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Efficacy of fluconazole in cryptococcal meningitis
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DIAGN MICROBIOLINFECTDIS 1989;12:235S-238S
Efficacy of Fluconazole in Cryptococcal Meningitis P.D. Jones, D. Marriott, and B.R. Speed
In this clinical trial, oral fluconazole was used to treat cryptococcal meningitis in 32 patients with Acquired Immune Deficiency Syndrome (AIDS). In 11 patients who received 200 to 400 rag~day of fluconazole as primary therapy, a favorable clinical response was obtained in 67% of all evaluable patients. A negative cerebrospinal fluid (CSF) culture was also reported for 86% of these cases. Fluconazole was used as second-line therapy in an additional 15 patients who were not responsive to therapy with amphotericin B or amphotericin B combined with flucytosine. Positive clinical and mycologic responses were then obtained in more than 60% of these cases. Following successful treatment with fluconazole as either the primary or secondary antifungal agent, 26 patients were evaluated
during maintenance therapy with 100 to 200 mg daily of fluconazole to prevent recurrence of disease. The relapse rate was 3.2 cases of cryptococcal meningitis per 1000 patient weeks, with a mean duration of 22 weeks for maintenance therapy. An additional six patients who were also treated with either amphotericin B alone or in combination with flucytosine but were asymptomatic or CSF culture negative when treatment with fluconazole was initiated were evaluated for the safety and efficacy of maintenance therapy. Thus, treatment of fluconazole appears to be efficacious as well as safe. The incidence of superimposed infections associated in these AIDS patients make it difficult to accurately assess any adverse effects.
INTRODUCTION
tember, 1987; during the subsequent 12 months, 51 patients with cryptococcal meningitis were enrolled in a clinical trial of this drug, AIDS was the primary disease in 38 of the cases in this study. The efficacy and safety of fluconazole were d e t e r m i n e d for initial as well as subsequent maintenance therapy in the treatment of patients with cryptococcal meningitis.
Fluconazole has been reported to produce excellent results in animal studies of cryptococcal meningitis even t h o u g h it demonstrates only a moderate degree of in vitro activity against Cryptococcus neoformans (Odds, 1986; Palou de Fernandez, 1986). In addition to its antifungal activity, fluconazole is considered to be a potentially effective drug in the treatment of cryptococcal meningitis because of high oral bioavailability, prolonged serum half-life, and good cerebrospinal fluid (CSF) penetration (Brammer and Tarbit, 1987). In addition, fluconazole has been s h o w n to achieve drug levels in CSF that are 40 to 60% of those obtained in plasma with normal meninges, and as high as 90% of the plasma levels in the presence of meningitis. Fluconazole was introduced in Australia in SepFrom the Department of Infectious Diseases, Prince Henry Hospital (P.D.J.), the Department of Microbiology, St. Vincent's Hospital, Sydney, Australia (D.W.), and the Fairfield Infectious Diseases Hospital, Melbourne, Australia (B.R.S.). Address reprint requests to: Dr. P.D. Jones, Department of Infectious Diseases, Prince Henry Hospital, P.O. Box 233, Matraville, N.S.W. 2036, Australia. Received May 18, 1989; revised and accepted May 30, 1989. © 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/89/$3.50
PATIENTS A N D M E T H O D S The study data were derived from case reports on patients receiving fluconazole on an individual patient usage basis. Six of the 38 patients treated with fluconazole for cryptococcal meningitis as a complication of AIDS were excluded from the analysis. Patients were w i t h d r a w n from the s t u d y for the following reasons: cryptococcal meningitis was not proven in one patient; two patients were being treatm e n t concurrently with amphotericin B; one patient received less t h a n 4 weeks of treatment during the study period; and there was inadequate data for two patients. In all cases, the oral formulation of fluconazole was used: The treatment period was divided into two phases that included both a therapeutic a n d a maintenance period. In the therapeutic phase, pa-
236S
tients were treated with either 200 or 400 mg of fluconazole per day for up to 6 weeks. One patient received 800 mg daily for the 6-week treatment period. Following the therapeutic phase, patients received either 100 or 200 mg a day for maintenance therapy. The higher dosage regimen was instituted after the first six months of treatment. However, there were not enough patients in the two different dosage groups for statistical comparison; hence, study data for both drug doses were combined for analysis. The 32 evaluable patients were divided into three treatment groups: Group A included 11 patients who had received no other systemic antifungal therapy for cryptococcal meningitis prior to commencing treatment with fluconazole. Group B was comprised of 15 patients who were initially treated with either amphotericin B alone or in combination with flucytosine but remained either symptomatic and/or CSF culture positive. The mean duration of amphotericin therapy was 9.5 weeks. Group C was comprised of six patients who were initially treated with amphotericin B either alone or concomitantly with flucytosine and were asymptomatic as well as CSF culture negative when maintenance therapy with fluconazole was instituted. In this group, the mean duration of amphotericin B therapy was 8.7 weeks. Clinical, mycologic, and serologic responses were measured upon completion of the therapeutic phase for patients in groups A and B. In group C, patients were evaluated for efficacy and safety of fluconazole therapy only during the maintenance phase. Clinical efficacy was assessed as follows: complete, which entailed resolution of all signs and symptoms related to cryptococcal meningitis; partial, which included improvement in signs and symptoms related to cryptococcal meningitis; nil, or no clinical response; and nonassessable, which included those patients who could not be clinically evaluated due to coexistence of neurologic disorders as a result of human immunodeficiency virus (HIV) infection. Mycologic responses were categorized as positive when CSF cultures were negative for cryptococcus, negative when CSF cultures remained positive for cryptococcus, or nonassessable when no CSF was obtained for post-treatment evaluation. The following assessments were used for serologic responses: positive, for a greater than or equal to fourfold fall in cryptococcal latex agglutination titer in CSF; negative, for a rising, stable, or less than fourfold fall in cryptococcal latex agglutination titer in the CSF; or nonassessable for those cases in which the CSF was not obtained for post-treatment evaluation.
P.D. Jones et al.
TABLE 1. Clinical Response to Fluconazole Therapy Patient Groups Group A (n = 9)
Group B (n = 14)
6 (67%)a 3 (33%) ---
8 (67%)~ 3 (25%) 1 (8%) 2
Complete Partial Nil Nonassessable
~Percentage response in assessable group.
RESULTS Clinical Efficacy of Fluconazole One patient in group A and two patients in group B were excluded from the analysis of clinical efficacy because they were asymptomatic before treatment with fluconazole. Complete clinical responses were obtained in more than 60% of evaluable patients receiving fluconazole as either first-line (group A) or second-line (group B) therapy (Table 1). Only one patient failed to respond clinically to treatment with fluconazole. This patient was previously treated with amphotericin B for 2 weeks with no clinical response to that drug, and he died 3 weeks following the start of fluconazole therapy. Eight patients in Group B were not analyzed mycologically because their CSF cultures were negative for cryptococcus following treatment with amphotericin B before instituting maintenance therapy with fluconazole. A positive mycologic response was obtained in 80% or more of evaluable patients in both groups A and B (Table 2), although in one patient in each group repeat CSF cultures remained persistently positive. The patient in group A who failed to show any mycologic response did have a partial clinical response; however, therapy was discontinued after 3 weeks, and he subsequently died. One patient each in groups A and B whose CSF antigen tests were negative before treatment with fluconazole were not included in the evaluation. A positive serologic response was obtained in 71% of
TABLE 2. Mycologic Response to Fluconazole Therapy Patient Groups
Positive Negative Nonassessable
Group A (n = 11)
Group B (n = 7)
6 (86%)a 1 (14%) 4
4 (80%)a 1 (20%) 2
aPercentage response in assessable group.
Fluconazole for Cryptococcal Meningitis
TABLE 3.
Serologic Response to Fluconazole Therapy Patient Groups
Positive Negative Nonassessable
Group A (n = 10)
Group B (n = 14)
5 (71%) a 2 (29%) 3
7 (54%)~ 6 (46%) 1
aPercentage response in assessable group. patients receiving fluconazole as first-line therapy (group A) and 54% of patients previously treated with amphotericin B alone or in combination with flucytosine (group B; Table 3). A total of 28 of the 32 efficacy evaluable patients in the treatment phase also were treated with fluconazole as maintenance therapy. Two of the patients who were excluded from the analysis of maintenance therapy reportedly had inadequate followup data as well as intermittent usage of fluconazole. The duration of maintenance therapy ranged from 7 to 51 weeks, with a mean treatment period of 22 weeks and a median of 19 weeks. There were 2 cases of cryptococcal meningitis that occurred at 16 and 17 weeks, respectively, after treatment with fluconazole. In both cases, fluconazole had been the drug used for primary therapy. One of these patients achieved satisfactory clinical, mycologic, and serologic responses. The second patient had a complete clinical response, but a follow-up lumbar puncture that would confirm the therapeutic outcome was not performed. In both of these cases, fluconazole 200 mg daily was administered for maintenance therapy; amphotericin B was subsequently used successfully to treat the recurrence of disease in both patients. For all of the study patients treated with fluconazole as maintenance therapy for cryptococcal meningitis, the relapse rate was 3.2 cases per 1000 patient weeks. A total of eight deaths occurred in patients enrolled in the study. Three patients died during the therapeutic phase with fluconazole, and two of these deaths were a direct result of cryptococcal meningitis. In the remaining six cases, there was no evidence of active disease at the time of death, although postmortem studies were not performed in all of these patients. In addition, duration of the followup period as well as the number of deaths were not sufficient to assess the effects of fluconazole on patient survival.
Clinical Safety of Fluconazole Assessment of fluconazole adverse effects was difficult in these patients because of coexisting HIV-
237S
related disorders and concurrent therapies. During treatment with fluconazole, four patients developed gastrointestinal symptoms, including nausea and vomiting. However, none of these patients discontinued therapy due to adverse events. One additional patient developed a maculopapular skin eruption during the second week of treatment which resolved after fluconazole therapy was withdrawn. Abnormal liver function tests were reported in four other patients; although therapy was continued in all of these cases, there was no evidence of progressive hepatic abnormalities.
DISCUSSION In this study, oral fluconazole was clinically effective in the treatment of cryptococcal meningitis associated with AIDS when administered as first-line therapy and in those patients treated with amphotericin B who had not achieved either a complete clinical or mycologic response. However, we believe that further comparative studies are needed to determine if fluconazole is as effective as amphotericin B in the treatment of this disease. Additional studies should also be performed to assess whether fluconazole can be effectively combined with amphotericin B. In this study, maintenance therapy with fluconazole following successful initial treatment with either fluconazole or amphotericin B alone or combined with flucytosine resulted in a relapse rate of cryptococcal meningitis of only 3.2 episodes per 1000 patient weeks. This rate was very similar to the rate of 3.6 episodes per 1000 patient weeks reported in patients who were treated with fluconazole on a compassionate basis in the United States (Robinson and Knirsch, 1988). These results also compare favorably with previously reported relapse rates of 40 to 50% at 6 months post-treatment in patients who were not given any type of maintenance antifungal therapy (Kovacs et al., 1985; Zuger et al., 1986). Although fluconazole treatment appeared to be safe in this group of study patients, possible side effects due to the study drug were difficult to assess because of the occurrence of other HIV-related disorders and concomitant therapies. In particular, the relationship of hepatotoxicity to treatment with fluconazole has not been substantiated. The incidence of side effects with fluconazole in the treatment of other fungal infections has been reported to be very low; however, the frequency of adverse events may differ in patients with cryptococcal meningitis because of the need to use higher doses and a prolonged therapeutic course.
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P.D. Jones et al.
REFERENCES Brammer KW, Tarbit MH (1987) A review of the pharmacokinetics of fluconazole (UK-49858) in laboratory animals and man. In Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Ed., RA Fromtling. Barcelona: JR Prous Science Publishers. Kovacs JA, Kovacs AA, Polis M, Wright WC, Gill VJ, Tuazon CU, Geimann EP, Lane HC, Longfield R, Overturf G, Macher AM, Fauci AS, Parrillo JE, Bennett JE, Masur H (1985) Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 103:533. Odds FC, Cheesman SL, Abbott AB (1986) Antifungal effects of fluconazole (UK 49858), a new triazole antifungal, in vitro. J Antimicrob Chemother 10:473.
Palou de Fernandez E, Patino MM, Graybill JR, Tarbit MH (1986) Treatment of cryptococcal meningitis in mice with fluconazole. J Antimicrob Chemother 18:261. Robinson PA, Knirsch AK (1988) Fluconazole treatment for serious fungal infections in patients who have failed conventional antifungal therapy. Twenty-eighth ICAAC, Los Angeles (abstract): 578. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ (1986) Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of the treatment. Ann Intern Med 104:234.
DIAGN MICROBIOLINFECTDIS 1989;12:235S-238S
Efficacy of Fluconazole in Cryptococcal Meningitis P.D. Jones, D. Marriott, and B.R. Speed
In this clinical trial, oral fluconazole was used to treat cryptococcal meningitis in 32 patients with Acquired Immune Deficiency Syndrome (AIDS). In 11 patients who received 200 to 400 rag~day of fluconazole as primary therapy, a favorable clinical response was obtained in 67% of all evaluable patients. A negative cerebrospinal fluid (CSF) culture was also reported for 86% of these cases. Fluconazole was used as second-line therapy in an additional 15 patients who were not responsive to therapy with amphotericin B or amphotericin B combined with flucytosine. Positive clinical and mycologic responses were then obtained in more than 60% of these cases. Following successful treatment with fluconazole as either the primary or secondary antifungal agent, 26 patients were evaluated
during maintenance therapy with 100 to 200 mg daily of fluconazole to prevent recurrence of disease. The relapse rate was 3.2 cases of cryptococcal meningitis per 1000 patient weeks, with a mean duration of 22 weeks for maintenance therapy. An additional six patients who were also treated with either amphotericin B alone or in combination with flucytosine but were asymptomatic or CSF culture negative when treatment with fluconazole was initiated were evaluated for the safety and efficacy of maintenance therapy. Thus, treatment of fluconazole appears to be efficacious as well as safe. The incidence of superimposed infections associated in these AIDS patients make it difficult to accurately assess any adverse effects.
INTRODUCTION
tember, 1987; during the subsequent 12 months, 51 patients with cryptococcal meningitis were enrolled in a clinical trial of this drug, AIDS was the primary disease in 38 of the cases in this study. The efficacy and safety of fluconazole were d e t e r m i n e d for initial as well as subsequent maintenance therapy in the treatment of patients with cryptococcal meningitis.
Fluconazole has been reported to produce excellent results in animal studies of cryptococcal meningitis even t h o u g h it demonstrates only a moderate degree of in vitro activity against Cryptococcus neoformans (Odds, 1986; Palou de Fernandez, 1986). In addition to its antifungal activity, fluconazole is considered to be a potentially effective drug in the treatment of cryptococcal meningitis because of high oral bioavailability, prolonged serum half-life, and good cerebrospinal fluid (CSF) penetration (Brammer and Tarbit, 1987). In addition, fluconazole has been s h o w n to achieve drug levels in CSF that are 40 to 60% of those obtained in plasma with normal meninges, and as high as 90% of the plasma levels in the presence of meningitis. Fluconazole was introduced in Australia in SepFrom the Department of Infectious Diseases, Prince Henry Hospital (P.D.J.), the Department of Microbiology, St. Vincent's Hospital, Sydney, Australia (D.W.), and the Fairfield Infectious Diseases Hospital, Melbourne, Australia (B.R.S.). Address reprint requests to: Dr. P.D. Jones, Department of Infectious Diseases, Prince Henry Hospital, P.O. Box 233, Matraville, N.S.W. 2036, Australia. Received May 18, 1989; revised and accepted May 30, 1989. © 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/89/$3.50
PATIENTS A N D M E T H O D S The study data were derived from case reports on patients receiving fluconazole on an individual patient usage basis. Six of the 38 patients treated with fluconazole for cryptococcal meningitis as a complication of AIDS were excluded from the analysis. Patients were w i t h d r a w n from the s t u d y for the following reasons: cryptococcal meningitis was not proven in one patient; two patients were being treatm e n t concurrently with amphotericin B; one patient received less t h a n 4 weeks of treatment during the study period; and there was inadequate data for two patients. In all cases, the oral formulation of fluconazole was used: The treatment period was divided into two phases that included both a therapeutic a n d a maintenance period. In the therapeutic phase, pa-
236S
tients were treated with either 200 or 400 mg of fluconazole per day for up to 6 weeks. One patient received 800 mg daily for the 6-week treatment period. Following the therapeutic phase, patients received either 100 or 200 mg a day for maintenance therapy. The higher dosage regimen was instituted after the first six months of treatment. However, there were not enough patients in the two different dosage groups for statistical comparison; hence, study data for both drug doses were combined for analysis. The 32 evaluable patients were divided into three treatment groups: Group A included 11 patients who had received no other systemic antifungal therapy for cryptococcal meningitis prior to commencing treatment with fluconazole. Group B was comprised of 15 patients who were initially treated with either amphotericin B alone or in combination with flucytosine but remained either symptomatic and/or CSF culture positive. The mean duration of amphotericin therapy was 9.5 weeks. Group C was comprised of six patients who were initially treated with amphotericin B either alone or concomitantly with flucytosine and were asymptomatic as well as CSF culture negative when maintenance therapy with fluconazole was instituted. In this group, the mean duration of amphotericin B therapy was 8.7 weeks. Clinical, mycologic, and serologic responses were measured upon completion of the therapeutic phase for patients in groups A and B. In group C, patients were evaluated for efficacy and safety of fluconazole therapy only during the maintenance phase. Clinical efficacy was assessed as follows: complete, which entailed resolution of all signs and symptoms related to cryptococcal meningitis; partial, which included improvement in signs and symptoms related to cryptococcal meningitis; nil, or no clinical response; and nonassessable, which included those patients who could not be clinically evaluated due to coexistence of neurologic disorders as a result of human immunodeficiency virus (HIV) infection. Mycologic responses were categorized as positive when CSF cultures were negative for cryptococcus, negative when CSF cultures remained positive for cryptococcus, or nonassessable when no CSF was obtained for post-treatment evaluation. The following assessments were used for serologic responses: positive, for a greater than or equal to fourfold fall in cryptococcal latex agglutination titer in CSF; negative, for a rising, stable, or less than fourfold fall in cryptococcal latex agglutination titer in the CSF; or nonassessable for those cases in which the CSF was not obtained for post-treatment evaluation.
P.D. Jones et al.
TABLE 1. Clinical Response to Fluconazole Therapy Patient Groups Group A (n = 9)
Group B (n = 14)
6 (67%)a 3 (33%) ---
8 (67%)~ 3 (25%) 1 (8%) 2
Complete Partial Nil Nonassessable
~Percentage response in assessable group.
RESULTS Clinical Efficacy of Fluconazole One patient in group A and two patients in group B were excluded from the analysis of clinical efficacy because they were asymptomatic before treatment with fluconazole. Complete clinical responses were obtained in more than 60% of evaluable patients receiving fluconazole as either first-line (group A) or second-line (group B) therapy (Table 1). Only one patient failed to respond clinically to treatment with fluconazole. This patient was previously treated with amphotericin B for 2 weeks with no clinical response to that drug, and he died 3 weeks following the start of fluconazole therapy. Eight patients in Group B were not analyzed mycologically because their CSF cultures were negative for cryptococcus following treatment with amphotericin B before instituting maintenance therapy with fluconazole. A positive mycologic response was obtained in 80% or more of evaluable patients in both groups A and B (Table 2), although in one patient in each group repeat CSF cultures remained persistently positive. The patient in group A who failed to show any mycologic response did have a partial clinical response; however, therapy was discontinued after 3 weeks, and he subsequently died. One patient each in groups A and B whose CSF antigen tests were negative before treatment with fluconazole were not included in the evaluation. A positive serologic response was obtained in 71% of
TABLE 2. Mycologic Response to Fluconazole Therapy Patient Groups
Positive Negative Nonassessable
Group A (n = 11)
Group B (n = 7)
6 (86%)a 1 (14%) 4
4 (80%)a 1 (20%) 2
aPercentage response in assessable group.
Fluconazole for Cryptococcal Meningitis
TABLE 3.
Serologic Response to Fluconazole Therapy Patient Groups
Positive Negative Nonassessable
Group A (n = 10)
Group B (n = 14)
5 (71%) a 2 (29%) 3
7 (54%)~ 6 (46%) 1
aPercentage response in assessable group. patients receiving fluconazole as first-line therapy (group A) and 54% of patients previously treated with amphotericin B alone or in combination with flucytosine (group B; Table 3). A total of 28 of the 32 efficacy evaluable patients in the treatment phase also were treated with fluconazole as maintenance therapy. Two of the patients who were excluded from the analysis of maintenance therapy reportedly had inadequate followup data as well as intermittent usage of fluconazole. The duration of maintenance therapy ranged from 7 to 51 weeks, with a mean treatment period of 22 weeks and a median of 19 weeks. There were 2 cases of cryptococcal meningitis that occurred at 16 and 17 weeks, respectively, after treatment with fluconazole. In both cases, fluconazole had been the drug used for primary therapy. One of these patients achieved satisfactory clinical, mycologic, and serologic responses. The second patient had a complete clinical response, but a follow-up lumbar puncture that would confirm the therapeutic outcome was not performed. In both of these cases, fluconazole 200 mg daily was administered for maintenance therapy; amphotericin B was subsequently used successfully to treat the recurrence of disease in both patients. For all of the study patients treated with fluconazole as maintenance therapy for cryptococcal meningitis, the relapse rate was 3.2 cases per 1000 patient weeks. A total of eight deaths occurred in patients enrolled in the study. Three patients died during the therapeutic phase with fluconazole, and two of these deaths were a direct result of cryptococcal meningitis. In the remaining six cases, there was no evidence of active disease at the time of death, although postmortem studies were not performed in all of these patients. In addition, duration of the followup period as well as the number of deaths were not sufficient to assess the effects of fluconazole on patient survival.
Clinical Safety of Fluconazole Assessment of fluconazole adverse effects was difficult in these patients because of coexisting HIV-
237S
related disorders and concurrent therapies. During treatment with fluconazole, four patients developed gastrointestinal symptoms, including nausea and vomiting. However, none of these patients discontinued therapy due to adverse events. One additional patient developed a maculopapular skin eruption during the second week of treatment which resolved after fluconazole therapy was withdrawn. Abnormal liver function tests were reported in four other patients; although therapy was continued in all of these cases, there was no evidence of progressive hepatic abnormalities.
DISCUSSION In this study, oral fluconazole was clinically effective in the treatment of cryptococcal meningitis associated with AIDS when administered as first-line therapy and in those patients treated with amphotericin B who had not achieved either a complete clinical or mycologic response. However, we believe that further comparative studies are needed to determine if fluconazole is as effective as amphotericin B in the treatment of this disease. Additional studies should also be performed to assess whether fluconazole can be effectively combined with amphotericin B. In this study, maintenance therapy with fluconazole following successful initial treatment with either fluconazole or amphotericin B alone or combined with flucytosine resulted in a relapse rate of cryptococcal meningitis of only 3.2 episodes per 1000 patient weeks. This rate was very similar to the rate of 3.6 episodes per 1000 patient weeks reported in patients who were treated with fluconazole on a compassionate basis in the United States (Robinson and Knirsch, 1988). These results also compare favorably with previously reported relapse rates of 40 to 50% at 6 months post-treatment in patients who were not given any type of maintenance antifungal therapy (Kovacs et al., 1985; Zuger et al., 1986). Although fluconazole treatment appeared to be safe in this group of study patients, possible side effects due to the study drug were difficult to assess because of the occurrence of other HIV-related disorders and concomitant therapies. In particular, the relationship of hepatotoxicity to treatment with fluconazole has not been substantiated. The incidence of side effects with fluconazole in the treatment of other fungal infections has been reported to be very low; however, the frequency of adverse events may differ in patients with cryptococcal meningitis because of the need to use higher doses and a prolonged therapeutic course.
238S
P.D. Jones et al.
REFERENCES Brammer KW, Tarbit MH (1987) A review of the pharmacokinetics of fluconazole (UK-49858) in laboratory animals and man. In Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Ed., RA Fromtling. Barcelona: JR Prous Science Publishers. Kovacs JA, Kovacs AA, Polis M, Wright WC, Gill VJ, Tuazon CU, Geimann EP, Lane HC, Longfield R, Overturf G, Macher AM, Fauci AS, Parrillo JE, Bennett JE, Masur H (1985) Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 103:533. Odds FC, Cheesman SL, Abbott AB (1986) Antifungal effects of fluconazole (UK 49858), a new triazole antifungal, in vitro. J Antimicrob Chemother 10:473.
Palou de Fernandez E, Patino MM, Graybill JR, Tarbit MH (1986) Treatment of cryptococcal meningitis in mice with fluconazole. J Antimicrob Chemother 18:261. Robinson PA, Knirsch AK (1988) Fluconazole treatment for serious fungal infections in patients who have failed conventional antifungal therapy. Twenty-eighth ICAAC, Los Angeles (abstract): 578. Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ (1986) Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of the treatment. Ann Intern Med 104:234.