Eumycetoma is a chronic debilitating fungal disease endemic to tropical and subtropical regions, ... more Eumycetoma is a chronic debilitating fungal disease endemic to tropical and subtropical regions, with Sudan featuring the highest eumycetoma incidence. Among the 50 species of fungi most commonly associated with eumycetoma Madurella mycetomatis (M. mycetomatis) is often referenced as the most common pathogen. However, there is an enormous knowledge gap related to this neglected disease and its pathogenesis, epidemiological features, and host-specific factors that could contribute to either the host susceptibility and resistance. In this study, we were able to utilize a metagenomic approach and samples collected from clinical black grains (BG) and familiar household environments aimed to assay both the habitat of eumycetoma-associated fungi and its possible connection with eumycetoma patients living in two different eumycetoma endemic villages within the White Nile State of Sudan. DNA sequencing targeting the fungal ITS2 domain was performed on soil, animal dung, housing walls and ro...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Species of the genus Microascus are uncommon agents of human diseases despite their ubiquitous pr... more Species of the genus Microascus are uncommon agents of human diseases despite their ubiquitous presence in the environment. In this communication, the first case of white grain eumycetoma caused by the fungus Microascus gracilis is reported. The patient was initially misdiagnosed as having actinomycetoma based on the grains morphological and cytological features and was treated with antimicrobial therapy with no clinical improvement. She underwent wide local surgical excision to improve the response to medical treatment and further grain cultural, molecular and taxonomy techniques were conducted and the diagnosis of mycetoma due to M. gracilis was established. The antifungal susceptibilities of this isolate to nine drugs were tested in vitro and they showed poor activity. Combination therapy with surgery and itraconazole led to complete recovery. A medical literature search revealed no previous report on M. gracilis as a causative agent of eumycetoma and hence we are reporting this ...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Background Mycetoma is a chronic granulomatous inflammatory disease that affects the cutaneous an... more Background Mycetoma is a chronic granulomatous inflammatory disease that affects the cutaneous and subcutaneous tissues, leading to gruesome complications if not treated early. As a neglected disease, it has received scant attention in developing curable drugs. Mycetoma treatment is still based on expert opinions in the absence of guidelines. Methods This descriptive, cross-sectional, hospital-based study aimed to determine and assess the disease treatment outcomes observed at Mycetoma Research Center, Sudan. Results In this study, 75% of patients had eumycetoma, all of whom were treated with itraconazole and 37.4% underwent surgical excision, while 25% of the patients had actinomycetoma, 99.2% of whom were treated with a combination of cotrimoxazole and amoxicillin-clavulanate. The cure rate was 12.7% and 14.3% for patients with eumycetoma and actinomycetoma, respectively. Only 6.1% of eumycetoma patients underwent amputation. Remarkably, no patient with actinomycetoma underwent an...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Mycetoma recently had gained international attention and conscious awareness after its inclusion ... more Mycetoma recently had gained international attention and conscious awareness after its inclusion under the WHO/NTD list in 2016. The journey to achieve that was both long, challenging as well as it was exciting and hard. In this article, the milestones and various events that took place in this journey were documented and highlighted.
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2021
Mycetoma is a chronic granulomatous disease that significant affects the subcutaneous tissue and ... more Mycetoma is a chronic granulomatous disease that significant affects the subcutaneous tissue and deep structures. Mycetoma is caused by certain fungi (eumycetoma) or higher bacteria (actinomycetoma). The clinical presentation is variable and depends on the causative agent. For proper treatment and patient management, an accurate diagnosis of the species is mandatory. The disease mainly involves the extremities and it is rarely seen in the head and neck or other sites. In this communication, we present an interesting case of both invasive and aggressive mastoid bone eumycetoma caused by Madurella mycetomatis. Such cases are defied by complex challenges in finding effective surgical and medical treatments when the patient does not respond to both prolonged and different antifungal therapies.
Eumycetoma is a neglected tropical disease, and Madurella mycetomatis, the most common causative ... more Eumycetoma is a neglected tropical disease, and Madurella mycetomatis, the most common causative agent of this disease forms black grains in hosts. Melanin was discovered to be one of the constituents in grains. Melanins are hydrophobic, macromolecular pigments formed by oxidative polymerisation of phenolic or indolic compounds. M. mycetomatis was previously known to produce DHN-melanin and pyomelanin in vitro. These melanin was also discovered to decrease M. mycetomatis’s susceptibility to antifungals itraconazole and ketoconazole in vitro. These findings, however, have not been confirmed in vivo. To discover the melanin biosynthesis pathways used by M. mycetomatis in vivo and to determine if inhibiting melanin production would increase M. mycetomatis's susceptibility to itraconazole, inhibitors targeting DHN-, DOPA- and pyomelanin were used. Treatment with DHN-melanin inhibitors tricyclazole, carpropamid, fenoxanil and DOPA-melanin inhibitor glyphosate in M. mycetomatis infect...
