Fluconazole Arm Research Articles

1734. Antifungal Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience in Colombia

BackgroundInvasive fungal infections (IFI) are significant causes of morbidity and mortality among patients with hematopoietic stem cell transplantation (HSCT). Primary antifungal prophylaxis has lowered the IFI cases however there is no clear guidance regarding which mold active agent is most useful if mold-active prophylaxis. We aim to present the incidence of IFI in patients with allogeneic HSCT, and the impact of primary antifungal prophylaxis regimen.MethodsRetrospective cohort study. We included patients older than 18 years, with allogeneic HSCT from Fundación Valle del Lili, between January 2008 and April 2017. The patients received antifungal prophylaxis with fluconazole, itraconazole, or posaconazole from conditioning day to +100 post-transplant day. The prophylactic antifungal agent was selected according to the initial diagnosis, transplant type, conditioning regimen and the risk of developing GVHD. All patients received myeloablative conditioning regimens and were hospitalized in laminar airflow rooms during their period with neutropenia. The cases were defined according to the EORTC/MSG Consensus Group. We analyzed patients with probable or confirmed IFI, in the first 120 post-transplant days.ResultsWe enrolled a total of 101 patients who received HSCT over the course of the study. The median age was 32 (23–43). Posaconazole prophylaxis was used in 73%, fluconazole in 18% and itraconazole 10% of the patients. The IFI incidence was 3.9% (4 cases) and the median time from HSCT to the diagnosis of IFI was 60 days. The percentages of patients who experienced probable IFI in the itraconazole arm was 22% (2/9 patients) and in the fluconazole arm 11.1% (2/18), there was no infection in the posaconazole group (P = 0.001). Donor sources were HLA-matched sibling (42%), Haploidentical (48%), and cord blood (10%). The cumulative incidence of grade I–IV aGVHD was 63.4% and that of grade III–IV aGVHD was 37.5%.ConclusionIn patients undergoing HSCT posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole. Disclosures All authors: No reported disclosures.

Paroxetine and fluconazole therapy for HIV-associated neurocognitive impairment: results from a double-blind, placebo-controlled trial.

Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2×2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20mg/day, (2) fluconazole 100mg every 12h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change=0.25 vs - 0.19, p=0.049), CalCAP sequential test reaction time (mean change=0.34 vs -0.23, p=0.014), Trail Making Part B test performance (mean change=0.49 vs - 0.33, p=0.041), and FAS verbal fluency (mean change=0.25 vs 0.02, p=0.020) but a decline in the Letter number sequencing test (mean change=- 0.40 vs 0.26, p=0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.

Cost-effectiveness analysis of anidulafungin vs fluconazole for the treatment of invasive candidiasis (IC) in Turkey.

Anidulafungin has been shown to be non-inferior to, and possibly more efficacious, than fluconazole in treating patients with invasive candidiasis (IC). This study aimed to determine the cost-effectiveness of anidulafungin vs fluconazole for treatment of IC in the Turkish setting. A decision analytic model was constructed to depict downstream economic consequences of using anidulafungin or fluconazole for treatment of IC in the Turkish hospitals. Transition probabilities (ie treatment success, observed or indeterminate treatment failures) were obtained from a published randomised clinical trial. Cost inputs were from the latest Turkish resources. Data not available in the literature were estimated by expert panels. Sensitivity analyses were performed to assess the robustness of the model outcome. While anidulafungin [TL 17171 (USD 4589)] incurred a higher total cost than fluconazole [TL 8233 (USD 2200) per treated patient, treatment with anidulafungin was estimated to save an additional 0.58 life-years, with an incremental cost-effectiveness ratio of TL 15410 (USD 4118) per life-years saved. Drug acquisition cost and hospitalisation were the main cost drivers for anidulafungin and fluconazole arms respectively. The model findings were robust over a wide range of input variables except for anidulafungin drug cost. Anidulafungin appears to be a cost-effective therapy in treating IC from the Turkish hospital perspective.

