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Invasive pulmonary aspergillosis and mucormycosis are life-threatening complications in immunocompromised patients. A rapid diagnosis followed by early antifungal treatment is essential for patient survival. Given the limited spectrum of biomarkers for invasive mold infections, recent studies have proposed the use of radiolabeled siderophores or antibodies as molecular probes to increase the specificity of radiological findings by nuclear imaging modalities. While holding enormous diagnostic potential, most of the currently available molecular probes are tailored to the detection of Aspergillus species, and their cost-intensive and sophisticated implementation restricts their accessibility at less specialized centers. In order to develop cost-efficient and broadly applicable tracers for pulmonary mold infections, this study established streamlined and high-yielding protocols to radiolabel amphotericin B (AMB) with the gamma emitter technetium-99m ( 99m Tc-AMB) and the positron emitter gallium-68 ( 68 Ga-AMB). The radiochemical purity of the resulting tracers consistently exceeded 99%, and both probes displayed excellent stability in human serum (>98% after 60 to 240 min at 37°C). The uptake kinetics by representative mold pathogens were assessed in an in vitro Transwell assay using infected endothelial cell layers. Both tracers accumulated intensively and specifically in Transwell inserts infected with Aspergillus fumigatus , Rhizopus arrhizus , and other clinically relevant mold pathogens compared with their accumulation in uninfected inserts and inserts infected with bacterial controls. Inoculum-dependent enrichment was confirmed by gamma counting and autoradiographic imaging. Taken together, this pilot in vitro study proposes 99m Tc-AMB and 68 Ga-AMB to be facile, stable, and specific probes, meriting further preclinical in vivo evaluation of radiolabeled amphotericin B for molecular imaging in invasive mycoses., (Copyright © 2020 American Society for Microbiology.)

As antifungal agents are frequently used in hematology and oncology, economic data on the empirical therapy of suspected systemic fungal infection are pivotal. Data were analyzed according to: (1) the rate of nephrotoxicity related to treatment with caspofungin in comparison to liposomal amphotericin B (L-AmB) from a randomized clinical trial, (2) the effect of nephrotoxicity on length of hospital stay from a European observational study, and (3) an example of total bottom-up cost in a department of hematology in Germany. All estimates include 95% confidence intervals (CI) using two-stage Monte Carlo simulation on binominal and Gaussian random variables from separate studies with comparable populations. Overall, 8.9 (95% CI 5.9-12.1) fewer patients (of 100 randomized) experienced worsening of renal function with caspofungin vs L-AmB, giving a number needed to treat for one patient to be harmed by L-AmB of 12 (95% CI 8-17). This was estimated to translate into 5.3 extra days in hospital (95% CI 1.6-9.1) per event or 0.48 days (95% CI 0.14-0.88) worth 298 euro (95% CI 89-554) per patient receiving L-AmB rather than caspofungin. From the hospital perspective, use of caspofungin was estimated to be cost-neutral compared to L-AmB at a per diem total hospital cost of 428 euro with, and 1284 euro without, consideration of supplementary reimbursement (Zusatzentgelt) of both L-AmB and caspofungin. The data presented in this scenario show that use of caspofungin in hematology-oncology departments in Germany results in shorter hospital stays and is at least cost-neutral compared to use of L-AmB.

Amphotericin B, a broad spectrum antifungal agent, is widely used despite significant adverse events including nephrotoxicity. Nephrotoxicity occurs frequently in patients receiving amphotericin B. Different definitions for nephrotoxicity are reviewed in the context of outcome in patients with invasive fungal diseases. In most publications, mortality was higher in patients experiencing nephrotoxicity and mean hospital length of stay was prolonged. As a consequence, the use of less nephrotoxic antifungal agents could improve treatment outcomes.

Objectives: Invasive pulmonary aspergillosis is associated with high mortality. To assess new antifungal therapy options, animal models have to be developed to assess, in an appropriate setting, the activity of new drugs., Methods: Male albino CD rats (125-150 g) were fed with a protein-free diet and received dexamethasone thrice weekly subcutaneously during the whole experiment. After 2 weeks, an inoculum of 10(6) conidia of Aspergillus fumigatus (H11-20) was injected intratracheally. Antifungal treatment was initiated and continued for a total of 7 days. Animals were grouped in numbers of 10. One group of animals served as untreated control, whereas the others were treated with amphotericin B intraperitoneally (2 and 4 mg/kg) and posaconazole via gavage (2, 4, 10 and 20 mg/kg). Survival and log(10) cfu/g of the lungs were the endpoints. The strain H11-20 was tested for susceptibility in vitro to amphotericin B and posaconazole, respectively. Fungal burden of the lungs was expressed as log(10) cfu/g. Survival analysis was performed by the Kaplan-Meier method. Differences in fungal burden were assessed by the Mann-Whitney test., Results: All untreated animals died within a week. Amphotericin B and posaconazole at 2 mg/kg demonstrated survival benefits over control (P = 0.01 and P = 0.04). Dosages of 4 mg/kg were superior to 2 mg/kg for amphotericin B (P = 0.02) and posaconazole (P < 0.05), respectively. No further survival benefits were demonstrated beyond dosages of 10 mg/kg. Rats treated with 20 mg/kg posaconazole, however, had a lower fungal burden than all the other treatment groups (P = 0.0002)., Conclusions: Posaconazole and amphotericin B are effective in a dosage-dependent manner in this pulmonary aspergillosis model in immunocompromised rats.

