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Clinical Microbiology Reviews Jun 2024SUMMARYIn 2023, the World Health Organization designated eumycetoma causative agents as high-priority pathogens on its list of fungal priority pathogens. Despite this... (Review)
Review
SUMMARYIn 2023, the World Health Organization designated eumycetoma causative agents as high-priority pathogens on its list of fungal priority pathogens. Despite this recognition, a comprehensive understanding of these causative agents is lacking, and potential variations in clinical manifestations or therapeutic responses remain unclear. In this review, 12,379 eumycetoma cases were reviewed. In total, 69 different fungal species were identified as causative agents. However, some were only identified once, and there was no supporting evidence that they were indeed present in the grain. was by far the most commonly reported fungal causative agent. In most studies, identification of the fungus at the species level was based on culture or histology, which was prone to misidentifications. The newly used molecular identification tools identified new causative agents. Clinically, no differences were reported in the appearance of the lesion, but variations in mycetoma grain formation and antifungal susceptibility were observed. Although attempts were made to explore the differences in clinical outcomes based on antifungal susceptibility, the lack of large clinical trials and the inclusion of surgery as standard treatment posed challenges in drawing definitive conclusions. Limited case series suggested that eumycetoma cases caused by species were less responsive to treatment than those caused by . However, further research is imperative for a comprehensive understanding.
Topics: Mycetoma; Humans; Antifungal Agents; Madurella; Treatment Outcome
PubMed: 38690871
DOI: 10.1128/cmr.00034-23 -
Antimicrobial Agents and Chemotherapy May 2024Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and...
Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as , consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to screening against two fungal strains of and three bacterial strains of and . Seven NIQs, mostly dimers, showed promising activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-,-dimethylmichellamine A (), inhibited all tested fungal and bacterial strains (IC = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (), inhibited a strain of and significantly enhanced the survival rate of larvae infected with at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like and with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.
Topics: Mycetoma; Antifungal Agents; Animals; Alkaloids; Microbial Sensitivity Tests; Madurella; Isoquinolines; Actinomadura; Naphthoquinones; Larva; Moths
PubMed: 38602413
DOI: 10.1128/aac.01612-23 -
PLoS Neglected Tropical Diseases Nov 2023Mycetomas are endemic diseases in tropical and sub-tropical countries of Africa, Asia and America, mainly affecting rural populations living below the poverty line. We...
Mycetomas are endemic diseases in tropical and sub-tropical countries of Africa, Asia and America, mainly affecting rural populations living below the poverty line. We report a particular case of a mycetoma associated with pregnancy whose evolution was good, but at the cost of significant financial expenses. This was a 39-year-old woman who developed a fungal mycetoma due to Madurella mycetomatis from the ingunocrural region. The patient had to develop several previous pregnancies on this site of mycetoma, the outcome of which was favorable. The last pregnancy was accompanied by an aggravation of the mycetoma in the form of polyfistulized inflammatory swelling of the right inguino-crural region emitting black grains. Magnetic Resonance Imaging (MRI) of the region showed invasion of the adductor muscles at the level of the root of the thigh on its antero-internal side with no sign of pelvic extension or underlying bone lesion. The patient was treated by surgery associated with antifungal treatment. The evolution was favorable for pregnancy and mycetoma.
Topics: Female; Humans; Pregnancy; Adult; Mycetoma; Antifungal Agents; Africa; Madurella; Asia
PubMed: 37956163
DOI: 10.1371/journal.pntd.0011372 -
PLoS Neglected Tropical Diseases Oct 2020Mycetoma is a chronic infectious disease that can be caused by fungi or bacteria, Madurella mycetomatis and Nocardia brasiliensis are frequent etiologic agents of this...
