Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma.

Eumycetoma is a chronic subcutaneous neglected tropical disease that can be caused by more than 40 different fungal causative agents. The most common causative agents produce black grains and belong to the fungal orders Sordariales and Pleosporales. The current antifungal agents used to treat eumycetoma are itraconazole or terbinafine, however, their cure rates are low. To find novel drugs for eumycetoma, we screened 400 diverse drug-like molecules from the Pandemic Response Box against common eumycetoma causative agents as part of the Open Source Mycetoma initiative (MycetOS). 26 compounds were able to inhibit the growth of Madurella mycetomatis, Madurella pseudomycetomatis and Madurella tropicana, 26 compounds inhibited Falciformispora senegalensis and seven inhibited growth of Medicopsis romeroi in vitro. Four compounds were able to inhibit the growth of all five species of fungi tested. They are the benzimidazole carbamates fenbendazole and carbendazim, the 8-aminoquinolone derivative tafenoquine and MMV1578570. Minimal inhibitory concentrations were then determined for the compounds active against M. mycetomatis. Compounds showing potent activity in vitro were further tested in vivo. Fenbendazole, MMV1782387, ravuconazole and olorofim were able to significantly prolong Galleria mellonella larvae survival and are promising candidates to explore in mycetoma treatment and to also serve as scaffolds for medicinal chemistry optimisation in the search for novel antifungals to treat eumycetoma.

The use of traditional medicines among mycetoma patients.

BACKGROUND: Mycetoma patients frequently present with advanced disease, the cause of which is multi-factorial, but the use of traditional medicine modalities has been shown to be an important one. Traditional medicine is an integral part of the Sudanese culture and many mycetoma patients revert to it because it is accessible, cheap and available. METHODS: To confirm this anecdotal observation, the pattern and characteristics of traditional medicine use among a group of mycetoma patients seen at the Mycetoma Research Center in Khartoum, Sudan, were studied. RESULTS: In this descriptive, cross-sectional, hospital-based study, 389 mycetoma-confirmed patients were included. All of them had used traditional medicine at some stage of their mycetoma treatment. Among them, 66% had first consulted traditional healers for mycetoma treatment. In this study, 58% had consulted religious healers known as fakis, while the majority (72%) of those who consulted specialist healers had consulted herbalists. The most frequent type of traditional medicine received by patients from religious healers was al-azima (31%) and the most common treatment given by the specialist healers was herbal medicine (46%). CONCLUSION: Traditional medicine can lead to a delay in seeking medical care and serious complications. Collaboration with traditional healers, and training and educating them to refer mycetoma patients to specialised centres is vital to ensure that they receive proper treatment in a timely and efficient manner.

Sarocladium and Acremonium infections: New faces of an old opportunistic fungus.

The genera Acremonium and Sarocladium comprise a high diversity of morphologically and genetically related fungi generally found in the environment, although a few species, mainly Sarocladium kiliense and Acremonium egyptiacum, can also be involved in many human infections. Clinical management of opportunistic infections caused by these fungi is very complex, since their correct identification is unreliable, and they generally show poor antifungal response. More than 300 clinical cases involving a broad range of Acremonium/Sarocladium infections have so far been published, and with this review we aim to compile and provide a detailed overview of the current knowledge on Acremonium/Sarocladium human infections in terms of presentation, diagnosis, treatments and prognoses. We also aim to summarise and discuss the data currently available on their antifungal susceptibility, emphasising the promising results obtained with voriconazole as well as their impact in terms of animal infections.

Mycetoma: reviewing a neglected disease.

Mycetoma caused by either filamentous fungi (eumycotic) or bacteria (actinomycotic) has recently been recognized by the World Health Organization as a neglected tropical disease. Although mycetoma is preventable and treatable, especially in the early stages, it carries high morbidity and a huge socioeconomic burden. Skin and subcutaneous tissue is affected, with a classic presentation of hard woody swellings, discharging sinuses and presence of grains (containing the causative organism). Variants with swelling without sinuses have also been described. Left untreated it may involve underlying bone and muscle, leading to permanent disability. Common actinomycotic species include Streptomyces somaliensis, Actinomadura madurae, Actinomadura pelletieri, Nocardia brasiliensis and Nocardia asteroides, while Madurella mycetomatis, Madurella grisea, Pseudoallescheria boydii and Leptosphaeria senegalensis are common eumycotic agents. Men are more commonly affected than women, and the leg is the most frequently affected site. Diagnosis in suspected lesions is made with the help of grain examination, microscopy, imaging (radiography, ultrasonography, magnetic resonance imaging) and culture, and more recently by molecular methods such as PCR and molecular sequencing. Molecular sequencing for both fungi and bacteria is important for rapid and correct diagnosis, especially in culture-negative cases. Treatment is long, more successful in actinomycetoma than eumycetoma, and may require a holistic approach comprising antimicrobials, surgery and rehabilitation. Mycetoma can be prevented by simple measures such as wearing protective garments and shoes, especially in rural areas and during outdoor activities.

Disseminated actinomycetoma due to Nocardia wallacei.