Background: Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking., Methods: In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated., Results: Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P>.05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P>.05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group., Conclusions: In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.

Background: Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis., Methods: We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288., Findings: 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B., Interpretation: Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Background: Amphotericin B is a widely used broad-spectrum antifungal agent, despite being associated with significant adverse events, including nephrotoxicity., Methods: The present prospective study collected data on outcomes for 418 adult patients treated consecutively with polyenes in hematology and oncology wards in 20 hospitals in Europe., Results: Patients initially received amphotericin B deoxycholate (62% of patients), liposomal amphotericin B (27%), or other lipid formulations of amphotericin B (11%). Of the patients initially treated with amphotericin B deoxycholate, 36% had therapy switched to lipid formulations of amphotericin B, primarily because of increased serum creatinine levels (in 45.7% of patients) or other amphotericin B-attributable adverse events (in 41.3% of patients). Nephrotoxicity, which was defined as a > or = 50% increase in the serum creatinine level, developed in 57% of patients with normal kidney function at baseline. Predictors of nephrotoxicity included formulation type and duration of treatment. Compared with patients without nephrotoxicity, patients with nephrotoxicity had a higher mortality rate (24%), and their mean length of stay in the hospital was prolonged by 8.6 days. Slight increases in the serum creatinine level (i.e., > or = 50%) were associated with a significantly longer stay in the hospital. Severe nephrotoxicity (i.e., a > or = 200% increase in the serum creatinine level) was a significant predictor of death, as were severe underlying medical conditions and documented fungal infection., Conclusion: This prospective study confirmed that, in European hospitals, amphotericin B formulations have a major influence on the length of stay in the hospital and nephrotoxicity-associated mortality.

Objective: To assess the costs and cost-effectiveness of voriconazole in comparison to conventional amphotericin B (CAB) for the treatment of invasive aspergillosis in Germany., Methods: The cost-effectiveness of voriconazole in comparison to CAB was evaluated with a lifetime Markov model, focusing on the long-term survival of patients treated for invasive aspergillosis. Long-term survival was extrapolated from survival after 12 weeks of treatment, obtained from a randomized aspergillosis study. Information on medical resource consumption and treatment pathways were obtained from this study and an expert committee. With probabilistic analysis the cost-effectiveness of voriconazole compared with amphotericin B was analyzed and expressed in incremental costs per life-weeks gained. The evaluation was performed from a limited societal perspective (both inpatient and outpatient costs) and hospital perspective (only inpatient costs)., Results: Average survival of patients treated with voriconazole was 174.4 life-weeks (95% confidence interval [CI] 159.4-191.3), compared with 119.4 life-weeks (95% CI 106.4-132.3) for amphotericin B. With voriconazole, the mean total costs per patient were 30,026 euros (95% CI 23 euros ,118-37,947) compared with 26,669 euros for amphotericin B (95% CI 21,259-34,263 euros ) from the limited societal perspective. The corresponding incremental cost-effectiveness ratio was 62 euros per life-week gained (i.e., 3224 euros per life-year gained). Hospital costs were approximately 90% of the mean total costs., Conclusions: In the treatment of invasive aspergillosis, voriconazole is cost-effective in comparison to amphotericin B. Hospital costs are comparable for both treatments and are expected to be reimbursed based on the German diagnosis-related groups (DRG) system 2005.

Flow cytometric quantification of CD154+ mould specific T-cells in antigen-stimulated peripheral blood mononuclear cells (PBMCs) or whole blood has been described as a supportive biomarker to diagnose invasive mould infections and to monitor therapeutic outcomes. As patients at risk frequently receive immunosuppressive and antifungal medication, this study compared the matrix-dependent impact of representative drugs on CD154+ T-cell detection rates. PBMCs and whole blood samples from healthy adults were pre-treated with therapeutic concentrations of liposomal amphotericin B, voriconazole, posaconazole, cyclosporine A (CsA) or prednisolone. Samples were then stimulated with an Aspergillus fumigatus lysate or a viral antigen cocktail (CPI) and assessed for CD154+ T-helper cell frequencies. Specific T-cell detection rates and technical assay properties remained largely unaffected by exposure of both matrices to the studied antifungals. By contrast, CsA and prednisolone pre-treatment of isolated PBMCs and whole blood adversely impacted specific T-cell detection rates and caused elevated inter-replicate variation. Unexpectedly, the whole blood-based protocol that uses additional α-CD49d co-stimulation was less susceptible to CsA and prednisolone despite prolonged drug exposure in the test tube. Accordingly, addition of α-CD49d during PBMC stimulation partially attenuated the impact of immunosuppressive drugs on test performance. Translating these results into the clinical setting, false-negative results of CD154+ antigen-specific T-cell quantification need to be considered in patients receiving T-cell-active immunosuppressive medication. Optimized co-stimulation regimes with α-CD49d could contribute to an improved feasibility of functional T-cell assays in immunocompromised patient populations. [ABSTRACT FROM AUTHOR]

