Zygomycosis in Immunocompromised non-Haematological Patients

G. Petrikkos and M. Drogari-Apiranthitou

4st Dept. of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, "ΑΤΤΙΚΟΝ" Hospital, RΙΜΙΝΙ 1 – Haidari , Athens - 12464. Greece

Correspondence to: Dr. Miranda  Drogari-Apiranthitou, email: mdrogari@hotmail.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction
The term ‘Zygomycosis’ refers to a group of rare infections caused by hyaline filamentous fungi belonging to the class of Zygomycetes. This class is subdivided in two orders, Mucorales and Entomophthorales, both involved in human disease.[1]
Mucorales are saprobiotic organisms ubiquitous in nature; some members of this order are weak plant parasites or plant pathogens and opportunistic pathogens for man.[2] The vast majority of human zygomycotic disease is caused by genera of the Mucorales order, therefore, the term ‘mucormycosis’ is used interchangeably with the term ‘zygomycosis’ (the term ‘phycomycosis’ has also been used in the past). The most common genera confirmed in human disease are: Rhizopus, Mucor, Lichtheimia (formerly known as Absidia corymbifera or Mycocladus), Rhizomucor, Apophysomyces, Saksenaea, and Cunninghamella.[1]
For Mucorales the portals of entry in the human body are the respiratory tract through inhalation of fungal spores, the skin and less frequently the gut. They grow rapidly and produce wide hyaline, aseptate or poorly septated ribbon-like hyphae in tissues. They invade blood vessels and cause thrombosis and necrosis of the infected tissues. Disease in humans is limited to severely immunocompromised individuals, those with diabetic ketoacidosis, or those with burns or trauma. Infection usually progresses rapidly and the case fatality rate is very high. Depending on the underlying condition and the portal of entry they can cause rhinocerebral, pulmonary, cutaneous, gastrointestinal or even disseminated infection.[1]
Human infections caused by Entomophthorales, which are mainly insect pathogens, constitute a completely different clinical entity (entomopfthoramycoses). Genera involved in human disease are Conidiobolus and Basidiobolus. They affect mainly immunocompetent individuals, are prevalent in the tropics and do not disseminate.[3] In recent years the geographic distribution of basidiobolomycosis expanded and is reported also in immunocompromised hosts involving more tissues, but these cases are extremely rare.[4,5] Therefore, the present review focuses only on the zygomycotic infections caused by mucorales.
The most important risk factors for mucormycosis include prolonged neutropenia, diabetic ketoacidosis, iron overload and major trauma. Other important predisposing factors of mucormycosis include prolonged use of corticosteroids, illicit intravenous drug use, neonatal prematurity, malnourishment and broad-spectrum antimicrobial agents, as well as antifungal agents with no activity against zygomycetes, such as voriconazole and caspofungin.[6,7] The same may also be true for the other echinocandins, but data are lacking as they are not as widely used as caspofungin. Risk factors, mechanisms leading to mucormycosis and clinical presentation forms are illustrated in Table 1.

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Table 1.  Predisposing conditions for mucormycosis, pathogenetic mechanisms and clinical presentation.

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The recent years, mucormycosis incidence is seemingly increasing, particularly in patients with haematological malignancies or haematopoietic stem cell transplantation, at least in western countries.[8,9,10] However, accurate estimation of the incidence is a challenge.  Data from a global registry are not available yet and moreover there are difficulties in collecting well defined denominator data. Much information has been derived from the first most comprehensive study by Roden et al. 2005, [6] in which all data on zygomycosis recorded in the English language literature ever since the first report by Platauf in 1885,[11] were analyzed. More recent data from individual countries and institutions have also been reported [12-17] and percentages of clinical cases according to underlying condition are presented in Table2.

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Table 2. Percentages of mucormycosis cases according to underlying conditions. Data from 7 studies.

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Underlying Conditions
Diabetes – Ketoacidosis: Diabetes mellitus as a predisposing factor has been reported in 36–88% of all mucormycosis cases.[6,18-20] More susceptible are patients with uncontrolled hyperglycemia, particularly those with ketoacidosis.[21,22,23] Mucormycosis can also be observed in metabolically controlled diabetic patients24 and was found to be the first clinical manifestation of some patients with undiagnosed diabetes mellitus.[25] Type 1, type 2, and secondary diabetes mellitus have all been reported as risk factors in patients with mucormycosis.[26]
In the normal host protection from mucormycosis is provided by macrophages. They prevent the initiation of infection by phagocytosis and oxidative killing of the fungal spores. In case infection is established, neutrophils are activated and play a pivotal role in fungal killing. Activation happens in four phases:
a)    neutrophils are chemotactically attracted to the hyphae,
b)    they attach and
c)    spread on the hyphae and finally,
d)   using their oxidative cytotoxic system, neutrophils damage and kill the fungal elements without accompanying phagocytosis.
In diabetes, each of the four phases of neutrophil activation is impaired.[27] Hyperglycemia per se does not seem to play a major role in the pathogenesis of mucormycosis. Chemotaxis, the phagocytic functions (adherence and spreading), and finally the oxidative burst are all inhibited in the ketoacidotic state, essentially inducing functional neutropenia.[26-29]
The most common clinical presentation of mucormycosis in patients with diabetes mellitus is sinus disease (66%).6 Diabetes mellitus was recognized as a major risk factor for developing rhinocerebral mucormycosis very early on. The publication by Gregory et al. in 1943 on a case of uncontrolled diabetes was the first to describe fulminant rhinocerebral mucormycosis.[30]
Disease in diabetics can also present as pulmonary mucormycosis, a clinical presentation more common in neutropenic patients with malignancies or HSCT.[6]
The epidemiology in diabetic patients is variable. Roden et al.[6] showed that diabetic patients represented 36% of the 929 reported cases. They also reported a decreased incidence of mucormycosis in diabetic patients over time. This is in contrast to the increased prevalence of diabetes in the world.[31] The role of statins, used at least in the western world, has been speculated in an effort to explain this phenomenon.[32,33] In France, however, a population- based study of medical records of mucormycosis cases reported from 1997 to 2006 showed a 9% yearly increase in the annual incidence rate in the diabetic population.[12] Another retrospective study from the USA, reviewing cases with rhino-orbital-cerebral mucormycosis from two teaching tertiary-care hospitals revealed that 83% of cases were observed in diabetic patients and more importantly, 41% of them had no known history of their condition.[34] A striking finding in this study was that 56% of the patients were of Hispanic origin, a much larger proportion than that in the general population (≈25% expected incidence of Hispanic ethnicity based on demographic characteristics at the study hospitals). Data from a tertiary-care centre in India35 were also overwhelming, as 73.6% of cases were observed in patients with uncontrolled diabetes and in 42.7% of these cases diabetes was diagnosed for the first time. These findings also underline the association between diabetes and socioeconomic status. Low income individuals have the tendency not to seek medical attention as healthcare is unaffordable to them, unless complications manifest. Almost 80% of type 2 diabetes deaths occur in low- and middle-income countries (WHO Fact sheet: Diabetes, ref.36). With diabetes control programs in place, also many cases of mucormycosis could be prevented.
The overall mortality of diabetic patients with mucormycosis who undergo treatment is approximately 44%, and this is lower compared to other immunocompromising conditions.[6] This can be explained by the relatively easy management of acute complications of diabetes compared to the management of other conditions. This percentage can be further decreased with improved management. [37]
Besides diabetic ketoacidosis, chronic metabolic acidosis due to other causes, such as chronic renal failure with uremia, [38] chronic salicylate poisoning, [39] and methylmalonicaciduria,[40] has also been reported as a risk factor for mucormycosis.

