Activity of terbinafine against Pneumocystis carinii in vitro and its efficacy in the treatment of experimental pneumonia

Abstract

The antiprotozoan and antifungal agent, the terbinafine, was investigated for its potential activity against Pneumocystis carinii infection of the A549 cell line culture and on immunosuppressed Sprague Dawley rats in comparison with trimethoprim-sulphamethoxazole and pentamidine isethionate. Terbinafine suppressed P. carinii growth at doses up to 3 g/L within 24 h and it was able to inhibit cyst forms at 60 h post inoculation. With respect to trimethoprim-sulphamethoxazole and pentamidine isethionate P. carinii organisms decreased at the same time interval but cyst form elimination was less apparent than with terbinafine. The results of the in-vitro culture were consistent with the in-vivo observations. Of the 3 groups of rats tested, the occurrence of P. carinii pneumonia was documented in 18 (60%) of the control rats (group 3) which showed a high degree of P. carinii burden and a marked weight loss with respect to the beginning of the experiment. Among terbinafine treated rats (group 1), P. carinii pneumonia was present in one rat (3.3%), while no P. carinii infection occurred in the pentamidine isethionate and in trimethoprim-sulphamethoxazole treatment rat groups (group 2). All the agents investigated showed no particular signs of toxicity. These preliminary results suggest further explorations of the terbinafine in clinical trials for treatment and prophylaxis of P. carinii pneumonia.

Evaluation Of Terbinafine Activity On Pneumocystis Carinii At The Rat Model

“…There are also data to suggest that terbinafine may be effective in treating histoplasmosis, Pneumocystis infection, fungal mycetoma, and cutaneous leishmaiasis. [4][5][6] The present study has shown that, in our rat model of pneumocystosis, Terbinafine had a dose dependent activity. Walzer et al [1] studied the usage of terbinafine in mouse and rat models of PCP.…”

“…[4] The investigators of two studies found that terbinafine given at oral doses of 15 to 80 mg/kg/day had an efficacy equal to or greater than that of known anti-P. carinii drugs in rats with PCP. [5,6] In another study Walzer et al [1] showed that terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively.…”

Inhibitors of Sterol Biosynthesis and Amphotericin B Reduce the Viability of Pneumocystis carinii f. sp. carinii

“…In that regard, Bartlett et al (2) demonstrated that six imidazole antifungal agents (fluconazole, ketoconazole, miconazole, itraconazole, etanidazole, and Sch39304) that target sterol nucleus demethylation in ergosterol biosynthesis had little or no activity in clearing P. carinii pneumonia (PCP) in experimental animals or in reducing P. carinii proliferation in primary culture. On the other hand, terbinafine (see Table 1), an inhibitor of squalene epoxidase in the sterol biosynthetic pathway, was shown by Contini et al (6) to be effective in clearing PCP in experimental animals. Terbafine also suppressed organism proliferation in short-term cultures (5,6).…”

“…On the other hand, terbinafine (see Table 1), an inhibitor of squalene epoxidase in the sterol biosynthetic pathway, was shown by Contini et al (6) to be effective in clearing PCP in experimental animals. Terbafine also suppressed organism proliferation in short-term cultures (5,6). Furthermore, inhibitors of sterol C-24 alkylation were shown by Urbina et al (25) to inhibit the biosynthesis of P. cariniispecific sterols and the proliferation of P. carinii in short-term cultures.…”

Plasminogen Activator Production in a Rat Model of Pneumocystis carinii Pneumonia

“…Touch preparations were stained either with methenamine silver stain or Giemsa and examined by two independent examiners as previously described (14). BAL samples were centrifuged at 300 X 9 for 10 min and aliquots of cell pellets were stained with methenamine silver stain (40).…”