Zygomycosis

Infect Dis Clin N Am 16 (2002) 895–914

Zygomycosis Corina E. Gonzalez, MDa,*, Michael G. Rinaldi, PhDb, Alan M. Sugar, MDc a

Division of Pediatric Hematology-Oncology, Department of Pediatrics, Georgetown University Hospital, 3800 Reservoir Road NW, Washington DC 20007, USA b Department of Microbiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA c Evans Memorial Department of Clinical Research and the Department of Medicine, Boston University School of Medicine, Boston Medical Center, 88 East Newton Street, Boston, MA 02118, USA

Zygomycosis is a relatively new term that refers to a group of uncommon but frequently fatal mycoses caused by fungi of the class Zygomycetes. This class is subdivided into two orders, both containing human pathogens, the Mucorales and the Entomophthorales (Table 1). The members of the order Mucorales cause most human disease characterized by a rapidly evolving course, tissue destruction, and invasion of blood vessels. The mycoses caused by Entomophthorales historically have been limited to tropical and subtropical areas, and involve rather indolent courses affecting the subcutaneous, nasal, and sinus tissue of immunocompetent hosts [1–3]. In recent years, however, the geographic distribution, histopathology, and range of affected hosts associated with the infections caused by Entomophthorales have broadened [4,5]. At this point, it is virtually impossible to differentiate fungi from these two orders based on histopathologic or epidemiologic grounds. Other widely used terms to refer to zygomycosis, such us phycomycosis or mucormycosis, are confusing and taxonomically incorrect. The term mucormycosis, which refers only to infections caused by the order Mucorales, has been used extensively and is still retained as a medical subhead for indexing by the National Library of Medicine. It conveys useful clinical information to practicing clinicians and continues to be accepted in the medical lexicon. The spectrum of zygomycosis ranges from cutaneous to disseminated disease; the rhinocerebral manifestation, which particularly affects diabetic patients, is the most common form of this condition [2,6–8]. The literature

* Corresponding author. E-mail address: [email protected] (C.E. Gonzalez). 0891-5520/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 9 1 - 5 5 2 0 ( 0 2 ) 0 0 0 3 7 - 5

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Table 1 Classification of pathogenic zygomycetes and clinical features of zygomycosis Zygomycosis clinical features

Zygomycetes Order 1: Mucorales Family 1: Genus (species)

Family 2:

Mucoraceae Absidia (A. Corymbifera), Apophysomyces (A. Elegans) Mucor (circinelloides, hiemalis, racemosus, ramosissimus, rouxianus) Rhizomucor (R. pusillus, mieheia) Rhizopus (R. arrhizus, microsporus, schipperae, stolonifer) Cunninghamellaceae Cunninghamella (C. Bertholletiae)

Family 3: Family 4:

Mortierellaceaea Saksenaceae Saksenaea (S. vasiforms)

Family 5:

Syncephalastraceae Syncephalastrum (S. racemosum) Thamnidaceae Cokeromyces (C. recurvatus)

Family 6:

Order 2: Entomophthorales Family 1:

Family 2: a

Ancylistaceae Conidiobolus (C. coronatus, incongruus)

Basidobolaceae Basidiobolus (B. ranarum)

Rhinocerebral, rhinoorbital, paranasal, pulmonary, skin and soft tissue, disseminated, cardiac, osteomyelitis, peritonitis, meningitis, and corneal disease

Disseminated, rhinocerebral, soft tissue, pulmonary, cardiac, and articular disease Skin and soft tissue, rhinocerebral, disseminated, and cerebral disease Skin and soft tissue disease

Chronic cystitis, diarrhea, pleuritis, and peritonitis

Subcutaneous granuloma, rhinopharyngeal, sinus, pulmonary, cardiac, and disseminated disease Subcutaneous granuloma, adenopathy

Has not been identified causing human disease.

on zygomycosis is vast. Given the rarity of the disease, however, it is limited to case reports, small case series, and reviews. This article reviews the epidemiologic, clinical, diagnostic, and therapeutic aspects of zygomycosis with special focus on reviewing novel therapeutic strategies. Epidemiology The organisms of the class Zygomycetes are ubiquitous in soil and are commonly found in decaying organic matter, such as fruit and bread [1,2,9,10]. The human pathogens grow rapidly on virtually any carbohydrate

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substrate and produce large numbers of hyphae and asexual sporangiospores, which permit the organism to propagate into the environment. Many of the Zygomycetes are able to grow at temperatures above 37°C. These properties of wide ecologic distribution, rapid growth, and thermotolerance are of particular importance in developing human disease. Most commonly, zygomycosis develops in a susceptible host, including patients with diabetes, hematologic or oncologic diseases, transplant recipients, and high-risk newborns [11–26]. General or cardiac surgical patients [27–32], patients with burns [33], and those having sustained trauma or undergoing deferoxamine therapy [34–40] are also susceptible to zygomycosis. The major mode of disease transmission for the Zygomycetes is through inhalation of spores from environmental sources [7,41–44]. Cutaneous or percutaneous routes of exposure, however, are also common [21,22,35, 38–40,45–49]. Pathogenesis and host defense Healthy humans have a strong natural immunity against Zygomycetes. Most commonly, the infection presents as an opportunistic disease in patients with underlying risk factors [6,8,13,18–20,24,29,33–35,50]. Predisposing conditions to zygomycosis include the following: Immunosuppression Neutropenia Corticosteroid therapy Organ transplantation HIV infection Metabolic Diabetic ketoacidosis Uncontrolled diabetes Deferoxamine therapy Chronic metabolic acidosis Skin or soft tissue breakdown Burn wounds Traumatic inoculation Surgical wounds Miscellaneous Intravenous illicit drug use Neonatal prematurity Malnourishment The most important exception to this generalization is the disease caused by Entomophthorales, which commonly affects normal hosts [1,3]. Other exceptions are rare reports of zygomycosis caused by the agents of the order Mucorales in immunocompetent individuals with no identifiable risk factors [43,51–53] and in employees of both the malt and lumber industries [41,44].

