A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group.

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 (greater than or equal to 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 less than 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 less than 0.001). Serious drug-related 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.     

A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. California Collaborative Treatment Group

BACKGROUND AND METHODS. In patients with the acquired immunodeficiency syndrome (AIDS), the rate of relapse after primary treatment for cryptococcal meningitis remains high. We conducted a controlled, double-blind trial to evaluate the efficacy of maintenance therapy with fluconazole. At entry into the study, all participants had sterile cultures of cerebrospinal fluid, blood, and urine after following a standardized course of therapy for culture-proved cryptococcal meningitis. The patients were randomly assigned to take either fluconazole or placebo as maintenance therapy. The dose of fluconazole was 100 mg daily in the first phase of study and 200 mg daily in the second phase. RESULTS. Of 84 patients initially enrolled, 16 (19 percent) were found to have silent, persistent infection on the basis of cultures that became positive after entry into the study; 7 other patients were lost to follow-up shortly after entry. Of the remaining 61 patients, 10 of 27 assigned to placebo (37 percent) and 1 of 34 assigned to fluconazole (3 percent) had a recurrence of cryptococcal infection at any site (difference in risk, 34 percent; 95 percent confidence interval, 15 to 53). Of the 11 recurrent infections, 7 were detected in urine obtained after prostatic massage. There were four recurrent meningeal infections in the patients taking placebo, but none in those taking fluconazole (mean duration of follow-up, 164 days) (P = 0.03). In multivariate analyses, the best predictors of recurrence-free survival were fluconazole treatment (P = 0.02; relative hazard, 13.2), a lower serum cryptococcal-antigen titer (P = 0.05; relative hazard, 1.2), and more prolonged primary therapy with flucytosine (P = 0.09; relative hazard, 1.1). Survival and toxicity were similar in the two maintenance-treatment groups. CONCLUSIONS. In patients with AIDS, silent persistent infection is common after clinically successful treatment for cryptococcal meningitis. Maintenance therapy with fluconazole is highly effective in preventing recurrent cryptococcal infection.     

Timed-kill curves for Cryptococcus neoformans isolated from patients with AIDS.

Infection with Cryptococcus neoformans is an increasing problem in immunocompromised patients, particularly those with acquired immune deficiency syndrome (AIDS). Amphotericin B and fluconazole are currently acceptable therapies for cryptococcal meningitis; however, their effects remain suboptimal and recurrence or treatment failure is still a problem. Antifungal susceptibility testing may be an important tool for guiding therapy, but for C. neoformans, a reliable method is still not available. This retrospective study evaluated minimal inhibitory concentration (MIC) for amphotericin B and fluconazole, and minimal fungicidal concentration (MFC) and timed-kill curves for amphotericin B against 16 clinical isolates of C. neoformans obtained from AIDS patients with cryptococcal meningitis. No correlation between clinical outcome and MIC was observed for amphotericin B. In selected cases, the MFC seemed to be a better predictor of outcome than MIC. In this study, amphotericin B timed-kill curves appeared to show a correlation with clinical outcome of the 16 patients with AIDS-associated cryptococcal meningitis. These in vitro tests must be further evaluated in prospective studies to confirm their potential usefulness for guiding cryptococcal meningitis therapy.     

Use of fluconazole in the treatment of non-AIDS cryptococcal meningitis.

The treatment of non-acquired immunodeficiency syndrome (AIDS) cryptococcal meningitis has not been well defined as yet. The current recommendation is amphotericin B with or without flucytosine. However, due to the many side effects of these drugs, fluconazole is becoming an attractive alternative in patients who cannot tolerate amphotericin B and flucytosine. This case study demonstrates the successful use of fluconazole in a patient with underlying diabetes mellitus and cryptococcal meningitis.     

Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome

We reviewed the records of 106 patients with cryptococcal infections and the acquired immunodeficiency syndrome (AIDS) treated at San Francisco General Hospital. We examined four issues: the efficacy of treatment with amphotericin plus flucytosine as compared with amphotericin alone, the efficacy of suppressive therapy, the prognostic clinical characteristics, and the course of nonmeningeal cryptococcosis. In 48 of the 106 patients (45 percent), cryptococcosis was the first manifestation of AIDS. Among the 89 patients with cryptococcal meningitis confirmed by culture, survival did not differ significantly between those treated with amphotericin plus flucytosine (n = 49) and those treated with amphotericin alone (n = 40). Flucytosine had to be discontinued in over half the patients because of cytopenia. Long-term suppressive therapy with either ketoconazole or amphotericin was associated with improved survival, as compared with survival in the absence of suppressive therapy (median survival, greater than or equal to 238 vs. 141 days; P less than 0.004). The only clinical features independently associated with a shorter cumulative survival were hyponatremia and a positive culture for cryptococcus from an extrameningeal source. The 14 patients with nonmeningeal cryptococcosis had a median survival (187 days) and rate of relapse (20 percent) similar to those in the patients with meningitis (165 days and 17 percent, respectively). From this retrospective study of cryptococcal infections in patients with AIDS we conclude that the addition of flucytosine to amphotericin neither enhances survival nor prevents relapse, but long-term suppressive therapy appears to benefit these patients.     

