Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease.

ABSTRACT: Over the past 10 years, there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady-state blood production, affecting both hematopoietic stem and progenitor cells as well as differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis. Furthermore, the state of the microbiome is now recognized to affect outcomes from hematopoietic stem cell transplant, immunotherapy, and cellular therapies for hematologic malignancies. Here we review the mechanisms by which microbiotas influence hematopoiesis in development and adulthood as well as the avenues by which microbiotas are thought to impact stem cell transplant engraftment, graft-versus-host disease, and efficacy of cell and immunotherapies. We highlight areas of future research that may lead to reduced adverse effects of antibiotic use and improved outcomes for patients with hematologic conditions.

Interplay Between the Intestinal Microbiota and Acute Graft-Versus-Host Disease: Experimental Evidence and Clinical Significance.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for many hematological disorders and autoimmune diseases, but acute graft-versus-host disease (aGVHD) has remained a major obstacle that limits allo-HSCT and exhibits a daunting mortality rate. The gastrointestinal system is among the most common sites affected by aGVHD. Experimental advances in the field of intestinal microbiota research enhanced our understanding - not only of the quantity and diversity of intestinal microbiota - but also their association with homeostasis of the immune system and disease pathogenesis, including that of aGVHD. Meanwhile, ever-growing clinical evidence suggest that the intestinal microbiota is dysregulated in patients who develop aGVHD and that the imbalance may affect clinical outcomes, indicating a potential predictive role for microbiota dysregulation in aGVHD severity and prognosis. The current animal and human studies investigating the intestinal microbiota in aGVHD and the understanding of the influence and management of the microbiota in the clinic are reviewed herein. Taken together, monitoring and remodeling the intestinal microecology following allo-HSCT may provide us with promising avenues for diagnosing, preventing or treating aGVHD in the clinic.

Clinical characteristics and drug susceptibility patterns of Corynebacterium species in bacteremic patients with hematological disorders.

The aim of this study was to clarify the clinical and microbiological characteristics of Corynebacterium bacteremia in hematological patients. We retrospectively reviewed the medical records of patients with Corynebacterium bacteremia from April 2013 to June 2018. The causative Corynebacterium species were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Drug susceptibility tests were performed using the broth microdilution method recommended by the Clinical and Laboratory Standards Institute. In total, 147 cases of Corynebacterium bacteremia were identified during the study period. Corynebacterium striatum was the most frequent pathogen. Catheter-related bloodstream infection was diagnosed in 19.7% of all patients, and moderate/severe oral or severe gastrointestinal mucosal impairment was detected in 19.7%. Polymicrobial infection was found in about 20% of cases, with Enterococcus faecium being the most frequent isolate. The overall 30-day mortality was 34.7% (51/147). Multivariate analysis showed that E. faecium co-infection (odds ratio (OR) 9.3; 95% confidence interval (CI) 2.1-40), systemic corticosteroids (OR 3.6; 95% CI 1.4-8.9), other immunosuppressive drugs (OR 0.32; 95% CI 0.13-0.76), and a Pitt bacteremia score ≥4 (OR 12; 95% CI 3.9-40) were significant risk factors for overall 30-day mortality. The drug susceptibility rates for beta-lactam antimicrobial agents were quite low. All isolates were susceptible to glycopeptides and linezolid. However, some C. striatum isolates were resistant to daptomycin. Corynebacterium bacteremia can occur in the presence of several types of mucosal impairment. Our drug susceptibility data indicate that Corynebacterium bacteremia in hematological patients could be treated by glycopeptides or linezolid.

Epidemiology of invasive fungal disease in haematologic patients.

