Efficacy of humanized single large doses of caspofungin on the lethality and fungal tissue burden in a deeply neutropenic murine model against Candida albicans and Candida dubliniensis
Received 18 December 2018
Accepted for publication 30 March 2019
Published 1 July 2019 Volume 2019:12 Pages 1805—1814
Checked for plagiarism Yes
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Peer reviewers approved by Ms Justinn Cochran
Peer reviewer comments 3
Editor who approved publication: Dr Joachim Wink
Eszter Prépost,1 Zoltán Tóth,1 David S Perlin,2 Rudolf Gesztelyi,3 Gábor Kardos,1 Renátó Kovács1,4 Fruzsina Nagy,1 Lajos Forgács,1 László Majoros1
1Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 2Public Health Research Institute, New Jersey Medical School-Rutgers, Newark, NJ, USA; 3Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 4Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
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.
Keywords: humanized caspofungin doses, intermittent dosing regimen of echinocandins, Candida albicans complex, fungal tissue burden, echinocandin resistance
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