear genesis against the background of a dekompensirovanny sakharnogodiabet expressed to a neutropenia and immunosuppression. Diagnosis is based on identification of the activator in material from the defeat centers. Techniques of PTsR of diagnosis of a zigomikoz are at the moment developed.

More often Zygomycetes define at microscopy of the studied substrates, is more rare - at crops. The activator is very seldom allocated in blood crops even at the disseminated zigomikoz. Therefore the material microscopy from the defeat centers with coloring by a kalkofluor white or specific methods is the main method of early diagnosis of a zigomikoz. At the same time reveal characteristic wide (10-50 microns) the neseptirovanny or redkoseptirovanny mycelium branching at right angle. However in connection with the low diagnostic importance of microscopy and crops of aspirate from a nose, phlegms and the BALL, the repeated research is quite often necessary. It should be noted that storage of material in the refrigerator, homogenization it before crops, etc. can also reduce probability of allocation of zigomitset in culture.

In addition to mycologic methods, important components of successful diagnosis are the computer tomography (CT) and the magnetic and resonant tomography (MRT) which help not only to reveal the defeat centers, but also to determine the volume of surgical intervention - the main treatment of an invasive zigomikoz.

Diagnostic methods
- KT or X-ray analysis of lungs;
- MPT or KT, a X-ray analysis of adnexal bosoms of a nose, at neurologic symptomatology - brain MPT or KT;
- receiving material from the defeat centers;
- microscopy and crops of material from the centers of the defeat separated from adnexal bosoms, phlegms, the BALL, biopsy material;
- histologic research of biopsy material.

Criteria of diagnosis:
clinical or radiological (KT, MPT and so forth) symptoms of a local infection in combination with identification of zigomitset at microscopy, a histologic research and/or crops of material from the defeat center.

Treatment of a zigomikoz:

In tactics of treatment of a zigomikoz it is necessary to consider four factors: speed of diagnosis, treatment of a basic disease (if it is possible - a complete elimination of risk factors), surgical removal of the struck fabrics and the corresponding antifungal therapy.

Naturally, results of therapy significantly depend on successful treatment of a basic disease. So, at patients with a diabetes mellitus the level of sugar and pH of blood serum has to be normalized. Whenever possible, after diagnosis "зигомикоз", it is necessary to stop therapy or to reduce the appointed doses of Deferoxaminum, immunosuppressors, corticosteroids. Besides, it is necessary to remember that these inspections at the initial stages of development of a disease are often negative or have minor changes.

We already know that the X-ray pattern lags behind clinical manifestations at this category of patients, but negative takes do not aim at the termination of diagnostic search, especially, if there is a characteristic symptomatology. Emergence of characteristic changes in fabrics can be also late. The mucous membrane in an initial stage of a fungal infection can look healthy and viable at endoscopic inspection. Therefore if suspicion against a zigomikoz rather serious, then for specification of the diagnosis it is necessary to do blind biopsies of a mucous membrane of bosoms and/or reinforced paraorbital muscles.

Often underestimate the speed of spread of an infection as patients can keep normal intelligence and inadequately treat the state. Besides, it is necessary to remember that antifungal therapy is not the only solution, it is more correct - to combine various methods of treatment.

Zigomikoz - quickly progressing infection, and one antifungal therapy often is not enough to control an infection.

Activators of a zigomikoz can be steady against Amphotericinum of B (AMV) and even if the activator is sensitive to the used antifungal drug in vitro, but it can be not effective in vivo.

Besides, the angioinvaziya, thrombosis, a necrosis of fabrics can be as on places of penetration of zigomitset into a macroorganism, and on the sites remote from entrance gate инфек tion. In these cases it is necessary to take, as soon as possible, bioptata from all suspicious places with the subsequent microscopy and a cultural research.

Surgical intervention is necessary in the presence of the massive necrosis of fabric which is found at a zigomikoz which cannot be prevented only by antimycotics. At a rinotserebralny zigomikoz early surgical treatment of the infected bosom and the respective paraorbital areas, perhaps, will allow to prevent spread of an infection. For confirmation of efficiency of the manipulation which is carried out earlier there can be necessary a repeated research of bosoms and an orbit.

At patients with a pulmonary zigomikoz the combination of surgical treatment to anti-mycotic drugs also improves survival indicators in comparison with use only of antifungal treatment [60-63]. Authors of one of researches established in the work decrease in a lethality to 11% at a combination of methods, in comparison with 68%, in cases when patients received only antimycotics.

Unfortunately, for clinical physicians the choice of the antimycotics used for treatment of this pathology is limited. It is connected with extremely high lethality at a zigomikoza, with low interest of an izlechennost of this disease at notorious monotherapy and with other reasons.

Still the authentic analysis of efficiency of various strategy of treatment is not made. It induced researchers to carrying out tests for animals in whom it was succeeded to create well managed models for use of various classes of antimycotics.

Until recently included in schemes of antifungal therapy of a zigomikoz only polyenes which, unfortunately, are highly toxic: Amphotericinum In (AMV) and its lipidic complex, been rather effective in the recommended doses - from 1 to 1,5 mg/kg/days.

Now there are not enough data on mechanisms of effect of drug, its molecular interaction with resistant microorganisms is not known. But it should be noted that develop a series of new methods which can change the results which are available today and soon to become quite available.

The AMV lipidic complex is much less toxic, than AMV, and can be appointed in higher doses to longer span. However use of high doses of the AMV lipidic complex is accompanied by adverse economy, for example, for comparison: the cost of treatment of AMV in a dose 1мг/кг/сут manages, on average, US of $5 a day, and AMV of a lipidic complex in therapeutic doses from 5 to 15 mg/kg/days fluctuates between US$500 and US$3000. Both drugs are rather effective and enter standards of treatment of a zigomikoz now. The international agreement according to which treatment of a zigomikoz should be begun with high doses of AMV of a lipidic complex is accepted.

In experiments on animals with disseminated zigomikozy (the activator - R. оryzae), against the background of diabetic ketoacidosis, for treatment high doses of liposomal AMV (LAMB) - 15 mg/kg/days used that it was more effective than use of AMV in a dose of 1 mg/kg/days. Result of a research – decrease in a lethality almost twice. Further, in support of LAMB as choice drug, it is possible to give results of the recent retrospective review of 120 cases of a zigomikoz at patients with gematologicheky pathology. In this review at treatment of LAMB survival increased to 67%, in comparison with 39% of cases when to patients appointed AMV (P ═0,02, χ2). Considering retrospective character of the review, there is a possibility of unauthenticity of results, however, of the main collected retrospective clinical data, AMV, in comparison with LAMB was less effective.

In researches on animals it is shown that the maintenance of LAMB in a brain by 5 times exceeded concentration of AMV (a lipidic complex) in the same fabrics. It turned out that the maintenance of the AMV lipidic complex in a brain is lower than the level actually AMV in spite of the fact that AMV appointed a lipidic complex in higher doses (by 5 times). Besides, in experiments on animals with disseminated zigomikozy (the activator - R. оryzae) at use of AMV of a lipidic complex in doses 5, 20, or 30 mg/kg/days did not improve survival indicators (in comparison with placebo or AMV).

Separate messages on comparative efficiency of LAMB and AMV (lipidic complex) are published, but no unambiguous conclusions in this occasion can be done. Now in the analysis of experimental data of tests for animals and the retrospective analysis of therapy of a zigomikoz at people observed the best clinical effect at purpose of high doses of LAMB (especially - at defeat of TsNS) that testifies to need of its use as choice drug, and high doses of AMV of a lipidic complex - as reserve drug.

There are ambiguous observations concerning efficiency of other antimycotics at a zigomikoza. For example, итраконазол - drug which in vitro is effective against mushrooms from Mucorales order. The message on successful monotherapy of a zigomikoz itrakonazoly is published, are available also this that preventive treatment by this drug can be risk factor of developing of this disease. Besides, at experiments on animals it is shown that итраконазол it is inefficient concerning Rhizopus and Mucor spp., even in that case when isolate was sensitive in vitro; on the contrary, итраконазол in vivo against Absidia spp was effective. (MIC 0,03 g/ml). Thus, use of an itrakonazol can be considered as alternative therapy in situations when activators are sensitive to this drug.

