ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1991, p. 1669-1671
0066-4804/91/081669-03$02.00/0 Copyright © 1991, American Society for Microbiology
Vol. 35, No. 8
Interactions of Amphotericin B and SCH 39304 in the Treatment of Experimental Murine Candidiasis: Lack of Antagonism of a Polyene-Azole Combination ALAN M. SUGAR Evans Memorial Department of Clinical Research and Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118 Received 21 February 1991/Accepted 14 May 1991
Mice infected intravenously with Candida albicans were treated with SCH 39304, a new triazole antifungal compound, amphotericin B, or both. Two dose levels of each drug were evaluated in an attempt to identify potential helpful or harmful effects on survival and kidney colony counts. Contrary to theoretical predictions, combination therapy was not antagonistic and some additive or synergistic effects were observed. The results obtained in this study suggest that antagonism between polyene and azole antifungal drugs is not inevitable and that additive or synergistic effects may be possible. SCH 39304 is a new triazole derivative, with a long half-life and good absorption following oral administration (3). It has been noted to be active in experimental animal models against different fungal pathogens, including Aspergillus species, Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, and other fungi (1, 2, 5, 6, 8). Its major mode of action is thought to be similar to those of other azole antifungal agents, i.e., inhibition of ergosterol synthesis secondary to blocking of the demethylation of lanosterol. Despite promising results obtained in preclinical and early clinical investigations, further development of SCH 39304 was stopped because of the unexpected toxicity of chronically administered doses administered to rodents. However, results of the present study are still relevant, since the general question of polyene-azole interactions in the in vivo setting may be applicable to other drugs in both classes of compounds. Because polyenes, such as amphotericin B, bind to fungal membrane ergosterol as one mechanism of action of their antifungal activity, combinations of azoles and amphotericin B may be antagonistic, at least on theoretical grounds. Since no previous work has examined the interactions of azoles with amphotericin B in experimental murine candidiasis, I conducted this study to address the question of the possible synergy, indifference, or antagonism of SCH 39304 when it is used in combination with amphotericin B. Male ICR mice (age, 3 to 4 weeks) were purchased from Harlan Sprague Dawley (Indianapolis, Ind.). At the start of the experiments, the mean weight of the mice was 25.8 g. Mice were housed, eight per cage, in filter-topped cages, fed standard mouse chow, and given water ad libitum. Mice were injected through a lateral tail vein with 0.1 ml of sterile saline containing 106 blastoconidia. Candida albicans 64, from my laboratory collection, was maintained on Sabouraud dextrose agar slants at 4°C. Fortyeight hours prior to an experiment, a large loopful of organisms was suspended in yeast nitrogen broth (Difco, Detroit, Mich.) and incubated for 24 h at 37°C. One Sabouraud dextrose agar plate was inoculated with this yeast suspension and was incubated overnight at 37°C. Blastoconidia were recovered from the plate with a wire loop and were washed twice in sterile buffered saline (pH 7.4) by
centrifugation. Cells were counted in a hemacytometer and adjusted to a concentration of 107/ml. SCH 39304 was provided as a powder by Schering-Ploug& Corp. It was suspended in Emulphor EL-719P (polyethylene glycol 40 castor oil) and prepared every 2 to 3 days at the appropriate concentration for administration to the mice. SCH 39304 was administered by oral gavage in 0.2 ml once daily. Amphotericin B (Sigma, St. Louis, Mo.) was prepared fresh daily in sterile water and administered by injection of 0.1 ml into the peritoneum. Therapy was begun 24 h following inoculation of mice with C. albicans and was continued for a total of 14 consecutive days. Mice were weighed weekly, and drug doses were adjusted accordingly. Two control groups were used: one received sterile 5% glucose in water intraperitoneally once daily, and the other received Emulphor EL-719P by oral gavage once daily. Cages were observed twice daily for deaths. Randomly selected mice in each group were sacrificed at designated intervals, and the right kidney was removed aseptically. The kidneys were manually homogenized in small volumes of saline, and 10-fold dilutions were plated onto Sabouraud dextrose agar. The plates were incubated for 24 to 48 h at 37°C, at which time the colonies were enumerated. The Mann-Whitney U test and Fisher exact test were performed when appropriate by using a commercially available statistics program (Number Cruncher Statistical System, Kaysville, Utah) suitable for use on IBM PC-comnpatible equipment. Significance was defined as P < 0.05. In animals with an acute infection, with a 90% lethal dose reached in 9 days, significant protection was provided by amphotericin B, 0.1 mg/kg/day, and SCH 39304, 0.1 mg/kg/ day (Fig. 1A; P < 0.01). However, when both SCH 39304 and amphotericin B were combined in these lower doses, 42% of the mice were alive at day 35, whereas 25% of the mice were alive when both drugs were used alone (P = 0.08 compared with SCH 39304 alone and P < 0.05 compared with amphotericin B alone). In this same experiment, amphotericin B, 1.0 mg/kg/day, yielded results similar to those obtained with the 10-fold lower dose of amphotericin B, but SCH 39304, 1.25 mg/kg/ day, afforded mice greater survival at the end of the experiment compared with that afforded by the lower-dose SCH 1669
1670
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
100
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.
