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1.
Clin Microbiol Rev ; 37(2): e0003423, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38690871

RESUMO

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. Madurella mycetomatis 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 Fusarium species were less responsive to treatment than those caused by Madurella mycetomatis. However, further research is imperative for a comprehensive understanding.


Assuntos
Antifúngicos , Micetoma , Micetoma/microbiologia , Micetoma/tratamento farmacológico , Micetoma/diagnóstico , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Madurella/efeitos dos fármacos , Resultado do Tratamento
2.
Antimicrob Agents Chemother ; 68(5): e0161223, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38602413

RESUMO

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 Madurella mycetomatis, 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 in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro 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'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.


Assuntos
Alcaloides , Antifúngicos , Madurella , Testes de Sensibilidade Microbiana , Micetoma , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Antifúngicos/farmacologia , Animais , Alcaloides/farmacologia , Alcaloides/química , Madurella/efeitos dos fármacos , Isoquinolinas/farmacologia , Actinomadura/efeitos dos fármacos , Naftoquinonas/farmacologia , Larva/microbiologia , Larva/efeitos dos fármacos , Mariposas/microbiologia
3.
Med Mycol ; 62(6)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38935904

RESUMO

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.


Assuntos
Antifúngicos , Micetoma , Organização Mundial da Saúde , Humanos , Micetoma/epidemiologia , Micetoma/microbiologia , Incidência , Antifúngicos/uso terapêutico , Fatores de Risco , Masculino , Feminino , Qualidade de Vida
4.
Mycoses ; 67(1): e13664, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37872649

RESUMO

INTRODUCTION: (1,3)-ß-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-ß-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-ß-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated. MATERIALS AND METHODS: In this study, we measured (1,3)-ß-D-glucan concentrations in serum with the WAKO (1,3)-ß-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-ß-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-ß-D-glucan concentrations and clinical outcome was evaluated. RESULTS: The concentration of (1,3)-ß-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-ß-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-ß-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-ß-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-ß-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-ß-D-glucan concentration was noted. CONCLUSION: Although in general (1,3)-ß-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in ß-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-ß-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.


Assuntos
Madurella , Micetoma , Proteoglicanas , Humanos , Glucanos , Azóis/uso terapêutico , Micetoma/diagnóstico , Micetoma/tratamento farmacológico
5.
Eur Arch Otorhinolaryngol ; 281(1): 509-513, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37816840

RESUMO

BACKGROUND: Mycetoma is a slowly progressive chronic granulomatous disease of the skin, subcutaneous tissue, and underlying or adjacent cartilage or bone. Most commonly involves the foot region. Other parts such as the knee, arm, leg, head, neck, thigh, perineum, chest, abdominal walls, facial bones, mandible, paranasal sinuses, eyelid, vulva, orbit, and scrotum are seldom affected. METHODS: This is a rare presentation of Eumycotic mycetoma involving the nasal septum. Surgical debridement is done under local anesthesia. Histopathological examination of debrided specimen guided in the diagnosis and treatment. RESULTS: Histopathological examination is the one that confirms the diagnosis and rules out the other granulomatous conditions and fungal rhinitis causing septal perforation. CONCLUSIONS: In an immunocompromised state, we know that mucormycosis and zygomycosis are known to cause aggressive complications like orbital invasion and palatal perforation by vascular route. However, other fungal infections also can lead to septal perforations whenever there is lessened resistance by the mucosal barrier due to trauma (nasal intubations).


Assuntos
Micetoma , Micoses , Seios Paranasais , Masculino , Feminino , Humanos , Micetoma/diagnóstico , Micetoma/microbiologia , Micetoma/patologia , Diálise Renal , Micoses/diagnóstico , Seios Paranasais/patologia , Septo Nasal/cirurgia , Septo Nasal/patologia
6.
Mycopathologia ; 189(1): 6, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38231295

RESUMO

Madurella fahalii is a causative agent of the implantation mycosis mycetoma with decreased susceptibility to itraconazole, the preferred therapeutic drug to combat mycetoma. Here, we report the M. fahalii type-strain CBS 129176 genome assembly and annotation to identify a glutamic acid insert near the azole-binding pocket in the Cyp51A protein.


