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Antimicrobial Agents and Chemotherapy, February 2004, p. 384-387, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.384-387.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Efficacies of the New Triazole Albaconazole against Cryptococcus neoformans

J. L. Miller,¹ W. A. Schell,¹ E. A. Wills,¹ D. L. Toffaletti,¹ M. Boyce,¹ D. K. Benjamin Jr.,² J. Bartroli,³ and J. R. Perfect^1*

Department of Medicine, Pediatrics,¹ Duke Clinical Research Institute, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina,² Drug Discovery, J. Uriach & Cia, Palau-solità i Plegamans, Barcelona, Spain³

Received 23 July 2003/ Returned for modification 2 October 2003/ Accepted 14 October 2003

Top Abstract Introduction Materials and Methods Results Discussion References

 
The activity of albaconazole (UR-9825; J. Uriach & Cía. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albaconazole was 100-fold more potent in vitro than fluconazole on a per-weight basis and was fungicidal at potentially relevant concentrations for two isolates. MICs ranged from 0.0012 to 1.25 µg/ml, with the MICs for most isolates being between 0.039 and 0.156 µg/ml. Isolates were from human immunodeficiency virus (HIV)-infected and non-HIV-infected patients and were of serotypes A, B, and C; and the fluconazole MICs for some of the isolates were elevated. Infected rabbits were treated with either fluconazole or albaconazole at dosages ranging from 5 to 80 mg/kg of body weight/day. The peak concentrations of albaconazole in serum and cerebrospinal fluid (CSF) averaged 4.14 and 0.62 µg/ml, respectively, in animals receiving 80 mg/kg/day. Comparison of the concentrations in serum and CSF suggested a level of CSF penetration of approximately 15%. Despite limited penetration into the subarachnoid space, at all three doses tested albaconazole was as effective as fluconazole for the treatment of cryptococcal meningitis in rabbits.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Cryptococcosis has dramatically increased in frequency as a result of the pandemic of human immunodeficiency virus (HIV) infection and an enlarging population of other immunocompromised individuals. Significant improvements in the management of cryptococcal meningitis have been made during the last several decades. Amphotericin B, fluconazole, and amphotericin B in combination with flucytosine have been carefully studied for their efficacies in the treatment of cryptococcal meningitis with and without coexisting HIV infection (2, 6, 20). Amphotericin B and flucytosine are successful for initial induction treatment, but fluconazole is generally used for long-term suppressive therapy (4) or prophylaxis (18) in patients with AIDS. However, cryptococcal meningitis still has a treatment failure rate of 10 to 25%, despite excellent clinical trials and evidence-based treatment guidelines. Furthermore, there is concern that the number of Cryptococcus neoformans isolates relatively resistant to current therapies such as fluconazole (10, 22) might increase.

The new triazole albaconazole (J. Uriach & Cía. S.A., Barcelona, Spain) (Fig. 1) is known to possess in vitro potency, broad-spectrum antifungal activity, good pharmacokinetics, and excellent oral bioavailability (1, 19). In this study we examined its in vitro and in vivo activities against the basidiomycetous pathogen C. neoformans. The activity of albaconazole was compared to that of fluconazole in vitro, and albaconazole was found to be very active against all 12 C. neoformans isolates tested, including an isolate for which the fluconazole MIC was 64 µg/ml. The in vivo efficacy of albaconazole was evaluated by using a standardized rabbit model of cryptococcal meningitis (11-17, 21, 24). The efficacy of albaconazole was compared to that of fluconazole, an agent with which there is significant experience for the prophylaxis, suppression, and treatment of cryptococcosis in humans and animals (4, 8, 9, 18, 20). Fluconazole and albaconazole were found to have similar therapeutic activities in this experimental model.

