Original Article
A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome
N Engl J Med 1992; 326:793-798March 19, 1992
- Abstract
- Abstract
Background.
After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse.
Methods.
We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (≥15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture.
Results.
Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P<0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P<0.001). Serious drugrelated toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002).
Conclusions.
Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B. (N Engl J Med 1992;326:793–8.)
Media in This Article
Figure 1
Kaplan–Meier Estimates of the Proportion of Patients Remaining Free of Cryptococcal Disease after One Year.Figure 2
Kaplan–Meier Estimates of the Proportion of Surviving Patients Who Remained Free of Cryptococcal Disease and Dose-Limiting Toxicity after One Year.Article Activity
- Article
CRYPTOCOCCAL disease is a common opportunistic infection in patients in the United States who have the human immunodeficiency virus (HIV), occurring in 5 to 10 percent of those with the acquired immunodeficiency syndrome (AIDS).1 Early in the AIDS epidemic, experience suggested that the complete cure of cryptococcal disease was rare and that most patients with AIDS who completed primary therapy for cryptococcal meningitis remained at risk for relapse.2 3 4 5 Retrospective studies have reported relapse rates of 50 to 60 percent and a shorter life expectancy for patients who did not receive some form of chronic suppressive (or maintenance) therapy.2 3 4
Several regimens have been used to prevent relapses after treatment for acute cryptococcal meningitis, including weekly infusions6 of amphotericin B and daily administration of fluconazole, an oral triazole antifungal agent.7 8 9 10 We conducted a randomized clinical trial to compare fluconazole with amphotericin B as suppressive therapy to prevent the relapse of cryptococcal meningitis in patients with AIDS.
Methods
Study Population
The participants were HIV-infected persons over 18 years of age who had successfully completed a course of primary therapy for culture-proved acute cryptococcal meningitis that was diagnosed within the six months before enrollment. A minimal course of primary therapy was defined as 15 mg of amphotericin B per kilogram of body weight (either alone or in combination with flueytosine); no maximal course was specified. The study design was reviewed and approved by the institutional review board at each participating institution, and all participants gave written informed consent before enrollment.
Successful primary therapy was confirmed by at least two consecutive negative cultures of cerebrospinal fluid at least one week apart, the second of which was obtained at the end of the primary therapy. Patients with urine cultures positive for Cryptococcus neofor- mans were permitted to enter the study, provided that no cultures from other sites were positive in the two weeks before enrollment. Patients with persistent hydrocephalus, cranial-nerve palsies, and papilledema were permitted to enter the study. Patients with positive India-ink preparations of cerebrospinal fluid or skin lesions were eligible for enrollment, provided cultures from these sites were negative.
Randomization occurred within six weeks of the conclusion of primary therapy and after at least one week of incubation of the base-line cerebrospinal fluid culture (the one obtained at the end of primary therapy). Patients whose base-line cultures became positive after randomization were considered ineligible and were excluded from the study. Patients were permitted to have received amphotericin B as maintenance therapy for a maximum of six weeks between the conclusion of primary therapy and the time of randomization. The administration of the study drug was required to begin within one week after randomization.
Patients were excluded if they had any of the following: a history of intolerance to azoles or amphotericin B; moderate or severe aminotransferase abnormalities (concentrations more than five times the upper limit of normal); a serum creatinine concentration above 309 μmol per liter (3.5 mg per deciliter), a creatinine clearance of less than 0.333 ml per second (20 ml per minute), or both; an inability to take oral medication; or concomitant acute or chronic meningitis that was not cryptococcal in origin. Women who were pregnant or lactating were also excluded, as were patients who were receiving other systemic antifungal therapy, immunomodulatory agents, or drugs (such as phenytoin) that had potential interactions with the study drugs. Zidovudine use and prophylactic therapy for Pneumocystis carinii were permitted.
