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1.  Mycetoma: Experience of 482 Cases in a Single Center in Mexico 
Mycetoma is a chronic granulomatous disease. It is classified into eumycetoma caused by fungi and actinomycetoma due to filamentous actinomycetes. Mycetoma can be found in geographic areas in close proximity to the Tropic of Cancer. Mexico is one of the countries in which this disease is highly endemic. In this retrospective study we report epidemiologic, clinical and microbiologic data of mycetoma observed in the General Hospital of Mexico in a 33 year-period (1980 to 2013). A total of 482 cases were included which were clinical and microbiology confirmed. Four hundred and forty four cases (92.11%) were actinomycetomas and 38 cases (7.88%) were eumycetomas. Most patients were agricultural workers; there was a male predominance with a sex ratio of 3∶1. The mean age was 34.5 years old (most ranged from 21 to 40 years). The main affected localization was lower and upper limbs (70.74% and 14.52% respectively). Most of the patients came from humid tropical areas (Morelos, Guerrero and Hidalgo were the regions commonly reported). The main clinical presentation was as tumor-like soft tissue swelling with draining sinuses (97.1%). Grains were observed in all the cases. The principal causative agents for actinomycetoma were: Nocardia brasiliensis (78.21%) and Actinomadura madurae (8.7%); meanwhile, for eumycetomas: Madurella mycetomatis and Scedosporium boydii (synonym: Pseudallescheria boydii) were identified. This is a single-center, with long-follow up, cross-sectional study that allows determining the prevalence and characteristics of mycetoma in different regions of Mexico.
Author Summary
Mycetoma is a chronic, subcutaneous granulomatous disease that usually begins after traumatic inoculation with causative microorganisms. Based on its etiology, mycetoma is referred to eumycetoma when the infection is caused by filamentous fungi, and actinomycetoma when the infection is due to aerobic actinomycetes (in Mexico predominantly Nocardia brasiliensis). Establishing the etiology is extremely important since it impacts treatment regimens. Mycetoma typically presents around the Tropic of Cancer between latitude 15° South and 30° North (also known as “mycetoma belt”) affecting poor populations in Africa, Asia, and Latin America, including Mexico, which represents a highly endemic area with higher frequencies of actinomycetomas. Mycetoma usually affects males (male∶female ratio of 3∶1), agricultural or rural workers (age range 20–40 years) that typically do not have access to protective equipment. The main clinical presentation is as soft tissue swelling with sinus tract formation draining grains, which leads to diagnosis. The foot is the most commonly affected localization; however, when disease presents in high risk areas, such as the trunk, it can disseminate to the lungs and spinal cord. This report represents a single center study which provides epidemiologic, clinical, and microbiological data of mycetoma cases in different regions of Mexico.
PMCID: PMC4140667  PMID: 25144462
2.  Phylogenetic Findings Suggest Possible New Habitat and Routes of Infection of Human Eumyctoma 
Eumycetoma is a traumatic fungal infection in tropical and subtropical areas that may lead to severe disability. Madurella mycetomatis is one of the prevalent etiologic agents in arid Northeastern Africa. The source of infection has not been clarified. Subcutaneous inoculation from plant thorns has been hypothesized, but attempts to detect the fungus in relevant material have remained unsuccessful. The present study aims to find clues to reveal the natural habitat of Madurella species using a phylogenetic approach, i.e. by comparison of neighboring taxa with known ecology. Four species of Madurella were included in a large data set of species of Chaetomium, Chaetomidium, Thielavia, and Papulaspora (n = 128) using sequences of the universal fungal barcode gene rDNA ITS and the partial LSU gene sequence. Our study demonstrates that Madurella species are nested within the Chaetomiaceae, a family of fungi that mainly inhabit animal dung, enriched soil, and indoor environments. We hypothesize that cattle dung, ubiquitously present in rural East Africa, plays a significant role in the ecology of Madurella. If cow dung is an essential factor in inoculation by Madurella, preventative measures may involve the use of appropriate footwear in addition to restructuring of villages to reduce the frequency of contact with etiologic agents of mycetoma. On the other hand, the Chaetomiaceae possess a hidden clinical potential which needs to be explored.
Author Summary
Eumycetoma caused by Madurella mycetomatis is a common subcutaneous, mutilating fungal infection endemic in arid climate zones. Still there are many controversies on the route of infection, but traumatic inoculation of the subcutaneous tissue with the thorn or soil causative organism through minor skin trauma is a popular theory. This is due to the fact that, the origin and natural habitat of Madurella species, the prevalent mycetoma agents are still unknown. In order to predict the natural habitat of M. mycetomatis we investigated its phylogenetic relationships to species with known ecology. Two genes phylogeny based on LSU and ITS was performed for the species of the genus Madurella and representative genera from the family of Chaetomiaceae. Our findings confirmed that Madurella species are phylogenetically member of the family Chaetomiaceae. Members of this family are often found in dung and manure-enriched soil. We therefore suggest that animal dung, abundantly present in endemic villages, could be a possible niche for Madurella and plays an essential role in the onset of eumycetoma. This will help in understanding the origin of the disease and could be a base for future in depth study to investigate the presence of Madurella in dung from endemic areas.
