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To evaluate the efficacy of itraconazole capsules in prophylaxis for fungal infections in neutropenic patients, we conducted
a prospective, double-blind, placebo-controlled, randomized trial. Patients with hematologic malignancies or those who received
autologous bone marrow transplants were assigned either a regimen of itraconazole (100 mg orally...
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We investigated the effects of anidulafungin alone and in combination with amphotericin B against Aspergillus fumigatus. Indifference was the only type of interaction observed in vitro. Anidulafungin at 1 and 5 mg/kg of body weight/day, amphotericin
B at 1 mg/kg/day, and combination therapy prolonged the survival of mice with invasive aspergillosis...
The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed
to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0
days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5%...
ABSTRACT Endogenous endophthalmitis is a rare, and frequently devastating, ophthalmic disease. It occurs mostly in immunocompromised patients, or those with diabetes mellitus, cancer or intravenous drugs users. Candida infection is the most common cause of endogenous endophthalmitis. Ocular candidiasis develops within days to weeks of fungemia. The...
A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 80...
A 12-year retrospective analysis was done to identify and evaluate in detail cases of invasive pulmonary aspergillosis (IPA)
caused by Aspergillus terreus. We identified 13 A. terreus infections among 133 total cases of confirmed invasive aspergillosis; 11 were IPA and 2 were primary peritoneal infections.
Of the 11 patients with IPA, 7 developed n...
Citations
... Consequently, itraconazole was introduced as a potential prophylactic with some evidence that itraconazole may be a superior antifungal for prophylaxis than fluconazole. 62,63 However, there also was concern regarding its GI side effects. 63 In 2004, Marr published a prospective comparative study between fluconazole and itraconazole, which reiterated the abovementioned aspects, including reduced IFI with itraconazole compared with fluconazole. ...
The advent of bone marrow transplant has opened doors to a different approach and offered a new treatment modality for various hematopoietic stem-cell-related disorders. Since the first bone marrow transplant in 1957, there has been significant progress in managing patients who undergo bone marrow transplants. Plasma-cell disorders, lymphoproliferative disorders, and myelodysplastic syndrome are the most common indications for hematopoietic stem-cell transplant. Despite the advances, invasive fungal infections remain a significant cause of morbidity and mortality in this high-risk population. The overall incidence of invasive fungal infection in patients with hematopoietic stem-cell transplant is around 4%, but the mortality in patients with allogeneic stem-cell transplant is as high as 13% in one study. Type of stem-cell transplant, conditioning regimen, and development of graft- versus-host disease are some of the risk factors that impact the risk and outcomes in patients with invasive fungal infections. Aspergillus and candida remain the two most common organisms causing invasive fungal infections. Molecular diagnostic methods have replaced some traditional methods due to their simplicity of use and rapid turnaround time. Primary prophylaxis has undoubtedly shown to improve outcomes even though breakthrough infection rates remain high. The directed treatment has seen a significant shift from amphotericin B to itraconazole, voriconazole, and echinocandins, which have shown better efficacy and fewer adverse effects. In this comprehensive review, we aim to detail epidemiology, risk factors, diagnosis, and management, including prophylaxis, empiric and directed management of invasive fungal infections in patients with hematopoietic stem-cell transplant.
... Nucci M et al, showed that Itraconazole prophylaxis reduces the frequency of systemic fungal infections and use of empirical amphotericin B in a double-blind, randomised, placebo-controlled study (25). In line with their ndings we had no proven fungal infections and used amphotericin B on no patients during the study period. ...
