Apophysomyces elegans: epidemiology, amplified fragment length polymorphism typing, and in vitro antifungal susceptibility pattern

Apophysomyces elegans is an emerging pathogen in India. We planned the present study to analyze the clinical pattern of the disease, to perform molecular strain typing, and to determine the in vitro activities of eight antifungal drugs against A. elegans. A total of 16 clinical and two environmental A. elegans isolates were included in the study. The clinical histories of the patients were noted. MICs or minimum effective concentrations (MECs) were determined for antifungal drugs by microdilution testing in accordance with CLSI standard M38-A2 guidelines. Of 16 patients, seven had rhino-cerebral, five had cutaneous, and three had renal zygomycosis. One patient had osteomyelitis. Uncontrolled diabetes was observed in 63% of the patients. Amplified fragment length polymorphism (AFLP) analysis divided the strains into two clearly different clades. The fingerprints of the environmental strains (including the type strain) were clearly different from those of the clinical strains. The MIC50s and MIC90s for amphotericin B, itraconazole, posaconazole, and isavuconazole were 2 and 4, 1 and 2, 0.5 and 1, and 2 and 4 μg/ml, respectively. The strains had high MICs for fluconazole, voriconazole, and echinocandins. The study indicates a possible change in the clinical pattern of zygomycosis due to A. elegans in India. The fungus caused not only cutaneous or subcutaneous infection but also other deep-seated infections, and the disease is commonly associated with uncontrolled diabetes. The AFLP patterns show a clear difference between environmental and clinical strains. Posaconazole is the most active drug against the isolates, followed by itraconazole. The MICs of amphotericin B against A. elegans were higher than those of the other drugs.     

Pathology of fungal infections of the central nervous system: 17 years' experience from Southern India

Aims:  To describe the pathology of central nervous system (CNS) fungal infections with particular reference to India.
Methods and results:  This was a retrospective study from 1988 to 2004 constituting 130 cases. The diagnosis was based on morphology of biopsy/autopsy material. These included aspergillosis ( n  = 73), zygomycosis ( n  = 40), cryptococcosis ( n  = 2), rhodotorulosis ( n  = 1), candidiasis ( n  = 5), maduramycosis ( n  = 1), pheohyphomycosis ( n  = 3) and mixed infections ( n  = 5). Predisposing risk factors were present in 49 (38%) patients only. The majority of the patients were immunocompetent. The commonest risk factor was diabetes mellitus, the commonest route of infection was from a contiguous site and the commonest pathology was granuloma. Culture positivity was seen in only 31%.
Conclusion:  Environmental factors in tropical countries such as India play a significant role in the pathogenesis of CNS fungal infections.     

Cutaneous zygomycosis

The prevalence of cutaneous and soft tissue zygomycosis appears to have increased in recent years. We reviewed 78 case reports of cutaneous zygomycosis published from 2004 through 2008. Most patients with cutaneous zygomycosis have underlying conditions such as haematological malignancies, diabetes mellitus or solid organ transplantation, but a large proportion of them are immunocompetent. Trauma is the most common predisposing factor leading to zygomycosis in immunocompetent patients. If the patient is immunocompromised, the infection may disseminate. Cutaneous zygomycosis may be localized, may extend to deep underlying tissues, or may be disseminated. The most common clinical presentation is induration of the skin with surrounding erythema, rapidly progressing to necrosis. Histological examination and culture of soft tissue are important for the diagnosis of cutaneous zygomycosis. Treatment consists of surgical debridement, administration of antifungal agents (amphotericin B formulations and/or posaconazole) and, occasionally, hyperbaric oxygen. Mortality rates are approximately 30%.     

Posaconazole treatment for Apophysomyces elegans rhino-orbital zygomycosis following trauma for a male with well-controlled diabetes

We report a case of rhino-orbital zygomycosis in a 43-year-old male with well-controlled diabetes mellitus. The patient initially received liposomal amphotericin B, but the infection continued to progress, so posaconazole treatment was begun and eventually led to the cure of his infection. The causative agent was identified as Apophysomyces elegans, an emerging cause of zygomycosis in immunocompetent hosts.     