Integrated therapy for HIV and cryptococcosis

Cryptococcosis has been one of the most common opportunistic infections and causes of mortality among HIV-infected patients, especially in resource-limited countries. Cryptococcal meningitis is the most common form of cryptococcosis. Laboratory diagnosis of cryptococcosis includes direct microscopic examination, isolation of Cryptococcus from a clinical specimen, and detection of cryptococcal antigen. Without appropriate treatment, cryptococcosis is fatal. Early diagnosis and treatment is the key to treatment success. Treatment of cryptococcosis consists of three main aspects: antifungal therapy, intracranial pressure management for cryptococcal meningitis, and restoration of immune function with antiretroviral therapy (ART). Optimal integration of these three aspects is crucial to achieving successful treatment and reducing the mortality. Antifungal therapy consists of three phases: induction, consolidation, and maintenance. A combination of two drugs, i.e. amphotericin B plus flucytosine or fluconazole, is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases. In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality. Aggressive control of intracranial pressure should be done. Management options include therapeutic lumbar puncture, lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt. Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used. ART has proven to have a great impact on survival rates among HIV-infected patients with cryptococcosis. The time to start ART in HIV-infected patients with cryptococcosis has to be deferred until 5 weeks after the start of antifungal therapy. In general, any effective ART regimen is acceptable. Potential drug interactions between antiretroviral agents and amphotericin B, flucytosine, and fluconazole are minimal. Of most potential clinical relevance is the concomitant use of fluconazole and nevirapine. Concomitant use of these two drugs should be cautious, and patients should be monitored closely for nevirapine-associated adverse events, including hepatotoxicity. Overlapping toxicities of antifungal and antiretroviral drugs and immune reconstitution inflammatory syndrome are not uncommon. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with cryptococcosis.     

A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis.

We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P less than 0.001) and less nephrotoxicity (P less than 0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis.     

Cryptococcus neoformans var. neoformans resistant to fluconazole in an HIV-negative patient with chronic lymphocytic leukemia

Cases of fluconazole-resistant Cryptococcus neoformans have been reported in AIDS patients previously treated with fluconazole. We report a case of fluconazole-resistant cryptococcal meningitis in an HIV-negative patient not previously exposed to fluconazole. The patient experienced a clinical relapse after discontinuation of therapy with amphotericin B and subsequent initiation of fluconazole therapy. In vitro resistance was initially verified by Etest and tablet diffusion and later confirmed by NCCLS broth microdilution.     

Comparison of flucytosine and fluconazole combined with amphotericin B for the treatment of HIV-associated cryptococcal meningitis: a systematic review and meta-analysis

Treatment guidelines recommend combination antifungal therapy with amphotericin B (AmB) as an induction therapy for cryptococcal meningitis. The objective of this study was to compare the survival benefit between 5-FC (flucytosine) and fluconazole as second-line drugs given in combination with AmB. We carried out a systematic review and meta-analysis of prospective controlled studies reporting early combination treatment for human immunodeficiency virus (HIV)-associated cryptococcal meningitis. We searched MEDLINE, EMBASE and the Cochrane Library up to October 2013. Randomised trials and prospective cohort studies were selected. The primary outcome was mortality in the first 14 and 70 days. The secondary outcome was early fungicidal activity (EFA) in the first 2 weeks. Four trials were included in our study. All included studies could be considered to be of fair quality in their methodology. The meta-analysis suggested that mortality was lower in patients who were given AmB and 5-FC at the 2 weeks point (Fig. 2); the overall reduction in mortality with the 5-FC combination group was 44 % [risk ratio (RR) 0.56, 95 % confidence interval (CI) 0.33–0.95, p?=?0.03]. EFA was significantly shorter in patients receiving AmB plus 5-FC [mean difference (MD) ?0.10 log₁₀ colony-forming units (CFU) per day, 95 % CI ?0.11–0.09, p?<?0.00001]. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (p?= 0.15) (Fig. 4). Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.     

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due toCandida glabrata orCandida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p=0.39; one-sided 95% Cl, –8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p=0.66: one-sided 95% Cl, –12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p=0.52; chi-square test) and remained similar throughout the course of follow-up. Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.     

Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group

BACKGROUND. Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS. We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS. As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS. Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.     