Assuntos
Madurella , Micetoma , Itraconazol/farmacologia , Azóis
7.
Int J Mol Sci ; 25(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38892422

RESUMO

OBJECTIVES: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. METHODS: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. RESULTS: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. CONCLUSION: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.


Assuntos
Antifúngicos , Madurella , Micetoma , Madurella/efeitos dos fármacos , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Antifúngicos/farmacologia , Animais , Testes de Sensibilidade Microbiana , Larva/efeitos dos fármacos , Larva/microbiologia , Humanos
8.
Molecules ; 29(8)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38675665

RESUMO

In the search for new bioactive agents against the infectious pathogen responsible for the neglected tropical disease (NTD) mycetoma, we tested a collection of 27 essential oils (EOs) in vitro against Madurella mycetomatis, the primary pathogen responsible for the fungal form of mycetoma, termed eumycetoma. Among this series, the EO of Santalum album (Santalaceae), i.e., East Indian sandalwood oil, stood out prominently with the most potent inhibition in vitro. We, therefore, directed our research toward 15 EOs of Santalum species of different geographical origins, along with two samples of EOs from other plant species often commercialized as "sandalwood oils". Most of these EOs displayed similar strong activity against M. mycetomatis in vitro. All tested oils were thoroughly analyzed by GC-QTOF MS and most of their constituents were identified. Separation of the sandalwood oil into the fractions of sesquiterpene hydrocarbons and alcohols showed that its activity is associated with the sesquiterpene alcohols. The major constituents, the sesquiterpene alcohols (Z)-α- and (Z)-ß-santalol were isolated from the S. album oil by column chromatography on AgNO3-coated silica. They were tested as isolated compounds against the fungus, and (Z)-α-santalol was about two times more active than the ß-isomer.


Assuntos
Madurella , Micetoma , Óleos Voláteis , Óleos de Plantas , Santalum , Sesquiterpenos , Madurella/efeitos dos fármacos , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Micetoma/microbiologia , Micetoma/tratamento farmacológico , Santalum/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Antifúngicos/farmacologia , Antifúngicos/química , Testes de Sensibilidade Microbiana
9.
J Assoc Physicians India ; 72(8): 83-85, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39163074

RESUMO

Mycetoma is a chronic skin and subcutaneous tissue infection characterized by a triad of localized swelling, draining sinuses, and grains or granules (composed of aggregations of the causative organism) within the sinus tracts. It is caused by filamentous higher bacteria (known as actinomycetoma) or fungus (known as eumycetoma). Usually actinomycetoma presents with white-yellow grains and majority of eumycetoma causes black grains. However, actinomycetoma caused by Streptomyces sp. produces large brown-black grain, which is often misdiagnosed as eumycetoma, therefore confirmation by culture is necessary. Here, we present a case of 28-year-old female presenting with typical features of mycetoma at cervicofacial region. On direct microscopy (40×) with potassium hydroxide (KOH) mount of discharge released from sinuses showed large and black grains, initially raising a suspicion of eumycetoma, but later, it was confirmed by culture as actinomycetoma caused by Streptomyces sp. Patient is now symptomatically better on treatment. Production of black grain by actinomycetoma is a rare clinical scenario.


Assuntos
Micetoma , Humanos , Feminino , Micetoma/diagnóstico , Micetoma/microbiologia , Adulto , Streptomyces/isolamento & purificação , Pescoço/microbiologia , Antibacterianos/uso terapêutico
10.
Med Mycol ; 61(11)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37960934