BACKGROUND: Actinomycetoma caused by Nocardia usually responds well to antibiotics. Emerging species of Nocardia, such as N. wallacei, can be a therapeutic challenge. AIMS: Confirm the therapeutic effectivity of linezolid in multidrug resistant Nocardia Wallacei actinomycetoma. MATERIALS AND METHODS: We evaluated the medical management of an 18-year-old man with multidrug resistant actinomycetoma of the left leg caused by N. transvalensis complex treated 17 years ago with linezolid 1200 mg a day. This bacteria was recently reclassified as Nocardia Wallacei by specific molecular biology technique. RESULTS: The infection was cured after 3 months of treatment; the patient remained asymptomatic for the past 17 years. No adverse effects were found. DISCUSSION: Frequently, strains of N. transvalensis complex have aminoglycoside resistance; in this case, we highlight the effectiveness of linezolid for the successful medical management of multidrug resistant actinomycetoma. CONCLUSION: Linezolid can be an alternative for the treatment of multidrug resistant Nocardia Wallacei.

Case report: Non-invasive management of Madura foot with oral posaconazole and ciprofloxacin.

Madura foot is a chronic infection caused by fungus and/or bacteria. Traditionally, treatment has been surgical debridement or amputation. Non-invasive management with long-term antimicrobials alone has been reported as successful. We report a case of Madura foot in a Somali refugee successfully managed with oral posaconazole and ciprofloxacin.

Mycetoma medical therapy.

Medical treatment of mycetoma depends on its fungal or bacterial etiology. Clinically, these entities share similar features that can confuse diagnosis, causing a lack of therapeutic response due to inappropriate treatment. This review evaluates the response to available antimicrobial agents in actinomycetoma and the current status of antifungal drugs for treatment of eumycetoma.

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.

Mycetoma herbal treatment: the Mycetoma Research Centre, Sudan experience.

It is still challenging and difficult to treat patients with eumycetoma; the current treatment has many side effects and has proven to be expensive and characterized by high recurrence rate, hence the poor patients' treatment compliance. Most of the patients are of low socio-economic status, have many financial constraints and hence, many of them rely on alternative and herbal medicine for the treatment of their disease. With this background, the current study was conducted to determine the prevalence of herbal medicine usage among patients with eumycetoma. This cross-sectional, observational, questionnaire-based study was conducted at the Mycetoma Research Center, University of Khartoum, Khartoum, Sudan. A convenience cohort of 311 patients with confirmed eumycetoma was invited to participate in the study after informed consent. The study showed that 42.4% of the study population used herbal medicine for the treatment of eumycetoma at some stage of their illness. The commonly used herbs were Moringa oleifera, Acacia nilotica, Citrullus colocynthis and Cuminum cyminum. Most of the patients claimed no benefits from the herbal treatment. Ninety one patients (29.3%) had encountered complications with herbal treatment. The high prevalence of herbal treatment encountered in the study can be explained by the patients' dissatisfaction with the current medical therapeutic modalities. To reduce the high prevalence of herbal medicine usage, governmental control and health policies are mandatory; likewise, native healers need to be educated in that. Moringa oleifera was the commonly used herb in this study and many reports claimed medicinal properties of this tree; hence, further in-depth studies to determine the active ingredients in the different parts of the tree and its effect are required.

In vitro susceptibility of Madurella mycetomatis, prime agent of Madura foot, to tea tree oil and artemisinin.

OBJECTIVES: Eumycetoma caused by Madurella mycetomatis is treated with surgery and high doses of itraconazole and ketoconazole. These agents are toxic, and new therapies are required. METHODS: MICs were determined for artemisinin and tea tree oil, two natural herbal compounds. RESULTS: Artemisinin was not active against M. mycetomatis, but tea tree oil did inhibit its growth. Since tea tree oil's prime component easily penetrates the skin, tea tree oil could be a useful agent in the treatment of eumycetoma. CONCLUSIONS: Tea tree oil is active in vitro against M. mycetomatis.

Scedosporium apiospermum soft tissue infection successfully treated with voriconazole: potential pitfalls in the transition from intravenous to oral therapy.

An immunocompromised patient with an invasive soft tissue infection due to Scedosporium apiospermum was successfully treated with voriconazole and surgical debridement. After transition from intravenous to oral therapy, successive adjustments of the oral dose were required to achieve complete resolution. For soft tissue infections due to molds characterized by thin, septate hyphae branching at acute angles, voriconazole should be considered a first-line antifungal agent. The potential usefulness of plasma voriconazole levels for guiding optimal therapy should be investigated.

Antifungal activities of posaconazole and granulocyte-macrophage colony-stimulating factor ex vivo and in mice with disseminated infection due to Scedosporium prolificans.