Treatment
The patients were randomly assigned to receive either fluconazole (200 mg by mouth once daily) or amphotericin B (1 mg per kilogram by intravenous infusion once weekly). The dosage of fluconazole was reduced by half for patients with estimated creatinine clearances of less than 0.83 ml per second (50 ml per minute). Randomization was blocked centrally according to individual centers in a 1:1 proportion and was also stratified according to zidovudine use at base line. The investigators at each center remained unaware of the study-drug assignments until after randomization.
The study medications were continued for 12 months or until one of the following occurred: a recurrence of cryptococcal infection (documented by culture or biopsy) at any site other than the urinary tract, another infection requiring systemic antifungal therapy, serious drug-related side effects, other AIDS-related events sufficiently severe to preclude further antifungal prophylaxis, death, or withdrawal of consent by the patient.
Evaluation
The patients' conditions were evaluated weekly for the first four weeks and biweekly thereafter. Each evaluation included an assessment of signs and symptoms and the determination of complete blood counts and serum chemistries. Serum cryptococcal-antigen titers were measured monthly. Cultures of blood for fungi were performed at 1, 3, 6, 9, and 12 months. Cultures and analyses of cerebrospinal fluid were performed at the same intervals and as clinically indicated.
Study Design
The primary goal for this study was to determine whether fluconazole would be as effective (or nearly as effective) as amphotericin B in preventing the relapse of cryptococcal meningitis in patients with AIDS. It was thought that the reduced toxicity and oral administration of fluconazole might give it an advantage over amphotericin B, even if fluconazole was slightly less effective. Therefore, the null hypothesis was that the relapse rate with amphotericin B would be at least 15 percent lower than that with fluconazole. For a Type I error of 0.025 (one-sided, since the hypothesis was inherently one-sided) and an 80 percent power of rejecting the null hypothesis, the sample was estimated to require 165 patients in each treatment arm.11 This sample was based on the assumption that 25 percent of the patients enrolled would prove to be ineligible.
Interim analyses at planned intervals were reviewed by an independent Data Safety Monitoring Board. The levels of significance in these analyses were chosen to preserve a level of significance of approximately 0.05 in the final analysis, with the method of O'Brien and Fleming.12
Statistical Analysis
Analyses were performed according to the initial treatment assignments for all eligible patients. The groups were compared by the chi-square test or Fisher's exact test for categorical variables, and by Student's t-test or the Wilcoxon rank-sum test for continuous variables.13
Since the duration of treatment was less than one year for many patients, the probabilities of relapse and their standard errors were estimated by techniques of survival analysis, and the treatment groups were compared by the log-rank test.14 Treatment regimens were compared by the calculation of the simple difference between the estimated probabilities of relapse at 12 months in order to estimate the true difference. A 95 percent confidence interval was constructed about the difference to determine whether the interval contained the specified difference of 0.15.
All the patients were included in a Cox proportional-hazards model in order to assess the effect of potentially confounding variables on the risk of relapse.15 The following base-line variables were coded as dichotomous: type of therapy (amphotericin B vs. fluconazole); presence or absence of papilledema, headache, visual changes, hearing loss, dysphagia, other cranial-nerve deficits, ataxia, fever, cough, and dyspnea; presence or absence of a positive cerebrospinal fluid India-ink preparation; receipt of zidovudine therapy; cerebrospinal fluid leukocyte count (0 vs. ≥1×106 cells per liter); serum creatinine concentration (≤177 vs. >177 μmol per liter); serum sodium concentration (<140 vs. ≥140 mmol per liter); cerebrospinal fluid cryptococcal-antigen titer (≤1:8 vs. >1:8); and serum cryptococcal-antigen titer (≤1:8 vs. >1:8).
Results
Study Population
A total of 218 patients were enrolled at 45 centers from 1987 through April 1990, when the study was discontinued on the advice of the Data Safety Monitoring Board after its review of the second scheduled interim analysis.