Mycetoma is a neglected tropical chronic granulomatous inflammatory disease of the skin and subcu... more Mycetoma is a neglected tropical chronic granulomatous inflammatory disease of the skin and subcutaneous tissues. More than 70 species with a broad taxonomic diversity have been implicated as agents of mycetoma. Understanding the full range of causative organisms and their antibiotic sensitivity profiles are essential for the appropriate treatment of infections. The present study focuses on the analysis of full genome sequences and antibiotic resistance profiles of actinomycetoma strains from patients seen at the Mycetoma Research Centre in Sudan with a view to developing rapid diagnostic tests. Seventeen pathogenic isolates obtained by surgical biopsies were sequenced using MinION and Illumina methods, and their antibiotic resistance profiles determined. The results highlight an unexpected diversity of actinomycetoma causing pathogens, including three Streptomyces isolates assigned to species not previously associated with human actinomycetoma and one new Streptomyces species. Thus...
Background: Eumycetoma is a debilitating chronic subcutaneous granulomatous disease, endemic in S... more Background: Eumycetoma is a debilitating chronic subcutaneous granulomatous disease, endemic in Sudan and many other tropical and subtropical countries. It can be caused by eight different fungal orders and Madurella mycetomatis as the main causative species. The gold standard diagnostic test is culture, however culture-independent methods as imaging, histopathological and molecular techniques can support diagnosis, especially in case of negative cultures. Methods: Amplicon-based Internal Transcribed Spacer 2 (ITS2) metagenomic technique was used to study black grains isolated from 14 tissue biopsies from patients with mycetoma. Furthermore, grains mycological culture and surgical biopsies histopathological examination were done. Results: M. mycetomatis (n=5) and Falciformispora spp. (n=4) organisms were identified by culture and confirmed by metagenomics. Metagenomics recognised, at the species level, Falciformispora as F. tompkinsii (n=3) and F. senegalensis (n=1), while in culture-negative cases (n=5), M. mycetomatis (n=3), F. senegalensis (n=1) and Fusarium spp. (n=1) were identified. Interestingly, the metagenomics results showed a “consortium” of different fungi in each sample, mainly Ascomycota phylum, including various species associated with eumycetoma. The microbial co-occurrence in eumycetoma showed the co-presence of Madurella with Trichoderma, Chaetomium, Malasseziales and Sordariales spp. While, Falciformispora was co-presented with Inocybe and Alternaria, and mutual exclusion with Subramaniula, Aspergillus and Trichothecium. Interpretation: Metagenomics had provided new insight into the aetiology of eumycetoma in samples with negative culture. Furthermore, into diversity and complexity of grains mycobiota, and it questioned the accuracy of traditional culture for the identification of causative agents. Funding Information: This study was supported by the Italian Agency for Development 62 Cooperation (AICS) (Grants AID10821 and AID10861). Declaration of Interests: The research work of Dr. Aleksandra Barac was supported by the Ministry of Education, Science and Technology, the Republic of Serbia (No. III45005). Ethical Approval Statement: The study was approved by the Mycetoma Research Center IRB, No. 12/2018. Informed consent was obtained from each adult patient, while an assent was taken from minors (age less than 18 years) with approval of their guardian.
Introduction Mycetoma is a chronic specific, granulomatous, progressive, destructive inflammatory... more Introduction Mycetoma is a chronic specific, granulomatous, progressive, destructive inflammatory disease. It usually involves the subcutaneous tissue most probably after traumatic inoculation of the causative organism. Mycetoma may be caused by true fungi or by higher bacteria and hence it is classified as eumycetoma and actinomycetoma respectively.(1,2,3) A large variety of microorganisms from various genera and species are capable of producing mycetoma.(1,4) The triad of painless subcutaneous mass, multiple sinuses and sero-purulent discharge containing grains is pathognomic of mycetoma. It may spread to involve the skin and the deep structures resulting in destruction, deformity and loss of function. Mycetoma commonly produces various disabilities and deformities & in many cases is difficult to treat and can be fatal. (3,5)
Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it i... more Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by low cure rate and high recurrence rates. Hence, an alternative therapy is needed to address this. Here we determined the antifungal activity of seven Sudanese medicinal plant species against Madurella mycetomatis. Of these, only three species; Boswellia papyrifera, Acacia nubica and Nigella sativa, showed some antifungal activity against M. mycetomatis and were further studied. Crude methanol, hexane and defatted methanol extracts of these species were tested for their antifungal activity. B. papyrifera had the highest antifungal activity (MIC50 of 1 ug/ml) and it was further fractionated. The crude methanol and the soluble ethyl acetate fractions of B. papyrifera showed some antifungal activity. The G...