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FIG. 1. Chemical structure of albaconazole.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Animals. New Zealand White rabbits (weight, 2 to 3 kg) were housed in separate cages and given rabbit chow (Purina) and water ad libitum. Intramuscular injections of 115 mg of ketamine (KetaFlo; Abbott Laboratories. North Chicago, Ill.) plus 15 mg of xylazine (Vedco, Inc., St. Joesph, Mo.) were given as anesthesia for all invasive procedures. The animals were killed with an intravenous injection of sodium pentobarbital (Euthasol; Delmarva Laboratories, Midlothian, Va.) at the termination of the experiment or before, based on prescribed humane endpoints. Animals requiring euthanasia were recorded as deaths on the following day for purposes of survival analysis.

Antifungal agents. For in vitro testing, 2 mg of albaconazole was dissolved in 2 ml of 100% dimethyl sulfoxide, which yielded a concentration of 1,000 µg/ml (50x solution), and was stored by a standard protocol (5). For in vivo testing at 80 mg/kg of body weight/day, albaconazole was prepared fresh daily by suspending 3.024 g in 27 ml of sterile 0.2% carboxymethyl cellulose with 1% Tween 80. Lower dosages were prepared accordingly so that the vehicle volume given in each regimen was the same. The suspension was made by first grinding drug with a small amount of 0.2% carboxymethyl cellulose-1% Tween in a mortar and pestle and then gradually adding the remainder of the solvent vehicle. The albaconazole suspension was administered by oral gavage with a 3-in. 18-gauge gavage needle. Fluconazole (a 40-mg/ml oral suspension; Diflucan; Pfizer, New York, N.Y.) was given daily by gavage at a dose of 5, 20, or 80 mg/kg.

Organisms. C. neoformans H99 (DUMC 135.97) was the clinical isolate used to establish meningitis in the rabbits (11, 14, 21). Eleven additional C. neoformans isolates chosen for in vitro susceptibility testing consisted of isolates from both AIDS and non-AIDS patients of serotypes A, B, and C; and the fluconazole MICs for the various isolates covered a broad range. The isolates studied were serotype B isolate DUMC 114.95; serotype C isolate 119.95; and serotype A isolates 109.97, 251.86, 124.96, 163.99, 133.95, 114.96, 135.97, 123.96, 158.03, and 125.96.

In vitro susceptibility testing. An approved method for yeast susceptibility testing, as modified for C. neoformans, was followed (7). This broth macrodilution method specifies the use of an inoculum of approximately 10³ CFU/ml in RPMI 1640 medium with 3-(N-morpholino)propanesulfonic acid incubated at 35°C for 72 h. A total of 100 µl of each inoculum was plated so that an exact baseline count for each isolate could be established. The MIC endpoint for azole compounds is defined as an 80% reduction in growth compared to the growth of the drug-free control. For determination of fungicidal concentrations, tubes showing no growth were vortexed and a 100-µl aliquot from each was plated onto Sabouraud agar plates. The lowest drug concentration that killed at least 97% of the baseline inoculum was recorded as the minimum fungicidal concentration (MFC).

Antimicrobial assay. The concentration of albaconazole in serum and cerebrospinal fluid (CSF) samples was measured by a bioassay with yeast nitrogen base, agar diffusion (bioassay) plates, and Candida kefyr ATCC 46764 (3). Known concentrations of albaconazole were dissolved in dimethyl sulfoxide and prepared in serum and CSF obtained from infected, untreated control rabbits. The CSF standards contained albaconazole at concentrations ranging from 0.03125 to 1.0 µg/ml, and the serum standards contained albaconazole at concentrations ranging from 0.625 to 5 µg/ml. Controls included rabbit serum and CSF. The data were plotted by using Microsoft Excel software, and concentrations were calculated from the R² value.

