Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis

2017 ◽  
Vol 58 (12) ◽  
pp. 2981-2982 ◽  
Author(s):  
Marine Baron ◽  
Jean Marc Zini ◽  
Thibaut Challan Belval ◽  
Marguerite Vignon ◽  
Blandine Denis ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Fungal Infections ◽  
Cryptococcal Meningoencephalitis

scholarly journals Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib

Blood ◽  
2018 ◽  
Vol 131 (17) ◽  
pp. 1955-1959 ◽  
Author(s):  
David Ghez ◽  
Anne Calleja ◽  
Caroline Protin ◽  
Marine Baron ◽  
Marie-Pierre Ledoux ◽  
...  
Keyword(s):  
Risk Factors ◽  
Invasive Aspergillosis ◽  
Early Onset ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Key Points

Key Points Ibrutinib may be associated with invasive fungal infections especially IA. Most infections usually occur during the first months of treatment, often in patients with other risk factors for fungal infections.

scholarly journals Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

2017 ◽  
Vol 9 (3) ◽  
pp. 271-280 ◽  
Author(s):  
Jaleesa M. Garth ◽  
Chad Steele
Keyword(s):  
Invasive Aspergillosis ◽  
Defense Mechanisms ◽  
Fungal Infections ◽  
Immunosuppressive Agents ◽  
Innate Immune ◽  
Pulmonary System ◽  
Continued Use ◽  
Primary Risk Factor ◽  
Primary Agent ◽  
Lung Defense

Invasive aspergillosis (IA) is one of the most difficult to treat and, consequently, one of the most lethal fungal infections known to man. Continued use of immunosuppressive agents during chemotherapy and organ transplantation often leads to the development of neutropenia, the primary risk factor for IA. However, IA is also becoming more appreciated in chronic diseases associated with corticosteroid therapy. The innate immune response to Aspergillus fumigatus, the primary agent in IA, plays a pivotal role in the recognition and elimination of organisms from the pulmonary system. This review highlights recent findings about innate host defense mechanisms, including novel aspects of innate cellular immunity and pathogen recognition, and the inflammatory mediators that control infection with A. fumigatus.

scholarly journals Itraconazole Oral Solution for Primary Prophylaxis of Fungal Infections in Patients with Hematological Malignancy and Profound Neutropenia: a Randomized, Double-Blind, Double-Placebo, Multicenter Trial Comparing Itraconazole and Amphotericin B

2000 ◽  
Vol 44 (7) ◽  
pp. 1887-1893 ◽  
Author(s):  
J. L. Harousseau ◽  
A. W. Dekker ◽  
A. Stamatoullas-Bastard ◽  
A. Fassas ◽  
W. Linkesch ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Hematological Malignancy ◽  
Fungal Infections ◽  
Treated Group ◽  
Multicenter Trial ◽  
Oral Solution ◽  
Double Blind ◽  
Systemic Fungal Infection

ABSTRACT Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 × 109 neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%];P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.

scholarly journals Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Marion Aruanno ◽  
Emmanouil Glampedakis ◽  
Frédéric Lamoth
Keyword(s):  
Invasive Aspergillosis ◽  
Fungal Infections ◽  
Heat Shock Protein 90 ◽  
Hyphal Growth ◽  
Content Type ◽  
Complex Interactions ◽  
Drug Classes ◽  
Paradoxical Growth ◽  
Glucan Synthesis

ABSTRACT Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host’s response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).

Liposomal Amphotericin B (L-AMB) as Initial Therapy for Invasive Filamentous Fungal Infections (IFFI): A Randomized, Prospective Trial of a High Loading Regimen vs. Standard Dosing (AmBiLoad Trial).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3222-3222 ◽  
Author(s):  
Oliver A. Cornely ◽  
Johan Maertens ◽  
Mark Bresnik ◽  
Raoul Herbrecht
Keyword(s):  
Drug Treatment ◽  
Invasive Aspergillosis ◽  
Hematological Malignancies ◽  
Fungal Infections ◽  
Prospective Trial ◽  
Study Drug ◽  
Initial Therapy ◽  
High Loading ◽  
Double Blind Study ◽  
Overall Response