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Day 100
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Day FIG. 1. Survival of mice infected with C. albicans, acute infection. (A) Open triangles, controls; open circles, SCH 39304, 0.1 mg/kg/day; closed triangles, SCH 39304, 0.1 mg/kg/day, plus amphotericin B, 0.1 mg/kg/day; open square, amphotericin B, 0.1 mg/kg/day. (B) Closed inverted triangle (superimposed on closed circle), SCH 39304, 1.25 mg/kg/day; closed circle, SCH 39304, 1.25 mg/kg/day, plus amphotericin B, 1 mg/kg/day; closed square, amphotericin B, 1 mg/kg/day. Note that the group receiving SCH 39304, 1.25 mg/kg/day, and the combination treatment group overlap.
39304 regimen, 50 versus 25% (Fig. 1B; P < 0.01). The combination of SCH 39304 and amphotericin B at these higher doses did not result in a decrease in survival compared with survival after monotherapy with SCH 39304 alone, but the combination was superior to amphotericin B alone (P < 0.01). In a more indolent infection, with a 50% lethal dose reached in 18 to 26 days, results were similar (Fig. 2). SCH 39304 at both doses resulted in increased survival compared with the survival of controls (P < 0.001). Similar to results obtained in the first experiment, the addition of SCH 39304, 1.25 mg/kg/day, to amphotericin B, 1 mg/kg/day, did not diminish the effect of the amphotericin B. In fact, survival was increased in the group receiving the combination (P < 0.01 compared with either drug alone) for treatment of the more indolent infection. The effect of a single large dose of amphotericin B (5 mg/kg) with or without daily SCH 39304 (for 14 days) was
0
10
20
Days FIG. 2. Survival of mice infected with C. albicans, more indolent infection. (A) Open squares, controls given vehicle by oral gavage; open triangle, amphotericin B, 1 mg/cg/day; closed squares, SCH 39304, 1.25 mg/kg/day; closed circles, SCH 39304, 1.25 mg/kg/day, plus amphotericin B, 1 mg/kg/day. (B) Ticks, controls given 5% sterile water by intraperitoneal injection; open circles, amphotericin B, 5 mg once; closed triangles, SCH 39304, 0.1 mg/kg/day; open squares, SCH 39304, 0.1 mg/kg/day, plus amphotericin B, 5 mg once. The bars just above the x axes represent the interval during which mice received treatment.
also evaluated in this experiment (Fig. 2B). The single dose of amphotericin B 24 h after the mice were infected was sufficient to result in 100% survival at day 40, the end of the experiment (P < 0.01 compared with controls). The addition of SCH 39304, 0.1 mg/kg/day, did not decrease the perfect survival afforded by the treatment of mice with a single dose of amphotericin B. In this experiment, the one large of dose of amphotericin B was superior to lower daily doses of amphotericin B (P < 0.001). Colony counts of C. albicans in the kidneys of infected mice supported the survival data. On the last day of therapy of mice with the indolent infection, control mice were heavily infected (Table 1). Few colonies were recovered from mice treated with SCH 39304, 1.25 mg/kg/day, or amphotericin B, 1 mg/kg/day, plus SCH 39304, 1.25 mg/kg/ day. Combination therapy with the lower doses of both
VOL. 35, 1991
NOTES
TABLE 1. Colony counts in kidneys obtained from mice on day 14 of experiment 2 Group
CFU/kidneya
Control ......................................... >10,000 Amphotericin B, 1 mg/kg/day .................................. 1,455 SCH 39304, 1.25 mg/kg/day ..................................... 21 Amphotericin B, 1 mg/kg/day, plus SCH 39304, 1.25 mg/kg/day ......................................... 156 Amphotericin B, 5 mg once ..................................... 56,180 SCH 39304, 0.1 mg/kg/day ...................................... 448,500 Amphotericin B, 5 mg once, plus SCH 39304, 0.1 mg/kg/day ........................ 0 ................. a Mean number of colonies recovered from one kidney from each of two mice cultured in duplicate.
