<p>Efficacy of humanized single large doses of caspofungin on the lethality and fungal tissue burden in a deeply neutropenic murine model against <em>Candida albicans</em> and <em>Candida dubliniensis</em></p>

Abstract

Background Echinocandins are the first-line therapy for treatment of invasive Candida infections, but the mortality rate remains high, calling for novel strategies. Giving single larger echinocandin doses infrequently is an alternative regimen. Our aim was to test this novel approach in a neutropenic murine model. Materials and methods We compared the in vivo efficacy of single 10 and 40 mg/kg of caspofungin (2.5× and 10× the normal humanized dose) to that of the same cumulative doses of daily 2 and 8 mg/kg doses for 5 days against 2 each of wild-type C. albicans and C. dubliniensis as well as echinocandin resistant C. albicans . As a comparator, we tested daily 1 mg/kg amphotericin B. Results In lethality experiments, all caspofungin and amphotericin B regimens improved survival against wild-type C. albicans and C. dubliniensis clinical isolates ( P <0.0001) and decreased the mean fungal kidney burdens of both species compared to controls. However, fungal kidney burden decreases were not always statistically significant, especially with single 10 or 40 mg/kg caspofungin doses. Amphotericin B was the least active drug against wild-type C. albicans . Against echinocandin-resistant strains, monodose 40 mg/kg caspofungin and 1 mg/kg of daily amphotericin B were effective in lethality experiments. Although, significant kidney CFU decreases were never found, except for amphotericin B against one of the isolates ( p <0.05 at day 3 and p <0.001 at day 6). Conclusion Single 40 mg/kg caspofungin and 1 mg/kg amphotericin B proved to be effective in the lethality experiments against wild-type and echinocandin-resistant C. albicans and wild-type C. dubliniensis . This was not always shown regarding fungal tissue burdens. Single caspofungin doses used in mice in this study are attainable in humans as well, suggesting a potential place of this dosing strategy not only in prevention but also in curative treatment of evolved invasive Candida infections.

Comparison of in vivo pathogenicity of four Candida auris clades in a neutropenic bloodstream infection murine model

“…Fungal tissue burden was determined by quantitative culturing. The lower limit of detection was 100 CFU/g of tissue [18].…”

“…C. auris isolates were identified by a combination of ribosomal DNA gene sequencing targeting the 28S rRNA and/or ITS1 regions, which was also used for clade delineation [9,10]. C. albicans isolates were derived from a previous study [18]. Strains were stored at -70°C.…”

“…BALB/c male mice (23-25 g) were given cyclophosphamide 4 days before infection (150 mg/kg), 1 day before infection (100 mg/kg), 2 and 5 days post-infection (100 mg/kg) in the fungal tissue burden experiments; in the lethality experiments, immunosuppression was continued by administration of 100 mg/kg cyclophosphamide every third day until the end of the experiment at the 21st day [18]. The Guidelines for the Care and Use of Laboratory Animals were strictly followed during maintenance of the animals; experiments were approved by the Animal Care Committee of the University of Debrecen (permission no.…”

“…Dead animals (1-2 from each clade) were dissected for histopathology. Survival rates were compared within the same clade using the Kaplan-Meier log rank test; then data of isolates of the same clade were aggregated and survival was also analysed between different fungal clades [18]. Statistical tests were performed in Graph Pad 6.0.3.…”

“…Mean fungal tissue burdens produced by different isolates/clades in the same organs on day 2 or 6 were compared using the Kruskal-Wallis test with Dunn's post-test. T-test (with Welch's correction, where appropriate) was used to compare the mean fungal tissue burdens at day 2 with day 6 for the same organ with each isolate [18].…”