In Vitro Activities of Miltefosine and Two Novel Antifungal Biscationic Salts against a Panel of 77 Dermatophytes

Tong, Zhongsheng; Widmer, Fred; Sorrell, Tania C.; Guse, Zofia; Jolliffe, Katrina A.; Halliday, Catriona; Lee, Ok Cha; Kong, Fanrong; Wright, Lesley C.; Chen, Wen

doi:10.1128/aac.01382-06

Cited by 42 publications

(32 citation statements)

References 29 publications

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“…A larger spectrum of MIC values (0.5-4 mg ml 21 ) was reported by Brilhante et al (2014) for the treatment of the mycelial form of S. brasiliensis. The MIC values for miltefosine reported here are in line with the 2 mg ml 21 value reported for the treatment of Candida albicans, Candida glabrata, Candida krusei, Crytococcus gatti, Crytococcus neoformans, Aspergillus fumigatus and Trichophyton mentagrophytes with this drug (Widmer et al, 2006;Tong et al, 2007;Ravu et al, 2013).…”

Section: Discussionsupporting

confidence: 88%

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Borba-Santos

Gagini

Ishida

et al. 2015

Journal of Medical Microbiology

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Sporotrichosis is a common mycosis caused by dimorphic fungi from the Sporothrix schenckii complex. In recent years, sporotrichosis incidence rates have increased in the Brazilian state of Rio de Janeiro, where Sporothrix brasiliensis is the species more frequently isolated from patients. The standard antifungals itraconazole and amphotericin B are recommended as first-line therapy for cutaneous/lymphocutaneous and disseminated sporotrichosis, respectively, although decreased sensitivity to these drugs in vitro was reported for clinical isolates of S. brasiliensis. Here, we evaluated the activity of the phospholipid analogue miltefosine -already in clinical use against leishmaniasis -towards the pathogenic yeast form of S. brasiliensis isolates with low sensitivity to itraconazole or amphotericin B in vitro. Miltefosine had fungicidal activity, with minimum inhibitory concentration (MIC) values of 1-2 mg ml "1 . Miltefosine exposure led to loss of plasma membrane integrity, and transmission electron microscopy (TEM) analysis revealed a decrease in cytoplasmic electron density, alterations in the thickness of cell wall layers and accumulation of an electron-dense material in the cell wall. Flow cytometry analysis using an antimelanin antibody revealed an increase in cell wall melanin in yeasts treated with miltefosine, when compared with control cells. The cytotoxicity of miltefosine was comparable to those of amphotericin B, but miltefosine showed a higher selectivity index towards the fungus. Our results suggest that miltefosine could be an effective alternative for the treatment of S. brasiliensis sporotrichosis, when standard treatment fails. Nevertheless, in vivo studies are required to confirm the antifungal potential of miltefosine for the treatment of sporotrichosis. INTRODUCTIONSporotrichosis is the most frequent subcutaneous mycosis in Latin America, and has high incidence rates in Brazil, especially in the Rio de Janeiro state, where zoonotic transmission prevails (Barros et al., 2010). This disease is caused by dimorphic fungal species from the Sporothrix schenckii complex (Marimon et al., 2007;, including Sporothrix brasiliensis, the most virulent species (ArrillagaMoncrieff et al., 2009;Fernandes et al., 2013) and the most prevalent in the clinical cases from the Rio de Janeiro state (Oliveira et al., 2011;Rodrigues et al., 2013a;Borba-Santos et al., 2014). In zoonotic transmission, sporotrichosis is mainly acquired by scratches, bites or direct contact with lesion secretion from contaminated animals, where yeasts are the infective forms (Rodrigues et al., 2013b).The 'gold standard' treatment for cutaneous and lymphocutaneous forms of sporotrichosis is itraconazole, while amphotericin B is the first-line drug of choice for disseminated forms of the disease (Kauffman et al., 2007). However, recent reports demonstrated that these drugs are less potent against S. brasiliensis isolates, which have high minimum inhibitory concentration (MIC) values in vitro for these antifungals (Ottonelli Stopiglia et a...

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Section: Discussionsupporting

confidence: 88%

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Borba-Santos

Gagini

Ishida

et al. 2015

Journal of Medical Microbiology

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“…The contribution of surgery is also difficult to assess. Other compounds, such as miltefosine, widely used in the treatment of visceral leishmaniasis and exhibiting in vitro fungicidal activity against several molds, may need evaluation (29,33). Adjuvant therapies with cytokines, such as gamma interferon, and growth factors, such as granulocyte colony-stimulating factor (G-CSF), have been used to treat IFIs, including Scopulariopsis infections (14,25,27,30).…”