Abstract Background: L-AMB exhibits non-linear pharmacokinetics, with maximal values for Cmax and AUC achieved at a dose of 10 mg/kg/d. Maximal tolerated dose is >15 mg/kg/d. In animal models improved efficacy has been demonstrated with higher doses of L-AMB, but comparative clinical data for efficacy of higher than standard doses of L-AMB are lacking. A randomized, double blind study was performed to compare the efficacy and safety of a high loading dose regimen (HD) to standard dosing (SD) as initial therapy of IFFI. Methods: Patients with proven or probable IFFI by modified EORTC/MSG criteria were randomized to receive L-AMB 3 or 10 mg/kg/d x14d, then 3 mg/kg/d until investigator-defined end of study drug treatment (EOT). Study drug was blinded for the first 14 days of treatment. The primary endpoint was favorable overall response (FOR) assessed at EOT. FOR=complete responses + partial responses. Survival was followed up to 12 wks. An independent Data Review Board (DRB) confirmed all IFFI diagnoses and response assessments. Results: 201 patients with DRB confirmed IFFI diagnoses comprised the MITT population. 107 received SD, 94 HD. Groups were well matched in terms of risk factors. 93% of patients in each group had underlying hematological malignancies. 16% of SD and 19% of HD patients had allogeneic SCT. Neutropenia was present at baseline in 73% of patients overall, and persisted through EOT in 42%. Invasive aspergillosis (IA) accounted for 97% of cases. Median duration of study drug treatment was SD 15d (range 1–60d) and HD 14d (range 1–57d). FOR at EOT was 50% for SD vs. 46% for HD (p= NS). No significant differences in FOR by treatment group were seen for the subsets of IA, allo-SCT, neutropenia subsets, or site of IFFI. Survival at 12 wks was 72% SD vs. 59% HD (p= NS). Nephrotoxicity (serum creatinine ≥ 2x baseline) occurred in 14% SD vs. 31% HD (p<.01). Grade 3 or greater hypokalemia (K+<3.0 mmol/L) developed in 16% SD vs. 30% HD (p<.02), but no difference was found in grade 4 hypokalemia (K+ ≤ 2.5 mmol/L) 3% SD vs. 4% HD (p= NS). Conclusions: In a population of highly immunocompromised patients (93% with underlying hematological malignancies, 73% with neutropenia at study entry), L-AMB as initial treatment of invasive aspergillosis and other filamentous fungal infections at a standard dose of 3 mg/kg/d had an overall favorable response rate of 50% and a 12 wk survival rate of 72%. L-AMB given as a high loading regimen of 10 mg/kg/d x14d did not demonstrate any benefit in overall response or survival, and was associated with higher rates of nephrotoxicity and hypokalemia.

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

Micafungin Versus Fluconazole Or Itraconazole For Prophylaxis Against Invasive Fungal Infections During Neutropenia In Patients Undergoing Haplo-Identical Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4564-4564
Author(s):  
el-Cheikh Jean ◽  
Crocchiolo Roberto ◽  
Fürst Sabine ◽  
Bramanti Stefania ◽  
Sarina Barbara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Invasive Aspergillosis ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Conditioning Regimen ◽  
Invasive Fungal Infections ◽  
Hematopoietic Stem

