Evaluation of the Efficacies of Amphotericin B, Posaconazole, Voriconazole, and Anidulafungin in a Murine Disseminated Infection by the Emerging Opportunistic Fungus Sarocladium (Acremonium) kiliense

Abstract

We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1¡3)-␤-D-glucan serum levels. In general, the four antifungal drugs showed high MICs and poor in vitro activity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (>16 g/ ml), showed the highest efficacy. The (1¡3)-␤-D-glucan serum levels were equally reduced by all drugs evaluated.A cremonium kiliense is a saprobic fungus with a worldwide distribution which has been reported in recent years as an emerging opportunistic pathogen able to cause a wide range of human infections (1-4). Localized infections, such as mycetoma, keratitis, or onychomycosis, are acquired mainly by immunocompetent patients through trauma (5-11). Invasive infections generally affect immunosuppressed hosts such as those undergoing transplantation or those with AIDS, resulting in a high degree of fatality (12-16). More rarely, though, invasive infections have also been reported in immunocompetent individuals (17,18). Recently, based on molecular studies, this fungus has been transferred to the genus Sarocladium as Sarocladium kiliense (1). This species is the most clinically relevant of the genus and apparently also the most virulent (4,19,20). Considering that the morphological identification of these fungi is difficult, it is likely that some clinical isolates of this species have been misidentified as Acremonium strictum, another clinically important species of Acremonium (19). Infections by Acremonium spp. are difficult to treat due to the intrinsic resistance to the current antifungal agents, and an effective treatment has not yet been determined (19,(21)(22)(23). Amphotericin B (AMB) is the drug most commonly used to treat severe fungal infections caused by opportunistic molds (4). Despite its poor in vitro activity and variable clinical results, this drug still remains the first therapeutic choice against invasive Acremonium infections (2, 4, 19). Clinical experience with other drugs, such as posaconazole (PSC), voriconazole (VRC), and the echinocandins, is very poor.To evaluate possible therapeutic strategies, we tested the efficacies of PSC, VRC, and anidulafungin (AFG) compared to that of AMB against S. kiliense in a recently developed murine model of disseminated infection (20). MATERIALS AND METHODSThree clinical strains of Sarocladium kiliense, UTHSC 01-2238, UTHSC 03-3197, and UTHSC 07-550, previously identified by...

SarocladiumandAcremoniuminfections: New faces of an old opportunistic fungus

“…It is of note that most treatment in the reviewed cases was based on AMB therapy (Table 1), which contrasts with the available in vitro susceptibility data, 1,8,26,148,149 and also with the in vivo data retrieved from murine models, in which, very interestingly, PSC and the combination AFG + PSC were the treatments with the most favourable outcomes. 154,155 However, according to most of the cases summarised in this review, VRC-based therapy together with, if necessary, surgical debridement is the most likely successful treatment when initiated early.…”

“…Regarding in vivo antifungal studies, monotherapies consisting of PSC, VRC, AFG or AMB as well as combined treatments of AFG + PSC, AFG + VRC and AMB + VRC against experimental infections have been tested against A kiliense in a murine model and compared to in vitro data 154,155 . In this case, although PSC was inactive in the in vitro setting, treatment with this drug in mice showed the best efficacy among the antifungals tested.…”

Phylogeny of <I>Sarocladium</I> (<I>Hypocreales</I>)

“…Traditionally, species of Sarocladium have been reported as plant pathogens or as saprobes ( Gams & Hawksworth 1975 , Chen et al 1986 , Helfer 1991 ). However, numerous recent studies have demonstrated that some might also be involved in human infections ( Das et al 2010 , de Hoog et al 2011 , Khan et al 2011 , Perdomo et al 2011 , Summerbell et al 2011 , Fernández-Silva et al 2013 , Júnior et al 2013 , Sharma et al 2013 ). Specifically, the new species described here, i.e., S. bifurcatum , S. hominis , S. pseudostrictum and S. subulatum , were isolated from human samples.…”

Brote de fungemias por Sarocladium kiliense en ocho hospitales públicos por contaminación intrínseca de ondansetrón intravenoso

“…A pesar del alto número de casos identificados, no se registraron fallecidos con letalidad causada por la infección y sólo en uno de los dos fallecidos la auditoría realizada por médicos locales estimó que la infección pudo contribuir al fallecimiento, sin ser la causa de ella. Esta situación pudo asociarse a una baja virulencia del hongo, a pesar de tratarse de una población mayoritaria con inmunocompromiso y a la alta resistencia encontrada a los tratamientos antifúngicos, reflejada en las elevadas CIMs a los distintos compuestos antifúngicos estudiados, resultado consistente con otras publicaciones 12, 21 .…”