Background
Sepsis is the main cause of non-relapse mortality and there are no published data on applicability of supportive care protocols from high-income countries in Sri Lanka. The aim of the study was to investigate management and mortality of neutropenic episodes among Haemato-Oncology patients. Methods
We analysed retrospectively clinical characteristics, management, morbidity and mortality of neutropenic adult Haemato-Oncology patients from 01.01.2019 to 31.12.2019. ResultsA total of 169 neutropenic episodes were identified; 115 (68%) of such episodes were related to chemotherapy. Acute leukaemia, Lymphoproliferative disorders and Plasma cell disorders accounted for 23%, 69% and 8% of patients respectively. The median age of patients who had sepsis was 56 while that of those who had no sepsis was 53 (p-value 0.49). Median time to neutropenia was 9 days for those in the sepsis group compared to 8 days in the group that had no sepsis (0.64). Median neutrophil count in the group who had sepsis was 0.06 while it was 0.69 in the group that had no sepsis (p-value 0.000). Median time to commencement of antibiotics was 20 minutes. There were no deaths in the group of chemotherapy induced neutropenic sepsis. Conclusion
This is the only documented study relating to outcome and successful applicability of western supportive care protocols to Sri Lankan patients with neutropenia. In this study we have shown that survival data comparable to developed countries can be achieved in the setting of limited resources with service development, following guidelines and staff training.
... A total of 239 records were captured after initially searching 3 targeted databases. After removing duplicate records, checking the eligibility of the remaining studies, and then adding additional eligible studies, 35 studies [31][32][33][34][35][36][37][38][39][40][41][42][43][44] involving 37 RCTs were included in this network meta-analysis. The reasons for excluding ineligible studies according to the selection criteria are summarized in Fig. 1. ...
... The studies were reported between 1993 and 2019. Of these 35 studies, 16 [1,2,38,40,[43][44][45][46][47][48][49][50] used multiple-center design, 14 [2,13,33,37,38,41,42,44,46,47,49,51] did not report details of follow-up, 1 [45] was a three-arm design, and 2 [49,52] were retrieved from clinicaltrial.gov. The sample size of individual study varied from 25 to 602, with 8513 participants. ...
Background and aim
Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not clear. This study aimed to determine the optimal agent against IFIs for patients with hematological malignancies.
Methods
Randomized controlled trials (RCTs) comparing the effectiveness of triazole, polyene, and echinocandin antifungal agents with each other or placebo for IFIs in patients with hematological malignancies were searched. This Bayesian network meta-analysis was performed for all agents.
Results
The network meta-analyses showed that all triazoles, amphotericin B, and caspofungin, but not micafungin, reduced IFIs. Posaconazole was superior to fluconazole [odds ratio (OR), 0.30; 95% credible interval (CrI), 0.12–0.60], itraconazole (OR, 0.40; 95% CrI, 0.15–0.85), and amphotericin B (OR, 4.97; 95% CrI, 1.73–11.35). It also reduced all-cause mortality compared with fluconazole (OR, 0.35; 95% CrI, 0.08–0.96) and itraconazole (OR, 0.33; 95% CrI, 0.07–0.94), and reduced the risk of adverse events compared with fluconazole (OR, 0.02; 95% CrI, 0.00–0.03), itraconazole (OR, 0.01; 95% CrI, 0.00–0.02), posaconazole (OR, 0.02; 95% CrI, 0.00–0.03), voriconazole (OR, 0.005; 95% CrI, 0.00 to 0.01), amphotericin B (OR, 0.004; 95% CrI, 0.00–0.01), and caspofungin (OR, 0.05; 95% CrI, 0.00–0.42) despite no significant difference in the need for empirical treatment and the proportion of successful treatment.
Conclusions
Posaconazole might be an optimal prophylaxis agent because it reduced IFIs, all-cause mortality, and adverse events, despite no difference in the need for empirical treatment and the proportion of successful treatment.
... These studies have focused on oral candidiasis, aspergillosis, cryptococcosis, and coccidioidomycosis (Table 1). However, not all studies have reported such a correlation (25,26). The relationship between toxicity and ITZ concentrations is less clear. ...
We analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (correlation coefficient 0.7838), and OH-ITZ levels were generally higher than that of ITZ (median OH-ITZ:ITZ ratio 1.73; range 0.13 to 8.96). However, marked variability was observed throughout the range of ITZ concentrations. Thus, it is difficult to predict OH-ITZ concentrations based solely on ITZ levels.