Invasive fungal disease (IFD) is frequent in patients with haematologic malignancies and in recipients of haematopoietic cell transplantation (HCT). An epidemiologic study conducted in Brazil reported a high incidence of IFD in haematologic patients, and invasive fusariosis was the leading IFD. A limitation of that study was that galactomannan was not available for at least half of the study period. In order to characterise the epidemiology and burden of IFD in three cohorts, HCT, acute myeloid leukaemia (AML) or myelodysplasia (MDS), and acute lymphoid leukaemia (ALL), we conducted a prospective multicentre cohort study in four haematologic Brazilian centres. From August 2015 to July 2016, all patients receiving induction chemotherapy for newly diagnosed or relapsed AML, MDS or ALL, and all HCT recipients receiving conditioning regimen were followed during the period of neutropenia following chemotherapy or the conditioning regimen. During a 1-year period, 192 patients were enrolled: 122 HCT recipients (71 allogeneic, 51 autologous), 46 with AML, and 24 with ALL. The global incidence of IFD was 13.0% (25 cases, 11 proven and 14 probable). Invasive aspergillosis (14 cases) was the leading IFD, followed by candidemia (6 cases) and fusariosis (3 cases). The incidence of IFD was 26.1% in AML/MDS, 16.7% in ALL, 11.3% in allogeneic HCT, and 2.0% in autologous HCT. The burden of IFD in haematologic patients in Brazil is high, with a higher frequency in AML and ALL. Invasive aspergillosis is the leading IFD, followed by invasive candidiasis and fusariosis.

[The Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers (the 6th revision)].

The Chinese Invasive Fungal Infection Working Group published the first edition of guidelines for the diagnosis and treatment of IFD in patients with hematological disorders and cancers in 2005, and has been revised several editions thereafter. Recently, new treatments such as targeted therapy have emerged in the field of hematological cancers. These advances are modifying the definition of high-risk IFD, the epidemiology of IFD, and the strategies in IFD diagnosis and treatment. Meanwhile, diagnostic methods of IFD were evaluated in a lot of clinical studies. Therefore, the Chinese Working Group of Invasive Fungal Infections issued the latest Chinese guideline, based on Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORTC-IDG) and the American Mycoses Study Group (MSG) standards, the Infectious Diseases Society of America (IDSA) guidelines and the European Conference on Infections in Leukemia (ECIL) guidelines. The IFD is still classified as Proven, Probable, Possible and Undefined; the management strategies include prophylaxis, empirical antifungal therapy, diagnostic-driven antifungal therapy and targeted anti-fungal therapy. The major revisions include the epidemiology of IFD, in vitro susceptibility tests of anti-fungal drugs, and therapeutic drug concentration monitoring.

[The impact of carbapenem-resistance Pseudomonas aeruginosa infections on mortality of patients with hematological disorders].

Objective: To assess the risk factors for mortality and clinical outcome of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections in patients with hematological disorders. Methods: The data of in-patients with hematological disorders infected by CRPA or carbapenem-susceptible Pseudomonas aeruginosa (CSPA) were recorded in a seven-year retrospective cohort study. Risk factors for CRPA infections and impact of on mortality were identified. The primary end point was 30-day all-cause mortality. Results: A total of 81 patients with PA infections were included in the study, including 58 CSPA and 23 CRPA. Most of the primary diseases were acute leukemia or lymphoma (79.0%, 64/81). The median absolute neutrophil count at infection onset was 0.24×10(9)/L. Independent risk factors associated with carbapenem-resistance included longer duration of hospital stay (P=0.013, OR=1.045) and carbapenem exposure one month prior to infections (P=0.005, OR=8.132). The 30-day all-cause mortality of the whole cohort was 29.6%(24/81), and 30-day attributable mortality was 13.6%(11/81). Pulmonary infection was the leading cause of death, accounting for 41.7%(10/24). The adjusted 30-day mortality rate was significantly higher in patients with CRPA compared with CSPA [60.9%(14/23) vs. 17.2%(10/58), P<0.001, respectively]. CRPA infection was an independent prognostic factor for 30-day mortality(P=0.011, OR=5.427). Other factors included old age, longer duration of neutropenia and poor functional performance. Conclusions: Patients with hematological disorders have high mortality rate and poor prognosis caused by CRPA infections, which mainly develop in lungs.

The clinical impact of Stenotrophomonas maltophilia bacteremia on the 30-day mortality rate in patients with hematologic disorders: a single-institution experience.