Iron overload and Deferoxamine (DFO) iron/aluminium chelation therapy: Many microorganisms require iron to grow, and conditions of iron excess have been known to predispose to infection with certain bacteria.[41,42] Iron acquisition is a critical step in the pathogenetic mechanism of mucormycosis.[43]
Therapy with DFO, an iron chelator used for the treatment of iron and/or aluminum overload in dialysis patients, was found paradoxically to be a risk factor for angioinvasive mucormycosis.[44,45] Although the first dialysis patient with mucormycosis, reported in 1979 by Gluskin et al,[46] was not noted to be receiving DFO, subsequent cases of mucormycosis in patients undergoing dialysis have been in those receiving DFO for aluminum or iron excess.[45] A report of an international registry [47] showed that 78% of dialysis patients with mucormycosis were being treated with DFO.  In addition to patients with renal failure, patients with hematologic disorders, all of whom were treated with DFO, have been reported with mucormycosis.[45] Subsequent research showed that DFO can act as a siderophore for Mucorales: DFO forms a Fe-DFO complex with iron, which then binds to unidentified receptors on the surface of the zygomycetes. The iron is subsequently liberated by the fungus and is likely transported into the fungal cell by a high-affinity iron permease (rFTR1).[43] The increased sensitivity of dialysis patients to DFO-related mucormycosis is explained by the pharmacokinetic changes during uremia, which lead to a prolonged accumulation of Fe-DFO after DFO administration.[48]
Besides DFO, iron overload per se, either transfusional or due to dyserythropoiesis has also been recognized as a risk factor for mucormycosis.[49–51] In vitro and in vivo studies have shown that iron and DFO can enhance both growth and pathogenicity of Rhizopus spp. In a study reviewing a series of five cases of invasive mucormycosis among 263 allogeneic bone marrow transplant recipients,[51] the association between severe iron overload and mucormycosis was demonstrated. The mean values of serum ferritin level, transferrin saturation, and number of transfused units of erythrocytes in the study group were significantly higher compared with the matched control group.
Patients with diabetic ketoacidosis have elevated levels of available serum iron, likely due to the release of iron from binding proteins in the presence of low pH. Iron is then internalized by the zygomycetes with the help of copper oxidase (Cu-oxidase) and the high affinity iron permease rFTR1. Therefore, the increased susceptibility of patients with diabetic ketoacidosis to mucormycosis is likely due, at least in part, to an elevation in available serum iron during diabetic ketoacidosis following proton-mediated dissociation of iron from transferrin.[43]
The most common presentation of mucormycosis in patients receiving DFO appears to be the disseminated form (44%) and is associated with high mortality, reaching 80%.[6,47]
In contrast to DFO, two other iron chelators, deferiprone and deferasirox, do not supply iron to the fungus. This could be either because of their different structures and smaller size, rendering them inaccessible to fungal iron uptake systems, or because they share higher affinity constants for iron.[52] Deferiprone and deferasirox were shown to have fungicidal activity against Zygomycetes in vitro. Further, both iron chelators were shown to effectively treat mucormycosis in animal models, and one has been successfully used as salvage therapy for a patient with rhinocerebral mucormycosis.[43]

Solid organ malignancies and solid organ transplantation (SOT): The incidence of mucormycosis in transplant recipients, including both hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) patients has increased. Although global surveys of the incidence of mucormycosis are still lacking, data from individual countries and institutions show that mucormycosis in SOT is rare, but seems to be a concern because of the high mortality rate.
The estimated incidence ranges from 0.4 – 16%.[6,12,52,53] Data from the Transplant Associated Infection Surveillance Network (TRANSNET) showed that among 1063 solid organ transplant recipients mucormycosis represented 2% of invasive fungal infections. Neutropenia predisposing to mucormycosis [6] was notably absent in SOT recipients as were acidosis with or without hyperglycemia and use of DFO. In contrast, all patients were receiving immunosuppression and the overwhelming majority was on corticosteroids. Furthermore, dissemination to distant organs occurred more frequently after rejection and its treatment. 
The lung seems to be the most common site of infection in SOT recipients with mucormycosis.[6,54] Dissemination occurred preferentially to cutaneous and soft tissues, and not the brain. Mycocladus (Lichtheimia) corymbifer as causative pathogen appeared to be associated with a higher risk for dissemination in SOT with pulmonary mucormycosis in one study.[55]
In a matched case-controlled study [54] SOT recipients with mucormycosis were prospectively studied. Renal failure, diabetes mellitus, and prior voriconazole and/or caspofungin use were associated with a higher risk, whereas tacrolimus was associated with a lower risk of mucormycosis. Liver transplant recipients were more likely to have disseminated disease and developed mucormycosis earlier after transplantation than did other SOT recipients (median, 0.8 versus 5.7 months).

HIV/AIDS - Intravenous drug abuse: Mucormycosis in HIV/AIDS patients is very rare. Antinori et al.[56] in a large retrospective study of 1630 autopsies of patients who died of AIDS during 1984 through 2002, found only 2 cases with mucormycosis. However, it can be the presenting opportunistic infection in AIDS.[57]
Recently, human immunodeficiency virus (HIV) infection has been recognized as a risk factor for mucormycosis, but most cases in HIV-infected patients are also associated with intravenous drug abuse.[58,59,60,61] Cerebral mucormycosis with basal ganglia involvement is the usual clinical presentation in such cases, regardless of previous exposure to HIV.[62] The disease may develop insidiously or may progress rapidly with a fulminant course.
Endocarditis as well as the rhinocerebral form can also occur. Merchant et al.[63] reported on a patient with rhinocerebral mucormycosis and also reviewed another 6 cases reported in the literature. It is of note that 3 of them had hyperglycemia or diabetic ketoacidosis.
Mucormycosis in the HIV+ can also present in the kidneys, the skin, the gastrointestinal tract, the respiratory tract, or may be disseminated.[64-75] How the fungus enters the body is not very clear. The fact that most of the infections occur at sites remote from the needle stick however, suggest that most probably this happens through spores contained in the illicit drugs.[1]
Corticosteroids/Rheumatic diseases: Corticosteroid therapy is another primary risk factor that enhances a patient’s susceptibility to mucormycosis by causing either defects in macrophages and neutrophils or steroid-induced diabetes.[1]
Corticosteroids have a wide range of complex immunosuppressive effects, mainly by affecting cellular immunity, and increase host susceptibility to invasive fungal infections.[76] The mechanism by which the corticosteroids enhance susceptibility to developing mucormycosis is probably twofold. First, steroids suppress the normal inflammatory cell response that would otherwise occur, and second, they may induce a diabetic state.[77] In a recent study only 21% of patients with corticosteroid induced diabetes were receiving medication for diabetes.[34]
Of the few cases of mucormycosis in patients with lupus erythematosus (SLE) reported in English language literature[78-93] it appears that disease can present with any clinical form, but disseminated mucormycosis is usual in this group of patients. Mok et al.[78] reviewed all SLE cases published from 1970 through 2002 and reported a very high overall mortality of mucormycosis (88%). Additional predisposing factors for opportunistic infection included hypocomplementemia, nephrotic syndrome, uremia, leukopenia, and diabetes mellitus. The diagnosis often was made only at autopsy (63%). The cutaneous form appeared to have the best prognosis with combined medical and surgical treatment.[78]
Mucormycosis in other autoimmune diseases are scarce, but in cases such as in Wegener’s granulomatosis it may mimic disease relapse and remain underdiagnosed.[94]