Rhino-orbitocerebral mucormycosis caused by Apophysomyces elegans

Rhino-orbitocerebral mucormycosis (ROCM) caused by more common zygomycetes (e.g., Mucor) is known to cause rapidly fatal infections in immunocompromised patients. Apophysomyces elegans is an emerging zygomycete that has been reported to cause invasive cutaneous and rhino-orbitocerebral infections in immunocompetent individuals. Limited data exist describing the syndrome of ROCM caused by A. elegans. We describe a recent case and performed a comprehensive literature review to delineate the clinical characteristics of ROCM caused by A. elegans. Our case is a 50-year-old man with diabetes mellitus who presented with facial pain and right eye proptosis. Endoscopic sinus sampling revealed A. elegans. He was treated with liposomal amphotericin B and multiple debridements, with no disease on 1.5-year follow-up examination. Seven cases were identified on literature review, including the present case. Most patients (86%) were male, with a mean age of 40 years. Most patients (71%) did not have predisposing medical conditions. Three patients had predisposing head trauma. All presented with facial and/or periorbital pain. All had magnetic resonance imaging or computed tomography of the head showing intraorbital and/or sinus inflammation. Diagnosis was confirmed by histopathology and deep tissue culture in all cases. All patients required eye exenteration and extensive surgical debridement, in addition to intravenous amphotericin B. Six of the seven patients (86%) recovered. ROCM caused by A. elegans is rarely reported in the literature. Most such infections occurred in immunocompetent patients, often after facial trauma. Survival in ROCM caused by A. elegans is favorable in reported cases, with prompt surgical debridement and antifungal therapy.     

Apophysomyces elegans: an emerging zygomycete in India

Apophysomyces elegans was considered a rare but medically important zygomycete. We analyzed the clinical records of eight patients from a single center in whom zygomycosis due to A. elegans was diagnosed over a span of 25 months. We also attempted a DNA-based method for rapid identification of the fungi and looked for interstrain polymorphism using microsattelite primers. Three patients had cutaneous and subcutaneous infections, three had isolated renal involvement, one had rhino-orbital tissue infection, and the final patient had a disseminated infection involving the spleen and kidney. Underlying illnesses were found in two patients, one with diabetes mellitus and the other with chronic alcoholism. A history of traumatic implantation was available for three patients. All except two of the patients responded to surgical and/or medical therapy; the diagnosis for the two exceptions was made at the terminal stage of infection. Restriction enzyme (MboI, MspI, HinfI) digestion of the PCR-amplified internal transcribed spacer region helped with the rapid and specific identification of A. elegans. The strains could be divided into two groups according to their patterns, with clustering into one pattern obtained by using microsatellite [(GTG)(5) and (GAC)(5)] PCR fingerprinting. The study highlights the epidemiology, clinical spectrum, and diagnosis of emerging A. elegans infections.     

Invasive zygomycosis in neonates and children

Invasive zygomycosis in neonates and children has both similarities to and differences from that in adults. We searched PubMed and individual references for English-language reports of single cases or case series of neonatal (<1 month) and paediatric (≤18 years) zygomycosis and compared the results with published results in adults. Cases were included if they fulfilled pre-specified criteria. A total of 59 cases of neonatal zygomycosis were reported to July 2007; 157 paediatric cases were published up to 2004 and an additional 30 paediatric cases were reported more recently. Prematurity was a major underlying factor among neonatal cases. The most common manifestations of zygomycosis were gastrointestinal (54%) and cutaneous (36%). This pattern differs from the sinopulmonary and rhinocerebral patterns typical in older children and adults. Overall mortality was 64% in neonates, 56% in children and 53% in adults. A tendency for dissemination was higher in neonates than adults. Dissemination and young age (<1 year) were independent risk factors for death in children. Most patients who survived received antifungal therapy. Surgery combined with antifungal therapy was a protective factor against death. Most neonates and children who survived had received an amphotericin B formulation. Zygomycosis is a life-threatening infection in children and neonates with differing patterns of involvement in individuals of different ages. The most common management strategy in survivors involved a combination of amphotericin B and surgery.     

Apophysomyces elegans - renal mucormycosis in a healthy host: a case report from south India

Zygomycosis is an opportunistic fungal infection that seldom occurs in individuals with a competent immune system. Isolated involvement of any organ is rare and only a few cases of renal zygomycosis have been reported. We present an unusual case of renal zygomycosis caused by Apophysomyces elegans in a patient with no known predisposing factor. He presented with flakes in the urine and was found to have a poorly functioning right kidney. Ureterorenoscopy was performed, fungal elements removed and pathological confirmation obtained. The patient subsequently underwent nephrectomy after treatment with amphotericin B. He made an uneventful recovery.     