Of the 218 patients enrolled, 119 were randomly assigned to receive fluconazole, and 99 to receive amphotericin B. Twenty-three patients (15 assigned to amphotericin B and 8 assigned to fluconazole) were found to be ineligible and were excluded from further analysis. The primary reason for ineligibility was the presence of active cryptococcal disease (as determined by positive cultures of cerebrospinal fluid) at base line (in 18 patients). Other reasons included an inability to take oral medications, azotemia at base line, concurrent tuberculous meningitis, and receipt of more than six months of primary therapy. Six additional patients never received any study drug and were lost to follow-up; all had been randomly assigned to receive amphotericin B. Of these, five declined therapy after learning of their assigned treatment and one died before receiving any treatment.
The remaining 189 patients (111 in the fluconazole group and 78 in the amphotericin B group) were evaluated for clinical outcomes, including relapse of cryptococcal disease and adverse events. There were no significant differences between the two groups with respect to base-line characteristics before the start of maintenance therapy (Table 1Table 1
Base-Line Characteristics of the Study Population.). The median CD4 lymphocyte count at base line was 0.056×109 per liter (56 cells per cubic millimeter), and this count was similar in the two groups. There was also no difference in the number of patients receiving zidovudine at base line.The two groups were well matched with regard to factors that might have been expected to influence the response to treatment. Similar proportions of patients (35 percent) had extrameningeal cryptococcosis as part of their initial acute illness. Both groups received similar amounts of amphotericin B as primary treatment (median dose, 22 mg per kilogram). The median interval between the end of primary therapy and the initial administration of the study drug was three days in both groups. The percentage of patients with positive India-ink preparations of cerebrospinal fluid at the start of prophylaxis was also similar. The median cryptococcal-antigen titer in the cerebrospinal fluid was higher (1:64) in the amphotericin B group than in the fluconazole group (1:16), although this difference was not significant (P = 0.66 by the Wilcoxon test). Conversely, the median serum cryptococcal-antigen titer was higher in the fluconazole group ( 1:64) than in the amphotericin B group (1:16) (P = 0.24 by the Wilcoxon test).
Duration of Study
Fifty-one patients successfully completed one year of maintenance therapy, and an additional 22 patients who were treated for less than one year were receiving the study medication when the study was stopped (Table 2Table 2
Outcomes of Maintenance Therapy with Fluconazole or Amphotericin B.). The remaining 116 patients left the study prematurely. Eighty-two of these were considered to have had successful suppressive therapy: 16 left the study because of intercurrent AIDS-related illness; 20 left because of noncompliance; 20 patients were excluded from the study by the investigators when fluconazole became commercially available in March 1990; and 26 died from causes unrelated to cryptococcal disease. Thirty-four patients discontinued the study medication because of a failure of maintenance therapy: 16 because of relapses of cryptococcal disease and 18 because of toxicity attributed to the assigned study drug. Two patients who were excluded because of toxicity later had relapses of cryptococcal meningitis. For the 163 patients who did not die during the study, the study medication was taken for a median of 279 days in the fluconazole group and 140 days in the amphotericin B group (P<0.001 by the Wilcoxon test). For all 189 patients, the median duration of follow-up was 286 days.Clinical End Points
Fourteen patients assigned to amphotericin B (18 percent) and two patients assigned to fluconazole (2 percent) (P<0.001 by Fisher's exact test) (Table 2) had relapses while receiving the study drug. Fourteen patients had relapses of meningitis, one patient had cryptococcal lymphadenitis, and one patient had hepatic cryptococcal disease. All the relapses were symptomatic and occurred between scheduled visits. The scheduled routine lumbar punctures did not predict the relapses. The median time between a negative scheduled lumbar puncture and a clinical relapse was 48 days. Two additional cases of meningitis occurred after the study drug was discontinued. In one patient assigned to amphotericin B, therapy was discontinued after 4 months because of systemic side effects; the patient was switched to fluconazole and had a relapse 10 months later. In another patient, assigned to fluconazole, a rash developed after 10 days; the patient was switched to weekly amphotericin B and had a relapse 10 months later.