This article presents an overview of mycetoma and offers guidelines for orthopaedic surgeons who ... more This article presents an overview of mycetoma and offers guidelines for orthopaedic surgeons who may be involved in the care of patients with this condition.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2011
This prospective study aimed to determine the safety and efficacy of itraconazole for the treatme... more This prospective study aimed to determine the safety and efficacy of itraconazole for the treatment of patients with mycetoma due to Madurella mycetomatis. The study consisted of 13 patients with confirmed disease; all were treated with oral itraconazole in a dose of 400mg daily for three months after which the dose was reduced to 200mg daily for nine months. All patients showed good clinical response to 400mg itraconazole daily, but when the dose was reduced to 200mg daily, the clinical response was gradual and slow. Post-treatment surgical exploration showed that, in all patients, the lesions were well localized, encapsulated with thick capsule and they were easily removed surgically. In all these lesions, grains colonies were encountered and they were viable on culture. Post-operative biopsies showed no significant changes in the morphology of the grains. A constant finding was the presence of between 5-7 grains in a single cavity walled by fibrous tissue. The reaction surrounding the grains was a Type I tissue reaction characterized by a neutrophil zone around grains. Patients were followed up post-operatively for variable periods (range 18-36 months) and only one patient had recurrence. Initial pre-operative treatment with itraconazole may be recommended for eumycetoma patients to enhance lesions encapsulation and localization which can facilitate wide local excision to avoid unnecessary massive mutilating surgery and recurrence.
Eumycetoma is a chronic debilitating fungal disease endemic to tropical and subtropical regions, ... more Eumycetoma is a chronic debilitating fungal disease endemic to tropical and subtropical regions, with Sudan featuring the highest eumycetoma incidence. Among the 50 species of fungi most commonly associated with eumycetoma Madurella mycetomatis (M. mycetomatis) is often referenced as the most common pathogen. However, there is an enormous knowledge gap related to this neglected disease and its pathogenesis, epidemiological features, and host-specific factors that could contribute to either the host susceptibility and resistance. In this study, we were able to utilize a metagenomic approach and samples collected from clinical black grains (BG) and familiar household environments aimed to assay both the habitat of eumycetoma-associated fungi and its possible connection with eumycetoma patients living in two different eumycetoma endemic villages within the White Nile State of Sudan. DNA sequencing targeting the fungal ITS2 domain was performed on soil, animal dung, housing walls and ro...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Species of the genus Microascus are uncommon agents of human diseases despite their ubiquitous pr... more Species of the genus Microascus are uncommon agents of human diseases despite their ubiquitous presence in the environment. In this communication, the first case of white grain eumycetoma caused by the fungus Microascus gracilis is reported. The patient was initially misdiagnosed as having actinomycetoma based on the grains morphological and cytological features and was treated with antimicrobial therapy with no clinical improvement. She underwent wide local surgical excision to improve the response to medical treatment and further grain cultural, molecular and taxonomy techniques were conducted and the diagnosis of mycetoma due to M. gracilis was established. The antifungal susceptibilities of this isolate to nine drugs were tested in vitro and they showed poor activity. Combination therapy with surgery and itraconazole led to complete recovery. A medical literature search revealed no previous report on M. gracilis as a causative agent of eumycetoma and hence we are reporting this ...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Background Mycetoma is a chronic granulomatous inflammatory disease that affects the cutaneous an... more Background Mycetoma is a chronic granulomatous inflammatory disease that affects the cutaneous and subcutaneous tissues, leading to gruesome complications if not treated early. As a neglected disease, it has received scant attention in developing curable drugs. Mycetoma treatment is still based on expert opinions in the absence of guidelines. Methods This descriptive, cross-sectional, hospital-based study aimed to determine and assess the disease treatment outcomes observed at Mycetoma Research Center, Sudan. Results In this study, 75% of patients had eumycetoma, all of whom were treated with itraconazole and 37.4% underwent surgical excision, while 25% of the patients had actinomycetoma, 99.2% of whom were treated with a combination of cotrimoxazole and amoxicillin-clavulanate. The cure rate was 12.7% and 14.3% for patients with eumycetoma and actinomycetoma, respectively. Only 6.1% of eumycetoma patients underwent amputation. Remarkably, no patient with actinomycetoma underwent an...
