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BACKGROUND: Eumycetoma is an implantation mycosis characterised by a large subcutaneous mass in the extremities commonly caused by the fungus Madurella mycetomatis. Despite the long duration of treatment, commonly a minimum of 12 months, treatment failure is frequent and can lead to amputation. We aimed to compare the efficacy of two doses of fosravuconazole, a synthetic antifungal designed for use in onychomycosis and repurposed for mycetoma, with standard-of-care itraconazole, both in combination with surgery. METHODS: This phase 2, randomised, double-blind, active-controlled, superiority trial was conducted in a single centre in Sudan. Patients with eumycetoma caused by M mycetomatis, who were aged 15 years or older, with a set lesion diameter (>2 cm and ≤16 cm) requiring surgery were included. There was a limit of 20 female patients in the initial enrolment, owing to preclinical toxicity concerns. Exclusion criteria included previous surgical or medical treatment for eumycetoma; presence of loco-regional lymphatic extension; osteomyelitis, or other bone involvement; pregnancy or lactation; severe concomitant diseases; a BMI under 16 kg/m2; contraindication to use of the study drugs; pre-existing liver disease; lymphatic extension; osteomyelitis; transaminase levels more than two times the laboratory's upper limit of normal, or elevated levels of alkaline phosphatase or bilirubin; or any history of hypersensitivity to any azole antifungal drug. Patients were randomly allocated in a 1:1:1 ratio to 300 mg fosravuconazole weekly for 12 months (group 1); 200 mg fosravuconazole weekly for 12 months (group 2); or 400 mg itraconazole daily for 12 months (group 3) using a random number list with non-disclosed fixed blocks of size 12, with equal allocation to each of the three arms within a block. To ensure masking between groups, placebo pills were used to disguise the difference in dosing schedules. All groups took pills twice daily with meals. In all groups, surgery was performed at 6 months. The primary outcome was complete cure at end of treatment at the month 12 visit, as evidenced by absence of mycetoma mass, sinuses, and discharge; normal ultrasonography or MRI examination of the eumycetoma site; and, if a mass was present, negative fungal culture from the former mycetoma site. The primary outcome was assessed in the modified intention-to-treat (mITT) population (all patients who received one or more treatment dose with one or more primary efficacy assessment). Safety was assessed in all patients who received one or more doses of the study drug. This study is registered with ClinicalTrials.gov (NCT03086226) and is complete. FINDINGS: Between May 9, 2017, and June 10, 2021, 104 patients were randomly allocated (34 in group 1 and 2, respectively, and 36 in group 3). 86 (83%) of 104 patients were male and 18 (17%) patients were female. After an unplanned second interim analysis, the study was terminated early for futility. Complete cure at 12 months in the mITT population was 17 (50%) of 34 (95% CI 32-68) for group 1, 22 (65%) of 34 (47-80) for group 2, and 27 (75%) of 36 (58-88) in group 3. Neither dose of fosravuconazole was superior to itraconazole (p=0·35 for 200 mg fosravuconazole vs p=0·030 for 300 mg fosravuconazole). 83 patients had a total of 205 treatment-emergent adverse events, and two patients had serious adverse events that led to discontinuation, neither related to treatment. INTERPRETATION: Treatment with either dose of fosravuconazole was not superior to itraconazole, and the two doses had a numerically lower efficacy. However, fosravuconazole presented no new safety signals, and its lower pill burden and reduced risk of drug-drug interactions compared with the relatively expensive and inaccessible itraconazole suggests further research into effective treatments with a shorter duration and higher cure rate, without the need for surgery are warranted. FUNDING: Drugs for Neglected Diseases initiative.
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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 new causative agent of human eumycetoma. Also, the difficulty in the management of this patient emphasizes the need for accurate and appropriate diagnostic tests for the identification of mycetoma-causative organisms and thus proper management.
Assuntos
Micetoma , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Ascomicetos , Feminino , Humanos , Micetoma/diagnóstico , Micetoma/tratamento farmacológico , SudãoRESUMO
BACKGROUND: Eumycetoma is a chronic subcutaneous granulomatous disease that is endemic in Sudan and other countries. It can be caused by eight different fungal orders. The gold standard diagnostic test is culture, however, culture-independent methods such as imaging, histopathological and molecular techniques can support diagnosis, especially in cases of negative cultures. METHODS: The amplicon-based internal transcribed spacer 2 metagenomic technique was used to study black grains isolated from 14 tissue biopsies from patients with mycetoma. Furthermore, mycological culture and surgical biopsy histopathological examinations of grains were performed. RESULTS: Madurella 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 Falciformispora tompkinsii (n=3) and Falciformispora senegalensis (n=1), while in culture-negative cases (n=5), Madurella mycetomatis (n=3), Falciformispora 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 co-presented with Inocybe and Alternaria and was in mutual exclusion with Subramaniula, Aspergillus and Trichothecium. CONCLUSION: Metagenomics provides new insights into the aetiology of eumycetoma in samples with negative culture and into the diversity and complexity of grains mycobiota, calling into question the accuracy of traditional culture for the identification of causative agents.
