GROLL AH, MICKIENE D, PETRAITIS V, PETRAITIENE R, HEMMINGS M, ROUSSILLON K, BACHER JS, WALSH TJ; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. J-1606.
Immunocompromised Host Section, National Cancer Institute, Bethesda, MD
BACKGROUND: Multilamellar liposomal nystatin (L-Nys) is a novel antifungal polyene compound with distinct pharmacokinetic properties. Little is known, however, about the pharmacokinetic and pharmacodynamic relationships of L-Nys in tissue-invasive Candida infections. METHODS: Efficacy and concentration-effect relationships of IV L-Nys were investigated in a non-immunocompromised rabbit model of disseminated candidiasis. Eight animals each received L-Nys at 2.5 mg/kg BID or at 5mg/kg QD for 7 days starting 48 hours after IV inoculation with 1x10[6] blastoconidia of C.albicans. Untreated animals and animals treated with amphotericin B (D-AmB; 1mg/kg QD) and liposomal amphotericin B (L-AmB; 5mg/kg QD) served as controls. Plasma and tissues were sampled after the 6th dose and at autopsy, respectively, for assay of nystatin. Responses to treatment were assessed by survival through day 8 post inoculation and the residual fungal tissue burden at autopsy. RESULTS: The two dosage regimens of L-Nys had similar efficacy as D-AmB and L-AmB on the residual fungal tissue burden of kidney, liver, spleen and lungs, but not the brain, where both L-Nys regimens were less active (p<0.01). In comparison to animals receiving D-AmB, L-AmB (p<0.01) and L-Nys at 2.5 mg/kg BID (p<0.05), rabbits receiving L-Nys at 5 mg/kg QD had significantly decreased survival due to severe CNS-candidiasis with occurrence of generalized seizures. Both dosage regimens of L-Nys produced mean brain tissue levels that were below the MIC of the infecting isolate at 0.5 and 12 hours post dose. The clinical failure of the QD regimen correlated with a shorter mean Ttau>MIC in plasma as compared to the BID regimen. CONCLUSIONS: L-Nys was as effective as D-AmB and L-AmB in clearing extracerebral tissues, but was significantly less active in the CNS. This reduced activity in the CNS correlated with tissue concentrations below the MIC of the infecting isolate.
Publication Types:
Keywords:
- Amphotericin B
- Animals
- Antifungal Agents
- Candidiasis
- Kidney
- Liposomes
- Microbial Sensitivity Tests
- Nystatin
- Polyenes
- Rabbits
- pharmacokinetics
- pharmacology
Other ID:
UI: 102268802
From Meeting Abstracts