l-693989 and Pneumonia--Pneumocystis

A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B0 (L-688,786) (R. E. Schwartz et al., J. Antibiot. 45:1853-1866, 1992), and > 100 times more potent than cilofungin. One compound in particular, L-733,560, had a 90% effective dose against P. carinii cysts of 0.01 mg/kg of body weight when delivered parenterally (subcutaneously, twice daily for 4 days). This compound was also effective when given orally for the treatment and prevention of P. carinii pneumonia. For treating acute P. carinii pneumonia, oral doses of 2.2 mg/kg twice daily for 4 days were required to eliminate 90% of the cysts. A once-daily oral prophylactic dose of 2.2 mg/kg prevented cyst development, and a dose of 6.2 mg/kg prevented any development of P. carinii organisms (cysts and trophozoites), as determined through the use of a P. carinii-specific DNA probe (P. A. Liberator et al., J. Clin. Microbiol. 30:2968-2974, 1992). These results demonstrate that the antipneumocystis activities of the pneumocandins can be significantly improved through synthetic modification. Several of these compounds are also extremely effective against candidiasis (K. Bartizal et al., Antimicrob. Agents Chemother. 39:1070-1076, 1995) and aspergillosis (G. K. Abruzzo et al., Antimicrob. Agents Chemother. 39:860-894, 1995) in murine models, making them attractive as broad-spectrum antifungal agents.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Dexamethasone; Echinocandins; Glucans; Lung; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Pneumocystis; Pneumonia, Pneumocystis; Rats

Water-soluble pneumocandin L-693,989, a potent antipneumocystis agent in the rat model for Pneumocystis carinii pneumonia (PCP), inhibits P. carinii cyst development and effectively prevents the development of PCP when used as a prophylactic agent (D. M. Schmatz, M. A. Powles, D. C. McFadden, L. Pittarelli, J. Balkovec, M. Hammond, R. Zambias, P. Liberator, and J. Anderson, Antimicrob. Agents Chemother. 36:1964-1970, 1992). However, because of limited oral bioavailability, this compound would likely be restricted to parenteral use in humans. As an alternative, the aerosol delivery of L-693,989 was explored to determine the dosing regimen required to prevent the onset of PCP. Rats with latent P. carinii infections were immunosuppressed continuously with dexamethasone to promote the onset of PCP. During the 6-week immunosuppression period, L-693,989 was delivered to rats as a nebulized solution (volume median diameter of 3.8 microns) via a nose exposure inhalation chamber. The efficiency of aerosol delivery to the lungs and the rate of clearance were determined by using radiolabelled compound. It was found that a daily dose of 0.7 micrograms of L-693,989 per lung or a weekly dose of 77.9 micrograms/lung effectively prevented the development of P. carinii cysts and trophozoites as well as the associated pneumonia commonly seen in rats with acute P. carinii infections. These results demonstrate that L-693,989 is potentially useful as an aerosol prophylactic agent for PCP.

Topics: Aerosols; Animals; Antifungal Agents; Male; Peptides, Cyclic; Pneumonia, Pneumocystis; Rats; Rats, Sprague-Dawley

Water-soluble lipopeptide L-693,989 was evaluated for its antipneumocystis activity in rats. Rats from colonies with latent Pneumocystis carinii infections were immunosuppressed with dexamethasone for 6 weeks to facilitate the development of acute P. carinii pneumonia (PCP). After 6 weeks, the rats were maintained on dexamethasone and were treated twice daily for 4 days with various concentrations of L-693,989. At a dose of 0.15 mg/kg of body weight, the compound effectively eliminated 90% of the cysts in 4 days. Trophozoite forms of P. carinii were still present in these animals, as determined by using a P. carinii-specific DNA probe. A 3-week therapy study showed that the trophozoite load did not expand during treatment and that the trophozoites already present at the initiation of therapy appeared to persist. This may be a consequence of the stage specificity of the compound for cyst development and the severe immunosuppressive effects of dexamethasone on rats. When evaluated as a daily parenteral prophylactic agent, L-693,989 was effective in preventing the development of both P. carinii cysts and trophozoites, demonstrating its potential for use in prophylaxis and implying that the cyst stage of P. carinii is an obligatory step in trophozoite multiplication. The foamy exudate commonly associated with P. carinii infections was absent in the lungs of rats on prophylaxis. The compound was also evaluated via oral administration and was found to have a 90% effective dose of 32 mg/kg for therapy of acute infections and 5 mg/kg for daily prophylaxis.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Lung; Male; Microbial Sensitivity Tests; Peptides, Cyclic; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Sprague-Dawley; Trimethoprim, Sulfamethoxazole Drug Combination