Neutrophils are essential in the first line defense against moulds. This in vitro study assessed different neutrophil effector mechanisms in the presence of clinically relevant antifungal and immunosuppressive agents. Therapeutic concentrations of liposomal amphotericin B led to reduced IL-8 and oxidative burst response to the synthetic stimulus PMA, whereas no major alterations of oxidative burst, phagocytosis, or cytokine response to germinated stages of Aspergillus fumigatus and no supra-additive effects of antifungal and immunosuppressive drugs were observed. Conventional and liposomal amphotericin B as well as voriconazole, however, led to reduced neutrophil extracellular trap formation in response to A. fumigatus germ tubes. [ABSTRACT FROM AUTHOR]

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption. [ABSTRACT FROM AUTHOR]

In 2001, caspofungin received market authorisation by the FDA and EMA and is globally licensed for several indications, including candidiasis, empirical antifungal therapy in patients with neutropenic fever of unknown origin and treatment of invasive aspergillosis in patients refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or itraconazole. Despite the lack of phase III data in first-line treatment of invasive aspergillosis, increasing evidence supports the use of first-line therapy. Here, we analyse the evidence of therapeutic activity, represented by favourable response rates, of caspofungin for invasive aspergillosis. A systematic literature search was conducted to identify international presentations and papers reporting monotherapy with caspofungin. Efficacy data are summarised separately for first-line and salvage therapy. Thirty-one papers and published abstracts reported caspofungin therapy for aspergillosis. Fifteen full papers and two abstracts fulfilled the criteria of reporting significant outcome data for caspofungin monotherapy for invasive aspergillosis. Consistent with other analyses and the known safety profile, few adverse events and associated terminations of caspofungin medication have been reported. Although a randomised, comparative, prospective study using caspofungin in this indication is still lacking, growing evidence supports the efficacy of this echinocandin not only for salvage but also for first-line therapy. [ABSTRACT FROM AUTHOR]

The incidence of invasive candidiasis caused by non- albicans Candida ( NAC) spp. is increasing. The aim of this analysis was to evaluate the efficacy of micafungin, caspofungin and liposomal amphotericin B in patients with invasive candidiasis and candidaemia caused by different Candida spp. This post hoc analysis used data obtained from two randomised phase III trials was conducted to evaluate the efficacy and safety of micafungin vs. caspofungin and micafungin vs. liposomal amphotericin B. Treatment success, clinical response, mycological response and mortality were evaluated in patients infected with C. albicans and NAC spp. Treatment success rates in patients with either C. albicans or NAC infections were similar. Outcomes were similar for micafungin, caspofungin and liposomal amphotericin B. Candida albicans was the most prevalent pathogen recovered (41.0%), followed by C. tropicalis (17.9%) , C. parapsilosis (14.4%), C. glabrata (10.4%), multiple Candida spp. (7.3%) and C. krusei (3.2%). Age, primary diagnosis (i.e. candidaemia or invasive candidiasis), previous corticosteroid therapy and Acute Physiology and Chronic Health Evaluation II score were identified as potential predictors of treatment success and mortality. Micafungin, caspofungin and liposomal amphotericin B exhibit favourable treatment response rates that are comparable for patients infected with different Candida spp. [ABSTRACT FROM AUTHOR]

Summary Managing fungal diseases remains a major challenge for clinicians despite the improved armamentarium of antifungal agents. This review identified 19 publications reporting safety data on micafungin. Two of these publications were spin off publications, the remaining 17 (15 prospective, two retrospective) were included in the main assessment. Major adverse events reported which occurred in more than 2% in the study populations were infusion-related, gastro-intestinal and hepatic (LFT parameters elevations). Micafungin demonstrated significantly less renal events compared with liposomal amphotericin B and less hepatic events compared with voriconazole. Compared with fluconazole no significant treatment-related adverse events were found except one trial reporting significantly less somnolence but more chills. Micafungin has a similar favourable safety profile in comparison with other echinocandins or fluconazole. [ABSTRACT FROM AUTHOR]

Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection. [ABSTRACT FROM AUTHOR]

Background: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA).Methods: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel.Results: Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA.Conclusions: Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups. [ABSTRACT FROM AUTHOR]