Pranatharthi H. Chandrasekar

A Controlled Trial of Fluconazole to Prevent Fungal Infections in Patients Undergoing Bone Marrow Transplantation

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

Treatment of Invasive Aspergillosis with Posaconazole in Patients Who Are Refractory to or Intolerant of Conventional Therapy: An Externally Controlled Trial

BACKGROUND Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Intravenous and Oral Itraconazole versus Intravenous and Oral Fluconazole for Long-Term Antifungal Prophylaxis in Allogeneic Hematopoietic Stem-Cell Transplant Recipients: A Multicenter, Randomized Trial

Context Fungal infections after allogeneic hematopoietic stem-cell transplantation are a serious problem. Current prophylactic regimens are limited by toxicity and the emergence of resistant infections. Contribution This open-label randomized trial of 140 patients undergoing stem-cell transplantation found that prophylaxis with itraconazole for 100 days after transplantation prevented more invasive fungal infections than did prophylaxis with fluconazole (absolute difference, 16 percentage points [95% CI, 29 to 5 percentage points]). More fungal pathogens were resistant to fluconazole. Nausea, vomiting, diarrhea, and abdominal pain were more common in patients receiving itraconazole. Implications Itraconazole is better than fluconazole for preventing invasive fungal infections in allogeneic stem-cell transplant recipients but causes more gastrointestinal side effects. The Editors Fungal infections have become an increasing cause of morbidity and death after allogeneic hematopoietic stem-cell transplantation. Indeed, with better prevention of cytomegalovirus disease, invasive fungal infections are now the leading cause of death from infection at many transplantation centers (1, 2). Consequently, antifungal agents are often used for prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. An amphotericin B formulation or fluconazole has been most commonly used (3-11). Each of these agents, however, has substantial limitations for prophylaxis. The amphotericin B formulations are limited by toxicity, and the lipid preparations of amphotericin B can be expensive. Furthermore, the prophylactic efficacy of standard amphotericin B and the newer lipid formulations of amphotericin has not been consistently demonstrated in randomized, controlled trials (1, 5-11). Routine use of fluconazole for prophylaxis has been associated with the emergence of fluconazole-resistant Candida infections (12-14). Fluconazole also lacks reliable activity against Aspergillus species, which have now become the primary cause of invasive fungal infection at many transplantation centers (15, 16). Itraconazole is an azole antifungal agent that may overcome some of the limitations of fluconazole and the amphotericin B formulations as prophylactic agents in allogeneic hematopoietic stem-cell transplant recipients. Itraconazole has excellent in vitro activity against many opportunistic fungi that are resistant to fluconazole, including Aspergillus and some Candida species (17, 18). Itraconazole is less toxic than the amphotericin B formulations. It is now available in an oral hydroxypropyl--cyclodextrin solution as well as an intravenous formulation. Compared with itraconazole capsules, itraconazole oral solution is much better absorbed and has been used successfully for antifungal prophylaxis in neutropenic patients who had not received an allogeneic hematopoietic stem-cell transplant (19-21). Intravenous itraconazole is the only azole approved for empirical antifungal therapy in febrile neutropenic patients (22). We performed a randomized trial to compare intravenous and oral itraconazole with intravenous and oral fluconazole for prevention of fungal infections in allogeneic hematopoietic stem-cell transplant recipients. Methods Patients Patients of either sex who were 13 years of age or older and undergoing allogeneic hematopoietic stem-cell transplantation were eligible for the study if they had no history of an invasive yeast or mold infection within 8 weeks before initiation of therapy with the study drug. Because of the paucity of efficacy and safety data on the use of intravenous and oral itraconazole in children at the time this study was initiated, patients younger than 13 years of age were excluded. Patients with liver enzyme values greater than five times the upper limit of normal, a bilirubin level greater than 85.5 mol/L (5.0 mg/dL), an allergy to imidazoles or azoles, or a body temperature greater than 38.0 C within 48 hours of starting therapy with the study drug were also excluded. Similarly, patients who had received a previous bone marrow or peripheral stem-cell transplant and patients requiring concomitant therapy with drugs (rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, midazolam, triazolam, cisapride, terfenadine, or astemizole) having potential interactions with azole antifungal agents were not eligible for the study. Women were required to have a negative result on a pregnancy test. Informed consent was obtained from each patient or appropriate relative in a manner approved by the institutional review board at each study center. Study Drugs and Design Eligible patients were randomly assigned to receive prophylaxis with either itraconazole or fluconazole. We used blocked randomization, which was done in a 1:1 ratio and stratified by study center. The randomization process was performed by the pharmacy department at each study site. The study design was open