Efficacy of Intravenous Liposomal Amphotericin B (AmBisome) against Coccidioidal Meningitis in Rabbits

Abstract

The efficacy of intravenously administered liposomal amphotericin B (AmBisome [AmBi]) for the treatment of experimental coccidioidal meningitis was compared with those of oral fluconazole (FLC) and intravenously administered conventional amphotericin B (AMB). Male New Zealand White rabbits were infected by intracisternal inoculation of arthroconidia of Coccidioides immitis. Starting 5 days postinfection, animals received one of the following: 5% dextrose water diluent; AMB given at 1 mg/kg of body weight; AmBi given at 7.5, 15, or 22.5 mg/kg intravenously three times per week for 3 weeks; or oral FLC given at 80 mg/kg for 19 days. One week after the cessation of therapy, all survivors were euthanatized, the numbers of CFU remaining in the spinal cord and brain were determined, and histological analyses were performed. All AmBi-, FLC-, or AMB-treated animals survived and had prolonged lengths of survival compared with those for the controls (P < 0.0001). Treated groups had significantly lower numbers of white blood cells and significantly lower protein concentrations in the cerebrospinal fluid compared with those for the controls (P < 0.01 to 0.0005) and had fewer clinical signs of infection (e.g., weight loss, elevated temperature, and neurological abnormalities including motor abnormalities). The mean histological scores for AmBi-treated rabbits were lower than those for FLC-treated and control rabbits (P < 0.016 and 0.0005, respectively); the scores for AMB-treated animals were lower than those for the controls (P < 0.0005) but were similar to those for FLC-treated rabbits. All regimens reduced the numbers of CFU in the brain and spinal cord compared with those for the controls (P <0.0005). AmBi-treated animals had 3-to 11-fold lower numbers of CFU than FLC-treated rabbits and 6-to 35-fold lower numbers of CFU than AmB-treated rabbits. Three of eight animals given 15 mg of AmBi per kg had no detectable infection in either tissue, whereas other doses of AmBi or FLC cleared either the brain or the spinal cord of infection in fewer rabbits. In addition, clearance of the infection from both tissues was achieved in none of the rabbits, and neither tissue was cleared of infection in AMB-treated animals. Overall, these data indicate that intravenously administered AmBi is superior to oral FLC or intravenous AMB and that FLC is better than AMB against experimental coccidioidal meningitis. These data indicate that AmBi may offer an improvement in the treatment of coccidioidal meningitis. Additional studies are warranted.

Nanoparticle transport across the blood brain barrier

“…Groll and colleagues 41 23 Recently, the authors studied the efficacy of AmBisome, micafungin (MICA), caspofungin (CAS), amphotericin B, voriconazole (VCZ), given alone or in combination, after administration in immune-suppressed mice, infected intracerebrally with Aspergillus fumigates. In the first study, the brain infection was significantly reduced by Ambisome treatment if compared with fluconazole and amphotericine B treatments.…”

Eficiência terapêutica das formulações lipídicas de anfotericina B

“…Observou-se que, em coelhos, a eficiência de AmBisome era parcialmente dose-dependente, já que concentrações entre 7,5 e 15 mg/kg/dia aumentavam a eficiência, mas doses acima desta faixa não resultavam em maior controle da infecção (Clemons et al, 2002).…”

“…Observou-se que os animais tratados com AmBisome mostraram melhora clínica aparente, mínimas manifestações neurológicas, reduzido comprometimento histopatológico e maior tempo de sobrevivência. A terapia com fluconazol e AB-DOC também foi eficiente, mas inferior a AmBisome (Clemons et al, 2002).…”

Pharmacokinetic-Pharmacodynamic Comparison of Amphotericin B (AMB) and Two Lipid-Associated AMB Preparations, Liposomal AMB and AMB Lipid Complex, in Murine Candidiasis Models

“…However, it is generally accepted that the lipid formulations of AMB are not as potent as conventional AMB on an mg/kg basis. Most clinical trials and current dosing conventions with each of the lipid preparations use doses 4-to 10-fold in excess of those for amphotericin B deoxycholate (1,8,9,10,18,24,25). However, few studies have performed systematic analyses to define the relative in vivo potencies of these compounds to discern if these dose escalations are optimal.…”