Randomized trial of micafungin versus fluconazole as prophylaxis against invasive fungal infections in hematopoietic stem cell transplant recipients

Invasive fungal infections (IFIs) cause significant morbidity and mortality among recipients of hematopoietic stem cell transplantation (HSCT). Although fluconazole is used widely as an antifungal prophylactic agent in these patients, it is not reliably effective against mold infection including invasive aspergillosis. Micafungin provides antifungal activity against Candida and Aspergillus species, and previous studies have demonstrated its efficacy when used as a prophylactic agent for fungal infection in neutropenic patients. Here, we evaluated and compared the incidence of proven or probable IFIs after antifungal prophylaxis using micafungin or fluconazole. This was a prospective, single-center, phase II study involving adult patients who received allogeneic or autologous HSCT. Patients were randomly assigned to micafungin or fluconazole arms in a ratio of 2:1, and the treatment was initiated within 24h of HSCT and maintained for up to 21 days. The primary end point was the incidence of proven or probable IFIs during the 100 days after HSCT. The secondary end points were the incidence rates of possible, proven, or probable IFIs, need to change the antifungal agent before engraftment, IFI-related mortality, and survival within 100 days after transplantation. Between March 2010 and May 2015, a total of 257 patients were enrolled. After exclusion of seven patients who did not receive at least one dose of a study treatment, 250 patients (micafungin, n=165; fluconazole, n=85) were included in the analysis of clinical efficacy. The median age was 47 years (range, 20-64). Allogeneic and autologous transplantations were performed in 56.0% (n=140) and 44.0% (n=110) of the patients, respectively. Baseline characteristics were well balanced between the two groups. Overall, the incidence of proven and probable IFIs within 100 days of HSCT was 7.6% (n=19). The percentages of patients who experienced proven or probable IFIs did not differ significantly between the micafungin and fluconazole groups: 7.3% and 8.2%, respectively (p=0.786). Thirteen patients in the micafungin arm (7.9%) and eight patients in the fluconazole arm (9.4%) needed a change in antifungal agent before engraftment (p=0.824). Mortality within 100 days after HSCT did not differ significantly between groups: 9.1% vs 12.9% in the micafungin and fluconazole arms, respectively (p=0.345). Micafungin is comparable to fluconazole for the prevention of IFIs in HSCT recipients.

Fluconazole Prophylaxis in Neonates (Non-Systematic) Literature Review

Background: Nosocomial infection remains an important contributing factor for morbidity and mortality in neonates. Coagulase-negative staphylococci have emerged as the predominant pathogens of late onset sepsis. This is followed by staphylococcus aurous, gram negative bacilli, and fungi. Old studies noted that mortality due to candidemia was higher in infants weigh less than 2000 g after being exposed to risk factors. The prophylactic use of fluconazole for the prevention of IC in extremely low birth weight was first reported in 2001. Methods: Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016. Conclusion: Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms. Risk-based approach towards fluconazole prophylaxis seems to be safe and effective.

Randomized Trial of Micafungin Versus Fluconazole in Prophylaxis Against Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients

Introduction: Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) recipients. Although fluconazole has been widely used as an antifungal prophylactic agent in these patients, it is not reliably effective against mold infection including invasive aspergillosis. Micafungin provides antifungal activity against Candida and Aspergillus species, and previous studies have demonstrated its efficacy when used as a prophylactic agent for fungal infection in neutropenic patients. Here, we evaluated and compared the incidence rate of proven or probable invasive fungal infections (IFIs) with antifungal prophylaxis using micafungin or fluconazole.Methods: This is a prospective, single center, phase II study involving adult patients who received allogeneic or autologous HSCT. Patients were randomly assigned to micafungin or fluconazole arms in the ratio of 2:1, and the treatment was initiated within 24 hour of hematopoietic stem cell infusion and maintained for up to 21 days. Primary objective was the incidence of proven or probable invasive fungal infections (IFIs) during the 100 days after HSCT. Secondary objectives involved the incidence of possible, proven or probable IFIs, need for change of anti-fungal agents before engraftment, IFI-related mortality and survival within 100 days after transplantation.Results: Between March 2010 and May 2015, a total of 257 patients were enrolled. Excluding 7 patients who did not receive at least one dose of study treatment, 250 patients (micafungin, n=165; fluconazole, n=85) were examined for clinical efficacy. The median age was 47 years (20-64) and allogeneic and autologous transplantation comprised 56.0% (n=140) and 44.0% (n=110) of the patients. Baseline characteristics were well balanced between the two groups. Overall, the incidence of proven and probable IFIs within 100 days of HSCT was 7.6% (n=19), and there was no significant difference in the proportion of patients who experienced proven or probable IFIs between the micafungin and the fluconazole groups (7.3% in micafungin group versus 8.2% in fluconazole group, p=0.786). Thirteen patients of micafungin arm (7.9%) and 8 patients of fluconazole arm (9.4%) had to have changed antifungals before engraftment (p=0.824). There was no significant difference in the mortality within 100 days after HSCT (9.1% in micafungin arm vs 12.9% in fluconazole arm, p=0.345).Conclusion: Micafungin is comparable to fluconazole in the prevention of IFIs in HSCT recipients.Table 1Clinical outcomes including invasive fungal infections within 100 days after transplantationCharacteristics (total n=250)Total patients(n=250)Fluconazole(n=85)Micafungin(n=165)p-valueProven IFIsAllCandidiasisAspergillosisMucormycosis5 (2.0%) 2 (0.8%) 1 (0.4%) 2 (0.8%)3 (3.5%) 1 (1.2%) 0 (0.0%) 2 (2.4%)2 (1.2%) 1 (0.6%) 1 (0.6%) 0 (0.0%)0.341 1.000 1.000 0.115Probable IFIs16 (6.4%)5 (5.9%)11 (6.7%)0.810Possible IFIs7 (2.8%)1 (1.2%)6 (3.6%)0.428Proven, probable IFIs19 (7.6%)7 (8.2%)12 (7.3%)0.786Proven, probable, possible IFIs26 (10.4%)8 (9.4%)18 (10.9%)0.713Invasive mold infections Proven, probable Proven, probable, possible18 (7.2%)25 (10.0%)6 (7.1%)7 (8.2%)12 (7.3%)18 (10.9%)0.9510.504Need for anti-fungal agents change before engraftment21 (8.4%)8 (9.4%)13 (7.9%)0.824Mortality within 100 days after HSCT26 (10.4%)11 (12.9%)15 (9.1%)0.345IFI related mortality within 100 daysafter HSCT5 (2.0%)3 (3.5%)2 (1.2%)0.34128 invasive fungal infections were observed in 26 patientsAbbreviations: IFI=invasive fungal infection, HSCT=Hematopoietic stem cell transplantation DisclosuresNo relevant conflicts of interest to declare.