1671
multiple strains may have to be evaluated to uncover unusual effects. In addition, the results should not be extrapolated to other mycoses, since one such study suggested that ketoconazole and amphotericin B have antagonistic effects in murine aspergillosis (7). However, the interaction of polyenes and azoles is a clinically important problem, which will become compounded when newer azole derivatives become available and when the opportunity for sequential and/or concomitant polyene-azole therapy arises. This study should serve as a basis for more thorough examination of the topic. I thank Michele Picard for expert technical assistance. Support for this project was provided, in part, by a grant from
Schering-Plough Corp.
drugs yielded more impressive results, with mice receiving the combination having sterile cultures (Table 1). Results for cultures obtained at various time intervals in two other experiments were similar to the data presented in Table 1. There has been an increase in awareness concerning the theoretical reasons for avoiding the combined use of polyene and azole antifungal agents. However, there is little information available yet to address this problem. Somewhat surprisingly, the data in this study suggest that when administered simultaneously, there are no apparent antagonistic effects of the antifungal agents in mice with either an acute or indolent C. albicans infection. This was demonstrated by survival and culture data. The mechanisms responsible for the lack of antagonism and, in some instances, the additive to synergistic activity of combination polyene-azole therapy are unclear. Simplistic explanations of polyene binding to the fungal membrane ergosterol and azole inhibition of ergosterol synthesis are not tenable when attempting to explain findings such as those presented here. One possibility that is amenable to experimental verification is that polyene binding to the fungus destabilizes the membrane so that uptake of the azole is enhanced. Once internalized, effects on fungal metabolism other than mere inhibition of ergosterol synthesis may then become important correlates of the antifungal effect. It should be stressed that this study addressed the effects of combination therapy by using one strain of Candida, and as previous in vitro work from this laboratory suggests (4),
REFERENCES 1. Clemons, K. V., L. H. Hanson, A. M. Perlman, and D. A. Stevens. 1990. Efficacy of SCH 39304 and fluconazole in a murine model of disseminated coccidioidomycosis. Antimicrob. Agents Chemother. 34:928-930. 2. Kobayashi, G. S., S. J. Travis, M. G. Rinaldi, and G. Medoff. 1990. In vitro and in vivo activities of SCH 39304, fluconazole, and amphotericin B against Histoplasma capsulatum. Antimicrob. Agents Chemother. 34:524-528. 3. Kosoglou, T., G. P. Perentesis, M. B. Affrime, C.-C. Lin, P. Mojaverian, E. Radwanski, and P. H. Vlasses. 1990. The effect of antacid and cimetidine on the oral absorption of the antifungal agent SCH 39304: J. Clin. Pharmacol. 30:638-642. 4. Meshulam, T., S. M. Levitz, R. D. Diamond, and A. M. Sugar. 1989. Effect of cilofungin (LY 121019), a fungal cell wall synthesis inhibitor, on interactions of Candida albicans with human neutrophils. J. Antimicrob. Chemother. 24:741-745. 5. Perfect, J. R., K. A. Wright, M. M. Hobbs, and D. T. Durack. 1989. Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH 39304. Antimicrob. Agents Chemother. 33:1735-1740. 6. Restrepo, B. I., J. Ahrens, and J. R. Graybili. 1989. Efficacy of SCH 39304 in murine cryptococcosis. Antimicrob. Agents Chemother. 33:1242-1246. 7. Schaffner, A., and P. G. Frick. 1985. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J. Infect. Dis. 151:902-910. 8. Sugar, A. M., M. Picard, and L. Noble. 1990. Treatment of murine pulmonary blastomycosis with SCH 39304, a new triazole antifungal agent. Antimicrob. Agents Chemother. 34:896-898.