PMCID: PMC3656121  PMID: 23696914
3.  Active Matrix Metalloprotease-9 Is Associated with the Collagen Capsule Surrounding the Madurella mycetomatis Grain in Mycetoma 
Madurella mycetomatis is the main causative organism of eumycetoma, a persistent, progressive granulomatous infection. After subcutaneous inoculation M. mycetomatis organizes itself in grains inside a granuloma with excessive collagen accumulation surrounding it. This could be contributing to treatment failure towards currently used antifungal agents. Due to their pivotal role in tissue remodelling, matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) or tissue inhibitor of metalloproteinases (TIMP) might be involved in this process. Local MMP-2 and MMP-9 expression was assessed by immunohistochemistry while absolute serum levels of these enzymes were determined in mycetoma patients and healthy controls by performing ELISAs. The presence of active MMP was determined by gelatin zymography. We found that both MMP-2 and MMP-9 are expressed in the mycetoma lesion, but the absolute MMP-2, -9, and TIMP-1 serum levels did not significantly differ between patients and controls. However, active MMP-9 was found in sera of 36% of M. mycetomatis infected subjects, whereas this active form was absent in sera of controls (P<0.0001). MMP-2, MMP-9, and TIMP-1 polymorphisms in mycetoma patients and healthy controls were determined through PCR-RFLP or sequencing. A higher T allele frequency in TIMP-1 (+372) SNP was observed in male M. mycetomatis mycetoma patients compared to controls. The presence of active MMP-9 in mycetoma patients suggest that MMP-9 is activated or synthesized by inflammatory cells upon M. mycetomatis infection. Inhibiting MMP-9 activity with doxycycline could prevent collagen accumulation in mycetoma, which in its turn might make the fungus more accessible to antifungal agents.
Author Summary
Eumycetoma, mainly caused by the fungus Madurella mycetomatis, is a chronic infection which, without treatment, results in deformation of the infected body part. Inside the body, the fungus organises itself in grains which are surrounded by collagen. This collagen could act as a natural barrier for antifungal agents. Since collagen modulation is regulated by matrix metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitors of metalloproteinases (TIMPs), these enzymes could play a role in the formation of the collagen capsule surrounding the fungal grain. Indeed, we demonstrated that MMPs were found surrounding the mycetoma grain and that measurable levels of both MMPs were found in serum of both mycetoma patients and healthy controls. Only in mycetoma patients the active form MMP-9 was found. The presence of active MMP-9 in the serum of mycetoma-patients was not the result of lower levels TIMP-1 but more likely from differences in allele frequencies in the TIMP-1 gene. In conclusion, our results showed an increased MMP-9 activity in mycetoma patients. We hypothesize that inhibition of MMP-9 activity by doxycycline will result in breakdown of the collagen capsule surrounding the grain, which in turn will make the entrance of antifungal drugs into the grain easier.
PMCID: PMC3967957  PMID: 24675764
4.  Does the Benefit of Salvage Amputation Always Outweigh Disability in Drug-Failure Mycetoma?: A Tale of Two Cases 
Indian Journal of Dermatology  2015;60(1):74-76.
It is popularly believed that eumycetoma cases should be dealt with using surgical amputation for a better chance of cure especially when chemotherapy has failed. However, amputation leads to disability on one hand and on the other it may also fail to be curative. We present two cases with contrasting treatment options and outcome. In the eumycetoma case reported here, a 40-year-old male presented with right foot swelling for 16 years, from which Scedosporium apiospermum was isolated. He responded poorly to antifungal therapy and refused below-knee amputation 12 years ago. With counseling and wound care his condition improved, and Foot and Ankle Ability Measure (FAAM) score remained almost stable at 90% for 16 years, which is much better than the average functional outcome after amputation. Another 46-year-old female underwent below-knee amputation after receiving incomplete courses of antibiotics and antifungals for mycetoma of unknown etiology. She presented to us after recurrence of mycetoma on an amputated stump and was successfully treated by proper courses of antibiotics after detecting the causal agent, Actinomadura madurae. Her post-amputation disability and depression could have been avoided if the hasty decision of amputation had not been taken. In our opinion, living with drug-non-responsive mycetoma, supported by symptomatic management, may be a better option than amputation and its associated morbidities. So before taking the path of salvage amputation, we must consider many aspects, including patient's livelihood, psychological aspects and chances of recurrence even after the procedure.
PMCID: PMC4318067  PMID: 25657401
Amputation; depression; foot and ankle Ability measure score; mycetoma
5.  Mycetoma in Iran: Causative Agents and Geographic Distribution 
Mycetoma is a chronic granulomatous disease caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma). It usually involves the subcutaneous tissue after a traumatic inoculation of the causative organism. We reviewed retrospectively 13 patients with mycetoma.
Materials and Methods:
This study reports the etiologic agents and distribution of mycetoma in 35 cases from 1994 to2009 in Iran. The diagnostic of mycetoma were confirmed by histopathology and direct preparation, culture techniques, and histopathology of granules and surgical biopsies, radiological examination of the affected site.