Objectives Over the past decade, invasive fungal infections (IFI) have remained an important problem in patients undergoing hematopoietic stem cell transplantation (HSCT). The optimal approach for prophylactic antifungal therapy has yet to be determined. Patients and Methods we conducted a retrospective, bi-institutional comparative clinical study, (Institut Paoli-Calmettes at Marseille France and Humanitas cancer center at Rozzano, Italy), and we compared the efficacy and safety of Micafungin 50mg/day (iv) with those of fluconazole (400mg/day) or itraconazole 200mg/day (iv) as prophylaxis for adult patients with various haematological diseases receiving haplo-identical allogeneic stem cell transplantation (haplo-SCT). Patients received prophylaxis with the beginning of the transplant conditioning regimen until the hospital discharge, or until occurrence of an IFI. We compared the incidence of proven or probable IFI (the primary end point) between the micafungin and fluconazole or itraconazole groups; death from any cause and time to death was secondary end points. Patients were followed for 100 days after haplo-SCT and for 30 days after the last dose of the prophylaxis drug administrated. Results From January 2009 to May 2013, a total of 99 patients were identified; 30 patients received micafungin, and 69 patients received fluconazole or itraconazole. 81 patients (82%) received a non myeloabaltive conditioning regimen (NMA), with Fludarabine, Cyclophosphamide and Total body irradiation (TBI) 2 Gy based , or Fludarabine, Busulfan, and Cyclophosphamide based (3%) or other (9%), while five patients (5%) received a thiotepa-based conditioning regimen. The patients and transplant details are shown in the table 1. Proven or probable invasive fungal infections were reported in 2 patients (7%) in the micafungin group and 8 patients (12%) in the fluconazole or itraconazole group (absolute reduction in the micafungin group, −5%; 95% confidence interval, 0.0565-3.1395, P=0.72). Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 5 [7%], P=0.6). A total of 4 (13%) patients in the micafungin group and 23 (33%) patients in the fluconazole or itraconazole group received empirical antifungal therapy (P = 0.14). No serious adverse events related to treatment were reported by patients and there was no treatment discontinuation because of drug related adverse event in both groups. Overall Survival and disease free survival were similar among the two groups (P = 0.97). 6 patients (20%) in the micafungin group died within 100 days, as did 10 patients (14%) in the fluconazole or itraconazole group (P = 0.57). Interestingly the transplant related mortality (TRM) at 100 days was 0% in the micafungin group vs 13% in the second group [CI 95% (0-22)] (p=0,06), whereas the relapse or progression rate at 100 days was 27% vs. 8% respectively [CI 95% (14-44)] (p=0,14). Conclusions In patients undergoing to haplo-SCT, antifungal prophylaxis with micafungin is well tolerated and effective to prevent IFI. Furthermore, the incidence of IFI and invasive aspergillosis seems lower even if this did not attend statistical power, probably due to low number of patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analytical and Clinical Evaluation of the PathoNostics AsperGenius Assay for Detection of Invasive Aspergillosis and Resistance to Azole Antifungal Drugs Directly from Plasma Samples

2017 ◽  
Vol 55 (8) ◽  
pp. 2356-2366 ◽  
Author(s):  
P. Lewis White ◽  
Raquel B. Posso ◽  
Rosemary A. Barnes
Keyword(s):  
Clinical Study ◽  
Invasive Aspergillosis ◽  
Clinical Performance ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
European Organization ◽  
Content Type ◽  
Enhanced Sensitivity ◽  
Resistant Disease ◽  
Single Positive

ABSTRACT With the proposal to include Aspergillus PCR in the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions for fungal disease, commercially manufactured assays may be required to provide standardization and accessibility. The PathoNostics AsperGenius assay represents one such test that has the ability to detect a range of Aspergillus species as well as azole resistance in Aspergillus fumigatus . Its performance has been validated on bronchoalveolar lavage (BAL) fluid and serum specimens, but recent evidence suggests that testing of plasma may have enhanced sensitivity over that with serum. We decided to evaluate the analytical and clinical performances of the PathoNostics AsperGenius assay for testing of plasma. For the analytical evaluations, plasma was spiked with various concentrations of Aspergillus genomic DNA before extraction following international recommendations, using two automated platforms. For the clinical study, 211 samples from 10 proven/probable invasive aspergillosis (IA) and 2 possible IA cases and 27 controls were tested. The limits of detection for testing of DNA extracted using the bioMérieux EasyMag and Qiagen EZ1 extractors were 5 and 10 genomes/0.5-ml sample, respectively. In the clinical study, true positivity was significantly greater than false positivity ( P < 0.0001). The sensitivity and specificity obtained using a single positive result as significant were 80% and 77.8%, respectively. If multiple samples were required to be positive, specificity was increased to 100%, albeit sensitivity was reduced to 50%. The AsperGenius assay provided good clinical performance, but the predicted improvement of testing with plasma was not seen, possibly as a result of target degradation attributed to sample storage. Prospective testing is required to determine the clinical utility of this assay, particularly for the diagnosis of azole-resistant disease.

scholarly journals Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi

2016 ◽  
Vol 60 (9) ◽  
pp. 5483-5491 ◽  
Author(s):  
Amit Desai ◽  
Laura Kovanda ◽  
Donna Kowalski ◽  
Qiaoyang Lu ◽  
Robert Townsend ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Fungal Infections ◽  
Phase 1 ◽  
Water Soluble ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Phase 3 ◽  
Absorption Function ◽  
The Mean

ABSTRACTIsavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated fromin vivoPD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0–24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.

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