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The increased risk for developing zygomycosis seems to involve two main processes: failure to clear and suppress germination of spores, and failure to kill hyphal elements. In the normal host, macrophages prevent the initiation of infection by phagocytosis and oxidative killing of the spores [54,55]. If macrophage function is impaired, these cells may fail to clear spores, permitting their germination into hyphae. These hyphae cause local invasion and tissue destruction. Neutrophils are the main host defense against zygomycetous and other filamentous fungi hyphae [54–56]. Functional or numerical deficiencies of tissue macrophages, neutrophils, and monocytes may result in invasive disease. Ketoacidosis may be a key factor in predisposing diabetic patients to zygomycosis. In fact, zygomycosis also has been reported complicating the course of patients with other causes of metabolic acidosis [57,58]. It has been demonstrated that low serum pH diminishes the phagocytic and chemotactic ability of neutrophils [59]. Normal human serum can inhibit the growth of Rhizopus, whereas sera from ketoacidotic diabetic patients or normal sera made acidotic by the addition of hydrochloric acid cannot. Although it is unknown if there are other serum components responsible for the inhibition of growth of Rhizopus, interactions between transferrin, iron molecules, and fungus have been described and may be important in enhancing fungal growth by acidotic serum. In fact, the transferrin system is less functional at acid pH conditions, allowing unbound iron to circulate in the serum; this available iron is then used by the fungus [60]. The importance of iron availability in host-fungus interactions was underscored by the observations of disseminated zygomycosis development in patients receiving iron chelation therapy [34]. Since 1987, treatment with deferoxamine, used as a chelator of aluminum or iron, has been linked to the development of zygomycosis, particularly in patients with chronic renal failure. In vitro assays and experimental animal models have shown that deferoxamine binds iron, which can be used by the fungus to enhance its growth [61].

Clinical manifestations Clinical manifestations of zygomycosis can be classified by the tissue site affected (eg, rhinocerebral, sinus, pulmonary, cutaneous, disseminated, abdominopelvic and gastric, and miscellaneous). There are no specific signs or symptoms of the disease; however, suggestive clinical manifestations in the right clinical setting should alert physicians for the possibility of zygomycosis (Table 2). Respiratory tract infection Rhinocerebral and sinus zygomycosis Rhinocerebral disease is the most common form of zygomycosis [3,6,8]. Approximately two thirds of the cases of rhinocerebral zygomycosis occur

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Table 2 Risk factors and most common clinical presentation of zygomycosis Predisposing conditions

Clinical presentation

Immunosuppression Metabolic Deferoxamine therapy Skin and soft tissue breakdown Intravenous illicit drug use Neonatal prematurity Malnourishment

Respiratory tract infection, disseminated infection Respiratory tract infection, rhinocerebral infection Disseminated infection Primary cutaneous and soft tissue infection Endocarditis, cerebral infection Gastrointestinal infection, disseminated infection Gastrointestinal infection

in the setting of diabetic ketoacidosis [2,6,7,8]. The disease also has been associated with immunosuppression [17,19,24,62,63]. The infection originates in the paranasal sinuses following inspiration of fungal spores and may evolve rapidly or may be slowly progressive [64] extending to neighboring tissue. The manifestations of the disease may reflect the sequential involvement of the nose, sinuses, eye, and brain. Symptoms may include nasal congestion, occasionally dark blood-tinged rhinorrhea or epistaxis, sinus tenderness, retro-orbital headache, fever, and malaise [65]. Symptoms may progress to include facial or periorbital swelling, blurred vision, lacrimation, chemosis, periorbital numbness, diplopia, proptosis, and loss of vision in the affected eye [62,66,67]. Progression from the sinuses into the mouth often occurs, eventually producing a painful black necrotic ulceration on the hard palate. Examination of the nasal cavities may also reveal a black eschar on septum or turbinates. Direct bony involvement is common as a result of pressure effects associated with expansion of the infectious process or because of direct invasion and infarction. A deterioration of the mental status is an ominous sign, often heralding cerebral involvement. Extension of the disease into the brain can progress by the optic nerve or through the venous drainage of paranasal sinuses by the cavernous sinus [68,69]. Manifestations of cavernous sinus thrombosis include loss of vision, internal and external ophthalmoplegia, corneal anesthesia, and facial anhidrosis [69,70]. Thrombosis of the internal carotid artery also can occur and causes contralateral hemiplegia [71,72]. The complaints of sinus symptoms, diplopia, or acute onset of blurred vision in a diabetic or immunocompromised patient should prompt careful examination for early recognition of this disease. Radiographic evaluation is needed to assess the anatomic extent of suspected disease. CT scan or MRI is best for defining the extent of infection and guiding the surgical debridement. Radiographic manifestations of rhinocerebral zygomycosis include fluid levels in or opacification of the paranasal sinuses, bone destruction, and osteomyelitis [73,74]. Pulmonary disease Most cases of pulmonary zygomycosis have occurred in profoundly neutropenic patients, such as those with hematologic malignancies or bone

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marrow transplantation and in patients on prolonged corticosteroid therapy [7,19,24,43,75]. More infrequently, pulmonary zygomycosis has been reported in patients with diabetes, renal transplantation, or HIV infection [13,20,50]. In addition, zygomycosis of the lung may occur as part of disseminated or rhinocerebral disease [15,19,76,77]. A wide variety of pulmonary manifestations exist, including solitary nodular [78,79], segmental or lobar consolidation, cavitary, and bronchopneumonic lesions [7,43]. In neutropenic patients, pulmonary zygomycosis resembles pulmonary aspergillosis. These patients present with persistent fever and pulmonary infiltrates refractory to broad-spectrum antibiotics [15,19,80]. The infection usually progresses rapidly. Chronic and spontaneously resolving lesions, however, have been reported [78,81,82]. Extensive necrosis that progresses to pulmonary vascular invasion and infarction with subsequent dissemination to both thoracic and distant extrapulmonary tissues is often seen if adequate treatment is not instituted promptly. In fact, Zygomycetes may invade directly across planes to involve the chest wall, pericardium, myocardium, superior vena cava, and diaphragm [83–85]. Cases of fatal hemoptysis associated with erosion and invasion of the pulmonary artery or aorta by the Zygomycetes also have been described [24,84–86]. Radiographic findings are varied and not specific but help localize and define the extent of disease to perform adequate diagnostic procedures [7,43]. Disseminated zygomycosis Disseminated zygomycosis is associated with an exceedingly high mortality rate, and generally occurs in severely immunocompromised patients or in patients undergoing deferoxamine therapy [15,16,18,19,34,76,87–89]. It may originate from any of the primary sites of infection [23,25,30,90]. Lung involvement is the single most common site associated with disseminated zygomycosis [15,18,19,76,77]. Diagnostic strategies in disseminated zygomycosis are directed at obtaining a biopsy of easily approachable lesions, such as skin nodules, or defining the cause of pulmonary infiltrates. Cutaneous and soft tissue zygomycosis Cutaneous and soft tissue disease may occur from primary inoculation or as a result of disseminated disease [12,29,33,40,46,91–95]. It most commonly occurs as an infection of a pre-existing lesion causing acute inflammation, tissue swelling, and pus formation and often progresses to necrosis [29,31, 33,37,39,40,91,92,94,96]. Primary cutaneous disease may be very invasive locally, involving not only cutaneous and subcutaneous tissue but also fat, muscle, fascial layers, and bone [39,48,97]. Necrotizing fasciitis may occur [98,99]. Cutaneous lesions from hematogenous seeding tend to be nodular with minimal destruction of the epidermis. They rapidly progress, however, developing an ecchymotic center [93,95,96]. The diagnosis is established by direct histopathologic examination and by fungal culture.