Mycetoma was identified in 35 patients of 168 suspected patients (20.8%). They occurred in 22 male and 13 females. Their ages ranged from 14 to 80 years. The duration of the disease ranged from two months to 38 years. Sixteen patients had eumycetoma, and 19 patients had actinomycetoma, one of them had mix infections by eumycetoma and actinomycetoma. The majority of the patients were from central and states in south and north of Iran. The feet were most affected site (65.7%) of the cases, followed by hands (25.7%), face (2.8%), and trunk (2.8%), and buttock (2.8%). Most patients (68.5%) were more than 40 year-old. The male to female ratio was 5:3. The disease was abundant among housewife in urban and farmer in rural area of Iran. The most common prevalent mycetoma agents in this study were Actinomyces sp. There was a history of risk factors in 28.6% of patients in this study.
Mycetoma occasionally occurs particularly in the South, Central, and North of Iran, and seen most often in persons, who live in hot, humid climates. If there are risk factors for invasive fungal infections traumatic inoculation with any fungus may result in rapid local spread and systemic disease, often with fatal outcome.
PMCID: PMC4171940  PMID: 25284877
Actinomycetoma; eumycetoma; fungal infections; mycetoma; subcutaneous fungal infection
6.  The Combination of Amoxicillin-Clavulanic Acid and Ketoconazole in the Treatment of Madurella mycetomatis Eumycetoma and Staphylococcus aureus Co-infection 
Eumycetoma is a chronic progressive disabling and destructive inflammatory disease which is commonly caused by the fungus Madurella mycetomatis. It is characterized by the formation of multiple discharging sinuses. It is usually treated by antifungal agents but it is assumed that the therapeutic efficiency of these agents is reduced by the co-existence of Staphylococcus aureus co-infection developing in these sinuses. This prospective study was conducted to investigate the safety, efficacy and clinical outcome of combined antibiotic and antifungal therapy in eumycetoma patients with superimposed Staphylococcus aureus infection. The study enrolled 337 patients with confirmed M. mycetomatis eumycetoma and S. aureus co-infection. Patients were allocated into three groups; 142 patients received amoxicillin-clavulanic acid and ketoconazole, 93 patients received ciprofloxacin and ketoconazole and 102 patients received ketoconazole only. The study showed that, patients who received amoxicillin-clavulanic acid and ketoconazole treatment had an overall better clinical outcome compared to those who had combined ciprofloxacin and ketoconazole or to those who received ketoconazole only. In this study, 60.6% of the combined amoxicillin-clavulanic acid/ketoconazole group showed complete or partial clinical response to treatment compared to 30.1% in the ciprofloxacin/ketoconazole group and 36.3% in the ketoconazole only group. The study also showed that 64.5% of the patients in the ciprofloxacin/ketoconazole group and 59.8% in the ketoconazole only group had progressive disease and poor outcome. This study showed that the combination of amoxicillin-clavulanic acid and ketoconazole treatment is safe and offers good clinical outcome and it is therefore recommended to treat eumycetoma patients with Staphylococcus aureus co-infection.
Author Summary
Mycetoma, a unique neglected tropical disease, is characterised by massive deformity and disability presenting with painless subcutaneous mass, multiple sinuses that produce sero-purulent discharge. Secondary bacterial infection is common in mycetoma and it is assumed that, this bacterial co-infection reduces the effectiveness of the antifungal treatment and is responsible for the poor treatment outcome. To investigate this hypothesis, this study examined the combination of Ketoconazole and antibiotics in two groups of patients with eumycetoma and Staphylococcus aureus (S. aureus) co-infection. The first group received ketoconazole and amoxicillin-clavulanic and the second group received ciprofloxacin and ketoconazole. The study also included a historical group of patients who had only ketoconazole as a control group. Patients who had amoxicillin-clavulanic acid and ketoconazole had an overall better clinical outcome and superior infection eradication compared to the two other groups. It can be concluded that the combination of amoxicillin-clavulanic acid and ketoconazole is safe treatment and offers better clinical outcome in eumycetoma patients with S. aureus co-infection.
PMCID: PMC4063734  PMID: 24945499
7.  Infections Caused by Scedosporium spp. 
Clinical Microbiology Reviews  2008;21(1):157-197.
Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.
PMCID: PMC2223844  PMID: 18202441
8.  Molecular Identification of Black-Grain Mycetoma Agents 
Journal of Clinical Microbiology  2006;44(10):3517-3523.
Black-grain mycetomas are subcutaneous devastating chronic infections due to several dematiaceous fungi. They are diagnosed mostly in tropical countries. Identification of these fungi with standard mycological procedures is difficult because of their poor or delayed sporulation. The aim of this study was thus to assess the accuracy of molecular identification of these fungi. A total of 54 strains, mostly of clinical origin, were used, including 15 Madurella mycetomatis, 6 Madurella grisea, 12 Leptosphaeria senegalensis, 4 Leptosphaeria tompkinsii, 6 Pyrenochaeta spp., 4 Curvularia lunata, and 7 Exophiala jeanselmei strains. The internal transcribed spacer 1 (ITS1)-5.8S-ITS2 DNA region was amplified by using universal fungal primers and sequenced. Both intra- and interspecies sequence similarities were assessed. Madurella mycetomatis appeared to be a homogeneous species. More intraspecies variations were found for C. lunata and E. jeanselmei, leading, in some instances, to changes in the initial identification. L. senegalensis and L. tompkinsii showed intraspecies similarities of >99%, but similarity between the two species was <88%. Intergenera and interspecies variations were important, with sequence homologies of <81% between genera. In contrast, Pyrenochaeta romeroi and M. grisea appeared to be heterogeneous, with intraspecies similarities of 40 to 100% and 53 to 100%, respectively, which suggest either erroneous identification or the need for taxonomic revision. Epidemiological and therapeutic studies could benefit from a precise identification of the fungi responsible for black-grain mycetoma based not only on phenotypical characteristics but also on ITS sequencing.
