Effect of recombinant human interleukin 2 in experimental murine coccidioidomycosis.

The therapeutic effect of recombinant human interleukin 2 (rH IL-2) was assessed in experimental murine coccidioidomycosis by daily IV injection for 30 days of doses ranging decimally from 2.5 X 10(1) to 2.5 X 10(5) units. The treatment with rH IL-2 had neither adverse nor salutary effects.

Entry of five antifungal agents into the ovine lung.

The passage of antifungal agents into pulmonary parenchyma was studied in normal sheep prepared by cannulation of the right external jugular vein and the efferent duct of the right caudal mediastinal lymph node. Five sheep were given single, sequential, intravenous injections of flucytosine, ketoconazole, BAY n 7133, amphotericin B methyl ester, and amphotericin B. Venous blood plasma and pulmonary lymph were collected before infusion and from 5 min to 24 h postinfusion; the concentrations of the drugs were assayed by a well-agar diffusion method. All drugs appeared promptly in the pulmonary lymph and disappeared at approximately exponential rates from both liquids. The lymph/plasma ratios of the drug concentrations did not differ between flucytosine and the two azoles but were lower for both polyenes. Binding by plasma proteins did not appear to be a determinant of pulmonary entry.

Effect of buffers on testing of Candida species susceptibility to flucytosine.

Synthetic amino acid medium for fungi (SAAMF) is a totally defined, nutritionally adequate, macromolecule-free culture medium for fungi that is buffered with an organic weak acid-weak base pair: 2-(N-morpholino)-propanesulfonic acid (MOPS) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris). In 1984, it was reported that MOPS-Tris in SAAMF antagonized the activity of flucytosine against Candida albicans (D. L. Calhoun and J. N. Galgiani, Antimicrob. Agents Chemother. 26:364-367, 1984). Accordingly, we evaluated the buffering capacity of seven synthetic organic buffers and monobasic potassium phosphate, both singly and in pairs, over the pH range 7.4 to 6.0. Of these buffers, MOPS, BES [N,N-bis(2-hydroxyethyl)-2-aminomethanesulfonic acid], a BES-MOPS combination, and KH2PO4 provided the best buffering. Growth of C. albicans, in unbuffered SAAMF was equivalent overall to that in SAAMF containing buffers, singly or in pairs. Twelve strains of C. albicans and five strains of Candida lusitaniae were tested for susceptibility to flucytosine in SAAMF, with and without buffers. In the presence of Tris, the geometric mean MICs were 6.5- and 3.6-fold higher, respectively, for C. albicans and C. lusitaniae. We recommend replacing Tris with the nonantagonistic MOPS.

Comparative efficacy of forphenicinol, cyclosporine, and amphotericin B in experimental murine coccidioidomycosis.

Cohorts of ten mice, uninfected and infected (intratracheal injection of coccidioidal arthroconidia), were treated for 23 days by intravenous injections of either 5% glucose solution, an immunostimulant (forphenicinol), an immunodepressant (cyclosporine), or amphotericin B. All mice were autopsied (survivors at 26 days postinoculation) and suspensions of lungs, livers, and spleens were cultured. All uninfected animals survived and gained weight, whereas, only 20% of the infected controls survived, and all lost weight. Treatment with forphenicinol had no effect on survival or weight. Cyclosporine secured 90% survival at the lowest dose and 60% at the higher doses, with no net loss of weight; however, all cultures of organs yielded heavy growth of Coccidioides immitis. With amphotericin B, all mice survived and gained weight; four mice from each of the two treatment groups yielded modest growth of C. immitis from the lungs, and one mouse of each group yielded sparse growth from liver and spleen. The paradox of no effect from an immunostimulant and therapeutic effect from an immunodepressant correlated with susceptibility testing of C. immitis in vitro.

Ovine pulmonary transit of tetracycline and minocycline.

