ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients



## Ecil-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients introduction
The European Conference on Infections in Leukemia (ECIL) is the result of a collaboration between the European Organization for Research and Treatment of Cancer (EORTC), the European Society for Blood and Marrow Transplantation (EBMT), the European Leukemia Net (ELN), and the International Immunocompromised Host Society (ICSH). First recommendations for the treatment of Candida and Aspergillus infections in hematologic patients were published in 2007 after the first conference (ECIL-1) and have then been updated at ECIL-2 and ECIL-3. 1,2 First recommendations for the diagnosis and treatment of mucormycosis have been published after ECIL-3. [bib_ref] Diagnosis and treatment of mucormycosis in patients with hematological malignancies, Skiada [/bib_ref] ECIL-4 updates for antifungal therapy were only available as slides on the websites of these participating societies without publication of a manuscript in consideration of the lack of substantial new data and the limited modifications compared to the latest publication.
With respect to the targeted treatment of fungal infections, the goals for ECIL-5 were to update the recommendations with analysis of the new data for invasive candidiasis, aspergillosis and mucormycosis in hematologic patients. The update was also necessary to change the prior 5-level grading (A to E) used during the ECILs 1 to 4 for the strength of recommendations for Candida and Aspergillus infections into the 3-level grading (A to C) already used during ECIL-3 for the first recommendation for mucormycosis [fig_ref] Table 1: Evolution over time of the grading system used for treatment of invasive... [/fig_ref]. [bib_ref] Treatment of invasive Candida and invasive Aspergillus infections in adult haematological patients, Herbrecht [/bib_ref] [bib_ref] European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant..., Maertens [/bib_ref] [bib_ref] Diagnosis and treatment of mucormycosis in patients with hematological malignancies, Skiada [/bib_ref] The grading for quality of evidence has not been modified.

# Methods
The ECIL-5 meeting was held in September 2013 and involved 57 experts from 21 countries, including 3 non-European countries. Slides of the conclusions of the ECIL-5 were made available on the websites of the EORTC, EBMT, ELN, and ICHS. The ECIL-6 meeting was held in September 2015 with the presence of 55 experts from 24 countries, including 4 non-European countries (see list of collaborators at the end of this Review).
At both the ECIL-5 and the ECIL-6 meetings, the antifungal therapy working group made a search for new publications regarding treatment of invasive candidiasis, aspergillosis and mucormycosis. The group was divided into three subgroups, each being responsible for one of each fungal infection type. The literature search was performed in Pubmed and Cochrane databases. Abstracts presented at major congresses during the previous two years were also retrieved and integrated into the ECIL recommendation. All recommendations referring to an abstract, however, were classified as provisional until the publication of the final manuscript.
The working group presented its recommendations during the plenary session at the ECIL-5 meeting and then incorporated the suggestions coming from the assembly. In cases in which full consensus was not obtained, the decision was put to the vote, and the final decision was based on a majority of votes from the full ECIL-5 assembly. The updated recommendations were presented on the next day during a second plenary session for final approval. Recommendations were graded on the basis of the strength of recommendations (3-level scale: A, B, or C) and quality of evidence (3-level scale: I, II, or III), as detailed in [fig_ref] Table 1: Evolution over time of the grading system used for treatment of invasive... [/fig_ref].
The manuscript of the ECIL-5 was put on hold after a debate arose on differences between ECIL and European Society for Clinical Microbiology and Infectious Diseases (ESCMID) / European Confederation of Medical Mycology (ECMM) recommendations on guidelines for prophylaxis and treatment of invasive aspergillosis (draft presented at the ECCMID 2014).Two joint meetings were subsequently held (December 2014 and April 2015) to identify the differences and the exact reasons for these differences. The aim was not to modify the recommendations made by each of the two groups but rather to add explanations on the differences in the manuscript. For further clarification, a joint presentation was given at the ECIL-6 by members of the ECIL group and of the ESCMID/ECMM group. This resulted in a delay in publication of the ECIL-5 recommendations and during the ECIL-6 plenary session, the ECIL assembly approved a new search for publications or abstracts until September 2015 with inclusion of all relevant data on aspergillosis, candidiasis and mucormycosis for a full update of the guidelines. Final approval by the majority of the members of the group was obtained in Autumn 2015. The current manuscript includes updates from both the ECIL-5 and the ECIL-6 and is called "ECIL-6 guidelines for the treatment of inva-sive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients".