Production of cryptococcal meningitis. Beginning 1 day prior to inoculation and for the duration of the experiment, all animals received a daily intramuscular injection of hydrocortisone acetate (5.0 mg/kg; Sigma, St. Louis, Mo.). C. neoformans (H99) was grown at 35°C for 3 days on Sabouraud agar plates with chloramphenicol, harvested with a cotton swab, and suspended in 0.015 M phosphate-buffered saline at pH 7.4 to a density of 1.0 x 10⁹ CFU/ml, as verified by quantitative culture. The rabbits were sedated and inoculated intracisternally with 0.3 ml of the yeast inoculum. On predetermined days following inoculation, intracisternal taps were performed, and approximately 0.5 ml of CSF was aspirated. The CSF was diluted in phosphate-buffered saline and cultured on Sabouraud agar with chloramphenicol. The results were expressed as the log₁₀ CFU per milliliter of CSF.

Treatment regimens. Treatment regimens of 80 mg/kg/day for 14 days, 20 mg/kg/day for 23 days, or 5 mg/kg/day for 19 days were begun 2 days after inoculation of the rabbits. Six rabbits were assigned to the albaconazole group, and five rabbits each were assigned to the fluconazole and the untreated control group for each dose. The experiment with albaconazole at 5 mg/kg did not include an untreated control group. This exclusion was based on findings of consistent mortality in the control rabbits used in the experiments with the other two dosages and thus allowed us to minimize the number of deaths.

Statistical methods. Survival time data were analyzed by Kaplan-Meier curve analysis; P values derived from Kaplan-Meier curves are based on log-rank (nonparametric) testing. Fisher's exact test was used for categorical data. Because multiple tests were performed, the Bonferroni correction was used to interpret P values. The analysis was repeated by the Wilcoxon rank-sum test for continuous variables with multivariable regression modeling to account for multiple observations, and the results (not presented) were similar. In order to compare the organism burdens achieved with fluconazole and albaconazole, the data were analyzed by the generalized estimating equation (GEE). Analysis by GEE is a regression technique that accounts for multiple observations for each individual animal. An unstructured within-group correlation matrix was used in the regression with GEE. The outcome was the organism concentration, and the independent variable was the treatment (fluconazole or albaconazole).

Top Abstract Introduction Materials and Methods Results Discussion References

 
The albaconazole MICs were low and relatively uniform for all isolates, including different isolates of serotypes and isolates from AIDS and non-AIDS patients. The albaconazole MICs and MFCs for strain H99, which was used to infect the rabbits, were 0.0195 and 20 µg/ml, respectively, whereas the fluconazole MICs and MFCs for the strain were 4 and >64 µg/ml, respectively; thus, albaconazole was 100-fold more potent on a weight basis. The albaconazole MICs for the majority of cryptococcal isolates were between 0.0024 and 0.156 µg/ml (Table 1). The albaconazole MFCs ranged from 0.078 to >20 µg/ml, with the MFCs for only two isolates being of potential clinical relevance.

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TABLE 1. MICs and MFCs of fluconazole and albaconazole for 12 isolates of C. neoformans

For albaconazole doses of 80 and 20 mg/kg/day, the concentrations in serum at 1 to 2 and 24 h postdosing averaged 4.14 and 3.99 µg/ml and 3.59 and 0.81 µg/ml, respectively. For the albaconazole dose of 5 mg/kg/day the concentration in serum was 1.18 µg/ml at 1 to 2 h postdosing (the concentration was not determined at 24 h postdosing). Albaconazole could be detected in CSF only at the highest dosage tested, with concentrations averaging 0.62 µg/ml by day 7 of therapy (Table 2). Comparison of the drug concentrations in serum and CSF suggested a level of penetration into CSF from serum of approximately 15% by day 7 when treatment with 80 mg/kg/day was used.