label because blinding of intravenous and oral itraconazole against intravenous and oral fluconazole was technologically impossible at the time the study was conducted. Prophylaxis with each study medication was started on the first day after transplantation. Because a previous trial had shown both a reduction in fungal infections and improved survival when prophylactic fluconazole was used for 75 days after transplantation (4), use of the study drug was continued until day 100 after transplantation. Patients randomly assigned to receive itraconazole were initially given intravenous itraconazole at a loading dose of 200 mg every 12 hours for 2 days, followed by 200 mg every 24 hours for 12 days. Patients were then switched to oral itraconazole solution at a dose of 200 mg every 12 hours until day 100 after transplantation. Similarly, patients randomly assigned to receive fluconazole were initially given intravenous fluconazole at a dose of 400 mg once daily for 14 days and were then switched to oral fluconazole tablets at a dose of 400 mg once daily until day 100 after transplantation. If patients could not take or tolerate oral medications, they resumed prophylaxis with the intravenous form of the study drug. The dose of itraconazole was not adjusted in patients with renal failure. However, if the serum creatinine level increased to greater than 354 mol/L (4.0 mg/dL) during treatment with intravenous itraconazole, patients were changed to itraconazole oral solution because of the prolonged elimination rate of intravenous hydroxypropyl--cyclodextrin with severe renal impairment. The daily dose of fluconazole was decreased by 50% for a creatinine clearance of 0.33 to 0.84 mL/s (20 to 50 mL/min) and by 75% for a creatinine clearance of less than 0.33 mL/s (20 mL/min). After transplantation, prophylaxis with the study drug was discontinued if an invasive fungal infection was documented, a serious adverse event definitely related to the study drug occurred, or the patient died. Patients with a documented superficial fungal infection could be treated with a topical antifungal agent while continuing prophylaxis with the study drug. Use of the study drug was temporarily discontinued when empirical therapy with amphotericin B was administered for suspected but undocumented fungal infection. After the empirical amphotericin B therapy was stopped, prophylaxis with the study drug was resumed. Transplantation Regimen Investigators at each study center were allowed to use the preparative regimens of chemoradiation therapy and the immunosuppressive agents for prophylaxis and treatment of graft-versus-host disease that were considered standard practice at their institutions. Similarly, each study center used its own standard agents to prevent and treat bacterial and viral infections. The criteria used to diagnose and grade graft-versus-host disease have been previously published (23, 24). Laboratory Procedures We obtained complete blood counts with differential leukocyte count and platelet count, blood urea nitrogen levels, serum creatinine and electrolyte determinations, urinalyses, and liver function studies (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels) at study entry, at least once weekly during the study, and within 3 days of completion of prophylaxis with the study drug. Serum cyclosporine levels, measured by using high-pressure liquid chromatography, were also monitored during the study (25). In patients receiving itraconazole, trough plasma levels of itraconazole and its active metabolite, hydroxy-itraconazole, were measured by using high-performance liquid chromatography on days 3 and 7 of the study and then once every 1 or 2 weeks thereafter (26). We obtained cultures of the blood and other suspected sites of fungal infection whenever a patients clinical condition suggested the possibility of infection. Chest radiography, computed tomography, bronchoscopy, and biopsies were also done when clinically indicated to diagnose fungal infection. We determined minimum inhibitory concentrations (MICs) of itraconazole and fluconazole for yeast and filamentous fungi isolated from patients with documented fungal infections to evaluate the possible emergence of resistant organisms. Antifungal susceptibility testing was performed by a central reference laboratory according to guidelines of the National Committee for Clinical Laboratory Standards (27, 28). Definitions of Fungal Infection Superficial fungal infections were diagnosed by the isolation of a fungus from the skin, oropharynx, gastrointestinal tract, or vagina in association with signs of inflammation, ulcerations, plaques, exudates, or other manifestations of infection not explainable by other pathogens. Invasive fungal infections were diagnosed by using criteria published by the National Institutes of Health Mycoses Study Group and the European Organization for Research and Treatment of Cancer (29). The diagnosis of invasive fungal infection

A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients.

We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P<.001) in patients treated with ABCD. Rates of drug-related toxicity in patients receiving ABCD and AmB, respectively, were 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia) and 22% versus 24% (toxicity requiring study drug discontinuation). ABCD appears to have equivalent efficacy and superior renal safety, compared with AmB, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more frequently in patients receiving ABCD than in those receiving AmB.