PMCID: PMC1594755  PMID: 17021076
9.  Autochthonous Cases of Mycetoma in Europe: Report of Two Cases and Review of Literature 
PLoS ONE  2014;9(6):e100590.
Mycetoma is a chronic granulomatous infection involving cutaneous and subcutaneous tissues. It is endemic in tropical and subtropical areas, but sporadic cases have been reported also in countries of temperate climate. The purpose of this paper is to review the cases of mycetoma in European subjects (and presumably acquired in Europe), to give an insight in the main factors associated with this condition, and to describe two previously unpublished cases observed at our Centre.
Methods and Findings
PubMed was systematically searched for case reports and case series of mycetoma in Europeans reported between 1980 and 2014, using specific search strategies. Two further cases diagnosed by the authors are described. Forty-two cases were collected. Eleven cases were caused by Scedosporium apiospermium, mainly in immunosuppressed patients from Bulgaria, Germany, the Netherlands, Portugal, Slovenia, Spain and the United Kingdom. Excluding all patients with immunosuppression, 29 cases remain. Most of them were reported from Bulgaria and in Albanian patients (all diagnosed outside Albania). In the Bulgarian case series many different micro-organisms, both bacteria and fungi, were isolated, while all the 5 cases from Albania were caused by Actinomadura spp. Other countries reporting cases were Greece, Italy and Turkey. In general, Actinomadura spp is the most frequent causative agent isolated, followed by Nocardia spp and Madurella mycetomatis. The foot was the most reported site involved. Most patients were medically treated, but unfortunately a long-term follow up (at least one year) was available only in a few cases.
Our review and our own cases suggest that Europeans without travel history can be affected by Madura foot. The lack of a surveillance system is likely to cause an underreporting of cases. Moreover, the unfamiliarity of Western doctors with this peculiar infection may cause a mismanagement, including unnecessary amputations.
PMCID: PMC4070928  PMID: 24963778
10.  Rapid Identification of Black Grain Eumycetoma Causative Agents Using Rolling Circle Amplification 
Accurate identification of mycetoma causative agent is a priority for treatment. However, current identification tools are far from being satisfactory for both reliable diagnosis and epidemiological investigations. A rapid, simple, and highly efficient molecular based method for identification of agents of black grain eumycetoma is introduced, aiming to improve diagnostic in endemic areas. Rolling Circle Amplification (RCA) uses species-specific padlock probes and isothermal DNA amplification. The tests were based on ITS sequences and developed for Falciformispora senegalensis, F. tompkinsii, Madurella fahalii, M. mycetomatis, M. pseudomycetomatis, M. tropicana, Medicopsis romeroi, and Trematosphaeria grisea. With the isothermal RCA assay, 62 isolates were successfully identified with 100% specificity and no cross reactivity or false results. The main advantage of this technique is the low-cost, high specificity, and simplicity. In addition, it is highly reproducible and can be performed within a single day.
Author Summary
Treatment of eumycetoma largely depends on the causative pathogen. Identification of mycetoma agent with phenotypic features is too limited, and physiological and biochemical techniques are laborious, time-consuming and nonspecific, whereas the currently available molecular methods based on DNA sequencing are specific but extremely expensive. We describe rolling circle amplification method for identification of black grain eumycetoma using species-specific padlock probes. Eight probes were designed and successfully used for species identification and the results were easily visualized in 1% agarose gel. RCA provides a simple, reproducible, and cost-effective method for rapid identification of mycetoma agent that can be used in low-resource clinical settings.
PMCID: PMC4256478  PMID: 25474355
11.  Refractory Scedosporium apiospermum Keratitis Successfully Treated with Combination of Amphotericin B and Voriconazole 
Aim. To report a case of refractory fungal keratitis caused by Scedosporium apiospermum. Methods. Interventional case report. Results. A 47-year-old Malay housewife presented with left eye cornea ulcer as her first presentation of diabetes mellitus. There was no history of ocular trauma, contact lens used, or cornea foreign body. Scedosporium apiospermum was isolated from the cornea scrapping. Her cornea ulcer initially responded well to topical Amphotericin B within 3 days but subsequently worsened. Repeat cornea scrapping also yields Scedosporium apiospermum. This refractory keratitis was successfully treated with a combination of topical Amphotericin B and Voriconazole over 6 weeks. Conclusion. Scedosporium apiospermum keratitis is an opportunistic infection, which is difficult to treat despite tight control of diabetes mellitus and intensive antifungal treatment. The infection appeared to have very quick onset but needed long duration of treatment to completely heal. Surgical debridement always plays an important role as a therapeutic procedure as well as establishes the diagnosis through repeat scrapping.