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Gastrointestinal zygomycosis Gastrointestinal disease is relatively uncommon. All portions of the gastrointestinal tract can be affected [11,23,27,36,100–102]. It usually presents with fungal invasion into the mucosa, submucosa, and vessels. The intestinal wall may rupture and cause peritonitis [103]. Symptoms include abdominal pain, distention, nausea, vomiting, diarrhea, fever, hematemesis, and hematochezia. The disease is often fatal. Miscellaneous zygomycosis Endocarditis caused by Zygomycetes is unusual, occurring principally in association with cardiac surgery and particularly with prosthetic valve placement [28,30,32]. The myocardial wall and pericardium can also be involved [32,90]. Infection of prosthetic valves presents with large vegetations and frequent embolizations to major arteries. Isolated cerebral zygomycosis is a rare condition occasionally reported in leukemic patients, intravenous drug abusers with and without HIV infection [16,45,50], and patients with open head trauma [104]. Isolated renal zygomycosis is very rare and almost always associated with serious underlying pathology [105,106]. Isolated peritonitis infection associated with peritoneal dialysis also has been described [107]. Laboratory diagnosis Diagnosis of zygomycosis relies on direct morphologic identification of mycotic elements and recovery of Zygomycetes in culture from specimens obtained on the site of presumed involvement. Examination of wet mounts of sputum, paranasal sinuses secretions, or bronchoalveolar lavage is frequently negative [75]. The recovery of Zygomycetes from these specimens, however, should not be dismissed as a contaminant [24,108,109]. Rather, it should be considered a strong evidence for invasive zygomycosis particularly in the setting of suggestive clinical evidences of disease in susceptible hosts who poorly tolerate more invasive diagnostic procedures. Blood cultures or urine cultures are rarely positive [15]. More invasive diagnostic tests include radiographically guided fine-needle aspirates of approachable lesions in deep tissues, transbronchial biopsies of pulmonary lesions, samples from sinus tissue biopsies or debridement, scrapings of necrotic mucocutaneous lesions, and open biopsies of deep tissue lesions. Any suspicious cutaneous lesion should undergo biopsy. These diagnostic procedures are necessary not only for diagnostic purposes but also to distinguish zygomycosis from other fungal infections (Fig. 1, Table 3). Infected specimens may exhibit broad, irregular, branching often in perpendicular angles, usually nonseptate (coenocytic) hyphae. Hyphae are often observed invading tissue and blood vessels with or without thrombosis. The recovery rate of Zygomycetes in culture is enhanced if the tissue is sliced into small pieces. This

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Fig. 1. Diagnostic algorithm of zygomycosis.

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Table 3 Morphologic and Histopathologic features of the Zygomycetes, other filamentous fungi, and Candida spp. in tissue sections Morphologic feature

Zygomycetes

Filamentous fungia

Candida spp

Fungal elements

Hyphae

Hyphae

Pseudohyphae, hyphae, and blastoconidia

Broad (15–20 lm) Nearly aseptate Irregular walls Frequently perpendicular Absent Generally absentc Present

Narrow (4–5 lm) Distinctive septa Paralleled walls Frequently acute

Narrow (2–3 lm) Distinctive septa Paralleled walls

Absent Absentb Present

Present Not applicable May be present

Hyphal characteristics Width Septations Walls Branching Blastoconidia Sporulation Angioinvasion a

Including Aspergillus spp, Fusarium spp, Pseudallescheria boydii. May be present if infected space communicates with air. c There have been reports of chlamydoconidia formation in tissue in four cases of zygomycosis. b

is an important consideration for clinicians and infectious disease specialists who need to alert the microbiologist of their clinical suspicion for proper handling of the specimen. Identification of species of Zygomycetes should be attempted whenever possible [1,2]. Treatment and prevention Successful therapy for zygomycosis involves a combined approach. As depicted in Fig. 2, it is based on early diagnosis, which leads to both prompt institution of medical therapy and extensive surgical debridement of all devitalized tissue. The overall survival rate in zygomycosis has been about 50% and in the last 10 years about 80%. This number, however, represents a composite of the proportion of different predisposing conditions, treatment approaches, and extent of zygomycotic disease influenced by the tendency to reporting successful outcomes in the last years. Nevertheless, whenever detailed retrospective analyses have been performed comparing recent zygomycosis cases and therapies with historic controls the survival rate has been improved [8,43,66,75]. The authors believe that this combined treatment approach has been mainly responsible for the improved outcome of patients affected with zygomycosis. Early diagnosis In the last two decades there has been a dramatic improvement in the diagnosis of zygomycosis. As illustrated in a report of cases that occurred in a single institution over five decades, premortem diagnosis was performed only in 22% of cases before 1970 and in 93% of cases after 1970 [110]. In

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Fig. 2. Combined approach in the treatment of zygomycosis.