Assuntos
Micetoma , Negro ou Afro-Americano , Ascomicetos , Humanos , Metagenômica , Micetoma/diagnóstico , SudãoRESUMO
OBJECTIVES: Infection with the bacteria Helicobacter pylori has been classified as class one carcinogen associated with increasing susceptibility of gastritis and gastric carcinoma. This study is aiming at investigating the prevalence of H. pylori among colon polyps and colon cancer patients. A descriptive cross-sectional hospital-based study was conducted between February and June 2017. Sixty-nine formalin-fixed paraffin blocks collected from colon polyps and colon cancer patients to detect H. pylori using immunohistochemistry technique. RESULTS: Of the 69 patients included in the study, 39 (56.5%) males and 30 (43.5%) were females, their age ranged from 21 to 80 years with a mean age of 47.1 ± 19.7. Of the 69 colon polyps and colon cancer patients, 44 (63.8%) were diagnosed as adenocarcinoma, 10 (14.5%) colitis, 15 (21.7%) juvenile polyposis syndrome. The results of immunohistochemistry technique showed the presence of 16 (23.2%) positive patients for H. pylori infection. Of these 16, 13 (81.3%) patients were diagnosed with adenocarcinoma and 3 (18.7%) patients were diagnosed with juvenile polyps. The results of H. pylori detection among the different colon polyps and colon cancer patients were showing a statistically significant association for H. pylori infection and adenocarcinoma, P value 0.028.
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Neoplasias do Colo/microbiologia , Pólipos do Colo/microbiologia , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Adulto , Idoso , Neoplasias do Colo/patologia , Pólipos do Colo/patologia , Estudos Transversais , Feminino , Infecções por Helicobacter/microbiologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prevalência , Sudão/epidemiologiaRESUMO
Appropriate diagnosis and treatment of eumycetoma may vary significantly depending on the causative agent. To date, the most common fungus causing mycetoma worldwide is Madurella mycetomatis. This species fails to express any recognizable morphological characteristics, and reliable identification can therefore only be achieved with the application of molecular techniques. Recombinase polymerase amplification (RPA) and loop-mediated isothermal amplification (LAMP) are proposed as alternatives to phenotypic methods. Species-specific primers were developed to target the ribosomal DNA (rDNA) internal transcribed spacer (ITS) region of M. mycetomatis. Both isothermal amplification techniques showed high specificity and sufficient sensitivity to amplify fungal DNA and proved to be appropriate for detection of M. mycetomatis. Diagnostic performance of the techniques was assessed in comparison to conventional PCR using biopsy specimens from eumycetoma patients. RPA is reliable and easy to operate and has the potential to be implemented in areas where mycetoma is endemic. The techniques may be expanded to detect fungal DNA from environmental samples.
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Madurella/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Micetoma/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Primers do DNA/genética , DNA Fúngico/genética , DNA Espaçador Ribossômico/genética , Humanos , Micetoma/microbiologia , Sensibilidade e EspecificidadeRESUMO
Mycetoma is a progressive and destructive chronic granulomatous subcutaneous inflammatory disease caused by bacteria and fungi. The genetic determinants for susceptibility to and the development of mycetoma are unclear. Polymorphisms in genes encoding for cytokines and chemokines usually influence the efficiency of the immune response to infection and are associated with disease susceptibility and progression. Therefore, we hypothesized that polymorphisms of CC chemokine ligand 5 (CCL5) and interleukin-10 (IL-10) promoter regions might contribute to the initiation, susceptibility, and severity of eumycetoma. This case-control study included 149 mycetoma patients and 206 healthy matched controls. In the study population, three functional single nucleotide polymorphisms (SNPs) in CCL5 and two in IL-10 were genotyped using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Significant differences in allele distribution were demonstrated for CCL5 -28 C/G (P < 0.0001), CCL5 In1.1 T/C (P < 0.0001) and IL-10 -592 A/C. Since in previous studies it was demonstrated that the genotypes obtained for CCL5 and IL-10 were connected with CCL5 and IL-10 production we measured the serum levels of CCL5 and IL-10 in mycetoma patients and healthy controls. Elevated serum levels for both CCL5 and IL-10 were found in mycetoma patients and we describe that genetic differences in CCL5 and IL-10 are associated with the development of the mycetoma granuloma.