Diagnostic challenge of zygomycosis in compromised hosts.

Rhinocerebral zygomycosis was classically associated with diabetes and diabetic ketoacidosis in the past. In recent years, hematological malignancies and immunocompromised states have become increasingly more frequent underlying conditions for patients with pulmonary and disseminated zygomycosis. In this study we identified 37 patients with a histopathologic diagnosis of zygomycosis and 21 patients with a positive culture for zygomycetes seen at the National Taiwan University Hospital, Taipei, during 1986-2003. Of these, 39 cases with probable or proven invasive zygomycosis were included in these studies. The major underlying diseases were immunocompromised states (74%), and diabetes mellitus (26%). The frequency of zygomycosis in immunocompromised hosts increased from 1.86 during 1986-1991 to 4.13 per 100,000 discharges during 1998-2003. Rhinocerebral involvement was the most common site (74%). An antemortem diagnosis by sinus biopsy was made in 93.1%. Immunocompromised patients were more likely to be younger than diabetics, to have an onset during hospitalization, a positive culture and a postmortem diagnosis. They were less likely than patients with diabetes to receive surgery and more likely to die in the hospital (p < 0.05). Of the 29 patients with invasive rhinocerebral zygomycosis, cerebral involvement (adjusted odds ratio [OR]: 31.7, 95% confidence interval [CI]: 2.4-426.8, p = 0.009) and positive cultures (adjusted OR: 23.8, 95% CI: 1.7-338.6, p = 0.019) were associated with in-hospital mortality by multivariate analysis. Hematological disease and steroid use have become the most important predisposing factors for zygomycosis. Aggressive diagnostic approaches, effective antifungal therapy and surgical debridement are essential for a successful outcome.     

肾移植后1年存活者空腹血糖变化及预后

背景：肾移植后糖尿病是移植脏器的重要代谢并发症,严重影响患者生活质量与长期生存率,是移植肾失功能、心血管疾病的危险因素。 目的：观察肾移植后存活1年以上患者空腹血糖变化规律以及对预后的影响。 方法：选取2003年1月至2013年1月接受过肾移植后来仙桃市第一人民医院就诊的患者42例,其中移植前糖尿病患者7例、空腹血糖受损组11例和空腹血糖正常患者24例,观察各组患者移植后1,7,14 d以及1,3,6,12个月空腹血糖变化,并比较各组移植后生存情况,采用Cox比例风险模型分析影响肾移植患者生存的因素。 结果与结论：糖尿病组患者移植前及移植后各时间段空腹血糖明显高于空腹血糖受损和空腹血糖正常组患者(P < 0.05),糖尿病、空腹血糖受损和空腹血糖正常组患者空腹血糖在移植后第1天均升高(P < 0.05),各组空腹血糖在移植后3个月趋于平稳;空腹血糖正常组生存率明显高于糖尿病组和空腹血糖受损组(P < 0.05)。Cox比例风险模型分析结果显示,移植前空腹血糖、年龄、移植后肿瘤和感染是肾移植患者死亡的独立危险因素,其中移植后发生肿瘤的死亡危险比最高,为2.376。结果证实,移植前糖尿病对肾移植后存活1年以上患者生存率有一定的影响,移植后糖尿病对患者生存率的无明显影响。  中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Apophysomyces elegans causing acute otogenic cervicofacial zygomycosis involving salivary glands.

Zygomycosis is an invasive, life threatening fungal infection that usually affects immunocompromised hosts. In the head and neck region, rhino-orbito-cerebral zygomycosis is more common than the cervicofacial variety. We report the first case of otogenic cervicofacial zygomycosis caused by Apophysomyces elegans involving the salivary glands, an uncommon site of infection. The case began after a trivial trauma in a diabetic patient and despite surgical debridement and liposomal amphotericin B therapy, the patient died due to extensive involvement and metabolic/hemodynamic complications.     