## Invasive candidiasis
Like previous ECIL recommendations, the current guidelines for invasive candidiasis cover the hematologic population as well as the general population of patients. Although hematologic patients are the main focus of the recommendation, this distinction is maintained because available data from the original randomized controlled trials mainly include non-neutropenic patients. Chronic infections are not considered. Twenty-two major publications were identified [fig_ref] Table 2: Trials for first-line therapy of invasive candidiasis [/fig_ref]. Fifteen reported primary results from clinical trials. [bib_ref] A randomized trial comparing fluconazole with amphotericin B for the treatment of..., Rex [/bib_ref] [bib_ref] Evaluation in a multicenter, prospective, observational study, Nguyen [/bib_ref] [bib_ref] Management of invasive candidal infections: results of a prospective, randomized, multicenter study..., Anaissie [/bib_ref] [bib_ref] Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched..., Anaissie [/bib_ref] [bib_ref] Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia..., Phillips [/bib_ref] [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] [bib_ref] A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus..., Rex [/bib_ref] [bib_ref] Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia..., Kullberg [/bib_ref] [bib_ref] International, open-label, noncomparative, clinical trial of micafungin alone and in combination for..., Ostrosky-Zeichner [/bib_ref] [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] [bib_ref] Micafungin versus caspofungin for treatment of candidemia and other forms of invasive..., Pappas [/bib_ref] [bib_ref] Anidulafungin versus fluconazole for invasive candidiasis, Reboli [/bib_ref] [bib_ref] Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy..., Queiroz-Telles [/bib_ref] [bib_ref] A Multicenter, double-blind trial of a highdose caspofungin treatment regimen versus a..., Betts [/bib_ref] One publication analyzed results of a subgroup of cancer patients from a previously published trial. [bib_ref] Invasive candidiasis in cancer patients: observations from a randomized clinical trial, Dinubile [/bib_ref] One publication reported the analysis of pooled data from 2 trials previously published with a focus on patients with an underlying malignancy. [bib_ref] Efficacy and safety of micafungin for treatment of serious Candida infections in..., Cornely [/bib_ref] All these studies were published before the ECIL-4. Since then, 5 studies have been identified, including one patientlevel quantitative review of 7 published trials on invasive candidiasis, one pooled patient-level data analysis from 5 prospective trials on anidulafungin, one systematic review of 17 randomized clinical trials focusing on invasive candidiasis in neutropenic patients, one prospective non-comparative trial evaluating a strategy of early oral switch from anidulafungin for invasive candidiasis, and one observational study comparing the initial use of echinocandin-based versus azole-based regimen for C. parapsilosis candidemia. [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] [bib_ref] Treatment of invasive candidiasis in neutropenic patients: systematic review of randomized controlled..., Kanji [/bib_ref] [bib_ref] Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole..., Vazquez [/bib_ref] [bib_ref] Efficacy of anidulafungin in the treatment of invasive candidiasis in neutropenic patients:..., Herbrecht [/bib_ref] [bib_ref] Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis..., Fernandez-Ruiz [/bib_ref] These publications were the reasons for the change in guidelines. Characteristics of these studies and main results are shown in [fig_ref] Table 2: Trials for first-line therapy of invasive candidiasis [/fig_ref].