PMCID: PMC3590499  PMID: 23509650
12.  Mycetoma: Nonvenereal perineal lesions 
Mycetoma is a chronic, granulomatous disease of the skin, and subcutaneous tissue, which sometimes involves muscle, bones, and neighboring organs. It is characterized by tumefaction, abscess formation, and fistulae with discharge of grains from sinuses. Mycetoma can be caused by various species of fungi (eumycetoma) and aerobic actinomycetes (actinomycetoma), which occur as saprophytes in soil or plants. A tentative diagnosis sufficient to initiate treatment may be made on the basis of grain color. For instance, melanoid grains are always caused by fungi and ochroid or pale grains by actinomycetes. Although this is not the thumbrule, there are exceptional reports too. As trauma favors infection, most lesions are on the foot and lower leg but they may occur anywhere on the body mimicking actinomycosis. However, lab investigations and culture are important tool to differentiate apart from the clinical picture. We are reporting atypical case with unusual site of presentation (perineum and thigh) of mycetoma.
PMCID: PMC3140148  PMID: 21808436
Eumycetoma; melanoid; mycetoma
13.  Tracking the Emerging Human Pathogen Pseudallescheria boydii by Using Highly Specific Monoclonal Antibodies ▿  
Pseudallescheria boydii has long been known to cause white grain mycetoma in immunocompetent humans, but it has recently emerged as an opportunistic pathogen of humans, causing potentially fatal invasive infections in immunocompromised individuals and evacuees of natural disasters, such as tsunamis and hurricanes. The diagnosis of P. boydii is problematic since it exhibits morphological characteristics similar to those of other hyaline fungi that cause infectious diseases, such as Aspergillus fumigatus and Scedosporium prolificans. This paper describes the development of immunoglobulin M (IgM) and IgG1 κ-light chain monoclonal antibodies (MAbs) specific to P. boydii and certain closely related fungi. The MAbs bind to an immunodominant carbohydrate epitope on an extracellular 120-kDa antigen present in the spore and hyphal cell walls of P. boydii and Scedosporium apiospermum. The MAbs do not react with S. prolificans, Scedosporium dehoogii, or a large number of clinically relevant fungi, including A. fumigatus, Candida albicans, Cryptococcus neoformans, Fusarium solani, and Rhizopus oryzae. The MAbs were used in immunofluorescence and double-antibody sandwich enzyme-linked immunosorbent assays (DAS-ELISAs) to accurately differentiate P. boydii from other infectious fungi and to track the pathogen in environmental samples. Specificity of the DAS-ELISA was confirmed by sequencing of the internally transcribed spacer 1 (ITS1)-5.8S-ITS2 rRNA-encoding regions of environmental isolates.
PMCID: PMC2681584  PMID: 19321690
14.  Abdominal Wall Mycetoma Presented as Obstructed Incisional Hernia of Cesarean Section in Eastern Sudan 
Mycetoma a worldwide disease frequently occurs in the tropics with the highest prevalence being in Africa. Madurella mycetomatis is the main causative organism of human eumycetoma in Sudan. The legs and feet were commonly the sites of the infection. A 22-year-old lady was presented with painful abdominal swelling around a previous caesarian section scar. A provisional diagnosis of obstructed incisional hernia was put. Histopathological examination revealed macroscopically four masses of soft tissue. Microscopic sections showed grains of Madurella mycetomatis.
PMCID: PMC1847505  PMID: 17485822
15.  A rare case of cytomegalovirus, scedosporium apiospermum and mycobacterium tuberculosis in a renal transplant recipient 
BMC Infectious Diseases  2014;14:259.
Renal transplant recipients are at high risk of developing multiple infections, often concomitantly because of their immunocompromised status. Post renal transplant infections are often elusive and require extensive evaluation for proper diagnosis and treatment. A high index of suspicion is required and an attempt should be made to confirm the microbiological diagnosis from each site involved to rule out multiple infections.
Case presentation
We report a 50-year-old female, a renal allograft recipient who presented with left hemiplegia, esophageal ulcers and fever 3 months after her transplant. Esophageal biopsy revealed Cytomegalovirus (CMV) inclusions and the whole blood quantitative CMV polymerase chain reaction (PCR) was positive. Neuroimaging showed a brain abscess, stereotactic biopsy from which revealed Scedosporium apiospermum on fungal culture. Her tacrolimus and mycophenolate were stopped and she was managed with intravenous ganciclovir and voriconazole. With these measures, she showed marked improvement in her general and neurological condition. Two months later, she developed recurrence of fever with dry cough. Radiological investigation revealed a cavitating lung lesion, a needle aspiration from which demonstrated acid-fast bacilli. She was started on antituberculous treatment. With these measures, she recovered completely and maintained good graft function despite being on only prednisolone 10 mg once a day.
