Journal of Antimicrobial Chemotherapy (2002) 49, 813-820
© 2002 The British Society for Antimicrobial Chemotherapy
Enhanced antifungal efficacy in experimental invasive pulmonary aspergillosis by combination of AmBisome with Fungizone as assessed by several parameters of antifungal response
Departments of 1Medical Microbiology and Infectious Diseases and 2Biostatistics, Erasmus Medical Centre, PO Box 1738, 3000 DR Rotterdam, The Netherlands
Received 15 October 2001; returned 14 December 2001; revised 23 January 2002; accepted 28 January 2002.
In common with a proportion of patients with invasive pulmonary aspergillosis (IPA), the efficacy of AmBisome treatment regimens in our rat model remains suboptimal. To investigate whether this might be the result of initially low antifungal activity of amphotericin B at the site of infection when administered in the liposomal form, Fungizone was added to AmBisome at the start of treatment. Groups of granulocytopenic rats with left-sided IPA received 10 day treatment regimens with either AmBisome 10 mg/kg/day (n = 25) or AmBisome 10 mg/kg/day combined with a single dose of Fungizone 1 mg/kg at day 1 (n = 27). Parameters of treatment response included survival, serum galactomannan (GM), size and quality of pulmonary macroscopic lesions, lung weight, viable fungal counts (cfu) and chitin content of the infected lung, and extra-pulmonary disseminated fungal infection. In a separate experiment the significance of early start of treatment to obtain therapeutic efficacy was investigated. Compared with untreated controls, both treatment regimens showed a significant increase in survival and change in parameters of fungal infection except left lung cfu. The combination treatment showed a significant increase in survival compared with AmBisome monotherapy (P = 0.02) and a significant decrease in left lung chitin content (P = 0.03). Differences in circulating GM concentrations between the two treatment regimes approached significance (P = 0.06). Delay in the start of treatment from 16 to 24 h after fungal inoculation resulted in a significant decrease in therapeutic efficacy (P = 0.02). It is concluded that the efficacy of AmBisome therapy can be enhanced by the addition of Fungizone at the start of treatment. This is probably a result of active amphotericin B being immediately available in the lung at the start of treatment.
* Correspondence address. Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Tel: +31-10-4087827; Fax: +31-10-4089454; E-mail: becker{at}kmic.fgg.eur.nl
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