Standards of CARE: what is considered 'best practice' for the management of invasive fungal infections? A haematologist's and a mycologist's perspective.

Patients at risk of, or diagnosed with, an invasive fungal infection benefit from an early antifungal intervention. Different strategies have been explored, each with particular strengths and weaknesses. The use of broad-spectrum antifungal prophylaxis seems logical, but selective use is important given its potential for major collateral damage, including interference with diagnostic assays, selection of resistance, toxicity and drug interactions. Hence, anti-mould prophylaxis should be restricted to well-defined high-risk groups. An empirical approach is still widely applied but incurs the clinical and cost penalties associated with overtreatment. Nowadays there is a growing interest in delaying antifungal treatment until an invasive fungal infection is highly suspected ('pre-emptive' management) or confirmed, prompted by the development of more-sensitive diagnostic techniques. While pre-emptive treatment looks appealing, the necessary monitoring and detailed treatment algorithms can be rather complex and often require a multidisciplinary effort. This article aims to bring together different perspectives on 'best practice' for the management of invasive fungal infections, using haematology patients as a model.

Clinical considerations in the early treatment of invasive mould infections and disease.

Different therapeutic strategies for invasive fungal diseases have been explored, each with particular strengths and weaknesses. Broad-spectrum antifungal prophylaxis seems logical, but selective use is important due to its substantial disadvantages, including interference with diagnostic assays, selection for resistance, drug toxicity and drug-drug interactions. Antimould prophylaxis should be restricted to high-risk groups, such as patients undergoing intensive chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome, allogeneic HSCT patients with prior invasive fungal infection, graft-versus-host-disease or extended neutropenia, recipients of a solid organ transplant, or patients with a high-risk inherited immunodeficiency. An empirical approach, whereby mould-active therapy is started in neutropenic patients with fever unresponsive to broad-spectrum antibiotics, is widely applied but incurs the clinical and cost penalties associated with overtreatment. A benefit for all-cause mortality using empirical therapy has not been shown, but it is recommended for high-risk patients who remain febrile after 4-7 days of broad-spectrum antibiotics and in whom extended neutropenia is anticipated. There is growing interest in delaying antifungal treatment until an invasive fungal infection is confirmed ('pre-emptive' or 'diagnostics-driven' management), prompted by the development of more sensitive diagnostic techniques. Comparisons of empirical versus pre-emptive regimens are sparse, particularly with modern triazole agents, but treatment costs are lower with pre-emptive therapy and the available evidence has not indicated reduced efficacy. Pre-emptive treatment may be appropriate in neutropenic patients who remain febrile after administration of broad-spectrum antibiotics but who are clinically stable. Further work is required to define accurately the specific patient subgroups in which each management approach is optimal.

Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease.

OBJECTIVES: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. METHODS: Patients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin). RESULTS: Mean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). CONCLUSIONS: Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk. TRIAL REGISTRY AND NUMBER: ClinicalTrials.gov, NCT01075984.

Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial.

BACKGROUND: Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. FINDINGS: Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. The most common grade 3 or 4 treatment-emergent adverse events were stomatitis (grade 3, 52 [29%] of 181 patients in the defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome). INTERPRETATION: Defibrotide did not show a benefit in the prophylaxis of sinusoidal obstruction syndrome. Additional studies of carefully selected patients at high risk of sinusoidal obstruction syndrome after HSCT are warranted. FUNDING: Jazz Pharmaceuticals.

Treatment and timing in invasive mould disease.

Invasive mould disease is a growing threat for immunocompromised patients. The optimum time to use mould-active antifungal agents is much debated. Current approaches to antifungal prophylaxis, early treatment (empirical and pre-emptive therapy) and treatment of documented mould infections in onco-haematology patients are discussed.

Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.

PURPOSE: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA. METHODS: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population). RESULTS: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment. CONCLUSION: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.

Posaconazole in prophylaxis and treatment of invasive fungal infections: a pharmacokinetic, pharmacodynamic and clinical evaluation.

INTRODUCTION: Invasive fungal infections (IFIs) are associated with a high morbidity and mortality and their incidence is rising. Posaconazole is a triazole antifungal drug that has an important place in the prophylaxis and salvage treatment of these infections. AREAS COVERED: This review focuses on the efficacy, safety, pharmacokinetics, pharmacodynamics, and drug-drug interactions of posaconazole. Literature search was conducted in PubMed. EXPERT OPINION: Posaconazole has a broad antifungal spectrum for both yeasts and molds, with a manageable safety profile. Its efficacy for IFIs is shown in both prophylaxis and salvage treatment. This drug is available as a suspension, tablet, and solution for intravenous administration. The suspension is associated with an erratic absorption, but this is (largely) overcome with the new formulations. Posaconazole is a CYP3A4 inhibitor and substrate for UGT1A4 and P-gp so drug-drug interactions can occur. The exposure in certain subgroups needs to be studied further and the place of routine therapeutic drug monitoring is still to be established.

The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Moulds: diagnosis and treatment.

Changes in fungal epidemiology and the emergence of resistance have increased the complexity of the management of patients with invasive fungal infections, as timely diagnosis and initiation of adequate antifungal therapy are key factors for improving outcomes. Therefore, alternative approaches to the empirical use of antifungal agents, which incorporate non-culture-based microbiological tools and high-resolution computed tomography of the chest, are under increasing investigation.

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.

BACKGROUND: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS: In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). INTERPRETATION: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients.

BACKGROUND: Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS: The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS: Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS: A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.