... Many commonly available antifungal agents (AFAs) have demonstrated variable efficacy when used as a prophylactic agent to prevent OC among patients receiving cancer treatment (Bodey, Samonis, & Rolston, 1990;Buchanan et al., 1985;Case lli et al., 1990;Cuttner, Troy, Funaro, Brenden, & Bottone, 1986;Orlandi, Bernasconi, 1994;Egger et al., 1995;Hann et al., 1982;Huijgens et al., 1999;Menichetti et al., 1994aMenichetti et al., , 1999Nucci et al., 2000;Owens et al., 1984;Palmblad et al., 1992;Rozenberg-Arska, Dekker, Branger, & Verhoef, 1991a;Vogler, Malcom, & Winton, 1987;Williams, Whitehouse, Lister, & Wrigley, 1977;Winston, 1993;Yeo, Alvarado, Fainstein, & Bodey, 1985). Previous reviews have demonstrated that AFAs that are fully or partially absorbed from the gastrointestinal tract could be more effective in reducing the risk of OC among patients receiving cancer treatment when compared to agents that are not absorbed from the gastrointestinal tract (Clarkson, Worthington, & Eden, 2007;Worthington & Clarkson, 2002). ...
... Overall, 2,878 articles were identified after exclusion of dupli- were identified and included in the NMA for OC incidence (Bodey et al., 1990;Buchanan et al., 1985;Case lli et al., 1990;Cuttner et al., 1986;Orlandi et al., 1994;Egger et al., 1995;Hann et al., 1982;Huijgens et al., 1999;Menichetti et al., 1994aMenichetti et al., , 1999Nucci et al., 2000;Owens et al., 1984;Palmblad et al., 1992;Rozenberg-Arska et al., 1991a;Vogler et al., 1987;Williams et al., 1977;Winston, 1993;Yeo et al., 1985). These included twelve 2-arm trials (Bodey et al., 1990;Buchanan et al., 1985;Cuttner et al., 1986;Orlandi et al., 1994;Menichetti et al., 1999;Nucci et al., 2000;Owens et al., 1984;Palmblad et al., 1992;Winston, 1993;Yeo et al., 1985), one 3-arm trial (Williams et al., 1977) and one 4-arm trial (Case lli et al., 1990) of individual AFA compared to a placebo (PBO), while the remaining six 2-arm trials involved comparison between different AFAs (Egger et al., 1995;Hann et al., 1982;Huijgens et al., 1999;Menichetti et al., 1994a;Rozenberg-Arska et al., 1991a;Vogler et al., 1987). ...
... Overall, 2,878 articles were identified after exclusion of dupli- were identified and included in the NMA for OC incidence (Bodey et al., 1990;Buchanan et al., 1985;Case lli et al., 1990;Cuttner et al., 1986;Orlandi et al., 1994;Egger et al., 1995;Hann et al., 1982;Huijgens et al., 1999;Menichetti et al., 1994aMenichetti et al., , 1999Nucci et al., 2000;Owens et al., 1984;Palmblad et al., 1992;Rozenberg-Arska et al., 1991a;Vogler et al., 1987;Williams et al., 1977;Winston, 1993;Yeo et al., 1985). These included twelve 2-arm trials (Bodey et al., 1990;Buchanan et al., 1985;Cuttner et al., 1986;Orlandi et al., 1994;Menichetti et al., 1999;Nucci et al., 2000;Owens et al., 1984;Palmblad et al., 1992;Winston, 1993;Yeo et al., 1985), one 3-arm trial (Williams et al., 1977) and one 4-arm trial (Case lli et al., 1990) of individual AFA compared to a placebo (PBO), while the remaining six 2-arm trials involved comparison between different AFAs (Egger et al., 1995;Hann et al., 1982;Huijgens et al., 1999;Menichetti et al., 1994a;Rozenberg-Arska et al., 1991a;Vogler et al., 1987). The duration of prophylactic treatment and clinical or mycological assessment on the incident of outcome for all included trials ranged from 10 days to 10 weeks. ...
Objective
This review examined the comparative efficacy and safety of antifungal agents in preventing oral candidiasis among patients on cancer treatment.