The number of neutropenic patients included in each of these studies was low and limited the level of evidence of the recommendation for this group of patients. The review published by showed that, in the univariate analysis, neutropenia was one of the factors significantly and negatively associated both with clinical outcome and with survival. [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] In the multivariate analysis, however, the effect of neutropenia disappeared, but there was a significant association of immunosuppressive therapy (including steroids) with lower survival. Other factors significantly associated with lower survival were the APACHE score, infection by C. . [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] The strength of recommendation is the same (A) for anidulafungin, caspofungin and micafungin and is also the same for the overall and the hematologic population. However, the quality of evidence is lower for hematologic patients (II) compared to the overall population, as the number of neutropenic patients recruited in the clinical trials was low. A recent communication on a patient-level pooled analysis of one randomized clinical trial and 4 open label studies focusing on anidulafungin in 46 neutropenic patients with candidemia showed comparable response and survival rates to those observed with caspofungin and micafungin in other studies. [bib_ref] Efficacy of anidulafungin in the treatment of invasive candidiasis in neutropenic patients:..., Herbrecht [/bib_ref] Therefore, the grading is now similar (A II) for all three echinocandins F. Tissot et al.
for the treatment of invasive candidiasis in hematologic patients.
Liposomal amphotericin B has also been graded A I for the overall population and A II for hematologic patients due to similar efficacy in comparison to micafungin. [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] [bib_ref] Efficacy and safety of micafungin for treatment of serious Candida infections in..., Cornely [/bib_ref] However, its safety profile is less favorable and therefore liposomal amphotericin B should be considered as an alternative in case of contraindication to echinocandins. Fluconazole and voriconazole are potential alternatives for first-line treatment in the overall population provided there is no previous exposure to azoles and the infection is not severe (fluconazole).
After species identification, susceptibility testing should guide the treatment. In general, echinocandins remain the drug of choice, except for C. parapsilosis where fluconazole is more appropriate [fig_ref] Table 5: ECIL-6 recommendations for first-line treatment of candidemia after species identification [/fig_ref]. However, a recent observational study reported no difference in 30-day mortality and persistent candidemia at 72 hours of an echinocandinbased regimen compared to an azole-based therapy for patients with C. parapsilosis candidemia. [bib_ref] Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis..., Fernandez-Ruiz [/bib_ref] Therefore, the continuing use of echinocandins might be considered in patients with a clinical and microbiological response. When Candida species is azole-susceptible, step-down to fluconazole can be considered in stable patients after five days of intravenous (iv) therapy. [bib_ref] Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole..., Vazquez [/bib_ref] In patients with Candida krusei infection, switch to oral voriconazole is an option.
Although the role of catheter removal in the management of candidemia has long been controversial, most recent studies suggest a beneficial effect on outcome. [bib_ref] Evaluation in a multicenter, prospective, observational study, Nguyen [/bib_ref] [bib_ref] Management of invasive candidal infections: results of a prospective, randomized, multicenter study..., Anaissie [/bib_ref] [bib_ref] Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched..., Anaissie [/bib_ref] [bib_ref] Comparison of caspofungin and amphotericin B for invasive candidiasis, Mora-Duarte [/bib_ref] [bib_ref] A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus..., Rex [/bib_ref] [bib_ref] Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase..., Kuse [/bib_ref] [bib_ref] Micafungin versus caspofungin for treatment of candidemia and other forms of invasive..., Pappas [/bib_ref] [bib_ref] A Multicenter, double-blind trial of a highdose caspofungin treatment regimen versus a..., Betts [/bib_ref] [bib_ref] Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis..., Fernandez-Ruiz [/bib_ref] [bib_ref] Epidemiology and management of candidaemia--a retrospective, multicentre study in five hospitals in..., Chalmers [/bib_ref] [bib_ref] Factors related to survival and treatment success in invasive candidiasis or candidemia:..., Horn [/bib_ref] [bib_ref] Should vascular catheters be removed from all patients with candidemia? An evidence-based..., Nucci [/bib_ref] [bib_ref] Impact of early central venous catheter removal on outcome in patients with..., Rodriguez [/bib_ref] [bib_ref] Factors prompting early central venous catheter removal from cancer patients with candidaemia, Velasco [/bib_ref] [bib_ref] Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and..., Rex [/bib_ref] [bib_ref] Management of central venous catheters in patients with cancer and candidemia, Raad [/bib_ref] Garnacho-Montero et al. showed in a large number of candidemia that early adequate therapy and removal of central venous line were independently associated with lower mortality. [bib_ref] Impact on hospital mortality of catheter removal and adequate antifungal therapy in..., Garnacho-Montero [/bib_ref] The patient-level quantitative analysis by Andes et al. also demonstrated in a multivariate analysis that removal of catheter was associated with a decreased mortality (OR 0.50; 95%CI: 0.35-0.72; P=0.0001). [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] The recommendation is, therefore, to rapidly remove the catheter in the overall population (grade A II) as well as in hematologic patients (grade B II) irrespective of the Candida species. If central venous catheter cannot be removed, treatment should include an echinocandin or a lipid formulation of amphotericin B due to their better activity on Candida biofilms. [bib_ref] Activities of systemically administered echinocandins against in vivo mature Candida albicans biofilms..., Kucharikova [/bib_ref] [bib_ref] Liposomal amphotericin B eradicates Candida albicans biofilm in a continuous catheter flow..., Seidler [/bib_ref] [bib_ref] Evaluation of caspofungin and amphotericin B deoxycholate against Candida albicans biofilms in..., Shuford [/bib_ref] Invasive Aspergillus infections Nine prospective trials (only 4 being randomized comparative trials) had been published before the ECIL-4 and provided the basis of the previous guidelines for first-line therapy in invasive aspergillosis [fig_ref] Table 6: Trials for first-line therapy of invasive aspergillosis [/fig_ref]. [bib_ref] An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages..., Ellis [/bib_ref] [bib_ref] Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary..., Caillot [/bib_ref] [bib_ref] A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin..., Bowden [/bib_ref] [bib_ref] Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis, Herbrecht [/bib_ref] [bib_ref] Caspofungin as first line therapy of pulmonary invasive fungal infections in 32..., Candoni [/bib_ref] [bib_ref] Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized..., Cornely [/bib_ref] [bib_ref] An EORTC Phase II study of caspofungin as first-line therapy of invasive..., Viscoli [/bib_ref] [bib_ref] Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant..., Herbrecht [/bib_ref] [bib_ref] Phase II dose escalation study of caspofungin for invasive Aspergillosis, Cornely [/bib_ref] An additional paper reported a post-hoc analysis of the trial comparing standard dose of liposomal amphotericin B to high-dose liposomal amphotericin B. [bib_ref] Efficacy outcomes in a randomised trial of liposomal amphotericin B based on..., Cornely [/bib_ref] This post-hoc analysis comparing outcome in possible versus mycologically documented aspergillosis underscored the limited number of mycologically documented infections but did not lead to any change in the grading for liposomal amphotericin B. A second post-hoc analysis was performed on the voriconazole versus amphotericin B deoxycholate trial. [bib_ref] Application of the 2008 Definitions for Invasive Fungal Diseases to the Trial..., Herbrecht [/bib_ref] Integration of the results of baseline galactomannan detection tests performed after primary analysis and re-categorization according to the 2008 EORTC/MSG definition criteria allowed more mycologically documented cases of invasive aspergillosis to be identified. [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] Conclusions of this post-hoc analysis were similar to those of the primary analysis and therefore its results did not affect the grading for voriconazole and for amphotericin B deoxycholate.