OBJECTIVE: Stenotrophomonas maltophilia (SM) is an important nosocomial pathogen, particularly in immunocompromised patients due to their adverse antimicrobial susceptibility pattern. The objective of this article was to investigate the clinical impact of SM bacteremia on the 30-day mortality rate and identify the risk factors of the cause of mortality in patients with hematologic disorders. METHODS: We retrospectively reviewed the clinical data in patients diagnosed with hematological disorders and SM bacteremia over an 8-year period from July 2010 to July 2018 at a 248-bed hematology department. We compared patients' clinical characteristics and outcomes between the non-survivor and survivor groups. RESULTS: The overall incidence of SM bacteremia was 25.1 per 10,000 admissions. There were 59 patients (median age: 35 years; 57.6% males) included in the study with an overall SM bacteremia-related 30-day mortality of 44.1%. Multi-drug resistance was common. In vitro susceptibility is higher to ceftazidime (72.9%), ciprofloxacin (66.1%) and cefoperazone/sulbactam (59.3%). The risk factors identified in the univariate analysis were catheter re-implantation, accompanying polymicrobial infection, inadequate initial antimicrobial treatment, APACHE II score, temperature > 39 °C, septic shock, respiratory failure, and non-remission post treatment for primary diseases. Multivariate analysis further confirmed that inadequate initial antimicrobial treatment, respiratory failure, and non-remission after treatment for hematological diseases are independent risk factors associated with mortality (P = 0.001, 0.002 and 0.007, respectively). CONCLUSIONS: Our study suggests that SM bacteremia is highly associated with increased mortality in patients with hematologic diseases. Early detection, prompt comprehensive management including initiation of combined sensitive antibiotics, respiratory monitoring and support, platelet infusion, and strategies to improve patients' remission status are recommended to improve the overall survival in patients with SM bacteremia.

Bloodstream infections caused by Escherichia coli carrying mcr-1 gene in hospitalized patients in northern Italy from 2012 to 2018.

PURPOSE: The recurrence of multi-drug resistant (MDR) pathogens to the latest antibiotics and the limited development of new antibacterial agents have reduced the options for the treatment of severe infections. The reintroduction of old antibiotics, such as colistin, represents an effective strategy, since the latest antibiotics are over-consumed and ineffective against MDR pathogens. In 2015, Liu (Lancet Infect Dis 16:161-168, 2016) reported Escherichia coli (E. coli) isolates carrying plasmid-mediated colistin resistance gene mcr-1. The first of mcr-1 positive colistin-resistant (col-R) E. coli from a human blood culture was observed in 2012 in Latin America, while in Italy was reported for the first time by our center in 2016. The present study aimed to describe the prevalence of mcr-1 positive col-R strains in E. coli-related bloodstream infection among patients hospitalized in Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, from 2012 to 2018, including the three cases already published. METHODS: All col-R E. coli strains isolated from blood cultures collected during the study period were analyzed. The minimal inhibitory concentration of colistin was determined using broth microdilution and detection of mcr-1 and mcr-2 genes was performed by PCR. The sequence type of E. coli mcr-1 positive was determined according to Multilocus sequence typing. RESULTS: Out of 1557 samples, 14 strains (0.90%) were col-R. and positive for the presence of the mcr-1 gene, with no mcr-2 detected. The most common ST was ST10 (n = 3), followed by ST410 (n = 2). The remaining strains exhibited different MLST profiles, indicating that they were genetically unrelated. CONCLUSIONS: Proper reporting of the presence of mcr-1 genes is an essential component to anticipate the spread of colistin resistance. This public health issue is particularly alarming in Italy due to the consistent circulation of MDR bacteria.

Lateral flow assays for diagnosing invasive pulmonary aspergillosis in adult hematology patients: A comparative multicenter study.