RESUMO

Mycetoma is a neglected tropical disease commonly caused by the fungus Madurella mycetomatis. Standard treatment consists of extensive treatment with itraconazole in combination with surgical excision of the infected tissue, but has a low success rate. To improve treatment outcomes, novel treatment strategies are needed. Here, we determined the potential of manogepix, a novel antifungal agent that targets the GPI-anchor biosynthesis pathway by inhibition of the GWT1 enzyme. Manogepix was evaluated by determining the minimal inhibitory concentrations (MICs) according to the CLSI-based in vitro susceptibility assay for 22 M. mycetomatis strains and by in silico protein comparison of the target protein. The synergy between manogepix and itraconazole was determined using a checkerboard assay. The efficacy of clinically relevant dosages was assessed in an in vivo grain model in Galleria mellonella larvae. MICs for manogepix ranged from <0.008 to >8 mg/l and 16/22 M. mycetomatis strains had an MIC ≥4 mg/ml. Differences in MICs were not related to differences observed in the GWT1 protein sequence. For 70% of the tested isolates, synergism was found between manogepix and itraconazole in vitro. In vivo, enhanced survival was not observed upon admission of 8.6 mg/kg manogepix, nor in combination treatment with 5.7 mg/kg itraconazole. MICs of manogepix were high, but the in vitro antifungal activity of itraconazole was enhanced in combination therapy. However, no efficacy of manogepix was found in an in vivo grain model using clinically relevant dosages. Therefore, the therapeutic potential of manogepix in mycetoma caused by M. mycetomatis seems limited.


Treatment of Madurella mycetomatis-caused mycetoma consists of extensive exposure to antifungals and surgery. To improve therapy, we evaluated manogepix, a novel antifungal agent, as a therapeutic option against M. mycetomatis. Our findings suggest limited therapeutic potential for manogepix.


Assuntos
Madurella , Micetoma , Animais , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Micetoma/veterinária , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico
11.
Med Mycol ; 61(8)2023 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-37451815

RESUMO

Eumycetoma is a subcutaneous implantation mycosis often found in the foot. One of the hallmarks of eumycetoma is the formation of grains. These grains are either black or white, and the consistency and morphology differs per causative agent. The two most common causative agents of black-grain eumycetoma are Madurella mycetomatis and Falciformispora senegalensis. Since grains cannot be formed in vitro, in vivo models are needed to study grain formation. Here, we used the invertebrate Galleria mellonella to establish an in vivo grain model for F. senegalensis. Three different F. senegalensis strains were selected, and four different inocula were used to infect G. mellonella larvae, ranging from 0.04 mg/larvae to 10 mg/larvae. Larval survival was monitored for 10 days. Grain formation was studied macroscopically and histologically. The efficacy of antifungal therapy was determined for itraconazole, amphotericin B, and terbinafine. A concentration of 10 mg F. senegalensis per larva was lethal for the majority of the larvae within 10 days. At this inoculum, grains were formed within 24 h after infection. The grains produced in the larvae resembled those formed in human patients. Amphotericin B given at 1 mg/kg 4 h, 28 h, and 52 h after infection prolonged larval survival. No enhanced survival was noted for itraconazole or terbinafine. In conclusion, we developed a F. senegalensis grain model in G. mellonella larvae in which grains were formed that were similar to those formed in patients. This model can be used to monitor grain formation over time and study antifungal efficacy.


Within eumycetoma lesions, the causative agents are embedded in grains. However, the grains differ per causative agent. In this study, we developed a grain model of Falciformispora senegalensis in the larvae of Galleria mellonella. This model can be used in the future to study the efficacy of novel antifungal agents.


Assuntos
Mariposas , Micetoma , Humanos , Animais , Antifúngicos/farmacologia , Larva/microbiologia , Anfotericina B/farmacologia , Terbinafina , Itraconazol , Micetoma/microbiologia , Micetoma/veterinária , Modelos Animais de Doenças , Mariposas/microbiologia
12.
Mycoses ; 66(5): 420-429, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36583225