Fluconazole prophylaxis against fungal colonization and infection in preterm infants.

BACKGROUND: Invasive fungal infection is associated with substantial morbidity and mortality in preterm infants. We evaluated the efficacy of prophylactic fluconazole in preventing fungal colonization and invasive infection in extremely-low-birth-weight infants. METHODS: We conducted a prospective, randomized, double-blind clinical trial over a 30-month period in 100 preterm infants with birth weights of less than 1000 g. The infants were randomly assigned during the first five days of life to receive either intravenous fluconazole or placebo for six weeks. We obtained weekly surveillance cultures from all patients. RESULTS: The 50 infants randomly assigned to fluconazole and the 50 control infants were similar in terms of birth weight, gestational age at birth, and base-line risk factors for fungal infection. During the six-week treatment period, fungal colonization was documented in 30 infants in the placebo group (60 percent) and 11 infants in the fluconazole group (22 percent; difference in risk, 0.38; 95 percent confidence interval, 0.18 to 0.56; P=0.002). Invasive fungal infection with positive growth of fungal isolates from the blood, urine, or cerebrospinal fluid developed in 10 infants in the placebo group (20 percent) and none of the infants in the fluconazole group (difference in risk, 0.20; 95 percent confidence interval, 0.04 to 0.36; P=0.008). The sensitivities of the fungal isolates to fluconazole did not change during the study, and no adverse effects of the fluconazole therapy were documented. CONCLUSIONS: Prophylactic administration of fluconazole during the first six weeks of life is effective in preventing fungal colonization and invasive fungal infection in infants with birth weights of less than 1000 g.     

The effect of warfarin on mortality and reinfarction after myocardial infarction

BACKGROUND AND METHODS. The use of oral anticoagulation in the long-term treatment of survivors of acute myocardial infarction has been highly controversial. We therefore randomly assigned 1214 patients who had recovered from acute myocardial infarction (mean interval from the onset of symptoms to randomization, 27 days) to treatment with warfarin (607 patients) or placebo (607 patients) for an average of 37 months (range, 24 to 63). RESULTS. At the end of the treatment period, there had been 123 deaths in the placebo group and 94 in the warfarin group--a reduction in risk of 24 percent (95 percent confidence interval, 4 to 44 percent; P = 0.027). A total of 124 patients in the placebo group had reinfarctions, as compared with 82 in the warfarin group--a reduction of 34 percent (95 percent confidence interval, 19 to 54 percent; P = 0.0007). Furthermore, we observed a reduction of 55 percent (95 percent confidence interval, 30 to 77 percent) in the number of total cerebrovascular accidents in the warfarin group as compared with the placebo group (44 vs. 20; P = 0.0015). Serious bleeding was noted in 0.6 percent of the warfarin-treated patients per year. CONCLUSIONS. Long-term therapy with warfarin has an important beneficial effect after myocardial infarction and can be recommended in the treatment of patients who survive the acute phase.     

Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group

BACKGROUND: In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. METHODS: We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. RESULTS: The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001). CONCLUSIONS: Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.     

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.

BACKGROUND. Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. METHODS. Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. RESULTS. Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. CONCLUSIONS. In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.     

Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis.

An all oral treatment for cryptococcal meningitis is attractive, particularly where amphotericin B use is impractical. Both fluconazole and flucytosine are available in oral formulations and have activity against Cryptococcus neoformans. We conducted a prospective phase II dose escalation study employing doses of fluconazole ranging from 800 to 2000 mg daily for 10 weeks used alone or combined with flucytosine at 100 mg/kg per day for the first 4 weeks. We found that increasing doses of fluconazole were associated with an increase in survival and a decrease in the time to conversion of the cerebrospinal fluid from culture positive to culture negative. Addition of flucytosine to fluconazole improved outcomes in each dosing cohort. High doses of fluconazole alone or combined with flucytosine were well tolerated.     

Fluconazole monotherapy for cryptococcosis in non-AIDS patients

Treatment with 200 to 400 mg/day fluconazole was evaluated in 44 patients without AIDS who had cryptococcosis (19 with cryptococcal meningitis, 22 with pulmonary cryptococcosis, 3 with other cryptococcal infections). For all patients, the clinical response rate was 89% (48% were clinically cured and 41 % clinically improved). Of the patients with cryptococcal meningitis, 89% were mycologically cured. These rates are comparable to those obtained in the treatment of AIDS patients with cryptococcal disease. In the group of patients with cryptococcal meningitis, there was a high rate of agreement between the mycological response to therapy and cryptococcal antigen test results. The use of cryptococcal antigen testing is recommended in all patients with cryptococcosis.     

A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.