Fast diagnosis of invasive pulmonary aspergillosis (IPA) is essential as early adequate therapy improves survival. However, current microbiological methods suffer from a low sensitivity or a long turnaround time, often as a result of batching. Recently, two lateral flow assays for diagnosing IPA have been CE (Conformité Européenne)-marked and commercialized. These assays can be used for fast single sample testing. However, clinical validation and comparative studies are lacking. We therefore sought to evaluate and compare these assays in adult hematology patients. We retrospectively tested 235 bronchoalveolar lavage fluid (BALf) samples of adult hematology patients from four centers using the AspLFD (OLM Diagnostics) and the sona Aspergillus galactomannan LFA (IMMY). Both tests were read out independently by two researchers and by a digital reader. We included 11 patients with proven IPA, 64 with probable IPA, 43 with possible fungal disease, and 117 controls with no signs of IPA. In cases of proven IPA, the performance of both assays was similar. In cases of proven and probable IPA, we found an identical specificity for both assays, but a higher sensitivity (0.83 vs 0.69, P = .008) and a better negative predictive value (0.89 vs 0.82, P = .009) for the LFA. Digital readout improved the diagnostic performance of both tests. In conclusion, both assays showed a good performance for the diagnosis of IPA in BALf from adult hematology patients. Results were further improved by using a digital reader, especially for weakly positive results.

Defining standards of CARE for invasive fungal diseases in adult haematology patients: antifungal prophylaxis versus treatment.

Despite the availability of four different classes of antifungal agents, invasive fungal infections, in particular mould diseases, continue to have a high crude mortality rate in adult haematology patients, especially when diagnosed late. Early diagnosis, resulting in prompt and adequate antifungal intervention, is of great importance when trying to improve the overall outcome of these infections, but depends on the availability of rapid and sensitive diagnostic tools. The medical community has developed and continues to evaluate a continuum of antifungal strategies (starting with prophylaxis followed by empirical therapy and more recently a diagnostic-driven or pre-emptive approach) to better tackle these life-threatening diseases. While the empirical approach seems to have lost some of its popularity, the jury is still out about the pros and cons of universal antifungal prophylaxis in at-risk adult haematology patients compared with an approach that uses radiological and mycological diagnostic methods with good to excellent negative predictive values (also erroneously called pre-emptive), trying to exclude the presence of an invasive fungal disease. Whilst awaiting the results of comparative clinical studies, believers and non-believers around the globe continue to argue about the advantages and shortcomings of both strategies. The debate presented here provides a rationale for both prophylaxis for 'high-risk' haematology patients as well as for a more targeted approach based on the appropriate use of mycological, radiological, immunological (and genetic) methods for the diagnosis of invasive fungal diseases.

Helicobacter pylori and hematological disorders.

Helicobacter pylori (H. pylori) is one of the most common worldwide infections, which can affect both adults and children. The prevalence of this bacterium is variable in different countries, depending on various hygienic and socioeconomic conditions and living customs. The major damaged tissues of the infection are in the upper gastrointestinal tract, causing gastritis, gastric and duodenal ulcer and gastrointestinal malignancy. Nevertheless, other disorders are associated with this pathogen, including several hematological diseases, such as iron deficiency anemia, immune thrombocytopenia and vitamin B12 deficiency. A huge of data in literature support these associations, enough to recognize them in the last Maastricht V/Florence Consensus Report by European Study Group. The pathogenic mechanisms underlying the linkage between H. pylori and these hematological disorders are not clearly identified, but certainly the good hematological response reaches after eradication therapy confirm a central role of the bacterium in this scenario. Instead, the pathogenic mechanisms of H. pylori infection, which lead to the occurrence of mucosa-associated lymphoid tissue (MALT) lymphoma are clearer and more consolidated; so much that nowadays eradication therapy alone represents the only treatment in this disorder, when localized and with a concomitant H. pylori infection. This review focuses on the hematologic diseases related to H. pylori, particularly on iron deficiency anemia, vitamin B12 deficiency, immune thrombocytopenia and gastric MALT lymphoma.

Combination antifungal treatment for invasive fungal disease after hematopoietic stem cell transplantation in children with hematological disorders.