fact, this shift from postmortem to premortem diagnosis allowed the prompt initiation of aggressive surgical and medical therapy and, more importantly, impacted favorably in survival after zygomycosis diagnosis (Fig. 3). Several factors facilitated premortem diagnosis of zygomycosis after 1970, including more accurate imaging studies; new techniques for performing invasive diagnostic procedures, such as bronchoscopy or radiograpy-guided biopsy procedures; identification of patient populations at risk; and improved microbiologic techniques for isolation and identification of the Zygomycetes. Later studies have determined the effect of early diagnosis in survival after zygomycosis. One large retrospective study of rhinocerebral disease showed that survival rate begins to decline when the interval between onset of symptoms referable to zygomycosis to treatment with amphotericin B or surgery was longer than 6 days [8]. These observations underscore the importance of maintaining a high level of suspicion in any patient with predisposing conditions for developing zygomycosis (Table 2). Once clinical suspicion of zygomycosis is raised, diagnosis should be attempted readily initially by noninvasive procedures followed by rapid implementation of more aggressive approaches if the initial procedures fail to demonstrate fungi (see Fig. 1). Medical therapy Reversal of the underlying predisposing condition Reversal of the metabolic disturbance. Correction of the underlying predisposing condition, when possible, is a vital component of therapy against zygomycosis. Hyperglycemia and metabolic acidosis caused by diabetic ketoacidosis or other conditions should be corrected rapidly. Several

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Fig. 3. Direct association between premortem diagnosis of zygomycosis and survival. (Adapted from Parfrey NA. Improved diagnosis and prognosis of mucormycosis: a clinicopathologic study of 33 cases. Medicine (Baltimore) 1986;65:113–23; with permission.)

laboratory and clinical observations have supported the rationale for correction of the metabolic disarrangement as an integral part of therapy. Early experimental models of rabbits with alloxan-induced diabetes have demonstrated that susceptibility to zygomycosis was highest during the acute acidotic stage [111]. In clinical grounds, there has been evidence of resolution of zygomycosis in patients whose underlying metabolic disease is controlled. For example, in a review of 145 cases of rhinocerebral zygomycosis occurring in patients with different underlying predisposing conditions, such as diabetes mellitus, renal failure, hematologic malignancies, or autoimmune diseases, the highest survival rate was noted in diabetics. The authors attributed this improved survival rate to the ability of easily reversing the underlying hyperglycemia or ketoacidosis in diabetic patients [8]. Reversal of immunosuppression. Reversal of immunosuppression is also essential for resolution of zygomycosis. In organ transplant recipients or patients with underlying malignancies, the need to treat the underlying disease and the immunosuppressive effects of such therapy often poses a therapeutic dilemma when these patients develop zygomycosis. Nevertheless, the authors favor reducing or temporarily withholding corticosteroids or other immunosuppressive drugs until the fungal infection has been brought under

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control. Several reports of invasive zygomycosis developing in patients with chemotherapy-induced neutropenia have shown that the improvement of clinical manifestations and the outcome of the infection have been related to neutrophil recovery [15,24,112,113]. It also has been shown that antifungal therapy was completely ineffective in those patients with persistent neutropenia. Recovery from neutropenia may occur spontaneously or may be promoted by hematopoietic growth factors, such as granulocyte colony– stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF). The administration of these cytokines to patients receiving myelosuppressive chemotherapy has reduced the degree and duration of neutropenia and diminished the frequency of infections [114]. G-CSF and GM-CSF have been proved not only to stimulate production of neutrophils or monocytes in patients with compromised bone marrows but also to enhance the function of these cells. In vitro and in vivo studies have indicated that monocyte-macrophages and neutrophils play a major role in host defense against filamentous fungi and that both G-CSF and GM-CSF are effective in enhancing monocyte and neutrophil activity against fungal hyphae and conidia [115]. In light of these reports, two pilot studies using GM-CSF or M-CSF in combination with amphotericin B for treatment of invasive fungal infections in patients with cancer have been conducted [116,117]. In general, cytokine therapy was well tolerated and outcomes were favorable. Candidal infection was the most prevalent mycosis in these patients and the small number of patients in both studies precluded the demonstrations of any statistical benefit of cytokine adjuvant therapy on disease-related survival. In addition to these studies, several individual reports using either G-CSF, GM-CSF, or interferon-c as adjuvant therapy for zygomycosis have been published [15,24,39,112,113,118]. In general, these reports also have shown favorable outcomes. Nevertheless, despite the potential benefit, the use of cytokines as adjuvant therapy for zygomycosis is so far anecdotal, and should be evaluated on an individual patient basis. Granulocyte transfusions have been given sporadically to neutropenic patients for the treatment of fungal infections, but evidence of efficacy in the treatment of zygomycosis is lacking [63,119] and there may be potential complications associated with this therapy [120]. Antifungal therapy Amphotericin B is the drug of choice for treatment of zygomycosis. Because the fungi exhibit relative microbiologic and clinical resistance to the drug, higher doses than usual are recommended and proved effective. Amphotericin B efficacy against Zygomycetes has been proved in both laboratory and clinical studies, whereas experience with other antifungal agents has been limited and disappointing [121,122]. The addition of other drugs, such as flucytosine, rifampin, or tetracycline, to amphotericin B to obtain synergistic antifungal activity is controversial and not recommended [6,62]. Amphotericin B remains the only reliable agent currently available for the

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treatment of zygomycosis. Doses of amphotericin B typically range from 1 to 1.5 mg/kg/d. In addition, rapid escalation of amphotericin B to full therapeutic level is essential. Daily high-dose therapy with amphotericin B should be continued for as long as possible to control the infection and facilitate surgical debridement. Duration of therapy is not clearly defined but prolonged treatment until resolution of symptoms seems prudent. The total amount of amphotericin B that should be given for zygomycosis is unknown. In most studies, a total dose of at least 2 g of amphotericin B is administered, although some patients have received up to 4 g. Therapy should be individualized according to patient’s response and underlying condition. This is particularly important in immunocompromised patients, such as those undergoing chemotherapy or immunosuppressive treatment for an underlying malignancy or a transplant. In these patients, after the infection has been brought under control, a chronic suppressive course with amphotericin B, such as alternate-day or three-times-a-week therapy, may be considered for as long as the profound immunosuppression lasts. Medical management of high-dose conventional amphotericin B therapy is often complicated by toxicity, particularly acute reactions during infusion and nephrotoxicity. In the recent literature on zygomycosis, conventional amphotericin B–related toxicity is the most common indication for therapy with lipid formulations of amphotericin B, followed only by disease progression. All lipid formulations of amphotericin B including, colloidal dispersion (ABCD), lipid complex (ABLC), and liposomal (Ambisome), have been used in the treatment of zygomycosis and in general all were associated with successful outcomes [15,25,39,43,48,62,63,77,80,106,112,113,118,123–129]. Nevertheless, the experience with amphotericin B lipid formulations in the treatment of zygomycosis remains limited. In comparisons with historic controls for the treatment of fungal infections and in few comparative studies, the lipid formulations of amphotericin B consistently seemed to be at least as active as conventional amphotericin B. In addition, they have been associated with less infusion-related toxicity and nephrotoxicity. In fact, lipid formulations of amphotericin B allowed antifungal therapy to be administered at higher dosages with acceptable tolerance up to 10 mg/kg/d. These formulations may prove to be particularly useful in allowing for large amounts of amphotericin B to be delivered to patients in a relatively short period of time. Anecdotal reports suggest that high doses of amphotericin B (ie, 15 to 20 mg/kg/d of liposomal amphotericin B or ABLC) may result in better outcomes in many invasive mycotic infections compared with maximally tolerated doses of conventional amphotericin B. In summary, lipid formulations of amphotericin B are appropriate alternatives to conventional amphotericin B and may represent a potential advance in antifungal therapy for zygomycosis. They seem to be clinically efficacious and have a favorable safety profile with less nephrotoxicity than conventional amphotericin B. Although some restrict the use of these lipid formulations of amphotericin B as a secondary alternative to conventional