The Kaplan–Meier estimates of the probability of remaining relapse-free at 12 months were 97 percent for fluconazole and 78 percent for amphotericin B (Fig. 1). This difference of 19 percent (95 percent confidence interval, 7 percent to 31 percent) in the risk of relapse was significant (P<0.001 by the log-rank test), and it enabled us to reject the null hypothesis that amphotericin B had a relapse rate 15 percent lower than that of fluconazole. These data formed the basis of the recommendation by the Data Safety Monitoring Board to end the study early. If the six patients randomly assigned to amphotericin B who never received a study drug and were lost to follow-up are included in an intention-to-treat analysis as having had successful prophylaxis, none of the conclusions are altered.
We also performed a Kaplan–Meier analysis of the risk of death, relapse of cryptococcal disease, or development of serious toxicity (sufficient to necessitate stopping therapy) during treatment (Fig. 2Figure 2
Kaplan–Meier Estimates of the Proportion of Surviving Patients Who Remained Free of Cryptococcal Disease and Dose-Limiting Toxicity after One Year.). The probability of death, relapse, or drug toxicity one year after the start of the study was 39 percent in the fluconazole group and 56 percent in the amphotericin B group. This difference of 17 percent (95 percent confidence interval, 4 percent to 30 percent) was significant (P = 0.03 by the log-rank test). One patient died of the Stevens—Johnson syndrome, an event that was possibly related to treatment with fluconazole. All the other reported deaths were due to the progression of AIDS or to noncryptococcal AIDS-related opportunistic disease; among the latter, disseminated Mycobacterium avium infection, cytomegalovirus infection, and lymphoma were the most common.Multivariate Analysis
The only significant independent base-line predictors of a relapse of cryptococcal disease were assignment to amphotericin B (P<0.001; relative risk, 28.2; 95 percent confidence interval, 4.8 to 164.6) and the presence of papilledema at entry into the study (P = 0.001; relative risk, 22.2; 95 percent confidence interval, 3.3 to 149.1). However, only five patients had papilledema at entry, two of whom had relapses. No other base-line variables were independently predictive of outcome.
Adverse Events
As shown in Table 3Table 3
Number of Patients Reporting Adverse Events during Treatment with Amphotericin B or Fluconazole., 62 percent of the fluconazole group reported no adverse events, as compared with 33 percent of the amphotericin B group (P<0.001). Fever, chills, and hypotension (associated with the infusion of the study drug) were more common in the amphotericin B group, whereas skin rashes were more common in the fluconazole group. There was no difference in the reported incidence of other subjective variables, including nausea.There was no statistically significant difference between the treatment groups in the frequency of severe elevations of hepatic-enzyme levels (to more than five times normal). Hepatotoxicity developed in 12 patients assigned to fluconazole (11 percent), as compared with 5 assigned to amphotericin B (6 percent) (P = 0.29).
Bacterial infections were more common in the patients assigned to amphotericin B. A total of 45 episodes of bacterial infection occurred in 28 patients receiving amphotericin B (36 percent), as compared with 24 episodes in 19 patients receiving fluconazole (17 percent) (P = 0.004). Bacteremia was also more common in the amphotericin B group (14 patients) than in the fluconazole group (4 patients) (P = 0.002). Staphylococcus aureus and Pseudomonas aeruginosa were the bacterial pathogens most frequently isolated.
The study drug was discontinued in 18 patients because of severe drug-related toxic effects: 12 patients in the amphotericin B group (15 percent), and 6 in the fluconazole group (5 percent) (P = 0.02). Among the side effects attributed to amphotericin B that led to the termination of the drug were gastrointestinal toxicity (severe nausea and vomiting in four patients), constitutional symptoms including intractable fever and chills (in two), anemia (in two), nephrotoxicity (in two), and seizures (in two). The side effects related to fluconazole that prompted the discontinuation of the drug included skin rash in three patients, abnormal liver-function tests in two, and nausea in one. As mentioned previously, one patient died of Stevens—Johnson syndrome while taking fluconazole. Although this patient was receiving other drugs potentially related to this reaction (including trimethoprim–sulfamethoxazole), a causative role for fluconazole cannot be excluded.