BACKGROUND: Invasive fungal disease (IFD) has a poor prognosis in children with hematological disorders after hematopoietic stem cell transplantation (HSCT). We assessed if drug combinations with different targets may improve the outcome. METHODS: Retrospective study to assess the outcome of combination antifungal therapy (CAT) for proven-probable IFD (PP-IFD) in children with hematological disorders after HSCT from January 2008 to June 2018. RESULTS: Over the 10-year period, 95 PP-IFD were diagnosed in pediatric recipients, median age of 5.6 years. Twenty-seven patients received combinations of caspofungin and voriconazole, 28 patients received combinations of caspofungin and amphotericin B, and 40 patients received combinations of voriconazole and amphotericin B. The overall response rate of PP-IFD was 77.9%, while the 100-day overall survival rates were 66.8%. Univariate analysis showed that factors that significantly affected the response to combination treatments were type of combination (P = 0.02), the stem cell source (P = 0.04), the donor type (P = 0.03), HLA-match (P = 0.03), aGVHD (P = 0.02), period of treatment (P = 0.044), use of corticosteroids (0.036), CD4:CD8 ratio (P = 0.014), and CMV viremia (P = 0.033). In addition, multivariate analysis demonstrated that only the type of combination remained a significant factor (odds ratio = 0.335, 95% confidence interval: 0.071-0.812, P = 0.042). Forty-three children suffered from mild and reversible adverse reactions, no serious side effects during treatment. CONCLUSION: A variety of factors can affect the outcome of CAT. Combination of caspofungin with voriconazole is a safe and helpful treatment option for HSCT recipients with IFD.

Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders.

BACKGROUND: The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. METHODS: Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation. RESULTS: Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. CONCLUSIONS: We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.

Diagnosing Invasive Pulmonary Aspergillosis in Hematology Patients: a Retrospective Multicenter Evaluation of a Novel Lateral Flow Device.

Invasive pulmonary aspergillosis (IPA) is a potentially lethal infection in patients with hematological diseases or following allogeneic stem cell transplantation. Early diagnosis is essential, as delayed treatment results in increased mortality. Recently, a lateral flow device (LFD) for the diagnosis of IPA was CE marked and made commercially available by OLM Diagnostics. We retrospectively analyzed bronchoalveolar lavage fluid (BALf) collected from adult hematology patients from 4 centers in The Netherlands and Belgium. Galactomannan was retested in all samples. All samples were applied to an LFD and read out visually by two independent researchers blinded to the diagnosis of the patient. All samples were also read out using a digital reader. We included 11 patients with proven IPA, 68 patients with probable IPA, 44 patients with possible IPA, and 124 patients with no signs of IPA (controls). In cases of proven IPA versus controls, sensitivity and specificity were 0.82 and 0.86 for visual readout and 0.82 and 0.96 for digital readout, respectively. When comparing patients with proven and probable IPA as cases versus controls, sensitivity and specificity were found to be 0.71 and 0.86, respectively. When excluding serum and BALf galactomannan as mycological criteria from the 2008 European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group (EORTC)/Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (MSG) consensus definitions, the LFD was less specific than galactomannan when comparing subjects with proven and probable IPA to controls (0.86 versus 0.96; P = 0.005) but had similar sensitivity (0.76 versus 0.85; P = 0.18). In conclusions, in this large study of the CE-marked LFD in BALf from hematology patients, the LFD had a good performance for the diagnosis of IPA.

An Analysis of the Clinical Benefit of 37 Bronchoalveolar Lavage Procedures in Patients with Hematologic Disease and Pulmonary Complications.

Objective Since pulmonary complications are a major cause of mortality in patients with hematologic diseases, their rapid detection and treatment are essential. Bronchoalveolar lavage (BAL) is widely performed to diagnose pulmonary infiltrates not evident with non-invasive investigations; however, reports on its clinical benefits for patients with hematologic diseases are limited. The aim of our study was to investigate the utility of diagnostic bronchoscopy with BAL for those patients. Methods We retrospectively reviewed the clinical records of 37 consecutive BAL procedures in 33 adult patients with hematological diseases and pulmonary infiltrates with at least 6 months of follow-up between August 2013 and September 2017 (total 747 BAL procedures). The BAL results, ensuing treatment modifications, treatment outcomes, survival times, and adverse events were evaluated. Results Microbiological findings were detected in 11 (29.7%), even though wide-spectrum antibiotics and antifungal drugs had been empirically administered to most patients (>70%) prior to the bronchoscopy procedure. Overall, 25 of the 37 BAL procedures (67.6%) had some impact on the diagnosis of pulmonary diseases. Patients without specific diagnostic findings from BAL had a significantly poorer survival than those with diagnostic findings via BAL (30-day survival: 33.3% vs. 92.0%; 180-day survival: 8.3% vs. 64.0%). Four patients (12.1%) experienced complications associated with bronchoscopy; there were no procedure-related deaths. Conclusion BAL seems still important for diagnosing pulmonary infiltrates and/or excluding some of the important respiratory tract pathogens in patients with hematological diseases; furthermore, negative specific diagnostic findings from BAL may be associated with poor prognoses.