No underlying disease: A considerable proportion of patients with mucormycosis have no apparent immune deficiency.[6] These patients have usually primary mucormycosis of the skin associated with burns, trauma, insect bites, tattooing and also complicating surgical wounds and catheter insertion sites. Recently, Skiada and Petrikkos reviewed 67 cases of cutaneous mucormycosis in English language literature, from 2004 -2008.[95] Most of the patients had an underlying immunocompromising condition such as haematologic malignancy, diabetes, or solid organ transplantation, but the immunocompetent represented a large proportion (40%).
Infection usually occurs through direct inoculation. It can be very invasive locally, penetrating the cutaneous and subcutaneous tissues into the adjacent fat, muscle, fascia and bone. In rare cases it can even disseminate to deep organs. Road traffic accidents, crush injuries, but also minor traumas such as those caused by plant thorns or insect bites, can lead to traumatic implantation of contaminated soil and subsequent mucormycosis. Major burn injury is another well described cause of cutaneous mucormycosis. An increased risk for developing mucormycosis in burn patients is the development of a condition called “burned stressed pseudodiabetes”, which is marked by hyperglycemia and glycosuria.[96,97]
In a new PubMed search from 2008 - 2010, we found 27 additional cases of cutaneous mucormycosis occurring in non immunocompromised hosts.[98-110] Risk factors in these cases included soil contaminated wounds, insect bites, burns, but the majority of cases (N=12) were iatrogenic, either after surgery or at injection sites. Infections with Mucorales occurring in nosocomial settings have been repeatedly reported and have even caused small hospital outbreaks in the USA, the UK and in Europe.[111] Sources of infection included contaminated bandages, Elastopad adhesive dressings, wooden tongue depressors and non-sterile karaya ostomy bags.
The clinical presentation is variable. The clinical signs initially are non specific, consisting of erythema and induration. Eventually the lesions may form blisters, pustules, or necrotic ulcerations. Cotton wool-like material may also be observed on the margins of the wound. The lesions may mimic pyoderma gangrenosum, bacterial synergistic gangrene or infections produced by Pseudomonas, Aspergillus, Histoplasma etc. Biopsy specimens for histology and cultures are necessary to establish diagnosis.
Strains involved are usually Rhizopus spp. (the majority), Lichtheimia corymbifera (syn. Absidia, Mycocladus), Apohysomyces elegans, Mucor spp., Cunninghamella bertholetiae and Saksenaea vasiformis. In the cases reported after 2008 the cultured species were R. arrhizus in 3 cases,[99,101] Lichtheimia spp.in [5,98,100,107,109] A. elegans in 4,[98] S.  vasiformis in 3,[98,102,110] and  Rhizomucor variabilis in 7.[103-104] The later, a non-thermophile species of the genus Rhizomucor, in contrast to other mucorales can cause large but slowly progressing opportunistic infections of the skin in immune-competent individuals. These fungi seem to have an increasing incidence in farmers from China.
The prognosis of mucormycosis in the immunocompetent is better than that in other patient groups but mortality remains high depending on the site, extension of infection and time of initiation of antifungal therapy. Iatrogenic cutaneous mucormycosis could easily be prevented with proper preoperative preparation and postoperative dressing of the surgical sites.

Diagnosis
The clinical diagnosis of mucormycosis among non haematological immunocompromised patients is notoriously difficult because of the similarity with aspergillosis or other mycoses caused by filamentous fungi. Diagnosis is usually delayed, as   the majority of the physicians are not so much familiar with the disease. The leading signs and symptoms of mucormycosis are presented in Table 3.

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Table 3. Clinical forms and relevant signs and symptoms

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When clinical presentation may suggest mucormycosis, imaging techniques are helpful, but cultures and histopathology are required for confirmation.
In case of rhinocerebral involvement, CT and particularly MRI are helpful in enabling an early detection of orbital, sinus, meningeal, bone, and cerebral lesions as well as intracranial vascular occlusion even before clinical signs develop. In pulmonary mucormycosis, lung biopsies (endoscopic, CT-guided or surgical) should be performed, depending on the radiological findings obtained by CT scans.  CT guided percutaneous lung biopsy has been found highly efficient to early differentiate aspergillosis from mucormycosis in haematological patients. Whatever the initial clinical site involved, a sinus and chest CT are mandatory in addition to brain imaging. This is of major importance for the indicated therapeutic approach.[112]
The laboratory diagnosis of mucormycosis is challenging and requires expertise and proper sampling. Proper clinical samples include scrapings and aspirates from sinuses, nasal discharges, BAL, needle biopsies from pulmonary lesions, skin scrapings from cutaneous lesions and biopsy tissues.  Zygomycetes are almost never isolated from blood and very rarely isolated from cultures of cerebrospinal fluid, sputum, urine or faeces, or swabs of infected areas.[113]
The significance of the isolates grown in cultures may be doubtful, especially when grown from samples of non sterile sites, as they are commonly encountered as contaminants. Histopathologic evidence of fungal invasion of tissue is required to confirm clinical or radiological diagnosis and/or reliability of culture.
The direct microscopic examination of biopsy material in 10%-20% KOH and/or calcofluor-white wet mount shows characteristic broad (6–15 μm in diameter), thin walled, mostly aseptate, ribbon-like hyaline hyphae with almost right –angle branching at irregular intervals. In tissue, Zygomycetes hyphae can be distinguished from the regularly septated hyphae of more common opportunistic molds such as Aspergillus spp.  Histopathologic sections occasionally show folded, twisted, and compressed hyphae, which may be mistaken for septated hyphae. Sporangia, the reproductive hyphal structures that contain spores, are seen rarely in tissue in patients infected with zygomycetes. These hyphae are poorly stained with PAS and Gram stains but are very well seen by H&E, GMS, or Periodic-acid Schiff stain. Hyphae may be observed within necrotic tissue and signs of angioinvasion and infarction; neutrophilic infiltrates or granuloma formation may be present in patients who are not granulocytopenic or with more chronic infection, respectively.[114]
Identification of zygomycetes at the genus and species levels requires culture studies, because all members of this group are morphologically similar in tissue. Poor recovery of Zygomycetes may reflect limited septation of the hyphae, making the fungi more liable to damage resulting from tissue excessive grinding. Samples should be kept at room temperature until culture plating, as these fungi may not survive refrigerator temperatures, and excessive grinding should be avoided. The zygomycetes can be easily grown on conventional media like SDA with antibiotics, at temperatures 25o C to 37oC, without cycloheximide as this substance is inhibitory to most of them except A. elegans. If all other media fail, sterile bread without preservatives in a test tube may recover zygomycetes from clinical samples, since these fungi are commonly associated with bread.[115] The rapidly growing mycelia are described as fibrous or cotton-candy.
There are no reliable serologic or skin tests for mucormycosis and the recently introduced antigen tests for Aspergillus (galactomannan) and other fungal species (b-D-glucan) do not detect Zygomycetes because of the limited amount of galactomannan and glucan in their cell walls.[116]
When cultures are negative, molecular identification of zygomycetes from fresh frozen or paraffin embedded tissue can help to confirm diagnosis and identify the fungus to the genus and species level. Different techniques have been reported: DNA probes targeting the ribosomal 18S subunit, ITS1 sequencing after PCR with pan-fungal primers, 18S-targeted semi-nested PCR and real-time PCR targeting cytochrome b gene.[117-122] The identification to the species level of a strain isolated in culture and the identification of a zygomycete in tissue by PCR make the diagnosis much easier. However, at present, there is no standardized method available. Nevertheless, problems remain, since cultures are positive in only 50% of cases 6 and tissue for examination is not always available.
 Sequencing of PCR products leads to a presumptive identification of the Zygomycetes, which provides some guidance in selecting antifungal therapy that would not have been available using histopathology alone. Molecular typing is most useful for characterizing zygomycete epidemiology in the setting of a cluster of nosocomial cases, outbreaks, or pseudo-outbreaks, in order to rule out clonal spread or a common infecting source.

Treatment
The prognosis of patients with zygomycosis due to Mucorales without treatment is very poor approaching 100%, depending on the underlying condition and form of mucormycosis.[123] Given the rapid development of the disease, early diagnosis and immediate initiation of treatment is critical for a favourable outcome.[124]
The therapeutic approach to mucormycosis is multimodal, with an equally important three-point strategy that includes (a) antifungal therapy, (b) surgical debridement and (c) correction of the underlying condition predisposing the patient to the disease. Moreover, management of co-morbid factors and adjunctive treatments may improve host response.
Because of the relative rarity of mucormycosis, prospective, comparative studies of antifungal agents and strategies have not been conducted. Therefore, the management of mucormycosis is so far based on the results of case series and case reports, animal model studies and in vitro susceptibility data.
The most frequently used antifungal agents to treat mucormycosis are listed in Table 4.