Mycetoma is a chronic infectious disease that can be caused by fungi or bacteria, Madurella mycetomatis and Nocardia brasiliensis are frequent etiologic agents of this disease. Mycetoma produced by bacteria is known as actinomycetoma. In mycetoma produced by fungi (eumycetoma) and actinomycetoma, diagnosis of the disease is based on clinical findings: severe inflammation, with deformities of affected tissues, abscesses, fistulae, sinuses and discharge of purulent material that contains micro colonies of the etiologic agent. Microscopic examination of infected tissue is similar regardless of the offending microbe; hallmark of infected tissue is severe inflammation with abundant neutrophils around micro colonies and granuloma formation with macrophages, lymphocytes, dendritic and foamy cells. Even though medical treatment is available for mycetoma patients, amputation, or surgical intervention is frequently needed. The pathogenesis of actinomycetoma is little known, most information was obtained from experimental animal models infected with bacteria. In other experimental mice infections with different microbes, it was demonstrated that nitric oxide is responsible for the intracellular killing of Mycobacterium tuberculosis by activated macrophages. Nitric oxide is a free radical with potent stimulatory and suppressive effects in innate and adaptive immunity. The unstable nitric oxide molecule is produced by action of nitric oxide synthases on L-arginine. There are three nitric oxide synthases expressed in different cells and tissues, two are constitutively expressed one in neurons, and the other in endothelial cells and one that is inducible in macrophages. Aminoguanidine is a competitive inhibitor of inducible nitric oxide synthase. Its administration in experimental animals may favor or harm them. We used aminoguanidine in mice infected with Nocardia brasiliensis, and demonstrated that all treated animals were protected from actinomycetoma development. Anti N. brasiliensis antibodies and T cell proliferation were not affected, but inflammation was reduced.
Topics: Animals; Disease Progression; Female; Guanidines; Humans; Macrophages; Mice; Mice, Inbred BALB C; Mycetoma; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Nocardia
PubMed: 33091049
DOI: 10.1371/journal.pntd.0008775 -
International Journal of Dermatology Jan 2023Mycetoma is a neglected tropical infectious disease which runs a prolonged and protracted course. Microbiological confirmation is diagnostic yet unreliable due to poor...
BACKGROUND
Mycetoma is a neglected tropical infectious disease which runs a prolonged and protracted course. Microbiological confirmation is diagnostic yet unreliable due to poor sensitivity and variable availability of culture facilities in resource poor settings.
METHODS
A retrospective review was performed on electronic records (histopathology, microbiology, and radiology) of all patients who underwent skin biopsies with mycetoma as one of the clinical differential diagnoses from year 2016 to 2020.
RESULTS
Out of 73 patients biopsied with a differential of mycetoma, 42 fit the clinical triad of swelling-sinuses-granules. After clinical, microbiological, pathological, and radiological correlation, 31 cases were of eumycetoma and seven were of actinomycetoma. Mean patient age was 37.58 ± 13.8 years with a male to female ratio 2.45 : 1 and mean disease duration of 11.31 ± 10.9 years. Histopathological findings revealed fungal hyphae in 18 cases and gram-positive bacteria in six cases. Fungal culture was positive in 13 cases with the three commonest organisms being Madurella mycetomatis in five cases, Fusarium and Aspergillus nidulans in two cases each. X-ray changes of soft tissue, bones, and joints were seen in 25 cases, and "dot-in-circle" sign was seen in eight of nine MRIs.
CONCLUSION
Eumycetoma was more common than actinomycetoma in our setup, ratio being 4.43 : 1. A clinical triad of swelling, multiple sinuses and grainy discharge with any one diagnostic support (histopathology/radiology) is sufficient to make a definitive diagnosis of mycetoma in the absence of microbiological identification.
Topics: Humans; Male; Female; Young Adult; Adult; Middle Aged; Mycetoma; Retrospective Studies; Tertiary Care Centers; Madurella; Biopsy
PubMed: 36030528
DOI: 10.1111/ijd.16384 -
Medical Mycology Jun 2024The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic...
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%-73.5% of patients. Potential risk factors included male gender (56.6%-79.6%), younger age (11-30 years; 64%), and farming occupation (62.1%-69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%-76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100 000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100 000 persons between two consecutive 10-year periods (2000-2009 and 2010-2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.
Topics: Humans; Mycetoma; Incidence; Antifungal Agents; World Health Organization; Risk Factors; Male; Female; Quality of Life
PubMed: 38935904
DOI: 10.1093/mmy/myae044 -
Antimicrobial Agents and Chemotherapy Dec 2019The use of the Sensititre YeastOne YO10 alamarBlue assay for the susceptibility testing of was evaluated in isolates with and without pyomelanin secretion. Pyomelanin...
Pyomelanin Secretion in Madurella mycetomatis Interferes with Spectrophotometric Endpoint Reading Using the Sensititre YeastOne alamarBlue Assay but Not with Visual Endpoint Reading.