Bacterial Pathogens Differed Between Neutropenic and Non-neutropenic Patients in the Same Hematological Ward: An 8-Year Survey.

Background: Bacterial infections are very common among patients with hematological diseases. Scant data are available regarding differences in the epidemiology and biological features of bacterial infections in neutropenic and non-neutropenic patients. Methods: The aim of this survey was to compare the bacterial pathogens in neutropenic and non-neutropenic patients in the same ward during an 8-year period. Results: A total of 1139 bacterial strains were isolated from 1071 patients with hematological diseases. The percentage of Gram-negative bacteria was significantly higher in neutropenic patients than in non-neutropenic patients (70.4% vs. 55.0%, respectively, P < .01). In neutropenic patients, the most commonly-isolated bacterium was Pseudomonas aeruginosa, followed by Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In respiratory exudates, Gram-negative bacteria were also more frequently isolated from neutropenic patients than from non-neutropenic patients (79.1% vs. 56.1%, respectively, P < .01). The proportion of non-fermentative Gram-negative bacilli was significantly higher in neutropenic patients than in non-neutropenic patients (52.9% vs. 30.5%, respectively, P < .01). In blood culture samples from neutropenic patients, the most frequently identified pathogens, apart from coagulase negative staphylococcus, were Gram-negative bacilli (58.2%). In addition, the proportion of Escherichia coli in neutropenic patients was significantly higher than that in non-neutropenic patients (P < .01). Escherichia coli and Klebsiella pneumoniae strains from neutropenic patients also produced extended-spectrum ß-lactamases at a higher rate of than those strains from non-neutropenic patients (Escherichia coli, 57.6% vs. 30.3%, respectively, P < .01; Klebsiella pneumonia, 31.9% vs. 13.0%, respectively, P < .01). Conclusions: This study showed that there are significant differences in the epidemiology and biological features of bacteria isolated from neutropenic and non-neutropenic patients.

European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia.

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

Pharmacokinetics of extended dose intervals of micafungin in haematology patients: optimizing antifungal prophylaxis.

Background: Extended dosing intervals for micafungin could overcome the need for hospitalization for antifungal prophylaxis. Objectives: This multicentre, open-label, randomized trial compared the pharmacokinetics of 300 mg of micafungin given twice weekly with 100 mg once daily as antifungal prophylaxis in adult haematology patients at risk of developing invasive fungal disease. Secondary objectives were assessment of adequate exposure with an alternative dosing regimen of micafungin (700 mg once weekly) through Monte Carlo simulations and assessment of safety in this patient population. Patients and methods: Twenty adult patients were randomized to receive either 300 mg of micafungin twice weekly or 100 mg once daily for 8 days. Blood samples were drawn daily and pharmacokinetic curves were determined on days 4/5 and 8. Monte Carlo simulations were performed for both investigated regimens as well as a frequently proposed alternative regimen (700 mg once weekly). Results: The predicted median AUC0-168h (IQR) for a typical patient on the investigated regimens of 100 mg once daily and 300 mg twice weekly and the hypothetical regimen of 700 mg once weekly were 690 (583-829), 596 (485-717) and 704 (585-833) mg·h/L, respectively. Conclusions: We observed comparable exposure with 300 mg of micafungin twice weekly and 100 mg of micafungin once daily. We provide the pharmacokinetic proof for an extended dosing regimen, which now needs to be tested in a clinical trial with hard endpoints.