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amphotericin B because of their high costs and lack of data showing superior efficacy in the treatment of zygomycosis, consideration should be given on a case-by-case basis for using these newer amphotericin B formulations as initial therapy. Local irrigation with conventional amphotericin B in nasal sinuses and orbit and intracavitary-interstitial and cerebrospinal fluid administration have been attempted; however, there are insufficient data to support these procedures [118]. Hyperbaric oxygen Hyperbaric oxygen also has potential value in the treatment of zygomycosis. Several studies have reported the successful use of hyperbaric oxygen in rhinocerebral, cutaneous, and soft tissue zygomycosis as adjunctive therapy to surgery and amphotericin B [39,40,118,130], but reporting bias makes it impossible to interpret these reports accurately. Surgical therapy Surgical debridement has remained a key feature of the management of zygomycosis. This is in part because of the difficulty in eradicating Zygomycetes with antifungal therapy from areas of tissue necrosis. All necrotic tissue should be removed when possible and repeatedly if needed; frozen section–guided debridement is preferable. There is very compelling information about the efficacy of surgical debridement in zygomycosis. As noted in several clinical studies, survival of zygomycosis in patients treated only medically was much worse than that for patients who underwent combined medical and surgical therapy [43,66,75]. Prevention of zygomycosis There are no proved therapeutic regimens for prevention of zygomycosis. Appropriate environmental control measures, careful metabolic control of the underlying condition, and judicious use of deferoxamine and corticosteroids are important factors in preventing zygomycosis. References [1] Kwon-Chung KJ, Bennett JE. Mucormycosis (physomycosis, zygomycosis). In: Medical mycology. Philadelphia: Lea & Febiger Philadelphia; 1992. p. 524–59. [2] Rinaldi MG. Zygomycosis. Infect Dis Clin North Am 1989;3:19–41. [3] Sugar AM. Agents of mucormycosis and related species. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases, vol. 2. 5th edition. Philadelphia: Churchill Livingstone; 2000. p. 2685–95. [4] Eckert HL, Khoury GH, Pore RS, et al. Deep Entomophthora phycomycosis infection reported for the first time in the United States. Chest 1972;61:392–4. [5] Walsh TJ, Renshaw G, Andrews J, et al. Invasive zygomycosis due to Conidiobolus incongruus. Clin Infect Dis 1994;19:423–30.

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[6] Rangel-Guerra R, Martinez HR, Saenz C, et al. Rhinocerebral and systemic mucormycosis: clinical experience with 36 cases. J Neurol Sci 1996;143:19–30. [7] Walsh TJ, Rinaldi MR, Pizzo PA. Zygomycosis of the respiratory tract. In: Sarosi GA, Davies SF, editors. Fungal diseases of the lung. 2nd edition. New York: Raven Press; 1993. p. 149–70. [8] Yohai RA, Bullock JD, Aziz AA, et al. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994;39:3–22. [9] Ribes JA, Vanover-Sams CL, Baker DJ. Zyogmycetes in human disease. Clin Microbiol Rev 2000;13:236–301. [10] Richardson MD, Shankland GS. Rhizopus, Rhizomucor, Absidia, and other agents of systemic and subcutaneous zygomycosis. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. 7th edition. Washington, DC: ASM Press; 1999. p. 1242–58. [11] Amin SB, Ryan RM, Metlay LA, et al. Absidia corymbifera infections in neonates. Clin Infect Dis 1998;26:990–2. [12] Bearer EA, Nelson PR, Chowers MY, et al. Cutaneous zygomycosis caused by Saksenaea vasiformis in a diabetic patient. J Clin Microbiol 1994;32:1823–4. [13] Brown RB, Johnson JH, Kessinger JM, et al. Bronchovascular mucormycosis in the diabetic: an urgent surgical problem. Ann Thorac Surg 1992;53:854–5. [14] Darrisaw L, Hanson G, Vesole DH, et al. Cunninghamella infection post bone marrow transplant: case report and review of the literature. Bone Marrow Transplant 2000; 25:1213–6. [15] Gonzalez CE, Couriel DR, Walsh TJ. Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocyte colonystimulating factor. Clin Infect Dis 1997;24:192–6. [16] Hagensee ME, Bauwens JE, Kjos B, et al. Brain abscess following bone marrow transplantation: experience at Fred Hutchinson Cancer Research Center, 1984–1992. Clin Infect Dis 1994;19:402–8. [17] Hyatt DS, Young YM, Haynes KA, et al. Rhinocerebral mucormycosis following bone marrow transplantation. J Infect 1992;24:67–71. [18] Kontoyianis DP, Vartivarian S, Anaissie EJ, et al. Infections due to Cunninghamella bertholetiae in patients with cancer: report of three cases and review. Clin Infect Dis 1994;18:925–8. [19] Kontoyianis DP, Wessel VC, Bodey GP, et al. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000;30:851–6. [20] Latif S, Saffarian N, Bellovich K, et al. Pulmonary mucormycosis in diabetic renal allograft recipients. Am J Kidney Dis 1997;29:461–4. [21] Leeming JG, Moss HA, Elliott TS. Risk of tongue depressors to the immunocompromised. Lancet 1996;348:889. [22] Mitchell SJ, Gray J, Morgan MEI, et al. Nosocomial infection with Rhizopus microsporus in preterm infants: association with wooden tongue depressors. Lancet 1996;348:441–3. [23] Mooney JE, Wanger A. Mucormycosis of the gastrointestinal tract in children: report of a case and review of the literature. Pediatr Infect Dis J 1993;12:872–6. [24] Pagano L, Ricci P, Tonso A, et al. Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. Br J Haematol 1997;99:331–6. [25] Tsaousis G, Koutsouri A, Gatsiou C, et al. Liver and brain mucormycosis in a diabetic patient type II successfully treated with liposomal amphotericin B. Scand J Infect Dis 2000;32:335–7. [26] White CB, Barcia PJ, Bass JW. Neonatal zygomycotic necrotizing cellulitis. Pediatrics 1986;78:100–2. [27] Carr EJ, Scott P, Gradon JD. Fatal gastrointestinal mucormycosis that invaded the postoperative abdominal wall wound in an immunocompetent host. Clin Infect Dis 1999;29:956–7.