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TABLE 2. Albaconazole concentrations in serum and CSF of rabbits with cryptococcal meningitis

Figure 2a to c demonstrates that fluconazole and albaconazole at each of the three doses tested (80, 20, and 5 mg/kg/day) resulted in continuous and significant drops in yeast counts in CSF over the period of treatment. We did not observe a difference in the yeast burdens in CSF between the fluconazole- and the albaconazole-treated animals (P = 0.65). Compiled survival data from all experiments showed a significant difference (P < 0.001) in survival for animals treated with both drugs compared to that for untreated control animals (Fig. 3). We were not able to detect a difference between the drugs for the treatment of experimental cryptococcosis with the three drug regimens used (P = 0.99).

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FIG. 2. Results of treatment of cryptococcal meningitis with albaconazole or fluconazole or no treatment (controls). (a) Dosing at 80 mg/kg/day; (b) dosing at 20 mg/kg/day; (c) dosing at 5 mg/kg/day.

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FIG. 3. Comparison of survival of rabbits treated with albaconazole or fluconazole at all dosages or not treated (controls). Kaplan-Meier survival estimates predict a survival advantage for treated animals (P < 0.001).

Top Abstract Introduction Materials and Methods Results Discussion References

 
In vitro susceptibility testing of clinical isolates has been shown to have some value for predicting the outcome of cryptococcal meningitis. Witt et al. (23) found that human cryptococcal meningitis caused by C. neoformans isolates for which fluconazole MICs are higher was more difficult to treat, and a correlation between the fluconazole MIC and the outcome of infection was also shown in an animal model of cryptococcosis (22). In this study, we examined the activity of albaconazole in vitro against a series of C. neoformans isolates for which the fluconazole MICs were as high as 64 µg/ml. Albaconazole was active against all isolates, and the results suggest that albaconazole is more potent than fluconazole on a direct-weight basis.

For in vivo testing we used a model of cryptococcal meningitis in immunosuppressed rabbits, and we standardized the model using C. neoformans isolate H99. The activity of albaconazole was compared to that of fluconazole, the azole with which there is the most experience in the management of cryptococcal infections in humans and animals. From pharmacokinetic measurements of albaconazole, we determined that the concentrations achievable in rabbit serum and CSF when a dose of 80 mg/kg was used were approximately 4 and 0.5 µg/ml, respectively. This concentration is more than 100-fold (serum) and 10-fold (CSF) higher than the MICs for most clinical isolates tested, including isolate H99, which was used for the in vivo studies.

Three dosage regimens were compared in the treatment experiments, and the results demonstrated that all doses of albaconazole and fluconazole have equivalent therapeutic activities in this animal model. In comparison to the C. neoformans yeast counts in the CSF of untreated animals, both albaconazole and fluconazole significantly reduced the yeast counts in the CSF over 2 weeks of treatment and produced a survival advantage. There was slow, consistent killing of C. neoformans over 2 weeks of treatment, but the subarachnoid space of most animals was not sterilized by the end of treatment.

Our interpretation of the results suggests that the pharmacokinetics and the potencies of these two triazoles are proportional for the treatment cryptococcosis. Specifically, fluconazole at the 80-mg/kg dose produces much higher concentrations in serum (65 to 75 µg/ml) and CSF (40 to 45 µg/ml) at 1 to 2 h postdosing (15). This translates into a level of penetration into CSF of 60%. These levels are approximately 10-fold higher than the fluconazole MIC for isolate H99. Similarly, albaconazole at the 80-mg/kg dose achieved concentrations in CSF (0.5 µg/ml) that were more than 10-fold higher than the albaconazole MIC for H99. However, albaconazole concentrations in CSF did not approach the MFC for H99 (20 µg/ml), and this might be the reason that albaconazole, like fluconazole, exhibited a slow onset of action and a gradual reduction in the yeast counts in CSF rather than rapid killing. Albaconazole possesses potent in vitro activity against C. neoformans isolates and shows signs of some fungicidal activity against certain isolates. It is possible that cryptococcal isolates in the subarachnoid space for which MFCs are lower might be killed more rapidly by albaconazole treatment. The rabbit model of cryptococcal meningitis has been an accurate predictor of drug activity in humans. Thus, this study suggests that further in vivo investigations of this triazole for the treatment of fluconazole-resistant isolates of C. neoformans in the rabbit are warranted and that albaconazole could potentially be effective for the treatment of human cryptococcosis.