0066-4804/91/081669-03$02.00/0 Copyright © 1991, American Society for Microbiology
Vol. 35, No. 8
Interactions of Amphotericin B and SCH 39304 in the Treatment of Experimental Murine Candidiasis: Lack of Antagonism of a Polyene-Azole Combination ALAN M. SUGAR Evans Memorial Department of Clinical Research and Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118 Received 21 February 1991/Accepted 14 May 1991
Mice infected intravenously with Candida albicans were treated with SCH 39304, a new triazole antifungal compound, amphotericin B, or both. Two dose levels of each drug were evaluated in an attempt to identify potential helpful or harmful effects on survival and kidney colony counts. Contrary to theoretical predictions, combination therapy was not antagonistic and some additive or synergistic effects were observed. The results obtained in this study suggest that antagonism between polyene and azole antifungal drugs is not inevitable and that additive or synergistic effects may be possible. SCH 39304 is a new triazole derivative, with a long half-life and good absorption following oral administration (3). It has been noted to be active in experimental animal models against different fungal pathogens, including Aspergillus species, Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, and other fungi (1, 2, 5, 6, 8). Its major mode of action is thought to be similar to those of other azole antifungal agents, i.e., inhibition of ergosterol synthesis secondary to blocking of the demethylation of lanosterol. Despite promising results obtained in preclinical and early clinical investigations, further development of SCH 39304 was stopped because of the unexpected toxicity of chronically administered doses administered to rodents. However, results of the present study are still relevant, since the general question of polyene-azole interactions in the in vivo setting may be applicable to other drugs in both classes of compounds. Because polyenes, such as amphotericin B, bind to fungal membrane ergosterol as one mechanism of action of their antifungal activity, combinations of azoles and amphotericin B may be antagonistic, at least on theoretical grounds. Since no previous work has examined the interactions of azoles with amphotericin B in experimental murine candidiasis, I conducted this study to address the question of the possible synergy, indifference, or antagonism of SCH 39304 when it is used in combination with amphotericin B. Male ICR mice (age, 3 to 4 weeks) were purchased from Harlan Sprague Dawley (Indianapolis, Ind.). At the start of the experiments, the mean weight of the mice was 25.8 g. Mice were housed, eight per cage, in filter-topped cages, fed standard mouse chow, and given water ad libitum. Mice were injected through a lateral tail vein with 0.1 ml of sterile saline containing 106 blastoconidia. Candida albicans 64, from my laboratory collection, was maintained on Sabouraud dextrose agar slants at 4°C. Fortyeight hours prior to an experiment, a large loopful of organisms was suspended in yeast nitrogen broth (Difco, Detroit, Mich.) and incubated for 24 h at 37°C. One Sabouraud dextrose agar plate was inoculated with this yeast suspension and was incubated overnight at 37°C. Blastoconidia were recovered from the plate with a wire loop and were washed twice in sterile buffered saline (pH 7.4) by
centrifugation. Cells were counted in a hemacytometer and adjusted to a concentration of 107/ml. SCH 39304 was provided as a powder by Schering-Ploug& Corp. It was suspended in Emulphor EL-719P (polyethylene glycol 40 castor oil) and prepared every 2 to 3 days at the appropriate concentration for administration to the mice. SCH 39304 was administered by oral gavage in 0.2 ml once daily. Amphotericin B (Sigma, St. Louis, Mo.) was prepared fresh daily in sterile water and administered by injection of 0.1 ml into the peritoneum. Therapy was begun 24 h following inoculation of mice with C. albicans and was continued for a total of 14 consecutive days. Mice were weighed weekly, and drug doses were adjusted accordingly. Two control groups were used: one received sterile 5% glucose in water intraperitoneally once daily, and the other received Emulphor EL-719P by oral gavage once daily. Cages were observed twice daily for deaths. Randomly selected mice in each group were sacrificed at designated intervals, and the right kidney was removed aseptically. The kidneys were manually homogenized in small volumes of saline, and 10-fold dilutions were plated onto Sabouraud dextrose agar. The plates were incubated for 24 to 48 h at 37°C, at which time the colonies were enumerated. The Mann-Whitney U test and Fisher exact test were performed when appropriate by using a commercially available statistics program (Number Cruncher Statistical System, Kaysville, Utah) suitable for use on IBM PC-comnpatible equipment. Significance was defined as P < 0.05. In animals with an acute infection, with a 90% lethal dose reached in 9 days, significant protection was provided by amphotericin B, 0.1 mg/kg/day, and SCH 39304, 0.1 mg/kg/ day (Fig. 1A; P < 0.01). However, when both SCH 39304 and amphotericin B were combined in these lower doses, 42% of the mice were alive at day 35, whereas 25% of the mice were alive when both drugs were used alone (P = 0.08 compared with SCH 39304 alone and P < 0.05 compared with amphotericin B alone). In this same experiment, amphotericin B, 1.0 mg/kg/day, yielded results similar to those obtained with the 10-fold lower dose of amphotericin B, but SCH 39304, 1.25 mg/kg/ day, afforded mice greater survival at the end of the experiment compared with that afforded by the lower-dose SCH 1669
1670
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
100
1
100 90 80 *j 70 05 60
80
.>
am
=X
60
c
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CO)
0.