910

C.E. Gonzalez et al / Infect Dis Clin N Am 16 (2002) 895–914

[28] Chaudhry R, Venugopal P, Chopra P. Prosthetic mitral valve mucormycosis caused by Mucor species. Int J Cardiol 1987;17:333–5. [29] Paparello SF, Parry RL, MacGillivray DC, et al. Hospital-acquired wound mucormycosis. Clin Infect Dis 1992;14:350–2. [30] Sanchez-Recalde A, Merino JL, Dominguez F, et al. Successful treatment of prosthetic aortic valve mucormycosis. Chest 1999;116:1818–20. [31] Vainrub B, Macareno A, Mandel S, et al. Wound zygomycosis (mucormycosis) in otherwise healthy adults. Am J Med 1988;84:546–8. [32] Virmani R, Connor DH, McAllister HA. Cardiac mucormycosis: a report of five patients and review of 14 previously reported cases. Am J Clin Pathol 1982;78:42–7. [33] Nash G, Foley FD, Goodwin MN, et al. Fungal burn wound infections. JAMA 1971; 215:1664–6. [34] Boelaert JR, Fenves AZ, Coburn JW. Deferoxamine therapy in dialysis patients: report of an international registry. Am J Kidney Dis 1991;18:660–7. [35] Cocanour CS, Miller-Crotchett P, Reed RL, et al. Mucormycosis in trauma patients. J Trauma 1992;32:12–5. [36] Eiser AR, Slifkin RF, Neff MS. Intestinal mucormycosis in hemodialysis patients following deferoxamine. Am J Kidney Dis 1987;10:71–3. [37] Kimura M, Smith MB, McGinnis MR. Zygomycosis due to Apophysomyces elegans: report of two cases and review of the literature. Arch Pathol Lab Med 1999;123:386–90. [38] Melsom SM, Khangure MS. Craniofacial mucormycosis following assault: an unusual presentation of an unusual disease. Australas Radiol 2000;44:104–6. [39] Okhuysen PC, Rex JH, Kapusta M, et al. Successful treatment of extensive posttraumatic soft-tissue and renal infections due to Apophysomyces elegans. Clin Infect Dis 1994;19: 329–31. [40] Scalise A, Barchiesi F, Viviani MA, et al. Infection due to Absidia corymbifera in a patient with a massive crush trauma of the foot. J Infect 1999;38:191–2. [41] Belin L. Clinical and immunological data on ‘‘wood trimmer’s disease’’ in Sweden. Eur J Respir Dis 1980;107:169–76. [42] Goldstein MF, Dvorin DJ, Dunsky EH, et al. Allergic Rhizomucor sinusitis. J Allergy Clin Immunol 1992;90:394–404. [43] Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med 1999;159:1301–9. [44] Wimander K, Belin L. Recognition of allergic alveolitis in the trimming department of a Swedish sawmill. Eur J Respir Dis 1980;107:163–7. [45] Hopkins RJ, Rothman M, Fiore A, et al. Cerebral mucormycosis associated with intravenous drug use: three case reports and review. Clin Infect Dis 1994;19:1133–7. [46] Jain JK, Markowitz A, Khilanani PV. Localized mucormycosis following intramuscular corticosteroid: case report and review of the literature. Am J Med Sci 1978; 275:209–16. [47] Mead JH, Lupton GP, Dillavou CL, et al. Cutaneous Rhizopus infection: occurrence as a postoperative complication associated with an elasticized adhesive dressing. JAMA 1979; 242:272–4. [48] Meis JF, Kullberg BJ, Pruszczynski M, et al. Severe osteomyelitis due to the zygomycete Apophysomyces elegans. J Clin Microbiol 1994;32:3078–81. [49] Verweij PE, Voss A, Donnelly JP, et al. Wooden sticks as a source of a pseudoepidemic of infection with Rhizopus microsporus var rhizopodiformis among immunocompromised patients. J Clin Microbiol 1997;35:2422–3. [50] Nagy-Agren SE, Chu P, Smith GJ, et al. Zygomycosis (mucormycosis) and HIV infection: report of three cases and review. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 10:441–9. [51] Radner AB, Witt MD, Edwards JE. Acute invasive rhinocerebral zygomycosis in an otherwise healthy patient: case report and review. Clin Infect Dis 1995;20:163–6.