Although CMV disease is not uncommon in the first three months post transplant, Scedosporium is a rare cause of brain abscess. On the other hand, tuberculosis is common in transplant recipients, especially in developing countries, like India. However, this is the first case report of occurrence of these three infections in the same patient, demonstrating the importance of a good microbiological work-up from each site involved in immunosuppressed subjects.
PMCID: PMC4032160  PMID: 24885965
Cytomegalovirus; Scedosporium apiospermum; Renal transplant; Brain abscess; Post transplant tuberculosis
16.  Monoclonal Antibodies Against Peptidorhamnomannans of Scedosporium apiospermum Enhance the Pathogenicity of the Fungus 
Scedosporium apiospermum is part of the Pseudallescheria-Scedosporium complex. Peptidorhamnomannans (PRMs) are cell wall glycopeptides present in some fungi, and their structures have been characterized in S. apiospermum, S. prolificans and Sporothrix schenckii. Prior work shows that PRMs can interact with host cells and that the glycopeptides are antigenic. In the present study, three monoclonal antibodies (mAbs, IgG1) to S. apiospermum derived PRM were generated and their effects on S. apiospermum were examined in vitro and in vivo. The mAbs recognized a carbohydrate epitope on PRM. In culture, addition of the PRM mAbs increased S. apiospermum conidia germination and reduced conidial phagocytosis by J774.16 macrophages. In a murine infection model, mice treated with antibodies to PRM died prior to control animals. Thus, PRM is involved in morphogenesis and the binding of this glycopeptide by mAbs enhanced the virulence of the fungus. Further insights into the effects of these glycopeptides on the pathobiology of S. apiospermum may lead to new avenues for preventing and treating scedosporiosis.
Author Summary
The incidence of fungal infections has increased dramatically over the last 50 years, largely because of the increasing size of the population at risk, which especially includes immunocompromised hosts. Scedosporium apiospermum is a filamentous fungus that causes a variety of infections, ranging from localized disease to life-threatening disseminated infections. Glycoproteins are molecules present in the fungal surface and are comprised of carbohydrate and protein components. They are involved in different important functions in the fungal cell. Monoclonal antibodies can be used as therapeutic agents for infectious disease, but some factors involved in their efficacy are often not well understood. We found that monoclonal antibodies to glycoproteins present in fungal surface can be nonprotective and can even enhance the disease. The administration of these antibodies can affect functions of the fungal cell and the immune cells, resulting in a survival advantage for the fungus during interactions with the host.
PMCID: PMC2957425  PMID: 20976055
17.  Clinical and morphologic findings in disseminated Scedosporium apiospermum infections in immunocompromised patients 
Scedosporium apiospermum is a ubiquitous, saprophytic, filamentous mold that may cause localized, subcutaneous infections in immunocompetent hosts, but disseminated infection in severely immunocompromised patients. This mold is often highly resistant to multiple commonly used antifungal drugs. Even with treatment, there is a high mortality rate. We present two patients with fatal disseminated S. apiospermum infections after bone marrow and lung transplantation. This infection can be rapidly fatal, and survival may be improved by early recognition.
PMCID: PMC4059584  PMID: 24982580
18.  Treatment of Scedosporiosis with Voriconazole: Clinical Experience with 107 Patients▿  
The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with >98% of those responding receiving ≥28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P = 0.0259) and were more likely to die from fungal infection (P = 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC50, 0.25 μg/ml) than for S. prolificans-infected patients (40% response; MIC50, 4.0 μg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated.
PMCID: PMC2346616  PMID: 18212110
19.  Global Burden of Human Mycetoma: A Systematic Review and Meta-analysis 
Mycetoma is a chronic infectious disease of the subcutaneous tissue with a high morbidity. This disease has been reported from countries between 30°N and 15°S since 1840 but the exact burden of disease is not known. It is currently unknown what the incidence, prevalence and the number of reported cases per year per country is. In order to estimate what the global burden of mycetoma is, a meta-analysis was performed. In total 50 studies were included, which resulted in a total of 8763 mycetoma cases. Most cases were found in men between 11 and 40 years of age. The foot was most commonly affected. Most cases were reported from Mexico, Sudan and India. Madurella mycetomatis was the most prevalent causative agent world-wide, followed by Actinomadura madurae, Streptomyces somaliensis, Actinomadura pelletieri, Nocardia brasiliensis and Nocardia asteroides. Although this study represents a first indication of the global burden on mycetoma, the actual burden is probably much higher. In this study only cases reported to literature could be used and most of these cases were found by searching archives from a single hospital in a single city of that country. By erecting (inter)national surveillance programs a more accurate estimation of the global burden on mycetoma can be obtained.
Author Summary
Mycetoma is a chronic infection resulting in large masses of the subcutaneous tissue of mainly the foot. It can be caused by bacteria or fungi. Treatment for most mycetoma cases is poor and amputations are common. Although this disease was already described almost 200 years ago, it is currently not known how many people over the globe actually suffer from this disease and which countries are mostly affected. These data are useful because they can be used to concentrate medical help in places where it is really needed and to focus to search on new medication on the most common causative agents. Since mycetoma is not a reportable disease, a meta-analysis was performed based from reports in literature, in order to estimate what the global burden of mycetoma is. In total 8763 mycetoma cases were analysed. It appeared that most cases were reported from Mexico, Sudan and India and that the fungus Madurella mycetomatis was the most prevalent causative agent world-wide. Although this study represents a first indication of the global burden on mycetoma, the actual burden is probably much higher. By erecting (inter)national surveillance programs a more accurate estimation of the global burden on mycetoma can be obtained.