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Table 4. Most frequently used antifungal agents to treat mucormycosis and entomophthoramycosis (adapted from ref. 123)

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Amphotericin B has the most significant in-vitro activity against Zygomycetes and has been successfully used to treat mucormycosis for many years. Amphotericin B deoxycholate (d-AmB) is the only antifungal agent that has been approved by the US Food and Drug Administration for primary treatment of mucormycosis. However, this formulation has significant toxicity. The newer lipid formulations of amphotericin B that include liposomal AmB (L-AmB), AmB lipid complex (ABLC), and AmB colloidal dispersion (ABCD) are less nephrotoxic and have almost completely replaced amphotericin B deoxycholate in the recent years. It seems reasonable to recommend either L-AmB or ABLC as first-line treatment for mucormycosis.[125-128] The optimal daily dose, as well as the length of treatment, are both undefined yet. Starting dosages of 5–7.5 mg/kg/day for L-AMB and of 5mg/kg/day for ABLC, respectively, are commonly used for adults and children.[129]
Of the azoles only posaconazole has in vitro activity against Zygomycetes and has been shown to be active as salvage therapy.[130,131] Some physicians are using the combination of posaconazole with amphotericin B, but the efficiency of this approach has not been proven in clinical trials.
Zygomycetes are resistant to caspofungin and 5-flucytosine in vitro.[132,133] Itraconazole may have some activity against certain strains of Rhizomucor and Lichtheimia [134] and could be an option especially in cases of cutaneous infection.  However, despite rare case reports,[135-138] data are insufficient to support its use as monotherapy of mucormycosis in clinical practice.
There is some evidence that combination of amphotericin B with caspofungin may be active, but these results are preliminary.[139]
Certain Mucorales species have however variable susceptibilities to amphotericin, with MICs ranging from <1 to 100 μg/ml and treatment may be unsuccessful. Moreover, the drug may not reach the target because of tissue infarction and thrombosis.[140] In order to increase oxygen concentration in tissues hyperbaric oxygen has been used as adjunctive therapy in limited studies, but evidence is insufficient to define the efficacy of this expensive intervention.[141]
Another option for the treatment of mucormycosis is the adjunctive use of iron-chelators deferasirox and deferiprone. A clinical trial is currently underway, testing the combination of deferasirox with liposomal amphotericin B.
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and GM-CSF are routinely given to neutropenic patients with mucormycosis or another invasive fungal disease. These two cytokines have also be used in a limited number of cases of mucormycosis in non-neutropenic patients as adjunctive treatment with favorable outcomes.[142,143]
Treating a patient’s underlying medical condition and reducing immunosuppression are essential to therapy. Rapid correction of metabolic abnormalities is mandatory in uncontrolled diabetes. Corticosteroids should be discontinued, if feasible, and other immunosuppressive drugs should be tapered as much as possible.
Diabetics may have a more favourable outcome than non-diabetics. An overall survival rate of 60-77% for rhino-orbito-cerebral mucormycosis has been reported in diabetics, versus 20-34% in non-diabetics.144,145 Combined surgical and medical therapy leads to reduced mortality rates compared to medical treatment alone.6,146
Despite the progress in the treatment of mucormycosis, many problems are yet unsolved and the mortality of the disease is still high.

Conclusions
Depending on the underlying condition of   immunocompromised non- haematological patients, mucormycosis can manifest in various clinical forms: mostly as rhino-orbital or rhino-cerebral in diabetes patients, pulmonary infection in patients with malignancy or solid organ transplantation, disseminated infection in iron overloaded or deferoxamine treated patients, cerebral - with no sinus involvement - in ID users, gastrointestinal in premature infants, and cutaneous after direct inoculation in the immunocompetent.
Although there are many unresolved issues concerning the epidemiology, diagnosis and treatment of mucormycosis, advances have been made. Knowledge of the differential patterns of clinical presentation can raise the suspicion index for these rare but highly lethal infections. This is very important since prompt and appropriate management can reduce mortality and morbidity considerably.