RESUMO

OBJECTIVES: Mycetoma is a neglected tropical implantation disease caused by 70 different infectious agents. Identifying the causative organism to the species level is essential for appropriate patient management. Ultrasound, histopathology, culture and two species-specific PCRs are most the commonly used methods for species identification in endemic regions. The aim of this study was to compare the diagnostic performance of these commonly used assays using sequencing of barcoding genes as the gold standard. METHODS: This descriptive cross-sectional study was conducted at the Mycetoma Research Centre, University of Khartoum, Sudan. It included 222 patients suspected of fungal mycetoma caused by Madurella mycetomatis. RESULTS: 154 (69.3%) were correctly identified by ultrasound, histology, culture and both species-specific PCRs. In 60 patients, at least one of the diagnostic tests failed to identify M. mycetomatis. Five patients had no evidence of eumycetoma, and for three, only the ultrasound was indicative of mycetoma. The two species-specific PCRs were the most sensitive and specific methods, followed by culture and histology. Ultrasound was the least specific as it only allowed differentiation between actinomycetoma and eumycetoma. The time to result was 9.38 minutes for ultrasound, 3.76 hours for PCR, 8.5 days for histopathology and 21 days for grain culturing. CONCLUSION: Currently, PCR directly on DNA isolated from grains is the most rapid and reliable diagnostic tool to identify M. mycetomatis eumycetoma.


Assuntos
Madurella , Micetoma , Humanos , Micetoma/diagnóstico , Estudos Transversais , Sudão/epidemiologia , Reação em Cadeia da Polimerase , Madurella/genética , Testes Diagnósticos de Rotina
13.
Mycoses ; 66(6): 477-482, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36740735

RESUMO

BACKGROUND: Eumycetoma is a chronic subcutaneous inflammatory fungal infection most often caused by the fungus Madurella mycetomatis. Using a species-specific PCR on DNA directly isolated from grains is currently the most reliable method for species identification. However, so far, PCR has been performed on grains obtained through deep-seated surgical biopsies, which are invasive procedures. Grains can also be obtained via ultrasound-guided fine-needle aspiration (US-FNA). Here we determined the diagnostic performance of species-specific PCRs performed on samples obtained through US-FNA. METHODS: From 63 patients, US-FNA was performed to obtain eumycetoma grains; 34 patients also underwent a deep-seated biopsy. From the grains, DNA was isolated, and one pan-fungal and two M. mycetomatis-specific PCRs were performed. The sensitivity and specificity were determined. RESULTS: Of the 63 patients who underwent US-FNA, 78% (49/63) had evidence of eumycetoma based on cytology and 93.7% (59/63) based on species-specific PCRs. In the 34 patients for whom surgical biopsies were performed as well, 31 patients had a positive PCR for M. mycetomatis when DNA was isolated from the deep-seated biopsy, and 30 had a positive PCR when DNA was obtained from the US-FNA material. This resulted in a 96.8% sensitivity, and 100% specificity with 97.1% diagnostic accuracy for PCR performed on US-FNA. CONCLUSION: PCR performed on the US-FNA material has a similar sensitivity and specificity as PCR performed on deep-seated biopsies. Therefore, when using PCR, a deep-seated biopsy may not be necessary to obtain grains.


Assuntos
Madurella , Micetoma , Humanos , Biópsia por Agulha Fina , Madurella/genética , Micetoma/diagnóstico , Reação em Cadeia da Polimerase , Técnicas de Amplificação de Ácido Nucleico , Inflamação
14.
J Eur Acad Dermatol Venereol ; 37(4): 783-786, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36201367

RESUMO

BACKGROUND: Eumycetoma is a neglected tropical infection of the subcutaneous tissue commonly caused by the fungus Madurella mycetomatis. Previously, we demonstrated that ß-D-glucan was present in the serum of eumycetoma patients. OBJECTIVE: To compare the performance of the recently approved easy-to-use Wako ß-D-glucan assay to that of the Fungitell assay in eumycetoma patients. METHODS: Using sera obtained from 41 eumycetoma, 12 actinomycetoma and 29 healthy endemic controls, we measured the ß-glucan serum concentrations using the Wako assay and compared the performance to that of the Fungitell assay. RESULTS: With the Fungitell assay, median ß-glucan serum concentrations of 208, 70 and 27 pg/ml were obtained for the 41 eumycetoma patients, the 12 actinomycetoma patients and the 29 healthy endemic controls, respectively. With the Wako assay these concentrations were 14.45, 11.57 and 2.5 pg/ml, respectively. We demonstrated that when using the optimized cut-off value (5.5 pg/ml) for the Wako assay, the Wako and Fungitell assays had comparable performance in terms of sensitivity and specificity. CONCLUSION: The Wako assay is comparable to the Fungitell assay for measurement of serum ß-glucan in mycetoma patients and hence can be used in combination with current diagnostic tools. However, this test should be used in combination with other tests to differentiate actinomycetoma from eumycetoma.


