Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis.
OBJECTIVE
Evaluation of the potential of caspofungin, in relation to pharmacokinetics, in order to optimize its use in the treatment of filamentous fungal infections.


METHODS
The in vitro antifungal activity, pharmacokinetics and therapeutic efficacy of caspofungin versus amphotericin B was investigated in vitro as well as in a model of aerogenic Aspergillus fumigatus infection in neutropenic rats, using rat survival and decrease in fungal burden as parameters for therapeutic efficacy.


RESULTS
In contrast to amphotericin B, caspofungin shows a concentration-dependent gradual decrease in fungal growth in vitro, which makes it difficult to perform visual readings of antifungal activity (CLSI guidelines). The quantitative XTT [2,3-bis(2-methoxy-4-nitro-5-[(sulphenylamino) carbonyl]-2H-tetrazolium-hydroxide] assay measuring a decrease in fungal metabolic activity seems more appropriate for caspofungin susceptibility testing. Using this assay, in vitro caspofungin was 4-fold less active than amphotericin B. In the infection model, therapy was started 16 h after fungal inoculation, and continued once daily for 10 days. Caspofungin was administered intraperitoneally at 1, 2, 3 or 4 mg/kg/day (CAS 1, 2, 3 or 4), amphotericin B at 1 mg/kg/day (AMB 1). Treatment with CAS 1 or AMB 1 provided modest prolongation of animal survival. The combination of caspofungin and amphotericin B did not show additive effects. Increasing the dosage of caspofungin to 2, 3 or 4 mg/kg/day resulted in a dose-dependent significant increase in efficacy. There was 100% survival among rats in the CAS 4 group, which was correlated with a significant decrease in fungal burden, based on the concentration of A. fumigatus galactomannan in serum and lung tissue and quantification of A. fumigatus DNA in lung tissue. Pharmacokinetic analysis suggested that the CAS 4 dose in rats produced drug exposure comparable to the human situation, visualized by similar 24 h AUC and trough concentrations.


CONCLUSIONS
The therapeutic efficacy of caspofungin is superior to amphotericin B, which seemed to be discrepant with their in vitro antifungal activity.
van Vianen
Wim
W
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, The Netherlands. w.vanvianen@erasmusmc.nl
de Marie
Siem
S
ten Kate
Marian T
MT
Mathot
Ron A A
RA
Bakker-Woudenberg
Irma A J M
IA
D000666:Amphotericin B / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000077336:Caspofungin; D004195:Disease Models, Animal; D054714:Echinocandins; D006801:Humans; D055666:Lipopeptides; D008168:Lung / Q000737:chemistry / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D016896:Treatment Outcome
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000666:Amphotericin B; D000077336:Caspofungin