Dosing algorithm for concomitant administration of sirolimus, tacrolimus, and an azole after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplant patients are at risk of invasive fungal infections and prophylaxis with azole agents is common practice. The concomitant use of these agents with sirolimus and tacrolimus for the prevention of graft-versus-host disease may result in excessive immunosuppression or toxicity. This retrospective study identified hospitalized patients who underwent allogeneic hematopoietic stem cell transplantation between August 2009 and April 2011 at Rush University Medical Center. From this group, patients who underwent concomitant tacrolimus, sirolimus, and azole therapy were included for evaluation. The immunosuppression dosing in conjunction with azole use at discharge was analyzed to develop a dosing algorithm dependent on whether fluconazole, posaconazole, or voriconazole was used. A total of 36 patients were screened for inclusion, of which 8 were excluded due to acute renal failure and/or hemolysis. The remaining patients were stratified by the azole they were concomitantly taking with tacrolimus and sirolimus. The fluconazole arm required the lowest magnitude of dose reductions, while voriconazole required the greatest. Dose reductions of 50-75% for both sirolimus and tacrolimus, in combination with standard dosing of azole antifungal agents, were necessary to achieve therapeutic drug concentrations for immunosuppressants and potentially avoid toxicities.

Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans

BackgroundData from retrospective studies have suggested that there may be an interaction between fluconazole and nevirapine, increasing nevirapine concentrations and potentially leading to hepatotoxicity.MethodsThis study was nested within a large double-blind placebo-controlled study designed to determine if primary prophylaxis with fluconazole (200 mg three times per week) could reduce cryptococcal disease [CRYPTOPRO (ISRCTN 76481529)] in HIV-infected adults in rural south-western Uganda. Detailed pharmacokinetic studies were performed on 49 participants (22 on placebo and 27 on fluconazole) who had been on fluconazole or placebo with nevirapine for ≥4 weeks.ResultsThe geometric mean pre-dose concentrations of nevirapine were 3865 ng/mL [95% confidence interval (95% CI) 3452–4758 ng/mL] and 5141 ng/mL (95% CI 4760–6595 ng/mL) (P = 0.009) in the placebo and fluconazole arms, respectively. The change in the peak nevirapine concentration in plasma (Cmax) was also higher in the fluconazole arm compared with the placebo arm [median 6546 (95% CI 6040–7974) versus 5126 (95% CI 4739–5773) ng/mL, P = 0.012]. Fluconazole increased the nevirapine area under the curve (AUC) from 0 to 8 h by 29% [geometric mean AUC0–8 46 135 (95% CI 42 432–57 173) versus 35 871 (95% CI 32 808–41 372) ng·h/mL, P = 0.016]. In the larger cohort from which the participants were drawn, co-administration of fluconazole did not increase the risk of hepatotoxicity.ConclusionsFluconazole led to significant increases in nevirapine exposure, but was not associated with evidence of increased hepatotoxicity.