Assuntos
Madurella , Micetoma , beta-Glucanas , Humanos , Micetoma/diagnóstico , Micetoma/microbiologia , Glucanos , Sensibilidade e Especificidade
15.
Chem Biodivers ; 20(5): e202300151, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37067830

RESUMO

Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC50 =1.4 µM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies.


Assuntos
Besouros , Madurella , Mariposas , Micetoma , Naftoquinonas , Animais , Antifúngicos/farmacologia , Micetoma/tratamento farmacológico , Micetoma/microbiologia , Antraquinonas/farmacologia , Larva , Naftoquinonas/farmacologia
16.
Curr Opin Infect Dis ; 35(5): 379-383, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35942857

RESUMO

PURPOSE OF REVIEW: to review recent advances in the epidemiology, diagnosis, and treatment of deep fungal infections. RECENT FINDINGS: Mycetoma and chromoblastomycosis are the only deep fungal infections incorporated in the list of neglected tropical diseases. These infections start in the skin but progress to deep tissues if not recognized early. A wide array of fungal pathogens are the causative agents. Molecular methods allow for early and accurate identification of the pathogens, but are unfortunately not available in endemic areas. Treatment options are mostly based upon clinical experience rather than on well-designed clinical trials. SUMMARY: Deep fungal infections of the skin and soft tissues are rare conditions of wide world distribution but mostly reported from tropical countries. Urgent need for affordable and easily accessible molecular methods and well-conducted studies to allow for accurate diagnosis and to provide evidence to guide proper therapy are urgently needed.


Assuntos
Cromoblastomicose , Micetoma , Cromoblastomicose/diagnóstico , Cromoblastomicose/tratamento farmacológico , Cromoblastomicose/epidemiologia , Humanos , Micetoma/diagnóstico , Micetoma/tratamento farmacológico , Micetoma/epidemiologia , Pele/microbiologia
17.
J Antimicrob Chemother ; 78(1): 155-160, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36315595

RESUMO

OBJECTIVES: Actinomycetoma is a chronic granulomatous disease affecting skin, subcutaneous tissue, fascia, muscle and bones. With increasing resistance against commonly used treatment regimens, susceptibility testing is urgently needed. METHODS: We developed an in vitro susceptibility assay for Actinomadura madurae, one of the common causative agents of actinomycetoma, employing resazurin for endpoint reading. Using this assay, reproducible MICs were determined for the most commonly used antibacterial agents for actinomycetoma treatment. The tested antibacterial agents included trimethoprim/sulfamethoxazole, amikacin, streptomycin, amoxicillin, ceftriaxone, gentamicin, ciprofloxacin, doxycycline, imipenem, linezolid, penicillin G and rifampicin. RESULTS: Following the clinical breakpoints as stated by CLSI, 100% of the tested strains were susceptible to trimethoprim/sulfamethoxazole (MIC 0.03/0.59-1/19 mg/L), amikacin (MIC 0.0078-0.25 mg/L), doxycycline (MIC <0.25-1 mg/L) and linezolid (MIC <0.25-2 mg/L), 90% to ciprofloxacin (MIC <0.25-2 mg/L), 80% to ceftriaxone (MIC <0.5 to >64 mg/L) and imipenem (MIC <0.25-32 mg/L) and only 20% to amoxicillin (MIC <0.5 to >64 mg/L) and rifampicin (MIC 0.5 to >32 mg/L). CONCLUSIONS: Determinations of MICs by visual readings of colour changes versus spectrophotometric readings were comparable. This convenient visual reading has the advantage of feasible implementation in endemic settings.