Discussion
The control of cryptococcal disease in patients with AIDS is difficult. Retrospective studies have reported relapse rates of 50 to 60 percent among patients who have not received any chronic suppressive therapy.2 , 3 , 16 A recent placebo-controlled study of maintenance therapy with fluconazole10 found a relapse rate of 37 percent in the patients given placebo, who were followed for a median of 125 days. Relapse probably represents a failure of the initial therapy to eradicate infection completely, rather than a new infection. One possible factor in the high rate of relapse is the observation that standard therapy that succeeds in sterilizing the cerebrospinal fluid may not eradicate infection from extrameningeal sites, such as the urinary tract, which may then serve as foci for relapse. A persistent focus of infection in the urinary tract (presumably of prostatic origin) has been reported in approximately 20 percent of patients completing therapy with amphotericin B.5 , 10
Our study was designed to compare daily treatment with fluconazole, an oral triazole antifungal agent, with weekly infusion of amphotericin B, as maintenance therapy for patients with AIDS who had completed primary amphotericin B therapy for cryptococcal meningitis. The initial hypothesis was based on the presumption that amphotericin B would be superior to fluconazole as suppressive therapy. It was thought that fluconazole, although perhaps less effective, would be clinically acceptable because of its ease of administration and relative lack of toxicity. In fact, our findings indicate that the probability of being relapse-free with fluconazole maintenance therapy (97 percent after one year) was significantly higher than that with amphotericin B (78 percent). These data allow us to conclude that fluconazole was at least as effective as weekly amphotericin B (within a 15 percent margin of error). Indeed, the 19 percent difference in the probability of relapse at one year (95 percent confidence interval, 7 percent to 31 percent) suggests that fluconazole was more effective than amphotericin B in preventing a relapse of cryptococcal disease in this population of patients. A multivariate proportional-hazards analysis confirmed that assignment to amphotericin B was the most important factor predictive of failure.
Although this study was not specifically designed to look at mortality, we did not detect an advantage in terms of survival for fluconazole as compared with amphotericin B, despite the superior ability of fluconazole to prevent relapse. The lack of difference was almost certainly due to the profound effect of other AIDS-related illnesses in this study population.
All the patients who had relapses presented with clinically evident disease, usually with fever; those with meningitis also had recurrent headache. Relapse was not predicted by routine sampling of the cerebrospinal fluid in any of the patients with meningitis. This observation would suggest that regular periodic clinical monitoring with attention to the signs and symptoms of cryptococcal disease is needed to detect a relapse but that routine lumbar puncture is of doubtful value.
Fluconazole was well tolerated. Serious adverse reactions were rare, although skin reactions (generally mild) were reported more frequently than had been noted in an earlier study.8 Serious hepatotoxicity attributable to fluconazole was not observed. Bacterial infections were significantly more common in the patients given amphotericin B (36 percent) than in those given fluconazole (17 percent), as was also true of bacteremia (18 percent vs. 4 percent). The increased frequency of bacterial infections in the amphotericin B group was probably due to the required use of intravenous catheters in these patients. The use of fluconazole obviates the need to obtain venous access.
The value of fluconazole as suppressive therapy has also been shown in a recent placebo-controlled, double-blind study in a select population of patients with AIDS who were treated for acute cryptococcal meningitis.10 Bozzette et al. included patients with negative cultures from all sites, including the urinary tract, and showed that fluconazole was superior to placebo, with relapse rates at any site (including the urinary tract) of 3 percent for fluconazole and 37 percent for placebo (difference in risk, 34 percent; 95 percent confidence interval, 15 percent to 53 percent).10 It is important to note that both our study and that of Bozzette et al. used prolonged courses of amphotericin B (with or without flucytosine) as primary therapy for the acute episode of cryptococcal meningitis. Larsen has recently advocated shorter courses of primary therapy with amphotericin B or fluconazole alone.17 The effectiveness of fluconazole as suppressive therapy in patients treated in this manner is untested and may in fact be less than that shown in this study.