Impact of Antifungal Prophylaxis on Colonization and Azole Susceptibility of Candida Species

Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomyces yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabrata cultures increased by two- and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. krusei cultures increased twofold. C. glabrata was the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing C. glabrata isolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the C. albicans and C. glabrata isolates confirmed that the majority of the baseline and end-of-treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candida species were very rare (approximately 1%), and C. glabrata was the colonizing species that was the most frequently associated with breakthrough infections.

Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis

To compare available antifungal treatments for invasive candidiasis, a leading cause of nosocomial bloodstream infections. We performed a systematic review and meta-analysis of randomized controlled trials that compared different antifungal agents for the treatment of candidemia and other forms of invasive candidiasis. Two reviewers independently appraised the quality of trials and extracted data. The primary outcome was all-cause mortality, and secondary outcomes were microbiological failure, treatment failure, and adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled. Of the 15 included trials, 9 compared fluconazole with other drugs (amphotericin B, itraconazole, or a combination of fluconazole and amphotericin B), 4 compared echinocandins with other drugs (fluconazole, amphotericin B, liposomal amphotericin B), 1 compared micafungin and caspofungin, and 1 compared amphotericin B plus fluconazole and voriconazole. No difference in mortality was observed with fluconazole vs amphotericin B (RR, 0.92; 95% CI, 0.72-1.17); however, the rate of microbiological failure increased in the fluconazole arm (RR, 1.52; 95% CI, 1.12-2.07). Anidulafungin decreased the rate of microbiological failure compared with fluconazole (RR, 0.50; 95% CI, 0.29-0.86) with fewer adverse events. Caspofungin was comparable to amphotericin B in mortality and efficacy, with fewer adverse events requiring discontinuation (RR, 0.11; 95% CI, 0.04-0.36). Micafungin was comparable to liposomal amphotericin B in mortality. All assessed antifungal agents showed similar efficacy, but the rate of microbiological failure increased with fluconazole vs amphotericin B or anidulafungin. Amphotericin B is associated with a higher rate of adverse events than fluconazole and echinocandins.

A randomized controlled trial assessing the efficacy of fluconazole in the treatment of pediatric tinea capitis

Griseofulvin is considered first-line therapy for tinea capitis, and the Physician's Desk Reference currently recommends 11 mg/kg per day microsize formulation for use in children. Diverse selective pressures have resulted in waning clinical efficacy of griseofulvin, such that higher doses and longer courses of treatment are required. These events have prompted the search for therapeutic alternatives. Fluconazole is one such treatment option, and a variety of studies using this drug have shown promise in the treatment of pediatric tinea capitis. We sought to assess the efficacy, safety, and optimal dose and duration of fluconazole therapy compared with standard-dose griseofulvin (11 mg/kg per day microsize formulation) in the treatment of pediatric tinea capitis. This randomized, multicenter, third-party-blind, 3-arm trial was designed as a superiority study to identify a therapeutically superior agent/regimen from the 3 treatment arms: (1) fluconazole 6 mg/kg per day for 3 weeks followed by 3 weeks of placebo, (2) fluconazole 6 mg/kg per day for 6 weeks, and (3) griseofulvin 11 mg/kg per day for 6 weeks. Efficacy variables included mycological, clinical, and combined outcomes. The primary efficacy variable was the combined outcome of the modified intent-to-treat population at week 6. Patient safety was assessed throughout the study. Statistical analysis of the efficacy variables was conducted by means of the Cochran-Mantel-Haenszel test. At the end of treatment, mycological cures were present in 44.5%, 49.6%, and 52.2% of the fluconazole 3-week, fluconazole 6-week, and griseofulvin groups, respectively. Analysis of the primary efficacy variable failed to identify any superior agent, and differences between the combined outcomes of the fluconazole 6-week and griseofulvin groups at week 6 were not significant (P = .32). Regarding mycological, clinical, and combined outcomes, no significant differences between the fluconazole 6-week and griseofulvin groups were detected at any time point in the study. No new safety concerns were raised by this trial, and the incidence of treatment-related adverse events noted in this study is concordant with previous reports. Patients in the fluconazole arms of the study fared similarly. At the end of the trial, the difference in mycological cures between the fluconazole arms was only 7.5%, and increases in the incidence of certain treatment-related adverse events were observed in the fluconazole 6-week group. Adjunctive topical therapies and the impact of infected contacts were not assessed in this trial. Systemic therapy with fluconazole 6 mg/kg per day and standard-dose griseofulvin produces comparable but low mycological and clinical cure rates. The limited efficacy of standard-dose griseofulvin and the lack of consensus regarding dose and duration of griseofulvin therapy in tinea capitis emphasize the need for controlled trials to identify optimal treatment parameters. Although the efficacy of fluconazole is no better than that of standard-dose griseofulvin, it may still be useful in select patients with a contraindication or intolerance to high-dose griseofulvin. The outcomes observed in this trial highlight the need to more clearly define the relative importance of adjunctive topical therapies and the evaluation and treatment of infected contacts as factors affecting cure rates.

