deoxycholic-acid and Meningitis--Cryptococcal

Cryptococcal meningitis (CM) is the most fatal adult meningitis in patients with human immunodeficiency virus (HIV). There is no conclusive evidence for the superiority of 1-week amphotericin B deoxycholate (AmphB) + flucytosine (5-FC) regimen over other antifungals in the management of HIV patients with CM (HIV-CM patients). We aimed to evaluate the differences in efficacy and tolerability of different antifungal agents in HIV-CM patients by conducting a current network meta-analysis NMA. Overall, 19 randomized controlled trials were included with 2642 participants. A regimen indicated a possibly lower early mortality rate, namely, AmphB + 5-FC + Azole (OR = 1.1E-12, 95% CIs = 1.3E-41 to 0.06) comparing to AmphB + 5-FC. The current NMA provides evidence that AmphB + 5-FC + Azole are superior to all the investigated treatments for induction regimen in HIV-CM patients.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Flucytosine; Humans; Induction Chemotherapy; Meningitis, Cryptococcal; Treatment Outcome

Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7-1.0 mg/kg). Five were exposed to 200-800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Clinical Trials as Topic; Cryptococcus neoformans; Deoxycholic Acid; Disease Management; Drug Combinations; Female; Fluconazole; HIV Infections; Humans; Meningitis, Cryptococcal; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Uganda; Young Adult

Raised intracranial pressure in the absence of ventricular dilatation is common in cryptococcal meningitis and associated with increased mortality. We report the case of a patient with HIV-associated cryptococcal meningitis, who developed increasing CSF pressure and visual impairment on therapy despite serial lumbar punctures. Insertion of a temporary lumbar drain controlled the opening pressure and resulted in full visual recovery. The advantages and necessary precautions with this approach are reviewed, and alternative protocols for the use of lumbar drains discussed.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cerebrospinal Fluid Pressure; Cryptococcus neoformans; Deoxycholic Acid; Drainage; Drug Combinations; Female; Fluconazole; Flucytosine; HIV-1; Humans; Meningitis, Cryptococcal; Spinal Puncture; Treatment Outcome

Amphotericin-induced phlebitis is a common infusion-related reaction in patients managed for cryptococcal meningitis. High-quality nursing care is critical component to successful cryptococcosis treatment. We highlight the magnitude and main approaches in the management of amphotericin-induced phlebitis and the challenges faced in resource-limited settings.. We prospectively determined the incidence of amphotericin-induced phlebitis during clinical trials in Kampala, Uganda from 2013 to 2018. We relate practical strategies and challenges faced in clinical management of phlebitis.. Overall, 696 participants were diagnosed with HIV-related cryptococcal meningitis. Participants received 7-14 doses of intravenous (IV) amphotericin B deoxycholate 0.7-1.0 mg/kg/day for induction therapy through peripheral IV lines at a concentration of 0.1 mg/mL in 5% dextrose. Overall, 18% (125/696) developed amphotericin-induced phlebitis. We used four strategies to minimize/prevent the occurrence of phlebitis. First, after every dose of amphotericin, we gave one liter of intravenous normal saline. Second, we rotated IV catheters every three days. Third, we infused IV amphotericin over 4 h. Finally, early ambulation was encouraged to minimize phlebitis. To alleviate phlebitis symptoms, warm compresses were used. In severe cases, treatment included topical diclofenac gel and oral anti-inflammatory medicines. Antibiotics were used only when definite signs of infection developed. Patient/caregivers' education was vital in implementing these management strategies. Major challenges included implementing these interventions in participants with altered mental status and limited access to topical and oral anti-inflammatory medicines in resource-limited settings.. Amphotericin-induced phlebitis is common with amphotericin, yet phlebitis is a preventable complication even in resource-limited settings.. The ASTRO-CM trial was registered prospectively. ClincalTrials.gov : NCT01802385 ; Registration date: March 1, 2013; Last verified: February 14, 2018.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Health Resources; HIV Infections; Humans; Incidence; Infusions, Intravenous; Male; Meningitis, Cryptococcal; Phlebitis; Poverty Areas; Uganda

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Topics: Adult; Amphotericin B; Anemia; Antifungal Agents; Blood Cell Count; Coinfection; Creatinine; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Female; Flucytosine; Hemoglobins; HIV; HIV Infections; Humans; Hypokalemia; Induction Chemotherapy; Kidney; Male; Meningitis, Cryptococcal; Neutropenia; Survival Analysis; Treatment Outcome