Assuntos
Amicacina , Micetoma , Humanos , Linezolida/farmacologia , Doxiciclina , Ceftriaxona , Rifampina , Micetoma/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Amoxicilina , Combinação Trimetoprima e Sulfametoxazol , Imipenem , Ciprofloxacina , Ifosfamida , Testes de Sensibilidade Microbiana
18.
Trop Med Int Health ; 27(12): 1059-1064, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36329624

RESUMO

OBJECTIVE: Mycetoma is a neglected tropical disease caused by more than 70 different microorganisms and identified by the WHO as one of the high-priority diseases for developing diagnostic tests. To ensure the production of diagnostic assays for use by clinical staff in endemic regions, target product profiles (TPPs) were designed. METHODS: We describe the development of two TPPs: one for a diagnostic test able to identify the causative agent of mycetoma and another that would determine when treatment could be stopped. The TPPs were developed by considering product use, design, performance, product configuration and costs. RESULTS: Version 1.0 TPPs for two uses were posted by WHO for a 1-month online public consultation on 25 October 2021, and the final TPP was posted online on 5 May 2022. CONCLUSION: A major difficulty encountered in developing both TPPs was the large number of agents able to cause mycetoma and the lack of specific biomarkers for most of them.


Assuntos
Micetoma , Humanos , Micetoma/diagnóstico , Micetoma/tratamento farmacológico , Doenças Negligenciadas/diagnóstico , Bioensaio , Custos e Análise de Custo , Encaminhamento e Consulta
19.
Med Mycol ; 60(7)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35833294

RESUMO

Eumycetoma is a neglected tropical infection of the subcutaneous tissue, characterized by tumor-like lesions and most commonly caused by the fungus Madurella mycetomatis. In the tissue, M. mycetomatis organizes itself in grains, and within a single lesion, thousands of grains can be present. The current hypothesis is that all these grains originate from a single causative agent, however, this hypothesis was never proven. Here, we used our recently developed MmySTR assay, a highly discriminative typing method, to determine the genotypes of multiple grains within a single lesion. Multiple grains from surgical lesions obtained from 11 patients were isolated and genotyped using the MmySTR panel. Within a single lesion, all tested grains shared the same genotype. Only in one single grain from one patient, a difference of one repeat unit in one MmySTR marker was noted relative to the other grains from that patient. We conclude that within these lesions the grains originate from a single clone and that the inherent unstable nature of the microsatellite markers may lead to small genotypic differences. LAY ABSTRACT: In lesions of the implantation mycosis mycetoma many Madurella mycetomatis grains are noted. It was unknown if grains arose after implantation of a single isolate or a mixture of genetically diverse isolates. By typing the mycetoma grains we showed that all grains within a single lesion were clonal and originated from a single isolate.


Assuntos
Madurella , Micetoma , Animais , Genótipo , Madurella/genética , Micetoma/diagnóstico , Micetoma/microbiologia , Micetoma/veterinária
20.
Med Mycol ; 60(4)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35244718

RESUMO

Scedosporium species are emerging opportunistic fungal pathogens causing various infections mainly in immunocompromised patients, but also in immunocompetent individuals, following traumatic injuries. Clinical manifestations range from local infections, such as subcutaneous mycetoma or bone and joint infections, to pulmonary colonization and severe disseminated diseases. They are commonly found in soil and other environmental sources. To date S. aurantiacum has been reported only from a handful of countries. To identify the worldwide distribution of this species we screened publicly available sequencing data from fungal metabarcoding studies in the Sequence Read Archive (SRA) of The National Centre for Biotechnology Information (NCBI) by multiple BLAST searches. S. aurantiacum was found in 26 countries and two islands, throughout every climatic region. This distribution is like that of other Scedosporium species. Several new environmental sources of S. aurantiacum including human and bovine milk, chicken and canine gut, freshwater, and feces of the giant white-tailed rat (Uromys caudimaculatus) were identified. This study demonstrated that raw sequence data stored in the SRA database can be repurposed using a big data analysis approach to answer biological questions of interest. LAY SUMMARY: To understand the distribution and natural habitat of S. aurantiacum, species-specific DNA sequences were searched in the SRA database. Our large-scale data analysis illustrates that S. aurantiacum is more widely distributed than previously thought and new environmental sources were identified.


Assuntos
Doenças do Cão , Micetoma , Scedosporium , Animais , Cães , Hospedeiro Imunocomprometido , Micetoma/microbiologia , Micetoma/veterinária , Scedosporium/genética , Especificidade da Espécie
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