References 

1. Ribes J.A., Vanover-Sams C. L. and Baker D. J. Zygomycetes in Human Disease. Clinical Microbiology Reviews, April 2000, p. 236-301, Vol. 13, No. 2.
2. De Hoog, J. Guarro, J. Gené and M.J. Figueras, Atlas of clinical fungi (2nd ed.), Centraalbureau voor Schimmelcultures / Universitat Rovira i Virgili, Utrecht 2000. Pp. 81-123.
3. Drouhet E, Ravisse P. Entomophthoromycosis. Curr Top Med Mycol.  1993;5:215-45.
4. Dworzack, D. L., A. S. Pollok, G. R. Hodges, W. C. Barnes, L. Ajello and A. Padhye. 1978. Zygomycosis of the maxillary sinus and palate caused by Basidiobolus haptosporus. Arch. Intern. Med. 138:1274–1276. doi:10.1001/archinte.138.8.1274 PMid:567045
5. Roy, A. D., and H. M. Cameroon. 1972. Rhinophycomycosis entomophthorae occurring in a chimpanzee in the wild in East Africa. Am. J. Trop. Med. Hyg. 21:234–237. PMid:5062225
6. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, Sein M, Sein T, Chiou CC, Chu JH, Kontoyiannis DP, Walsh TJ. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005 Sep 1;41:634-53. Epub 2005 Jul 29. doi:10.1086/432579 PMid:16080086
7. Ramos A, Cuervas-Mons V, Noblejas A, Baños I, Duran P, Marcos R, Sánchez-Turrión V, Jiménez M, Arellano B, Corbacho C, Sánchez-Romero I. Breakthrough rhinocerebral mucormycosis in a liver transplant patient receiving caspofungin. Transplant Proc. 2009 Jun;41:1972-5. doi:10.1016/j.transproceed.2009.01.077 PMid:19545771
8. Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18:556–69 doi:10.1128/CMR.18.3.556-569.2005 PMid:16020690 PMCid:1195964
9. Prabhu RM, Patel R. Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004 Mar;10 Suppl 1:31-47.doi:10.1111/j.1470-9465.2004.00843.x  PMid:14748801
10. Chakrabarti A, Das A, Mandal J, et al. The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus. Med Mycol 2006; 44:335-42. doi:10.1080/13693780500464930 PMid:16772227
11. Platauf, A. P. (1885). Mycosis mucorina. Virchows Archiv: An International Journal of Pathology 102, 543–64.doi:10.1007/BF01932420 
12. Bitar D, Van Cauteren D, Lanternier F, Dannaoui E, Che D, Dromer F, Desenclos JC, Lortholary O. Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006. Emerg Infect Dis. 2009 Sep;15:1395-401. doi:10.3201/eid1509.090334  PMid:19788806 PMCid:2819884
13. Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology). Pagano L, Valentini CG, Posteraro B, Girmenia C, Ossi C, Pan A, Candoni A, Nosari A, Riva M, Cattaneo C, Rossini F, Fianchi L, Caira M, Sanguinetti M, Gesu GP, Lombardi G, Vianelli N, Stanzani M, Mirone E, Pinsi G, Facchetti F, Manca N, Savi L, Mettimano M, Selva V, Caserta I, Scarpellini P, Morace G, D'Arminio Monforte A, Grossi P, Giudici D, Tortorano AM, Bonini A, Ricci L, Picardi M, Rossano F, Fanci R, Pecile P, Fumagalli L, Ferrari L, Capecchi PL, Romano C, Busca A, Barbui A, Garzia M, Minniti RR, Farina G, Montagna MT, Bruno F, Morelli O, Chierichini A, Placanica PM, Castagnola E, Bandettini R, Giordano S, Monastero R, Tosti ME, Rossi MR, Spedini P, Piane R, Nucci M, Pallavicini F, Bassetti M, Cristini F, LA Sorda M, Viviani M. J Chemother. 2009 Jun;21:322-9. PMid:19567354
14. Saegeman V, Maertens J, Meersseman W, Spriet I, Verbeken E, Lagrou K. Increasing incidence of mucormycosis in university hospital, Belgium. Emerg Infect Dis. 2010 Sep;16:1456-8. doi:10.3201/eid1609.100276 PMid:20735932
15. Rüping MJ, Heinz WJ, Kindo AJ, Rickerts V, Lass-Flörl C, Beisel C, Herbrecht R, Roth Y, Silling G, Ullmann AJ, Borchert K, Egerer G, Maertens J, Maschmeyer G, Simon A, Wattad M, Fischer G, Vehreschild JJ, Cornely OA. Forty-one recent cases of invasive zygomycosis from a global clinical registry. J Antimicrob Chemother. 2010 Feb;65:296-302. doi:10.1093/jac/dkp430 PMid:20008047
16. Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, Lass-Florl C, Bouza E, Klimko N, Gaustad P, Richardson M, Hamal P, Akova M, Meis JF, Rodriguez-Tudela JL, Roilides E, Mitrousia-Ziouva A, Petrikkos G; for the European Confederation of Medical Mycology Working Group on Zygomycosis. Zygomycosis in Europe: Analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011 Jan 2. doi: 10.1111/j.1469-0691.2010.03456.x. [Epub ahead of print] doi:10.1111/j.1469-0691.2010.03456.x PMid:21199154
17. Chakrabarti A, Chatterjee SS, Das A, Panda N, Shivaprakash MR, Kaur A, Varma SC, Singhi S, Bhansali A, Sakhuja V. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J. 2009 Nov;85(1009):573-81.doi:10.1136/pgmj.2008.076463 PMid:19892892
18. Nithyanandam S, Jacob MS, Battu RR, Thomas RK, Correa MA, D’Souza O (2003) Rhino-orbito-cerebral mucormycosis. A retrospective analysis of clinical features and treatment outcomes. Indian J Ophthalmol 51:231–236 PMid:14601848
19. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW (1999) Infections in patients with diabetes mellitus. N Engl J Med 341:1906–1912. doi:10.1056/NEJM199912163412507 PMid:10601511
20. M. Chayakulkeeree . M. A. Ghannoum . J. R. Perfect. Zygomycosis: the re-emerging fungal infection. Eur J Clin Microbiol Infect Dis. 2006; 25:215-29.doi:10.1007/s10096-006-0107-1 PMid:6756909
21. Sugar AM (2005) Agents of mucormycosis and related species. In: Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Elsevier Churchill Livingstone, Philadelphia, pp 2973–2984.
22. Gonzalez CE, Rinaldi MG, Sugar AM (2002) Zygomycosis. Infect Dis Clin North Am 16:895–914. doi:10.1016/S0891-5520(02)00037-5
23. Greenberg RN, Scott LJ, Vaughn HH, Ribes JA (2004). Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis 17:517–525.doi:10.1097/00001432-200412000-00003 PMid:15640705
24. Helderman JH, Cooper HS, Mann J (1974) Chronic phycomycosis in a controlled diabetic. Ann Intern Med 80:419. PMid:4816193
25. Bhansali A, Bhadada S, Sharma A, Suresh V, Gupta A, Singh P, Chakarbarti A, Dash RJ (2004) Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgrad Med J 80:670–674. doi:10.1136/pgmj.2003.016030   PMid:15537854 PMCid:1743145
26. Bagdade, J. D. 1976. Phagocytic and microbiocidal function in diabetes mellitus. Acta Endocrinol. 83:27–33.
27. Bybee, J. D., and D. E. Rogers. 1964. The phagocytic activity of polymorphonuclear leukocytes obtained from patients with diabetes mellitus. J. Lab. Clin. Med. 64:1–13. PMid:14192564
28. Mowat, A. G., and J. Baum. 1971. Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N. Engl. J. Med. 284:621–627. doi:10.1056/NEJM197103252841201 PMid:5545603
29. Sheldon, W. H., and H. Bauer. 1959. The development of the acute inflammatory response to experimental cutaneous mucormycosis in normal and diabetic rabbits. J. Exp. Med. 110:845–852. doi:10.1084/jem.110.6.845 PMid:14445772 PMCid:2137039
30. Gregory, J. E., A. Golden, and W. Haymaker. 1943. Mucormycosis of the central nervous system: a report of three cases. Bull. Johns Hopkins Hosp.73:405–419.
31. Ludvigsson J. Why diabetes incidence increases--a unifying theory. Ann N Y Acad Sci. 2006 Oct;1079:374-82. doi:10.1196/annals.1375.058 PMid:17130582
32. Kontoyiannis DP. Decrease in the number of reported cases of zygomycosis among patients with diabetes mellitus: a hypothesis. Clin Infect Dis. 2007 Apr 15;44:1089-90. doi:10.1086/512817 PMid:17366455
33. Chamilos G, Lewis RE, Kontoyiannis DP. Lovastatin has significant activity against zygomycetes and interacts synergistically with voriconazole. Antimicrob Agents Chemother. 2006 Jan;50:96-103. doi:10.1128/AAC.50.1.96-103.2006 PMid:16377673 PMCid:1346800