Following cannulation of the right external jugular vein and the efferent duct of the right caudal mediastinal lymph node (the caudal end of this node was ligated to cut off the inflow of systemic lymph, i.e., 90%-95% of the efferent lymph was of pulmonary origin), sheep were given either tetracycline or minocycline as single doses of 5 mg/kg body weight infused intravenously over 30 min. Venous blood plasma and pulmonary lymph collected contemporaneously before infusion and from 5 min to 24 hr postinfusion were assayed by a well-agar diffusion method using Bacillus cereus. Peak concentrations of both drugs were observed in both plasma and lymph at 5 min postinfusion. Tetracycline penetrated into the lymph better than minocycline (percent penetration 67.3% of cf. 38.2%). The concentration of tetracycline was significantly higher in lymph during and 5 min postinfusion (p less than 0.01), a factor that may be of importance when selecting a tetracycline for the treatment of a pulmonary infection.

Influence of culture medium on susceptibility testing with BAY n 7133 and ketoconazole.

The effect of four culture media (two complex and undefined [Sabouraud glucose and Kimmig] and two synthetic and defined [synthetic amino acid medium, fungal, and modified yeast nitrogen base]) on the activity in vitro of two newer azole compounds (BAY n 7133 and ketoconazole) was assessed with five strains each of Candida albicans, Candida parapsilosis, and Cryptococcus neoformans. Also, the nutritional adequacy of the four media was evaluated with the same 15 strains of yeastlike fungi. While the MICs of BAY n 7133 were higher in the complex media, the activity of ketoconazole was little affected. The Candida spp. grew least well and the C. neoformans grew best in yeast nitrogen base.

Activity of BAY n 7133 and BAY 1 9139 in vitro and in experimental murine coccidioidomycosis.

The activity of two new antifungal azoles, BAY n 7133 and BAY 1 9139, against Coccidioides immitis was compared with that of ketoconazole in vitro and in experimental murine coccidioidomycosis. Daily intravenous injections were given for 30 days. All mice were autopsied and suspensions of lung, liver and spleen cultured. BAY n 7133 was as active as ketoconazole while Bay 1 9139 was les active. All three drugs were coccidioidostatic only both in vitro and in vivo.

In vitro activities of two new antifungal azoles.

The antifungal activities of equimolar quantities of three azole compounds, Bay n 7133 [1-(4-chlorophenoxy)-3,3-dimethyl-2-(1,2,4-triazole-1-yl)methylbutan-2-O1], Bay 1 19139 [1-(4-chlorophenoxy)-1-(1-imidazolyl)-3,3-dimethyl-2-butanol hydrochloride], and ketoconazole, were compared by testing the susceptibility in vitro of 10 clinical isolates each of Candida albicans, Candida parapsilosis, Torulopsis glabrata, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Rhizopus spp., Mucor spp., and Coccidioides immitis. Molecule for molecule, ketoconazole was consistently the most active drug. All three azoles were primarily fungistatic, although they were fungicidal at clinically relevant concentrations against some strains of A. niger.

Entry of four cephalosporins into the ovine lung.

Following cannulation of the right external jugular vein and the efferent duct of the right caudal mediastinal lymph node (the caudal end of this node having been ligated to cut off the inflow of systemic lymph), sheep were each given one of four "cephalosporins" (cefazolin, moxalactam, cefoperazone, or ceftriaxone) as single doses injected iv over 30 min. All of the drugs appeared in the pulmonary lymph during iv infusion. Peak concentrations in the lymph were attained at 5 min postinfusion with cefazolin, cefoperazone, and ceftriaxone; the peak for moxalactam was attained at 30 min postinfusion. Cefazolin and cefoperazone penetrated better than did ceftriaxone, which penetrated better than did moxalactam. The concentrations of moxalactam, as compared with the other drugs, declined more gradually in both venous blood and pulmonary lymph. In view of the prompt entry and transit through the lungs and the high concentrations attained in the pulmonary lymph, these drugs should be effective in the treatment of pneumonias caused by susceptible bacteria.