Invasive infection due to Scedosporium prolificans is characterized by drug resistance and a high rate of mortality. The effects of posaconazole (POS), an investigational antifungal triazole, murine granulocyte-macrophage colony-stimulating factor (GM-CSF), and their combination against S. prolificans were evaluated ex vivo and in a newly developed murine model of disseminated infection due to this organism. When POS was combined with polymorphonuclear leukocytes from untreated or GM-CSF-treated mice (P < 0.01) ex vivo, it had increased activity in terms of the percentage of hyphal damage. Immunocompetent BALB/c mice were infected with 4 x 10(4) conidia of S. prolificans via the lateral tail vein. At 24 h postinfection the mice were treated with GM-CSF (5 microg/kg of body weight/day subcutaneously), POS (50 mg/kg/day by gavage), both agents, or saline only. Half of the brain, lung, liver, and kidney from each animal were cultured; and the other half of each organ was processed for histopathology. The mean survival times were 7.0 +/- 0.3 days for the controls, 7.4 +/- 0.4 days for POS-treated mice, 8.0 +/- 0.3 days for GM-CSF-treated mice (P = 0.08 compared with the results for the controls), and 7.3 +/- 0.3 days for POS-GM-CSF-treated mice. Fungal burdens (determined as the numbers of CFU per gram of tissue) were found in descending orders of magnitude in the kidneys, brains, livers, and lungs. The burdens were significantly reduced in the brains of GM-CSF-treated mice (P < 0.05) and the livers of POS-treated mice (P < 0.05). The numbers of lesions in the organs closely corresponded to the fungal burdens. GM-CSF tended to prolong survival (P = 0.08 compared with the results for the controls). While the combination of POS and GM-CSF showed enhanced activity ex vivo, it did not increase the activities of the two agents against this highly refractory filamentous fungus in mice.

Correlation between in vitro susceptibility of Scedosporium apiospermum to voriconazole and in vivo outcome of scedosporiosis in guinea pigs.

We have evaluated the efficacy of voriconazole (VRC) in a systemic infection by Scedosporium apiospermum in immunodepressed guinea pigs. Animals were infected with two strains; one required a VRC MIC of 0.5 to 1 microg/ml, common for this fungus, and the other required a high MIC (8 microg/ml), unusual in this species. VRC prolonged survival and reduced fungal load in kidney and brain tissues of the animals infected with the first strain but was unable to prolong survival or to reduce fungal load in brain tissue for the latter strain.

Scedosporium apiospermum keratitis treated with itraconazole.

Mycotic keratitis usually occurs in conjunction with trauma to the cornea. Scedosporium apiospermum, a dematiaceous fungus linked to the teleomorph Pseudallescheria boydii is not a common agent of mycotic keratitis. A 22-year old male patient with mycotic keratitis due to S. apiospermum is presented. In in vitro susceptibility testing, the isolate showed resistance against amphotericin B (minimum inhibitory concentration [MIC] 16 microg ml(-1)) but was susceptible to itraconazole (ITC) and fluconazole with MICs of 0.125 microg ml(-1) and 4 microg ml(-1), respectively. The patient was cured clinically after ITC treatment and surgical intervention. Azoles may be superior for eliminating S. apiospermum from infected ocular sites.

Cure of orthopaedic infection with Scedosporium prolificans, using voriconazole plus terbinafine, without the need for radical surgery.

Scedosporium prolificans infections of normal hosts usually require extensive debridement and sometimes amputation to effect cure, due to the intrinsic resistance of this species to available antifungal agents. Newer agents have not tested favourably. Variable results are obtained with voriconazole, and 100% resistance is described with echinocandins. Itraconazole and terbinafine has offered synergy against various moulds including S. prolificans. In vivo success is reported with the azole/terbinafine combination in S. apiospermum pulmonary infection and Pythium insidiosum periorbital cellulitis. We report a case of orthopaedic infection in a non-immunocompromised host with S. prolificans, in which the combinations of itraconazole/terbinafine and voriconazole/terbinafine showed synergy in vitro, and success was achieved without radical surgery, using voriconazole and terbinafine.

Breakthrough Scedosporium apiospermum (Pseudallescheria boydii) brain abscess during therapy for invasive pulmonary aspergillosis following high-risk allogeneic hematopoietic stem cell transplantation. Scedosporiasis and recent advances in antifungal therapy.

Systemic scedosporiasis due to the anamorph or asexual form Scedosporium apiospermum (Pseudallescheria boydii) has become an important cause of opportunistic mycosis, especially in patients undergoing high-risk hematopoietic stem cell transplantation. We report a case of rapidly progressive cerebellar hyalohyphomycosis due to Scedosporium apiospermum in an allogeneic marrow graft recipient receiving treatment for severe graft-versus-host disease. This fatal breakthrough intracranial abscess, due to amphotericin B-resistant (minimum inhibitory concentration > 16 micro g/ml) mold, developed during the course of systemic antifungal therapy given for multicentric pulmonary aspergillosis. Despite treatment with high-dose Abelcet (10 mg/kg daily), free amphotericin B was not detected in postmortem cerebellar tissue. A broad-spectrum triazole-based agent (voriconazole/UK-109, 496--Vfend), and a novel fungal cell wall inhibitor, an echinocandin/pneumocandin analog (caspofungin/MK-0991--Cancidas), which exhibit excellent in vitro activity against most clinical Pseudallescheria boydii-Scedosporium apiospermum isolates, have recently become available in the United States and may provide much needed treatment options for patients at risk.