A multicentre observational study on the epidemiology,risk factors,management and outcomes of mucormycosis in India

ObjectivesTo describe the epidemiology, management and outcome of individuals with mucormycosis; and to evaluate the risk factors associated with mortality.MethodsWe conducted a prospective observational study involving consecutive individuals with proven mucormycosis across 12 centres from India. The demographic profile, microbiology, predisposing factors, management and 90-day mortality were recorded; risk factors for mortality were analysed.ResultsWe included 465 patients. Rhino-orbital mucormycosis was the most common (315/465, 67.7%) presentation followed by pulmonary (62/465, 13.3%), cutaneous (49/465, 10.5%), and others. The predisposing factors included diabetes mellitus (342/465, 73.5%), malignancy (42/465, 9.0%), transplant (36/465, 7.7%), and others. Rhizopus species (231/290, 79.7%) were the most common followed by Apophysomyces variabilis (23/290, 7.9%), and several rare Mucorales. Surgical treatment was performed in 62.2% (289/465) of the participants. Amphotericin B was the primary therapy in 81.9% (381/465), and posaconazole was used as combination therapy in 53 (11.4%) individuals. Antifungal therapy was inappropriate in 7.6% (30/394) of the individuals. The 90-day mortality rate was 52% (242/465). On multivariate analysis, disseminated and rhino-orbital (with cerebral extension) mucormycosis, shorter duration of symptoms, shorter duration of antifungal therapy, and treatment with amphotericin B deoxycholate (versus liposomal) were independent risk factors of mortality. A combined medical and surgical management was associated with a better survival.ConclusionsDiabetes mellitus was the dominant predisposing factor in all forms of mucormycosis. Combined surgical and medical management was associated with better outcomes. Several gaps surfaced in the management of mucormycosis. The rarer Mucorales identified in the study warrant further evaluation.     

Treatment of deep mycoses with liposomal amphotericin B

Amphotericin B is the mainstay of therapy of many deep mycoses, but its use is seriously hampered by dose-limiting nephrotoxicity. In this study a liposomal formulation of amphotericin B was administered to ten patients with proven deep mycoses: invasive aspergillosis (n=4), deep candidiasis (n=4) and zygomycosis (n=2). The mean daily dosage of liposomal amphotericin B was 3.0 mg/kg (range 2.5 to 4 mg/kg), the mean total dosage of liposomal amphotericin B 2,781 mg (range 87 to 5,220 mg) and the mean duration of treatment 17 days (range 3 to 33 days). Treatment with liposomal amphotericin B was associated with little nephrotoxicity and an overall survival rate of 50 %. The median increase of serum creatinine from baseline levels was 0.38 mg/dl (–1.2 to 2.6 mg/dl).     

Zygomycosis: two case reports and review of reported cases in the literature in Japan]

This article reports two cases of zygomycosis and analyzes the zygomycosis cases reported in the literature in Japan. Case 1 was a 43-year-old male with malignant lymphoma who presented complications of pneumonia and cerebral bleeding, leading to his death. Autopsy findings showed pulmonary lesions were due to zygomycosis. Cerebral lesion was presumed to be due to zygomycosis without pathological examination. Case 2 was a 52-year-old male with acute lymphocytic leukemia from whom 4 sputum cultures were taken that were positive for Cunninghamella elegans. Combination therapy of itraconazole and amphotericin B (AMPH) was begun, and AMPH was changed to liposomal amphotericin B. During the neutropenic period after receiving premedication for a peripheral blood stem cell transplantation performed for his underlying disease, high fever was recognized and Staphylococcus epidermidis was isolated from the blood culture. Despite the change in antibiotics administered, pneumonia also developed as a complication, causing his death. Two hundred four cases of zygomycosis have been reported in the literature in Japan: 55 cases were rhinocerebral zygomycosis, including 29 cases with no underlying disease. A premortem diagnosis was made in 34 cases by pathological findings of operation materials or drainage samples, and 24 cases were postmortem. Pulmonary, disseminated, cardiovascular, gastrointestinal and thyroidal zygomycoses were found in 144 cases, including 66 cases with leukemia. A premortem diagnosis was made in 39 cases and 120 cases were postmortem. Prognosis of rhinocerebral type was better in operated or drainage cases, and for resected cases in all other types. Five cases with allergic zygomycosis were all alive. There were only 14 cases in which isolated fungi were identified (Cunninghamella spp. from 5 cases, Mucor spp. from 2, Rhizomucor spp. from 2, and Rhizopus spp. from 5).     