34. Reed C, Bryant R, Ibrahim AS, Edwards J Jr, Filler SG, Goldberg R, Spellberg B. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008 Aug 1;47:364-71. doi:10.1086/589857 PMid:18558882 PMCid:2793535
35. Chakrabarti A, Das A, Mandal J, Shivaprakash MR, George VK, Tarai B, Rao P, Panda N, Verma SC, Sakhuja V. The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus. Med Mycol. 2006 Jun;44:335-42. doi:10.1080/13693780500464930
36.  PMid:16772227 http://www.who.int/mediacentre/factsheets/fs312/en/index.html 
37. Perlroth J, Choi B, Spellberg B. Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol. 2007 Jun;45:321-46. doi:10.1080/13693780701218689 PMid:17510856
38. Gupta KL, Radotra BD, Sakhuja V, Banerjee AK, Chugh KS (1989) Mucormycosis in patients with renal failure. Ren Fail 11:195–199 doi:10.3109/08860228909054931 PMid:2485482
39. Espinoza CG, Halkias DG (1983) Pulmonary mucormycosis as a complication of chronic salicylate poisoning. Am J Clin Pathol 80:508–511 PMid:6624716
40. Lewis LL, Hawkins HK, Edwards MS (1990) Disseminated mucormycosis in an infant with methylmalonicaciduria. Pediatr Infect Dis J 9:851–854. doi:10.1097/00006454-199011000-00016
41. Bullen J J: The significance of iron in infection. Rev Infect Dis 1981; 3: 1127- 1138. doi:10.1093/clinids/3.6.1127
42. Payne SM: Iron and virulence in the family Enterobacteriaceae. CRC Crit Rev Microbio] 1988; 16: 81-111. doi:10.3109/10408418809104468 PMid:3067977
43. Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis. 2008 Dec;21:620-5. doi:10.1097/QCO.0b013e3283165fd1 PMid:18978530 PMCid:2773686
44. Artis WM, Fountain JA, Delcher HK, Jones HE: A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes 1982; 31: 1109-1114. doi:10.2337/diabetes.31.12.1109 PMid:6816646
45. Daly AL, Velazquez LA, Bradley SF, Kauffman CA. Mucormycosis: association with deferoxamine therapy. Am J Med. 1989 Oct;87:468-71.doi:10.1016/S0002-9343(89)80836-8
46. Gluskin, M., M. P. Solomon, B. Gold, M. L. Corrado, and J. Berger. 1979. Mucormycosis slough of nasal floor and palate in the anephric patient. J. Am. Dent. Assoc. 98:224-227.PMid:284067
47. Boelaert JR, Fenves AZ, Coburn JW. Deferoxamine therapy and mucormycosis in dialysis patients: report of an international registry. Am J Kidney Dis. 1991 Dec;18:660-7.PMid:1962650
48. Boelaert, J. R., J. Van Cutsem, M. De Locht, Y. J. Schneider, and R. R. Crichton. 1994. Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect. Kidney Int. 45:667–671.doi:10.1038/ki.1994.89 PMid:8196268
49. Sugar AM (1992) Mucormycosis. Clin Infect Dis 14(Suppl 1): S126–S129.
50. McNab AA, McKelvie P (1997) Iron overload is a risk factor for zygomycosis. Arch Ophthalmol 115:919–921.PMid:9230837
51. Maertens J, Demuynck H, Verbeken EK, Zachee P, Verhoef GE, Vandenberghe P, Boogaerts MA (1999) Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant 24:307–312. doi:10.1038/sj.bmt.1701885 PMid:10455371
52. Symeonidis AS. The role of iron and iron chelators in zygomycosis. Clin Microbiol Infect. 2009 Oct;15 Suppl 5:26-32.doi:10.1111/j.1469-0691.2009.02976.x PMid:19754753
53. Almyroudis NG, Sutton DA, Linden P, Rinaldi MG, Fung J, Kusne S. Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant. 2006 Oct;6:2365-74. doi:10.1111/j.1600-6143.2006.01496.x   PMid:16925570
54. Singh N, Aguado JM, Bonatti H, Forrest G, Gupta KL, Safdar N, John GT, Pursell KJ, Muñoz P, Patel R, Fortun J, Martin-Davila P, Philippe B, Philit F, Tabah A, Terzi N, Chatelet V, Kusne S, Clark N, Blumberg E, Julia MB, Humar A, Houston S, Lass-Flörl C, Johnson L, Dubberke ER, Barron MA, Lortholary O. Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis. 2009 Sep 15;200:1002-11. doi:10.1086/605445 PMid:19659439
55. Sun HY, Aguado JM, Bonatti H, Forrest G, Gupta KL, Safdar N, John GT, Pursell KJ, Muñoz P, Patel R, Fortun J, Martin-Davila P, Philippe B, Philit F, Tabah A, Terzi N, Chatelet V, Kusne S, Clark N, Blumberg E, Julia MB, Humar A, Houston S, Lass-Florl C, Johnson L, Dubberke ER, Barron MA, Lortholary O, Singh N; Zygomycosis Transplant Study Group. Pulmonary zygomycosis in solid organ transplant recipients in the current era. Am J Transplant. 2009 Sep;9:2166-71. doi:10.1111/j.1600-6143.2009.02754.x PMid:19681829
56. Antinori S, Nebuloni M, Magni C, Fasan M, Adorni F, Viola A, Corbellino M, Galli M, Vago G, Parravicini C, Ridolfo AL. Trends in the postmortem diagnosis of opportunistic invasive fungal infections in patients with AIDS: a retrospective study of 1,630 autopsies performed between 1984 and 2002. Am J Clin Pathol. 2009 Aug;132:221-7. doi:10.1309/AJCPRAAE8LZ7DTNE PMid:19605816
57. Moraru RA, Grossman ME. Palatal necrosis in an AIDS patient: a case of mucormycosis. Cutis. 2000 Jul;66:15-8. Review.PMid:10916685
58. Van den Saffele JK, Boelaert JR. Zygomycosis in HIV-positive patients: a review of the literature. Mycoses. 1996 Mar-Apr;39:77-84. doi:10.1111/j.1439-0507.1996.tb00106.x PMid:8766998
59. Nagy-Agren SE, Chu P, Smith GJ, Waskin HA, Altice FL. Zygomycosis (mucormycosis) and HIV infection: report of three cases and review. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Dec 1;10:441-9. doi:10.1097/00042560-199512000-00007 PMid:7583440
60. Sanchez MR, Ponge-Wilson I, Moy JA, Rosenthal S. Zygomycosis and HIV infection. J Am Acad Dermatol. 1994 May;30(5 Pt 2):904-8. doi:10.1016/S0190-9622(94)70110-5
61. Blatt SP, Lucey DR, DeHoff D, Zellmer RB (1991). Rhinocerebral zygomycosis in a patient with AIDS. J Infect Dis 164:215–216.PMid:2056212
62. Hopkins RJ, Rothman M, Fiore A, Goldblum SE. Cerebral mucormycosis associated with intravenous drug use: three case reports and review. Clin Infect Dis. 1994 Dec;19:1133-7.PMid:7888545
63. Merchant S, Reichman R, Koval CE. Rhinocerebral zygomycosis in an HIV-infected man during therapy with an investigational CCR5 inhibitor. AIDS. 2007 Jul 31;21:1666-9.doi:10.1097/QAD.0b013e328274257b PMid:17630574
64. Parra-Ruiz J, Peña-Monje A, Tomas-Jimenez C, Antelo-Lorenzo R, Escobar-Lara T, Hernández-Quero J. Septic arthritis due to Absidia corymbifera in a patient with HIV-1 infection. Infection. 2008 Jun;36:279-81. Epub 2007 Dec 14. doi:10.1007/s15010-007-6297-3 PMid:18084717
65. Bongiovanni M, Ranieri R, Ferrari D, Codecà C, Tartaro T, Uziel L. Prolonged survival of an HIV-infected subject with severe lymphoproliferative disease and rhinocerebral mucormycosis. J Antimicrob Chemother. 2007 Jul;60:192-3. doi:10.1093/jac/dkm148 PMid:17496057
66. Samant JS, Namgoong SH, Parveen T, Katner HP. Cytomegalovirus vasculitis and mucormycosis coinfection in late-stage HIV/AIDS. Am J Med Sci. 2007 Feb;333:122-4.doi:10.1097/00000441-200702000-00011 PMid:17301593
67. Boumis E, Chinello P, Conte A, Noto P, Cicalini S, Grillo LR, Petrosillo N. Rhino-orbital zygomycosis secondary to diabetic ketoacidosis in an HIV-positive patient: case report and literature review. AIDS. 2006 Jan 2;20:136-8.doi:10.1097/01.aids.0000198079.32207.5a PMid:16327338
68. Samanta TK, Biswas J, Gopal L, Kumarasamy N, Solomon S. Panophthalmitis due to rhizopus in an AIDS patient: a clinicopathological study. Indian J Ophthalmol. 2001 Mar;49:49-51. PMid:15887716
69. Virally ML, Riveline JP, Virally J, Chevojon P, Regnard JF, Belmekki A, Devidas A. Pulmonary mucormycosis in a diabetic patient with HIV. Diabetes Care. 2002 Nov;25:2105.doi:10.2337/diacare.25.11.2105 PMid:12401766
70. Guardia JA, Bourgoignie J, Diego J. Renal mucormycosis in the HIV patient. Am J Kidney Dis. 2000 May;35:E24.doi:10.1016/S0272-6386(00)70289-7