C.E. Gonzalez et al / Infect Dis Clin N Am 16 (2002) 895–914

911

[52] Solano T, Atkins B, Tambosis E, et al. Disseminated mucormycosis due to Saksenaea vasiformis in an immunocompetent adult. Clin Infect Dis 2000;30:942–3. [53] Weinberg WG, Wade BH, Cierny G, et al. Invasive infection due to Apophysomyces elegans in immunocompetent hosts. Clin Infect Dis 1993;17:881–4. [54] Levitz SM, Selsted ME, Ganz T, et al. In vitro killing of spores and hyphae of Aspergillus fumigatus and Rhizopus oryzae by rabbit neutrophil cationic peptides and bronchoalveolar macrophages. J Infect Dis 1986;154:483–9. [55] Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982;69:617–31. [56] Diamond RD, Clark RA. Damage to Aspergillus fumigatus and Rhizopus oryzae hyphae by oxydative and nonoxidative microbicidal products of human neutrophils in vitro. Infect Immunol 1982;38:487–95. [57] Espinoza CG, Halkias DG. Pulmonary zygomycosis as a complication of chronic salicilate poisoning. Am J Clin Pathol 1983;80:508–11. [58] Lewis LL, Hawkins HK, Edwards MS. Disseminated mucormycosis in an infant with methylmalonic aciduria. Pediatr Infect Dis J 1990;9:851–4. [59] Chinn RYW, Diamond RD. Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immunol 1982;38: 1123–9. [60] Baldwin DA, De Sousa DM, Von Wandruszka RM. The effect of pH on the kinetics of iron release from human transferrin. Biochim Biophys Acta 1982;719:140–6. [61] Boelaert JR, de Locht M, Van Cutsem J, et al. Mucormycosis during deferoxamine therapy is a siderophore mediated infection: in vitro and in vivo animal studies. J Clin Invest 1993;91:1979–86. [62] Nenoff P, Kellermann S, Schober R, et al. Rhinocerebral mucormycosis following bone marrow transplantation in chronic myelogenous leukemia: report of a case and review of the literature. Mycoses 1998;41:365–72. [63] Penalver FJ, Romero R, Fores R, et al. Rhinocerebral mucormycosis following donor leukocyte infusion: successful treatment with liposomal amphotericin B and surgical debridement. Bone Marrow Transplant 1998;22:817–8. [64] Goodnight J, Dulguerov P, Abemayor E. Calcified Mucor fungus ball of the maxillary sinus. Am J Otolaryngol 1993;14:209–10. [65] Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol Clin North Am 2000;33:349–65. [66] Blitzer A, Lawson W, Meyers BR, et al. Patient survival factors in paranasal sinus mucormycosis. Laryngoscope 1980;90:635–48. [67] Humphry RC, Wright G, Rich WJ, et al. Acute proptosis and blindness in a patient with orbital phycomycosis. J R Soc Med 1989;82:304–5. [68] Gokcil Z, Odabasi Z, Kutukcu Y, et al. Rhino-orbito-cerebral mucormycosis. Neurology 1998;245:689–90. [69] Onerci M, Gursel B, Hosal S, et al. Rhinocerebral mucormycosis with extension to the cavernous sinus: a case report. Rhinology 1991;29:321–4. [70] Van Johnson E, Kline LB, Julian BA, et al. Bilateral cavernous sinus thrombosis due to mucormycosis. Arch Ophthalmol 1988;106:1089–92. [71] Anaissie EJ, Shikhani AH. Rhinocerebral mucormycosis with internal carotid occlusion: report of two cases and review of the literature. Laryngoscope 1985;95:1107–13. [72] Galetta SL, Wulc AE, Goldberg HI, et al. Rhinocerebral mucormycosis: management and survival after carotid occlusion. Ann Neurol 1990;28:103–7. [73] Press GA, Weindling SM, Hesselink JR, et al. Rhinocerebral mucormycosis: MR manifestations. J Comput Assist Tomogr 1988;12:744–9.

912

C.E. Gonzalez et al / Infect Dis Clin N Am 16 (2002) 895–914

[74] Terk MR, Underwood DJ, Zee CS, et al. MR imaging in rhinocerebral and intracranial mucormycosis with CT and pathological correlation. Magn Reson Imaging 1992;10: 81–7. [75] Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994;57:1044–50. [76] Ingram CW, Sennesh J, Cooper JN, et al. Disseminated zygomycosis: report of four cases and review. Rev Infect Dis 1989;11:741–54. [77] St-Germain G, Robert A, Ishak M, et al. Infection due to Rhizomucor pusillus: report of four cases in patients with leukemia and review. Clin Infect Dis 1993;16:640–5. [78] Gale AM, Kleitsch WP. Solitary pulmonary nodule due to phycomycosis (mucormycosis). Chest 1972;62:752–5. [79] Matsushima T, Soejima R, Nakashima T. Solitary pulmonary nodule caused by phycomycosis in a patient without obvious predisposing factors. Thorax 1980;35:877–8. [80] Mazade MA, Margolin JF, Rossmann SN, et al. Survival from pulmonary infection with Cunninghamella bertholetiae: case report and review of literature. Pediatr Infect Dis J 1998;17:835–9. [81] Hoffman RM. Chronic endobronchial mucormycosis. Chest 1987;91:469. [82] Mendoza-Ayala R, Tapia R, Salathe M. Spontaneously resolving pulmonary mucormycosis. Clin Infect Dis 1999;29:1335–6. [83] Connor BA, Anderson RJ, Smith JW. Mucor mediastinitis. Chest 1979;75:525–6. [84] Kitabayashi A, Hirokawa M, Yamaguchi A, et al. Invasive pulmonary mucormycosis with rupture of the thoracic aorta. Am J Hematol 1998;58:326–9. [85] Watts WJ. Bronchopleural fistula followed by massive fatal hemoptysis in a patient with pulmonary mucormycosis: a case report. Arch Intern Med 1983;143:1029–30. [86] Dykhuizen RS, Kerr KN, Soutar RL. Air crescent sign and fatal haemoptysis in pulmonary mucormycosis. Scand J Infect Dis 1994;26:498–501. [87] Bloxham CA, Carr S, Ryan DW, et al. Disseminated zygomycosis and systemic lupus erythematosus. Intensive Care Med 1990;16:201–7. [88] Sands JM, Macher AM, Ley TJ, et al. Disseminated infection caused by Cunninghamella bertholetiae in a patient with beta-thalassemia: case report and review of the literature. Ann Intern Med 1985;102:59–63. [89] Tsai TW, Hammond LA, Rinaldi MG, et al. Cokeromyces recurvatus infection in a bone marrow transplant recipient. Bone Marrow Transplant 1997;19:301–2. [90] Naumann R, Kerkmann ML, Schuler U, et al. Cunninghamella bertholetiae infection mimicking myocardial infarction. Clin Infect Dis 1999;29:1580–1. [91] Hammond DE, Winkelmann RK. Cutaneous phycomycosis: report of three cases with identification of Rhizopus. Arch Dermatol 1979;115:990–2. [92] Kamalam A, Thambiah AS. Cutaneous infection by Syncephalastrum. Sabouraudia 1980; 18:19–20. [93] Kramer BS, Hernandez AD, Reddick RL, et al. Cutaneous infarction: manifestation of disseminated zygomycosis. Arch Dermatol 1977;113:1075–6. [94] Leong KW, Crowley B, White B, et al. Cutaneous mucormycosis due to Absidia corymbifera occurring after bone marrow transplantation. Bone Marrow Transplant 1997; 19:513–5. [95] Meyer RD, Kaplan MH, Ong M, et al. Cutaneous lesions in disseminated mucormycosis. JAMA 1973;225:737–8. [96] Adriaenssens K, Jorens PG, Meuleman L, et al. A black necrotic skin lesion in an immunocompromised patient. Diagnosis: cutaneous mucormycosis. Arch Dermatol 2000; 136:1165–70. [97] Cefai C, Elliott TSJ, Nutton RW, et al. Zygomycetic gangrenous cellulitis. Lancet 1987;2:1337–8. [98] Lakshmi V, Rani TS, Sharma S, et al. Zygomycotic necrotizing fasciitis caused by Apophysomyces elegans. J Clin Microbiol 1993;31:1368–9.

