Addition Of Flucytosine Research Articles

Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

BackgroundCryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa.MethodsA decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables.ResultsThe highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay.ConclusionsThe addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

Combination Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Whom, When, and Where?

To the editor—We appreciate the thoughtful comments raised by Wolbers and Day [1] in response to our article [2]. We agree with their primary point—that our meta-analysis summarized data across studies, and it is therefore best suited to evaluate study-level and not individual-level predictors of outcomes. We should have specified more clearly that our analysis is best suited for drawing inferences about relationships among patient populations, but not about individual patients. Indeed, this point is true for almost all meta-analysis, and it also applies to most individual randomized trials [3]. It is important to note that we did not intend to imply that combination amphotericin B and flucytosine conferred a benefit in patients with cryptococcal meningitis with altered mental status. Rather, in our meta-analysis, we were unable to identify a statistically significant treatment benefit across all published literature, for combination amphotericin B with flucytosine over amphotericin B alone. Although there was some implication of a benefit from adjunctive flucytosine in a subanalysis limited to studies that included patients with altered levels of consciousness, this estimate was not statistically significant (odds ratio = 0.56; 95% confidence interval [CI], .23–1.43) (Figure ​(Figure1).1). As such, we hypothesized in the discussion that populations with altered consciousness might be more likely to benefit from adjunctive flucytosine therapy. If this hypothesis were correct, it would require patient-level data for confirmation. Figure 1. Forrest plot from network meta-analysis comparing odds of early (2-week) and late (10-week) mortality between combination amphotericin B and flucytosine with amphotericin B alone for human immunodeficiency virus-associated cryptococcal meningitis. Abbreviations: ... In their recent large, randomized trial, Day et al [4] demonstrated superiority of combination amphotericin B and flucytosine over amphotericin B alone at 10 weeks. They now present a subanalysis with patient-level data that suggests that those with a normal Glasgow Coma Score (GCS) appeared to derive as much benefit (if not more) from the addition of flucytosine as those with a GCS < 15. Although their study was not powered to detect differences in these subgroups, their data do lend support to the use of flucytosine in individual patients with normal mental status within their study population. It should be noted that the overall mortality in their study was 36% at 10 weeks (and 30% among those who received amphotericin B and flucytosine combination therapy). In contrast, the only other large randomized trial to compare amphotericin B alone with amphotericin B and adjunctive flucytosine found no difference in mortality between groups at 10 weeks (6.7% versus 6.9%; relative risk = 0.97; 95% CI, .46–2.04) [5]. It is noteworthy that this other study was conducted in the United States, excluded comatose patients from enrollment, and had a lower prevalence of participants with altered mental status than the Day et al [4] study (11% vs 28%). We believe that the contrasting data from these 2 studies are in line with our overall conclusion: that current available evidence suggests that the adjunctive use of flucytosine might be beneficial in populations with advanced disease who are at high overall risk for mortality. As Wolbers and Day [4] point out, this does not necessarily mean that patients with normal mental status will not benefit from adjunctive flucytosine, only that populations with low overall risk of mortality are less likely to benefit. Unfortunately, for the time being, it appears that flucytosine is largely only available and in use in the areas of the world where the current data suggest it has the least benefit, whereas populations with the highest mortality often cannot access it [6, 7]. Indeed, the most important conclusion we draw from our study is that more data is required, across a range of patient populations and disease stages, to elucidate which drugs are needed for which patients, and to ensure that the optimal therapies are available to those who need them.

Amphotericin B and fluconazole, a potent combination therapy for cryptococcal meningitis.

We evaluated the antifungal activities of amphotericin B, fluconazole, and flucytosine, alone and in combination, in a murine model of cryptococcal meningitis. The objectives were to determine the greatest antifungal effects achievable with these drugs alone or in combination. Meningitis was established in male BALB/c mice weighing 23 to 25 g by intracerebral injection of Cryptococcus neoformans. Treatment was started on day 2. Amphotericin B was tested at 0.3 to 1.3 mg/kg of body weight/day by slow intravenous injection. Fluconazole at 10 to 40 mg/kg/day and flucytosine at 20 to 105 mg/kg/day were administered in the sole source of drinking water. The mice were killed at 16 days, and the numbers of fungal colonies in the brain were quantified. The association between the response and the dose combination was evaluated by local nonparametric response surface methods; 99% confidence intervals were used to evaluate the antifungal effects. Ninety-five percent of the mice treated with amphotericin B at 0.5 mg/kg survived to the end of the experiment, regardless of the fluconazole or flucytosine dose used. The greatest activity was seen with amphotericin B plus fluconazole with or without flucytosine. However, the addition of flucytosine did not increase the antifungal activity. Given the widespread availability of amphotericin B and fluconazole and the relative safety profile of fluconazole compared to that of flucytosine, the full potential of this two-drug combination deserves further evaluation.