71. Carvalhal GF, Machado MG, Pompeo A, Saldanha L, Sabbaga E, Arap S. Mucormycosis presenting as a renal mass in a patient with the human immunodeficiency virus. J Urol. 1997 Dec;158:2230-1. doi:10.1016/S0022-5347(01)68208-9
72. Blázquez R, Pinedo A, Cosín J, Miralles P, Lacruz C, Bouza E. Nonsurgical cure of isolated cerebral mucormycosis in an intravenous drug user. Eur J Clin Microbiol Infect Dis. 1996 Jul;15:598-9. doi:10.1007/BF01709370 PMid:6756909
73. Santos J, Espigado P, Romero C, Andreu J, Rivero A, Pineda JA. Isolated renal mucormycosis in two AIDS patients. Eur J Clin Microbiol Infect Dis. 1994 May;13:430-2.doi:10.1007/BF01972004 PMid:6756909
74. [No authors listed] Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 52-1990. A 31-year-old HIV-seropositive women with a cerebral lesion seven years after treatment of carcinoma of the cervix. N Engl J Med. 1990 Dec 27;323:1823-33. doi:10.1056/NEJM199012273232608 PMid:2247121
75. Smith AG, Bustamante CI, Gilmor GD. Zygomycosis (absidiomycosis) in an AIDS patient. Absidiomycosis in AIDS. Mycopathologia. 1989 Jan;105:7-10. doi:10.1007/BF00443823 PMid:2739694
76. Chamilos G, Lewis RE, Hu J, Xiao L, Zal T, Gilliet M, Halder G, Kontoyiannis DP. Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis. Proc Natl Acad Sci U S A. 2008 Jul 8;105:9367-72. doi:10.1073/pnas.0709578105 PMid:18583479    PMCid:2453716
77. McNulty, J. S. 1982. Rhinocerebral mucormycosis: predisposing factors. Laryngoscope 92:1140–1143. PMid:7132514
78. Mok CC, Que TL, Tsui EY, Lam WY. Mucormycosis in systemic lupus erythematosus. Semin Arthritis Rheum. 2003 Oct;33:115-24. doi:10.1016/S0049-0172(03)00081-7
79. Arce-Salinas CA, Pérez-Silva E. Mucormycosis complications in systemic lupus erythematosus. Lupus. 2010;19:985-8.doi:10.1177/0961203309357574 PMid:20064915
80. Shenoi S, Emery HM. Successful treatment of invasive gastric mucormycosis in a child with systemic lupus erythematosus. Lupus. 2010 Apr;19:646-9. doi:10.1177/0961203309349117 PMid:19939907
81. Peel T, Daffy J, Thursky K, Stanley P, Buising K. Posaconazole as first line treatment for disseminated zygomycosis. Mycoses. 2008 Nov;51:542-5. doi:10.1111/j.1439-0507.2008.01499.x PMid:18422921
82. Yu J, Li RY. Primary renal zygomycosis due to Rhizopus oryzae. Med Mycol. 2006 Aug;44:461-6. doi:10.1080/13693780500338951 PMid:16882613
83. Fujimoto A, Nagao K, Tanaka K, Yamagami J, Udagawa SI, Sugiura M. The first case of cutaneous mucormycosis caused by Rhizopus azygosporus. Br J Dermatol. 2005 Aug;153:428-30.doi:10.1111/j.1365-2133.2005.06593.x   PMid:16086761
84. Alsuwaida K. Primary cutaneous mucormycosis complicating the use of adhesive tape to secure the endotracheal tube. Can J Anaesth. 2002 Oct;49:880-2. doi:10.1007/BF03017426 PMid:12374722
85. Sungkanuparph S, Sathapatayavongs B, Kunachak S, Luxameechanporn T, Cheewaruangroj W. Treatment of invasive fungal sinusitis with liposomal amphotericin B: a report of four cases. J Med Assoc Thai. 2001 Apr;84:593-601.PMid:11460976
86. Liu MF, Chen FF, Hsiue TR, Liu CC. Disseminated zygomycosis simulating cerebrovascular disease and pulmonary alveolar haemorrhage in a patient with systemic lupus erythematosus. Clin Rheumatol. 2000;19:311-4. doi:10.1007/s100670070052  PMid:10941815
87. Hosseini M, Lee J. Gastrointestinal mucormycosis mimicking ischemic colitis in a patient with systemic lupus erythematosus. Am J Gastroenterol. 1998 Aug;93:1360-2.doi:10.1111/j.1572-0241.1998.00417.x PMid:9707066
88. Dickinson M, Kalayanamit T, Yang CA, Pomper GJ, Franco-Webb C, Rodman D Cutaneous zygomycosis (mucormycosis) complicating endotracheal intubation: diagnosis and successful treatment. Chest. 1998 Jul;114:340-2. doi:10.1378/chest.114.1.340 PMid:9674495
89. Fingerote RJ, Seigel S, Atkinson MH, Lewkonia RM. Disseminated zygomycosis associated with systemic lupus erythematosus. J Rheumatol. 1990 Dec;17:1692-4.PMid:2084248
90. Bloxham CA, Carr S, Ryan DW, Kesteven PJ, Bexton RS, Griffiths ID, Richards J. Disseminated zygomycosis and systemic lupus erythematosus. Intensive Care Med. 1990;16:201-7 doi:10.1007/BF01724803 PMid:2351780
91. Wong KL, Tai YT, Loke SL, Woo EK, Wong WS, Chan MK, Ma JT. Disseminated zygomycosis masquerading as cerebral lupus erythematosus. Am J Clin Pathol. 1986 Oct;86:546-9.PMid:3766468
92. Yu J, Li RY. Primary renal zygomycosis due to Rhizopus oryzae. Med Mycol. 2006 Aug;44:461-6. doi:10.1080/13693780500338951 PMid:16882613
93. Arce-Salinas CA, Pérez-Silva E. Mucormycosis complications in systemic lupus erythematosus. Lupus. 2010;19:985-8. doi:10.1177/0961203309357574 PMid:20064915
94. Nogueira EL, Ind PW, Friedland JS, Salama AD. Mucormycosis may mimic disease relapse in Wegener's granulomatosis. J Rheumatol. 2010 Jun;37:1364-5. doi:10.3899/jrheum.091423 PMid:20516047
95. Skiada A, Petrikkos G. Cutaneous zygomycosis. Clin Microbiol Infect. 2009 Oct;15 Suppl 5:41-5. doi:10.1111/j.1469-0691.2009.02979.x PMid:19754756
96. Arney, G. K., E. Pearsons, and A. B. Sutherland. 1960. Burn stress diabetes. Ann. Surg. 152:77–90. doi:10.1097/00000658-196007000-00012 PMid:13794351 PMCid:1613595
97. Rabin, E. R., G. D. Lundberg, and E. T. Mitchell. 1961. Mucormycosis in severely burned patients. N. Engl. J. Med. 264:1286–1289. doi:10.1056/NEJM196106222642504 PMid:13738817
98. Chander J, Kaur J, Attri A, Mohan H. Primary cutaneous zygomycosis from a tertiary care centre in north-west India. Indian J Med Res. 2010 Jun;131:765-70. PMid:20571164
99. Lumbang WA, Caufield BA. Vesicular eruption on the arm of an infant. Dermatol Online J. 2010 May 15;16:13.PMid:20492830
100. Woo PC, Lau SK, Ngan AH, Tung ET, Leung SY, To KK, Cheng VC, Yuen KY. Lichtheimia hongkongensis sp. nov., a novel Lichtheimia spp. associated with rhinocerebral, gastrointestinal, and cutaneous mucormycosis. Diagn Microbiol Infect Dis. 2010 Mar;66:274-84. doi:10.1016/j.diagmicrobio.2009.10.009 PMid:20159375
101. Tilak R, Raina P, Gupta SK, Tilak V, Prakash P, Gulati AK. Cutaneous zygomycosis: a possible postoperative complication in immunocompetent individuals. Indian J Dermatol Venereol Leprol. 2009 Nov-Dec;75:596-9. doi:10.4103/0378-6323.57722 PMid:19915241
102. Stewardson AJ, Holmes NE, Ellis DH, Howden BP. Cutaneous zygomycosis caused by Saksenaea vasiformis following water-related wound in a 24-year-old immunocompetent woman. Mycoses. 2009 Nov;52:547-9. doi:10.1111/j.1439-0507.2008.01648.x PMid:19682315
103. Lu XL, Liu ZH, Shen YN, She XD, Lu GX, Zhan P, Fu MH, Zhang XL, Ge YP, Liu WD. Primary cutaneous zygomycosis caused by rhizomucor variabilis: a new endemic zygomycosis? A case report and review of 6 cases reported from China. Clin Infect Dis. 2009 Aug 1;49:e39-43. doi:10.1086/600817 PMid:19566442
104. Zhao Y, Zhang Q, Li L, Zhu J, Kang K, Chen L. Primary cutaneous mucormycosis caused by Rhizomucor variabilis in an immunocompetent patient. Mycopathologia. 2009 Nov;168:243-7. doi:10.1007/s11046-009-9219-3 PMid:19562506
105. Saravia-Flores M, Guaran DM, Argueta V. Mycoses. Invasive cutaneous infection caused by Apophysomyces elegans associated with a spider bite. 2010 May;53:259-61.
106. Piazza RC, Thomas WL, Stawski WS, Ford RD. Mucormycosis of the face. J Burn Care Res. 2009 May-Jun;30:520-3.doi:10.1097/BCR.0b013e3181a28d2f 