Changing epidemiology of an emerging infection: zygomycosis

Aspergillosis and candidosis remain the most prevalent opportunistic fungal infections in immunocompromised patients, but diseases caused by the Zygomycetes have become of increasing importance. Exposure to antimycotic drugs with no activity against zygomycetes may be a new risk factor and an explanation for the increasing incidence of zygomycosis. The latter infection occurs only rarely in immunocompetent hosts, but in recent years Apophysomyces elegans has been described in many subtropical countries as an emerging pathogen causing mostly cutaneous infections after traumatic inoculation.     

Invasive cutaneous infection with Geotrichum candidum: sequential treatment with amphotericin B and voriconazole.

A rare case of an invasive cutaneous infection by Geotrichum candidum in an 80-year-old male patient with diabetes mellitus is reported. The primary site of infection manifested after trauma as an ulcerative lesion on the distal phalanx of the midfinger and extended throughout the right hand. Histological examination showed fungal invasion in the deep dermis without vascular involvement and G. candidum was grown in cultures from the biopsy material. Angiography revealed severe obstructive disease of the right brachial artery and its branches. Treatment, after susceptibility testing of the isolated strain, consisted of sequential administration of intravenous liposomal amphotericin B with oral voriconazole followed by liposomal amphotericin B, resulting in substantial improvement of the infection.     

Zygomycosis: the re-emerging fungal infection

Invasive fungal infections are major medical complications in immunocompromised patients. The recent rise in the incidence of cancer and the increased use of newer medical treatment modalities, including organ transplantations, have resulted in growing numbers of highly immunosuppressed individuals. Although aspergillosis and candidiasis are among the most common invasive mycoses in such patients, there is evidence that the incidence of infectious diseases caused by Zygomycetes has risen significantly over the past decade. Patients with diabetes, malignancies, solid organ or bone marrow transplants, or iron overload and those receiving immunosuppressive agents, deferoxamine therapy, or broad-spectrum antimicrobial drugs are at highest risk for zygomycosis. This review details the emergence and importance of zygomycosis in current clinical practice and its manifestations and management. The etiologic species, pathogenesis and risk factors for zygomycosis are reviewed and updated. The clinical spectrum of zygomycosis is now broader, and it can be difficult to distinguish between mucormycosis and enthomophthoramycosis, both of which can manifest as disease ranging from a superficial infection to an angioinvasive infection with high mortality. Finally, the three-part treatment strategy (antifungal drugs, surgery, control of underlying diseases) is reviewed. Lipid formulations of amphotericin B are the antifungal agents of choice for treatment of zygomycosis. A novel antifungal triazole, posaconazole, has been developed and may become approved for treatment of zygomycosis. The clinical experience with adjunctive treatments like colony-stimulating factors, interferon-gamma, and hyperbaric oxygen therapy is still limited.     

Clinical and mycological spectrum of cutaneous candidiasis in Bombay

A total of 150 patients with cutaneous candidiasis were studied. A detailed clinical history was taken. Scrapings were examined in 10% KOH, and the material cultured on Sabouraud's agar. Species were identified by the serum germ tube test, sugar fermentation and sugar assimilation tests. Of 150 patients 79 were females. The commonest presentation was intertrigo (75), vulvovaginitis (19) and paronychia (17). A history of chronic exposure to water was obtained in 94 cases, all had erosio interdigitalis blastomycetica and/or paronychia. Diabetes melltius as a predisposing factor was observed in 22 patients. The 10 cases of balanoposthitis had associated diabetes mellitus. Smear and culture were positive in all the patients. C. albicans was isolated in 136 cases, C. tropicalis in 12, and C. guillermondi in 2. The cultures of C. albicans had positive serum germ tube test. The 6 patients in the paediatric age group having perianal/genital involvement had a stools culture positive for C. albicans.     

Diagnosis of Disseminated Zygomycosis Using a Polymerase Chain Reaction Assay

Invasive pulmonary zygomycosis is an uncommon opportunistic infection in patients with haematological malignancies. Clinical manifestations are indistinguishable from the more frequent invasive aspergillosis. Standard diagnostic methods like culture and microscopy from respiratory secretions have a low diagnostic sensitivity. A case in which proven invasive pulmonary zygomycosis was confirmed using a panfungal polymerase chain reaction assay in blood is presented. Since zygomycosis requires more aggressive treatment than aspergillosis (high-dose amphotericin B and surgical intervention), the polymerase chain reaction assay may improve the outcome of these often fatal infections by guiding the therapeutic approach through an early, noninvasive diagnosis. Electronic Publication