Transactions of The Royal Society of Tropical Medicine and Hygiene
Mycetoma recently had gained international attention and conscious awareness after its inclusion ... more Mycetoma recently had gained international attention and conscious awareness after its inclusion under the WHO/NTD list in 2016. The journey to achieve that was both long, challenging as well as it was exciting and hard. In this article, the milestones and various events that took place in this journey were documented and highlighted.
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2021
Mycetoma is a chronic granulomatous disease that significant affects the subcutaneous tissue and ... more Mycetoma is a chronic granulomatous disease that significant affects the subcutaneous tissue and deep structures. Mycetoma is caused by certain fungi (eumycetoma) or higher bacteria (actinomycetoma). The clinical presentation is variable and depends on the causative agent. For proper treatment and patient management, an accurate diagnosis of the species is mandatory. The disease mainly involves the extremities and it is rarely seen in the head and neck or other sites. In this communication, we present an interesting case of both invasive and aggressive mastoid bone eumycetoma caused by Madurella mycetomatis. Such cases are defied by complex challenges in finding effective surgical and medical treatments when the patient does not respond to both prolonged and different antifungal therapies.
Eumycetoma is a neglected tropical disease, and Madurella mycetomatis, the most common causative ... more Eumycetoma is a neglected tropical disease, and Madurella mycetomatis, the most common causative agent of this disease forms black grains in hosts. Melanin was discovered to be one of the constituents in grains. Melanins are hydrophobic, macromolecular pigments formed by oxidative polymerisation of phenolic or indolic compounds. M. mycetomatis was previously known to produce DHN-melanin and pyomelanin in vitro. These melanin was also discovered to decrease M. mycetomatis’s susceptibility to antifungals itraconazole and ketoconazole in vitro. These findings, however, have not been confirmed in vivo. To discover the melanin biosynthesis pathways used by M. mycetomatis in vivo and to determine if inhibiting melanin production would increase M. mycetomatis's susceptibility to itraconazole, inhibitors targeting DHN-, DOPA- and pyomelanin were used. Treatment with DHN-melanin inhibitors tricyclazole, carpropamid, fenoxanil and DOPA-melanin inhibitor glyphosate in M. mycetomatis infect...
Mycetoma is a neglected tropical chronic granulomatous inflammatory disease of the skin and subcu... more Mycetoma is a neglected tropical chronic granulomatous inflammatory disease of the skin and subcutaneous tissues. More than 70 species with a broad taxonomic diversity have been implicated as agents of mycetoma. Understanding the full range of causative organisms and their antibiotic sensitivity profiles are essential for the appropriate treatment of infections. The present study focuses on the analysis of full genome sequences and antibiotic resistance profiles of actinomycetoma strains from patients seen at the Mycetoma Research Centre in Sudan with a view to developing rapid diagnostic tests. Seventeen pathogenic isolates obtained by surgical biopsies were sequenced using MinION and Illumina methods, and their antibiotic resistance profiles determined. The results highlight an unexpected diversity of actinomycetoma causing pathogens, including three Streptomyces isolates assigned to species not previously associated with human actinomycetoma and one new Streptomyces species. Thus...