Methods
We performed a systematic review and network meta‐analysis based on randomised controlled trials that compared antifungal agents to placebo or other antifungal agents used in patients undergoing cancer treatment. Relative ranking of antifungal agents was evaluated with surface under the cumulative ranking (SUCRA) probability score. A total of 20 randomised controlled trials (3215 participants) comparing 11 interventions were included.
Results
Compared with placebo, clotrimazole was ranked the best agent for preventing the incidence of oral candidiasis (risk ratio (RR), 0.21 [95% CI 0.08 to 0.55]; SUCRA= 0.89). Fluconazole was ranked the safest among other antifungal agents (SUCRA= 0.80), whereas clotrimazole (SUCRA= 0.36) and amphotericin B (SUCRA= 0.18) were ranked low for safety. Amphotericin B was associated with highest risk of adverse events (RR, 3.52 [95% CI 1.27 to 9.75]).
Conclusion
Clotrimazole is the most effective in preventing oral candidiasis, whereas fluconazole has the most favourable risk‐benefit profile in patients undergoing cancer treatment. However, we are unable to recommend clotrimazole as the best choice to prevent oral candidiasis due to unavailability of studies comparing clotrimazole with other antifungal agents.
... The itraconazole capsule formulation yields poor bioavailability and was not significantly different from the respective comparator drugs in three randomized clinical studies. 9,24,25 All studies using any formulation of amphotericin B were evaluated during the previous ECIL meetings and no change was necessary since our previous recommendations, as there is still no standard dose or frequency. 3 Finally, few properly designed studies with echinocandins have been undertaken in this patient population. ...
The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).
... [8][9][10] When given in capsules, itraconazole is absorbed poorly, and when given as oral suspension it has gastrointestinal side effects. 11 Micafungin and caspofungin can only be administered intravenously, are approved only for prophylaxis of Candida infections, and the effectiveness of prophylaxis in hematological patients has not been consistently reported. [12][13][14][15] Finally, unless there are contraindications to use of azole antifungals, amphotericin is not recommended for use as the primary prophylactic treatment. ...
... A total of 51,648 patients who met study criteria (Table 1). Among these, 58% of AML patients (11,482), 94% of MDS patients (11,382), 33% of HSCT patients (4,736), and 37% of GVHD patients (2,014) did not receive any of the selected antifungal medications during the index hospitalization (Table S3). Posaconazole, alone or in combination with another drug, was received in <10% of patients across the four cohorts. ...
... A total of 51,648 patients who met study criteria (Table 1). Among these, 58% of AML patients (11,482), 94% of MDS patients (11,382), 33% of HSCT patients (4,736), and 37% of GVHD patients (2,014) did not receive any of the selected antifungal medications during the index hospitalization (Table S3). Posaconazole, alone or in combination with another drug, was received in <10% of patients across the four cohorts. ...
Purpose
The objectives of this study were to present trends in posaconazole use over time and describe selected outcomes among patients at high risk of invasive fungal infections (IFIs) by use and type of antifungal medicine.
Methods
A retrospective observational study using data from the Premier Healthcare Database between January 2007 and March 2016 was conducted. Inpatient use of posaconazole by formulation and year is described. Separately, four cohorts of patients at high risk of IFI – those with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), hematopoietic stem-cell transplantation (HSCT), and graft-vs-host disease (GVHD) – but without a diagnosis code for IFI during the index encounter were identified as potential candidates for antifungal prophylaxis. Use of antifungal medication(s) in these patients was categorized. Index length of stay (LOS), index hospital costs, and subsequent inpatient and outpatient encounters with IFI at 30, 60, and 90 days post-index encounter are presented by antifungal group for each cohort. The percentage of patients with inpatient and outpatient encounters with IFI at 90 days post-index encounter was determined for each cohort by year.