Infectious complications after kidney transplantation: current epidemiology and associated risk factors

Abstract:  Background:  The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied.

Detection of Circulating Candida Enolase by Immunoassay in Patients with Cancer and Invasive Candidiasis

BACKGROUND Invasive candidiasis is a major nosocomial infection that is difficult to diagnose. Few biochemically defined markers of invasive candidiasis are known. Initial findings suggested that the presence of candida enolase in the blood may be a novel marker for invasive candidiasis. METHODS We tested 170 patients at high risk for invasive candidiasis for candida enolase antigenemia. All the patients had cancer and neutropenia. We detected antigen using a double-sandwich liposomal immunoassay for candida enolase in serially collected serum samples. Invasive candidiasis was proved by finding candida species in deep nonmucosal tissue, blood cultures, or both. Antigen testing was performed with the investigator blinded to tissue or culture diagnosis. RESULTS Among 24 patients with proved invasive candidiasis, 149 serum samples were tested for enolase antigenemia; 80 were positive and 69 negative (sensitivity per sample, 54 percent). Multiple sampling improved the detection of antigenemia, which was found in 11 of 13 proved cases of deep tissue infection (85 percent) and in 7 of 11 proved cases of fungemia (64 percent). Specificity was 96 percent as measured against control groups including patients with mucosal colonization, bacteremia, and other deep mycoses. Antigenemia was detected in the absence of fungemia in 5 cases of deep tissue candidiasis, but was not detected in 6 cases of fungemia alone. CONCLUSIONS Candida enolase antigenemia is a novel marker for invasive candidiasis. It may be a useful indicator of deep infection in patients with cancer and neutropenia and may complement the diagnostic usefulness of blood cultures.

Micafungin: A New Echinocandin

Micafungin, a potent inhibitor of 1,3-beta-D-glucan synthase, has become the second available agent in the echinocandins class that is approved for use in clinical practice. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans species of Candida, and Aspergillus species, as well as several but not all pathogenic molds. If anything, its in vitro activity appears to be superior to that of caspofungin, although the clinical relevance of this observation is unclear. The clinical role of micafungin appears to be similar to that of caspofungin, although clinical data are still lacking at this stage, with initial approval only for treatment of esophageal candidiasis and prophylaxis in subjects with neutropenia. Pharmacokinetic and pharmacodynamic studies and reports of adverse effects and safety have reported similar but not identical results to those of other agents in the echinocandin class. Factors such as acquisition costs and the potential for resistance development may be more relevant to its widespread use than in vitro and in vivo data comparisons with caspofungin.

Pharmacokinetics of Oral Posaconazole in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Graft-versus-Host Disease

Study Objective. To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft‐versus‐host disease (GVHD).

Aspergillus flavus: an emerging non-fumigatus Aspergillus species of significance.

Invasive aspergillosis is rare in immunocompetent people but contributes to significant morbidity and mortality in immunosuppressed patients. The majority (approximately 80%) of invasive Aspergillus infections is caused by Aspergillus fumigatus. The second most frequent (approximately 15–20%) pathogenic species is Aspergillus flavus and to a lesser extent, Aspergillus niger and Aspergillus terreus. Aspergillus flavus has emerged as a predominant pathogen in patients with fungal sinusitis and fungal keratitis in several institutions worldwide. To date, there has not been any publication exclusively reviewing the topic of A. flavus in the literature. This article reviews the microbiology, toxigenicity and epidemiology of A. flavus as well as describes the clinical characteristics, diagnosis and management of infections caused by this organism.

Disseminated toxoplasmosis in marrow recipients : a report of three cases and a review of the literature

Toxoplasma infection following bone marrow transplantation (BMT) is infrequently reported. We report three cases of disseminated toxoplasmosis in BMT recipients documented during an 8-year period at our institution: one after an unrelated marrow transplant in a toxoplasma-seronegative patient, the second complicating syngeneic marrow transplantation, and the third following allogeneic, related BMT. The disease is extremely rare in seronegative patients and has not been previously reported in syngeneic recipients. Toxoplasmosis was diagnosed at autopsy in two of the three cases. We also present a review of all reported cases of toxoplasmosis in marrow recipients from North American and other BMT centers. Heightened awareness of the occurrence of toxoplasmosis in marrow recipients and early diagnostic/therapeutic measures are needed for a better outcome.