At the time of the ECIL-5, results from the comparative study of voriconazole plus anidulafungin versus voricona-ECIL-6 guidelines: fungal infections in leukemia and HSCT patients

## Strength of recommendations grade ecil-1 to 4 ecil-5 and 6
A Strong evidence for efficacy and substantial clinical benefit: Good evidence to support a recommendation for use strongly recommended B
Strong or moderate evidence for efficacy, Moderate evidence to support a recommendation for use but only limited clinical benefit: generally recommended C Insufficient evidence for efficacy; or efficacy Poor evidence to support a recommendation for use does not outweigh possible adverse consequences (e.g. drug toxicity or interactions) or cost of chemoprophylaxis or alternative approaches: optional D Moderate evidence against efficacy or for adverse outcome: Omitted generally not recommended E Strong evidence against efficacy or for adverse outcome: Omitted never recommended The results have been discussed with a provisional grading that could be transformed in a definite grading, as no additional data available in the full paper suggested a need for change in provisional recommendations. [bib_ref] Combination antifungal therapy for invasive aspergillosis: a randomized trial, Marr [/bib_ref] This study failed to reach the primary endpoint of decreased all-cause mortality at week 6 (difference of -8.2% in favor of combination; P=0.087). However, in a subgroup of patients with an invasive aspergillosis documented by positive galactomannan in either serum or bronchoalveolar lavage, 6-week all-cause mortality was lower in patients receiving combination therapy (difference of -11.6% in favor of combination; P=0.037). A large majority of the ECIL members felt that this subgroup analysis, that had not been originally planned, was not sufficient to give a stronger recommendation although this subgroup included 80% of the modified intent-to-treat population. Therefore, the combination of voriconazole plus anidulafungin was graded C I for primary therapy of invasive aspergillosis while all other combinations were graded C III in the absence of well-designed studies for first-line therapy. [fig_ref] Table 6: Trials for first-line therapy of invasive aspergillosis [/fig_ref] summarizes the main characteristics and results of the various studies. Importantly, very few studies had a large number of patients with a mycological documentation. [bib_ref] A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin..., Bowden [/bib_ref] [bib_ref] Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis, Herbrecht [/bib_ref] [bib_ref] Combination antifungal therapy for invasive aspergillosis: a randomized trial, Marr [/bib_ref] As shown by the 2 post-hoc analyses, survival was substantially lower in mycologically-documented infections compared to possible cases. [bib_ref] Efficacy outcomes in a randomised trial of liposomal amphotericin B based on..., Cornely [/bib_ref] [bib_ref] Application of the 2008 Definitions for Invasive Fungal Diseases to the Trial..., Herbrecht [/bib_ref] Therefore, studies with a limited number of documented cases cannot lead to the strongest recommendations. As no study specifically addressed management of breakthrough aspergillosis after failure of posaconazole or voriconazole prophylaxis, no recommendation could be made on this issue.

## Quality of evidence
The clinical trial comparing the new triazole isavuconazole versus voriconazole for primary therapy of invasive aspergillosis could not be discussed during the ECIL-5 as results were only presented as an abstract in 2014. However, the group could review the data from these abstracts during the ECIL-6 meeting. Isavuconazole appears to be as effective as voriconazole for the treatment of invasive aspergillosis and has a better safety profile. Therefore, a grade A I similar to the grading for voriconazole has been given to isavuconazole [fig_ref] Table 7: ECIL-6 recommendations for first-line treatment of invasive aspergillosis [/fig_ref]. As the full paper was published shortly after the meeting, and confirms the results, the provisional grading attributed during the meeting has been transformed into a definite grading in this manuscript. [bib_ref] Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by..., Maertens [/bib_ref] Currently, amphotericin B deoxycholate is considered to have no role in the treatment of invasive aspergillosis when more effective and less toxic agents are available. Its limited efficacy and its poor safety profile led to a recommendation against its use. No substantial change has been made for second-line therapy in the absence of new data [fig_ref] Table 8: ECIL-6 recommendations for salvage therapy of invasive aspergillosis [/fig_ref].