BACKGROUND AND METHODS. Superficial and systemic fungal infections are a major problem among severely immunocompromised patients who undergo bone marrow transplantation. We performed a double-blind, randomized, multicenter trial in which patients receiving bone marrow transplants were randomly assigned to receive placebo or fluconazole (400 mg daily). Fluconazole or placebo was administered prophylactically from the start of the conditioning regimen until the neutrophil count returned to 1000 per microliter, toxicity was suspected, or a systemic fungal infection was suspected or proved. RESULTS. By the end of the treatment period, 67.2 percent of the 177 patients assigned to placebo had a positive fungal culture of specimens from any site, as compared with 29.6 percent of the 179 patients assigned to fluconazole. Among these, superficial infections were diagnosed in 33.3 percent of the patients receiving placebo and in 8.4 percent of the patients receiving fluconazole (P less than 0.001). Systemic fungal infections occurred in 28 patients who received placebo as compared with 5 who received fluconazole (15.8 percent vs. 2.8 percent, P less than 0.001). Fluconazole prevented infection with all strains of candida except Candida krusei. Fluconazole was well tolerated, although patients who received it had a higher mean increase in alanine aminotransferase levels than patients who received placebo. Although there was no significant difference in overall mortality between the groups, fewer deaths were ascribed to acute systemic fungal infections in the group receiving fluconazole than in the group receiving placebo (1 of 179 vs. 10 of 177, P less than 0.001). CONCLUSIONS. Prophylactic administration of fluconazole to recipients of bone marrow transplants reduces the incidence of both systemic and superficial fungal infections.     

Management of cryptococcosis in non-HIV-related patients.

Cryptococcosis is the third most common deep fungal infection in China and has not yet been reported to be associated with HIV infection there. We report the management of non-HIV-related cryptococcosis, including cutaneous cryptococcosis, pulmonary cryptococcosis and cryptococcal infection of central nervous system (CNS). Establishment of the diagnosis of cutaneous cryptococcosis and pulmonary cryptococcosis were mainly based on the histopathologic examination and mycologic culture, with CNS cryptococcal infection based on mycologic examination and latex agglutination test on cerebrospinal fluid. The treatment of cutaneous cryptococcosis included systemic administration of amphotericin B (AMB), 5-flucytosine and triazole agents such as fluconazole and itraconazole combined with topical ketoconazole cream. Treatment of pulmonary cryptococcosis included systemic use of antifungal medication combined with surgical removal of pulmonary lesions. The treatment of CNS cryptococcal infection was challenging. In this study, 53 patients with CNS cryptococcal infection were divided into three groups according to the antifungal regimens applied: eight patients (group I) received intravenous AMB alone or in combination with 5-flucytosine, five patients (group II) received intravenous fluconazole alone or with 5-flucytosine, and 40 patients (group III) received a two-phase therapy, active therapy and consolidation therapy. In active therapy, the patients received intrathecal and intravenous administration of AMB alone or with 5-flucytosine until the mycological culture of cerebrospinal fluid (CSF) became negative. Consolidation therapy followed active therapy by continuous use of oral fluconazole or itraconazole until direct microscopic examination of CSF was negative for three consecutive weeks. In group I, five patients were cured, two improved, one died and one had relapse. In group II, two patients were cured, one improved and two died. In group III, thirty-nine out of forty patients were cured without recurrence. These results indicate that the two-phase protocol was more desirable for the treatment of non-HIV associated cryptococcal infection of CNS.     

Refractory candidal meningitis in an immunocompromised patient cured by caspofungin

Candidal meningitis is a rare infectious disease that usually leads to substantial morbidity and mortality. We present a case of candidal meningitis refractory to systemic antifungal therapy (amphotericin B and fluconazole). A 63-year-old female with lymphoblastic lymphoma and myelodysplasia with leukemia transformation developed prolonged fever and headache on the seventh day following intrathecal prophylactic chemotherapy. A lumbar puncture showed neutrophilic pleocytosis, and a cerebrospinal fluid culture yielded Candida albicans. The clinical course was complicated by brain edema, subarachnoid hemorrhage, and hydrocephalus. Parenteral therapy with amphotericin B alone or amphotericin B in combination with fluconazole or intrathecal administration of amphotericin B failed to eradicate C. albicans in the cerebrospinal fluid. After 7 days of caspofungin therapy, however, the cerebrospinal fluid became sterile and the patient gradually regained consciousness. She was discharged 1 month after completing 4 weeks of caspofungin therapy. There were two critical issues we thought to be relevant to the favorable outcome of this case. First, isolation of C. albicans was achieved by inoculating enriched liquid medium with cerebrospinal fluid. Second, there is a potential therapeutic benefit of caspofungin in treating a fungal infection of the central nervous system.