Not effective in vitro against micromycetes from Mucorales order is rather recently offered вориконазол, possessing a broad spectrum of activity, but.

In too time позаконазол and равуконазол show efficiency concerning activators of a zigomikoz. In experiments on animals with disseminated zigomikozy позаконазол there was more effective, than итраконазол, but less, than AMV. The number of messages on successful treatment pozokonazoly increases in a combination with AMV at patients with a rinotserebralny zigomikoz which activators were rezistentna to therapy earlier.

Kaspofungin is the first representative of a class of ekhinokandin. It was registered in the USA as the drug having the minimum activity against activators of a zigomikoz in vitro]. However reliability of the carried-out tests remains not clear as in experiments on animals as the infectious agent used R. оryzae though it is known that it produces the enzyme inactivating каспофунгин. Are published also this about the combined use of a kaspofungin (1 mg/kg/days) with AMV a lipidic complex (5 mg/kg/days) in which note a synergism of their action. This combination for 50% increased survival of experimental animals (in comparison with monotherapy only kaspofunginy or AMV a lipidic complex).

Clinical experience of use of a kaspofungin for treatment of a zigomikoz is still poor. In literature there are data of only one of large clinical observations of patients with zigomikozy, receiving каспофунгин as monotherapy or in combination with vorikonazoly.

Emergence of other drug from group of ekhinokandin - a mikafungin encourages specialists in treatment perspectives. Mikafungin passes clinical tests in many countries, and there are messages on positive experience of its use. Ekhinokandina can play a role of drugs of a reserve for treatment of a zigomikoz, especially - in a combination with polyenes.

The important role of metabolism of iron serves as premises to a possibility of use of iron-binding drugs in a pathogeny of a zigomikoz in unison with antifungal therapy. Experimental data of impact of similar in vitro medicines on R. oryzae are described. Unlike Deferoxaminum, they prevent iron use by a microorganism for the growth. Moreover, while Deferoxaminum considerably worsened a current of the disseminated zigomikoz caused by R. oryzae, one of the mentioned drugs more than twice increased a survival indicator. Offer use of hyperbaric oxygenation in addition to the standard of treatment of this pathology, especially - for patients with rinotserebralny and skin forms of a zigomikoz. Possibly, more high pressure of oxygen improves killerny ability of neutrophils; besides, the high pressure of oxygen complicates germination a dispute and growth of a mycelium of in vitro. Whether hyperbaric oxygenation actually improves result of therapy of patients with zigomikozy, it will be possible to establish by means of carrying out the corresponding clinical tests.

Some authors consider necessary to include cytokines in the standard of therapy of a zigomikoz, proving it by the fact that they increase killerny ability of phagocytes concerning in vitro zigomitset. In the recent publication the good effect of treatment of a rinotserebralny form of a zigomikoz at the child with leukemia after accession to standard therapy of γ-interferon and a colony stimulating factor is described.

Forecast
Earlier, the diagnosis "зигомикоз" always meant a lethal outcome for the patient. Though the lethality at this pathology remains high, at this stage perhaps absolute recovery at early diagnosis of a disease and purpose of the corresponding anti-mycotic therapy in total with surgical intervention. The general survival at various forms of a zigomikoz makes about 50% though this figure can grow to 85% depending on clinical option, speed of diagnosis and adequacy of therapy. It is known what rinotserebralny зигомикоз has higher rates of survival, than pulmonary and disseminated because it is diagnosed, as a rule, earlier. At a pulmonary zigomikoz the lethality makes 65% as it is more difficult to diagnose this option, and unless it is howled more often at patients with a serious neutropenia. In one large research it is shown that only 44% of cases of a zigomikoz of lungs diagnosed during lifetime of patients, the survival percent among them made about 20%. In other research where 93% of cases were diagnosed during lifetime of patients, survival made 73%. The lethality among patients with disseminated zigomikozy approaches 100%.