Even so, all patients with AIDS who complete primary therapy for cryptococcal meningitis should receive lifelong suppressive therapy. At a dose of 200 mg per day, fluconazole is well tolerated and effective, and it should be regarded as the maintenance treatment of choice.
Supported by the Division of AIDS, National Institute of Allergy and Infectious Diseases; by a contract (NO1 AI52562) with the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases; by a grant (CA 13148) to the Comprehensive Cancer Center, University of Alabama at Birmingham; and by Pfizer Central Research.
Presented in part at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21–24, 1990.
Source Information
From the Division of Infectious Diseases, Washington University School of Medicine, and the St. Louis Veterans Affairs Medical Center, St. Louis (W.G.P.); 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 (M.S.S., G.A.C., W.E.D.); the Division of Infectious Diseases, Department of Medicine, Cedars—Sinai Medical Center, and the School of Medicine, UCLA (R.D.M.); the Division of Infectious Diseases, Department of Medicine, Mount Sinai Medical Center, New York, and the Bronx Veterans Affairs Medical Center, Bronx, N.Y. (J.M.J.); the University of Texas Health Sciences Center at San Antonio and the Audie Murphy Veterans Affairs Hospital, San Antonio (J.R.G.); the Department of Medicine, Boston City Hospital, and the University Hospital, Boston (A.M.S.); New York University Medical Center, New York (V.J.M.); Davies Medical Center, San Francisco (S.E.F.); the Division of Infectious Diseases, George Washington University, Washington, D.C. (C.U.T.); Pennsylvania Hospital, Philadelphia (J.J.S.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (J.F., R.H.); and Pfizer Central Research, Groton, Conn. (P.R.). Address reprint requests to Dr. Powderly at Box 8011, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110.
* Contributing members of the AIDS Clinical Trials Group and the Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (NIAID) and independent investigators are listed in the Appendix.
Appendix
The members of the NIAID AIDS Clinical Trials Group and the NIAID Mycoses Study Group and the independent investigators who contributed to this study are as follows.
AIDS Clinical Trials Group: Mt. Sinai Medical Center, New York: J. Jacobson, G. Hammer, N. Solomon, and C. Sanders; New York University Medical Center, New York: V.J. McAuliffe, K. Kerkorian, and F.T. Valentine; Memorial Sloan-Kettering Cancer Center, New York: K. Sepkowitz, J. Solan, and D. Armstrong; Washington University School of Medicine, St. Louis: W.G. Powderly, M. Klebert, and J.Voorhees; Cornell Medical School, New York: K. Squires; Northwestern University Medical School, Chicago: R. Murphy; University of Miami, Miami: R.B. Uttamchandani, S. Gagnon, M.A. Fischl, and B. Bryant; Ohio State University, Columbus: R.J. Fass, M.F. Para, S.L. Koletar, and J.L. Neidig; Montefiore Medical Center, Bronx, N.Y.: C. Harris, E. Feraru, A. Zuger, and P. Kahl; Tulane University—Louisiana State University, New Orleans: N. Hyslop, A. Rege, J. Zachary, and N. Porter; Harvard Medical School and New England Deaconess Hospital, Boston: A.W. Karchmer, J.D. Allan, L. Bouvier, and H. Fitch; Johns Hopkins University School of Medicine, Baltimore: J. Bartlett, R. King, E. Yamaguchi, and R. Becker; St. Luke's–Roosevelt Hospital, New York: M.H. Grieco, G.F. McKinley, and K. Ong; UCLA AIDS Clinical Research Center, Los Angeles: S.A. Miles, R. Mituyasu, and W.D. Hardy; Indiana University Medical School, Indianapolis: J. Deutsch and J.J. Relue; University of Rochester School of Medicine, Rochester, N.Y.: P. Graman and J. Reid; Case Western Reserve Medical School, Cleveland: J. Rosenthal, M. Lederman, J. Carey, and C. Smith; University of Cincinnati School of Medicine, Cincinnati: G. Roselle and K. Skahan; University of North Carolina School of Medicine, Chapel Hill: C. van der Horst; State University of New York, Stony Brook: W. Donlon, R.T. Steigbigel, J. Fuhrer, and H. Heller; Duke University Medical Center, Durham, N.C.: H.A. Waskin and R.A. Drew.
Mycoses Study Group: University of Texas Health Sciences Center, San Antonio: J.R. Graybill, P.K. Sharkey, and C. Watson; Boston University School of Medicine, Boston: A.M. Sugar and C. Saunders; George Washington University School of Medicine, Washington, D.C.: C. Tuazon, D. Parenti, G.L. Simon, and A. Katz; Medical College of Virginia, Richmond: T. Kerkering and M. Gurkin; University of Alabama at Birmingham School of Medicine: M.S. Saag, W. Dismukes, G. Cloud, B. Dean, and C. Bowles-Patton; Emory University School of Medicine, Atlanta: S.E. Thompson and L. Perry; Medical College of Georgia, Augusta: J. Fisher and C.L. Newman; University of Michigan, Ann Arbor: C.A. Kauffman; University of Arizona, Tucson: J. Galgiani and J. Higgs.
Independent Centers: Cedars—Sinai Medical Center, Los Angeles: R. Meyer and P. Gaut; Davies Medical Center, San Francisco: S. Follansbee, D. Cox, and B. Christiansen; Pennsylvania Hospital, Philadelphia: J. Stern, N. Pietroski, M. Braffman, and M. Buckley; St. Vincent's Hospital and Medical Center, New York: D. Kaufman and P. Caffrey; Infectious Diseases Consortium of Georgia, Atlanta: R. Dretler, D. Blum, V. Thomily, and R. Capparell; University of Florida, Gainesville: J.W. Shands, Jr., J. McKinney, C. Rodriguez, and V. Singh; Albany Medical College, Albany, N.Y.: S. Kowalsky, S. Remick, P. Gorman, and C. Ramnes; Cabrini Medical Center, New York: M. Davidson, D. Boyle, and A. Giosa; Group Health Care Cooperative, Seattle: R.L. Thompson; University of South Florida, Tampa: H. Chmel; Henry Ford Hospital, Detroit: L. Saravolatz and N. Markowitz; Harlem Hospital, New York: W. El-Sadr; Maine Medical Center, Portland: M. Bach and S. D'Amato; University of Texas, Galveston: R. Pollard and N. Murcar; St. Michael's Medical Center, Newark, N.J.: E. Johnson, E. Perez, and D. Vincent; Infections Limited, Tacoma, Wash.: P. Craven, T. Christiansen, I. Rice, and A. Tice.
National Institute of Allergy and Infectious Diseases, Bethesda, Md.: Division of AIDS, J. Feinberg and R. Hafner; Division of Microbiology and Infectious Diseases, D. Gwinn and M. Matthias.
Pfizer Central Research, Groton, Conn.: P. Robinson, D. Buell, J. Briganti, R. Casagrande, L. Conway, J. Jacobsen, J. Schalhoub, M. Szczesiul, and J. Stritar.
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- Citing Articles (79)
Citing Articles
1
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M Nelson, H Manji, E Wilkins. (2011) 2 Central nervous system opportunistic infections. HIV Medicine 12, 8-24
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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.
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John R. Perfect, Gary M. Cox. 2010. Cryptococcosis. .
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Su Jin Jeong, Yun Tae Chae, Sung Joon Jin, Ji-hyeon Baek, Bum Sik Chin, Sang Hoon Han, Chang Oh Kim, Jun Yong Choi, Young Goo Song, June Myung Kim. (2010) Cryptococcal Meningitis : 12 Years Experience in a Single Tertiary Health Care Center. Infection and Chemotherapy 42:5, 285
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(2009) Author's Reply to Four-week fluconazole treatment is recommended for localized granulomatous cryptococcal prostatitis in patients with liver cirrhosis. International Journal of Urology 16:12, 981-981
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