Correlation of in vitro activity and in vivo efficacy of itraconazole intravenous and oral solubilized formulations by testing Candida strains with various itraconazole susceptibilities in a murine invasive infection

• Published in: Journal of antimicrobial chemotherapy 2011-03, Vol.66 (3), p.626-634
• Main Authors: UCHIDA, Katsuhisa, SHIMOGAWARA, Kosuke, YAMAGUCHI, Hideyo
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacology; Antimicrobial agents; Biological and medical sciences; Candida; Candida - drug effects; Candidiasis - drug therapy; Disease Models, Animal; Fungal infections; Fungi; Injections, Intravenous; Itraconazole - administration & dosage; Itraconazole - pharmacology; Male; Medical sciences; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Microbiology; Pharmacology. Drug treatments; Rodent Diseases - drug therapy; Rodents; Survival Analysis; Treatment Outcome
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkq475

To examine whether in vitro antifungal susceptibility test results correlate with in vivo efficacy of two cyclodextrin-solubilized itraconazole formulations (intravenous and oral) against Candida in a murine model of invasive infection. A selected set of 12 Candida spp. strains with various itraconazole susceptibilities were tested. We studied the efficacy of intravenous and oral itraconazole administered once daily at dosages of 0.63, 2.5, 10 and 40 mg/kg body weight in mice lethally infected with each tested strain. Survival of mice in each treated group was monitored daily until the death of all control mice and compared between groups. Survival of mice infected with 9 of 12 Candida strains with itraconazole MICs of ≤0.016-2.0 mg/L was significantly prolonged by treatment with intravenous itraconazole at dosages of 2.5 or 10 mg/kg and above. In contrast, the other three strains resistant to 8 mg/L itraconazole in vitro were refractory to the therapy, even at the highest itraconazole dosage (40 mg/kg). Closely similar in vivo data were obtained with the oral itraconazole therapy. The effective doses of the two itraconazole formulations increased with increasing itraconazole MICs for the infecting strains. The in vivo efficacy of intravenous and oral itraconazole correlated with the in vitro susceptibility data.