Section: Case Reportmentioning

confidence: 99%

Fatal Invasive Infection with Fungemia Due to Microascus cirrosus after Heart and Lung Transplantation in a Patient with Cystic Fibrosis

et al. 2011

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Scopulariopsis species are rarely but increasingly recognized as opportunistic pathogens in immunocompromised patients. We report on a patient suffering from cystic fibrosis who developed disseminated fungal infection due to a rare Scopulariopsis species, Microascus cirrosus, after heart and lung transplantation. Despite antifungal combination therapy with voriconazole and caspofungin, the patient died 4 weeks after transplantation. Diagnostic difficulties and optimal management of disseminated Scopulariopsis/Microascus infections are discussed. CASE REPORTA 36-year-old man suffering from cystic fibrosis was admitted to our hospital in June 2009 for a heart and bilateral lung transplantation. He had a first lung transplantation in 1997 but had chronic rejection since 2001 in spite of several immunosuppressive regimens. His medical history also included renal failure (hemodialysis since 2007), diabetes mellitus, and airway colonization with a multiresistant Pseudomonas aeruginosa. Short antifungal therapy courses had been prescribed over the past years for various yeasts (Candida spp.) and molds (Aspergillus, Paecilomyces, and Fusarium species) colonizing his respiratory tract, but there was no evidence of previous isolation of a Scopulariopsis species. At the time of admission, sputum cultures grew only Candida albicans, and fluconazole was thus prescribed (200 mg intravenously [i.v.] after each dialysis).Following graft surgery, the immunosuppressive regimen included induction therapy with basiliximab (anti-CD25 antibody [20 mg i.v. on the day of transplantation and on day 4]) and solumedrol (10 mg/kg of body weight on the day of transplantation, followed by three 120-mg doses per day), followed by cyclosporine adjusted according to dialysis parameters to reach therapeutic blood levels (300 to 350 ng/ml) and solumedrol. Antimicrobial therapy consisted of a broad-spectrum antibiotherapy with tobramycin, vancomycin, piperacillin, and tazobactam. Although the patient seemed to do well in the early postoperative period, with apyrexia and extubation on day 3, his white blood cell count (WBC) increased slowly starting on the day after transplantation, reaching 20 ϫ 10 9 cells/liter by day 8 postsurgery. On day 11 after the operation (WBC ϭ 30 ϫ 10 9 cells/liter), a thoracic computed tomodensitometry (TDM) revealed bilateral pulmonary effusions (Fig. 1A), which were drained on day 19 without clinical improvement. Bilateral hemorrhagic pleural fluid specimens revealed several regular, hyaline, and branched septate hyphae on direct examination ( Fig. 2A), leading to the diagnosis of proven invasive fungal infection (IFI) according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria (8). The patient was given an antifungal combination therapy of voriconazole i.v. (6 mg/kg every 12 h as a loading dose followed by two 4-mg/kg doses a day) and caspofungin (70 mg/day ...

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“…Recently, some reports have attributed the development of resistance to miltefosine during the treatment of visceral leishmaniasis to the overexpression of an ABC transporter (Leishmania tropica MDR1 [LtrMDR1]) and to changes in membrane sterol composition (25,26). The broad-spectrum antifungal activity of miltefosine has been demonstrated in vitro against planktonic cells of several medically important fungi, including dermatophytes, Candida sp., Cryptococcus sp., Aspergillus sp., Fusarium sp., Scedosporium sp., Histoplasma capsulatum, Rhizopus sp., and Sporothrix schenckii (27)(28)(29)(30)(31)(32), and no reports about resistance development have been made so far.…”

mentioning

confidence: 99%

In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis

Vila

Chaturvedi

Rozental

et al. 2015

Antimicrob Agents Chemother

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The generation of a new antifungal against Candida albicans biofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potent in vitro activity against multiple fluconazole-susceptible and -resistant C. albicans clinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibits C. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library of C. albicans transcription factor mutants provided additional insight into the activity of miltefosine against C. albicans growing under planktonic and biofilm conditions. Finally, we demonstrate the in vivo efficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis.T he recent elevated incidence of fungal infections is related to the indiscriminate use of broad-spectrum antibiotics and corticosteroids, the increase in the number of invasive medical procedures, and the AIDS epidemic. The persistence of these infections is usually associated with the fungal ability to form biofilms on implantable medical devices (1). Candida spp. can adhere and form biofilms on the surface of different medical devices (such as catheters, prostheses, pacemakers, and heart valves) and on the mucosal surface, leading to a superficial infection with a complex structure in which hyphae, pseudohyphae, and yeasts grow surrounded by a dense extracellular matrix, composed mainly of proteins, polysaccharides, and extracellular DNA (eDNA) (2). Hematogenous dissemination may occur due to the detachment of yeasts from the top layer of the biofilm, a phenomenon known as dispersion (3). Candida albicans is the third leading cause of infections related to the use of catheters (4, 5). Development of candidemia during hospitalization when central venous catheters are used can happen in 72% of cases in Latin America (6), and the worldwide mortality rate for catheter-related candidemia can reach 41% (7). Oropharyngeal candidiasis (OPC) is characterized by Candida growth as a biofilm over the tongue and oral mucosa. OPC has been described as the most frequent opportunistic fungal infection among HIV-positive patients, and it is estimated that more than 90% of these patients develop this infection at some time during the progression of their disease (8, 9).The increased resistance to antifungal agents is the main clinical complication associated with biofilm formation. ...

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In Vitro Activities of Miltefosine and Two Novel Antifungal Biscationic Salts against a Panel of 77 Dermatophytes

Cited by 42 publications

References 29 publications

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Fatal Invasive Infection with Fungemia Due to Microascus cirrosus after Heart and Lung Transplantation in a Patient with Cystic Fibrosis

In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis

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