## Mucormycosis
Diagnostic and therapeutic strategies were discussed during the ECIL-5 and the ECIL-6. Rhizopus, Mucor, Lichtheimia (previously classified as Absidia), Cunninghamella, Rhizomucor, Apophysomyces, and Saksenaea are the genera most frequently involved in human disease. [bib_ref] Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygomycosis) and nomenclature of the..., Kj [/bib_ref] Cunninghamella species is more virulent in experimental models and may be associated with a higher mortality rate in patients. [bib_ref] Increased virulence of Cunninghamella bertholletiae in experimental pulmonary mucormycosis: correlation with circulating..., Petraitis [/bib_ref] So far, there has not been enough evidence that identification of mucormycosis to the genus and/or species level helps guide antifungal treatment. [bib_ref] Correlation between in vitro activity of posaconazole and in vivo efficacy against..., Rodriguez [/bib_ref] [bib_ref] In vitro and in vivo activities of posaconazole and amphotericin B in..., Salas [/bib_ref] Species identification remains, nevertheless, important for outbreak investigations. [bib_ref] Healthcare-associated mucormycosis, Rammaert [/bib_ref] However, the differentiation between mucormycosis and other invasive mold infection is of critical importance as it has major therapeutic implications.
While epidemiological aspects and some clinical (sinus disease, concomitant diabetes, occurrence under voriconazole therapy) and radiological (reverse halo sign on chest CT-scan) factors may help to suspect mucormycosis, the diagnosis remains difficult and biopsy of the lesion is often required. Identification of the pathogen most often comes from microscopic, culture and/or histopathological examination of relevant samples. New diagnostic approaches include molecular testing on serum and various other clinical samples including formalin-fixed tissues, MALDI-TOF and Mucorales-specific T-cell detection. [bib_ref] Development of a single tube multiplex realtime PCR to detect the most..., Bernal-Martinez [/bib_ref] [bib_ref] Efficacy of DNA amplification in tissue biopsy samples to improve the detection..., Buitrago [/bib_ref] [bib_ref] Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in..., Millon [/bib_ref] [bib_ref] Utility of PCR in diagnosis of invasive fungal infections: real-life data from..., Lass-Florl [/bib_ref] [bib_ref] DNA barcoding in Mucorales: an inventory of biodiversity, Walther [/bib_ref] [bib_ref] Species identification of Aspergillus, Fusarium and Mucorales with direct surface analysis by..., De Carolis [/bib_ref] [bib_ref] Direct analysis and identification of pathogenic Lichtheimia species by matrix-assisted laser desorption..., Schrodl [/bib_ref] [bib_ref] Mucorales-specific T cells emerge in the course of invasive mucormycosis and may..., Potenza [/bib_ref] Although these new approaches are very promising for an earlier diagnosis, no grading for their use can be given yet due to the lack of data.
Amphotericin B, posaconazole and isavuconazole are the most potent agents in vitro. [bib_ref] In vitro antifungal activity of isavuconazole against 345 mucorales isolates collected at..., Verweij [/bib_ref] [bib_ref] Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales, Vitale [/bib_ref] [bib_ref] In vitro antifungal susceptibility of filamentous fungi causing rare infections: synergy testing..., Drogari-Apiranthitou [/bib_ref] Currently, no validated minimum inhibitory concentration breakpoints for any of the drugs are available and thus determination of susceptibility categories is not possible for the agents of mucormycosis. The ECIL-3 recommendations for the treatment of mucormycosis were mostly based on retrospective studies, registry data and small prospective non-controlled studies. [bib_ref] Diagnosis and treatment of mucormycosis in patients with hematological malignancies, Skiada [/bib_ref] [bib_ref] Posaconazole as salvage therapy for zygomycosis, Greenberg [/bib_ref] [bib_ref] Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion, Herbrecht [/bib_ref] [bib_ref] The safety and efficacy of amphotericin B colloidal dispersion in the treatment..., Oppenheim [/bib_ref] [bib_ref] Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis, Reed [/bib_ref] [bib_ref] Epidemiology and outcome of zygomycosis: a review of 929 reported cases, Roden [/bib_ref] [bib_ref] Fortyone recent cases of invasive zygomycosis from a global clinical registry, Ruping [/bib_ref] [bib_ref] The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled..., Spellberg [/bib_ref] [bib_ref] Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of..., Van Burik [/bib_ref] [bib_ref] Mucormycosis