Interferon-gamma (IFNγ) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFNγ to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis.. Patients were randomized to amphotericin B 1 mg/kg per day and 5FC 100 mg/kg per day for 2 weeks (standard therapy), standard therapy and IFNγ1b 100 μg days 1 and 3 (IFNγ two doses), or standard therapy and IFNγ1b 100 μg days 1, 3, 5, 8, 10 and 12 (IFNγ six doses). Primary outcome was rate of clearance of cryptococcus from the cerebrospinal fluid (CSF) (early fungicidal activity, EFA) calculated from serial quantitative cultures, previously shown to be independently associated with survival.. Rate of fungal clearance was significantly faster in IFNγ containing groups than with standard treatment. Mean EFA [log colony forming unit (CFU)/ml per day] was -0.49 with standard treatment, -0.64 with IFNγ two doses, and -0.64 with IFNγ six doses. Difference in EFA was -0.15 [confidence interval (95% CI) -0.02 to -0.27, P=0.02] between standard treatment and IFNγ two doses, and -0.15 (95% CI -0.05 to -0.26, P=0.006) between standard treatment and IFNγ six doses. Mortality was 16% (14/88) at 2 weeks and 31% (27/87) at 10 weeks, with no significant difference between groups. All treatments were well tolerated.. Addition of short-course IFNγ to standard treatment significantly increased the rate of clearance of cryptococcal infection from the CSF, and was not associated with any increase in adverse events. Two doses of IFNγ are as effective as six doses.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Antiviral Agents; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Female; Flucytosine; HIV Infections; Humans; Interferon-gamma; Male; Meningitis, Cryptococcal; Treatment Outcome

BACKGROUND. It is generally acknowledged that amphotericin B is the most effective treatment for cryptococcal meningitis. However, administration of this drug is accompanied by substantial adverse effects. This double-blind study, performed before the routine availability of highly active antiretroviral therapy, was designed to compare the efficacy and safety of liposomal amphotericin B to conventional amphotericin deoxycholate in patients with acquired immunodeficiency syndrome (AIDS) and acute cryptococcal meningitis. METHODS. Patients were randomized (ratio, 1:1:1) from multiple sites in the United States and Canada to receive either amphotericin B at 0.7 mg/kg/day (n = 87), liposomal amphotericin B at 3 mg/kg/day (n = 86), or liposomal amphotericin B at 6 mg/kg/day (n = 94). RESULTS. Efficacy was similar among all 3 treatment groups. The overall incidence of infusion-related reactions was significantly lower for both the 3 mg/kg/day and 6 mg/kg/day dosages of liposomal amphotericin B, compared with conventional amphotericin B (P < .001). Significantly fewer patients who received the 3 mg/kg/day dosage of liposomal amphotericin B developed nephrotoxicity, indicated by a doubling of the serum creatinine value, compared with recipients of conventional amphotericin B (P = .004). Overall mortality at 10 weeks was 11.6%, with no significant differences among the treatment groups. CONCLUSIONS. Liposomal amphotericin B provides an equally efficacious alternative to conventional amphotericin B deoxycholate in patients with AIDS and acute cryptococcal meningitis. Liposomal amphotericin B at a dosage of 3 mg/kg/day is accompanied by significantly fewer adverse effects.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Canada; Child; Creatinine; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Humans; Kidney Diseases; Male; Meningitis, Cryptococcal; Middle Aged; Treatment Outcome; United States; Young Adult

Animal studies and case series have demonstrated the dose-dependent efficacy and long half-life of amphotericin B deoxycholate (ABd), providing the rationale for our randomized controlled study to compare once-daily (OD) (1 mg/kg) and alternate-d (AD) (2 mg/kg) administration of ABd in the treatment of cryptococcal meningitis in patients with AIDS hospitalized at King Chulalongkorn Memorial Hospital, Thailand, from 2003 to 2004. Of 28 patients, 15 and 13 received OD and AD administration, respectively. There was no significant difference between the 2 groups regarding the demography, clinical features, and laboratory data. After 2 weeks of the intensive-phase treatment, there was no significant difference in the clinical response between the OD (80%) and AD (76.9%) groups. Mycological response was observed in 33.3% and 10% of patients in the OD and AD groups, respectively (p = 0.3). There was no difference in nephrotoxicity and infusion-related events. In conclusion, this is the first randomized controlled study comparing OD and AD administration of ABd in the treatment of cryptococcal meningitis. Although our study was not sufficiently powered to draw conclusions on clinical efficacy and toxicities, the results are encouraging and should warrant further clinical trials evaluating the efficacy and adverse effects with a larger sample size.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cryptococcus neoformans; Deoxycholic Acid; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; Hospitalization; Humans; Male; Meningitis, Cryptococcal; Thailand; Treatment Outcome