Risk Factors for Poor Outcome of Fungal Peritonitis in Chinese Patients on Continuous Ambulatory Peritoneal Dialysis

Fungal peritonitis is rare among end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis (CAPD), but when it occurs, it is associated with a high risk of mortality and peritoneal membrane failure. In the present study, we identified risk factors for poor outcome and examined the effect of treatment profile on outcome in fungal peritonitis. We identified cases of fungal peritonitis in CAPD patients in a regional dialysis center and analyzed the possible risk factors for poor outcome in fungal peritonitis. To estimate the amount of dextrose presented to the peritoneum, we scored the dextrose content of the peritoneal dialysis fluid used by the patient at the time of admission to hospital (1 point to each bag of 1.5% fluid, 2 points to each bag of 2.3% or 2.5% fluid, and 3 points to each bag of 4.25% fluid daily). Among 471 episodes of CAPD-related peritonitis in 7.8 years, we identified 22 episodes of fungal peritonitis (4.7%). The ratio of men to women in the fungal peritonitis group was 1.4:1. Seventeen patients (77.3%) practiced dialysis without a helper. Within the 3 months preceding the fungal peritonitis, 12 patients (55%) had had bacterial peritonitis. Among the cases of fungal peritonitis, we identified 9 cases of Candida parapsilosis and 13 cases of non C. parapsilosis. All of the patients received fluconazole, and 7 patients (31.8%) also received flucytosine. The Tenckhoff catheter was removed in 17 patients (77.3%). Eight patients (36.4%) either died or lost peritoneal function. The risk of mortality was increased if the fungal organism was C. parapsilosis [odds ratio (OR): 4.25; 95% confidence interval (CI): 1.8 to 10.0; p = 0.002], if a helper was involved (OR: 11.3; 95% CI: 1.1 to 114; p = 0.024), or if CAPD duration was more than 26 months (OR: 2.2; 95% CI: 1.3 to 3.5; p = 0.034). Addition of flucytosine to fluconazole did not significantly improve the mortality rate in either the C. parapsilosis or non C. parapsilosis group. Multivariate analysis showed that C. parapsilosis was an independent factor associated with mortality (p = 0.013). A dextrose score greater than 5 was associated with a trend toward increased risk of peritoneal failure (OR: 3.4; 95% CI: 1.6 to 7.1; p = 0.021). C. parapsilosis is an independent risk factor for mortality in fungal peritonitis.

Saccharomyces cerevisiae infections and antifungal susceptibility studies by colorimetric and broth macrodilution methods

Saccharomyces cerevisiae was isolated in large numbers from operative specimens from two patients with perforated bowel and peritonitis and from the blood of another patient treated with extracorporeal membrane oxygenation. Susceptibility studies were performed on these three isolates and another 29 isolates that colonized or caused infection in a total of 19 patients seen over the last decade. All isolates had low minimum inhibitory concentration (MIC) values for amphotericin B (MIC 90 of ≤0.02 μg/ml) and flucytosine (MIC 90 of 0.2 μg/ ml), and a broader range of MIC values for itraconazole (MIC 90 of 0.8 μg/ml) and fluconazole (MIC 90 of 4 μg/ml). A colorimetric method using Alamar blue reagent showed good concordance with the standard broth macrodilution method for amphotericin B, flucytosine, and fluconazole, but less good concordance for itraconazole. Serious infections with S. cerevisiae probably should be treated with amphotericin B, with or without the addition of flucytosine.

In vitro evaluation of combination of fluconazole and flucytosine against Cryptococcus neoformans var. neoformans.

Amphotericin B and fluconazole are current acceptable therapies for cryptococcal meningitis; however, their effect remains suboptimal. The combination of fluconazole and flucytosine has yielded encouraging clinical results in human immunodeficiency virus patients with cryptococcal meningitis. To investigate the biological basis of this finding, we performed in vitro combination testing of fluconazole and flucytosine against 50 clinical strains of Cryptococcus neoformans var. neoformans. Synergy (fractional inhibitory concentration index of < 1.0) was observed in 62% of cases, while antagonism (fractional inhibitory concentration index of > 2.0) was not observed. For cases in which synergy was not achieved (autonomous or additive effects), the beneficial effect of the combination was still seen (i.e., there was still a decrease, although not as dramatic, in the MIC of one or both drugs when used in combination). The in vitro inhibitory action of flucytosine was greatly enhanced by the addition of fluconazole; the flucytosine MICs for Cryptococcus isolates were markedly decreased to concentrations which were severalfold lower than the achievable cerebrospinal fluid flucytosine concentration. On the other hand, the addition of flucytosine did not greatly enhance the in vitro activity of fluconazole if the initial fluconazole MIC for the isolate was > or = 8 micrograms/ml. Controlled clinical studies are warranted to further elucidate the potential utility of fluconazole-flucytosine combination therapy.