PMCID: PMC3820768  PMID: 24244780
20.  New Species of Madurella, Causative Agents of Black-Grain Mycetoma 
Journal of Clinical Microbiology  2012;50(3):988-994.
A new species of nonsporulating fungus, isolated in a case of black-grain mycetoma in Sudan, is described as Madurella fahalii. The species is characterized by phenotypic and molecular criteria. Multigene phylogenies based on the ribosomal DNA (rDNA) internal transcribed spacer (ITS), the partial β-tubulin gene (BT2), and the RNA polymerase II subunit 2 gene (RPB2) indicate that M. fahalii is closely related to Madurella mycetomatis and M. pseudomycetomatis; the latter name is validated according to the rules of botanical nomenclature. Madurella ikedae was found to be synonymous with M. mycetomatis. An isolate from Indonesia was found to be different from all known species based on multilocus analysis and is described as Madurella tropicana. Madurella is nested within the order Sordariales, with Chaetomium as its nearest neighbor. Madurella fahalii has a relatively low optimum growth temperature (30°C) and is less susceptible to the azoles than other Madurella species, with voriconazole and posaconazole MICs of 1 μg/ml, a ketoconazole MIC of 2 μg/ml, and an itraconazole MIC of >16 μg/ml. Since eumycetoma is still treated only with azoles, correct species identification is important for the optimal choice of antifungal therapy.
PMCID: PMC3295137  PMID: 22205798
21.  Infection with Scedosporium apiospermum and S. prolificans, Australia 
Emerging Infectious Diseases  2007;13(8):1170-1177.
S. prolificans has become a major pathogen in immunocompromised patients.
Scedosporium apiospermum and S. prolificans are fungi of increasing clinical importance, particularly in persons with underlying diseases. We reviewed the records of 59 patients in Australia from whom Scedosporium spp. were isolated from June 30, 1997, through December 31, 2003. S. apiospermum was isolated predominantly from the respiratory tracts of 28 of 31 patients with underlying lung diseases and resulted in 2 infections and 1 death. The annual number of S. apiospermum isolates remained constant. S. prolificans was isolated from 28 patients only after November 1999. Eight patients with acute myeloid leukemia or hematopoietic stem cell transplants had invasive infection; 4 had fungemia and 6 died from infection. S. prolificans caused locally invasive infection in 2 immunocompetent patients and was found in the respiratory tract of 18 patients with underlying respiratory disease but did not cause fungemia or deaths in these patients. Scedosporium spp. showed distinct clinical and epidemiologic features.
PMCID: PMC2828065  PMID: 17953087
Scedosporium prolificans; Scedosporium apiospermum; Australia; immunocompetence; immunocompromised host; fungemia; respiratory tract colonization; stem cell transplantation; organ transplantation; research
22.  Resolving the polyphyletic nature of Pyricularia (Pyriculariaceae) 
Studies in Mycology  2014;79:85-120.
Species of Pyricularia (magnaporthe-like sexual morphs) are responsible for major diseases on grasses. Pyricularia oryzae (sexual morph Magnaporthe oryzae) is responsible for the major disease of rice called rice blast disease, and foliar diseases of wheat and millet, while Pyricularia grisea (sexual morph Magnaporthe grisea) is responsible for foliar diseases of Digitaria. Magnaporthe salvinii, M. poae and M. rhizophila produce asexual spores that differ from those of Pyricularia sensu stricto that has pyriform, 2-septate conidia produced on conidiophores with sympodial proliferation. Magnaporthe salvinii was recently allocated to Nakataea, while M. poae and M. rhizophila were placed in Magnaporthiopsis. To clarify the taxonomic relationships among species that are magnaporthe- or pyricularia-like in morphology, we analysed phylogenetic relationships among isolates representing a wide range of host plants by using partial DNA sequences of multiple genes such as LSU, ITS, RPB1, actin and calmodulin. Species of Pyricularia s. str. belong to a monophyletic clade that includes all P. oryzae/P. grisea isolates tested, defining the Pyriculariaceae, which is sister to the Ophioceraceae, representing two novel families. These clades are clearly distinct from species belonging to the Gaeumannomyces pro parte/Magnaporthiopsis/Nakataea generic complex that are monophyletic and define the Magnaporthaceae. A few magnaporthe- and pyricularia-like species are unrelated to Magnaporthaceae and Pyriculariaceae. Pyricularia oryzae/P. grisea isolates cluster into two related clades. Host plants such as Eleusine, Oryza, Setaria or Triticum were exclusively infected by isolates from P. oryzae, while some host plant such as Cenchrus, Echinochloa, Lolium, Pennisetum or Zingiber were infected by different Pyricularia species. This demonstrates that host range cannot be used as taxonomic criterion without extensive pathotyping. Our results also show that the typical pyriform, 2-septate conidium morphology of P. grisea/P. oryzae is restricted to Pyricularia and Neopyricularia, while most other genera have obclavate to more ellipsoid 2-septate conidia. Some related genera (Deightoniella, Macgarvieomyces) have evolved 1-septate conidia. Therefore, conidium morphology cannot be used as taxonomic criterion at generic level without phylogenetic data. We also identified 10 novel genera, and seven novel species. A re-evaluation of generic and species concepts within Pyriculariaceae is presented, and novelties are proposed based on morphological and phylogenetic data.