We conducted a randomized, open-labeled clinical trial to compare the tolerability and efficacy of amphotericin B deoxycholate, prepared in 5% dextrose or Intralipid (Kabi Pharmacia, Saint-Quentin-en-Yvelines, France), in the treatment of AIDS-associated cryptococcal meningitis in Burundi. Forty-four patients were assigned to receive amphotericin B/dextrose (0.7 mg/[kg.d]) for 14 days; the dose was then reduced to 1 mg/kg every other day for 28 days (infused over 6 hours). Forty-six patients were assigned to receive Intralipid/amphotericin B at a 50% higher dosage (1 mg/[kg.d]) for 14 days; the dose was then reduced to 1.5 mg/kg every other day for 28 days (infused over 2 hours). Intralipid significantly decreased the incidence of fever (P = .02) and chills (P = .0001) related to the infusion of amphotericin B deoxycholate. Analysis of the time to the onset of increased levels of serum creatinine (creatinine level, > 150 mumol/L) showed that Intralipid/amphotericin B was more nephrotoxic (P = .03). The percentage of patients who were clinically cured or had improvement in their conditions and successful mycological outcome was similar in both therapeutic groups, but analysis of the time to the first negative cerebrospinal fluid culture showed a nearly significant difference that favored Intralipid/amphotericin B (P = .07). Intralipid reduced the infusion-related toxicity of amphotericin B deoxycholate without altering its antifungal efficacy but did not confer substantial benefit against renal toxicity that would allow the unitary dosage of amphotericin B deoxycholate to be increased safely.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Amphotericin B; Analysis of Variance; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fat Emulsions, Intravenous; Female; Glucose; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Survival Analysis

The most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective.. A prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups.. Fewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p < 0.05 for both comparisons). However, the differences in CSF culture sterility and mortality between the VCZ + 5FC group and the AmB-D + 5FC group were not statistically significant. VCZ plus 5FC had a significantly advantageous effect on the incidence of new AIDS-defining illness and length of hospital stay, compared with AmB-D plus 5FC. Laboratory adverse events (grade 3 or 4), such as severe anemia, were less frequent with VCZ + 5FC use than with AmB-D combined with 5FC or Flu use.. Our results suggest that AmB-D combined with 5FC remains the more efficacious induction regimen compared to AmB-D plus Flu, and that VCZ + 5FC might be a potential alternative when the standard regimen is not readily available, accessible, tolerated, or effective.. Registration number, ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Topics: Amphotericin B; Antifungal Agents; Cohort Studies; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fluconazole; Flucytosine; HIV Infections; Humans; Infertility; Meningitis, Cryptococcal; Prospective Studies; Voriconazole

Brain lesions caused by Cryptococcus neoformans or C. gattii (cryptococcomas) are typically difficult to diagnose correctly and treat effectively, but rapid differential diagnosis and treatment initiation are crucial for good outcomes. In previous studies, cultured cryptococcal isolates and ex vivo lesion material contained high concentrations of the virulence factor and fungal metabolite trehalose. Here, we studied the in vivo metabolic profile of cryptococcomas in the brain using magnetic resonance spectroscopy (MRS) and assessed the relationship between trehalose concentration, fungal burden, and treatment response in order to validate its suitability as marker for early and noninvasive diagnosis and its potential to monitor treatment in vivo. We investigated the metabolites present in early and late stage cryptococcomas using in vivo

Topics: Amphotericin B; Animals; Biomarkers; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Humans; Meningitis, Cryptococcal; Mice; Middle Aged; Trehalose