20
1001 90
80
= U'
10
Days
a;
km
A
0
10 15 20 25 30 35
I
.
0
40 30 20 10
Day 100
1..
_malom _
5
10 15 20 25 30 35
Day FIG. 1. Survival of mice infected with C. albicans, acute infection. (A) Open triangles, controls; open circles, SCH 39304, 0.1 mg/kg/day; closed triangles, SCH 39304, 0.1 mg/kg/day, plus amphotericin B, 0.1 mg/kg/day; open square, amphotericin B, 0.1 mg/kg/day. (B) Closed inverted triangle (superimposed on closed circle), SCH 39304, 1.25 mg/kg/day; closed circle, SCH 39304, 1.25 mg/kg/day, plus amphotericin B, 1 mg/kg/day; closed square, amphotericin B, 1 mg/kg/day. Note that the group receiving SCH 39304, 1.25 mg/kg/day, and the combination treatment group overlap.
39304 regimen, 50 versus 25% (Fig. 1B; P < 0.01). The combination of SCH 39304 and amphotericin B at these higher doses did not result in a decrease in survival compared with survival after monotherapy with SCH 39304 alone, but the combination was superior to amphotericin B alone (P < 0.01). In a more indolent infection, with a 50% lethal dose reached in 18 to 26 days, results were similar (Fig. 2). SCH 39304 at both doses resulted in increased survival compared with the survival of controls (P < 0.001). Similar to results obtained in the first experiment, the addition of SCH 39304, 1.25 mg/kg/day, to amphotericin B, 1 mg/kg/day, did not diminish the effect of the amphotericin B. In fact, survival was increased in the group receiving the combination (P < 0.01 compared with either drug alone) for treatment of the more indolent infection. The effect of a single large dose of amphotericin B (5 mg/kg) with or without daily SCH 39304 (for 14 days) was
0
10
20
Days FIG. 2. Survival of mice infected with C. albicans, more indolent infection. (A) Open squares, controls given vehicle by oral gavage; open triangle, amphotericin B, 1 mg/cg/day; closed squares, SCH 39304, 1.25 mg/kg/day; closed circles, SCH 39304, 1.25 mg/kg/day, plus amphotericin B, 1 mg/kg/day. (B) Ticks, controls given 5% sterile water by intraperitoneal injection; open circles, amphotericin B, 5 mg once; closed triangles, SCH 39304, 0.1 mg/kg/day; open squares, SCH 39304, 0.1 mg/kg/day, plus amphotericin B, 5 mg once. The bars just above the x axes represent the interval during which mice received treatment.
also evaluated in this experiment (Fig. 2B). The single dose of amphotericin B 24 h after the mice were infected was sufficient to result in 100% survival at day 40, the end of the experiment (P < 0.01 compared with controls). The addition of SCH 39304, 0.1 mg/kg/day, did not decrease the perfect survival afforded by the treatment of mice with a single dose of amphotericin B. In this experiment, the one large of dose of amphotericin B was superior to lower daily doses of amphotericin B (P < 0.001). Colony counts of C. albicans in the kidneys of infected mice supported the survival data. On the last day of therapy of mice with the indolent infection, control mice were heavily infected (Table 1). Few colonies were recovered from mice treated with SCH 39304, 1.25 mg/kg/day, or amphotericin B, 1 mg/kg/day, plus SCH 39304, 1.25 mg/kg/ day. Combination therapy with the lower doses of both
VOL. 35, 1991
NOTES
TABLE 1. Colony counts in kidneys obtained from mice on day 14 of experiment 2 Group
CFU/kidneya
Control ......................................... >10,000 Amphotericin B, 1 mg/kg/day .................................. 1,455 SCH 39304, 1.25 mg/kg/day ..................................... 21 Amphotericin B, 1 mg/kg/day, plus SCH 39304, 1.25 mg/kg/day ......................................... 156 Amphotericin B, 5 mg once ..................................... 56,180 SCH 39304, 0.1 mg/kg/day ...................................... 448,500 Amphotericin B, 5 mg once, plus SCH 39304, 0.1 mg/kg/day ........................ 0 ................. a Mean number of colonies recovered from one kidney from each of two mice cultured in duplicate.