Background: Eumycetoma is a debilitating chronic subcutaneous granulomatous disease, endemic in S... more Background: Eumycetoma is a debilitating chronic subcutaneous granulomatous disease, endemic in Sudan and many other tropical and subtropical countries. It can be caused by eight different fungal orders and Madurella mycetomatis as the main causative species. The gold standard diagnostic test is culture, however culture-independent methods as imaging, histopathological and molecular techniques can support diagnosis, especially in case of negative cultures. Methods: Amplicon-based Internal Transcribed Spacer 2 (ITS2) metagenomic technique was used to study black grains isolated from 14 tissue biopsies from patients with mycetoma. Furthermore, grains mycological culture and surgical biopsies histopathological examination were done. Results: M. mycetomatis (n=5) and Falciformispora spp. (n=4) organisms were identified by culture and confirmed by metagenomics. Metagenomics recognised, at the species level, Falciformispora as F. tompkinsii (n=3) and F. senegalensis (n=1), while in culture-negative cases (n=5), M. mycetomatis (n=3), F. senegalensis (n=1) and Fusarium spp. (n=1) were identified. Interestingly, the metagenomics results showed a “consortium” of different fungi in each sample, mainly Ascomycota phylum, including various species associated with eumycetoma. The microbial co-occurrence in eumycetoma showed the co-presence of Madurella with Trichoderma, Chaetomium, Malasseziales and Sordariales spp. While, Falciformispora was co-presented with Inocybe and Alternaria, and mutual exclusion with Subramaniula, Aspergillus and Trichothecium. Interpretation: Metagenomics had provided new insight into the aetiology of eumycetoma in samples with negative culture. Furthermore, into diversity and complexity of grains mycobiota, and it questioned the accuracy of traditional culture for the identification of causative agents. Funding Information: This study was supported by the Italian Agency for Development 62 Cooperation (AICS) (Grants AID10821 and AID10861). Declaration of Interests: The research work of Dr. Aleksandra Barac was supported by the Ministry of Education, Science and Technology, the Republic of Serbia (No. III45005). Ethical Approval Statement: The study was approved by the Mycetoma Research Center IRB, No. 12/2018. Informed consent was obtained from each adult patient, while an assent was taken from minors (age less than 18 years) with approval of their guardian.
Introduction Mycetoma is a chronic specific, granulomatous, progressive, destructive inflammatory... more Introduction Mycetoma is a chronic specific, granulomatous, progressive, destructive inflammatory disease. It usually involves the subcutaneous tissue most probably after traumatic inoculation of the causative organism. Mycetoma may be caused by true fungi or by higher bacteria and hence it is classified as eumycetoma and actinomycetoma respectively.(1,2,3) A large variety of microorganisms from various genera and species are capable of producing mycetoma.(1,4) The triad of painless subcutaneous mass, multiple sinuses and sero-purulent discharge containing grains is pathognomic of mycetoma. It may spread to involve the skin and the deep structures resulting in destruction, deformity and loss of function. Mycetoma commonly produces various disabilities and deformities & in many cases is difficult to treat and can be fatal. (3,5)
Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it i... more Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by low cure rate and high recurrence rates. Hence, an alternative therapy is needed to address this. Here we determined the antifungal activity of seven Sudanese medicinal plant species against Madurella mycetomatis. Of these, only three species; Boswellia papyrifera, Acacia nubica and Nigella sativa, showed some antifungal activity against M. mycetomatis and were further studied. Crude methanol, hexane and defatted methanol extracts of these species were tested for their antifungal activity. B. papyrifera had the highest antifungal activity (MIC50 of 1 ug/ml) and it was further fractionated. The crude methanol and the soluble ethyl acetate fractions of B. papyrifera showed some antifungal activity. The G...
This article presents an overview of mycetoma and offers guidelines for orthopaedic surgeons who ... more This article presents an overview of mycetoma and offers guidelines for orthopaedic surgeons who may be involved in the care of patients with this condition.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2011
This prospective study aimed to determine the safety and efficacy of itraconazole for the treatme... more This prospective study aimed to determine the safety and efficacy of itraconazole for the treatment of patients with mycetoma due to Madurella mycetomatis. The study consisted of 13 patients with confirmed disease; all were treated with oral itraconazole in a dose of 400mg daily for three months after which the dose was reduced to 200mg daily for nine months. All patients showed good clinical response to 400mg itraconazole daily, but when the dose was reduced to 200mg daily, the clinical response was gradual and slow. Post-treatment surgical exploration showed that, in all patients, the lesions were well localized, encapsulated with thick capsule and they were easily removed surgically. In all these lesions, grains colonies were encountered and they were viable on culture. Post-operative biopsies showed no significant changes in the morphology of the grains. A constant finding was the presence of between 5-7 grains in a single cavity walled by fibrous tissue. The reaction surrounding the grains was a Type I tissue reaction characterized by a neutrophil zone around grains. Patients were followed up post-operatively for variable periods (range 18-36 months) and only one patient had recurrence. Initial pre-operative treatment with itraconazole may be recommended for eumycetoma patients to enhance lesions encapsulation and localization which can facilitate wide local excision to avoid unnecessary massive mutilating surgery and recurrence.
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