Results
Use of posaconazole oral suspension increased through 2012, then declined as the tablet formulation became available in 2013. A total of 19,872 AML patients, 12,125 MDS patients, 14,220 HSCT patients, and 5,431 GVHD patients were considered potential candidates for antifungal prophylaxis; however, a large proportion of patients within each cohort (33%–94%) did not receive any antifungal drug during the index hospitalization. Index LOS, hospital costs, and subsequent encounters for IFI varied among cohorts and by antifungal group. Within each cohort, subsequent encounters for IFI at 90 days post-index encounter fluctuated but remained rare across different years.
Conclusion
Over time and as new posaconazole formulations became available, the frequency of use of each formulation changed. In addition, this study suggested a low rate of potential antifungal prophylaxis in high-risk patients. This is one of the first reports attempting to describe antifungal prophylaxis in a contemporary, large, all-payer, geographically representative hospital database.
... Another study also reported that concentrations were higher in patients who have complete responses and stable disease compared to those who failed therapy when itraconazole was used to treat invasive aspergillosis, although these differences were not statistically significant [17]. In contrast, other studies have not found correlations between itraconazole concentrations and clinical outcomes [19,23]. In terms of a relationship between itraconazole concentrations and adverse effects, Lestner et al. reported that the risk of toxicity was more likely when serum itraconazole levels exceeded 17.1 mg/L [24]. ...
Purpose of Review
Certain antifungals used as therapy for invasive fungal disease, including the extended-spectrum triazoles, may be limited by variable pharmacokinetics and drug interactions. This is especially important when drug exposure, as measured by trough concentrations, may be linked to either efficacy or toxicity. We review the rationale, indications, and controversies in TDM of antifungals.
Recent Findings
The monitoring of voriconazole drug levels is often practiced in patients that receive this triazole based on clinical data. Posaconazole delayed-release tablets achieve higher drug exposure more consistently, necessitating reconsideration of a role for therapeutic drug monitoring. Isavuconazole has predictable population kinetics, although exposure appears to be reduced in certain groups. However, the utility of isavuconazole therapeutic drug monitoring is unknown.
Summary
Therapeutic drug monitoring is warranted for certain antifungals, while its utility is being reconsidered for others.
... In the first, itraconazole was administered as an oral solution, and a significant reduction in IFI incidence with no differences in fungal-free survival was observed. 10 In the second study, 11 itraconazole was initially administered intravenously and then as an oral solution, resulting in fewer proven IFIs and lower fungal-related mortality, but similar overall mortality, compared with fluconazole after allo-HSCT. 9 Mild gastrointestinal side effects were observed in the itraconazole arm of both studies. ...
... 9 Mild gastrointestinal side effects were observed in the itraconazole arm of both studies. 10 The study of the GIMEMA-infection group (Gruppo Italiano Malattie Ematologiche dell'Adulto) comparing itraconazole oral solution with placebo found no advantage to itraconazole on the incidence of invasive aspergillosis but did report a significant reduction in candidemia. 11 The use of itraconazole as prophylaxis is limited by the drug's poor absorption when given in capsules, and by the gastrointestinal side effects when given as oral suspension. ...
... 11 The use of itraconazole as prophylaxis is limited by the drug's poor absorption when given in capsules, and by the gastrointestinal side effects when given as oral suspension. [10][11] The New Triazoles Voriconazole. Voriconazole has been available for clinical use since 2003 and was initially used for the targeted treatment of Aspergillus spp. ...
Invasive fungal infections (IFIs) represent significant complications in patients with hematological malignancies. Chemoprevention of IFIs may be important in this setting, but most antifungal drugs have demonstrated poor efficacy, particularly in the prevention of invasive aspergillosis.
Antifungal prophylaxis in hematological patients is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukemia, myelodysplastic syndromes, and autologous or allogeneic hematopoietic stem cell transplantation. Over the years, various scientific societies have established a series of recommendations for antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each agent must be personalized, adapting its administration to the characteristics of individual patients and taking into account possible interactions with concomitant medication.
... Itraconazole may be effective, but the conclusions of several prospective trials regarding efficacy are limited, because study designs did not include patients at significant risk for aspergillosis [523][524][525][526][527]. Itraconazole oral capsules have erratic bioavailability [528]. ...
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