after allogeneic haematopoietic stem cell transplantation: a French Multicentre Cohort Study, Xhaard [/bib_ref] [bib_ref] Survival factors in rhino-orbital-cerebral mucormycosis, Yohai [/bib_ref] Few new data are available for the treatment of mucormycosis since the ECIL 4 and, therefore, the current recommendations are very similar [fig_ref] Table 9: ECIL-6 recommendations for first-line therapy of mucormycosis [/fig_ref]. Numbers of patients refer to the modified intent to treat population when available or to the intent to treat population; for this reason and due to some inconsistencies numbers may be different in primary manuscript and in pooled analysis. b Neutropenia defined by less than 1000/mL; c neutropenia defined by less than 500/mL; d number of episodes. pts: patients; IS: immunosuppressive (including steroids therapy); iv: intravenous; ABLC: amphotericin B lipid complex; d-AmB: deoxycholate amphotericin B; L-AmB: liposomal amphotericin B; RCT: randomized controlled trial. A prospective non-comparative trial assessed the efficacy and safety of first-line therapy with high-dose liposomal amphotericin B given at 10 mg/kg/day combined with surgery when appropriate. [bib_ref] Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for..., Lanternier [/bib_ref] This trial demonstrated efficacy of high-dose liposomal amphotericin B plus surgery in mucormycosis with a survival rate of 62% at week 12. The only factor associated with mortality was the presence of hematologic malignancy or cancer (HR: 3.15; 95%CI: 1.12-8.91; P=0.02). Renal impairment of any degree was observed in 40% of the patients but was transient in most of them. These results confirm the beneficial role of liposomal amphotericin B but do not yet allow any recommendation for the administration of such a high dose of 10 mg/kg/day.

## Ecil-6 guidelines: fungal infections in leukemia and hsct patients
A short paper presented data from a retrospective analysis of a combination of posaconazole and a lipid formulation of amphotericin B. [bib_ref] Combined antifungal approach for the treatment of invasive mucormycosis in patients with..., Pagano [/bib_ref] tericin B (n=27) or amphotericin B lipid complex (n=5). Only 3 of them were treated with this combination in first line. Overall response rate was 56% but a large proportion of patients (59%) died before day 90. The low number of patients, the retrospective nature of the study, and the high mortality rate at day 90 only allowed for a B III recommendation for this combination for salvage therapy of mucormycosis [fig_ref] Table 1: Evolution over time of the grading system used for treatment of invasive... [/fig_ref].

# Discussion and conclusions
An update of the ECIL antifungal treatment recommendations was needed as there were important new data, and also because of necessary changes in the ECIL grading system so as to be in harmony with other ECIL recommendations. The most important data for invasive candidiasis came from a large review of patients included in 7 F. Tissot et al. haematologica | 2017; 102(3) [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] ; c favorable response rate includes only complete and partial responses; d two-month survival rates; d intent to treat population; e time point not specified (median follow up 10 months); f includes also other mold infections (4 and 2 in 3 mg/kg and 10 mg/kg arm, respectively); g after exclusion of the 6 other mold infections; h includes also a few non-Aspergillus invasive mold diseases (5 in isavuconazole arm and major trials. [bib_ref] Impact of treatment strategy on outcomes in patients with candidemia and other..., Andes [/bib_ref] The multivariate analysis now allows a very strong recommendation in favor of an echinocandin for the first-line therapy of candidemia irrespective of the underlying predisposing factors. The controversy on the beneficial role of catheter removal can now be considered to be resolved. The most interesting new data were the publication of a first-line combination study in invasive aspergillosis and the results of a randomized comparative trial comparing isavuconazole to voriconazole. Aspergillus guidelines now include the results of these 2 clinical trials and should help clinicians in their treatment decision making. Since few new data have been published since the last ECIL guidelines, no major changes were made to mucormycosis management. Importantly, the posology and indication of antifungal agents reported in the current guidelines do not necessarily reflect those licensed by the European Medicines Agency (EMA), but are the result of a consensus-based analysis of available literature within the ECIL group.
There has been controversy about some discrepancies between the ECIL-5 and the ESCMID recommendations for invasive aspergillosis in hematologic patients. These differences were identified during a joint meeting and an ESCMID representative was invited to discuss them at the ECIL-6 meeting. Most differences were minor and mostly reflected a difference in grading system. The ECIL Aspergillus recommendations are restricted to hematologic patients who represent more than 90% of the patients included in the major clinical trials. [bib_ref] Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis, Herbrecht [/bib_ref] [bib_ref] Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized..., Cornely [/bib_ref] [bib_ref] Combination antifungal therapy for invasive aspergillosis: a randomized trial, Marr [/bib_ref] [bib_ref] Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by..., Maertens [/bib_ref] No subgroup of hematologic patients deserving specific recommendation for Aspergillus infection treatment has been identified by the ECIL group. In contrast, the ESCMID group had a broader approach considering all other conditions predisposing to invasive aspergillosis, grading the diagnostic procedures, and including environmental measures in the prevention, also providing a grade for specific infection sites. In addition, the ESCMID group also segregated the hematologic patients into subgroups and provided specific grading for each of them, with usually weaker recommendations when there was not a sufficient number of patients with these specific underlying conditions included in the clinical studies. Finally, and importantly, some data were not available at the time of the ECIL-5 meeting but were in the public domain when the ESCMID group met. In September 2015, the ECIL-6 group was able to incorporate the new data, and this has helped to reduce the apparent differences with the ESCMID guidelines. Therefore, neither the ECIL group nor the ESCMID group felt any change other than this update was required.
Collaborators Monitoring of serum levels is indicated. In the absence of sufficient data for first-line monotherapy, anidulafungin, micafungin and posaconazole have not been graded. ECIL-6 guidelines: fungal infections in leukemia and HSCT patients
[table] Table 1: Evolution over time of the grading system used for treatment of invasive Candida and Aspergillus infections. [/table]
[table] Table 2: Trials for first-line therapy of invasive candidiasis: critical inclusion and exclusion criteria, treatment and relevant characteristics of the patients. AmB (0.6-0.7 mg/kg) DiNubile, 2005 12 Invasive candidiasis in cancer pts; subgroup analysis Caspofungin (70 on day 1 then 50 mg) on factors associated with improved outcome in C. albicans infections Queiroz-Telles, RCT; candidemia or deep-seated infections; [/table]
[table] Table 3: Trials for first-line therapy of invasive candidiasis: outcomes [/table]
[table] Table 5: ECIL-6 recommendations for first-line treatment of candidemia after species identification. NA: not available; MITT: modified intention-to-treat; d-AmB: deoxycholate amphotericin B; L-AmB: liposomal amphotericin B; pts: patients. [/table]
[table] Table 6: Trials for first-line therapy of invasive aspergillosis: main characteristics and outcome.Numbers of patients refer to the modified intent to treat population when available or to the intent to treat population; b includes positive microscopy or culture from relevant sites, positive histopathology, or positive galactomannan in serum, BAL or CSF as defined by EORTC/MSG 2008 criteria [/table]
[table] Table 7: ECIL-6 recommendations for first-line treatment of invasive aspergillosis. [/table]
[table] Table 8: ECIL-6 recommendations for salvage therapy of invasive aspergillosis. Monitoring of serum levels is indicated, especially if posaconazole oral suspension is used. F. Tissot et al. [/table]
[table] Table 9: ECIL-6 recommendations for first-line therapy of mucormycosis. mg/kg. Liposomal amphotericin B should be preferred in CNS infection and/or renal failure Amphotericin B lipid complex B II Amphotericin B colloidal dispersion C II Posaconazole C III No data to support its use as first-line treatment. Alternative when amphotericin B formulations are absolutely contraindicated. CNS: central nervous system. [/table]