Correlation of in vitro activity, serum levels, and in vivo efficacy of posaconazole against Rhizopus microsporus in a murine disseminated infection

Abstract

A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.

FIG. 1.

Cumulative mortality of mice infected with Rhizopus microsporus FMR 3542 (A), IHEM 4770 (B), UTHSC 01-983 (C), or UTHSC R-3466 (D) and treated with LAMB or POS. ^a, P < 0.05 for comparison with the control; ^b, P < 0.05 for comparison with POS 40; ^c, P < 0.05 for comparison with POS 20 BID. LAMB 10, liposomal amphotericin B administered at 10 mg/kg i.v. once a day; POS 40, posaconazole administered at 40 mg/kg p.o. once a day; POS 20 BID, posaconazole administered at 20 mg/kg p.o. twice a day. Groups of 10 mice were randomly established, one for each treatment and one as a control.

FIG. 2.

Effects of the antifungal treatment on colony counts of Rhizopus microsporus strains FMR 3542 (A), IHEM 4770 (B), UTHSC 01-983 (C), and UTHSC R-3466 (D) in the brains and kidneys of mice. ^a, P < 0.002 for comparison with the control; ^b, P < 0.002 for comparison with POS 40; ^c, P < 0.002 for comparison with POS 20 BID. Horizontal lines indicate mean values. LAMB 10, liposomal amphotericin B administered at 10 mg/kg i.v. once a day; POS 40, posaconazole administered at 40 mg/kg p.o. once a day; POS 20 BID, posaconazole administered at 20 mg/kg p.o. twice a day. Groups of 10 mice were randomly established, one for each treatment and one as a control.