Cryptococcal meningitis remains a common cause of mortality in low- and middle-income countries, where amphotericin B deoxycholate (amphotericin) plus fluconazole is the most common treatment. Flucytosine is almost uniformly absent as is outcome data on flucytosine use in routine care. The main goal of this study was identified the cumulative mortality at 2, 4, and 10 weeks after hospital admission.. We conducted a retrospective, observational cohort study among HIV-infected adults with cryptococcal meningitis receiving amphotericin plus flucytosine as induction therapy in Brazil. We assessed cumulative mortality at 2, 4, and 10 weeks and the cumulative proportion discontinuating amphotericin or flucytosine due to toxicity at 2 weeks. We performed multiple logistic regression to identify variables associated with in-hospital mortality.. In total, 77 individuals (n = 66 men) were included with median baseline CD4 of 29 (IQR, 9-68) cells/mcL. Twenty (26%) had at least one concurrent neurological disease diagnosed. Sixty (78%) patients received at least 14 days of amphotericin plus flucytosine. Cumulative mortality was 5% (4/77) at 2 weeks, 8% (6/77) at 4 weeks, and 19% (15/77) at 10 weeks. Cumulative proportion of patients that discontinuated amphotericin or flucytosine due to toxicity was 20% (16/77) at 2 weeks. In addition, in-hospital mortality was associated with receiving ≤ 10 days of induction therapy (odds ratio = 4.5, 95% CI 1.2-17.1, P = 0.028) or positive cerebrospinal fluid fungal culture after 2 weeks (odds ratio = 3.8, 95% CI 1.1-13.5, P = 0.035).. In this "real-world" study, amphotericin plus flucytosine shows low early mortality of patients with HIV-associated cryptococcal meningitis. Early discontinuation due to adverse events was moderate. More effective and safe antifungals are needed in order to improve the outcome of cryptococcal meningitis.

Topics: Adult; Amphotericin B; Antifungal Agents; Brazil; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fluconazole; Flucytosine; HIV Infections; Humans; Male; Meningitis, Cryptococcal; Referral and Consultation; Retrospective Studies

Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon.. This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day).. Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies.. Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Female; Fluconazole; HIV; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Myanmar; Phlebitis; Primary Health Care; Retrospective Studies; Treatment Outcome; Young Adult

The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug.. : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1).. Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died.. By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

Topics: Amphotericin B; Antifungal Agents; Chromatography, High Pressure Liquid; Deoxycholic Acid; Histoplasmosis; Humans; Leishmaniasis; Meningitis, Cryptococcal; Paracoccidioidomycosis

Deoxycholate amphotericin B (d-AMB) has a higher rate of acute kidney injury (AKI) in comparison of lipid formulations. However, lipid amphotericin B has high costs in developing countries. The aim of this study is to assemble a model of cost-minimization of amphotericin B lipid complex (ABLC) in patients with cryptococcal meningitis. This is a retrospective study done in a cohort of patients with cryptococcal meningitis to study the economic impact of its use in developing countries. Cost analysis were based on direct cost of different antifungal therapies, chronic dialysis after discharge, and survival of patients based on a retrospective cohort of 102 patients infected with human immunodeficiency virus with confirmed diagnosis of cryptococcal meningitis. From 102 patients treated with d-AMB, 60.78% developed any grade of AKI and 10.78% developed AKI demanding hemodialysis. The percentage of patients with meningeal cryptococcosis treated with d-AMB that requeired chronic HD was 2.39%. The same model was performed for patient that would be treated with ABLC, which resulted in 0.20% of patients demanding chronic HD due to its lower nephrotoxicity. When the model is applied in 100 patients, the total costs with d-AMB would be US$ 184,543 and with ABLC would be US$ 1,640,109 in 5 years. Treatment with ABLC would be cost saving in comparison to d-AMB treatment, if early switch of treatment occurred in patients presenting AKI. The change should be as soon as possible to avoid further complication, like dialysis, which is associated with a lower life expectancy.

Topics: Acute Kidney Injury; Amphotericin B; Antifungal Agents; Cost of Illness; Costs and Cost Analysis; Deoxycholic Acid; Drug Combinations; HIV Infections; Humans; Meningitis, Cryptococcal; Renal Dialysis; Retrospective Studies

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5-flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5-flucytosine in treating non-HIV- and non-transplant-associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5-flucytosine or deoxycholate-amphotericin B and 5-flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5-flucytosine or fluconazole and 5-flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5-flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5-flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20-69 days vs 21 days, 7-63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5-flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5-flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5-flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.

Topics: Adult; Amphotericin B; Antifungal Agents; Cryptococcus; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Female; Fluconazole; Flucytosine; HIV Infections; Humans; Immunocompetence; Male; Meningitis, Cryptococcal; Middle Aged; Organ Transplantation; Retrospective Studies; Treatment Outcome

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Antigens, Fungal; Child; Cryptococcus; Deoxycholic Acid; Drug Combinations; Fluconazole; Flucytosine; HIV Infections; Humans; Maintenance Chemotherapy; Meningitis, Cryptococcal; Practice Guidelines as Topic; World Health Organization

We report a 45-year-old male with AIDS who had a Cryptococcus neoformans central nervous system infection. He was treated with amphotericin B deoxycholate subsequently changed to voriconazole due to systemic toxicity of the former. Plasma levels of voriconazole were insufficient with a standard dose (0.7 μg/mL), therefore, the dose was increased thereafter to reach appropriate levels (4.5 μg/mL). Anti-retroviral therapy was started five weeks after voriconazole initiation with non-interacting drugs and he was discharged after a favorable evolution. He was re-admitted three months later due to seizures; a brain magnetic resonance showed new sub-cortical nodules. After excluding alternative causes and demonstrating fungal eradication, an immune reconstitution inflammatory syndrome (IRIS) event was suspected and treated with a short course of steroids. His evolution was satisfactory.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Humans; Immune Reconstitution Inflammatory Syndrome; Male; Meningitis, Cryptococcal; Middle Aged; Voriconazole

The first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management.. To determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM.. Retrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models.. From January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14-2.14); severe baseline intracranial pressure (≥35 cm H2O) (RR, 0.57; 95% CI, 0.33-0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39-0.95).. In a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe baseline intracranial pressure were negatively associated, and thus related to failure.

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Colony Count, Microbial; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Female; Fluconazole; HIV Infections; Humans; Immunocompromised Host; Male; Meningitis, Cryptococcal; Retrospective Studies; Risk Factors; Treatment Outcome

Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare.. HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed.. In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events.. CNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Central Nervous System Fungal Infections; Cryptococcosis; Deoxycholic Acid; Drug Combinations; Female; Hematologic Diseases; Hematologic Neoplasms; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Tertiary Care Centers; Young Adult

Topics: Amphotericin B; Antifungal Agents; Brain; Cryptococcus gattii; Cryptococcus neoformans; Deoxycholic Acid; Diagnosis, Differential; Drug Combinations; Early Diagnosis; Fluconazole; HIV Infections; Humans; Immunocompromised Host; Meningitis, Cryptococcal; Patient Care Management

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction.

Topics: Adult; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Creatinine; Deoxycholic Acid; Drug Combinations; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney; Male; Meningitis, Cryptococcal; Middle Aged; Tenofovir

Cryptococcal meningoencephalitis (CM) may present as an acute, subacute, or chronic infection. It manifests as a chronic process in over 75 % of cases, but, sometimes, it presents with a more acute onset, mostly in HIV-associated patients. Until now, there has been no study performed on the clinical features of HIV-negative CM patients with acute/subacute onset. We collected 106 HIV-negative patients diagnosed with CM in our hospital during a 15-year period, analyzed their epidemiological and clinical features, as well as the outcomes, and explored the independent prognosis factors and the factors related to the survival time among them. We found that impaired consciousness (23.4 % vs. 3.4 %, p = 0.017) was more common in CM patients with acute/subacute onset, while decreased cerebrospinal fluid (CSF) glucose (51.9 % vs. 75.9 %, p = 0.026) was less common. The ratio of CSF glucose/blood glucose [odds ratio (OR) 0.04, 95 % confidence interval (CI) 0.004-0.262, p = 0.02], impaired consciousness (OR 5.09, 95 % CI 1.477-17.522, p = 0.01), and hospitalization length (OR 0.98, 95 % CI 0.977-0.999, p = 0.04) were indicated to be not only independent prognosis factors in HIV-negative CM patients with acute/subacute onset, but also factors significantly related to the survival time. The results of our study demonstrated that the contact history and potential history risk factors would not affect the onset process of HIV-negative CM patients, and the mortality, hospitalization length, and survival time has not been related to the onset process. However, the ratio of CSF glucose/blood glucose, consciousness level, and hospitalization length of the HIV-negative CM patients with acute/subacute onset should be of greater focus in the clinical work.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Blood Glucose; Child; Child, Preschool; Chronic Disease; Consciousness Disorders; Cryptococcus; Deoxycholic Acid; Drug Combinations; Female; Glucose; HIV Infections; Hospitalization; Humans; Infant; Infectious Encephalitis; Male; Meningitis, Cryptococcal; Meningoencephalitis; Middle Aged; Retrospective Studies; Risk Factors; Young Adult

In the United States, cryptococcal meningitis causes approximately 3400 hospitalizations and approximately 330 deaths annually. The US guidelines recommend treatment with amphotericin B plus flucytosine for at least 2 weeks, followed by fluconazole for a minimum of 8 weeks. Due to generic drug manufacturer monopolization, flucytosine currently costs approximately $2000 per day in the United States, with a 2-week flucytosine treatment course costing approximately $28 000. The daily flucytosine treatment cost in the United Kingdom is approximately $22. Cost-effectiveness analysis was performed to determine the value of flucytosine relative to alternative regimens.. We estimated the incremental cost-effectiveness ratio (ICER) of 3 cryptococcal induction regimens: (1) amphotericin B deoxycholate for 4 weeks; (2) amphotericin and flucytosine (100 mg/kg/day) for 2 weeks; and (3) amphotericin and fluconazole (800 mg/day) for 2 weeks. Costs of care were calculated using 2015 US prices and the medication costs. Survival estimates were derived from a randomized trial and scaled relative to published US survival data.. Cost estimates were $83 227 for amphotericin monotherapy, $75 121 for amphotericin plus flucytosine, and $44 605 for amphotericin plus fluconazole. The ICER of amphotericin plus flucytosine was $23 842 per quality-adjusted life-year.. Flucytosine is currently cost-effective in the United States despite a dramatic increase in price in recent years. Combination therapy with amphotericin and flucytosine is the most attractive treatment strategy for cryptococcal meningitis, though the rising price may be creating access issues that will exacerbate if the trend of profiteering continues.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Cost-Benefit Analysis; Deoxycholic Acid; Drug Combinations; Fluconazole; Flucytosine; Humans; Meningitis, Cryptococcal; United States

We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities.. Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 -February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly.. Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524).. AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; HIV Infections; Hospitalization; Humans; Male; Meningitis, Cryptococcal; Prevalence; Retrospective Studies; South Africa

Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log10 CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3(+) CD4(+) or CD3(+) CD8(+) cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis.. Cryptococcal meningitis is a significant and neglected infection that is associated with excessive morbidity and mortality. In well-resourced health care settings, induction therapy with at least 2 weeks of amphotericin B deoxycholate (dAmB) is advocated. Multiple clinical studies suggest that dAmB is the drug of choice for cryptococcal meningitis. In many parts of the world where the burden of cryptococcal meningitis is highest, it is infeasible to administer dAmB for prolonged periods. This paper provides the experimental basis for the efficacy of abbreviated regimens of dAmB for cryptococcal meningitis. The concept was explored in two well-validated laboratory animal models of cryptococcal meningitis, and the results were bridged to humans by using a range of mathematical modeling techniques. A 3-day regimen is as effective as the standard 14-day course. An abbreviated regimen is significantly more feasible and may enable better antifungal therapy to be administered to many patients with this frequently lethal disease.

Topics: Amphotericin B; Animals; Antifungal Agents; Cerebrospinal Fluid; Cerebrum; Deoxycholic Acid; Disease Models, Animal; Drug Combinations; Male; Meningitis, Cryptococcal; Mice; Plasma; Rabbits

Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Cryptococcosis; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Fluconazole; Meningitis, Cryptococcal; Meningoencephalitis; Mice; Microbial Sensitivity Tests; Phosphorylcholine; Survival

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Female; Guidelines as Topic; HIV Seropositivity; Humans; Male; Meningitis, Cryptococcal

We measured fungicidal activity of continuous infusion of amphotericin B deoxycholate plus 5'flucytosine using quantitative cultures of cerebrospinal fluid (CSF) obtained from lumbar punctures of human immunodeficiency virus (HIV)-infected patients with neurocryptococcosis during 14 days of treatment. Glomerular renal function was preserved in all patients. Mycological efficacy with progressive reduction in CSF cryptococcal colony-forming units was comparable to standard 4-h infusion of amphotericin B.

Topics: Adult; Amphotericin B; Antifungal Agents; Cerebrospinal Fluid; Colony Count, Microbial; Cryptococcus; Deoxycholic Acid; Drug Combinations; Female; Flucytosine; HIV Infections; Humans; Infusions, Intravenous; Male; Meningitis, Cryptococcal; Microbial Viability; Middle Aged; Treatment Outcome; Young Adult

To report the clinical course of a woman with cryptococcal meningitis and no previous cardiac disease who developed a fatal cardiac arrhythmia after an acute overdose of amphotericin B and to review its toxicity.. A 41-year-old woman with a history of proliferative glomerulonephritis from systemic lupus erythematosus was admitted with a diagnosis of cryptococcal meningitis. Liposomal amphotericin B was prescribed at the standard dose of 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently administered (usual dose of the deoxycholate formulation is 0.5-0.8 mg/kg/day). The patient developed cardiac arrhythmias, acute renal failure, and anemia. The medication error was noticed after she had received 2 doses of amphotericin B deoxycholate, and it was then discontinued. Despite treatment in the intensive care unit, the woman died on the sixth day after admission.. Amphotericin B deoxycholate has been reported to produce significant cardiac toxicity, with ventricular arrhythmias and bradycardia reported in overdoses in children and in adults with preexisting cardiac disease, even when administered in conventional dosages and infusion rates. Use of the Naranjo probability scale indicated a highly probable relationship between the observed cardiac toxicity and amphotericin B deoxycholate therapy in this patient.. Given the fulminant course of amphotericin B deoxycholate overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place.

Topics: Acute Disease; Adult; Amphotericin B; Arrhythmias, Cardiac; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Drug Overdose; Fatal Outcome; Female; Humans; Medication Errors; Meningitis, Cryptococcal

The toxicity of amphotericin B deoxycholate has led to increased preference for lipid formulations with more favorable safety profiles. However, the primary use of lipid formulations is cost prohibitive, and many hospital formularies list both lipid and nonlipid formulations. A dispensing and administration error that caused amphotericin B deoxycholate to be given instead of liposomal amphotericin B related in a fatality. Measures to prevent confusion and aid in understanding the differences between lipid and nonlipid formulations of amphotericin B should be implemented.

Topics: Adult; Amphotericin B; Antifungal Agents; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Drug Overdose; Fatal Outcome; Female; Humans; Liposomes; Medication Errors; Meningitis, Cryptococcal

A case is reported of cryptococcal meningitis in a 27-y-old male suffering from X-linked hyper-IgM1 syndrome. This congenital disorder is characterized by multiple infections of the respiratory and gastrointestinal tracts, but also opportunistic infections commonly seen in patients with cell-mediated immunity. His clinical recovery was good but the need for life-long secondary chemoprophylaxis to prevent relapses is unknown.

Topics: Adult; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Fluconazole; Genetic Diseases, X-Linked; Humans; Hypergammaglobulinemia; Immunoglobulin M; Male; Meningitis, Cryptococcal

In the quest for safer and more effective antifungal agents, amphotericin B (AMB) has been placed in a variety of lipid preparations. In this study, we examined the efficacy of amphotericin B lipid complex (ABLC) on experimental cryptococcal meningitis and disseminated candidosis. This formulation is relatively safe compared to the parent compound, and therefore doses ten times greater than the commercial amphotericin B deoxycholate can be given to rabbits. Although at equal doses the ABLC preparation is less potent than AMB, a higher dose of ABLC was rapidly fungicidal in the contexts of both a central nervous system infection with Cryptococcus neoformans during immune suppression, and a heart and kidney infection with Candida albicans. Rapid sterilization of tissue should be a goal of antifungal drug therapy, particularly in the immune compromised host. From these studies, this AMB lipid formulation has the ability to produce rapid fungicidal activity in vivo, but it requires higher doses than AMB deoxycholate. Clinical trials in humans must examine carefully the therapeutic-toxic ratio in dose-escalation protocols to determine the optimal dosage strategy for this agent.

Topics: Amphotericin B; Animals; Blood Vessels; Candidiasis; Colony Count, Microbial; Cryptococcus neoformans; Deoxycholic Acid; Drug Combinations; Endocarditis; Kidney; Liposomes; Male; Meningitis, Cryptococcal; Rabbits