1671
multiple strains may have to be evaluated to uncover unusual effects. In addition, the results should not be extrapolated to other mycoses, since one such study suggested that ketoconazole and amphotericin B have antagonistic effects in murine aspergillosis (7). However, the interaction of polyenes and azoles is a clinically important problem, which will become compounded when newer azole derivatives become available and when the opportunity for sequential and/or concomitant polyene-azole therapy arises. This study should serve as a basis for more thorough examination of the topic. I thank Michele Picard for expert technical assistance. Support for this project was provided, in part, by a grant from
Schering-Plough Corp.
drugs yielded more impressive results, with mice receiving the combination having sterile cultures (Table 1). Results for cultures obtained at various time intervals in two other experiments were similar to the data presented in Table 1. There has been an increase in awareness concerning the theoretical reasons for avoiding the combined use of polyene and azole antifungal agents. However, there is little information available yet to address this problem. Somewhat surprisingly, the data in this study suggest that when administered simultaneously, there are no apparent antagonistic effects of the antifungal agents in mice with either an acute or indolent C. albicans infection. This was demonstrated by survival and culture data. The mechanisms responsible for the lack of antagonism and, in some instances, the additive to synergistic activity of combination polyene-azole therapy are unclear. Simplistic explanations of polyene binding to the fungal membrane ergosterol and azole inhibition of ergosterol synthesis are not tenable when attempting to explain findings such as those presented here. One possibility that is amenable to experimental verification is that polyene binding to the fungus destabilizes the membrane so that uptake of the azole is enhanced. Once internalized, effects on fungal metabolism other than mere inhibition of ergosterol synthesis may then become important correlates of the antifungal effect. It should be stressed that this study addressed the effects of combination therapy by using one strain of Candida, and as previous in vitro work from this laboratory suggests (4),
REFERENCES 1. Clemons, K. V., L. H. Hanson, A. M. Perlman, and D. A. Stevens. 1990. Efficacy of SCH 39304 and fluconazole in a murine model of disseminated coccidioidomycosis. Antimicrob. Agents Chemother. 34:928-930. 2. Kobayashi, G. S., S. J. Travis, M. G. Rinaldi, and G. Medoff. 1990. In vitro and in vivo activities of SCH 39304, fluconazole, and amphotericin B against Histoplasma capsulatum. Antimicrob. Agents Chemother. 34:524-528. 3. Kosoglou, T., G. P. Perentesis, M. B. Affrime, C.-C. Lin, P. Mojaverian, E. Radwanski, and P. H. Vlasses. 1990. The effect of antacid and cimetidine on the oral absorption of the antifungal agent SCH 39304: J. Clin. Pharmacol. 30:638-642. 4. Meshulam, T., S. M. Levitz, R. D. Diamond, and A. M. Sugar. 1989. Effect of cilofungin (LY 121019), a fungal cell wall synthesis inhibitor, on interactions of Candida albicans with human neutrophils. J. Antimicrob. Chemother. 24:741-745. 5. Perfect, J. R., K. A. Wright, M. M. Hobbs, and D. T. Durack. 1989. Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH 39304. Antimicrob. Agents Chemother. 33:1735-1740. 6. Restrepo, B. I., J. Ahrens, and J. R. Graybili. 1989. Efficacy of SCH 39304 in murine cryptococcosis. Antimicrob. Agents Chemother. 33:1242-1246. 7. Schaffner, A., and P. G. Frick. 1985. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J. Infect. Dis. 151:902-910. 8. Sugar, A. M., M. Picard, and L. Noble. 1990. Treatment of murine pulmonary blastomycosis with SCH 39304, a new triazole antifungal agent. Antimicrob. Agents Chemother. 34:896-898.