The use of the Sensititre YeastOne YO10 alamarBlue assay for the susceptibility testing of was evaluated in isolates with and without pyomelanin secretion. Pyomelanin secretion did not influence visual endpoint reading; however, it caused a shift in peak absorbance from 570 nm to 620 nm when read spectrophotometrically. Therefore, when choosing the method for endpoint reading, the presence of pyomelanin should be considered.
Topics: Azoles; Madurella; Melanins; Mycetoma
PubMed: 31611353
DOI: 10.1128/AAC.01532-19 -
Journal de Mycologie Medicale Dec 2019Eumycetomas are chronic subcutaneous pseudo-tumoral infections, endemic in arid tropical areas, which are caused by exogenous fungi that produce grains in vivo. The...
Eumycetomas are chronic subcutaneous pseudo-tumoral infections, endemic in arid tropical areas, which are caused by exogenous fungi that produce grains in vivo. The objective of our work is to establish their epidemiological, clinical and mycological profile in our Moroccan context. Therefore, we conducted a retrospective study, extending from 1975 to 2019, compiling all cases of eumycetomas that were diagnosed in the parasitology-mycology laboratory of the Ibn Sina University Hospital of Rabat. The diagnosis, based on the swabbing of exudates and eventual grains or the study of biopsies, included the direct examination of 30% KOH mounts, the realization of appositions colored by May-Grünwald-Giemsa and the incubation on 3 Sabouraud media at 27° and 37°C. In 44 years, 12 cases of eumycetoma have been diagnosed, with a male to female ratio of 5:1 and a mean age of 44.8 years. The lesions, evolving from 1 to 30 years, were podal in 10 cases, popliteal and gluteal in one case each, with osteolysis in 3 patients. The collected grains were black in 9 cases, white in 2 others. Direct examination was unanimously positive, revealing entangled hyphae, whilst culture isolated Madurella sp. in 9 cases, Trichophyton rubrum, Acremonium sp. in one case each and remained sterile in the last case. The treatment was medical in 8 cases, medico-surgical in 3 others, with loss of sight of most patients.
Topics: Adult; Antifungal Agents; Clinical Laboratory Techniques; Female; Fungi; Humans; Madurella; Male; Middle Aged; Morocco; Mycetoma; Retrospective Studies; Trichophyton; Young Adult
PubMed: 31587988
DOI: 10.1016/j.mycmed.2019.100902 -
Antimicrobial Agents and Chemotherapy Oct 2020
Correction for Nyuykonge et al., "Pyomelanin Secretion in Interferes with Spectrophotometric Endpoint Reading Using the Sensititre YeastOne alamarBlue Assay but Not with Visual Endpoint Reading".
PubMed: 33082231
DOI: 10.1128/AAC.01848-20 -
Scientific Reports Feb 2021Hydroxybenzoic acids, like gallic acid and protocatechuic acid, are highly abundant natural compounds. In biotechnology, they serve as critical precursors for various...
Hydroxybenzoic acids, like gallic acid and protocatechuic acid, are highly abundant natural compounds. In biotechnology, they serve as critical precursors for various molecules in heterologous production pathways, but a major bottleneck is these acids' non-oxidative decarboxylation to hydroxybenzenes. Optimizing this step by pathway and enzyme engineering is tedious, partly because of the complicating cofactor dependencies of the commonly used prFMN-dependent decarboxylases. Here, we report the crystal structures (1.5-1.9 Å) of two homologous fungal decarboxylases, AGDC1 from Arxula adenivorans, and PPP2 from Madurella mycetomatis. Remarkably, both decarboxylases are cofactor independent and are superior to prFMN-dependent decarboxylases when heterologously expressed in Saccharomyces cerevisiae. The organization of their active site, together with mutational studies, suggests a novel decarboxylation mechanism that combines acid-base catalysis and transition state stabilization. Both enzymes are trimers, with a central potassium binding site. In each monomer, potassium introduces a local twist in a β-sheet close to the active site, which primes the critical H86-D40 dyad for catalysis. A conserved pair of tryptophans, W35 and W61, acts like a clamp that destabilizes the substrate by twisting its carboxyl group relative to the phenol moiety. These findings reveal AGDC1 and PPP2 as founding members of a so far overlooked group of cofactor independent decarboxylases and suggest strategies to engineer their unique chemistry for a wide variety of biotechnological applications.
PubMed: 33542397
DOI: 10.1038/s41598-021-82660-z