107. Almaslamani M, Taj-Aldeen SJ, Garcia-Hermoso D, Dannaoui E, Alsoub H, Alkhal A. An increasing trend of cutaneous zygomycosis caused by Mycocladus corymbifer (formerly Absidia corymbifera): report of two cases and review of primary cutaneous Mycocladus infections. Med Mycol. 2009;47:532-8.doi:10.1080/13693780802595746 PMid:19184768
108. Chew HH, Abuzeid A, Singh D, Tai CC. Surgical wound mucormycosis necessitating hand amputation: a case report. J Orthop Surg (Hong Kong). 2008 Aug;16:267-9.
109. Chen CK, Wan SH, Kou SK. A rare cutaneous fungal infection complicating bacterial necrotising fasciitis. Hong Kong Med J. 2008 Aug;14:314-6. PMid:18685166
110. Lechevalier P, Hermoso DG, Carol A, Bonacorsi S, Ferkdadji L, Fitoussi F, Lortholary O, Bourrillon A, Faye A, Dannaoui E, Angoulvant F. Molecular diagnosis of Saksenaea vasiformis cutaneous infection after scorpion sting in an immunocompetent adolescent. J Clin Microbiol. 2008 Sep;46:3169-72. doi:10.1128/JCM.00052-08 PMid:18632909    PMCid:2546755
111. Antoniadou A. Outbreaks of zygomycosis in hospitals. Clin Microbiol Infect. 2009 Oct;15 Suppl 5:55-9.doi:10.1111/j.1469-0691.2009.02982.x PMid:19754759
112. Lass-Flörl C, Resch G, Nachbaur D, Mayr A, Gastl G, Auberger J, et al. The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis 2007;45:e101-4.doi:10.1086/521245 PMid:17806041
113. Greenberg RN, Scott LJ, Vaughn HH, et al. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis 2004; 17:517–25.doi:10.1097/00001432-200412000-00003 PMid:15640705
114. Chander J, Textbook of Medical Mycology; New Delhi :Mehta Publishers;2008.
115. Lass-Flörl C. Zygomycosis: conventional laboratory diagnosis. 2009 Oct;15 Suppl 5:60-5.
116. Kurukularatne C, Garcia-Diaz J, Kemmerly S, Reed D, et al. Beyond Rhizopus and Mucor: Hurricane Katrina stirs up Synephalastrum in New Orleans. Presented at Focus on Fungal Infections 16. Las Vegas, March 8–10, 2006.
117. Dannaoui E. Molecular tools for identification of Zygomycetes and the diagnosis of zygomycosis. Clin Microb Infect. 2009; 15 (Suppl. 5): 66–70.
118. Bialek R, Konrad F, Kern J, et al. PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue. J Clin Pathol 2005;58: 1180–4.
119. Kobayashi M, Togitani K, Machida H, et al. Molecular polymerase chain reaction diagnosis of pulmonary mucormycosis caused by Cunninghamella bertholletiae. Respirology 2004; 9:397–401.
120. Rickerts V, Just-Nubling G, Konrad F, et al. Diagnosis of invasive aspergillosis and mucormycosis in immunocompromised patients by seminested PCR assay of tissue samples. Eur J Clin Microbiol Infect Dis 2006;25:8–13.
121. Rickerts V, Mousset S, Lambrecht E, Tintelnot K, Schwerdtfeger R, Presterl E, et al. Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens. Clin Infect Dis 2007 15;44:1078-83.
122. Dannaoui E, Schwarz P, Slany M, Loeffler J, Jorde AT, Cuenca-Estrella M, et al. Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation J Clin Microbiol, 2010; 48: 2043 - 2046.
123. Prabhu R. M. and Patel R.  Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 2004; 10 (Suppl. 1): 31–7
124. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B–based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008; 47:503–9.
125. Herbrecht R, Letscher-Bru V, Bowden RA et al. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis 2001; 20: 460–6.
126. Ma B, Seymour JF, Januszewicz H, Slavin MA. Cure of pulmonary Rhizomucor pusillus infection in a patient with hairy-cell leukemia. Role of liposomal amphotericin B and GM-CSF. Leuk Lymphoma 2001; 42: 1393–9.
127. Roy V, Ali LI, Carter TH, Selby GB. Successful non-surgical treatment of disseminated polymicrobial fungal infection in a patient with pancytopenia and graft-versushost disease. J Infect 2000; 41: 273–5.
128. Larkin JA, Montero JA. Efficacy and safety of amphotericin B lipid complex for zygomycosis. Infect Med 2003; 20: 201–6.Bigby TD, Serota ML, Tierney LM Jr, Matthay MA. Clinical spectrum of pulmonary mucormycosis. Chest 1986; 89: 435–9.
129. Spellberg B, Walsh T, Kontoyiannis DP, et al.: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009, 48:1743-1751
130. Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, Herbrecht R, Langston A, Marr KA, Schiller G, Schuster M, Wingard JR, Gonzalez CE, Revankar SG, Corcoran G, Kryscio RJ, Hare R. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006 Jan;50:126-33.
131. van Burik JA, Hare RS, Solomon HF, Corrado ML, Kontoyiannis DP. Posaconazole  is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006 Apr 1;42:e61-5.
132. Gomez-Lopez A, Cuenca-Estrella M, Monzon A, Rodriguez-Tudela JL. In vitro susceptibilities of clinical isolates of Zygomycota to amphotericin B, flucytosine, itraconazole,and voriconazole. J Antimicrob Chemother 2001; 48: 919–21.
133. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36: 1445–57.
134. Alastruey-Izquierdo A, Castelli MV, Cuesta I, Zaragoza O, Monzón A, Mellado E, Rodríguez-Tudela JL. In vitro activity of antifungals against Zygomycetes. Clin Microbiol Infect. 2009 Oct;15 Suppl 5:71-6. doi:10.1111/j.1469-0691.2009.02984.x PMid:19754762
135. Eisen DP, Robson J. Complete resolution of pulmonary Rhizopus oryzae infection with itraconazole treatment: more evidence of the utility of azoles for zygomycosis. Mycoses 2004; 47(3-4):159-162. doi:10.1111/j.1439-0507.2004.00959.x PMid:15078434
136. Liao WQ, Yao ZR, Li ZQ, Xu H, Zhao J. Pyoderma gangrenosum caused by Rhizopus arrhizus. Mycoses 1995; 38(1-2):75-77. doi:10.1111/j.1439-0507.1995.tb00011.x PMid:7637685
137. Parthiban K, Gnanaguruvelan S, Janaki C, Sentamilselvi G, Boopalraj JM. Rhinocerebral zygomycosis. Mycoses 1998; 41(1-2):51-53. doi:10.1111/j.1439-0507.1998.tb00376.x PMid:9610134
138. Zhao Y, Zhang Q, Li L, Zhu J, Kang K, Chen L. Primary cutaneous mucormycosis caused by Rhizomucor variabilis in an immunocompetent patient. Mycopathologia 2009.
139. Ibrahim AS, Bowman JC, Avanessian V, Brown K, Spellberg B, Edwards JE, Jr. et al. Caspofungin inhibits Rhizopus oryzae 1,3-beta-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis. Antimicrob Agents Chemother 2005; 49:721-727. doi:10.1128/AAC.49.2.721-727.2005 PMid:15673756 PMCid:547300
140. Garey KW, Pendland SL, Huynh VT, Bunch TH, Jensen GM, Pursell KJ. Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature. Pharmacotherapy 2001; 21: 855–60. doi:10.1592/phco.21.9.855.34560 PMid:11444582
141. John BV, Chamilos G, Kontoyiannis DP. Hyperbaric oxygen as an adjunctive treatment for zygomycosis. Clin Microbiol Infect 2005;11:515-517 doi:10.1111/j.1469-0691.2005.01170.x PMid:15966968
142. Liles WC, Huang JE, van Burik JA, Bowden RA, Dale DC. Granulocyte colony-stimulating factor administered in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J Infect Dis 1997; 175: 1012-1015.doi:10.1086/513961 PMid:9086172
143. Garcia-Diaz JB, Palau L, Pankey GA. Resolution of rhinocerebral Zygomycosis associated with adjuvant administration of granulocyte-macrophage colony-stimulating factor. Clin Infect Dis 2001; 32: 145-150. doi:10.1086/320767  PMid:11360225
144. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39: 3–22. doi:10.1016/S0039-6257(05)80041-4
145. Blitzer A, Lawson W, Meyers BR, Biller HF. Patient survival factors in paranasal sinus mucormycosis. Laryngoscope 1980; 90: 635–48. doi:10.1288/00005537-198004000-00010 PMid:7359982
146. Sun HY, Forrest G, Gupta KL, Aguado JM, Lortholary O, Julia MB, et al. Rhino-orbito-cerebral zygomycosis in solid organ transplant recipients. Transplantation 2010;15:85-92.doi:10.1097/TP.0b013e3181dde8fc   PMid:20626095