In vitro activity of miltefosine as a single agent and in combination with voriconazole or posaconazole against uncommon filamentous fungal pathogens

Biswas, Chayanika; Sorrell, Tania C.; Djordjevic, Julianne T.; Zuo, Xiaoming; Jolliffe, Katrina A.; Chen, Sharon C.-A.

doi:10.1093/jac/dkt282

Cited by 63 publications

(57 citation statements)

References 18 publications

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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.…”

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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 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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“…In 2006, Widmer et al used a 50% inhibition endpoint (9), while more recently, other authors chose a 100% inhibition endpoint (17). For our study, we determined interactions using both of these endpoints.…”

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“…Recently, Biswas et al reported an in vitro synergistic effect for miltefosine in combination with azoles against some Fusarium or Scedosporium isolates as well as several mucormycete strains but decided not to test the combinations against azole-susceptible strains (17). However, even when a strain is susceptible to both drugs independently, a combination may still be useful to potentially clear the pathogen more quickly and stave off the emergence of resistance.…”

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confidence: 99%

In Vitro Combination of Voriconazole and Miltefosine against Clinically Relevant Molds

Imbert

Palous

Meyer

et al. 2014

Antimicrob Agents Chemother

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dInvasive infections caused by filamentous fungi are a major threat for immunocompromised patients. Innate/acquired resistance to antifungal drugs might necessitate combination therapies. We assessed the potential combination of voriconazole with miltefosine, an original drug with antifungal activity against 33 clinically relevant mold isolates, including both azole-susceptible and -resistant Aspergillus. Using complete inhibition as an endpoint, interactions were indifferent for 32/33 isolates. An alternative 50% inhibition endpoint showed synergistic interactions for 14/33 isolates. Antagonism was absent.

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“…describe the successful treatment of S. prolificans osteomyelitis in an immunocompetent child with miltefosine, terbinafine and voriconazole therapy . Interestingly, a recent study demonstrated in vitro synergy of miltefosine, voriconazole and posaconazole against S. prolificans …”

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confidence: 99%

Disseminated Scedosporium prolificans infection in an ‘extensive metaboliser’: navigating the minefield of drug interactions and pharmacogenomics

Trubiano

Paratz

Wolf

et al. 2014

Mycoses

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We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

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In vitro activity of miltefosine as a single agent and in combination with voriconazole or posaconazole against uncommon filamentous fungal pathogens

Cited by 63 publications

References 18 publications

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

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

In Vitro Combination of Voriconazole and Miltefosine against Clinically Relevant Molds

Disseminated Scedosporium prolificans infection in an ‘extensive metaboliser’: navigating the minefield of drug interactions and pharmacogenomics

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