The therapeutic efficacy of
amphotericin B (AmB),
imipenem/cilastatin (IPM/CS),
pazufloxacin (PZFX)
mesilate, and combinations of these, was evaluated using an experimental pulmonary
superinfection model in mice caused by Pseudomonas aeruginosa and Aspergillus fumigatus. The superinfected mice died within 3 days. Although the viable cell count of P. aeruginosa increased markedly from 10(3) to 10(8) CFU/lung on day 2 after
infection, that of A. fumigatus decreased from 10(3) to 10(2) CFU/lung on that day, showing that P. aeruginosa facilitated the mortality in the
superinfection. Extensive
necrosis in the lung parenchyma and moderate hyphae proliferation of A. fumigatus were observed on day 2 after
infection. Mice treated with PZFX
mesilate (50 mg/kg per day) and the combination of PZFX
mesilate (50 mg/kg per day) - AmB (2.5 mg/kg per day) showed prolonged survival in comparison to untreated control mice ( P < 0.05). In the PZFX
mesilate-treated group, no significant
necrosis was observed, but
necrosis due to the hyphae proliferation of A. fumigatus was still observed in the lung parenchyma on day 6 after
infection. However, neither significant
necrosis nor hyphae proliferation of A. fumigatus was observed in mice treated with the combination of PZFX
mesilate - AmB. On the other hand, the survival rates of mice treated with AmB (2.5 mg/kg per day), IPM/CS (50 mg/kg per day), and the IPM/CS-AmB combination were all less than 10%. The viable cell count of P. aeruginosa decreased in PZFX
mesilate-alone group and in the combination of PZFX
mesilate - AmB group, but no significant decrease in this count was observed in the IPM/CS and combination of IPM/CS-AmB group. The viable count of A. fumigatus was increased in the IPM/CS, PZFX
mesilate-alone, and combination of IPM/CS-AmB groups, but the count was suppressed in the AmB-alone and the combination of PZFX
mesilate - AmB group. In conclusion, this
superinfection model would be useful to evaluate the therapeutic potential of combinations of antibacterial and
antifungal agents, and the scheduling of
drug administration in terminal
infections caused by P. aeruginosa and A. fumigatus.