PMCID: PMC4255532  PMID: 25492987
Magnaporthaceae; Magnaporthe; Pyricularia; Pyriculariaceae; Phylogeny; Systematics
23.  Human Phagocytic Cell Responses to Scedosporium apiospermum (Pseudallescheria boydii): Variable Susceptibility to Oxidative Injury  
Infection and Immunity  2003;71(11):6472-6478.
Scedosporium apiospermum (Pseudallescheria boydii) is an emerging opportunistic filamentous fungus that causes serious infections in both immunocompetent and immunocompromised patients. To gain insight into the immunopathogenesis of infections due to S. apiospermum, the antifungal activities of human polymorphonuclear leukocytes (PMNs), mononuclear leukocytes (MNCs), and monocyte-derived macrophages (MDMs) against two clinical isolates of S. apiospermum were evaluated. Isolate SA54A was amphotericin B resistant and was the cause of a fatal disseminated infection. Isolate SA1216 (cultured from a successfully treated localized subcutaneous infection) was susceptible to amphotericin B. MDMs exhibited similar phagocytic activities against conidia of both isolates. However, PMNs and MNCs responded differently to the hyphae of these two isolates. Serum opsonization of hyphae resulted in a higher level of superoxide anion (O2−) release by PMNs in response to SA54A (amphotericin B resistant) than that seen in response to SA1216 (amphotericin B susceptible; P < 0.001). Despite this increased O2− production, PMNs and MNCs induced less hyphal damage to SA54A than to SA1216 (P < 0.001). To investigate the potential mechanisms responsible for these differences, hyphal damage was evaluated in the presence of antifungal oxidative metabolites as well as in the presence of a series of inhibitors and scavengers of antifungal PMN function. Mannose, catalase, superoxide dismutase, dimethyl sulfoxide, and heparin had no effect on PMN-induced hyphal damage to either of the two isolates. However, azide, which inhibits PMN myeloperoxidase activity, significantly reduced hyphal damage to SA1216 (P < 0.01) but not to SA54A. Hyphae of SA1216 were slightly more susceptible to oxidative pathway products, particularly HOCl, than those of SA54A. Thus, S. apiospermum is susceptible to antifungal phagocytic function to various degrees. The selective inhibitory pattern of azide with respect to hyphal damage and the parallel susceptibility to HOCl suggests an important difference in susceptibilities to myeloperoxidase products that may be related to the various levels of pathogenicity and amphotericin B resistance of S. apiospermum.
PMCID: PMC219606  PMID: 14573669
24.  Molecular Phylogeny of the Pseudallescheria boydii Species Complex: Proposal of Two New Species†  
Journal of Clinical Microbiology  2005;43(10):4930-4942.
Pseudallescheria boydii (anamorph Scedosporium apiospermum) is the species responsible for human scedosporiosis, a fungal infection with a high mortality rate and which is difficult to treat. Recently, it has been demonstrated that high genetic variation exists within this species. We have performed a morphological and molecular study involving numerous strains of clinical or environmental origins and from different countries. The analysis of partial sequences of the β-tubulin (two loci) and calmodulin genes and the internal transcribed spacer region of the rRNA gene has demonstrated that P. boydii is a species complex. The combined analysis of the sequences of the four loci of 60 strains has showed the presence of 44 haplotypes in the ingroup. Three species morphologically related to P. boydii sensu stricto, i.e., Pseudallescheria angusta, Pseudallescheria ellipsoidea, and Pseudallescheria fusoidea, which had previously been considered synonyms, could be differentiated genetically from P. boydii in our study. It is relevant that two of the three strains now included in P. ellipsoidea have caused invasive infections. The species Pseudallescheria minutispora and Scedosporium aurantiacum are clearly phylogenetically separated from the other species studied and are here proposed as new. Morphological features support this proposal. All the strains included in S. aurantiacum species have a clinical origin, while those included in P. minutispora are environmental. Further studies are needed to demonstrate whether all the species included in the P. boydii complex have different clinical spectra and antifungal susceptibility.
PMCID: PMC1248451  PMID: 16207945
25.  Diabetic Foot Ulcer Due to Scedosporium Apiospermum 
We report a case of diabetic foot ulcer caused by Scedosporium apiospermum in a seventy year old male patient with uncontrolled diabetes. Scedosporium apiospermum, the asexual phase of Pseudallescheria boydii a fungus isolated from a variety of natural substrates throughout the world including soil, polluted water, sewage and manure of poultry and cattle. P.boydii is now recognized as a medically important opportunistic fungus. This case has been reported for its rarity.
PMCID: PMC3879857  PMID: 24392407
Scedosporium apiospermum; Diabetic foot; Pseudoallescheria boydii

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