Antifungal treatment for pulmonary aspergillosis is more difficult if the fungal strain causing the infection is azole resistant. To investigate this problem, we used a murine model of pulmonary aspergillosis caused by azole resistant Aspergillus fumigatus strains V29 and V45, and compared treatment with voriconazole (Vr, oral 40 mg/kg, bid) or liposomal amphotericin B (L-AmB, 5 mg/kg, IV) used alone or in combination.
Mice (n=14/gp) were immunosuppressed with 24 mg/kg triamcinolone acetonide, IP, d-3, d-1 and d+1 relative to fungal challenge (d0). For two groups, Vr was given prophylactically (proph) d-3, d-2, d-1 followed by L-AmB or buffer, d+1, d+2, d+3. The other groups were given Vr, L-AmB, Vr+L-AmB or buffer d+1, d+2, d+3. On d0, mice were given 1.3-1.6x10ex7 A. fumigatus spores intranasally (Vr MIC = 64 ug/mL, V29; Vr MIC = 8 ug/mL, V45). On d+3, lungs were collected from 7 mice/gp and fungal burden determined by plating for colony forming units; 7 mice/gp were then monitored for morbidity to d+21.
Optimum treatment was observed when Vr was given proph, followed by L-AmB post-challenge (Vr/L-AmB), with better survival (100%) for both fungal strains vs buffer or Vr post-challenge (p ≤ 0.04); for V29, significantly better survival was also seen with Vr/L-AmB vs L-AmB or Vr+L-AmB post-challenge (p ≤ 0.01). For strain V45, lung fungal burden was significantly lower for Vr/L-AmB vs all other treatments (p ≤ 0.04), while for strain V29, fungal burden was lower for the Vf/L-AmB and L-AmB post-challenge groups vs the other groups, but the differences were not significant. Notably, although the lung fungal burden with Vr proph and Vr post-challenge were both similar to the buffer control, Vr proph yielded significantly better survival than Vr post-challenge (p ≤ 0.001).
These preclinical observations demonstrate that combining L-AmB with Vr for the post-challenge treatment of pulmonary aspergillosis caused by azole resistant strains is not an effective therapeutic option. However, the results do show that Vr proph, but not Vr post-challenge, can have some limited antifungal activity, and can significantly enhance the antifungal effects of post-challenge L-AmB. This regimen could be considered in areas where there is a high incidence of azole resistant A. fumigatus.
J. Adler-Moore, None