 
This work was supported by grants from J. Uriach & Cia. S.A. and from the Ministerio de Ciencia y Tecnología Programa de Fomento de la Investigación Técnica del Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (2000-2003). D. K. Benjamin, Jr., received support from NICHD grant R03HD42940-01.

 
* Corresponding author. Mailing address: P.O. Box 3353, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-4016. Fax: (919) 684-8902. E-mail: perfe001{at}mc.duke.edu.

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1
1. Bartroli, J., E. Turmo, M. Alguero, E. Boncompte, M. L. Vericat, L. Conte, J. Ramis, M. Merlos, J. Garcia-Rafanell, and J. Forn. 1998. New azole antifungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J. Med. Chem. 41:1869-1882.[CrossRef][Medline]
2
2. Bennett, J. E., W. Dismukes, R. J. Duma, G. Medoff, M. A. Sande, H. Gallis, J. Leonard, B. T. Fields, M. Bradshaw, H. Haywood, Z. A. McGee, T. R. Cate, C. G. Cobbs, J. F. Warner, and D. W. Alling. 1979. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N. Engl. J. Med. 301:126-131.[Abstract]
3
3. Bodet, CA, III, J. H. Jorgensen, and D. J. Drutz. 1985. Simplified bioassay method for measurement of flucytosine or ketoconazole. J. Clin. Microbiol. 22:157-160.[Abstract/Free Full Text]
4
4. Bozzette, S. A., R. A. Larsen, and J. Chin. 1991. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N. Engl. J. Med. 324:580-584.[Abstract]
5
5. Denning, D. W., R. M. Tucker, L. H. Hanson, J. R. Hamilton, and D. A. Stevens. 1989. Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch. Intern. Med. 149:2301-2308.[Abstract/Free Full Text]
6
6. Dismukes, W. E., G. Cloud, H. A. Gallis, T. M. Kerkering, G. Medoff, P. L. Craven, L. G. Kaplowitz, J. F. Fisher, C. R. Gregg, C. A. Bowles, S. Shadomy, A. M. Stamm, R. B. Diasio, L. Kaufman, S.-J. Soong, W. Blackwelder, and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. 1987. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N. Engl. J. Med. 317:334-341.[Abstract]
7
7. Galgiani, J. N., M. S. Barlett, M. A. Ghannoum, A. Espinel-Ingroff, M. V. Lancaster, F. C. Odds, M. A. Pfaller, M. G. Rinaldi, and T. J. Walsh. 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts, p. 1-29. Approved standard 17-9. National Committee for Clinical Laboratory Standards, Wayne, Pa.
8
8. Leenders, A. C., P. Reiss, P. Portegies, K. Clezy, N. C. J. Hop, J. Hoy, J. C. C. Borleffs, T. Alloworth, R. Kauffman, P. Jones, F. P. Kroon, H. A. Verbrugh, and S. deMarie. 1997. Liposomal amphotericin B (Ambisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 11:1463-1471.[Medline]
9
9. Pappas, P. G., J. R. Perfect, G. A. Cloud, R. A. Larsen, G. A. Pankey, D. J. Lancaster, H. Henderson, C. A. Kauffman, D. N. Haas, M. Saccente, R. Hamill, M. S. Holloway, R. M. Narven, and W. E. Dukes. 2001. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin. Infect. Dis. 33:690-699.[CrossRef][Medline]
10
10. Paugam, A., J. Dupuy-Camet, P. Blanche, J. P. Gangneux, C. Tourte-Schaefer, and D. Sicard. 1994. Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin. Infect. Dis. 19:975.[Medline]
11
11. Perfect, J. R., G. M. Cox, R. K. Dodge, and W. A. Schell. 1996. In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans. Antimicrob. Agents Chemother. 40:1910-1913.[Abstract]
12