C.E. Gonzalez et al / Infect Dis Clin N Am 16 (2002) 895–914

913

[99] Newton WD, Cramer FS, Norwood SH, et al. Necrotizing fasciitis from invasive phycomycetes. Crit Care Med 1987;15:331–2. [100] Hosseini M, Lee J. Gastrointestinal mucormycosis mimicking ischemic colitis in a patient with systemic lupus erythematosus. Am J Gastroenterol 1998;93:1360–2. [101] Pickeral JJ, Silverman JF, Sturgis CD. Gastric zygomycosis diagnosed by brushing cytology. Diagn Cytopathol 2000;23:51–4. [102] Singh N, Gayowsky T, Singh J, et al. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients. Clin Infect Dis 1995;20:617–20. [103] Munipalli B, Rinaldi MG, Greenberg SB. Cokeromyces recurvatus isolated from pleural and peritoneal fluid: a case report. J Clin Microbiol 1996;34:2601–3. [104] Dean DF, Ajello L, Irwin RS. Cranial zygomycosis caused by Saksenaea vasiformis: case report. J Neurosurg 1977;46:97–103. [105] Lussier N, Laverdiere M, Weiss K, et al. Primary renal mucormycosis. Urology 1998; 52:900–3. [106] Weng DE, Wilson WH, Little R, et al. Successful medical management of isolated renal zygomycosis: case report and review. Clin Infect Dis 1998;26:601–5. [107] Fergie JE, Fitzwater DS, Einstein P, et al. Mucor peritonitis associated with acute peritoneal dialysis. Pediatr Infect Dis J 1992;11:498–500. [108] Deshpande AH, Munshi MM. Rhinocerebral mucormycosis diagnosis by aspiration cytology. Diagn Cytopathol 2000;23:97–100. [109] Glazer M, Nusair S, Breuer R, et al. The role of BAL in the diagnosis of pulmonary mucormycosis. Chest 2000;117:279–82. [110] Parfrey NA. Improved diagnosis and prognosis of mucormycosis: a clinicopathologic study of 33 cases. Medicine (Baltimore) 1986;65:113–23. [111] Reinhardt DJ, Kaplan W, Ajello L. Experimental cerebral zygomycosis in alloxandiabetic rabbits. Infect Immunol 1970;2:404–13. [112] Leleu X, Sendid B, Fruit J, et al. Combined antifungal therapy and surgical resection as treatment of pulmonary zygomycosis in allogeneic bone marrow transplantation. Bone Marrow Transplant 1999;24:417–20. [113] Sahin B, Paydas S, Cosar E, et al. Role of granulocyte colony-stimulating factor in the treatment of mucormycosis. Eur J Clin Microbiol Infect Dis 1996;15: 866–9. [114] Antman K, Griffin J, Elias A, et al. Effect of recombinant human granulocytemacrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 1988;319:593–8. [115] Liles WC, Huang JE, Van Burik JA, et al. Granulocyte colony-stimulating factor administered in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J Infect Dis 1997;175:1012–5. [116] Bodey GP, Anaissie E, Gutterman J, et al. Role of granulocyte-macrophage colonystimulating factor as adjuvant therapy for fungal infection in patients with cancer. Clin Infect Dis 1993;17:705–7. [117] Nemunaitis J, Meyers JD, Buckner CD, et al. Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections. Blood 1991;78:907–13. [118] Gaviria JM, Grohskopf LA, Barnes R, et al. Successful treatment of rhinocerebral zygomycosis: a combined-strategy approach. Clin Infect Dis 1999;28:160–1. [119] Bhatia S, McCullough J, Perry EH, et al. Granulocyte transfusions: efficacy in treating fungal infections in neutropenic patients following bone marrow transplantation. Transfusion 1994;34:226–32. [120] Wright DG, Robichaud KJ, Pizzo PA, et al. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981; 304:1185–9.

914

C.E. Gonzalez et al / Infect Dis Clin N Am 16 (2002) 895–914

[121] Odds FC, Van Gerven F, Espinel-Ingroff A, et al. Evaluation of possible correlations between antifungal susceptibilities of filamentous fungi in vitro and antifungal treatment outcomes in animal infection models. Antimicrob Agents Chemother 1998;42:282–8. [122] Otcenasek M, Buchta V. In vitro susceptibility to 9 antifungal agents of 14 strains of zygomycetes isolated from clinical specimens. Mycopathologia 1994;128:135–7. [123] Fisher EW, Toma A, Fisher PH, et al. Rhinocerebral mucormycosis: use of liposomal amphotericin B. J Laryngol Otol 1991;105:575–7. [124] Linden P, Williams P, Chan KM. Efficacy and safety of amphotericin B lipid complex (ABLC) in solid-organ transplant recipients with invasive fungal infections. Clin Transplant 2000;14:329–39. [125] Maury S, Leblanc T, Feuilhade M, et al. Successful treatment of disseminated mucormycosis with liposomal amphotericin B and surgery in a child with leukemia. Clin Infect Dis 1998;26:200–2. [126] Moses AE, Rahav G, Barenholz Y, et al. Rhinocerebral mucormycosis treated with amphotericin B colloidal dispersion in three patients. Clin Infect Dis 1998;26:1430–3. [127] Munckhof W, Jones R, Tosolini FA, et al. Cure of Rhizopus sinusitis in a liver transplant recipient with liposomal amphotericin B. Clin Infect Dis 1993;16:183. [128] Saltoglu N, Tasova Y, Zorludemir S, et al. Rhinocerebral mucormycosis treated with liposomal amphotericin B and surgery. Mycoses 1998;41:45–9. [129] Strasser MD, Kennedy RJ, Adam RD. Rhinocerebral mucormycosis: therapy with amphotericin B lipid complex. Arch Intern Med 1996;156:337–9. [130] Ferguson BJ, Mitchell TG, Moon R, et al. Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect Dis 1988;10:551–9.