A Randomized Study of the Use of Fluconazole in Continuous versus Episodic Therapy in Patients with Advanced HIV Infection and a History of Oropharyngeal Candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40

In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections. We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P=.88, by log-rank test) or before the end of the study (P=.97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P<.0001) and fewer invasive fungal infections (15 vs. 28 episodes; P=.04, by chi2 test), but not with improved survival, compared with episodic fluconazole therapy. Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.

Fluconazole Prophylaxis in HIV Disease, Revisited

Goldman et al. [ 1] approach the question of emerging drug resistance associated with ongoing fluconazole prophylaxis for mucosal candidal infection in HIV disease. After a median of ~2 years of follow-up, the proportion of oropharyngeal and/or esophageal infections that were clinically refractory or resistant to fluconazole was higher among patients receiving continuous fluconazole therapy (9%) than among those receiving episodic fluconazole therapy (2%), but the risk of any infection was 4 times greater in the latter group. As a result, the risk of a clinically refractory or resistant oropharyngeal and/ or esophageal candidal infection was essentially the same in both groups, at slightly more than 4%. The median MICs of fluconazole increased 2-fold in the episodic fluconazole arm and 3-fold in the episodic fluconazole arm, but many of these patients were receiving treatment for several years. These results, coupled with the fact that there is no general risk to microbial ecology from the use of fluconazole, indicate that concern about resistance should not be a factor in the decision to provide prophylaxis. With this new information, and because

Micafungin versus Fluconazole for Prophylaxis against Invasive Fungal Infections during Neutropenia in Patients Undergoing Hematopoietic Stem Cell Transplantation

We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.

A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis

BackgroundCandida esophagitis remains an important cause of morbidity in patients with advanced human immunodeficiency virus (HIV) infection. Fluconazole is widely regarded as the treatment of choice for this condition. MethodsThe efficacy and safety of caspofungin were compared with fluconazole in adult patients with Candida esophagitis in a double-blind randomized trial. Eligible patients had symptoms compatible with esophagitis, endoscopic demonstration of mucosal plaques, and microscopic demonstration of Candida from the esophageal lesions. Patients were randomly assigned to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once daily for 7 to 21 days. The primary endpoint was the combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after discontinuation of treatment. Data were analyzed with a modified intention-to-treat analysis, which excluded 2 ineligible patients. ResultsMost patients (154/177; 87%) had HIV infection, with a median CD4 count of 30 cells/mm3. Candida albicans was the predominant isolate. Favorable response rates were achieved in 66 (81%) of the 81 patients in the caspofungin arm and in 80 (85%) of the 94 patients in the fluconazole arm (difference = −4%; 95% confidence interval: −15% to +8%). Symptoms had resolved in >50% of patients in both groups by the fifth day of treatment. No patient in the caspofungin group developed a serious drug-related adverse event; therapy was only discontinued in 1 patient (receiving fluconazole) due to a drug-related adverse experience. Four weeks after stopping study drug, symptoms had recurred in 18 (28%) of 64 patients given caspofungin and in 12 (17%) of 72 patients given fluconazole (P = 0.19). ConclusionIn this study, caspofungin appeared to be as efficacious and generally as well tolerated as fluconazole in patients with advanced HIV infection and documented Candida esophagitis.

Fluconazole for oropharyngeal candidiasis in anti‐HIV positive haemophiliacs

Candidiasis of the oropharynx and oesophagus is one of the most common problems encountered in patients with HIV disease. Fluconazole is a bis-triazole antifungal agent with a long serum half-life. Sixteen anti-HIV positive patients (15 haemophiliacs and one blood transfusion recipient) with a clinical diagnosis of oropharyngeal candidiasis were treated with 50 mg fluconazole daily for 14-28 days and then either 150 mg fluconazole or placebo weekly for 6 months in a prophylactic phase. Clinical cure occurred in all patients, and mycological cure occurred in 13/16 (81%) patients. In the prophylactic phase, there were 2/5 (40%) relapses in the placebo arm compared with 1/8 (12.5%) in the fluconazole arm, but this was not statistically significant by Fisher's one-sided exact test (P = 0.31). It is concluded that fluconazole is an effective treatment of oropharyngeal candidiasis and has potential for prophylactic use.