12. Perfect, J. R., and D. T. Durack. 1982. Treatment of experimental cryptococcal meningitis with amphotericin B, 5-fluorocytosine and ketoconazole. J. Infect. Dis. 146:429-435.[Medline]
13
13. Perfect, J. R., and D. T. Durack. 1985. Comparison of amphotericin B and N-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis. Antimicrob. Agents Chemother. 28:751-755.[Abstract/Free Full Text]
14
14. Perfect, J. R., S. D. R. Lang, and D. T. Durack. 1980. Chronic cryptococcal meningitis; a new experimental model in rabbits. Am. J. Pathol. 101:177-194.[Abstract]
15
15. Perfect, J. R., D. V. Savani, and D. T. Durack. 1986. Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob. Agents Chemother. 29:579-583.[Abstract/Free Full Text]
16
16. Perfect, J. R., and K. A. Wright. 1994. Amphotericin B lipid complex in the treatment of experimental cryptococcal meningitis and disseminated candidiasis. J. Antimicrob. Chemother. 33:73-81.[Abstract/Free Full Text]
17
17. Perfect, J. R., K. S. 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.[Abstract/Free Full Text]
18
18. Powderly, W. G., D. M. Finkelstein, J. Feinberg, P. Frame, W. He, C. van der Horst, S. L. Koletar, M. E. Eyster, J. Carey, H. Waskin, T. M. Hooton, N. Hyslop, S. A. Spector, and S. A. Bozzette. 1995. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N. Engl. J. Med. 332:700-705.[Abstract/Free Full Text]
19
19. Ramos, G., M. Cuenca-Estrella, A. Monzon, and J. L. Rodriguez-Tudela. 1999. In vitro comparative activity of UR-9825, itraconazole and fluconazole against clinical isolates of Candida spp. J. Antimicrob. Chemother. 44:283-286.[Abstract/Free Full Text]
20
20. Saag, M. S., W. G. Powderly, G. A. Cloud, P. Robinson, M. H. Grieco, P. K. Sharkey, S. E. Thompson, A. Sugar, C. U. Tuazon, J. F. Fisher, N. Hyslop, J. M. Jacobson, R. Hafner, and W. F. Dismukes. 1992. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N. Engl. J. Med. 326:83-89.[Abstract]
21
21. Schell, W. A., G. M. D. de Almeida, R. K. Dodge, K. Okonogi, and J. R. Perfect. 1998. In vitro and in vivo efficacy of the triazole TAK-187 against Cryptococcus neoformans. Antimicrob. Agents Chemother. 42:2630-2632.[Abstract/Free Full Text]
22
22. Velez, J. D., R. Allendoerfer, M. Luther, M. G. Rinaldi, and J. R. Graybill. 1993. Correlation of in vitro azole susceptibility with in vitro response in a murine model of cryptococcal meningitis. J. Infect. Dis. 168:508-510.[Medline]
23
23. Witt, M. D., R. J. Lewis, R. A. Larsen, E. N. Milefchik, M. A. E. Leal, R. H. Havbrick, J. A. Richie, J. E. Edwards, and M. A. Ghannoum. 1996. Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of antifungal susceptibility testing. Clin. Infect. Dis. 22:322-328.[Medline]
24
24. Wright, K. A., J. R. Perfect, and W. Ritter. 1990. The pharmacokinetics of BAY R3783 and its efficacy in the treatment of experimental cryptococcal meningitis. J. Antimicrob. Chemother. 26:387-397.[Abstract/Free Full Text]

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Antimicrobial Agents and Chemotherapy, February 2004, p. 384-387, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.384-387.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, J. L. Articles by Perfect, J. R. Search for Related Content PubMed PubMed Citation Articles by Miller, J. L. Articles by Perfect, J. R.