Treatment of invasive aspergillosis

Invasive aspergillosis is generally a life-threatening invasive opportunistic mycosis affecting principally the upper and lower respiratory tract. Therapeutic response rates vary considerably from one host group to another with particularly high mortality rates in bone marrow transplant, liver transplant and patients with aplastic anaemia or AIDS. Only two drugs are useful for therapy, amphotericin and itraconazole. Recent advances in the formulation of amphoterin B (AmBisome and Amphocil) have resulted in intravenous preparations with lower toxicity, particularly nephrotoxicity, but it has yet to be shown that they have an increased therapeutic index for the treatment of invasive aspergillosis. Itraconazole can only be used orally and in some particularly high-risk or critically ill patients adequate serum concentrations cannot be achieved. The addition of flucytosine or rifampicin to amphotericin B therapy has, at best, only a marginal benefit. Surgery is essential for some manifestations of invasive aspergillosis. This article reviews therapeutic strategies including criteria for initiation of therapy, combination and sequential therapy, duration of therapy and secondary prophylaxis and indications for surgery in invasive aspergillosis.

Hepatosplenic candidiasis: Successful treatment with fluconazole

purpose: To determine if fluconazole is effective treatment for hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine treatment. patients and methods: Six patients (ages 3 to 44) with acute leukemia and hepatosplenic candidiasis who did not respond to prior antifungal therapy were treated with fluconazole. results: All six patients had fever and three had nausea and vomiting, computed tomographic (CT) scan showed lucencies in the liver in six, lucencies in the spleen in five, and lucencies in the kidneys in three. Prior therapy with 1.6 to 4 g of amphotericin B in the five adults and 526 mg of amphotericin B in the child (with the addition of flucytosine in four) failed to improve clinical symptoms or lucencies in the liver, spleen, and kidneys seen on CT scan. Fluconazole was given at a dose of 200 to 400 mg daily (70 to 100 mg in the child) for 2 to 14 months. All patients had resolution of fever and other symptoms in 2 to 8 weeks. Improvement of the lesions noted on CT scan was seen in 4 to 8 weeks in all patients. Total resolution of lesions noted on CT scan occurred by 4 weeks in two patients, but took 4 to 5 months for three patients and 13 months for one patient. Three patients had relapse of their acute leukemia and two died, presumably cured of their candidiasis. Two patients underwent successful bone marrow transplantation without relapse of their candidiasis. conclusion: Fluconazole appears to be useful in the treatment of hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine therapy.

Candida and Aspergillus Infections in Immunocompromised Patients: An Overview

Infection is a major cause of morbidity and mortality in granulocytopenic patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia in patients with cancer, the risk of disseminated fungal infection has increased. Although Candida and Aspergillus species are known to be the most common fungal pathogens responsible for disseminated infection, diagnosis of such infection may be difficult. The use of empiric amphotericin B for presumed disseminated candida infection may reduce morbidity caused by this fungal pathogen; moreover, amphotericin B remains the agent of choice for established candida infection, although fluconazole shows promise. The addition of flucytosine may enhance the efficacy of amphotericin B against Candida. Aspergillus infection is more difficult to treat. Early recognition of invasive aspergillosis and use of high-dose amphotericin B (1.0-1.5 mg/[kg.d]) alone or in combination with flucytosine may reduce associated mortality. More active, less toxic antifungal agents are needed to improve the efficacy of treatment and prophylaxis of disseminated fungal infection.

Sino-orbital Aspergillosis Treated With Combination Antifungal Therapy

ASPERGILLOSIS of the paranasal sinus and orbit is well recognized. 1 Local invasion of the sinus or orbit by Aspergillus has been managed successfully with surgery, whereas amphotericin B as sole therapy is considered inadequate. 1 However, when sinus invasion is complicated by decreasing visual acuity and neurological signs, the course has invariably been fatal, even when aggressive surgery was combined with amphotericin B therapy. (A reference list will be provided with reprint requests.) We present a case of sinus aspergillosis that showed malignant progression despite surgery, treatment with amphotericin B, and the results of in vitro susceptibility testing for the fungus involved. When combination antifungal therapy (viz, addition of flucytosine and rifampin to the amphotericin B regimen) was instituted, a dramatic clinical response was noted, with gradual resolution of symptoms and neurological abnormalities. Materials and Methods Susceptibility testing was performed by the broth dilution method, using yeast nitrogen base