title: Caspofungin prolongs survival of transiently neutropenic rats with advanced-stage invasive pulmonary aspergillosis.
abstract: A high-dose-step-down strategy for caspofungin treatment was evaluated in an experimental model of advanced-stage invasive pulmonary aspergillosis. The therapeutic efficacy of caspofungin in relation to the severity of invasive pulmonary infection caused by Aspergillus fumigatus in transiently neutropenic rats was investigated by using rat survival and the decrease in the fungal burden as the parameters of efficacy. When treatment was started at either 16 h or 24 h after fungal inoculation, caspofungin administered intraperitoneally at 4 mg/kg of body weight/day for 10 days was highly effective (100% and 93% rat survival, respectively). However, only 27% rat survival was obtained when treatment was started at 72 h, when the rats had advanced-stage infection. Increasing the dose from 4 to 10 mg/kg/day could compensate for the decrease in efficacy and resulted in 67% rat survival. The high dose of 10 mg/kg/day for 10 days did not appear to be necessary since a high-dose-step-down dosing schedule with 10 mg/kg/day for 3 days followed by 4 mg/kg/day for 7 days was equally effective. At 10 days after the end of treatment with 10 mg/kg/day caspofungin, the level of neither A. fumigatus DNA nor A. fumigatus galactomannan in the infected left lung was significantly decreased. In contrast, A. fumigatus galactomannan concentrations in serum were significantly decreased. The levels of creatinine, blood urea nitrogen, alanine aminotransferase, and asparate aminotransferase were not elevated during treatment. Caspofungin is effective for the treatment of invasive pulmonary aspergillosis in transiently neutropenic rats and is even effective in rats with advanced-stage infection. In this model, the administration of high-dose-step-down treatment was as effective as treatment with high doses for the whole treatment period.
authors.affiliation: Erasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. w.vandesande@erasmusmc.nl
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: van de Sande
authors.forename: Wim
authors.initials: W
authors.lastname: van Vianen
authors.forename: Marian T
authors.initials: MT
authors.lastname: ten Kate
authors.forename: Jolanda
authors.initials: J
authors.lastname: Vissers
authors.forename: John
authors.initials: J
authors.lastname: Laurijsens
authors.forename: Mehri
authors.initials: M
authors.lastname: Tavakol
authors.forename: Bart J A
authors.initials: BJ
authors.lastname: Rijnders
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality*; D001232:Aspergillus fumigatus / Q000187:drug effects; D000077336:Caspofungin; D004195:Disease Models, Animal; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D055666:Lipopeptides; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality*; D009503:Neutropenia / Q000150:complications*; D051381:Rats; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin