Original Article
Comparison of Amphotericin B with Fluconazole in the Treatment of Acute AIDS-Associated Cryptococcal Meningitis
N Engl J Med 1992; 326:83-89January 9, 1992
- Abstract
- Abstract
Background.
Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease.
Methods.
In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period.
Results.
Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P<0.0001).
Conclusions.
Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined. (N Engl J Med 1992; 326:83–9.)
Media in This Article
Figure 1
Kaplan–Meier Estimates of the Length of Time to the First Negative Cerebrospinal Fluid Culture, According to Treatment Group.Table 1
Clinical and Laboratory Features of the Treatment Groups at Base Line.*Article Activity
- Article
CRYPTOCOCCAL meningitis, the most common life-threatening opportunistic fungal disease in patients infected with the human immunodeficiency virus (HIV) type 1, occurs in 5 to 8 percent of patients with the acquired immunodeficiency syndrome (AIDS).1 2 3 With the widespread implementation of more effective antiretroviral therapy and prophylactic treatment regimens designed to prevent the development of common life-threatening opportunistic infections, such as Pneumocystis carinii pneumonia, the incidence of cryptococcal disease will probably increase in parallel with improvement in survival over the next decade. Therefore, defining optimal approaches to the treatment of cryptococcal meningitis will become increasingly important.
Among patients with cryptococcal meningitis who did not have AIDS, the administration of amphotericin B combined with flucytosine over a period of four to six weeks led to success rates of 75 to 85 percent.4 , 5 This regimen has been less effective among patients with AIDS, in whom success rates with amphotericin B (0.3 to 0.5 mg per kilogram of body weight per day) with or without flucytosine are only 40 to 50 percent and drug intolerance is common, especially when flucytosine is used.1 , 5 6 7 8 9 By contrast, Larsen et al. reported success in all six patients treated with higher doses of amphotericin B (0.7 mg per kilogram per day for the first two weeks of therapy) plus flucytosine.10 However, even among patients successfully treated, high relapse rates necessitate the use of long-term maintenance therapy.1 , 6 7 8 , 11
Fluconazole, one of the recently developed triazole antifungal agents, represents a promising new approach to the treatment of cryptococcal meningitis in patients with AIDS. Unlike earlier antifungal azoles such as miconazole and ketoconazole, fluconazole is highly active against Cryptococcus neoformans infection induced in animals and possesses novel pharmacologic properties, including bioavailability after oral administration, excellent penetration of the cerebrospinal fluid, and renal excretion of more than 80 percent of active drug.12 13 14 15 Moreover, fluconazole has been used as therapy for AIDS-associated cryptococcosis in pilot studies, with encouraging results.3 , 8 , 16
Accordingly, we initiated a multicenter, randomized clinical trial to compare the efficacy and tolerability of orally administered fluconazole with that of intravenously administered amphotericin B as primary therapy for cryptococcal meningitis in patients with AIDS. This report describes the results of that trial.
Methods
Study Population
The criteria for enrollment included HIV infection documented by a positive test for the HIV antibody, age of at least 18 years, and a positive cerebrospinal fluid culture for C. neoformans. Patients could be enrolled on the basis of preliminary evidence of acute cryptococcal meningitis, including a positive cerebrospinal fluid titer for cryptococcal antigen, a positive cerebrospinal fluid India ink preparation, or evidence of C. neoformans on histopathological examination of tissues from other sites in combination with abnormal cerebrospinal fluid laboratory values. However, the cerebrospinal fluid culture must have been positive within 14 days of enrollment for the patient to be eligible. The episode of cryptococcal meningitis that we studied may have been an initial episode or represented a relapse after successful treatment. Patients could be enrolled if they had received no more than 1 mg of amphotericin B per kilogram within one week before entry.
Patients were excluded from the study if they were pregnant or comatose or were considered unlikely to survive for more than two weeks. They were also excluded if they had evidence of concomitant acute or chronic meningitis not due to C. neoformans, moderate-tosevere liver dysfunction, and a creatinine clearance rate of less than 0.333 ml per second (20 ml per minute). Concomitant therapy with anticoagulants similar to warfarin, oral hypoglycemic agents, barbiturates, phenytoin, immunostimulants, lymphocyte-replacement therapy, or investigational agents was not allowed. The study protocol was reviewed and approved by the institutional review board at each study site.
Treatment
After written informed consent was obtained from either the patient or the principal care giver, two patients were randomly assigned to fluconazole treatment for each patient assigned to amphotericin B treatment. Randomization was performed at each site by means of sealed envelopes and was stratified according to treatment site.
Fluconazole was administered orally in a single, 400-mg loading dose on the first day and in a dose of 200 mg daily thereafter. It could be administered intravenously in the same doses during the first week of treatment and for brief periods, up to three days, after the first week. Since the drug is excreted renally, the dose was decreased by 50 percent if the creatinine clearance rate was less than 0.83 ml per second (50 ml per minute). The dose could be increased to 400 mg after two weeks of therapy if the cerebrospinal fluid culture was still positive and either the patient's mental status deteriorated slightly or non—life-threatening cryptococcal disease developed at a new site.
Amphotericin B was administered intravenously in a dose of at least 0.3 mg per kilogram per day or in an equivalent dose given every other day. It was temporarily discontinued if serum creatinine levels exceeded 309 μmol per liter (3.5 mg per deciliter), and was reinstituted if they fell below 265 μmol per liter (3.0 mg per deciliter). The decision to use flucytosine (150 mg per kilogram per day in four divided doses) was left to the discretion of the investigator.
Evaluation
After a base-line evaluation, patients were evaluated every week for the first 4 weeks and every 2 weeks thereafter until the 10-week study period was completed. At each visit, a physical examination was performed and any adverse events were assessed and recorded. Serum electrolytes were measured, renal and hepatic function tested, and hemograms obtained to ensure the patients' safety and to compare the relative toxicity of the therapeutic agents. Serum titers of cryptococcal antigen were determined every two weeks. Lumbar punctures were performed every two weeks; the cerebrospinal fluid was analyzed for cell counts and the levels of protein, glucose, and cryptococcal antigen and was assessed by India ink staining and fungal culture. Tests for cryptococcal antigen were performed at each study site, rather than by a central laboratory.
Treatment was considered successful if the patient had clinical improvement or complete resolution of symptoms together with two consecutive negative cultures of cerebrospinal fluid samples obtained at least one week apart. Cultures of specimens from all other sites of C. neoformans infection except the urine must also have become negative by the end of therapy. Treatment was considered to have failed if the patient had quiescent disease, defined as clinically stable, progressive improvement or resolution of symptoms but persistently positive cultures for any site or body fluid other than the urine, or only one negative cerebrospinal fluid culture by the end of the 10-week treatment period; had progressive disease, defined as progressive clinical deterioration in the presence of persistently positive cultures; had a toxic reaction, defined as a serious or intolerable adverse event that was judged to be at least possibly related to the study drug by the investigator and that led to permanent discontinuation of the study drug; or died of progressive cryptococcal disease.
Study Design and Statistical Analysis
The primary efficacy analysis in this study compared the rates of successful treatment in the two groups. We assumed that if amphotericin B was no more than 30 percent more effective, as judged by successful sterilization of cerebrospinal fluid cultures, than fluconazole in the treatment of acute cryptococcal meningitis in patients with AIDS, then fluconazole could be considered to be a useful agent in treating cryptococcal meningitis.17 We sought to enroll 120 patients who could be evaluated — 80 to be assigned to fluconazole and 40 to amphotericin B. We assumed that amphotericin B treatment would result in clinical success in 60 percent of the patients, and we used a one-sided test with an alpha level of 0.025 and a power of 80 percent to detect a 30 percent lower response rate among fluconazole-treated patients. After an earlier study of cryptococcal meningitis, we estimated that 40 percent of the patients would not be compliant or eligible. Therefore, 161 patients (107 to be assigned to fluconazole and 54 to be assigned to amphotericin B) were scheduled to be enrolled. The initial analyses were performed on an intention-to-treat basis and included all eligible patients.
The treatment groups were compared by the Wilcoxon rank-sum test, Student's paired t-test, or chi-square analysis.18 The Kaplan–Meier method was used in survival analyses, and the treatment groups were compared by both the log-rank and the Gehan tests.19 Cox proportional-hazards linear modeling was used for multivariate assessment of the relative risk of death during therapy, after adjustment for potentially confounding factors.20
Results
Study Population
From April 1988 through November 1989, 235 patients were enrolled by investigators of the National Institute of Allergy and Infectious Diseases Mycoses Study Group and the AIDS Clinical Trials Group and investigators at seven independent sites. Of these 235 patients, 37 (10 [13 percent] assigned to amphotericin B and 27 [17 percent] assigned to fluconazole) were determined to be ineligible for the study for the following reasons: 17 patients were not infected with HIV (5 assigned to amphotericin B and 12 to fluconazole), 15 had negative base-line cerebrospinal fluid cultures for C. neoformans (5 assigned to amphotericin B and 10 to fluconazole), 4 assigned to fluconazole (but none assigned to amphotericin B) had received a dose of amphotericin B before enrollment greater than the dose allowed by the enrollment criteria, and 1 assigned to fluconazole had been reentered in the study after treatment failure during the study.
Four other patients were removed from the study before they received any study drug: three patients (assigned to amphotericin B) asked to be withdrawn, and the physician of the fourth patient (assigned to fluconazole) decided not to give the study drug. The outcomes of these four patients were included as treatment failures in an initial intention-to-treat analysis; however, because their inclusion made no difference to the overall outcome (P = 0.40 vs. P = 0.43) and because the inclusion of patients who never received the study drug was deemed to make the study less clinically applicable, only the 194 patients who did receive the drug were included in further analyses. Of these 194 patients, 63 were assigned to amphotericin B treatment and 131 to fluconazole. There were no significant differences between the treatment groups at base line with respect to demographic characteristics, laboratory values, or clinical signs and symptoms of cryptococcal disease (Table 1Table 1
Clinical and Laboratory Features of the Treatment Groups at Base Line.*).Outcomes
As shown in Table 2Table 2
Outcome at 10 Weeks According to Treatment Regimen.*, treatment was successful in 25 of the 63 patients assigned to amphotericin B (40 percent; 95 percent confidence interval, 26 percent to 53 percent), as compared with 44 of the 131 assigned to fluconazole (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40 by chi-square test). The relative risk of success of amphotericin B treatment was 1.3 (95 percent confidence interval, 0.69 to 2.44). Approximately one fourth of the patients in each treatment group (17 of 63 amphotericin B recipients [27 percent] and 34 of 131 fluconazole recipients [26 percent]) had so-called quiescent disease. When these patients were combined with patients who were successfully treated, the overall response rate was 67 percent in the amphotericin B group (42 of 63 patients) and 60 percent in the fluconazole group (78 of 131 patients) (P = 0.39 by chi-square test; relative risk of success of amphotericin B treatment, 1.5; 95 percent confidence interval, 0.79 to 2.86). Disease progression occurred in a higher proportion of the patients assigned to fluconazole (20 percent vs. 11 percent), whereas drug toxicity leading to treatment failure occurred in a greater percentage of the patients assigned to amphotericin B (8 percent vs. 2 percent); neither of these differences was statistically significant.Mortality due to progressive cryptococcal disease was 17 percent, with 9 deaths in the amphotericin B group and 24 in the fluconazole group (14 percent vs. 18 percent; P = 0.48 by chi-square test). Early deaths, defined as those occurring within the first two weeks of therapy, were more frequent in the fluconazole group (15 percent [19 of 131] vs. 8 percent [5 of 63]; P = 0.25 by chi-square test).
At 10 weeks, the response rate, determined by Kaplan–Meier estimates of the length of time to the first negative culture (Fig. 1Figure 1
Kaplan–Meier Estimates of the Length of Time to the First Negative Cerebrospinal Fluid Culture, According to Treatment Group.), was 43 percent in the fluconazole group and 46 percent in the amphotericin B group. The 95 percent confidence interval for the difference was -0.21 to 0.15, which allowed us to exclude as a reasonable possibility the assumption that amphotericin B was at least 30 percent more effective than fluconazole (P = 0.001 by one-sided t-test). The median length of time to the first negative cerebrospinal fluid culture was 42 days in the amphotericin B group (95 percent confidence interval, 28 to 71) and 64 days in the fluconazole group (95 percent confidence interval, 53 to 67). As shown in Figure 1, there was no significant difference between the two treatment groups in the length of time to the conversion of the cerebrospinal fluid culture from positive to negative (P = 0.25 by log-rank test). However, among the patients who were treated successfully, the median time to a negative culture was 16 days in the amphotericin B group (range, 12 to 71 days; n = 25), as compared with 30 days in the fluconazole group (range, 4 to 67 days; n = 44) (P = 0.02).Dosage
The median total dose of amphotericin B given the patients in whom treatment was successful was 24.3 mg per kilogram (range, 11.8 to 49.9), as compared with 23.1 mg per kilogram (range, 0.2 to 43.22) given the patients in whom it failed, including those who died within the first two weeks of treatment (P = 0.91 by Wilcoxon two-sample test). The mean daily dose of amphotericin B given the patients with successful treatment was no different from that given the patients with treatment failure (0.4 vs. 0.5 mg per kilogram per day; P = 0.34), and no dose–response effect was observed. Of the 63 patients assigned to amphotericin B treatment, only 9 also received flucytosine; in only 1 of these 9 patients was flucytosine discontinued because of toxicity (increased creatinine levels).
Eighty-three of the 141 fluconazole recipients received 200 mg of the drug per day throughout their course of therapy. The dose was increased to 400 mg per day in the other 48 patients for the following reasons: clinical deterioration in 16 patients, persistence of positive cerebrospinal fluid cultures in 14, no obvious reason in 10, noncompliance of an investigator in 7, and noncompliance of the patient in 1. The outcomes of these 48 patients who received an increased dose were similar to the outcomes observed in all 131 given fluconazole: 13 patients (27 percent) were successfully treated, 12 (25 percent) had quiescent disease, 15 (31 percent) had treatment failure due to disease progression, and 8(17 percent) died. The median length of time to the increase in dose was 22 days.
Factors Predicting Outcome
The pretreatment factors identified by univariate analysis as predictive of treatment failure were a positive India ink stain (P = 0.0005; relative risk = 4.72; 95 percent confidence interval, 1.88 to 11.82), the presence of visual abnormalities (blurred vision, photophobia, diplopia, or papilledema) (P = 0.005; relative risk = 2.57; 95 percent confidence interval, 1.35 to 4.85), an age of less than 35 years (P = 0.01; relative risk = 2.24; 95 percent confidence interval, 1.25 to 4.06), and the absence of therapy with zidovudine (P = 0.05; relative risk = 2.18; 95 percent confidence interval, 1.00 to 4.76). The pretreatment factors predictive of early death were an abnormal mental status, defined as lethargy or obtundation21 (P = 0.00002; relative risk = 5.99; 95 percent confidence interval, 2.44 to 14.73), a cerebrospinal fluid cryptococcal-antigen titer of more than 1:1024 (P = 0.02; relative risk = 4.31; 95 percent confidence interval, 1.17 to 15.80), and a positive blood culture for C. neoformans (P = 0.03; relative risk = 3.76; 95 percent confidence interval, 1.05 to 13.33). Other factors, such as previous cryptococcal infection, absence of headache, cranial-nerve dysfunction, hyponatremia, presence of C. neoformans at extraneural sites, and antifungal treatment, were not predictive of either early death or treatment failure. The base-line cerebrospinal fluid opening pressure was recorded in only 33 percent of the patients and therefore could not be included as a factor in the proportional-hazards analysis.
In a multivariate analysis, significant pretreatment predictors of death during therapy were an abnormal mental status (P<0.0001), a cerebrospinal fluid cryptococcal-antigen titer of more than 1:1024 (P = 0.01), and a cerebrospinal fluid white-cell count less than 0.02×109 per liter (20 cells per cubic millimeter) (P = 0.04). Using these predictive factors, we grouped the patients according to their risk of death during therapy, as being at low or high risk (Table 3Table 3
Proposed Groups for Risk of Death, Based on Pretreatment Factors.). Thus, a patient with an abnormal mental status, a cerebrospinal fluid cryptococcal-antigen titer above 1:1024, and a cerebrospinal fluid white-cell count below 0.02×109 per liter would have a high risk of death while receiving therapy. Among the patients at low risk, mortality was 2.6 percent among those treated with amphotericin B (1 of 39 patients) and 4.9 percent among those treated with fluconazole (4 of 81 patients) (P = 0.54 by chi-square test). In contrast, among the patients at high risk, mortality was 33 percent in amphotericin B recipients (8 of 24 patients) and 40 percent in fluconazole recipients (20 of 50 patients) (P = 0.58).Toxicity
Fluconazole was tolerated much better than amphotericin B; 73 percent of fluconazole recipients reported no adverse effects, as compared with 36 percent of amphotericin B recipients (P<0.0001 by chi-square test) (Table 4Table 4
Adverse Events According to Treatment Regimen.). In addition, severe toxicity requiring discontinuation of the drug was more frequent in the amphotericin B group; treatment failure due to drug toxicity occurred in 8 percent of amphotericin B recipients, as compared with 2 percent of fluconazole recipients (P = 0.12 by Fisher's exact test). Of the five amphotericin B recipients with treatment failure due to serious toxicity, three had superimposed bacterial infections related to the infusion catheter and two had serious renal insufficiency that developed during treatment. Of the three fluconazole recipients whose treatment was stopped because of adverse events, one had elevated levels of hepatic enzymes, one had agranulocytosis that developed during treatment, and one had a seizure considered possibly related to the drug treatment.Discussion
The primary objective of our study was to assess whether oral fluconazole was at least as effective as standard intravenous therapy with amphotericin B in the treatment of acute cryptococcal meningitis in patients with AIDS. It was assumed that owing to the advantages of oral therapy, if fluconazole was not more than 30 percent less effective than intravenous amphotericin B, then fluconazole would be an acceptable agent for treatment of primary cryptococcal meningitis. The confidence interval around the difference in success rates, along with the lack of a significant difference between the two treatment groups in the overall outcome (P = 0.40), indicates that fluconazole is an acceptable alternative to amphotericin B as primary therapy for acute AIDS-associated cryptococcal meningitis.
As in animal models,12 13 14 our study revealed differences between the two treatment regimens in the length of time until cultures were found to be negative. The median time to the first negative cerebrospinal fluid culture was 42 days in the amphotericin B group, as compared with 64 days in the fluconazole group. Although this difference of 22 days was not statistically significant, subgroup analysis of successfully treated patients showed that the cerebrospinal fluid cultures of the fluconazole recipients required twice as long to become negative as those of the amphotericin B recipients (30 vs. 16 days).
This observed difference in the sterilization rates for cerebrospinal fluid, together with the differences in rates of early death, is of potential concern. Although the differences between the two treatment groups in mortality and overall response rates during primary therapy were not statistically significant, the deaths in the fluconazole group occurred mostly during the first two weeks of therapy, whereas the deaths in the amphotericin B group were evenly distributed over the course of treatment. It is important to note that death was not an end point in our study and that the study population was not large enough to allow a difference in mortality rates to be detected, if one existed. To detect a difference of 10 percent on the basis of an early-death rate of 8 percent in the amphotericin B group, with an alpha of 0.05 and a power of 80 percent, 650 patients would have been required.
Identifying the pretreatment factors predictive of treatment failure in patients with cryptococcal meningitis who are at high risk of failure has been proposed previously. In a randomized clinical trial by Dismukes et al. in patients with cryptococcal meningitis, most of whom did not have AIDS, the pretreatment factors associated with a higher likelihood of treatment failure were an abnormal mental status, a cerebrospinal fluid white-cell count below 0.02×109 per liter, and the absence of headache.5 It is noteworthy that in that study, a negative cerebrospinal fluid India ink preparation and the absence or discontinuation of immunosuppressive therapy after four weeks of antifungal therapy were predictive of treatment success, implying that fungal burden and an effective immune response may be factors important to the outcome of treatment. In a more recent, retrospective analysis by Chuck and Sande of 108 patients with AIDS and cryptococcosis, the presence of an abnormal mental status, extraneural sites of infection, and hyponatremia were predictive of a poor response to therapy.1
In our study, an abnormal mental status was the strongest factor predictive of death; factors that were weaker yet significantly associated with death were a cerebrospinal fluid cryptococcal-antigen titer above 1:1024 and a cerebrospinal fluid white-cell count below 0.02×109 per liter (Table 3). Therefore, according to the pretreatment factors identified in our study, patients with a normal mental status, a cerebrospinal fluid cryptococcal-antigen titer below 1:1024, and a cerebrospinal fluid white-cell count above 0.02×109 per liter are at low risk of treatment failure. The majority of patients treated in this study (120 of 194 patients) were at low risk. However, even such patients must be frequently evaluated for response, especially during the first several weeks of therapy.
The question remains, What is the optimal therapy for patients classified as being at high risk? At least in the doses used in this study, both amphotericin B and fluconazole are suboptimal for treating these patients, with mortality rates of 33 percent and 40 percent, respectively. Data on the efficacy of higher doses of either drug, with or without flucytosine, are limited. In our study, only nine patients received amphotericin B plus flucytosine, with no difference noted in overall response rates. In contrast, Larsen and colleagues observed no treatment failures among 6 patients who received higher doses of amphotericin B plus flucytosine, as compared with 8 failures (57 percent) among 14 patients who received 400 mg of fluconazole per day.10 Although the differences in mortality between the two treatment groups only approached statistical significance, the small size of the study population underscores the authors' call for caution in the interpretation of their report. Squires and coworkers reported a satisfactory response in 8 of 14 patients with AIDS given 400 mg of fluconazole per day orally,22 and Pietroski et al. reported successful outcomes in 5 of 13 patients given 400 mg of fluconazole per day intravenously.23 To date, none of the studies that have addressed cryptococcal disease in patients with AIDS have specifically stratified treatment approaches according to the severity of illness at base line.
The findings in our study represent an important step in defining the most appropriate approach to the treatment of patients with AIDS who have cryptococcal meningitis. The observations about the initial clinical presentations of this population and the correlations of these features with their treatment outcomes represent the largest experience reported to date. However, several fundamental questions remain unanswered. What is the natural history and outcome of patients whose clinical condition improves yet whose cultures remain positive? Do these patients with so-called quiescent disease have a poorer prognosis than those who are successfully treated? What is the best treatment regimen and approach in patients at high risk for treatment failure? Can outcomes be improved by higher doses of drug (either fluconazole or amphotericin B) or novel combination-therapy regimens (e.g., fluconazole and flucytosine24)? In view of the clear efficacy of fluconazole administration as maintenance therapy after successful primary treatment with amphotericin B11 (and Powderly WG, et al.: unpublished data), what is the optimal timing for switching from intravenous therapy to oral therapy, especially in patients at high risk? What is the relative effectiveness of other triazole antifungal agents, such as itraconazole, in comparison with fluconazole?25 Finally, are the results observed in this clinical trial in patients with AIDS applicable to other groups of patients with either normal or suppressed host immune systems? The answers to these questions will require further targeted investigation and carefully designed clinical trials.
Supported by grants to the Mycoses Study Group (NO1-AI-15082) and the AIDS Clinical Trials Group (NIH-NIAID-DMID-91–04) from the National Institute of Allergy and Infectious Diseases, by a General Clinical Research Center grant (RR-00032) from the National Institutes of Health, and by Pfizer Central Research.
Presented in part at the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, September 20, 1989.
*Other contributing members of the Mycoses Study Group of the National Institute of Allergy and infectious Diseases (NIAID), the AIDS Clinical Trials Group, and independent investigators are listed in the Appendix.
We are indebted to Esther Pugmire and Jane Garrison for expert assistance in the preparation of the manuscript and to Susan Ellenberg and Roger Davis for their critical review of it.
Source Information
From the Division of Infectious Diseases, Department of Medicine, and the Division of Biostatistics, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, and the Birmingham Veterans Affairs Medical Center, Birmingham, Ala. (M.S.S., G.A.C., W.E.D.); the Division of Infectious Diseases, Washington University School of Medicine, and the St. Louis Veterans Affairs Medical Center, St. Louis (W.G.P.); St. Luke's–Roosevelt Hospital, Columbia University School of Medicine, New York (M.H.G.); the University of Texas, San Antonio, and the Audie L. Murphy Veterans Affairs Hospital, San Antonio, Tex. (P.K.S.); Grady Memorial Hospital, Emory University, Atlanta (S.E.T.); the Departments of Medicine, Boston City Hospital and University Hospital, Boston University, Boston (A.M.S.); the Department of Medicine, George Washington University, Washington, D.C. (C.U.T.); the Department of Medicine, Medical College of Georgia, Augusta (J.F.F.); the Department of Medicine, Tulane University, New Orleans (N.H.); the Department of Medicine, Division of Infectious Diseases, Mount Sinai Medical Center and Bronx Veterans Affairs Medical Center, Bronx, N.Y. (J.M.J.); the Division of AIDS and the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (R.H.); and Pfizer Central Research, Groton, Conn. (P.R.). Address reprint requests to Dr. Saag at the University of Alabama at Birmingham, BVAMC, 700 19th St. S., Rm. 2B–108, Birmingham, AL 35233.
Appendix
Members of the NIAID Mycoses Study Group and the AIDS Clinical Trials Group and independent investigators who contributed to this study are as follows.
Mycoses Study Group: University of Alabama at Birmingham: M. Mulligan, B. Dean, S. Robinson, C. Thomas, and C. Bowles-Patton; University of Texas, San Antonio: J.R. Graybill, C. Watson, and K. Seiler; Emory University, Atlanta: L. Perry; Boston University Medical Center, Boston: C. Saunders and the physicians at the Boston City Hospital Immunodeficiency Clinic; George Washington University, Washington, D.C.: D.M. Parenti, G.L. Simon, A. Katz, and C. Decker; Medical College of Georgia, Augusta: C.L. Newman; University of Michigan, Ann Arbor: C.A. Kaufman; Medical College of Virginia, Richmond: T. Kerkering and M. Gurkin; and University of Arizona, Tucson: J.N. Galgiani and J. Higgs.
AIDS Clinical Trials Group: St. Luke's–Roosevelt Hospital, New York: B. Kolatch, K. Ong, G.F. McKinley, and J. Linksman-Rivera; Louisiana State University, New Orleans: G. Karam, J. Walker, N. Porter, and D. Greenspan; Bronx Veterans Affairs Hospital, Bronx, N.Y.: N. Ostrow; Washington University, St. Louis: M. Klebert and J. Voorhees; Ohio State University, Columbus: S. Koletar, R. Fass, and J. Russell; University of North Carolina, Chapel Hill: C. van der Horst; University of Miami, Miami: M.A. Fischl and B. Bryant; Northwestern University, Evanston, Ill.: K. MacDonell and R. Murphy; Montefiore Medical Center, Bronx, N.Y.: R. Klein, P. Kahl, M. Hilton, and M. Rios; University of Cincinnati: G. Roselle and B.Jackson; Sloan Kettering Memorial Hospital, New York: D. Armstrong and W. Propper; and University of California, Los Angeles: D. Hardy and S. Chafey.
Independent Sites: Infectious Disease Consortium, Georgia: R. Dretler, R. Capparell, L. Diamond, P. Dubose, C. Lopez, R. Prokesch, W. Weinberg, D. Blum, and V. Thomily; St. Vincent's Hospital, New York: D. Kaufman and P. Caffrey; Wayne State University School of Medicine, Detroit: L.R. Crane, P. Chandrasekar, and A. Sauber; Pacific Presbyterian Medical Center, San Francisco: S. Gordon; Davies Medical Center, San Francisco: S. Follansbee, D. Cox, and B. Christiansen; Albany Medical College, Albany, N.Y.: S. Kowalsky, P. Gorman, and C. Ramnes; Columbia University, New York: H.C. Neu, F. Brionnes, and B. Scully; Henry Ford Hospital, Detroit: L. Saravolatz, N. Markowitz, and K. Waigaand; and Pfizer Central Research, Groton, Conn.: J.M. Briganti, R. Casagrande, L. Conway, J. Jacobsen, J. Schaloub, M. Szczesiul, D.N. Buell, and J. Stritar.
- References
References
1
Chuck
Full Text | Web of Science | Medline2
Levy
CrossRef | Web of Science | Medline3
Dismukes
CrossRef | Web of Science | Medline4
Bennett
Full Text | Web of Science | Medline5
Dismukes
Full Text | Web of Science | Medline6
Kovacs
Web of Science | Medline7
Zuger
Web of Science | Medline8
Sugar
CrossRef | Medline9
Clark
CrossRef | Medline10
Larsen
Web of Science | Medline11
Bozzette
Full Text | Web of Science | Medline12
Perfect
Web of Science | Medline13
Perfect
CrossRef | Medline14
Palou de Fernandez
CrossRef | Web of Science | Medline15
Saag
Web of Science | Medline16
Stem
CrossRef | Web of Science | Medline17
Blackwelder
CrossRef | Medline18
Snedecor GW, Cochran WG. Statistical methods. 6th ed. Ames: Iowa State University Press, 1967.
19
Kaplan
CrossRef | Web of Science20
Cox 21
Plum
Medline22
Squires K, Rowland V, Gassyuk E, et al. Fluconazole as therapy for acute cryptococcal meningitis. In: Programs and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21–24, 1990, Atlanta. Washington, D.C.: American Society for Microbiology, 1990. abstract.
23
Pietroski N, Buckley RM, Braffman MN, Stern JJ. Intravenous and oral fluconazole in treatment of acute cryptococcal meningitis. In: Program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 21–24, 1990, Atlanta. Washington, D.C.: American Society for Microbiology, 1990. abstract.
24
Jones BE, Larsen RA, Bozzette S, Haghighat D, Leedom JM, McCutchan JA. A phase II trial of fluconazole plus flucytosine for cryptococcal meningitis. In: Proceedings of the Seventh International Conference on AIDS, Florence, Italy, June 16–21, 1991. Rome: Istituto Superiore di Sanità, 1991. abstract.
25
Denning
- Citing Articles (132)
Citing Articles
1
Inger Hee Mabuza Mathiesen, Jenny Dahl Knudsen, Jan Gerstoft, Susan Cowan, Thomas Benfield. (2011) Outcome of HIV-1-associated cryptococcal meningitis, Denmark 1988–2008. Scandinavian Journal of Infectious Diseases1-4
CrossRef2
Yi-Chien Lee, Jann-Tay Wang, Hsin-Yun Sun, Yee-Chun Chen. (2011) Comparisons of clinical features and mortality of cryptococcal meningitis between patients with and without human immunodeficiency virus infection. Journal of Microbiology, Immunology and Infection 44:5, 338-345
CrossRef3
M Nelson, H Manji, E Wilkins. (2011) 2 Central nervous system opportunistic infections. HIV Medicine 12, 8-24
CrossRef4
Scott W. Mueller, Tyree H. Kiser. (2011) Pros and Cons of Extrapolating Animal Data on Antifungal Pharmacodynamics to Humans. Current Fungal Infection Reports 5:2, 59-66
CrossRef5
George R. Thompson, Thomas F. Patterson. (2011) Reply to Dr Yong. Medical Mycology 49:3, 336-336
CrossRef6
Melanie W. Pound, Mary L. Townsend, Vincent Dimondi, Dustin Wilson, Richard H. Drew. (2011) Overview of treatment options for invasive fungal infections. Medical Mycology1-20
CrossRef7
S. Yaich, N. El'Aoud, I. Maaloul, K. Charfeddine, M. Kharrat, M. Ben Jemaa, J. Hachicha. (2011) Early Onset of Paucisymptomatic Cryptococcal Meningitis in a Kidney Transplant Patient: A Case Report and Review of the Literature. Transplantation Proceedings 43:2, 663-665
CrossRef8
Su Jin Lee, Hee Kyoung Choi, Jungmin Son, Kye Hyung Kim, Sun Hee Lee. (2011) Cryptococcal Meningitis in Patients with or without Human Immunodeficiency Virus: Experience in a Tertiary Hospital. Yonsei Medical Journal 52:3, 482
CrossRef9
Lewis J Haddow, Robert Colebunders, Graeme Meintjes, Stephen D Lawn, Julian H Elliott, Yukari C Manabe, Paul R Bohjanen, Somnuek Sungkanuparph, Philippa J Easterbrook, Martyn A French, David R Boulware. (2010) Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. The Lancet Infectious Diseases 10:11, 791-802
CrossRef10
P. Portegies, P. Cinque, A. Chaudhuri, J. Begovac, I. Everall, T. Weber, M. Bojar, P. Martinez - Martin, P. G. E. Kennedy. 2010. Neurological Complications of HIV Infection. , 373-381.
CrossRef11
Nathan P. Wiederhold. (2010) Using Antifungal Pharmacodynamics to Improve Patient Outcomes. Current Fungal Infection Reports 4:2, 70-77
CrossRef12
John R. Perfect, Gary M. Cox. 2010. Cryptococcosis. .
CrossRef13
Michael A. Pfaller, Daniel J. Diekema. (2010) Epidemiology of Invasive Mycoses in North America. Critical Reviews in Microbiology 36:1, 1-53
CrossRef14
Derek J Sloan, Martin J Dedicoat, David G Lalloo. (2009) Treatment of cryptococcal meningitis in resource limited settings. Current Opinion in Infectious Diseases 22:5, 455-463
CrossRef15
Rhett M Shirley, John W Baddley. (2009) Cryptococcal lung disease. Current Opinion in Pulmonary Medicine 15:3, 254-260
CrossRef16
S. Schwartz, E. Thiel. (2009) Cerebral aspergillosis: tissue penetration is the key. Medical Mycology 47:s1, S387-S393
CrossRef17
Derek Sloan, Sipho Dlamini, Navin Paul, Martin Dedicoat, Derek Sloan. 2008. Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. .
CrossRef18
Daniel Podzamczer. (2008) Tratamiento de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el virus de la inmunodeficiencia humana en la era del tratamiento antirretroviral de gran actividad. Enfermedades Infecciosas y Microbiología Clínica 26:6, 356-379
CrossRef19
John Mohr, Melissa Johnson, Travis Cooper, James S Lewis, Luis Ostrosky-Zeichner. (2008) Current Options in Antifungal Pharmacotherapy. Pharmacotherapy 28:5, 614-645
CrossRef20
Kathleen R. Page, Richard Chaisson, Merle Sande. 2008. Cryptococcosis and other Fungal Infections (Histoplasmosis and Coccidioidomycosis) in HIV-infected Patients. , 375-391.
CrossRef21
Thana Khawcharoenporn, Anucha Apisarnthanarak, Linda M Mundy. (2007) Treatment of cryptococcosis in the setting of HIV coinfection. Expert Review of Anti-infective Therapy 5:6, 1019-1030
CrossRef22
John W. Baddley, Peter G. Pappas. (2007) Combination antifungal therapy for the treatment of invasive yeast and mold infections. Current Infectious Disease Reports 9:6, 448-456
CrossRef23
Methee Chayakulkeeree, John R. Perfect. 2007. Diagnosis of Cryptococcosis. , 239-266.
CrossRef24
O. Lortholary. (2007) Management of Cryptococcal Meningitis in AIDS: The Need for Specific Studies in Developing Countries. Clinical Infectious Diseases 45:1, 81-83
CrossRef25
Dimitrios I. Zonios, Judith Falloon, Chiung-Yu Huang, Doreen Chaitt, John E. Bennett. (2007) Cryptococcosis and Idiopathic CD4 Lymphocytopenia. Medicine 86:2, 78-92
CrossRef26
Karen L. Roos. 2007. Nonviral Infections. , 943-968.
CrossRef27
Tihana Bicanic, Thomas Harrison, Alina Niepieklo, Nontobeko Dyakopu, Graeme Meintjes. (2006) Symptomatic Relapse of HIV‐Associated Cryptococcal Meningitis after Initial Fluconazole Monotherapy: The Role of Fluconazole Resistance and Immune Reconstitution. Clinical Infectious Diseases 43:8, 1069-1073
CrossRef28
Richard J. Hamill. (2006) Editorial Commentary: Free Fluconazole for Cryptococcal Meningitis: Too Little of a Good Thing?. Clinical Infectious Diseases 43:8, 1074-1076
CrossRef29
Methee Chayakulkeeree, John R. Perfect. (2006) Cryptococcosis. Infectious Disease Clinics of North America 20:3, 507-544
CrossRef30
W. E. Dismukes. (2006) Antifungal Therapy: Lessons Learned over the Past 27 Years. Clinical Infectious Diseases 42:9, 1289-1296
CrossRef31
Fred Rincon, Neeraj Badjatia. (2006) Central nervous system infections in the neurointensive care unit. Current Treatment Options in Neurology 8:2, 135-144
CrossRef32
R. Helbok, S. Pongpakdee, S. Yenjun, W. Dent, R. Beer, P. Lackner, P. Bunyaratvej, B. Prasert, A. Vejjajiva, E. Schmutzhard. (2006) Chronic Meningitis in Thailand. Neuroepidemiology 26:1, 37-44
CrossRef33
Nina Singh, Olivier Lortholary, Barbara D. Alexander, Krishan L. Gupta, George T. John, Kenneth J. Pursell, Patricia Mu??oz, Goran B. Klintmalm, Valentina Stosor, Ramon del Busto, Ajit P. Limaye, Jyoti Somani, Marshall Lyon, Sally Houston, Andrew A. House, Timothy L. Pruett, Susan Orloff, Atul Humar, Lorraine A. Dowdy, Julia Garcia-Diaz, Andre C. Kalil, Robert A. Fisher, Joseph Heitman, Shahid Husain. (2005) Antifungal Management Practices and Evolution of Infection in Organ Transplant Recipients with Cryptococcus Neoformans Infection. Transplantation 80:8, 1033-1039
CrossRef34
Umesh G. Lalloo, Farida C. Amod. (2005) HIV-associated tuberculosis and cryptococcosis in resource-limited settings. Current HIV/AIDS Reports 2:3, 116-121
CrossRef35
PT Cantey, DS Stephens, D Rimland. (2005) Prevention of cryptococcosis in HIV-infected patients with limited access to highly active antiretroviral therapy: evidence for primary azole prophylaxis. HIV Medicine 6:4, 253-259
CrossRef36
Larry M. Baddour, John R. Perfect, Luis Ostrosky‐Zeichner. (2005) Successful Use of Amphotericin B Lipid Complex in the Treatment of Cryptococcosis. Clinical Infectious Diseases 40:S6, S409-S413
CrossRef37
J. D. Sobel. (2004) Combination Therapy for Invasive Mycoses: Evaluation of Past Clinical Trial Designs. Clinical Infectious Diseases 39:Supplement 4, S224-S227
CrossRef38
H.-Y. Sun, C.-C. Hung, S.-C. Chang. (2004) Management of Cryptococcal Meningitis with Extremely High Intracranial Pressure in HIV-Infected Patients. Clinical Infectious Diseases 38:12, 1790-1792
CrossRef39
Satoshi Sobue, Keith Tan, Gary Layton, Violette Leclerc, Angelika Weil. (2004) The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole. British Journal of Clinical Pharmacology 57:6, 773-784
CrossRef40
P. Portegies, L. Solod, P. Cinque, A. Chaudhuri, J. Begovac, I. Everall, T. Weber, M. Bojar, P. Martinez-Martin, P. G. E. Kennedy. (2004) Guidelines for the diagnosis and management of neurological complications of HIV infection. European Journal of Neurology 11:5, 297-304
CrossRef41
J. R. Azanza Perea, B. Sadaba Diaz de Rada, E. Garcia Quetglas, M. J. Munoz Juarez. (2004) Oral versus intravenous therapy in the treatment of systemic mycosis. Clinical Microbiology and Infection 10:s1, 96-106
CrossRef42
Fran??oise Dromer, Simone Mathoulin-P??lissier, Arnaud Fontanet, Olivier Ronin, Bertrand Dupont, Olivier Lortholary. (2004) Epidemiology of HIV-associated cryptococcosis in France (1985???2001). AIDS 18:3, 555-562
CrossRef43
L. D. Saravolatz, L. Ostrosky-Zeichner, K. A. Marr, J. H. Rex, S. H. Cohen. (2003) Amphotericin B: Time for a New "Gold Standard". Clinical Infectious Diseases 37:3, 415-425
CrossRef44
David W Denning, Christopher C Kibbler, Rosemary A Barnes. (2003) British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections. The Lancet Infectious Diseases 3:4, 230-240
CrossRef45
Emmanuel Roilides, Caron A Lyman, Paraskevi Panagopoulou, Stephen Chanock. (2003) Immunomodulation of invasive fungal infections. Infectious Disease Clinics of North America 17:1, 193-219
CrossRef46
John R Perfect, Arturo Casadevall. (2002) Cryptococcosis. Infectious Disease Clinics of North America 16:4, 837-874
CrossRef47
Robert Orenstein, Nickolaos Tsogas. (2002) Looking Beyond Highly Active Antiretroviral Therapy: Drug-Related Hepatotoxicity in Patients with Human Immunodeficiency Virus Infection. Pharmacotherapy 22:11, 1468-1478
CrossRef48
Kimberly J. Gambarin, Richard J. Hamill. (2002) Management of increased intracranial pressure in cryptococcal meningitis. Current Infectious Disease Reports 4:4, 332-338
CrossRef49
Meriem K. Bensalem, Joseph R. Berger. (2002) HIV and the central nervous system. Comprehensive Therapy 28:1, 23-33
CrossRef50
Joseph R Zunt. (2002) Central Nervous System Infection During Immunosuppression. Neurologic Clinics 20:1, 1-22
CrossRef51
S. K. Cinti, Wendy S. Armstrong, Carol A. Kauffman. (2001) Case Report. Recurrence of increased intracranial pressure with antiretroviral therapy in an AIDS patient with cryptococcal meningitis. Mycoses 44:11-12, 497-501
CrossRef52
CHI-LEUNG LAM, WAH-KIT LAM, YICK WONG, GAIK C. OOI, MARIA P. WONG, JAMES C. HO, BING LAM, KENNETH W. TSANG. (2001) Pulmonary cryptococcosis: A case report and review of the Asian-Pacific experience. Respirology 6:4, 351-355
CrossRef53
P. Pitisuttithum, S. Tansuphasawadikul, A.J.H. Simpson, P.A. Howe, N.J. White. (2001) A Prospective Study of AIDS-associated Cryptococcal Meningitis in Thailand Treated with High-dose Amphotericin B. Journal of Infection 43:4, 226-233
CrossRef54
Miloš Sedlák, Vladimı́r Buchta, Lenka Kubicová, Petr Šimůnek, Michal Holčapek, Pavla Kašparová. (2001) Synthesis and characterisation of a new amphotericin b–methoxypoly(ethylene glycol) conjugate. Bioorganic & Medicinal Chemistry Letters 11:21, 2833-2835
CrossRef55
Lourdes Irizarry. (2001) Cryptococcal meningitis. Current Treatment Options in Neurology 3:5, 413-426
CrossRef56
Michael E. Klepser. (2001) Antifungal Resistance Among Candida Species. Pharmacotherapy 21:8 Part 2, 124S-132S
CrossRef57
J. Garbino, L. Kolarova, D. Lew, B. Hirschel, P. Rohner. (2001) Fungemia in HIV-Infected Patients: A 12-Year Study in a Tertiary Care Hospital. AIDS Patient Care and STDs 15:8, 407-410
CrossRef58
Peter G. Pappas. (2001) Therapy of cryptococcal meningitis in non-HIV-infected patients. Current Infectious Disease Reports 3:4, 365-370
CrossRef59
Paul E. Sax. (2001) OPPORTUNISTIC INFECTIONS IN HIV DISEASE: DOWN BUT NOT OUT. Infectious Disease Clinics of North America 15:2, 433-455
CrossRef60
Steven I. Aronin, Vincent J. Quagliarello. (2001) Utility of prognostic stratification in adults with community-acquired bacterial meningitis. Comprehensive Therapy 27:1, 72-77
CrossRef61
Elizabeth S. Dodds, Richard H. Drew, John R. Perfect. (2000) Antifungal Pharmacodynamics: Review of the Literature and Clinical Applications. Pharmacotherapy 20:11, 1335-1355
CrossRef62
W.G Powderly. (2000) Current Approach to the Acute Management of Cryptococcal Infections. Journal of Infection 41:1, 18-22
CrossRef63
William G. Powderly. (2000) Cryptococcal meningitis in HIV-infected patients. Current Infectious Disease Reports 2:4, 352-357
CrossRef64
Zafar K. Khan, Ratna Katiyar. (2000) Potent Antifungal Activity of Garlic (Allium Sativum) Against Experimental Murine Dissemenated Cryptococcosis. Pharmaceutical Biology 38:2, 87-100
CrossRef65
M. S. Saag, R. J. Graybill, R. A. Larsen, P. G. Pappas, J. R. Perfect, W. G. Powderly, J. D. Sobel, W. E. Dismukes, . (2000) Practice Guidelines for the Management of Cryptococcal Disease. Clinical Infectious Diseases 30:4, 710-718
CrossRef66
J. R. Graybill, J. Sobel, M. Saag, C. van der Horst, W. Powderly, G. Cloud, L. Riser, R. Hamill, W. Dismukes, . (2000) Diagnosis and Management of Increased Intracranial Pressure in Patients with AIDS and Cryptococcal Meningitis. Clinical Infectious Diseases 30:1, 47-54
CrossRef67
A.M.E. Walenkamp, W.S. Chaka, A.F.M. Verheul, V.V. Vaishnav, R. Cherniak, F.E.J. Coenjaerts, I.M. Hoepelman. (1999) Cryptococcus neoformans and its cell wall components induce similar cytokine profiles in human peripheral blood mononuclear cells despite differences in structure. FEMS Immunology & Medical Microbiology 26:3-4, 309-318
CrossRef68
Ruth Orni‐Wasserlauf, Elena Izkhakov, Yardena Siegman‐Igra, Edna Bash, Itzhack Polacheck, Michael Giladi. (1999) Fluconazole‐Resistant Cryptococcus neoformans Isolated from an Immunocompetent Patient without Prior Exposure to Fluconazole. Clinical Infectious Diseases 29:6, 1592-1593
CrossRef69
C-H. Lu, W-N. Chang, H-W. Chang, Y-C. Chuang. (1999) The prognostic factors of cryptococcal meningitis in HIV-negative patients. Journal of Hospital Infection 42:4, 313-320
CrossRef70
Annemarie Polak. (1999) <tocheading>Review Article</tocheading>. Mycoses 42:5-6, 355-370
CrossRef71
Allan R. Tunkel. (1999) Chronic meningitis. Current Infectious Disease Reports 1:2, 160-165
CrossRef72
Eleftherios Mylonakis, Nathan A Merriman, Josiah D Rich, Timothy P Flanigan, Beverly C Walters, Karen T Tashima, Maria D Mileno, Charles M van der Horst. (1999) Use of cerebrospinal fluid shunt for the management of elevated intracranial pressure in a patient with active AIDS-related cryptococcal meningitis. Diagnostic Microbiology and Infectious Disease 34:2, 111-114
CrossRef73
O. LORTHOLARY, L. IMPROVISI, M. NICOLAS, F. PROVOST, B. DUPONT, F. DROMER. (1999) Fungemia during murine cryptococcosis sheds some light on pathophysiology 1. Medical Mycology 37:3, 169-174
CrossRef74
O. LORTHOLARY 2, L. IMPROVISI, M. NICOLAS, F. PROVOST, B. DUPONT, F. DROMER. (1999) Fungemia during murine cryptococcosis sheds some light on pathophysiology 1. Medical Mycology 37:3, 169-174
CrossRef75
Kris Ann K. Oursler, Richard D. Moore, Richard E. Chaisson. (1999) Risk Factors for Cryptococcal Meningitis in HIV-Infected Patients. AIDS Research and Human Retroviruses 15:7, 625-631
CrossRef76
Romeo L. Caballes, Romeo A. Caballes. (1999) Primary cryptococcal prostatitis in an apparently uncompromised host. The Prostate 39:2, 119-122
CrossRef77
Douglas Slain. (1999) Lipid-Based Amphotericin B for the Treatment of Fungal Infections. Pharmacotherapy 19:3, 306-323
CrossRef78
O. LORTHOLARY, L. IMPROVISI, M. NICOLAS, F. PROVOST, B. DUPONT, F. DROMER. (1999) Fungemia during murine cryptococcosis sheds some light on pathophysiology. Medical Mycology 37:3, 169-174
CrossRef79
Carlo Tascini, Anna Vecchiarelli, Roberta Preziosi, Daniela Francisci, Francesco Bistoni, Franco Baldelli. (1999) Granulocyte-macrophage colony-stimulating factor and fluconazole enhance anti-cryptococcal activity of monocytes from AIDS patients. AIDS 13:1, 49-55
CrossRef80
C L Terrell. (1999) Antifungal agents. Part II. The azoles.. Mayo Clinic Proceedings 74:1, 78-100
CrossRef81
R Patel. (1998) Antifungal agents. Part I. Amphotericin B preparations and flucytosine.. Mayo Clinic Proceedings 73:12, 1205-1225
CrossRef82
MITSUNOBU KAWAMURA, SHIGERU MIYAZAKI, SHIGERU MASHIKO, MASAMI SUMI, KEIKO ASHIDATE, HISAKO TOHDA, KAZUMASA HASE, NORIKO ANDO. (1998) Disseminated Cryptococcosis Associated With Adrenal Masses and Insufficiency. The American Journal of the Medical Sciences 316:1, 60-64
CrossRef83
Richard D. Fessler, Jack Sobel, Lisa Guyot, Lawrence Crane, Jose Vazquez, Mary Jo Szuba, Fernando G. Diaz. (1998) Management of Elevated Intracranial Pressure in Patients With Cryptococcal Meningitis. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 17:2, 137-142
CrossRef84
Alan M. Sugar. (1998) Antifungal combination therapy: where we stand. Drug Resistance Updates 1:2, 89-92
CrossRef85
M. Gulati, S. Bajad, S. Singh, A. J. Ferdous, M. Singh. (1998) Development of liposomal amphotericin B formulation. Journal of Microencapsulation 15:2, 137-151
CrossRef86
KORDOSSIS, AVLAMI, VELEGRAKI, STEFANOU, GEORGAKOPOULOS, PAPALAMBROU, N. J LEGAKIS. (1998) First report of Cryptococcus laurentii meningitis and a fatal case of Cryptococcus albidus cryptococcaemia in AIDS patients. Medical Mycology 36:5, 335
CrossRef87
C.L. Ho, B.C. Chang, G.C. Hsu, C.P. Wu. (1998) Pulmonary cryptococcoma with CD4 lymphocytopenia and meningitis in an HIV-negative patient. Respiratory Medicine 92:1, 120-122
CrossRef88
T. Kordossis, A. Avlami, A. Velegraki, I. Stefanou, G. Georgakopoulos, C. Papalambrou, N.J. Legakis. (1998) First report of Cryptococcus laurentii meningitis and a fatal case of Cryptococcus albidus cryptococcaemia in AIDS patients. Medical Mycology 36:5, 335-339
CrossRef89
(1997) Treatment of Cryptococcal Meningitis. New England Journal of Medicine 337:21, 1557-1558
Full Text90
A. Parisi, A. Malfitano, R. Bruno, W. Calderon, P. Sacchi, S. F. A. Patruno, G. Filice. (1997) Efficacy of a short-term amphotericin B + flucytosine combination therapy followed by itraconazole mono therapy in acute and chronic AIDS-associated cryptococcosis. Mycoses 40:5-6, 203-207
CrossRef91
Alexander C.A.P. Leenders, Peter Reiss, Peter Portegies, Kate Clezy, Wim C.J. Hop, Jennifer Hoy, Jan C.C. Borleffs, Tony Allworth, Robert H. Kauffmann, Philip Jones, Frank P. Kroon, Henri A. Verbrugh, Simon de Marie. (1997) Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 11:12, 1463-1471
CrossRef92
F DURDEN, B ELEWSKI. (1997) Fungal infections in HIV-infected patients. Seminars in Cutaneous Medicine and Surgery 16:3, 200-212
CrossRef93
van der Horst, Charles M., Saag, Michael S., Cloud, Gretchen A., Hamill, Richard J., Graybill, J. Richard, Sobel, Jack D., Johnson, Philip C., Tuazon, Carmelita U., Kerkering, Thomas, Moskovitz, Bruce L., Powderly, William G., Dismukes, William E., the National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. (1997) Treatment of Cryptococcal Meningitis Associated with the Acquired Immunodeficiency Syndrome. New England Journal of Medicine 337:1, 15-21
Full Text94
Mitchell S. Cappell. (1997) THE PANCREAS IN AIDS. Gastroenterology Clinics of North America 26:2, 337-365
CrossRef95
C. M. Rieder-Nelissen, J. Hasse, R. A. Yeates, E. Sarnow. (1997) Fluconazole concentrations in pulmonary tissue and pericardial fluid. Infection 25:3, 192-194
CrossRef96
P. F. Troke, . (1997) Large-scale multicentre study of fluconazole in the treatment of hospitalised patients with fungal infections. European Journal of Clinical Microbiology & Infectious Diseases 16:4, 287-295
CrossRef97
Grace Y. Minamoto, Amy S. Rosenberg. (1997) FUNGAL INFECTIONS IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. Medical Clinics of North America 81:2, 381-409
CrossRef98
Sylvia W. Wright, Richard A. Johnson. (1997) Human immunodeficiency virus in women: Mucocutaneous manifestations. Clinics in Dermatology 15:1, 93-111
CrossRef99
D.L. Goldman, Arturo Casadevall, L.S. Zuckier. (1997) Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis: implications for passive immunotherapy. Medical Mycology 35:4, 271-278
CrossRef100
J.R. Graybill, R. Bocanegra, C. Lambros, M.F. Luther. (1997) Granulocyte colony stimulating factor therapy of experimental cryptococcal meningitis. Medical Mycology 35:4, 243-247
CrossRef101
Scott F. Davies, George A. Sarosi. (1996) FUNGAL PULMONARY COMPLICATIONS. Clinics in Chest Medicine 17:4, 725-744
CrossRef102
David O. Beenhouwer, Joshua D. Nosanchuk, Barry S. Zingman. (1996) Recurrent meningitis in a 38-year-old man with cirrhosis. International Journal of Infectious Diseases 1:2, 98-101
CrossRef103
H. Yamaguchi, H. Ikemoto, K. Watanabe, A. Ito, K. Hara, S. Kohno. (1996) Fluconazole monotherapy for cryptococcosis in non-AIDS patients. European Journal of Clinical Microbiology & Infectious Diseases 15:10, 787-792
CrossRef104
Véronique Blanc, Véroniqne Lavarde, Nguyen Thi Thanh, Ho Huynh Quang Tri, Romain Guillemain, Catherine Amrein, Alain Carpentier. (1996) Postoperative Cryptococcus neoformans endocarditi. Clinical Microbiology and Infection 2:1, 66-69
CrossRef105
Carol B. Gable, Jonothan C. Tierce, Diane Simison, Douglas Ward, Katy Motte. (1996) Costs of HIV+/AIDS at CD4+ Counts Disease Stages Based on Treatment Protocols. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 12:4, 413-420
CrossRef106
SOUHA S. KANJ, KAREN WELTY-WOLF, JOHN MADDEN, VICTOR TAPSON, MAHER A. BAZ, R. DUANE DAVIS, JOHN R. PERFECT. (1996) Fungal Infections in Lung and Heart-Lung Transplant Recipients. Medicine 75:3, 142-156
CrossRef107
Nicholas M. Anstey, Laura M. Stewart, Mark Packard, William F. Graney, John A. Bartlett. (1996) Open-label titration study of the safety of RMP-7 in patients with the acquired immune deficiency syndrome. International Journal of Antimicrobial Agents 6:4, 183-187
CrossRef108
Z.K. Khan, Ratna Katiyar, R. Shukla, R. Kulshreshtha, Asha Mathur. (1996) Cryptococcosis Associated with HIV Negative Indian Patients and HIV Positive Indian Blood Donors. Zentralblatt für Bakteriologie 283:3, 360-374
CrossRef109
Maria-Anna Viviani. (1996) Cryptococcal meningitis: Diagnosis and treatment. International Journal of Antimicrobial Agents 6:3, 169-173
CrossRef110
Nicolas Jabbour, Jorge Reyes, Shimon Kusne, Maureen Martin, John Fung. (1996) CRYPTOCOCCAL MENINGITIS AFTER LIVER TRANSPLANTATION. Transplantation 61:1, 146-149
CrossRef111
R. Koçak, T. Tetiker, M. Koçak, F. Başlamişli, S. Zorludemir, G. Gönlüşen. (1995) Fluconazole in the treatment of three cases of mucormycosis. European Journal of Clinical Microbiology & Infectious Diseases 14:6, 559-561
CrossRef112
V.J. Quagliarello, C. Viscoli, R.I. Horwitz. (1995) Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients. The Lancet 345:8949, 548-552
CrossRef113
R.J. Hay. (1995) Cryptococcosis, AIDS, and clinical trials. The Lancet 345:8949, 530-531
CrossRef114
A.L. Correa, G. Velez, M. Albert, M. Luther, M.G. Rinaldi, J.R. Graybill. (1995) Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis. Medical Mycology 33:6, 367-374
CrossRef115
JulieE. Mangino, StephenA. Moser, KenB. Waites. (1995) When to use fluconazole. The Lancet 345:8941, 6-7
CrossRef116
R.G. Sawyer, R.B. Adams, L.K. Rosenlof, A.K. May, T.L. Pruett. (1995) Effectiveness of fluconazole in murine Candida albicans and bacterial C. albicans peritonitis and abscess formation. Medical Mycology 33:2, 131-136
CrossRef117
Adriana Ammassari, Angela Linzalone, Rita Murri, Giuseppe Marasca, Giulia Morace, Andrea Antinori. (1995) Fluconazole for Primary Prophylaxis of AIDS-associated Cryptococcosis: A Case-control Study. Scandinavian Journal of Infectious Diseases 27:3, 235-237
CrossRef118
Richard D. Meyer. (1994) Treatment of fungal infections in patients with HIV-infection or AIDS. Zentralblatt für Bakteriologie 281:1, 1-7
CrossRef119
H.A. Leake, M.N. Appleyard, J.P.R. Hartley. (1994) Successful treatment of resistant cryptococcal meningitis with amphotericin B lipid emulsion after nephrotoxicity with conventional intravenous amphotericin B. Journal of Infection 28:3, 319-322
CrossRef120
J.R. Graybill. (1994) Is there a correlation between serum antifungal drug concentration and clinical outcome?. Journal of Infection 28, 17-24
CrossRef121
Cabot, Richard C.Scully, Robert E., Mark, Eugene J., McNeely, William F., McNeely, Betty U., Sax, Paul E.Mattia, Anthony R.. (1994) Case 7-1994. New England Journal of Medicine 330:7, 490-496
Full Text122
Wood, Alastair J.J., , Como, Jackson A.Dismukes, William E.. (1994) Oral Azole Drugs as Systemic Antifungal Therapy. New England Journal of Medicine 330:4, 263-272
Full Text123
K.J. Kwon-Chung, T. Pfeiffer, Y.C. Chang, B.L. Wickes, D. Mitchell, J.J. Stern. (1994) Molecular biology of Cryptococcus neoformans and therapy of cryptococcosis. Medical Mycology 32:s1, 407-415
CrossRef124
Alphons M. Horrevorts, Frans T. M. Huysmans, Roland J. J. Koopman, Jacques F. G. M. Meis. (1994) Cellulitis as First Clinical Presentation of Disseminated Cryptococcosis in Renal Transplant Recipients. Scandinavian Journal of Infectious Diseases 26:5, 623-626
CrossRef125
P. Kujath, C. Boos, K. Lerch, P. Kochendörfer. (1993) Comparative study of the efficacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infection 21:6, 376-382
CrossRef126
Vassil St. Georgiev. (1993) Opportunistic/nosocomial infections. Treatment and developmental therapeutics. II. cryptococcosis. Medicinal Research Reviews 13:5, 507-527
CrossRef127
G. P. Bodey. (1993) What's New in Fungal Infection in Leukemic Patients. Leukemia & Lymphoma 11:s2, 127-135
CrossRef128
Mark Zervos, Françoise Meunier. (1993) Fluconazole (Diflucan®): a review. International Journal of Antimicrobial Agents 3:3, 147-170
CrossRef129
(1992) Suppressive Therapy for Cryptococcal Meningitis. New England Journal of Medicine 327:8, 565-566
Full Text130
(1992) Amphotericin versus Fluconazole in Cryptococcal Meningitis. New England Journal of Medicine 326:23, 1567-1569
Full Text131
D. Milatovic, A. Voss. (1992) Efficacy of fluconazole in the treatment of systemic fungal infections. European Journal of Clinical Microbiology & Infectious Diseases 11:5, 395-402
CrossRef132
J.L. Pellegrin, G. Brossard, P. Barbeau, Ph. Morlat, M. Dupon, D. Lacoste, J.M. Ragnaud. (1992) Cryptococcose neuro-méningée au cours du SIDA : à propos de 24 observations. La Revue de Médecine Interne 13:6, S80
CrossRef
- Letters
